Conditions: Healthy Volunteers
Keywords: GSK2330811 Healthy participants Japanese Pharmacokinetics Safety Subcutaneous dose
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: yes

Brief summary:
This is a randomized, double-blind (sponsor-open), placebo-controlled, single-center study involving Japanese participants. The purpose of the study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity after a single subcutaneous (SC) dose of GSK2330811 in healthy Japanese participants. GSK2330811 is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds and inhibits the action of Oncostatin M (OSM) and is being developed for the treatment of Crohn's disease (CD) and Systemic sclerosis (SSc). Participants will be randomized to receive either GSK2330811 (450 milligram \[mg\]) or placebo in an approximate ratio of 7:3.

Detailed description:

Arms:
arm 1: Participants will receive a single 450 mg SC dose of GSK2330811, administered as three separate SC injections of 150 milligrams per milliliter \[mg/mL\]). arm 2: Participants will receive GSK2330811 matching placebo administered as three separate SC injections.

Interventions: intervention 1: Placebo intervention 2: GSK2330811
Intervention descriptions: intervention 1: Placebo is 0.9 percent sodium chloride solution. It will be administered as SC injection to abdomen by study personnel. Three injections will be used to match active doses. intervention 2: GSK2330811 will be available as SC injection 150 mg/mL.

Protocol document:
Prot_000.pdf: 
2019N406151_00
CONFIDENTIAL
GlaxoSmithKline group of companies
208564
1
TITLE PAGE
Protocol Title: A phase 1, randomised, double-blind, placebo-controlled study of the 
safety, tolerability, pharmacokinetics and pharmacodynamics of single subcutaneous 
doses of GSK2330811 in healthy Japanese participants.
Protocol Number: 208564
Compound Number
or Name:
GSK2330811
Study Phase: Phase 1
Short Title: Safety, tolerability, pharmacokinetics, pharmacodynamics of GSK2330811 
after a subcutaneous dose in healthy Japanese participants.
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual (SRM).
Regulatory Agency Identifying Number(s):
EudraCT:  2019-003042-33
Approval Date: 11-SEP-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2019N406151_00
CONFIDENTIAL
208564
3
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................8
1.3.
Schedule of Activities (SoA)..........................................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Background ................................................................................................12
2.3.
Benefit/Risk Assessment ............................................................................13
2.3.1.
Risk Assessment .........................................................................14
2.3.2.
Benefit Assessment.....................................................................18
2.3.3.
Overall Benefit: Risk Conclusion..................................................18
3.
OBJECTIVES AND ENDPOINTS...........................................................................18
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Number of Participants ...............................................................................20
4.3.
Intervention Groups and Duration ...............................................................20
4.4.
Scientific Rationale for Study Design ..........................................................20
4.5.
Justification for Dose ..................................................................................21
4.6.
End of Study Definition ...............................................................................22
5.
STUDY POPULATION...........................................................................................23
5.1.
Inclusion Criteria.........................................................................................23
5.2.
Exclusion Criteria........................................................................................24
5.3.
Lifestyle Considerations..............................................................................26
5.3.1.
Meals and Dietary Restrictions ....................................................26
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................26
5.3.3.
Activity .........................................................................................26
5.4.
Screen Failures...........................................................................................26
6.
STUDY INTERVENTION........................................................................................27
6.1.
Study Intervention(s) Administered .............................................................27
6.2.
Preparation/Handling/Storage/Accountability..............................................28
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................29
6.3.1.
Randomisation and Intervention Assignment...............................29
6.3.2.
Blinding........................................................................................29
6.3.2.1.
Risk of Inferred Unblinding .........................................30
6.4.
Study Intervention Compliance ...................................................................30
6.5.
Concomitant Therapy..................................................................................30
6.6.
Dose Modification .......................................................................................31
6.7.
Intervention after the End of the Study........................................................31
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................31
7.1.
Discontinuation of Study Intervention..........................................................31
7.1.1.
Study Stopping Criteria................................................................31
7.1.2.
Liver Chemistry Enhanced Monitoring Criteria .............................32


2019N406151_00
CONFIDENTIAL
208564
4
7.1.3.
QTc Enhanced Monitoring Criteria...............................................32
7.1.4.
Haematological Enhanced Monitoring Criteria .............................32
7.2.
Participant Withdrawal from the Study ........................................................33
7.3.
Lost to Follow Up........................................................................................33
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
8.1.
Efficacy Assessments.................................................................................34
8.2.
Safety Assessments ...................................................................................34
8.2.1.
Physical Examinations.................................................................34
8.2.2.
Vital Signs....................................................................................34
8.2.3.
ECGs...........................................................................................35
8.2.4.
Clinical Safety Laboratory Assessments ......................................35
8.2.5.
Injection Site Reaction Assessments ...........................................35
8.2.6.
Hypersensitivity Reactions...........................................................36
8.3.
Adverse Events and Serious Adverse Events.............................................37
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................37
8.3.2.
Method of Detecting AEs and SAEs.............................................38
8.3.3.
Follow-up of AEs and SAEs.........................................................38
8.3.4.
Regulatory Reporting Requirements for SAEs .............................38
8.3.5.
Pre-Filled Syringe Deficiencies ....................................................38
8.3.5.1.
Time Period for Detecting Pre-Filled Syringe 
Deficiencies................................................................39
8.3.5.2.
Follow-up of Pre-Filled Syringe Deficiencies...............39
8.3.5.3.
Prompt Reporting of Pre-Filled Syringe 
Deficiencies to Sponsor..............................................39
8.3.5.4.
Regulatory Reporting Requirements for Pre-
Filled Syringe Incidents ..............................................39
8.4.
Treatment of Overdose...............................................................................40
8.5.
Pharmacokinetics .......................................................................................40
8.6.
Pharmacodynamics ....................................................................................41
8.6.1.
Total and Free OSM ....................................................................41
8.6.2.
Erythropoietin (EPO) and Thrombopoietin (TPO).........................41
8.7.
Biomarkers .................................................................................................41
8.8.
Genetics .....................................................................................................42
8.9.
Immunogenicity Assessments.....................................................................42
8.10.
Health Economics.......................................................................................42
9.
STATISTICAL CONSIDERATIONS........................................................................42
9.1.
Statistical Hypotheses.................................................................................42
9.2.
Sample Size Determination ........................................................................42
9.3.
Populations for Analyses ............................................................................44
9.4.
Statistical Analyses.....................................................................................44
9.4.1.
General Considerations ...............................................................44
9.4.2.
Primary Endpoint(s).....................................................................45
9.4.3.
Secondary Endpoint(s) ................................................................45
9.4.3.1.
Pharmacokinetic parameters......................................45
9.4.3.2.
Other secondary endpoints.........................................46
9.4.4.
Exploratory Endpoints..................................................................46
9.5.
Interim Analyses .........................................................................................46
9.6.
Interim Data Review Committee .................................................................46


2019N406151_00
CONFIDENTIAL
208564
5
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................47
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................47
10.1.1.
Regulatory and Ethical Considerations ........................................47
10.1.2.
Financial Disclosure.....................................................................47
10.1.3.
Informed Consent Process ..........................................................48
10.1.4.
Data Protection............................................................................48
10.1.5.
Committees Structure ..................................................................49
10.1.6.
Dissemination of Clinical Study Data ...........................................49
10.1.7.
Data Quality Assurance ...............................................................49
10.1.8.
Source Documents ......................................................................50
10.1.9.
Study and Site Start and Closure.................................................50
10.1.10. Publication Policy.........................................................................51
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................52
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................54
10.3.1.
Definition of AE............................................................................54
10.3.2.
Definition of SAE..........................................................................55
10.3.3.
Recording and Follow-Up of AE and SAE....................................56
10.3.4.
Reporting of SAE to GSK.............................................................58
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................59
10.5.
Appendix 5: Genetics..................................................................................60
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................61
10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................63
10.7.1.
Definition of AE and ADE.............................................................64
10.7.2.
Definition of SAE, SADE and USADE..........................................64
10.7.3.
Definition of Device Deficiency.....................................................65
10.7.4.
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies .................................................................................65
10.7.5.
Reporting of SAEs .......................................................................67
10.7.6.
Reporting of SADEs.....................................................................68
10.8.
Appendix 8: Country-specific requirements.................................................69
10.9.
Appendix 9: Abbreviations and Trademarks................................................70
11. REFERENCES.......................................................................................................74


2019N406151_00
CONFIDENTIAL
208564
6
1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A phase 1, randomised, double-blind, placebo-controlled study of the 
safety, tolerability, pharmacokinetics and pharmacodynamics of single subcutaneous 
doses of GSK2330811 in healthy Japanese participants.
Short Title: Safety, tolerability, pharmacokinetics, pharmacodynamics of GSK2330811 
after a subcutaneous dose in healthy Japanese participants.
Rationale:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity after single subcutaneous (SC) doses of 
GSK2330811 administered to healthy Japanese participants. This information is intended 
to enable future efficacy studies in Japanese patients with relevant diseases, and to 
support defining the optimal SC dose for future studies in this population.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary

To evaluate the safety and tolerability of a 
single SC dose of GSK2330811 in 
healthy Japanese participants

Number of participants reporting adverse 
events (AEs).

Number of participants reporting serious 
adverse events (SAEs).

Number of participants with vital signs 
(blood pressure, heart rate, body 
temperature) reaching a threshold of 
potential clinical importance.

Number of participants with treatment 
emergent abnormal electrocardiogram 
(ECG) findings.

Number of participants with Common 
Terminology Criteria for Adverse Events 
(CTCAE) grade 1 or higher safety 
laboratory results (clinical chemistry, 
haematology values where CTCAE
grading applies).

Number of participants with treatment 
emergent abnormal urinalysis findings
Secondary
Secondary


2019N406151_00
CONFIDENTIAL
208564
7
Objectives
Endpoints

To evaluate the pharmacokinetic (PK) 
profile of a single SC dose of 
GSK2330811 in healthy Japanese 
participants

Pharmacokinetic parameters (Cmax, 
AUC, CL/F, Tmax, t1/2, Vss/F)

To assess the potential for anti-drug 
antibody (ADA) formation following a 
single SC dose of GSK2330811 in 
healthy Japanese participants

Number of participants with anti-
GSK2330811 antibodies

To assess effects of GSK2330811 on 
platelets and haemoglobin in healthy 
Japanese participants

Platelet nadir

Time to platelet nadir

Haemoglobin nadir

Time to haemoglobin nadir
Overall Design:
This is a randomised, double-blind (sponsor-open), placebo-controlled, single-centre 
study with single SC doses of GSK2330811 administered to healthy male Japanese 
participants.

Participants will attend a screening visit at the clinical unit within 30 days of 
Study Day 1. If eligible for the study, participants will return on Day -1 for 
overnight admission to the unit.

Participants will be randomized to either GSK2330811 or placebo in an 
approximate ratio of 7:3.

Approximately 10 eligible participants will be admitted to the clinical unit on the 
day prior to dosing (Day-1). On Day 1, each participant will receive a single SC
dose of GSK2330811 or placebo, administered as three separate SC injections. 
Participants will then remain as an in-patient until discharged on Day 2 after 
assessments have been performed.

Participants will then return to the clinical unit for outpatient visits as per the 
Schedule of Activities (SoA).

The final follow up visit will be at the clinical unit on Day 126.

The maximum dose will not exceed 450 mg SC.
Disclosure Statement: 
This is a 2-arm, double-blind, parallel group, safety and PK study.


2019N406151_00
CONFIDENTIAL
208564
8
Number of Participants:
Approximately ten participants will be enrolled and dosed (7 GSK2330811: 3 Placebo) 
with a view to ensuring 8 are evaluable (6 GSK2330811: 2 Placebo). 
Up to a maximum of 14 participants may be enrolled and dosed.
Intervention Groups and Duration:
This study will include a single cohort of approximately 10 participants randomised to a 
single dose of 450mg SC GSK2330811 or placebo in a 7:3 ratio (active: placebo).
The study duration, including screening and follow-up, is not expected to exceed 163 
days for any participant in the study.
1.2.
Schema


2019N406151_00
CONFIDENTIAL
208564
9
1.3.
Schedule of Activities (SoA)
Screening Period
Screening Procedure
Screening (up to 30 days prior to Day 1)
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Exam (incl. weight and height)
X
Medical History and current medical conditions1
X
Concomitant Medication Review
X
12 lead ECG in triplicate
X
Vitals (blood pressure, heart rate, body temperature)2
X
Breath Alcohol Screen
X
Urine Drug Screen
X
Human Immunodeficiency Virus (HIV), Hepatitis B virus
(HBV) and Hepatitis C virus (HCV) Screen
X
Tuberculosis (TB) Screening QuantiFERON 
X
Haematology/Clinical Chemistry/Urinalysis/Clotting
X
SAE Review
X
1.
To include substance usage, family history of premature cardiovascular disease, medication, drug/alcohol history
2.
Vital signs are to be taken before blood collection for laboratory tests.


2019N406151_00
CONFIDENTIAL
208564
10
Treatment and Follow-Up Period
Procedure
Day-
1
Day 1
Day 
2
Day 
3
Day 
5
Day 
7
Day 
10 
Day 
14
Day 
21
Day 
28
Day 
42
Day 
56
Day 
84
Day 126 
(follow-up 
visit)/Early 
Withdrawal
+/- 1 
day
+/- 1 
day
+/- 1 
day
+/- 1 
day
+/- 2 
days
+/- 2 
days
+/- 7 
days
+/- 7 days
Admission
X
In-patient Stay
X
X
Discharge
X
Outpatient Visit
X
X
X
X
X
X
X
X
X
X
X
Inclusion and Exclusion Criteria
X
Breath Alcohol Screen
X
Urine Drug Screen
X
Pre-
dose
0h
1h
4h
8h
24h
Dosing3
X
Injection Site Reaction Assessment
X5
X5
X5
X5
X5
Brief Physical Exam
X
X1
Full Physical Exam6
X
Haematology/Clinical Chemistry
X
X2
X1
X
X
X
X
X
X2
X
X
X
X
X
Urinalysis
X
X
X
X
X
12 lead ECG (triplicate)
X
X
X
X
X
Vitals (blood pressure, heart rate, 
body temperature)4
X
X
X1
X1
X1
X1
X
X
X
X
X
X
X
X
X
X
X
PK Sampling
X
X1
X1
X
X
X
X
X
X
X
X
X
X
X
Free & Total OSM Sampling
X
X1
X1
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity Sampling
X
X
X
X
TPO Sampling
X
X
X
X
X
EPO Sampling
X
X
X
X
X


2019N406151_00
CONFIDENTIAL
208564
11
Procedure
Day-
1
Day 1
Day 
2
Day 
3
Day 
5
Day 
7
Day 
10 
Day 
14
Day 
21
Day 
28
Day 
42
Day 
56
Day 
84
Day 126 
(follow-up 
visit)/Early 
Withdrawal
Concomitant Medication Review
Monitored from screening until end of follow-up visit
SAE/AE Review
SAEs collected from signing of consent form, AEs collected continuously from time of dose
AE= adverse event; ECG= Electrocardiogram; EPO= Erythropoietin; TPO = Thrombopoietin; OSM= Oncostatin M; PK= 
pharmacokinetic; SAE= serious adverse event
Footnotes: 
1.
All post dose time points are in reference to the first injection of IMP.
2.
Day 1 Pre-dose sample and Day 21 sample will be fasted for approximately 12 hr and will include lipids
3.
IMP administration consists of 3 syringes, all 3 syringes are to be administered as closely together in time as possible 
4.
Vital signs are to be taken before blood collection for laboratory tests.
5.
Assessments should be conducted immediately before first injection (pre-dose) and immediately after last injection (0h). Post dose assessments  (4h and 24h) to be conducted in 
reference to the last injection of IMP. Any injection site reactions to be captured through AE reporting.
6.
Full physical exam at follow-up will not include height

The timing and number of planned study 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. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files but will not constitute a protocol amendment. The Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation.


2019N406151_00
CONFIDENTIAL
208564
12
2.
INTRODUCTION
GSK2330811 is a first in class, humanised IgG1 monoclonal antibody that binds and 
inhibits the action of Oncostatin M (OSM) and is being developed for the treatment of 
Crohn’s disease (CD) and Systemic sclerosis (SSc). 
The current strength of the liquid formulation is 150 mg/mL and is presented as a pre-
filled syringe (PFS) assembled in a safety syringe device for SC administration.
2.1.
Study Rationale
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity after single SC doses of 450 mg 
GSK2330811 administered to healthy Japanese participants. This information is intended 
to enable future efficacy studies in Japanese patients with relevant diseases, and to 
support defining the optimal SC dose for future studies in this population.
2.2.
Background
GSK2330811 is a humanised monoclonal antibody that binds and neutralises OSM and is 
being developed for the treatment of SSc and CD.
OSM is a member of the IL-6 family of cytokines, which is produced by a variety of 
immune cells including macrophages, activated T-cells and neutrophils in response to 
infection and tissue injury. OSM signalling on a variety of cell types, including
fibroblasts, epithelial, endothelial, smooth muscle cells and hematopoietic cells, drives 
inflammation, fibrosis and vasculopathy [Hermanns, 2015; Ayaub, 2017].
The safety profile of GSK2330811 has been evaluated in repeat-dose SC 13 and 26-week 
monkey toxicity studies. The key findings were of a reduction in red cell parameters in 
the peripheral blood and bone marrow with evidence of a regenerative reticulocyte 
response and of a transient reduction in platelet counts which showed partial to complete 
recovery by week 13. In the 13-week toxicity study, the no observed adverse effect level 
(NOAEL) was considered to be 300 mg/kg/week (the highest dose tested). In the 26-
week toxicity study, because of the magnitude of the pharmacology related effects on red 
blood cell parameters noted the NOAEL was not identified.  Of note, for non-
pharmacology related findings the NOAEL is considered to be 300 mg/kg/week (highest 
dose tested). Detailed information can be found in the Investigator’s Brochure (IB) for 
GSK2330811 [GlaxoSmithKline Document Number 2016N284919_02, 2019].
The safety, tolerability and PK of GSK2330811 has been evaluated in a Phase 1 single-
dose escalation study in healthy volunteers (201246, NCT02386436, [Reid, 2018]). 
Thirty participants were exposed to GSK2330811 at doses ranging from 0.1 mg/kg to 6.0 
mg/kg. GSK2330811 was well-tolerated, with no serious adverse events (SAEs) reported. 
The pharmacokinetic profile of GSK2330811 was consistent with that of an IgG1 
monoclonal antibody against a soluble cytokine and high levels of target engagement 
were observed. A reversible reduction in platelet count was observed at dose levels of 1 


2019N406151_00
CONFIDENTIAL
208564
13
mg/kg and above, and a low-grade reduction in haemoglobin and red cell count was 
observed at the highest dose level (6 mg/kg).  Both these effects are consistent with the 
inhibition of the known pharmacology of OSM by GSK2330811. Detailed information 
can be found in the IB for GSK2330811 [GlaxoSmithKline Document Number 
2016N284919_02, 2019].
A repeat dose, proof of mechanism study (201247, NCT03041025) with GSK2330811 in 
participants with SSc is ongoing, dosing up to 300 mg every two weeks for 6 doses.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2330811 may be found in the Investigator’s 
Brochure.


2019N406151_00
CONFIDENTIAL
208564
14
2.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention GSK2330811
Thrombocytopaenia

OSM has been shown to modulate haematopoiesis through an effect on 
bone marrow stromal cells, haematopoietic progenitors and bone marrow 
microenvironment [Wallace, 1995; Miyajima, 2000; Tanaka, 2003].

In the 13 and 26 week repeat dose monkey toxicology studies transient 
reduction in platelet counts were observed which showed partial to 
complete recovery by week 13.  In the 13 week repeat dose study, platelet 
counts were comparable to vehicle control monkeys following clearance of 
GSK2330811 (at the end of an 18 week off drug period).  Refer to IB for 
details [GlaxoSmithKline Document Number 2016N284919_02, 2019].

A First Time in Human (FTIH) study of single doses of GSK2330811 in 
healthy participants demonstrated a dose-dependent, reversible reduction 
in platelet count at doses between 1 mg/kg and 6 mg/kg. Refer to IB for 
details [GlaxoSmithKline Document Number 2016N284919_02, 2019].

Only participants with platelet count LLN will be 
included in the study. 

Participants with any history of known bleeding 
or coagulation disorders will be excluded.

The use of anti-platelet medications, other than 
occasional use of non-steroidal anti-inflammatory 
drugs (NSAIDs), will not be permitted. 

Platelet count will be tested at each scheduled 
visit, until the end of the follow-up period, to 
ensure careful monitoring. 

Haematological Study Stopping criteria and 
Individual participant enhanced monitoring 
criteria will be implemented.  


2019N406151_00
CONFIDENTIAL
208564
15
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Anaemia

OSM has been shown to modulate haematopoiesis through an effect on 
bone marrow stromal cells, haematopoietic progenitors and bone marrow 
microenvironment [Wallace, 1995; Miyajima, 2000; Tanaka, 2003].

In the 13 and 26 week repeat dose monkey toxicology study progressive 
decreases in red cell parameters and bone marrow myeloid to erythroid 
ratios with a compensatory increase in reticulocyte count were noted 
correlates. In the 13 week repeat dose study there was partial to complete 
recovery of red cell parameters and reticulocytes following clearance of 
GSK2330811 (at the end of an 18 week off drug period). Refer to IB for 
details [GlaxoSmithKline Document Number 2016N284919_02, 2019].

A FTIH study of single doses of GSK2330811 in healthy participants 
showed a reduction in haemoglobin / red cell count at 6 mg/kg. A 
reticulocytosis was evident from Day 21 in participants receiving 3 mg/kg 
and 6 mg/kg. Refer to IB for details [GlaxoSmithKline Document Number
2016N284919_02, 2019].

Only participants with haemoglobin LLN will be 
included in the study. 

Participants with any history of known bleeding 
or coagulation disorders will be excluded.

Participants will not receive anti-coagulant 
medications during the study. 

Haemoglobin will be tested at each scheduled 
visit, until the end of the follow-up period, to 
ensure careful monitoring. 

Haematological Study Stopping criteria and 
Individual participant enhanced monitoring 
criteria will be implemented.  
Infection including 
reactivation of 
Mycobacterium 
tuberculosis

OSM contributes to immunity in synergy with other cytokines such as TNF 
and IL-1 which may protect against infection. Therefore, the possibility of 
an increase in the frequency and/or severity of infection following dosing of 
GSK2330811 cannot be excluded.

In the 26-week cynomolgus monkey toxicology study decreases in 
neutrophils (associated with left shift) and eosinophils were noted.  Also 
observed were increases in total lymphocyte count, which was attributed to 
increased T helper and T cytotoxic cell numbers. Refer to IB for details 
[GlaxoSmithKline Document Number 2016N284919_02, 2019].

No dose-related fall in white cell count or leukocyte subsets was observed 
in the FTIH single ascending dose study of GSK2330811. No excess of 
infection adverse events was observed in participants receiving 
GSK2330811. Refer to IB for details [GlaxoSmithKline Document Number
2016N284919_02, 2019].

Participants will be screened for HIV, HBV, HCV
and TB and excluded if positive.

Participants with prior opportunistic or recurrent 
infection, or evidence of recent or ongoing 
infection, will be excluded; refer Section 5.2 for 
details.

Participants planning travel to regions of high 
endemic infection during the study will be 
excluded.

Participants will be monitored closely for 
infection, through regular review of symptoms, 
signs and laboratory tests during the study.


2019N406151_00
CONFIDENTIAL
208564
16
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Vaccination

Since an immunosuppressive effect of GSK2330811 cannot be excluded, 
there is a theoretical possibility that GSK2330811 could decrease an 
individual’s immune response to vaccines administered while on therapy

In the monkey 6 month repeat dose study, the antibody response to
Keyhole Limpet Hemocyanin (KLH) immunization (anti KLH IgM and IgG) 
was assessed. Although a delay in the antibody response following primary 
KLH immunisation was noted, these data are not considered indicative of 
an inability to mount a T cell dependent B cell response since an antibody 
response was observed. Refer to IB for details [GlaxoSmithKline 
Document Number 2016N284919_02, 2019].

Participants will not be allowed to receive live 
vaccines within the 4 weeks prior to Day 1, until 
the end of follow-up. 

Investigators should consider the benefit-risk of 
administering any non-live vaccines during the 
study.
Hypersensitivity

Monoclonal antibodies can be associated with systemic hypersensitivity 
reactions, including angioedema, hypotension and anaphylaxis.

There were no hypersensitivity reactions noted in the FTIH study with 
GSK2330811.

Participants with a history of hypersensitivity / 
allergy that may put them at increased risk of a 
hypersensitivity reaction will be excluded; refer 
Section 5.2 (eligibility) for details.

GSK2330811 will be administered by trained 
clinical staff and participants will be appropriately 
monitored after dosing in a setting with the 
capacity to manage any immediate 
hypersensitivity reactions.

Participants will be educated on the potential for 
hypersensitivity reactions and the appropriate 
emergency care.
Immunogenicity

Biopharmaceutical products may elicit anti-drug antibodies (ADA), which 
have the potential to modulate PK, PD and/ or produce adverse reactions.

There were no treatment-related anti-GSK2330811 antibodies detected in 
the FTIH study with GSK2330811.The risk of developing ADA and their 
clinical consequences are mitigated given that GSK2330811 is a 
humanized monoclonal antibody against a soluble target

Serum samples will be collected for detection of 
ADA at timepoints aligned with regulatory 
guidelines [EMA, 2017;FDA, 2019].


2019N406151_00
CONFIDENTIAL
208564
17
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity

A potential risk of hepatotoxicity is inferred from studies in OSMRβ 
knockout mice showing impaired hepatocyte proliferation and tissue 
remodelling with impaired liver regeneration after liver injury [Nakamura, 
2004]. Administration of OSM ameliorated liver injury in wild-type mice.

However, in the 13- and 26-week toxicity studies in healthy cynomolgus 
monkeys, treatment with GSK2330811 was not associated with any 
observed liver effects. Refer to IB for details [GlaxoSmithKline Document 
Number 2016N284919_02, 2019]

Mild, isolated, transient elevations in Alanine aminotransaminase (ALT), 
Aspartate Aminotransferase (AST) and bilirubin were observed in a 
small number of participants across treatment groups including placebo in
the FTIH study of single doses of GSK2330811 in healthy participants. 
Refer to IB for details [GlaxoSmithKline Document Number
2016N284919_02, 2019].

Participants will be screened for HCV and HBV
and excluded if positive.

Participants will be excluded if ALT or bilirubin 
1.5x upper limit of normal (ULN) (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%), 

Standard GSK phase 1 monitoring of liver 
chemistry and criteria for enhanced liver 
chemistry monitoring and follow up Assessments 
will be implemented.
Reproductive Toxicity

Animal reproductive toxicity studies have not yet been carried out with 
GSK2330811.

Animal reproductive toxicity studies have been carried out for GSK315234, 
another IgG anti-OSM monoclonal antibody. GSK2330811 and 
GSK315234 antibodies bind different epitopes but have similar affinity for 
OSM in the animal model used. No GSK315234 related effects on 
pregnancy, embryofoetal development, parturition and lactation and on 
survival, growth and postnatal development of the offspring were noted at 
doses up to 150 mg/kg/month, the highest dose tested.

The study will only recruit male participants. 

There are no specific contraception requirements 
for males participating in this study.
Carcinogenicity

There is conflicting evidence for the role of OSM in cell proliferation in 
metastatic cancer. Data are primarily from isolated cell-line systems and, 
depending on the cell type, OSM has been shown to act both as an anti-
proliferative and a proliferative factor.

Participants with a history of carcinoma in situ 
and malignant disease will be excluded with 
certain exceptions as described in Section 5.2.


2019N406151_00
CONFIDENTIAL
208564
18
2.3.2.
Benefit Assessment
There will be no direct benefit to the healthy participants in this study. However, 
information obtained in this study will inform the conduct of future clinical studies to 
contribute to the process of developing new therapies for diseases where there is unmet 
medical need, including CD and SSc.
2.3.3.
Overall Benefit: Risk Conclusion
The safety of each individual participant has been prioritised and the eligibility, 
monitoring, enhanced monitoring and study level stopping criteria described in Section 7
have been designed to minimise risks to participants associated with exposure to 
GSK2330811. Taking into account these measures designed to minimise risks, the 
potential risks identified in association with GSK2330811 are justified.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Primary

To evaluate the safety and tolerability of a 
single SC dose of GSK2330811 in healthy 
Japanese participants

Number of participants reporting AEs.

Number of participants reporting SAEs.

Number of participants with vital signs (blood 
pressure, heart rate, body temperature) 
reaching a threshold of potential clinical 
importance.

Number of participants with treatment 
emergent abnormal ECG findings.

Number of participants with CTCAE grade 1 
or higher safety laboratory results (clinical 
chemistry, haematology values where 
CTCAE grading applies).

Number of participants with treatment 
emergent abnormal urinalysis findings.
Secondary
Secondary

To evaluate the pharmacokinetic (PK) profile 
of a single SC dose of GSK2330811 in 
healthy Japanese participants

Pharmacokinetic parameters (Cmax, AUC, 
CL/F, Tmax, t1/2, Vss/F).


2019N406151_00
CONFIDENTIAL
208564
19
Objectives
Endpoints

To assess the potential for anti-drug 
antibody (ADA) formation following a single 
SC dose of GSK2330811 in healthy 
Japanese participants

Number of participants with anti-
GSK2330811 antibodies

To assess effects of GSK2330811 on 
platelets and haemoglobin in healthy 
Japanese participants

Platelet nadir

Time to platelet nadir

Haemoglobin nadir

Time to haemoglobin nadir
Tertiary/Exploratory
Tertiary/Exploratory

To explore the PD and the PK/PD 
relationship for GSK2330811 in the blood of 
healthy Japanese participants

Serum levels of free OSM

Serum levels of total OSM

Levels of Thrombopoietin (TPO)

Levels of Erythropoietin (EPO)
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind (sponsor-open), placebo-controlled, single-centre 
study with single SC doses of GSK2330811 administered to healthy male Japanese 
participants.

Participants will attend a screening visit at the clinical unit within 30 days of 
Study Day 1. If eligible for the study, participants will return on Day -1 for 
overnight admission to the unit.

Participants will be randomized to either GSK2330811 or placebo in an 
approximate ratio of 7:3.

Approximately 10 eligible participants will be admitted to the clinical unit on the 
day prior to dosing (Day-1). On Day 1, each participant will receive a single SC
dose of GSK2330811 or placebo, administered as three separate SC injections. 
Participants will then remain as an in-patient until discharged on Day 2 after 
assessments have been performed.

Participants will then return to the clinical unit for outpatient visits as described in 
the SoA.

The final follow up visit will be at the clinical unit on Day 126.

The maximum dose will not exceed 450 mg SC.


2019N406151_00
CONFIDENTIAL
208564
20
4.2.
Number of Participants
Approximately ten participants will be enrolled and dosed (7 GSK2330811: 3 Placebo) 
with a view to ensuring 8 are evaluable (6 GSK2330811: 2 Placebo). See Section 9.2 for 
details. Evaluable is defined as a participant who has received a full dose and has 
attended all visits up to Day 56 and at least one of Day 84 or Day 126.
In rare instances, a participant may not be able to receive all 3 required injections and 
will receive a partial dose. In such circumstances, the participant will not be considered 
evaluable, but will be encouraged to remain in the study for the planned duration.
If any participant is non-evaluable for any reason, the participant may be replaced at the 
discretion of the sponsor in consultation with the investigator and assigned to the same 
treatment. 
Up to a maximum of 14 participants may be enrolled and dosed.
4.3.
Intervention Groups and Duration
This study will include a single cohort of approximately 10 participants randomised to a 
single dose of 450 mg SC GSK2330811 or placebo in a 7:3 ratio (active: placebo).
The study duration, including screening and follow-up, is not expected to exceed 163 
days for any participant in the study. The follow-up may be extended if a SAE has not 
resolved by the final scheduled visit (see Section 8.3.3 and Section 10.3.3).
4.4.
Scientific Rationale for Study Design
The proposed 450 mg single SC dose in Japanese participants is anticipated to result in 
exposure comparable to the 6 mg/kg (average 417 mg, range 375-443 mg) single SC dose 
tested in Caucasian participants in the FTIH study 201246 allowing a comparative 
assessment of ethnic sensitivity in terms of safety, tolerability and PK and PD in a 
Japanese population. Furthermore, a dose of 450 mg SC aligns with the highest 
anticipated dose to be administered in the global clinical studies with GSK2330811.
In addition, this study will be conducted in healthy male participants for the following 
reasons:

Patients with inflammatory and fibrotic diseases may have existing comorbidities 
or be taking concomitant medications that may confound the analysis.

It is anticipated that patients would derive little or no benefit from a single dose of 
GSK2330811, but that taking part in the study might interfere with their ability to 
receive other potentially efficacious therapies.

Animal reproductive toxicity studies have not yet been carried out with 
GSK2330811 and therefore the benefit-risk of enrolling women of child-bearing 


2019N406151_00
CONFIDENTIAL
208564
21
potential in this study, where they are unlikely to derive any direct benefit from a 
single dose of GSK2330811, does not support their inclusion. Moreover, enrolling 
only male participants will facilitate comparison with data from study 201246, a 
single-dose FTIH study of GSK2330811 in predominantly male Caucasian 
participants [Reid, 2018].
This study will include a placebo arm to ensure that the treatment-attribution of adverse 
events (AEs) is appropriately blinded and to provide control data for the PD and safety 
laboratory assessments.
The duration of follow-up will be about 126 days, which will be approximately 5 half-
lives of GSK2330811 (half-life of between 19 to 25 days) [GlaxoSmithKline Document 
Number 2016N284919_02, 2019].
Exploratory endpoints have been chosen to confirm target engagement and further 
investigate PK/PD relationships in the blood.
4.5.
Justification for Dose
To date, GSK2330811 has been administered as single SC doses to healthy participants 
(0.1-6 mg/kg) in the FTIH study 201246. In the highest dose cohort in study 201246, the 
average administered dose was 417 mg (range 375-443 mg). GSK2330811 is currently 
being tested in a repeat SC dose study (201247) of participants with systemic sclerosis 
(100 and 300 mg every other week for 6 doses).
The 450 mg single SC dose proposed for this study in healthy Japanese participants is 
anticipated to result in exposure comparable to the 6 mg/kg single SC dose tested in 
healthy Caucasian participants in study 201246. The 450 mg single SC dose is 47x lower 
than the NOAEL dose for non-pharmacology-related findings (300 mg/kg/week, highest 
dose tested) observed in the 26-week toxicity study in monkeys. Safety margins for 
predicted exposure in this study are summarised in Table 1. Predicted exposure was 
simulated using the minimal Physiologically Based Pharmacokinetic (mPBPK) model 
developed from data from study 201246 [Reid, 2018]. Clearance and volume were 
allometrically scaled assuming median body weight for Japanese living in the Western 
hemisphere equal to 64.2 kg (based on 15 Japan PK studies run by GSK in the Western 
hemisphere) and minimum body weight equal to 45 kg, as per study inclusion criteria.
Allometric scaling is likely to over-predict exposure.


2019N406151_00
CONFIDENTIAL
208564
22
Table 1
Safety margins for predicted exposure for 450 mg SC single dose vs 
measured exposure in Study 201246 and 26-weeks toxicology study
Body 
weight (kg)
Predicted 
for 450 mg 
SC SD
Observed in 
2012461
Fold difference: observed 
in 2012462/ Predicted for 
450 mg SC SD
NOAEL3
Fold difference: 
NOAEL3/Predicted 
for 450 mg SC SD
Parameter: Cmax (ug/mL)
64.2
33
36.4 (28.7-48.9)
1.1x
9710
294x
45
39
0.9x
249x
Parameter: AUC (mg.hr/mL) 4
64.2
33
27.7 (19.8-37.7)
0.8x
1390
42x
45
43
0.6x
32x
1 Shown are observed geomean (range) for 6 mg/kg single dose (SD) SC.  2 Calculated using geomean 
observation in 201246.  3 NOAEL for non-pharmacodynamic related findings is 300 mg/kg/wk SC, which is 
the highest dose tested in the 26-weeks toxicology study in monkey. Shown are mean, gender averaged, 
exposures at Week 25.  4 Note that different AUCs are shown: Predicted for 450 mg SC SD: AUC(0-inf)-;
201246: AUC(0-inf); NOAEL: AUC(0-tau), where tau is 1 week.
The safety and tolerability of ascending single SC doses of GSK2330811 in the range of 
0.1 mg/kg to 6 mg/kg were studied in study 201246. GSK2330811 at these doses was 
generally well tolerated in healthy participants. Reversible, dose-dependent decreases in 
platelet counts were observed from the 1 mg/kg to the 6 mg/kg dose levels with recovery 
evident between Days 28 to 35. A reduction in haemoglobin from baseline values was 
observed in the GSK2330811 6 mg/kg group with all participants returning to within the 
normal range by Day 133. Further details can be found in Section 5 of the IB 
[GlaxoSmithKline Document Number 2016N284919_02, 2019].
The effect of GSK2330811 on platelets and haemoglobin is anticipated to be comparable 
in Japanese and Caucasian participants, since average exposure and target engagement 
are predicted to be comparable in the two populations. At the 6 mg/kg (average 417 mg) 
dose studied in study 201246, median maximum target engagement (TE) was 90% in 
serum. Therefore, a dose of 450 mg SC is appropriate to investigate the saturated PK/TE 
relationship. Furthermore, a dose of 450mg SC is the highest dose to be administered in 
the global clinical studies with GSK2330811.
4.6.
End of Study Definition
A participant is considered to have completed the study if he has completed the treatment 
and follow-up phases of the study including the last scheduled procedure shown in the 
SoA.


2019N406151_00
CONFIDENTIAL
208564
23
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participants must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests and 12-lead ECGs
3.
A participant with a clinical abnormality or laboratory parameter(s) outside the 
reference range for the healthy population being studied that is not specifically listed 
in the inclusion or exclusion criteria may be included if the investigator and GSK 
Medical Monitor agree and document that the finding is unlikely to introduce 
additional risk factors and will not interfere with the study procedures or 
interpretation.
Weight
4.
Body weight 45 kg and body mass index (BMI) within the range 18.5-29.9 kg/m2
(inclusive).
Sex
5.
Male
Informed Consent
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
Geographical Ancestry
7. Japanese ancestry, defined as having been born in Japan, being descendants of four 
ethnic Japanese grandparents and two ethnic Japanese parents, holding a Japanese 
passport or identity papers, and being able to speak Japanese. Participants should 
have lived outside Japan for less than 10 years at the time of screening.


2019N406151_00
CONFIDENTIAL
208564
24
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Sensitivity to any of the study treatments or components there of (including 
humanised monoclonal antibodies) or history of severe post treatment 
hypersensitivity reactions including erythema multiforme major, linear 
immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis and exfoliative 
dermatitis. 
2. Any other history of significant allergy that in the opinion of the investigator 
contraindicates their participation in this study. 
3. An active infection or a history of serious infections as follows:
a.
Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic 
agents) for an infection within 30 days prior to Day 1. Topical treatments may 
be allowed at the Investigator’s discretion (in consultation with the Medical 
Monitor).
b. A history of opportunistic or recurrent infections, as determined by the 
investigator. 
c.
Currently active or unresolved infection. Participants with ‘trivial’ infections 
such as tinea pedis may be eligible at the discretion of the investigator.
d. Symptomatic herpes zoster within 3 months prior to screening.
e.
History of TB (active or latent) irrespective of treatment status. 
f.
A positive diagnostic TB test at screening (defined as a positive 
QuantiFERON test).
NOTE: In cases where the QuantiFERON test is indeterminate, the participant 
may have the test repeated once and will be eligible if the second test is 
negative. 
4. Any planned major surgical procedure during the study. 
5. A history of haematological disease, for example (but not limited to): significant 
anaemia, platelet disorders including drug-induced thrombocytopaenia or primary 
immune thrombocytopaenia and coagulation disorders including von Willebrand’s 
disease.
6. A history of carcinoma in situ and malignant disease, with the exception of 
adequately treated non-metastatic basal or squamous cell cancer of the skin that has 
been fully treated and shows no evidence of recurrence after 3 years. 


2019N406151_00
CONFIDENTIAL
208564
25
7. QTc >450 msec at screening. 
NOTE: The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), or another method, machine-read or manually over-read. The same 
correction is to be used throughout the study.
Prior/Concomitant Therapy
8.
Use of prescription or non-prescription drugs (including recreational drugs and 
herbal medications) within 7 days or 5 half-lives (whichever is longer) prior to Day 1
unless in the opinion of the investigator (in consultation with the GSK Medical 
Monitor) the medication will not interfere with the study or compromise participant 
safety.
NOTE: Paracetamol at doses of 4 grams/day, and occasional use of NSAIDs at 
licensed doses, are permitted.
9.
Received live vaccination within 4 weeks prior to Day 1, or any plan to receive a live 
vaccination during the study (i.e. up to and including to the last follow-up visit).
Prior/Concurrent Clinical Study Experience
10. Participation in a clinical trial and has received an investigational medicine product
(IMP) within the following time period prior to Day 1: 3 months, 5 half-lives, or 
twice the duration of the biological effect of the IMP (whichever is longer).
11. Exposure to more than 4 new chemical entities within 12 months prior to Day 1.
12. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months.
Diagnostic assessments
13. Platelet count or haemoglobin below the normal range at any time during screening.
14. ALT >1.5x ULN at any time during screening. 
15. Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at any time during screening.
16. Presence of Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody 
(HBcAb), or positive HCV antibody result at screening
NOTE: Participants with positive HCV antibody due to prior resolved disease can be 
enrolled only if a confirmatory negative HCV RNA test is obtained.
17. Positive HIV antibody test at screening.
18. Positive pre-study drug/alcohol screen.
NOTE: Retesting of diagnostic assessments in the case of potentially spurious results 
or sample handling errors is allowed during the screening period. See Section 5.4 for 
details.


2019N406151_00
CONFIDENTIAL
208564
26
Other Exclusions
19. History of regular alcohol consumption within 6 months of the screening visit in 
excess of an average weekly intake of >21 units. One unit is equivalent to 8 g of 
alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 
(25 mL) measure of spirits. 
20. Planning to travel to regions of high endemic infection, as determined by the 
investigator, for the duration of the study.
21. Unstable lifestyle factors, to the extent that in the opinion of the investigator they 
would interfere with the ability of a participant to complete the study.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Participants will be required to fast for approximately 12 hours (no food or drink, 
except water) prior to collection of the Day 1 and Day 21 clinical chemistry blood 
sample. There will be no other caffeine, xanthine or dietary restrictions for the rest of 
the study.
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches and other delivery devices such as 
vaporizers) will not be permitted while they are in the clinical unit. Participants will 
abstain from alcohol for 24 hours prior to clinic visits. Thereafter a weekly intake of 
21 Units of alcohol is permitted. 
5.3.3.
Activity

Participants will abstain from strenuous exercise 24 hours prior to each blood 
collection for clinical laboratory tests. 
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled (randomized). A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations
and any SAEs.
Repeat assessments during the screening period: Assessments, including laboratory 
assessments, may be repeated once if determined necessary by the investigator, for 
example: (a) in cases of technical malfunction (e.g. loss of laboratory specimen), (b) in 
the event of a value close enough to the exclusionary threshold that it may reasonably lie 
within the degree of variability of the assay or an indeterminate result; (c) if there is 


2019N406151_00
CONFIDENTIAL
208564
27
reason to believe the result may be false (i.e. contradicts recent result for the same 
parameter). These are repeat assessments and not rescreening events. If the original result 
was exclusionary and is confirmed by repeat testing, the participant will be excluded. 
Rescreening: Individuals who do not meet the criteria for participation in this study 
(screen failure) may be rescreened once at the discretion of the investigator. Rescreened 
participants will be assigned a new participant number.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
This study will use a pre-filled syringe (PFS): Becton Dickinson’s UltraSafe Plus Safety 
Syringe Device. Instructions for use of the PFS medical device are provided in the Study 
Reference Manual (SRM).  
Intervention Name
GSK2330811
Placebo
Type 
Drug
Placebo
Dose Formulation
50mM Sodium Acetate Trihydrate, 
51mM Sodium Chloride, 1% (w/v) 
L-Arginine, 0.05mM Edetate Disodium 
Dihydrate (EDTA) and 0.02% 
Polysorbate 80 in Water for Injection 
USP, pH 5.5
Normal saline (0.9% sodium 
chloride)
Unit Dose Strength(s)
150mg/ml
N/A
Dosing Instructions
Administered by study personnel.  
3 injections to be used to provide 
450mg SC dose.
Administered by study 
personnel.  3 injections will be 
used to match active doses 
administered.
Route of 
Administration
SC injection to abdomen
SC injection to abdomen
IMP and Non-
investigational 
medicinal product
(NIMP)
IMP
NIMP


2019N406151_00
CONFIDENTIAL
208564
28
Intervention Name
GSK2330811
Placebo
Sourcing
Provided by the Sponsor
Provided by the Sponsor
Packaging and 
Labelling
Study intervention will be provided in a 
pre-filled safety syringe.  Label content 
will be in accordance with the
country’s regulatory requirements
Study intervention will be 
provided in a pre-filled safety 
syringe.  Label content will be in 
accordance with the country’s 
regulatory requirements
[Current/Former 
Name(s) or Alias(es)]
Anti-OSM
N/A
GSK2330811 is a humanised monoclonal antibody and all formulation ingredients have 
been previously used in the clinic. 
SC GSK2330811 is administered as multiples of 150 mg injections, each provided as a 
pre-filled safety syringe. 
In an individual participant, injections should be administered into the abdomen and 
should be separated by a minimum of 2 cm. The location of the injections (abdominal 
quadrant) will be recorded.
6.2.
Preparation/Handling/Storage/Accountability
Each syringe will be supplied as a single PFS within a labelled carton, detailing the 
appropriate content according to the country’s regulations.
Study treatment will be stored in the refrigerator. The PFS must be allowed to come up to 
room temperature for at least 30 minutes after taking out of the refrigerator prior to use. 
Refer to the SRM for further details.
Any malfunctions of the PFS must be documented and reported throughout the study (see 
Section 10.7 for reporting of syringe deficiencies and malfunctions).
The following will also apply in the study:
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.


2019N406151_00
CONFIDENTIAL
208564
29
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM.
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.3.
Measures to Minimize Bias: Randomization and Blinding
6.3.1.
Randomisation and Intervention Assignment
Participants who meet the screening eligibility criteria will be randomised to a treatment 
group through the Interactive Web Response System (IWRS). Before the study is 
initiated, the log in information and directions for the IWRS will be provided to the site. 
Once assigned, a randomisation number must not be reassigned to another participant in 
the study
6.3.2.
Blinding
This will be a double blind (sponsor-open) study with both the investigator and 
participant blinded to study treatment. Site personnel will remain blinded.
The following will apply:

The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. 

If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact GSK prior to unblinding a participant’s intervention 
assignment unless this could delay emergency intervention of the participant. 

If a participant’s intervention assignment is unblinded, GSK must be notified 
within 24 hours after breaking the blind.

The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable.

A participant may continue in the study if that participant’s intervention
assignment is unblinded. 


2019N406151_00
CONFIDENTIAL
208564
30

GSK’s Safety and Medical Governance (SMG) staff may unblind the intervention
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.

Sponsor-open refers to the potential need of the sponsor to unblind single or 
multiple participants at the request of the GSK2330811 Safety Review Team
(SRT) (see Section 10.1.5) to investigate important safety concerns. This would 
be done in accordance with GSK standard operating procedures, is expected to be 
very uncommon, and will be implemented in such a way as to maintain the 
integrity of the study as much as possible. 
6.3.2.1.
Risk of Inferred Unblinding
The treating physician and/or delegate (including the study nurse) will have sight of 
safety laboratory results to fulfil their responsibility for the medical care of study 
participants. Therefore, in this study there is a risk that the physician and/or delegate may 
infer a participant’s treatment allocation through this knowledge. 
Sites will be required to make every effort to ensure that the results of study laboratory 
tests are not proactively communicated to participants during the study unless essential 
for clinical care.
Study monitors, through their review of safety laboratory results, are also at risk of 
inferring a participant’s treatment.
PK and Free and Total OSM results that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
6.4.
Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, 
under medical supervision. The date and time of the dose administered in the clinic will 
be recorded in the source documents. The dose of study intervention and study participant
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study intervention.  
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving at the time of enrolment or receives during the study must be 
recorded along with:

reason for use

dates of administration including start and end dates


2019N406151_00
CONFIDENTIAL
208564
31

dosage information including dose and frequency
The GSK Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. Participants will be questioned about concomitant 
medication at each study visit.
Paracetamol (acetaminophen) at doses of 4 grams/day, and occasional NSAIDs at 
licensed doses, are permitted for use. 
Otherwise, participants must abstain from taking prescription or non-prescription drugs 
(including vitamins and dietary or herbal supplements) within 7 days or 5 half-lives 
(whichever is longer) before the start of study intervention until completion of the follow-
up visit unless, in the opinion of the investigator and GSK Medical Monitor, the 
medication will not interfere with the study. 
Live vaccination is prohibited within 4 weeks of Day 1 until after the Follow-Up visit.
6.6.
Dose Modification
No dose modifications are planned.
6.7.
Intervention after the End of the Study
This is a single dose study in healthy participants. No study intervention will be provided 
following the end of the study.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
This is a single dose study. In rare instances a participant may not be able to receive all 3 
injections and it may be necessary for the participant to permanently discontinue study 
intervention. If study intervention is discontinued, the participant will remain in the study 
for the planned duration. 
7.1.1.
Study Stopping Criteria
If any of the following occur, the study will be temporarily halted:

Any participant experiences a SAE that can be reasonably attributed to 
GSK2330811.

Two or more participants experience a severe adverse event that can be 
reasonably attributed to GSK2330811. 

Any participant experiences a CTCAE Grade 3 or greater reduction in platelet 
count (< 50x109/L) or haemoglobin (< 80 g/L). This should be confirmed by a 
repeat blood sample if there is any concern that the result may be spurious.


2019N406151_00
CONFIDENTIAL
208564
32
The Competent Authority and the Ethics Committee will be notified of a Temporary Halt. 
No further participants will be dosed until a full safety review by relevant GSK personnel 
has taken place.  If, following the safety review, a decision is made to restart dosing, this 
will be based on an updated assessment of the benefit risk and will only occur after 
Competent Authority and Ethics Committee approval via a substantial amendment.
7.1.2.
Liver Chemistry Enhanced Monitoring Criteria
Phase 1 Liver chemistry increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event aetiology.

Refer to Section 10.4 for liver safety required actions and follow-up assessments. 

Any participant meeting the liver chemistry criteria (ALT 3x ULN) will have 
enhanced monitoring as detailed in Section 10.4. The participant should continue 
in the study, given this is a single dose study.

Liver events meeting SAE criteria will be managed as detailed in Section 7.1.1
Study Stopping Criteria.
7.1.3.
QTc Enhanced Monitoring Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility and for all monitoring throughout the study. The formula must not 
be changed or substituted once the participant has been enrolled. 
For participants that meet either of the bulleted criterion below, additional monitoring 
will be undertaken until the QTc value is no longer clinically significant. The frequency 
of this monitoring and the decision as to when the QTc value is no longer clinically 
significant will be at the discretion of the investigator. The participant should continue in 
the study, given this is a single dose study.

QTc >500 msec.

Change from baseline: QTc >60 msec.
The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief recording period.
7.1.4.
Haematological Enhanced Monitoring Criteria
Any participant with platelet count <75x109/L (CTCAE Grade2) must have platelet count 
assessed at least weekly until platelet count is ≥75x109/L. This may necessitate 
unscheduled assessments.
Any participant with a haemoglobin <100 g/L (CTCAE Grade2) must have haemoglobin 
assessed at least weekly until haemoglobin is ≥100g/L. This may necessitate unscheduled 
assessments.


2019N406151_00
CONFIDENTIAL
208564
33
7.2.
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his own request or
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of withdrawal from the study, if possible, an early withdrawal visit 
should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be 
collected at the time of study withdrawal and follow-up and for any further 
evaluations that need to be completed.

The participant will be permanently withdrawn from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study. 
Discontinuation of the study as a whole is handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.


2019N406151_00
CONFIDENTIAL
208564
34

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

The actual date and time of each blood sample collection will be recorded. The 
collection, sample handling, processing, storage and shipping procedures are 
provided in the SRM.
8.1.
Efficacy Assessments
Efficacy assessments are not applicable to this study.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height (at screening only) and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).
8.2.2.
Vital Signs

Temperature (tympanic), pulse rate and blood pressure will be assessed.

Vital signs will be measured in a semi-supine position after 5 minutes rest in a 
quiet setting without distractions.


2019N406151_00
CONFIDENTIAL
208564
35

Vital signs will be measured with a completely automated device. Manual 
techniques will be used only if an automated device is not available.

Vital signs are to be taken before blood collection for laboratory tests.
8.2.3.
ECGs

Triplicate 12-lead ECGs will be obtained in a semi-supine position as outlined in 
the SoA (see Section 1.3) using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section  
7.1.3 for additional QTc readings that may be necessary.

The same QT correction formula must be used for each individual participant to 
determine study eligibility and enhanced monitoring, and this formula may not 
be changed or substituted once the participant has been screened.

Three individual ECG tracings should be obtained as closely as possible in 
succession, but no more than 2 minutes apart. 
8.2.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the case report form (CRF). The laboratory reports must be filed with 
the source documents. Clinically significant abnormal laboratory findings are 
those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
within 126 days after the last dose of study intervention should be repeated 
periodically until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or Medical Monitor. This 
monitoring may extend beyond the final scheduled follow-up visit. Also see 
Section 7.1.2 and Section 7.1.4 for protocol defined enhanced monitoring
requirements for specific assessments.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified, and the 
sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.2.5.
Injection Site Reaction Assessments
Trial staff will apply light pressure at the injection site and record any tenderness, 
erythema and induration in accordance with the SoA and SRM.


2019N406151_00
CONFIDENTIAL
208564
36
8.2.6.
Hypersensitivity Reactions 
As GSK2330811 is a humanized monoclonal antibody, it is considered unlikely that 
acute allergic reactions will occur in response to exposure; however, all participants 
should be monitored carefully for evidence of allergic response. 
Participants should be instructed to report the development of rash, hives, pruritus, 
flushing, urticaria, vomiting, or other symptoms that may represent a hypersensitivity 
reaction to study intervention. It is important to recognize early signs of a 
hypersensitivity reaction and prevent progression to a severe reaction. In the case of a 
mild local reaction during dosing, study intervention administration may be reinitiated 
(with appropriate pre-medication if thought necessary) at the discretion of the 
investigator. 
In the event of a suspected severe acute hypersensitivity reaction or anaphylaxis, sites 
should manage this in accordance with relevant local or national guidelines (for example, 
the Resuscitation Council (UK) Emergency Treatment of Anaphylactic Reactions 
Guidelines for Healthcare Providers (2008). In particular sites should:
Discontinue administration of study intervention (if still ongoing), and not delay 
initial treatment due to an indefinite diagnosis.
Ensure adrenaline, chlorphenamine, hydrocortisone, and a resuscitation trolley are 
immediately available.
Assess the participant using the Airway, Breathing, Circulation, Disability, 
Exposure approach. In the event of a cardiac arrest, initiate cardiopulmonary 
resuscitation.
Provide adrenaline according to relevant local/national guidelines if there is any 
compromise of the participant’s airway, breathing or circulation: 
Provide high concentration oxygen via a non-rebreather mask; fluid resuscitation; 
initiate ECG monitoring and pulse oximetry; and monitor blood pressure.
Administer an appropriate antihistamine (e.g., chlorphenamine maleate 10 mg by 
slow intravenous injection, or intramuscularly).
Administer hydrocortisone 200 mg by slow intravenous injection, or 
intramuscularly.
Acquire two blood samples for serum tryptase analysis:
o As soon as possible after the onset of symptoms, and
o Within 1-2 hours (but no later than 4 hours) from the onset of symptoms.


2019N406151_00
CONFIDENTIAL
208564
37
Discuss the clinical situation with the relevant hospital medical and/or intensive 
care team and arrange transfer to hospital for further treatment and observation as 
indicated.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
For the purpose of reporting safety events related to the PFS, the definitions of device-
related safety events, (adverse device effects (ADEs) and serious adverse device effects 
(SADEs), can be found in Section 10.7, (Appendix 7). PFS deficiencies are covered in 
Section 8.3.5.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative) and identified by the 
investigator/designee through clinical examination and review of laboratory 
investigations.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to withdraw from the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the final follow-up 
visit.

All AEs will be collected from the start of intervention until the final follow-up 
visit (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section. The exceptions are 
SAEs, which must be recorded in the CRF AE/SAE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.


2019N406151_00
CONFIDENTIAL
208564
38
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). This may require follow-up beyond the final scheduled follow-up 
visit. Further information on follow-up procedures is given in Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pre-Filled Syringe Deficiencies
PFS are being provided for use in this study for administering the study treatment. In the 
event that a deficiency or a malfunction occurs with the PFS, in order to fulfil regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and 
documentation of PFS deficiencies that occur during the study.
For the purpose of reporting deficiencies and malfunctions, the definition of a Medical 
Device Deficiency can be found in Appendix 7.


2019N406151_00
CONFIDENTIAL
208564
39
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol. 
8.3.5.1.
Time Period for Detecting Pre-Filled Syringe Deficiencies

PFS deficiencies will be detected, documented, and reported during all periods 
of the study in which the medical device is used. 

The method of documenting PFS deficiencies or malfunctions is provided in 
Appendix 7.
8.3.5.2.
Follow-up of Pre-Filled Syringe Deficiencies

Follow-up applies to all participants, including those who discontinue study 
intervention or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the deficiency.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
8.3.5.3.
Prompt Reporting of Pre-Filled Syringe Deficiencies to Sponsor

Device deficiencies will be reported to the sponsor within 72 hours after the 
investigator becomes aware of a deficiency or malfunction.

The PFS Deficiency/Malfunction Report Form will be sent to the sponsor.

The sponsor will be the contact for the receipt of PFS deficiency reports.
8.3.5.4.
Regulatory Reporting Requirements for Pre-Filled Syringe Incidents

The PFS to be used in the study is a combined medicinal product/medical 
device. The investigator will promptly report all deficiencies occurring with any 
medical device component provided for use in the study in order for the sponsor 
to fulfil the legal responsibility to notify appropriate regulatory authorities and 
other entities about certain safety information relating to medical devices being 
used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of any medical device component 
deficiencies to the IRB/IEC.

The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.


2019N406151_00
CONFIDENTIAL
208564
40

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC.
8.4.
Treatment of Overdose
For this study, any potential dose of GSK2330811 greater than 450 mg will be considered 
an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities weekly for 
at least 4 weeks or as otherwise advised by the Medical Monitor.
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
As this is a single dose study, in the event of an overdose no further study treatment will 
be administered to the participant.
8.5.
Pharmacokinetics

Approximately 2 mL EDTA blood will be collected at the time-points listed in 
the SOA for determination of GSK2330811 plasma concentrations.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded.

GSK2330811 plasma concentration analysis will be performed under the control 
of In Vitro/In Vivo Translation/Bioanalysis, Immunogenicity, Biomarkers
(IVIVT/BIB), GlaxoSmithKline.  Plasma concentrations of GSK2330811 will 
be determined using approved bioanalytical methodology.  The bioanalytical site 
will be detailed in the SRM and raw data will be archived by the bioanalytical 
site listed in the SRM.

Once the plasma has been analysed for GSK2330811, with the participant’s 
consent (see Section 10.1.3), residual samples may be stored and used for 
research to develop methods and assays including potential diagnostics related 
to targeting OSM in a range of potential conditions or to further understand the 
mechanism of action of GSK2330811.


2019N406151_00
CONFIDENTIAL
208564
41
8.6.
Pharmacodynamics
8.6.1.
Total and Free OSM
Pharmacodynamic parameters of GSK2330811 target engagement with OSM will be 
assessed by measuring free and total OSM in serum.

Approximately 2 mL blood will be collected and processed to serum at the time-
points listed in the SOA for determination of total and free OSM.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Sample analysis will be performed under the control of In Vitro/In Vivo 
Translation/Third Party Resourcing (IVIVT/TPR), GlaxoSmithKline.  Plasma 
concentrations of GSK2330811 will be determined using approved bioanalytical 
methodology.  The bioanalytical site will be detailed in the SRM and raw data 
will be archived by the bioanalytical site listed in the SRM.

In addition, with the participant’s consent (see Section 10.1.3), residual samples 
may be stored and used for research to develop methods and assays including 
potential diagnostics related to targeting OSM in a range of potential conditions
or to further understand the mechanism of action of GSK2330811.
8.6.2.
Erythropoietin (EPO) and Thrombopoietin (TPO)
Blood samples will be collected for biomarker assessments related to the mechanism of 
anaemia and thrombocytopenia. These may include (but are not restricted to) EPO and 
TPO.

Approximately 2 mL blood will be collected for each biomarker listed above at 
the time-points listed in the SOA to evaluate their association with the observed 
clinical responses to GSK2330811.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The date of each sample will be recorded.

In addition, with the participant’s consent, residual samples may be stored and 
used for research to develop methods and assays including potential diagnostics 
related to targeting OSM in a range of potential conditions or to further 
understand the mechanism of action of GSK2330811.
8.7.
Biomarkers
No additional samples other than those detailed in Section 8.6 will be analysed.


2019N406151_00
CONFIDENTIAL
208564
42
8.8.
Genetics
Genetics are not evaluated in this study.
8.9.
Immunogenicity Assessments
Blood samples will be collected for immunogenicity assessment.

Approximately 4 mL blood will be collected and processed to serum at the time-
points listed in the SOA for the determination anti-GSK2330811 antibodies.

Instructions for the collection and handling of biological samples will be 
provided in the SRM. The date of each sample will be recorded.

Sample analysis will be performed using a tiered approach involving screening, 
confirmation and titration [EMA, 2017;FDA, 2019] under the control of 
IVIVT/BIB, GlaxoSmithKline. The bioanalytical site will be detailed in the 
SRM and raw data will be archived by the bioanalytical site listed in the SRM.

If sera contain potential anti-GSK2330811 antibodies in the screening 
assessment, they will be confirmed by immune-competition using excess drug, 
followed by a titration assay. Results will include the incidence of 
immunogenicity and titres.

Samples testing positive for anti-GSK2330811 antibodies may be further 
characterised for the presence of GSK2330811 neutralizing activity (NAb). 
8.10.
Health Economics
Health Economics parameters are not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The primary objective of this study is to assess the safety, and tolerability of single SC
doses of GSK2330811 in healthy Japanese participants. No formal hypotheses are being 
tested in this study. 
9.2.
Sample Size Determination
There will be a minimum of 10 Japanese participants. The participants will be 
randomised in the ratio 7:3 to GSK2330811 (450 mg) or placebo.
From the number of adverse events of a specific type observed in 7 participants receiving 
GSK2330811, statistical inferences can be made about the 95% Credible Interval of the 
true event rate, as shown in Table 2, specifying a prior distribution (Beta [1,1]). The 95%
CrI for 6 participants is also presented, as the sample size was defined with a view to 


2019N406151_00
CONFIDENTIAL
208564
43
ensuring at least 6 participants receiving GSK2330811 are evaluable. Table 2 shows that 
if 0 particular safety events are observed out of 7 participants in the GSK2330811 group, 
the upper limit of the 95% Credible Interval indicates that a true event rate of 37% could 
not be ruled out.
Table 2
Upper 95% Credible Limit of the True Event Rate based on 7 
participants on GSK2330811 completing the study
Observed events / participants 
in cohort
Lower 95% Credible Limit of 
true event rate
Upper 95% Credible Limit of 
true event rate
0/7
0.3%
37%
1/7
3.2%
53%
2/7
8.5%
65%
0/6
0.4%
41%
1/6
3.7%
58%
2/6
9.9%
71%
The values in Table 3 are the geometric means of PK parameters observed in the FTIH 
study 201246 following GSK2330811 SC administration:
Table 3
AUC and Cmax Geometric Means and Percent Coefficient of 
Variation (%CVb) Observed in Caucasian PK Study 201246
Treatment group
Value (%CVb)
AUC (0-inf) 
(h*ug/mL)
Cmax
(ug/mL)
0.1 mg/kg
615 (26.2)
0.6 (32.3)
0.3 mg/kg
1605 (21.6)
1.5 (42.7)
1 mg/kg
5316 (42.5)
5.7 (43.5)
3 mg/kg
14656 (21.6)
19.0 (42.7)
6 mg/kg
27681 (23.3)
36.4(22.9)
The mean baseline weight in the 201246 study was 69.5kg and so the 6 mg/kg dose 
corresponds to an average dose of 417 mg; therefore, the PK parameters and CVb %’s 
presented in Table 3 for the 6 mg/kg group are a good approximation for a dose of 450 
mg.
Simulations were performed to determine the sample size based on comparing PK 
exposure in Japanese to PK exposure in Caucasians. The simulations were based on the 
data from the 6 participants who received 6 mg/kg of GSK2330811 in 201246, whose 
geometric mean of AUC(0-inf) was 27681 h*g/mL (95% Confidence interval (CI): 21748 
to 35233). Assuming the true AUC(0-inf) for the Japanese participants is the same as that 
of the 6 mg/kg dose from 201246 and a standard deviation on the loge scale of 0.23, the 
probability that the observed median will be within the 95% CI of the 6 mg/kg group is 
97.5% for 6 evaluable participants receiving GSK2330811 and 97.8% for 7 evaluable 
participants receiving GSK2330811. The probability that the median AUC(0-inf) will be 
within 0.5-2 fold change of the geometric mean from the 6 mg/kg group (13841 to 55363 
h*ug/mL) is 100% for either 6 or 7 evaluable participants receiving GSK2330811.


2019N406151_00
CONFIDENTIAL
208564
44
Additional simulations were performed factoring in the effect of body weight on 
exposure utilising the mPBPK model developed using data from study 201246. If the true 
AUC(0-inf) is affected by body weight according to allometric scaling and intra-individual 
variability is 30% (as estimated by the mPBPK model), the probability that the geometric 
mean of AUC(0-inf) is within 0.5-2 fold compared to that observed in study 201246 
remains 100% for 6 evaluable participants receiving GSK2330811.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Screened
All participants who signed the ICF and were screened for eligibility.
Enrolled
All participants who signed the ICF and are randomized into the study.
Safety
All randomized participants who received at least one dose of study 
treatment.
Participants will be analysed according to the treatment they 
received.
Note: In the very unlikely case a participant is not randomized but 
receives at least one dose of study treatment, these participants will 
be listed separately.
Pharmacokinetic
All participants in the Safety population who received at least one
active dose of study treatment and had at least 1 non-missing PK 
assessment (Non-quantifiable values will be considered as non-
missing values).
Participants will be analysed according to the study treatment they 
received.
9.4.
Statistical Analyses
The Reporting Analysis Plan (RAP) will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and 
secondary endpoints.
9.4.1.
General Considerations
No formal hypothesis testing will be performed in this study. Summary statistics and 
graphs will be presented where appropriate.
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 (or 


2019N406151_00
CONFIDENTIAL
208564
45
Day -1 where applicable) assessments are assumed to be taken prior to first dose and used 
as baseline.
If baseline data is missing, no derivation will be performed, and baseline will be set to 
missing.
9.4.2.
Primary Endpoint(s)
Analysis
Details
Endpoints

Number of participants reporting AEs and SAEs

Number of participants with vital signs (blood pressure, heart 
rate, body temperature) reaching a threshold of potential clinical 
importance

Number of participants with treatment emergent abnormal ECG 
findings.

Number of participants with CTCAE grade 1 or higher safety 
laboratory results (clinical chemistry, haematology values 
where CTCAE grading applies).

Number of participants with treatment emergent abnormal 
urinalysis findings.
Analysis

For count data, the number and percentage of participants will 
be presented.

In addition, where continuous data is available, descriptive 
statistics (i.e. n, arithmetic mean, standard deviation, minimum, 
median, and maximum) of both raw and change from baseline 
data will be also presented.

CTCAE criteria (version 5) will be used to categorise laboratory 
safety data.

Statistical 
Analysis 
(Modelled)

No statistical modelling is planned.
9.4.3.
Secondary Endpoint(s)
9.4.3.1.
Pharmacokinetic parameters
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population. 
Individual plasma concentration-time data will be graphically displayed and summary 
statistics will be produced by time point. Plasma GSK2330811 concentration-time data 
will be analysed by non-compartmental methods.  Calculations will be based on the 
actual sampling times recorded during the study. From the plasma concentration-time 
data, the following pharmacokinetic parameters will be determined, as data permit: 
maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the 
plasma concentration-time curve (AUC[0-t], AUC[0-inf]), terminal half-life (t1/2), apparent 
volume of distribution at steady state (Vss/F) and apparent systemic clearance (CL/F).
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum,) will be calculated for all pharmacokinetic parameters. In addition, for 


2019N406151_00
CONFIDENTIAL
208564
46
loge-transformed variables geometric mean, 95% confidence interval, standard deviation 
on the log scale and %CVb will be provided.
Full details of planned secondary analysis will be specified in the RAP.
9.4.3.2.
Other secondary endpoints
The number and percentage of participants with confirmed positive anti-GSK2330811
antibodies will be presented.  Where applicable the titres will be listed.
Descriptive statistics (n, arithmetic mean, standard deviation, median, minimum and 
maximum) will be calculated for nadirs (for platelet count and haemoglobin).
Descriptive statistics (n, median, minimum, maximum and range) will be calculated for 
time to nadir (for platelet count and haemoglobin).
Full details of planned secondary analysis will be specified in the RAP.
9.4.4.
Exploratory Endpoints

Summary statistics will be produced where appropriate by time point and 
treatment group. 

Graphical displays will be produced over time for serum free and total OSM, TPO 
and EPO levels.

Exploratory PK/PD analyses, if data permit, may be completed on selected free 
and total OSM measurements to examine the relationship between plasma 
concentrations of GSK2330811, and target OSM concentration (free and total). 

Exploratory PK/PD analyses, if data permit, may be conducted on the platelet 
endpoint to examine the relationship between plasma concentrations of 
GSK2330811, and platelet count.  
Full details of planned exploratory analysis will be specified in the RAP.
9.5.
Interim Analyses
No interim analyses are planned.
9.6.
Interim Data Review Committee
An interim data review committee will not be required.


2019N406151_00
CONFIDENTIAL
208564
47
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines.

Applicable International Council of Harmonization (ICH) Good Clinical 
Practice (GCP) Guidelines.

Applicable laws and regulations.

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC.

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures.

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.


2019N406151_00
CONFIDENTIAL
208564
48
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, where applicable, 
and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
Participants who are rescreened are required to sign a new ICF.
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK2330811 or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have the GSK2330811 approved 
for medical use or approved for payment coverage.
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate tick box will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 


2019N406151_00
CONFIDENTIAL
208564
49

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Committees Structure
In line with routine pharmacovigilance, oversight of study safety will be provided by the 
GSK2330811 Safety Review Team (SRT). The SRT will conduct in-stream periodic 
review of blinded safety data including AEs, SAEs, vital signs and laboratory data. Ad 
hoc reviews may be scheduled if required and under certain circumstances the SRT may 
request unblinding of events to address an emerging safety concern (see Section 6.3.2). 
10.1.6.
Dissemination of Clinical Study Data

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 participants, 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 protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized participant-level data from this trial available 
to external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.

A manuscript will be progressed for publication in the scientific literature.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 


2019N406151_00
CONFIDENTIAL
208564
50

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the electronic case report form (eCRF)
that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement. 
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 


2019N406151_00
CONFIDENTIAL
208564
51
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant follow-up
10.1.10.
Publication Policy

The results of this study will be progressed for publishing and may be presented 
at scientific meetings. If this is foreseen, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission. This allows the 
sponsor to protect proprietary information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


2019N406151_00
CONFIDENTIAL
208564
52
10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Reticulocyte
% Reticulocytes
Clinical 
Chemistry1
Urea
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein  
Albumin         
Glucose3
Calcium
Alkaline 
phosphatase
Lipids (fasted)2:
Total Cholesterol
HDL
LDL
Triglycerides
INR4
APTT4
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)


2019N406151_00
CONFIDENTIAL
208564
53
Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

Breath alcohol and urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)]

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis B 
core antibody [HBcAb], and HCV antibody) 

QuantiFERON test for TB
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 7 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (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).
2.
Blood for lipids (fasted) will be taken at pre-dose on day 1 and at day 21  
3.
Non-fasting sample except for pre-dose on day 1 and day 21. 
4.
Blood for INR and APTT will be taken at screening.


2019N406151_00
CONFIDENTIAL
208564
54
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

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 study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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 intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

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 participant’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 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.


2019N406151_00
CONFIDENTIAL
208564
55

Situations in which 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.
10.3.2.
Definition of SAE
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).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant 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 outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
Results in persistent or significant disability/incapacity

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 with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 


2019N406151_00
CONFIDENTIAL
208564
56
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include 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.
10.3.3.
Recording and Follow-Up of AE and SAE
AE 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) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


2019N406151_00
CONFIDENTIAL
208564
57
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in 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 in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant 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.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.


2019N406151_00
CONFIDENTIAL
208564
58
10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
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 or courier service.

Initial notification via 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 reporting can be found in the SRM.


2019N406151_00
CONFIDENTIAL
208564
59
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
Not applicable.


2019N406151_00
CONFIDENTIAL
208564
60
10.5.
Appendix 5: Genetics
Not applicable.


2019N406151_00
CONFIDENTIAL
208564
61
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 Liver chemistry stopping criteria and required follow up assessments have been 
designed to assure participant safety and to evaluate liver event etiology
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant 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, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 24 
hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, as soon as possible and at 
least within 7 days of liver event4 

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


2019N406151_00
CONFIDENTIAL
208564
62
Liver Chemistry Stopping Criteria 
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week)
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant 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, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; HCV RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’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.


2019N406151_00
CONFIDENTIAL
208564
63
10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting

The device to be used in this study is a combination medicinal product; the PFS

The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155. 

Both the investigator and the sponsor will comply with all local medical device 
reporting requirements.

The detection and documentation procedures described in this protocol apply to 
the PFS provided for use in this study.


2019N406151_00
CONFIDENTIAL
208564
64
10.7.1.
Definition of AE and ADE
AE and ADE Definition 

An AE is defined as any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device. This definition includes events related to the investigational medical 
device or comparator and events related to the procedures involved except for events 
in users or other persons, which only include events related to investigational 
devices.

An adverse device effect (ADE) is defined as an adverse event related to the use of 
an investigational medical device. This definition includes any adverse events 
resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational 
medical device as well as any event resulting from use error or from intentional 
misuse of the investigational medical device.
10.7.2.
Definition of SAE, SADE and USADE
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).
An SAE is an AE that:
a.
Led to death 
b.
Led to serious deterioration in the health of the participant, that either resulted in:
1. A life-threatening illness or injury. The term ‘life-threatening' in the definition of 
serious' refers to an event in which the participant 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
2. A permanent impairment of a body structure or a body function,
3. Inpatient or prolonged hospitalization, planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE
4. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function
c.
Led to fetal distress, fetal death or a congenital abnormality or birth defect
SADE definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.


2019N406151_00
CONFIDENTIAL
208564
65
USADE definition

A USADE is a serious adverse device effect which by its nature, incidence, severity 
or outcome has not been identified in the current version of the risk analysis report 
(see Section 2.3).
10.7.3.
Definition of Device Deficiency
Device Deficiency definition

A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequate labelling.
10.7.4.
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies
AE, SAE and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice, and on the appropriate form of the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the sponsor AE/SAE/device 
deficiency CRF page.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent recurrence.


2019N406151_00
CONFIDENTIAL
208564
66
Assessment of Intensity

The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe 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 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.

Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) in his/her 
assessment.

For each AE/SAE/device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/device deficiency and has provided an 
assessment of causality.

There may be situations in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


2019N406151_00
CONFIDENTIAL
208564
67
Follow-up of AE/SAE/device deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant 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.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.7.5.
Reporting of SAEs
SAE Reporting to GSK via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the GSK medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK 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 or courier service.

Initial notification via 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 reporting can be found in the SRM.


2019N406151_00
CONFIDENTIAL
208564
68
10.7.6.
Reporting of SADEs
SADE Reporting to GSK
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs that must fulfil the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to GSK
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency.

GSK shall review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These shall be reported to the regulatory 
authorities and IRBs/IECs as required by national regulations.

Contacts for SAE reporting can be found in the SRM.


2019N406151_00
CONFIDENTIAL
208564
69
10.8.
Appendix 8: Country-specific requirements
Non applicable


2019N406151_00
CONFIDENTIAL
208564
70
10.9.
Appendix 9: Abbreviations and Trademarks
Abbreviations
ADA
Anti-drug antibody
ADE
Adverse Device Effect
AE
Adverse event(s)
ALT
Alanine aminotransaminase 
ANOVA
Analysis of variance 
AST
Aspartate Aminotransferase
AUC
Area under the curve 
AUC(0-inf)
Area under the plasma concentration time-curve from time zero to infinity
AUC(0-t)
Area under the plasma concentration-time curve from time zero to the time of last 
quantifiable concentration
BMI
Body Mass Index
CA
Competent Authority
CD
Crohn’s Disease
CIOMS
Council for International Organizations of Medical Sciences 
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials 
CPK
Creatine phosphokinase 
CRF
Case Report Form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events 
CVb
Coefficients of variation 
EC
Ethics committee
ECG
Electrocardiogram


2019N406151_00
CONFIDENTIAL
208564
71
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EPO
Erythropoietin
F
Bioavailability 
FTIH
First Time In Human
GCP
Good Clinical Practice 
GSK
GlaxoSmithKline
HBcAb
Hepatitis B core antibody 
HBsAg
Hepatitis B surface antigen 
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
IB
Investigator(‘s) Brochure
ICF
Informed Consent Form
ICH
International Council of Harmonization
IDRC
Interim Data Review Committee
IEC
Independent Ethics Committees 
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
INR
International normalized ratio 
IRB
Institutional Review Boards
IVIVT/BBI
In Vitro/In Vivo Translation/ Bioanalysis, Immunogenicity, Biomarkers
IVIVT/TPR
In Vitro/In Vivo Translation/Third Party Resourcing
IWRS
Interactive Web Response System
KLH
Keyhole Limpet Hemocyanin 


2019N406151_00
CONFIDENTIAL
208564
72
LDH
Lactate dehydrogenase 
LLN
Lower Limit of Normal
MCH
Mean Corpuscular Haemoglobin
mPBPK
minimal Physiologically Based Pharmacokinetic
MSDS
Material Safety Data Sheet
NIMP
Non-investigational medicinal product
NOAEL
No Observed Adverse Effect Level
NSAID
Non-steroidal anti-inflammatory drug
OSM
Oncostatin M
PD
Pharmacodynamic
PK
Pharmacokinetic
QTc
Corrected QT interval
QTcF
Corrected QT interval (Fridericia’s formula)
RAP
Reporting Analysis Plan 
RBC
Red Blood Cell
SADE
Serious adverse device effect
SAE
Serious adverse event(s)
SC
Subcutaneous
SD
Single dose
SMG
Safety and Medical Governance 
SoA
Schedule of Activities 
SRM
Study Reference Manual
SSc
Systemic Sclerosis
SUSAR
Suspected unexpected serious adverse reactions
TB
Tuberculosis


2019N406151_00
CONFIDENTIAL
208564
73
TE
Target Engagement
Tmax
Time of occurrence of Cmax
TMDD
Target-mediated drug disposition 
TPO
Thrombopoietin
ULN
Upper limit of normal
USADE
Unexpected serious adverse device effect
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QuantiFERON
UltraSafe Plus


2019N406151_00
CONFIDENTIAL
208564
74
11.
REFERENCES
Ayaub E, Dubey A, Imani1 J, Botelho F, Kolb M, Richards C et al. Overexpression of 
OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development 
of bleomycin-induced lung fibrosis. Scientific Reportsvolume 7, Article number: 13281 
(2017)
European Medicines Agency (EMA). Guideline on immunogenicity assessment of 
monoclonal antibodies intended for in vivo clinical use. Committee for Medicinal 
Products for Human Use (CHMP), London; 2017. EMEA/CHMP/BMWP/14327/2006 
Rev 1.
Food and Drug Administration (FDA). Immunogenicity Testing of Therapeutic Protein 
Products —Developing and Validating Assays for Anti-Drug Antibody Detection: 
Guidance for Industry. Center for Drug Evaluation and Research (CERD), Silver Spring, 
Maryland, and Center for Biologics Evaluation and Research (CBER), Rockville, 
Maryland, 2019
GlaxoSmithKline Document Number 2016N284919_02. GSK2330811 Investigator’s 
Brochure. 24-JUN-2019.
Hermanns HM. Oncostatin M and interleukin-31: Cytokines, receptors, signal 
transduction and physiology. Cytokine Growth Factor Rev. 2015;26(5):545-58.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Miyajima A, Kinoshita T, Tanaka M, Kamiya A, Mukouyama Y, Hara T. Role of
Oncostatin M in hematopoiesis and liver development. Cytokine & Growth Factor
Reviews. 2000;11(3):117-183.
Nakamura K1, Nonaka H, Saito H, Tanaka M, Miyajima A. Hepatocyte proliveration and 
tissue remodeling is impaired after liver injury in Oncostatin M receptor knockout mice. 
Hepatology. 2004; Mar,39(3):635-44
Reid J, Zamuner S, Edward K, Rumley SA, Nevin K, et al. In viv anffinity and target 
engagement in skin and blood in a first-time-in human study of an anti-oncostatin M 
monoclonal antibody. Br J Clin Pharmacol. 2018;84(10):2280-2291 
Tanaka M, Hirabayashi Y, Sekiguchi T, Inoue T, Katsuki M, Miyajima A.  Targeted 
disruption of oncostatin M receptor results in altered hematopoiesis.  Blood, 
2003;102(9):3154-62.
Wallace PM, MacMaster JF, Rillema JR, Peng J, Burstein SA, Shoyab M.
Thrombocytopoietic properties of oncostatin M. Blood. 1995;86:1310-1315. 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
208564 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for study 208564: 
A phase 1, randomised, double-blind, placebo-controlled 
study of the safety, tolerability, pharmacokinetics and 
pharmacodynamics of single subcutaneous doses of 
GSK2330811 in healthy Japanese participants.  
Compound Number  : GSK2330811 
Effective Date  
: Refer to Document Date 
 
Description: 
• 
The purpose of the final RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 208564. 
• 
This RAP will be provided to the study team members to convey the Statistical 
Analysis Complete (SAC) deliverables. 
 
Author(s): 
Authors 
Date 
 
30-OCT-2020 
Statistician (Hep/GI Biostatistics) 
 
01-DEC-2020 
Senior Statistician (Hep/GI Biostatistics) 
 
30-NOV-2020 
Quantitative Clinical Pharmacology Director (Hep/GI CPMS) 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0
PPD
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
208564 
 
2 
 
RAP Team Review Confirmations 
(Method: E-mail) 
Reviewer 
Date 
 
02-DEC-2020 
Programming Manager (Hep/GI Clinical Programming) 
 
01-DEC-2020 
Senior Director Clinical Development (Hep/GI and Fibrosis) 
 
01-DEC-2020 
Global Clinical Development Manager 
  
01-DEC-2020 
Clinical Development Director (Hep/GI and Fibrosis) 
 
01-DEC-2020 
Clinical Data Manager 
  
02-DEC-2020 
Senior Director Therapeutic Group, Global Regulatory & 
Quality 
 
Clinical Statistics and Clinical Programming Line Approvals: 
(Method: Veeva Clinical Vault eSignature) 
Approver 
 
Director (Hep/GI Clinical Statistics) 
(On behalf of 
 (Line Manager, Head – Statistics)) 
 
Manager (Hep/GI Clinical Programming) 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
208564 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 5 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 5 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 5 
2.3. 
Study Design ................................................................................................ 6 
2.4. 
Statistical Analyses ....................................................................................... 6 
2.5. 
Interim Analyses ........................................................................................... 7 
2.6. 
Final Analyses .............................................................................................. 7 
3. 
ANALYSIS POPULATIONS ..................................................................................... 7 
3.1. 
Protocol Deviations ....................................................................................... 8 
4. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ....................................................................................................... 9 
4.1. 
Study Treatment & Sub-group Display Descriptors ....................................... 9 
4.2. 
Baseline Definitions ...................................................................................... 9 
4.2.1. 
Derivations and Handling of Missing Baseline Data ....................... 9 
4.3. 
Examination of Covariates, Other Strata and Subgroups ............................ 10 
4.4. 
Multiple Comparisons and Multiplicity ......................................................... 10 
4.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 10 
5. 
STUDY POPULATION ANALYSES ....................................................................... 11 
5.1. 
Overview of Planned Study Population Analyses ........................................ 11 
6. 
EFFICACY ANALYSES .......................................................................................... 11 
7. 
SAFETY ANALYSES ............................................................................................. 12 
7.1. 
Adverse Events Analyses ........................................................................... 12 
7.2. 
Clinical Laboratory Analyses ....................................................................... 12 
7.3. 
Other Safety Analyses ................................................................................ 12 
8. 
IMMUNOGENICITY ANALYSES ............................................................................ 13 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 14 
9.1. 
Secondary Pharmacokinetic Analyses ........................................................ 14 
9.1.1. 
Endpoint / Variables ..................................................................... 14 
9.1.1.1. 
Drug Concentration Measures .................................... 14 
9.1.1.2. 
Derived Pharmacokinetic Parameters......................... 14 
9.1.2. 
Summary Measure ...................................................................... 14 
9.1.3. 
Population of Interest ................................................................... 15 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 15 
10. PHARMACODYNAMIC AND / OR BIOMARKER ANALYSES ................................ 16 
10.1. 
Exploratory Pharmacodynamic (and / or Biomarker) Analyses .................... 16 
10.1.1. 
Endpoint / Variables ..................................................................... 16 
10.1.2. 
Summary Measure ...................................................................... 16 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
4 
 
10.1.3. 
Population of Interest ................................................................... 16 
10.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 16 
10.1.5. 
Statistical Analyses / Methods ..................................................... 17 
11. REFERENCES ....................................................................................................... 18 
12. APPENDICES ........................................................................................................ 19 
12.1. 
Appendix 1: Schedule of Activities .............................................................. 19 
12.1.1. 
Protocol Defined Schedule of Events ........................................... 19 
12.2. 
Appendix 2: Assessment Windows ............................................................. 22 
12.2.1. 
Definitions of Assessment Windows for Analyses ........................ 22 
12.3. 
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 25 
12.3.1. 
Study Phases .............................................................................. 25 
12.3.1.1. Study Phases for Concomitant Medication ................. 25 
12.3.2. 
Treatment Emergent Flag for Adverse Events ............................. 25 
12.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 26 
12.4.1. 
Reporting Process ....................................................................... 26 
12.4.2. 
Reporting Standards .................................................................... 26 
12.4.3. 
Reporting Standards for Pharmacokinetic .................................... 27 
12.4.4. 
Reporting Standards for Target Engagement ............................... 29 
12.5. 
Appendix 5: Derived and Transformed Data ............................................... 31 
12.5.1. 
General ........................................................................................ 31 
12.5.2. 
Study Population .......................................................................... 31 
12.5.3. 
Safety .......................................................................................... 31 
12.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 33 
12.6.1. 
Premature Withdrawals ................................................................ 33 
12.6.2. 
Handling of Missing Data ............................................................. 33 
12.6.2.1. Handling of Missing and Partial Dates ........................ 33 
12.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 35 
12.7.1. 
Laboratory Values ........................................................................ 35 
12.7.2. 
Laboratory Values – Haematology, Chemistry and Liver .............. 38 
12.7.3. 
ECG ............................................................................................. 39 
12.7.4. 
Vital Signs .................................................................................... 39 
12.8. 
Appendix 8: Abbreviations & Trademarks ................................................... 40 
12.8.1. 
Abbreviations ............................................................................... 40 
12.8.2. 
Trademarks ................................................................................. 41 
12.9. 
Appendix 9: List of Data Displays ............................................................... 42 
12.9.1. 
Data Display Numbering .............................................................. 42 
12.9.2. 
Mock Example Shell Referencing ................................................ 42 
12.9.3. 
Deliverables ................................................................................. 42 
12.9.4. 
Study Population Tables .............................................................. 43 
12.9.5. 
Safety Tables ............................................................................... 44 
12.9.6. 
Safety Figures ............................................................................. 48 
12.9.7. 
Pharmacokinetic Tables ............................................................... 49 
12.9.8. 
Pharmacokinetic Figures ............................................................. 50 
12.9.9. 
Pharmacodynamic (and / or Biomarker) Tables ........................... 51 
12.9.10. Pharmacodynamic (and / or Biomarker) Figures .......................... 53 
12.9.11. Pharmacokinetic / Pharmacodynamic Figures ............................. 54 
12.9.12. ICH Listings ................................................................................. 55 
12.9.13. Non-ICH Listings .......................................................................... 58 
12.10. Appendix 10: Example Mock Shells for Data Displays ................................ 59 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
5 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 208564: 
Revision Chronology: 
2019N406151_00 
11-SEP-2019 
Original 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There was an unplanned interim analysis conducted due to safety related temporary study 
hold criterion being met and was not specified in the protocol. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To evaluate the safety and tolerability 
of a single SC dose of GSK2330811 
in healthy Japanese participants 
• 
Number of participants reporting AEs. 
• 
Number of participants reporting SAEs. 
• 
Number of participants with vital signs (blood pressure, 
heart rate, body temperature) reaching a threshold of 
potential clinical importance 
• 
Number of participants with treatment emergent abnormal 
ECG findings. 
• 
Number of participants with CTCAE grade 1 or higher 
safety laboratory results (clinical chemistry, haematology 
values where CTCAE grading applies). 
• 
Number of participants with treatment emergent abnormal 
urinalysis findings 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the pharmacokinetic (PK) 
profile of a single SC dose of 
GSK2330811 in healthy Japanese 
participants 
• 
Pharmacokinetic parameters (Cmax, AUC, CL/F, Tmax, 
t1/2, Vss/F) 
• 
To assess the potential for anti-drug 
antibody formation following a single 
SC dose of GSK2330811 in healthy 
Japanese participants 
• 
Number of participants with anti-GSK2330811 antibodies 
• 
To assess effects of GSK2330811 on 
platelets and haemoglobin in healthy 
Japanese participants 
• 
Platelet nadir 
• 
Time to platelet nadir 
• 
Haemoglobin nadir 
• 
Time to haemoglobin nadir 
Exploratory Objectives 
Exploratory Endpoints 
• 
To explore the PD and the PK/PD 
relationship for GSK2330811 in the 
blood of healthy Japanese 
participants 
• 
Serum levels of free OSM 
• 
Serum levels of total OSM 
• 
Levels of Thrombopoietin (TPO) 
• 
  Levels of Erythropoietin (EPO) 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
6 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
This is a randomised, double-blind, placebo-controlled, single-centre study with single 
SC doses of GSK2330811 administered to healthy male Japanese participants. 
• 
Participants will attend a screening visit at the clinical unit within 30 days of Study 
Day 1. If eligible for the study, participants will return on Day -1 for overnight 
admission to the unit. 
• 
Participants will be randomized to either GSK2330811 or placebo in an approximate 
ratio of 7:3. 
• 
Approximately 10 eligible participants will be admitted to the clinical unit on the day 
prior to dosing (Day-1). On Day 1, each participant will receive a single SC dose of 
GSK2330811 or placebo, administered as three separate SC injections Participants 
will then remain as an in-patient until discharged on Day 2 after assessments have 
been performed. 
• 
Participants will then return to the clinical unit for outpatient visits as described in 
the Schedule of Activities (SoA). 
• 
The final follow up visit will be at the clinical unit on Day 126. 
• 
The maximum dose will not exceed 450mg SC. 
Dosing 
• 
Participants will be dosed once on Day 1 
Time & 
Events 
• 
Refer to Appendix 1: Schedule of Activities 
Treatment 
Assignment 
• 
Participants will be assigned to either 450mg GSK2330811 SC or placebo in a 7:3 
ratio. 
Interim 
Analysis 
• 
No interim analyses will be performed 
 
2.4. 
Statistical Analyses 
The primary objective of this study is to determine the safety and tolerability of single 
subcutaneous doses of GSK2330811 in healthy Japanese participants. No formal 
hypotheses are being tested in this study and therefore no statistical analysis is planned. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
7 
 
2.5. 
Interim Analyses 
An unplanned unblinded review of available exposure time-course data from the ongoing 
study cohort was initiated due to a safety related temporary study hold criterion being 
met. The unblinded data provided to CPMS and analysis report was documented in trial 
master file. 
 
2.6. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the following 
sequential steps: 
1. All participants have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
3. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who signed the ICF and were 
screened for eligibility 
• 
Study Population 
• 
Screen Failures 
Enrolled 
• 
All participants who signed the ICF and were 
randomized into the study. 
• 
Study Population 
Safety 
• 
All randomized participants who received a full dose 
of study treatment.  
• 
Participants will be analysed according to the 
treatment they received. 
• 
Note: In the very unlikely case a participant is not 
randomized but receives at least one dose of study 
treatment, these participants will be listed separately. 
• 
Study Population 
• 
Safety 
• 
PK/PD selected 
tables and figures 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety population who received 
at least one active dose of study treatment and had 
at least 1 non-missing PK assessment (Non-
quantifiable values will be considered as non-missing 
values). 
• 
Participants will be analysed according to the study 
treatment they received. 
• 
PK 
• 
PK/PD selected 
figures 
Refer to Appendix 9: List of Data Displays which details the population used for each display. 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
8 
 
3.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant 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 [Version 1, 25 Nov 2019]. 
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. 
A separate table and listing of all COVID-19 related protocol deviations will be provided 
to capture the impact on visits and assessments. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
9 
 
4. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
4.1. 
Study Treatment & Sub-group Display Descriptors 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
 
4.2. 
Baseline Definitions 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 (or 
Day -1 where applicable) assessments are assumed to be taken prior to first dose and used 
as baseline. 
In case that triplicate assessments are performed, the mean of triplicate assessments at any 
given time point will be used as the value for that time point. 
 
4.2.1. 
Derivations and Handling of Missing Baseline Data 
If baseline data is missing, no derivation will be performed, and baseline will be set to missing. 
The baseline definition will be footnoted on all change from baseline displays. 
 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit – Baseline) / Baseline] 
Nadir 
= Lowest post-baseline value of endpoint for a participant [1] 
Time (Days) to Nadir 
= Study Day of Nadir – 1[1] 
NOTES: 
• 
1:  When there are multiple instances of the lowest value then the nadir used for reporting will be the earliest 
occurrence of that value. 
• 
Unless otherwise specified, the baseline definitions specified in Section 4.2. 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. ‘Note:  Baseline is defined as the pre-
dose Day 1 assessment, unless unavailable, in which case it is the latest pre-dose assessment.’  
• 
If there are multiple measurements (i.e. ECG) the derivation will be based on the average values where available. 
 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TFL[1] 
A 
GSK2330811 450 mg SC - PARALLEL 
GSK2330811 450 mg 
2 
P 
Placebo - PARALLEL 
Placebo 
1 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
10 
 
4.3. 
Examination of Covariates, Other Strata and Subgroups 
There is no planned examination of covariates, other strata and subgroup analyses due to 
the small overall sample size. 
4.4. 
Multiple Comparisons and Multiplicity 
There is no adjustment for multiplicity in this phase 1 study. 
4.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
12.2 
Appendix 2: Assessment Windows 
12.3 
Appendix 3: Study Phases and Treatment Emergent Adverse Events 
12.4 
Appendix 4: Data Display Standards & Handling Conventions 
12.5 
Appendix 5: Derived and Transformed Data 
12.6 
Appendix 6: Reporting Standards for Missing Data 
12.7 
Appendix 7: Values of Potential Clinical Importance 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
11 
 
5. 
STUDY POPULATION ANALYSES 
5.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the ‘Safety’ population, unless otherwise 
specified. 
Study population analyses including analyses of subject’s disposition, protocol deviations, 
demographic and baseline characteristics, concomitant medications, and exposure and 
treatment compliance will be based on GSK Core Data Standards. Details of the planned 
displays are presented in Appendix 9: List of Data Displays. 
6. 
EFFICACY ANALYSES 
There are no efficacy analyses included in this study. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
12 
 
7. 
SAFETY ANALYSES 
The safety analyses will be based on the “Safety” population, unless otherwise specified. 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs) and Serious (SAEs) 
will be based on GSK Core Data Standards. The details of the planned displays are 
provided in Appendix 9: List of Data Displays. 
7.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, haematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 9: List of Data Displays. 
Descriptive statistics (n, arithmetic mean, standard deviation, median, minimum, and 
maximum) will be calculated for nadirs for platelet count and haemoglobin.  
Descriptive statistics (n, median, minimum, maximum and range) will also be calculated 
for time to nadir for platelet count and haemoglobin. 
Laboratory safety will be graded using CTCAE criteria version 5. CTCAE grade 1 or 
higher safety laboratory results will be presented (where CTCAE grading applies). 
7.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified.  
A separate listing to capture the COVID-19 infection assessment of participants based on 
new eCRF page will be provided. 
The details of the planned displays are presented in Appendix 9: List of Data Displays. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
13 
 
8. 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will be based on the “Safety” population, unless otherwise 
specified. The immunogenicity analysis summarises the incidence of confirmed anti-drug 
antibodies and lists the titre of immunogenicity results.  
Details of the planned displays are presented in Appendix 9: List of Data Displays. 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
14 
 
9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Secondary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
9.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 12.4.3 
Reporting Standards for Pharmacokinetic). 
9.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma 
concentration-time data, as data permits. 
Parameter 
Parameter Description 
Cmax 
• 
Maximum observed concentration. 
Determined directly from the concentration-time data. 
Tmax 
• 
Time to reach Cmax. 
Determined directly from the concentration-time data. 
AUC(0-t) 
• 
Area under the concentration-time curve from time zero to the time of last quantifiable 
concentration (C(t)). 
• 
Calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
AUC(0-inf) 
• 
Area under the concentration-time curve from time zero to infinity 
• 
Calculated as AUC(0-inf)=AUC(0-t)+C(t)/lambda_z. AUC(0-inf) should not be reported if 
the area coming from extrapolation is greater than 20% of AUC(0-inf). 
%AUCex 
• 
The percentage of AUC (0-inf) obtained by extrapolation will be calculated as: 
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100 
t1/2 
• 
Terminal half-life 
• 
Calculated as t1/2=ln2/lambda_z.  
CL/F 
• 
Apparent systemic clearance 
Vss/F 
• 
Apparent volume of distribution at steady state 
tlast 
• 
Time of last quantifiable concentration 
NOTES: 
• 
Additional parameters may be included as required. 
• 
lambda_z is the first order rate constant associated with the terminal (log-linear) portion of the curve. Estimated by 
linear regression of time vs. log concentration 
9.1.2. 
Summary Measure 
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum) will be calculated for all PK concentrations over time and for the 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
15 
 
derived PK parameters. In addition, for log-transformed PK parameter variables (i.e. 
Cmax, AUC(0-t), AUC(0-inf), CL/F, Vss/F, t1/2), geometric mean, 95% CI and %CVb will 
be provided. Plots of mean concentrations will also include standard deviation [SD] for the 
mean. 
9.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified. 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
A ‘While on-study’ strategy will be implemented for intercurrent events. 
• 
Withdrawn participants may be replaced in the study. Replacement participants will 
be dosed with the planned treatment of the withdrawn participant. 
• 
All available data from participants who were withdrawn from the study will be 
analysed and listed, and all available planned data will be included in summary tables and 
figures, unless otherwise specified. 
• 
Non quantifiable data will be handled as per GUI_51487 
• 
If anomalous concentration data is identified, the pharmacokineticist will: 
o excludes the PK concentration data deemed to be anomalous 
o documents the reason for exclusion in the ‘Code’ folder of the Phoenix Project 
o communicates exclusion to Statistics and Programming 
Note: Any exclusion of anomalous PK concentration data is documented in the clinical 
study report (CSR). Anomalous PK data is excluded from PK summaries and is flagged by 
asterisk or appropriate footnote in the PK data listings. 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
16 
 
10. 
PHARMACODYNAMIC AND / OR BIOMARKER 
ANALYSES 
10.1. 
Exploratory Pharmacodynamic (and / or Biomarker) 
Analyses 
10.1.1. 
Endpoint / Variables 
Parameter 
Parameter description  
Free OSM 
Free OSM concentration in serum 
Total OSM 
Total OSM concentration in serum 
TPO 
Thrombopoietin concentration in serum 
EPO 
Erythropoietin concentration in platelet-poor plasma 
10.1.2. 
Summary Measure 
Descriptive statistics (n, arithmetic mean, standard deviation [SD], 95% CI, minimum, 
median and maximum) will be calculated for free and total OSM concentrations over time. 
Descriptive statistics (n. geometric mean and standard deviation [SD] on log scale, CVb%) 
will be calculated for log transformed total OSM concentration and ratio to baseline. Plots 
of individual, mean concentrations with SD and median concentrations with range for total 
OSM will be produced.  
Total OSM parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Total OSM, Cmax, Tmax, AUC(0-t), AUC(0-inf), %AUCex, t1/2, CL/V, 
Vss/V, tlast might be calculated with non-compartmental analysis, from the serum 
concentration-time data, as data permits.  
Only data listing provided for TPO and EPO concentrations. 
10.1.3. 
Population of Interest 
The exploratory pharmacodynamics analyses will be based on the safety population, unless 
otherwise specified. 
10.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
A ‘While on-study’ strategy will be implemented for intercurrent events. 
All available data from participants 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. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
17 
 
10.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and will 
be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
18 
 
11. 
REFERENCES 
GSK Document Number 2019N406151_00. Study ID 208564: A phase 1, randomised, 
double-blind, placebo-controlled study of the safety, tolerability, pharmacokinetics and 
pharmacodynamics of single subcutaneous doses of GSK2330811 in healthy Japanese 
participants.11-SEP-2019. 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
19 
 
12. 
APPENDICES 
12.1. 
Appendix 1: Schedule of Activities 
12.1.1. 
Protocol Defined Schedule of Events 
Screening Period 
Screening Procedure 
Screening (up to 30 days prior to 
Day 1) 
Informed Consent 
X 
Inclusion and Exclusion Criteria 
X 
Demography 
X 
Full Physical Exam (incl. weight and height) 
X 
Medical History and current medical conditions1 
X 
Concomitant Medication Review 
X 
12 lead ECG in triplicate 
X 
Vitals (blood pressure, heart rate, body temperature)2  
X 
Breath Alcohol Screen 
X 
Urine Drug Screen 
X 
HIV, HBV and HCV Screen 
X 
Tuberculosis (TB) Screening QuantiFERON  
X 
Haematology/Clinical Chemistry/Urinalysis/Clotting 
X 
SAE Review 
X 
1. To include substance usage, family history of premature cardiovascular disease, medication, drug/alcohol 
history 
2. Vital signs are to be taken before blood collection for laboratory tests. 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
20 
 
Treatment and Follow-Up Period 
Procedure 
 
 
 
Day 
-1 
Day 1 
Day 
2 
Day 
3 
Day 
5 
Day 
7 
Day 
10  
Day 
14 
Day 
21 
Day 
28 
Day 
42 
Day 
56 
Day 
84 
Day 126 
(follow-up 
visit)/Early 
Withdrawal 
 
 
 
 
 
 
 
1 
day 
1 
day 
1 
day 
1 
day 
2 
days 
2 
days 
7 
days 
7 days 
Admission 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-patient Stay 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Pre- 
dose 
0h 
1h 
4h 
8h 
24h 
  
  
  
  
  
  
  
  
  
  
  
Dosing3 
 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Injection Site Reaction Assessment 
 
 X5 
X5 
  
 X5 
  
X5 
  
  
  
 
 
 
 
 
 
 
X 
Brief Physical Exam 
X 
  
  
  
  
  
X1 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Exam6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Haematology/Clinical Chemistry 
X 
X2 
  
  
  
  
X1 
X 
X 
X 
X 
X 
X2 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
12 lead ECG (triplicate) 
 
X 
  
  
  
  
X 
  
  
X 
  
  
  
 X 
X 
Vitals (blood pressure, heart rate, body 
temperature)4 
 
X 
X 
  
X1 
X1 
X1 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Sampling 
 
X 
  
  
  
X1 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free & Total OSM Sampling 
 
X 
  
  
  
X1 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity Sampling 
 
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
  
  
  
X 
TPO Sampling 
 
X 
  
  
  
  
  
  
 X 
 X 
  
X 
  
  
 
 X 
 
EPO Sampling 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
Concomitant Medication Review 
 
Monitored from screening until end of follow-up visit 
SAE/AE Review 
 
SAEs collected from signing of consent form, AEs collected continuously from time of dose 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
21 
 
Footnotes:  
1. 
All post dose time points are in reference to the first injection of IMP. 
2. 
Day 1 Pre-dose sample and Day 21 sample will be fasted for approximately 12 hr and will include lipids 
3. 
IMP administration consists of 3 syringes, all 3 syringes are to be administered as closely together in time as possible  
4. 
Vital signs are to be taken before blood collection for laboratory tests. 
5. 
Assessments should be conducted immediately before first injection (pre-dose) and immediately after last injection (0h). Post dose assessments (4h and 24h) to be conducted in 
reference to the last injection of IMP. Any injection site reactions to be captured through AE reporting. 
6. 
Full physical exam at follow-up will not include height 
• 
The timing and number of planned study 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.  
• 
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files but will not constitute a protocol amendment. The Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC before 
implementation. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
22 
 
12.2. 
Appendix 2: Assessment Windows 
For haematology, chemistry, vital signs, ECG, urinalysis, immunogenicity, PK and 
biomarker outputs (incl. summaries and figures), Unscheduled and early withdrawal 
assessments will be included (see Appendix 4: Data Display Standards & Handling 
Conventions and Appendix 9: List of Data Displays).   
Where unscheduled and early withdrawal visits are included in outputs, the following visit 
slotting will apply.  If more than one visit slots to the same analysis timepoint, the closest 
visit to the analysis timepoint will be included in the summary and figure.  
12.2.1. 
Definitions of Assessment Windows for Analyses 
Analysis Set / Domain 
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
Haematology and Chemistry 
Days less than 0 
 
Screening 
Day 1 
Day 1 
Day 1 
Day 2 
Day 2 
Day 2 
Day 3 
Day 4 
Day 3 
Day 5 
Day 6 
Day 5 
Day 7 
Day 8 
Day 7 
Day 9 
Day 12 
Day 10 
Day 13 
Day 17 
Day 14 
Day 18 
Day 24 
Day 21 
Day 25 
Day 34 
Day 28 
Day 35 
Day 49 
Day 42 
Day 50 
Day 63 
Day 56 
Day 64 
Day 105 
Day 84 
Day 106 
Day 133 
Day 126 
 
Analysis Set / Domain 
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
Vital signs 
Days less than 0 
 
Screening 
Day 1 - Pre dose 
 
Day 1 - Pre dose  
Day 1 - 1H 
 
Day 1 - 1H 
Day 1 - 4H 
 
Day 1 - 4H 
Day 1 - 8H 
 
Day 1 - 8H 
Day 2 
Day 2 
Day 2 
Day 3 
Day 4 
Day 3 
Day 5 
Day 6 
Day 5 
Day 7 
Day 8 
Day 7 
Day 9 
Day 12 
Day 10 
Day 13 
Day 17 
Day 14 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
23 
 
Analysis Set / Domain 
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
Day 18 
Day 24 
Day 21 
Day 25 
Day 34 
Day 28 
Day 35 
Day 49 
Day 42 
Day 50 
Day 63 
Day 56 
Day 64 
Day 105 
Day 84 
Day 106 
Day 133 
Day 126 
 
Analysis Set / Domain 
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
ECG and Urinalysis 
Days less than 0 
 
Screening 
Day 1 
Day 1 
Day 1 
Day 2 
Day 14 
Day 7 
Day 15 
Day 42 
Day 21 
Day 43 
Day 105 
Day 84 
Day 106 
Day 133 
Day 126 
 
Analysis Set / Domain 
Analysis Window 
Analysis Timepoint 
Beginning Timepoint 
Ending Timepoint 
PK/ Free and Total OSM  
Day 1 - Pre dose 
 
Day 1 - Pre dose 
Day 1 - 8H 
 
Day 1 - 8H 
Day 2 
Day 2 
Day 2 
Day 3 
Day 4 
Day 3 
Day 5 
Day 6 
Day 5 
Day 7 
Day 8 
Day 7 
Day 9 
Day 12 
Day 10 
Day 13 
Day 17 
Day 14 
Day 18 
Day 24 
Day 21 
Day 25 
Day 34 
Day 28 
Day 35 
Day 49 
Day 42 
Day 50 
Day 63 
Day 56 
Day 64 
Day 105 
Day 84 
Day 106 
Day 133 
Day 126 
 
Analysis Set / Domain 
 
Analysis Window 
Analysis 
Timepoint 
 
Beginning 
Timepoint 
Ending 
Timepoint 
Biomarker samples 
(EPO/ TPO) 
EPO 
Day 1 
Day 1 
Day 1 
 
Day 2 
 Day 9 
Day 7 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
24 
 
Analysis Set / Domain 
 
Analysis Window 
Analysis 
Timepoint 
 
Beginning 
Timepoint 
Ending 
Timepoint 
 
Day 10 
Day 17 
Day 14 
 
Day 18 
Day 34  
Day 21 
 
Day 35 
Day 133 
Day 56 
 
 
 
 
TPO 
Day 1 
Day 1 
Day 1 
 
Day 2 
Day 7 
Day 5 
 
Day 8 
Day 17 
Day 10 
 
Day 18 
Day 34  
Day 21 
 
Day 35 
Day 133 
Day 86 
 
Analysis Set / Domain 
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
 Immunogenicity 
Day 1 
Day 1 
Day 1 
Day 10 
Day 21 
Day 14 
Day 22 
Day 56 
Day 28 
Day 56 
Day 133 
Day 126 
 
For PK and PD planned and unplanned assessments will be summarised and listed. PK 
NCA will use all available data and will use actual relative time, not planned relative time. 
For all endpoints an early withdrawal assessment occurred at the time when a planned 
assessment for that endpoint would have occurred ( the visit window), the early 
withdrawal visit will be slotted to that planned assessment and included in summaries.  
Where the plots use time as the x-axis, the early withdrawal visit will be included regardless 
of when the data was collected relative to the study window.  For log type data (i.e. AEs), 
all early withdrawal data will be included in summaries. All early withdrawal data will be 
listed.  
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
25 
 
12.3. 
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events 
12.3.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date. 
Study Phase 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date/Time 
Treatment 
Emergent 
Date > Study Treatment Start Date/Time  
 
12.3.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is prior to study treatment 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 6: 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. 
12.3.2. 
Treatment Emergent Flag for Adverse Events 
Adverse Events will be flagged as Treatment Emergent as described in the table in Section 
12.3.1, where the AE Start Date/Time will be considered. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
26 
 
12.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
12.4.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: \\uk1salx00175.corpnet2.com 
HARP Compound 
Reporting effort (RE) 
name in RAP 
Type 
HARP folder / RE 
name 
Unplanned IA 
Interim analysis 
internal_01, 
internal_02 
SAC 
Pre-programming/ 
dry run 
data_look_01, 
data_look_02 
SAC 
Final 
final_01 
Analysis Datasets  
• 
Analysis datasets will be created according to Integrated Data Standards Library (IDSL) GSK A&R 
dataset standards. 
Generation of RTF Files 
• 
RTF files will be generated for SAC 
12.4.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
Formats 
• 
All data will be reported according to the actual treatment the participant received. 
• 
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, unless otherwise stated. 
• 
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. 
• 
Dates will be reported in the format DDMMMCCYY e.g. 01Jan2020 unless otherwise stated. 
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. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
27 
 
• 
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. 
Unscheduled Visits 
• 
Unscheduled visits will be included in summary tables and figures. Assessment windows for the 
unscheduled and early withdrawal assessments are specified in Appendix 2: Assessment Windows.  
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
N = the number of participants from the relevant analysis population for the group 
or subgroup. 
n = the number of participants counted for the summary statistic. 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
12.4.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
PC Windows Non-
Linear (WNL) File for 
GSK2330811 
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487.  
Note: Concentration values will be imputed as per GUI_51487. 
Note: GSK2330811 concentration values will be imputed as per GUI_51487. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived 
by 
Programmer 
None 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters 
Rule 
Being Followed 
Yes, refer to SOP_314000.. If one or more non-quantifiable (NQ) values occur in a 
profile before the first measurable concentration, they will be assigned a value of zero 
concentration. For linear plots, zero concentration value(s) before the first 
measurable concentration will be included in the plot. For log-linear plots, zero 
concentration value(s) before the first measurable concentration will be assigned a 
missing value. If a single NQ value occurs between measurable concentrations in a 
profile, the NQ should generally be omitted (set to missing) in the derivation of 
pharmacokinetic parameters, statistical analysis, and the individual subject plots. 
If two or more NQ values occur in succession between measurable concentrations, 
the profile will be deemed to have terminated at the last measurable concentration 
prior to these NQs. For the purpose of individual subject plots, these NQs will be set 
to 0, and the subsequent measurable concentrations will be retained. For the 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
28 
 
derivation of pharmacokinetic parameters, these NQs and any subsequent 
measurable concentrations will be omitted (set to missing). 
NQs which occur after the last measurable concentration will be omitted (set to 
missing) in the derivation of pharmacokinetic parameters and from the individual 
subject plots. In some circumstances, there may be a pharmacokinetic rationale for 
fluctuation resulting in non-measurable concentrations in the middle of the 
concentration-time profile (e.g., entero-hepatic recycling, erratic absorption from 
transdermal/inhaled formulations). In these cases, the NQ values could be set to 
missing or to some other values (e.g., ½ LLQ) and subsequent valid concentrations 
may be retained. A reference line indicating LLQ will be included in plots. 
For the calculation of mean or median pharmacokinetic profiles. When estimating the 
mean or median value for the concentration at a given time point (i.e., descriptive 
mean or median curve), the following guidelines should be considered: 
All NQ values will be set to zero except when an individual NQ falls between two 
quantifiable values, in which case it will be omitted from the calculation of mean or 
median profiles. Measurable concentrations which follow more than one consecutive 
mid-profile NQ will be omitted (set to missing). The mean/median value at a time-
point where one or more samples have NQ values will be reported (in tabular or 
graphical fashion) even if the mean/median value is below the LLQ of the assay. For 
linear plots, zero concentration value(s) will be included in the plot. For log-linear 
plots, zero concentration value(s) will be assigned a missing value. 
Zero mean or median values will be included in summary tables. In certain cases, 
the NQ values could be set to missing or to some other values (e.g., ½ LLQ) with 
proper scientific justification(s). A reference line indicating LLQ will be included in 
plots. 
It should be noted that a high proportion of NQ values may affect the standard 
deviation (SD); if more than 30% of values are imputed, then SD will not be displayed. 
Any table of summary statistics for concentration-time data will report N (number of 
subjects in the analysis population), n (number of subjects with non-missing values) 
and number imputed (number of subjects with imputed values (i.e., NQ assigned zero 
concentration). 
BQL (Below the Quantification Limit) may be displayed in listings by legacy systems 
instead of NQ; these abbreviations are interchangeable and mean that a sample has 
been received, analysed and a concentration below the LLQ of the assay found. 
Scientific judgement and prior knowledge should always be used in applying these 
guidelines. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to GUI_51487 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
29 
 
12.4.4. 
Reporting Standards for Target Engagement 
Total OSM Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
PC Windows Non-
Linear (WNL) File for 
Total OSM 
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487.  
Note: Total OSM concentration values will be imputed as per GUI_51487. 
Total OSM Parameter Derivation 
Total OSM Parameter 
to be Derived by 
Programmer 
None 
Total OSM Parameter Data 
Is NQ impacted Total 
OSM 
Parameters 
Rule Being Followed 
Yes, refer to SOP_314000. If one or more non-quantifiable (NQ) values occur in a 
profile before the first measurable concentration, they will be assigned a value of zero 
concentration. For linear plots, zero concentration value(s) before the first 
measurable concentration will be included in the plot. For log-linear plots, zero 
concentration value(s) before the first measurable concentration will be assigned a 
missing value. If a single NQ value occurs between measurable concentrations in a 
profile, the NQ should generally be omitted (set to missing) in the derivation of total 
OSM parameters, statistical analysis, and the individual subject plots. 
If two or more NQ values occur in succession between measurable concentrations, 
the profile will be deemed to have terminated at the last measurable concentration 
prior to these NQs. For the purpose of individual subject plots, these NQs will be set 
to 0, and the subsequent measurable concentrations will be retained. For the 
derivation of total OSM parameters, these NQs and any subsequent measurable 
concentrations will be omitted (set to missing). 
NQs which occur after the last measurable concentration will be omitted (set to 
missing) in the derivation of pharmacokinetic parameters and from the individual 
subject plots.  
For the calculation of mean or median total OSM profiles. When estimating the mean 
or median value for the concentration at a given time point (i.e., descriptive mean or 
median curve), the following guidelines should be considered: 
All NQ values will be set to zero except when an individual NQ falls between two 
quantifiable values, in which case it will be omitted from the calculation of mean or 
median profiles. Measurable concentrations which follow more than one consecutive 
mid-profile NQ will be omitted (set to missing). The mean/median value at a time-
point where one or more samples have NQ values will be reported (in tabular or 
graphical fashion) even if the mean/median value is below the LLQ of the assay. For 
linear plots, zero concentration value(s) will be included in the plot. For log-linear 
plots, zero concentration value(s) will be assigned a missing value. 
Zero mean or median values will be included in summary tables. In certain cases, 
the NQ values could be set to missing or to some other values (e.g., ½ LLQ) with 
proper scientific justification(s). A reference line indicating LLQ will be included in 
plots. 
It should be noted that a high proportion of NQ values may affect the standard 
deviation (SD); if more than 30% of values are imputed, then SD will not be displayed. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
30 
 
Any table of summary statistics for concentration-time data will report N (number of 
subjects in the analysis population), n (number of subjects with non-missing values) 
and number imputed (number of subjects with imputed values (i.e., NQ assigned zero 
concentration). 
BQL (Below the Quantification Limit) may be displayed in listings by legacy systems 
instead of NQ; these abbreviations are interchangeable and mean that a sample has 
been received, analysed and a concentration below the LLQ of the assay found. 
Scientific judgement and prior knowledge should always be used in applying these 
guidelines. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to GUI_51487 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
31 
 
12.5. 
Appendix 5: Derived and Transformed Data 
12.5.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Where multiple assessments are made, the mean of replicate assessments at any given time point 
will be used as the value for that time point. This derived mean will be reported in the listing in addition 
to the individual assessments. 
• 
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. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit 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 Dose Date: 
• 
Ref Date = Missing      → Study Day = Missing  
• 
Ref Date < Dose Date → Study Day = Ref Date – Dose Date 
• 
Ref Data ≥ Dose Date → Study Day = Ref Date – (Dose Date) + 1     
 
12.5.2. 
Study Population 
Cumulative Dose 
Placebo: 0 
GSK2330811: Number of Injections x 150 
 
Dose unit: Milligram 
Demographics 
Age 
• 
Only birth year is captured on the eCRF, therefore GSK standard ISDL algorithms will be used for 
calculating age where birth date will be imputed as follows: 
• 
The missing date and month will be imputed as ‘30th June’ 
• 
Birth date will be presented in listings as ‘YYYY’ 
Body Mass Index (BMI) 
• 
Calculated as Weight(kg)/Height(m)2 
 
12.5.3. 
Safety 
ECG Parameters 
RR Interval 
If RR interval (msec) is not provided directly, then RR can be derived using machine read QTcF 
as:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
32 
 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of decimal places in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 decimal places: ‘< x’ becomes x – 0.01 
o Example 2: 1 decimal places: ‘> x’ becomes x + 0.1 
o Example 3: 0 decimal places: ‘< x’ becomes x – 1. 
 
 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
33 
 
12.6. 
Appendix 6: Reporting Standards for Missing Data 
12.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e. as specified in the protocol) was defined as completion 
of all assessment on Day 126.  
• 
A maximum of 4 non-evaluable participants will be replaced. 
• 
All available data from participants 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.  
• 
Withdrawal visits will be slotted as per Appendix 2: Assessment Windows or will be 
summarised as withdrawal visits. 
12.6.2. 
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 participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
12.6.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• 
In case of partial dates (i.e. day missing, only month and year present) recorded for AE 
start and end, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start date 
of study treatment; in this case the study treatment start date will be used and hence 
the event is considered On-treatment as per Appendix 3: Study Phases and 
Treatment Emergent Adverse Events. 
o Missing Stop Day: If the partial date is a stop date, a '28/29/30/31' will be used for 
the day (dependent on the month and year) and 'Dec' will be used for the month. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed using 
the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
34 
 
 
12.6.2.2. 
Imputation of Missing Data for OSM Free and Total 
Element 
Reporting Detail 
LLQ/2 
• 
If data are missing due to readings being below the limits of quantification, then a value 
equivalent to LLQ/2 will be imputed.  
• 
If the readings are above the upper limit of quantification, the sample should be further 
diluted to be within the upper limit of quantification of the assay. The measured 
concentration should then be corrected for the additional dilution factor.  
• 
These values will be used for the computation of the change from baseline and for 
summaries, plots and analysis, if deemed applicable.  
• 
The number of data imputed will be highlighted in the summaries and figures, whereas 
listings will report the values as below LLQ.  
• 
The numeric values and LLQ will be presented in listing as a reference, and the LLQ will 
be mentioned in footnotes where appropriate (e.g. figures). 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
35 
 
12.7. 
Appendix 7: Values of Potential Clinical Importance 
12.7.1. 
Laboratory Values 
Haematology and chemistry parameters will use CTCAE grades (CTCAE criteria, V5.0: 
November 27, 2017) to highlight important results based on laboratory value only (i.e. no 
clinical judgement will be applied).  CTCAE grades will replace the category of “values of 
potential clinical importance” for haematology parameters, see table below for reference. 
Laboratory 
Parameter 
CTCAE 
v5.0 
Term for 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Haemoglobin Anemia 
Hemoglobin 
(Hgb)       <LLN 
- 100 g/L  
Hgb <100 - 
80g/L  
Hgb <80 g/L; 
transfusion 
indicated  
Life-
threatening 
consequences; 
urgent 
intervention 
indicated  
Death 
Haemoglobin 
Hemoglob
in 
increased 
Increase in >0 - 
2 g/dL above 
ULN or above 
baseline if 
baseline is 
above ULN 
Increase in 
>2 - 4 g/dL 
above ULN 
or above 
baseline if 
baseline is 
above ULN 
Increase in >4 
g/dL above ULN 
or above 
baseline if 
baseline is 
above ULN 
- 
- 
Lymphocyte 
count 
Lymphocy
te count 
decrease
d 
<LLN - 0.8 
GI/L  
<0.8 - 0.5 
GI /L  
<0.5 - 0.2 
GI /L  
<0.2 GI /L  
- 
Lymphocyte 
count 
Lymphocy
te count 
increased 
- 
>4 – 20  
GI/L  
>20 GI/L  
- 
- 
Neutrophil 
count 
Neutrophil 
count 
decrease
d 
<LLN - 1.5  
 GI /L  
<1.5 - 1.0 
GI /L  
<1.0 - 0.5 
 GI /L  
<0.5 GI/L  
- 
Platelet 
count 
Platelet 
count 
decrease
d 
<LLN - 75.0  GI 
/L  
<75.0 - 50.0  
GI /L  
<50.0 - 25.0  GI 
/L  
<25.0 GI/L  
- 
White blood 
cell count 
Leukocyto
sis 
- 
- 
>100 GI/L  
Clinical 
manifestations 
of leucostasis; 
urgent 
intervention 
indicated  
Death 
White blood 
cell count 
White 
blood cell 
<LLN - 3.0 
GI /L  
<3.0 - 2.0 
GI /L  
<2.0 - 1.0 
GI /L  
<1.0 GI /L  
- 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
36 
 
Laboratory 
Parameter 
CTCAE 
v5.0 
Term for 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
decrease
d 
Alanine 
Amino 
Transferase 
(IU/L) 
Alanine 
aminotran
sferase 
increased 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if 
baseline was 
normal; >3.0 
- 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 
x baseline if 
baseline was 
abnormal 
 
Aspartate 
Amino 
Transferase 
(IU/L) 
Aspartate 
aminotran
sferase 
increased 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if 
baseline was 
normal; >3.0 
- 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 
x baseline if 
baseline was 
abnormal 
 
Calcium 
(MMOL/L) 
Hypocalc
emia 
Corrected 
serum calcium 
of 
 <LLN - 2.0 
mmol/L; Ionized 
calcium <LLN 
- 1.0 mmol/L 
 
Corrected 
serum 
calcium of  
<2.0 - 1.75 
mmol/L; 
Ionized 
calcium <1.0 
- 0.9 
mmol/L; 
symptomatic 
Corrected 
serum calcium 
of  <1.75 - 1.5 
mmol/L; Ionized 
calcium <0.9 - 
0.8 mmol/L; 
hospitalization 
indicated 
Corrected 
serum calcium 
of; <1.5 
mmol/L; 
Ionized 
calcium <0.8 
mmol/L; life-
threatening 
consequences 
Death 
Cholesterol  
Cholester
ol - high 
>ULN - 7.75 
mmol/L 
>7.75 - 
10.34 
mmol/L 
>10.34 - 12.92 
mmol/L 
>12.92 mmol/L 
 
Creatinine  
Creatinine 
increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
baseline; 
>1.5 - 3.0 x 
ULN 
>3.0 x baseline; 
>3.0 - 6.0 x 
ULN 
>6.0 x ULN 
 
Glucose  
Hyperglyc
emia 
Abnormal 
glucose above 
baseline with no 
medical 
intervention 
Change in 
daily 
managemen
t from 
baseline for 
a diabetic; 
oral 
antiglycemic 
agent 
initiated; 
Insulin therapy 
initiated; 
hospitalization 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
37 
 
Laboratory 
Parameter 
CTCAE 
v5.0 
Term for 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
workup for 
diabetes 
Glucose  
Hypoglyc
emia 
<LLN - 3.0 
mmol/L 
 
<3.0 - 2.2 
mmol/L 
<2.2 - 1.7 
mmol/L 
<1.7 mmol/L; 
life threatening 
consequences; 
seizures 
Death 
Potassium  
Hyperkale
mia 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 
mmol/L; 
intervention 
initiated 
>6.0 - 7.0 
mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; 
life-threatening 
consequences 
Death 
Potassium 
Hypokale
mia 
<LLN - 3.0 
mmol/L 
Symptomatic 
with <LLN - 
3.0mmol/L; 
intervention 
indicated 
 
<3.0 - 2.5 
mmol/L; 
hospitalization 
indicated 
<2.5 mmol/L; 
life-threatening 
consequences 
Death 
Sodium 
Hypernatr
emia 
>ULN - 150 
mmol/L 
>150 - 155 
mmol/L; 
intervention 
initiated 
>155 - 160 
mmol/L; 
hospitalization 
indicated 
>160 mmol/L; 
life-threatening 
consequences 
Death 
Sodium 
Hyponatre
mia 
<LLN - 130 
mmol/L 
125-129 
mmol/L and 
asymptomati
c 
125-129 mmol/L 
symptomatic; 
120-124 mmol/L 
regardless of 
symptoms 
<120 mmol/L; 
life-threatening 
consequences 
Death 
Total 
Bilirubin 
Blood 
bilirubin 
increased 
>ULN - 1.5 x 
ULN if baseline 
was normal; > 
1.0 - 1.5 x 
baseline if 
baseline was 
abnormal 
>1.5 - 3.0 x 
ULN if 
baseline was 
normal; >1.5 
- 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 10.0 x 
ULN if baseline 
was normal; 
>3.0 - 10.0 x 
baseline if 
baseline was 
abnormal 
>10.0 x ULN if 
baseline was 
normal; >10.0 
x baseline if 
baseline was 
abnormal 
Death 
Triglycerides 
hypertrigly
ceridemia 
1.71 mmol/L - 
3.42 mmol/L 
 >3.42 
mmol/L - 5.7 
mmol/L 
>5.7 mmol/L - 
11.4 mmol/L 
 >11.4 mmol/L; 
life-threatening 
consequences 
Death 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
38 
 
12.7.2. 
Laboratory Values – Haematology, Chemistry and Liver 
Haematology 
Laboratory Parameter 
  
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 1 
Male 
  
0.54 
∆ from BL 
↓0.075 
  
Hemoglobin  
g/L 
  
Male 
  
180 
∆ from BL 
↓25 
  
Lymphocytes  
x109/ L 
  
0.8 
  
Neutrophil Count  
x109/ L 
  
1.5 
  
Platelet Count  
x109/ L 
  
100 
550 
While Blood Cell Count (WBC) 
x109/ L 
  
3 
20 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
30 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
umol/L 
 
 
>1.3*ULN 
Creatinine 
∆ from BL 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
≥ 2x ULN 
AST/SGOT  
U/L 
High 
≥ 2x ULN 
AlkPhos  
U/L 
High 
≥ 2x ULN 
T Bilirubin  
µmol/L 
High 
≥ 1.5x ULN 
T. Bilirubin + ALT 
µmol/L 
High 
 
 
1.5x ULN T. Bilirubin 
+ 
≥ 2x ULN ALT 
U/L 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
39 
 
12.7.3. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
> 450 
Absolute PR Interval 
msec 
< 110 
> 220 
Absolute QRS Interval 
msec 
< 75 
> 110 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
> 60 
12.7.4. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
Vital Sign Parameter 
(Change from Baseline) 
Units 
Clinical Concern 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 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
40 
 
12.8. 
Appendix 8: Abbreviations & Trademarks 
12.8.1. 
Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AUC 
Area Under the Curve 
A&R 
Analysis and Reporting  
CI 
Confidence Interval 
CL/F 
Apparent Clearance 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
LLN 
Lower Limit of Normal  
NCA 
Non-Compartmental Analysis 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
tlast 
Time of last quantifiable concentration 
Tmax 
Time of occurrence of Cmax 
t1/2 
Half-life 
ULN 
Upper Limit of Normal  
Vss/F 
Steady state apparent volume of distribution 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
41 
 
12.8.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
SAS 
 
 
WinNonlin 
 
 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
 
 
208564 
 
42 
 
12.9. 
Appendix 9: List of Data Displays 
12.9.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.11 
 
Safety 
3.1 to 3.23 
3.1 to 3.5 
Pharmacokinetic 
4.1 to 4.3 
4.1 to 4.3 
Pharmacodynamic and / or Biomarker 
6.1 to 6.6 
6.1 to 6.3 
Pharmacokinetic / Pharmacodynamic 
 
7.1 
Section 
Listings 
ICH Listings 
1 to 27 
Other Listings 
28 to 35 
 
12.9.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_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 /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
12.9.3. 
Deliverables 
Delivery [1] 
Description 
SAC 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
43 
 
12.9.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Safety 
ES1 
Summary of Subject Disposition 
Include total column 
SAC  
1.2. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
 
SAC  
Protocol Deviation 
1.3. 
Safety 
DV1 
Summary of Important Protocol Deviations Not Related to 
COVID-19 
 
SAC  
1.4. 
Safety 
DV1 
Summary of Important Protocol Deviations Related to COVID-19   
 
Population Analysed 
1.5. 
Screened 
SP1 
Summary of Study Populations  
 
SAC 
Demography 
1.6. 
Safety 
DM1 
Summary of Demographic Characteristics 
Include: Height, Weight, and BMI 
SAC 
1.7. 
Enrolled 
DM11 
Summary of Age Ranges 
 
SAC 
1.8. 
Safety 
DM6 
Summary of Race and Racial Combinations 
 
SAC 
Concomitant Medications and other Medical Conditions 
1.9. 
Safety 
MH4 
Summary of Past Medical Conditions 
 
SAC 
1.10. 
Safety 
MH4 
Summary of Current Medical Conditions 
 
SAC 
1.11. 
Safety 
CM8 
Summary of Concomitant Medications 
 
SAC  
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
44 
 
12.9.5. 
Safety Tables 
Safety: Tables 
No. 
Populati
on 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
 
SAC 
3.2.  
Safety 
AE5A 
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity 
 
SAC 
3.3.  
Safety 
AE1 
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
 
SAC 
3.4.  
Safety 
AE15 
Summary of Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) 
 
SAC 
Serious and Other Significant Adverse Events 
3.5.  
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
 
SAC 
3.6.  
Safety 
AE3 
Summary of Serious Drug-Related Adverse Events by Overall 
Frequency 
 
SAC 
3.7.  
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
by System Organ Class and Preferred Term 
 
SAC 
Chemistry  
3.8.  
Safety 
LB1 
Summary of Chemistry 
 
SAC 
3.9.  
Safety 
LB17 
Summary of Worst-Case Chemistry Results Relative to 
Potential Clinical Importance (PCI) Criteria Post-Baseline 
Relative to Baseline 
 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
45 
 
Safety: Tables 
No. 
Populati
on 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.10.  
Safety 
SAFE_T1 
Summary of Chemistry Results by Maximum CTCAE Grade 
Footnote: “CTCAE criteria, V5.0: 
November 27, 2017” 
SAC 
Haematology 
3.11. 
 
Safety 
LB1 
Summary of Haematology 
By parameter 
 
SAC 
3.12. 
 
Safety 
LB16 
Summary of Haematology Results by Maximum CTCAE Grade 
Increase Post-Baseline Relative to Baseline 
Footnote: “CTCAE criteria, V5.0: 
November 27, 2017” 
SAC 
3.13. 
 
Safety 
LB17 
Summary of Worst Case Haematology Results Relative to 
Potential Clinical Importance (PCI) Criteria Post-Baseline 
Relative to Baseline 
 
SAC  
3.14. 
 
Safety 
SAFE_T2 
Summary of Nadirs for Selected Haematology Parameters 
By parameter, treatment group 
Produce for Platelet count and 
Haemoglobin. 
Footnote: “Nadir is the lowest post-
baseline value of the parameter” 
SAC 
3.15. 
 
Safety 
SAFE_T3 
Summary of Days to Nadir of Selected Haematology 
Parameters  
by parameter, treatment group. 
Produce for Platelet count and 
Haemoglobin. 
Footnote: “Nadir is the lowest post-
baseline value of the parameter” 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
46 
 
Safety: Tables 
No. 
Populati
on 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Urinalysis 
3.16. 
 
Safety 
SAFE_T4 
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline 
Tests to include: 
Urine blood,  
Urine Glucose (dipstick), 
Urine Ketones (dipstick),  
Urine Microscopy – Bacteria,  
Urine Microscopy - Red Blood Cells,  
Urine Microscopy - White Blood Cells, 
Urine Protein (dipstick), 
Urine Specific Gravity 
 
SAC 
ECG 
3.17. 
 
 Safety 
EG1 
Summary of ECG Findings  
 
SAC 
3.18. 
 
Safety 
EG2 
Summary of ECG Values 
Footnote: Average used for triplicate 
ECG measurements 
SAC 
3.19. 
 
Safety 
EG2 
Summary of Change from Baseline in ECG Values  
Footnote: Average used for triplicate 
ECG measurements 
SAC 
Vital Signs 
3.20. 
 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
 
SAC 
3.21. 
 
Safety 
VS7 
Summary of Worst Case Vital Signs Results Relative to 
Potential Clinical Importance (PCI) Criteria Post-Baseline 
Relative to Baseline 
 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
47 
 
Safety: Tables 
No. 
Populati
on 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.22. 
 
Safety 
SAFE_T5 
Summary of Worst Case Vital Sign Results Relative to Change 
from Baseline Potential Clinical Importance (PCI) Criteria 
 
SAC 
Immunogenicity 
3.23. 
 
Safety 
IMM1 
Occurrence of Anti-Drug Antibodies 
Add footnote: 
Note: The denominator for confirmed 
positive is the total number of subjects at 
that visit who have immunogenicity data 
available. 
SAC 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
48 
 
12.9.6. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Haematology 
3.1.  
Safety 
SAFE_F1 
Subject Profiles for Haematology by Treatment 
Group 
By Haematology parameter. 
This output should be produced for: 
Platelet Count, Haemoglobin  
Use rules for CTCAE boundaries 
X axis use ‘Actual Relative Time (Days)’ from 
dose.  Show all observed values including 
unscheduled. 
Add footnote “Figure displays a subset of 
haematology parameters” 
Panel by treatment group 
SAC 
3.2.  
Safety 
SAFE_F2 
Mean Profile for Haematology by Treatment Group 
By Haematology parameter. 
This output should be produced for: 
Platelet Count, Haemoglobin  
X axis shows visits with approximate temporal 
spacing 
Add footnote “Figure displays a subset of 
haematology parameters” 
SAC 
3.3.  
Safety 
SAFE_F3 
LFT Patient Profiles 
ALT = Alanine Amino Transferase, AST = 
Aspartate Amino Transferase, Alk. Phos. = 
Alkaline Phosphatase,Total Bili. = Total Bilirubin 
SAC 
ECG 
3.4.  
Safety 
EG7 
Empirical Distribution Function for Maximum Change 
from baseline in QTcF Interval 
Both treatments in one plot. Calculate maximum 
change from baseline. 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
49 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.5.  
Safety 
EG8 
Distribution of QTcF Change by Visit and Treatment 
Use the 0, 30, 60 thresholds following shell. 
SAC 
12.9.7. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK 
PKCT1 
Summary of Plasma GSK2330811 Concentration-Time Data 
Note: LLQ=100 ng/mL. Values below 
LLQ have been imputed to 0. 
SD is set to missing if No. Imputed/n > 
0.3 . 
SAC  
Derived PK parameters 
4.2.  
PK 
PKPT1 
Summary of Derived Plasma Pharmacokinetic Parameters of 
GSK2330811   
 
SAC 
4.3.  
PK 
PKPT3 
Summary of Log-Transformed Derived Plasma 
Pharmacokinetic Parameters of GSK2330811   
 
SAC 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
50 
 
12.9.8. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK 
PKCF1P 
Individual GSK2330811 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log) 
Footnote for all PK and PK/PD figures: 
‘LLQ is calculated at 100 ng/mL. 
Values below LLQ have been imputed 
to 0.’ 
Use actual time (days) as x axis 
(where days is a continuous variable) 
SAC  
4.2.  
PK 
PKCF4 
Mean (SD) Plasma GSK2330811 Concentration-Time Plots 
by Treatment (Linear and Semi-log) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
SAC 
4.3.  
PK 
PKCF5 
Median (Range) Plasma GSK2330811 Concentration-Time 
Plots by Treatment (Linear and Semi-log) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
SAC 
 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
51 
 
12.9.9. 
Pharmacodynamic (and / or Biomarker) Tables 
Pharmacodynamic (and or Biomarker): Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Serum level of OSM 
6.1.  
Safety 
PD1 
Summary of Serum Level of Free OSM by Treatment Group 
Calculate confidence intervals and add 
number imputed 
Add footnote: 
[1] No. of subjects with BLQs assigned 
half of the lower limit of quantification 
(LLQ = 2.5pg/ml)  
SAC 
6.2.  
Safety 
PD1 
Summary of Serum Level of Total OSM by Treatment Group 
Calculate confidence intervals and add 
number imputed 
Add footnote: 
[1] No. of subjects with BLQs assigned 
half of the lower limit of quantification 
(LLQ = 2.5pg/ml) 
SAC 
6.3.  
Safety 
PD1 
Summary of Ratio of Serum Level of Total OSM to Baseline by 
Treatment Group 
Calculate confidence intervals and add 
number imputed 
Add footnote: 
[1] No. of subjects with BLQs assigned 
half of the lower limit of quantification 
(LLQ = 2.5pg/ml) 
SAC 
6.4.  
Safety 
PD2 
Summary of Log Transformed Serum Level of Total OSM by 
Treatment Group 
Calculate confidence intervals and add 
number imputed 
Add footnote: 
[1] No. of subjects with BLQs assigned 
half of the lower limit of quantification 
(LLQ = 2.5pg/ml) 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
52 
 
Pharmacodynamic (and or Biomarker): Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.5.  
Safety 
PKPT1 
Summary of Derived Serum Pharmacokinetic Parameters of 
Total OSM by Treatment Group   
 
SAC 
6.6.  
Safety 
PKPT3 
Summary of Log-Transformed Derived Serum 
Pharmacokinetic Parameters of Total OSM by Treatment 
Group   
 
SAC 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
53 
 
12.9.10. 
Pharmacodynamic (and / or Biomarker) Figures 
Pharmacodynamic (and or Biomarker): Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Serum levels of OSM 
6.1.  
Safety 
PKCF1P 
Individual Serum Level of Total OSM Concentration-Time Plot 
by Treatment (Linear and Semi-Log) 
Add LLQ reference line 
Conditionally add ULQ reference line 
Page by treatment 
Total OSM: LLQ is calculated at 
2.5pg/ml. Values below LLQ have 
been imputed to LLQ/2. 
Use actual time (days) as x axis 
(where days is a continuous variable) 
 
Add Footnote to indicate amount of 
imputed data. 
SAC 
6.2.  
Safety 
PKCF4 
Mean (SD) Serum Level of Total OSM Concentration-Time 
Plots by Treatment (Linear and Semi-log) 
Add LLQ reference line 
Conditionally add ULQ reference line 
Use planned time (days) as x axis 
(where days is a continuous variable) 
Total OSM: LLQ is calculated at 
2.5pg/ml. Values below LLQ have 
been imputed to LLQ/2. 
 
SAC 
6.3.  
Safety 
PKCF5 
Median (Range) Serum Level of Total OSM Concentration-
Time Plots by Treatment (Linear and Semi-log) 
Add LLQ reference line 
Conditionally add ULQ reference line 
Use planned time (days) as x axis 
(where days is a continuous variable) 
Total OSM: LLQ is calculated at 
2.5pg/ml. Values below LLQ have 
been imputed to LLQ/2. 
 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
54 
 
12.9.11. 
Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
OSM vs GSK2330811 concentration 
7.1.  
PK 
PKPD_F1 
Scatter Plot of Total Serum OSM vs Plasma Concentration 
of GSK2330811 
X axis:  PK 
Page by visit 
Add LLQ reference lines for both 
Conditionally add ULQ reference 
line for total 
Footnotes: 
GSK2330811:  LLQ  is calculated at 
100 ng/mL. Values below LLQ have 
been imputed to 0. 
Total OSM: LLQ is calculated at 
2.5pg/ml. Values below LLQ have 
been imputed to LLQ/2. 
 
SAC 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
55 
 
12.9.12. 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
 
SAC 
2.  
 Enrolled 
ES2 
Listing of Reasons for Study Withdrawal 
 
SAC 
3.  
 Enrolled 
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken 
 
SAC 
4.  
Enrolled 
TA1 
Listing of Planned and Actual Treatments 
 
SAC 
Protocol Deviations 
5.  
Enrolled 
DV2 
Listing of Important Protocol Deviations  
  
SAC 
6.  
Enrolled 
DV2 
Listing of COVID-19 related Protocol Deviations  
 
SAC 
7.  
Enrolled 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC 
Populations Analysed 
8.  
Enrolled 
SP3 
Listing of Subjects Excluded from Any Population 
 
SAC 
Demography 
9.  
Enrolled 
DM2 
Listing of Demographic Characteristics 
 
SAC 
10.  
Enrolled 
DM9 
Listing of Race 
 
SAC 
Prior and Concomitant Medications 
11.  
Enrolled 
CM3 
Listing of Concomitant Medications 
 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
56 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure and Treatment Compliance 
12.  
Enrolled 
EX3 
Listing of Exposure Data 
 Order by treatment, subject r. 
Include: Treamtent, Site ID/subjID, 
Start Datetime of Dose/Study day, 
Stop Datetime of Dose/Study day, 
Dose (this will be the cumulative 
dose) (eg450), Dose units, Root of 
administration, Number of 
injections 
 
SAC 
Adverse Events 
13.  
Enrolled 
AE8 
Listing of All Adverse Events 
 
SAC 
14.  
Enrolled 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
15.  
 Enrolled 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
 
SAC 
Serious and Other Significant Adverse Events 
16.  
Enrolled 
AE8CP 
Listing of Serious Adverse Events 
 
SAC 
17.  
 Enrolled 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
 
SAC  
18.  
Enrolled 
AE8CP 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
 
SAC 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
57 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Haematology 
19.  
Enrolled 
SAFE_L1 
Listing of All Haematology Values and Changes from Baseline 
See listing 23 in 201246.  Report: 
Standard result, Change from 
baseline and Percent change from 
baseline.  Do not flag CTCAE 
grades 
 
SAC 
20.  
Enrolled 
LB5 
Listing of Laboratory Values of CTCAE Grade 
Include Haematology and clinical 
chemistry laboratory data 
SAC 
21.  
Enrolled 
LB5 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance 
Include Haematology and clinical 
chemistry laboratory data 
SAC 
22.  
Enrolled 
LB14 
Listing of Laboratory Data with Character Results 
 
SAC 
Urinalysis 
23.  
Enrolled 
UR2 
Listing of Urinalysis Results 
 
SAC 
ECG 
24.  
Enrolled  
EG3 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance 
 
SAC 
25.  
Enrolled  
EG5 
Listing of Abnormal ECG Findings 
 
SAC 
Vital Signs 
26.  
Enrolled  
VS4 
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance 
 
SAC 
Immunogenicity 
27.  
Enrolled 
IMM2 
Listing of Immunogenicity Results 
 
SAC 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
58 
 
12.9.13. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK concentration and derived PK parameters 
28.  
PK 
PKCL1 
Listing of GSK2330811 Plasma Concentration-Time Data  
Add data dependent footnote: 
‘Note: NA=Not Available [data 
dependent], NQ=Non-Quantifiable, 
LLQ value=100ng/mL’ 
SAC 
29.  
PK 
PKCL1 
Listing of Derived GSK2330811 Pharmacokinetic Parameters  
 
SAC 
Serum levels of OSM 
30.  
PK 
PKCL1 
Listing of Serum Level of OSM 
Include both Free and Total OSM 
Add footnote: 
‘Note:  BLQ = Below the limit of 
quantification which is 2.5pg/ml for 
both free and total OSM’ 
SAC 
31.  
Safety 
PKCL1 
Listing of Derived Total OSM Pharmacokinetic Parameters  
 
SAC 
Serum levels of TPO and EPO 
32.  
PK 
PKCL1 
Listing of Level of Thrombopoietin in Serum 
 
SAC 
33.  
PK 
PKCL1 
Listing of level of Erythropoietin in Plasma 
 
SAC 
Other 
34.  
Enrolled 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessments 
for Subjects with COVID-19 Adverse Events 
 
SAC 
35.  
Enrolled 
PAN7 
Listing of All Subjects with Visits and Assessments Impacted by 
COVID-19 Pandemic 
 
SAC 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
59 
 
12.10. 
Appendix 10: Example Mock Shells for Data Displays 
Example: SAFE_T1 
Protocol: 208564   
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Safety 
Table XX.XX 
Summary of Chemistry Results by Maximum CTCAE Grade 
Test: Creatinine (UMOL/L)  
Event: Creatinine increased 
 
Treatment 
N 
Grade 1 Grade 2 Grade 3 Grade 4 
Placebo 
XX XX 
XX.X 
XX.XX 
XX.X 
GSK2330811 450 mg XX XX 
XX.X 
XX.XX 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: CTCAE criteria, V5.0: November 17, 2017 graded on laboratory test value.  
Only events with at least one graded value are shown.  
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
60 
 
Example: SAFE_T2 
Protocol: 208564                                                         
          Page 1 of n 
Population: Safety 
Table XX.XX 
Summary of Nadirs for Selected Haematology Parameters [as Percent Change from Baseline] 
 
 
Lab Test (unit) 
Treatment 
N 
n 
Mean SD 
Median Min 
Max 
Hemoglobin (G/L) Placebo 
XX XX XX.X XX.XX XX.X 
XX.X XX.X 
 
GSK2330811 450 mg XX XX XX.X XX.XX XX.X 
XX.X XX.X 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Nadir is the lowest post-baseline value of the parameter. 
 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
61 
 
Example: SAFE_T3 
Protocol: 208564                                                         
 
 
 
  Page 1 of n 
Population: Safety 
Table XX.XX 
Summary of Days to Nadir for Selected Haematology Parameters  
 
Lab Test (unit) 
Treatment 
N 
n 
Median Min Max Range 
Hemoglobin (G/L) Placebo 
XX XX XX 
XX 
XX 
XX 
 
GSK2330811 450 mg XX XX XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Note: Nadir is the lowest post-baseline value of the parameter. 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
62 
 
Example: SAFE_T4 
Programming note: please flag to study team/ statistics when summarizing if observe any character variables 
not the minimum value and not presented as an increase category. 
 
Tests to summarise as X=BACTM_URQ (minimum value=NONE SEEN) 
Tests to summarise as Y= BLD_URC, PROT_URG, KETO_URG, GLUC_URG (minimum value=NEGATIVE) 
Tests to summarise as Z= RBCM_URG, WBCM_URG (minimum value=NONE SEEN) 
Tests to summarise as W= SG_URG (minimum value=Low)  
 
Example modified from UR1 
Protocol: ABC123456                                                                        Page 1 of 1 
Population: Safety/Other study specific 
Table X 
Summary of Worst Case Urinalysis Results Post-Baseline Relative to Baseline 
Test 
 
Treatment A 
(N=248) 
Treatment B 
(N=247) 
X 
n 
230 
232 
 
No Change/Decreased 
222 (97%) 
223(96%) 
 
Any Increase 
  8 (3%)             9 (4%)        
 
  Increase to MANY 
  6 (3%) 
  5 (2%) 
 
 
 
 
Y 
n 
230 
232 
 
No Change/Decreased 
222 (96%) 
222 (96%) 
 
Any Increase 
  7 (3%) 
 10  (4%) 
 
  Increase to TRACE 
  2 (<1%) 
  5  (2%) 
 
  Increase to 1+ 
  1 (<1%) 
  4  (2%) 
 
  Increase to 2+ 
  1 (<1%) 
  0 
 
  Increase to 3+ 
  4  (2%) 
  1 (<1%) 
 
 
 
 
Z 
n 
230 
232 
 
No Change/Decreased 
222 (96%) 
222 (96%) 
 
Any Increase 
  7 (3%) 
 10  (4%) 
 
  Increase to 0-1 
  2 (<1%) 
  5  (2%) 
 
  Increase to 5-10 
  1 (<1%) 
  4  (2%) 
 
  Increase to 10-15 
  1 (<1%) 
  0 
 
  Increase to 15-20 
  2 (<1%) 
  1 (<1%) 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
63 
 
 
  Increase to 20-25 
  2 (<1%) 
  0 
 
  Increase to 25-50 
  4  (2%) 
  1 (<1%) 
 
 
 
 
W 
n 
230 
232 
 
No Change/Decreased 
222 (97%) 
223 (96%) 
 
Any Increase 
  8  (3%)            9  (4%)        
 
  Increase to NORMAL 
  6  (3%) 
  5  (2%) 
 
  Increase to HIGH 
  6  (3%) 
  5  (2%) 
 
 
 
 
 
 
 
Note: Little n does not include Not done or No results. 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
64 
 
Example: SAFE_T5 
Protocol: 208564  
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Safety 
 
Table 3.22 
Summary of Worst Case Vital Sign Results Relative to Change from Baseline Potential Clinical Importance (PCI) 
Criteria 
 
Test (Unit) 
Change Category 
Placebo 
(N=XX) 
GSK2330811 450 mg 
(N=XX) 
 
 
 
 
Diastolic blood pressure (mmHg) 
n  
xx 
xx 
 
Decrease >= 10 
xx (xx%) 
xx (xx%) 
 
Decrease >= 20 
xx (xx%) 
xx (xx%) 
 
Increase >= 10 
xx (xx%) 
xx (xx%) 
 
Increase >= 20 
xx (xx%) 
xx (xx%) 
 
 
 
 
Heart Rate (bmp) 
n  
xx 
xx 
 
Decrease >= 15 
xx (xx%) 
xx (xx%) 
 
Decrease >= 30 
xx (xx%) 
xx (xx%) 
 
Increase >= 15 
xx (xx%) 
xx (xx%) 
 
Increase >= 30 
xx (xx%) 
xx (xx%) 
 
 
 
 
Systolic blood pressure (mmHg) 
n  
xx 
xx 
 
Decrease >= 20 
xx (xx%) 
xx (xx%) 
 
Decrease >= 40 
xx (xx%) 
xx (xx%) 
 
Increase >= 20 
xx (xx%) 
xx (xx%) 
 
Increase >= 40 
xx (xx%) 
xx (xx%) 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
65 
 
Example: SAFE_F1 
Protocol: 208564  
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Safety 
 
Figure XX.XX 
Participant Profiles for Haematology by Treatment Group 
 
 
                     
    Placebo  
 
             GSK2330811 450mg 
 
Programming notes: 
One legend including all participants. 
Make plot as large as possible to fill space.  
add (P) to denote placebo participants. 
y-axis will be displayed on the left-hand side plot and the labels for the reference lines will be included on 
the right-hand side plot. 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
208564 
 
66 
 
Example: SAFE_F2 
Protocol: 208564  
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Safety 
 
Figure XX.XX 
Mean Profile for Haematology by Treatment Group 
 
 
 
Programming notes: 
See output 3.9 from 201247. 
Make plot as large as possible to fill space. 
Use different marker symbol, line pattern and colour by treatment group. 
Table: Include N after treatment group and use same colour as in the plot. 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


 
CONFIDENTIAL 
 
208564 
 
67 
 
Example: SAFE_F3 
Protocol: 208564  
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Safety 
 
Figure XX.XX 
LTF Patient Profiles 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
208564 
 
68 
 
Example: PKPD_F1 
Protocol: 208564  
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: PK 
 
Figure XX.XX 
Scatter Plot of Free Serum OSM vs Plasma Concentration of GSK2330811
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
208564 
 
69 
 
Example: SAFE_L1 
Protocol: 208564  
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Enrolled 
 
Listing XX 
Listing of All Haematology Values and Changes from Baseline 
Lab Test 
(Units) 
Treatment 
CentreID/
subjid 
Visit/Analysis 
visit 
Date of 
collection Study Day 
Standard 
Result 
Change from 
Baseline 
Percentage 
Change from 
Baseline 
xx 
 
Xx/xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0


Signature Page for  208564 TMF-7927164 v1.0
Signature Page for TMF-7927164 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 07-Dec-2020 08:33:02 GMT+0000
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 07-Dec-2020 14:00:17 GMT+0000
208564 | Statistical Analysis Plan  RAP Final_V1 07 Dec 2020 | TMF-7927164 | 1.0
PPD
PPD