Conditions: Hypertension, Pulmonary
Keywords: Pulmonary Arterial Hypertension Dose-escalation Safety Tolerability GSK2586881
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
GSK2586881, a purified intravenous (IV) formulation of soluble recombinant human Angiotensin Converting Enzyme (rhACE2) is being investigated as a treatment for PAH. This GlaxoSmithKline (GSK) study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK2586881 in subjects with PAH. This open-label, dose-escalation study will comprise of 4 separate groups based on the planned dose range, and subjects in each group will be administered a single dose of GSK2586881 ranging between 0.1, 0.2, 0.4 and 0.8 milligram per kilogram (mg/kg) via IV route. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. A maximum of 27 subjects will be included in the study and the total duration of the study will be up to a maximum of 59 days.

Detailed description:

Arms:
arm 1: Eligible subjects will receive a single dose of 0.1 mg/kg GSK2586881. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. arm 2: Eligible subjects will receive a single dose 0.2 mg/kg of GSK2586881 IV infusion. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. arm 3: Eligible subjects will receive a single dose of 0.4 mg/kg of GSK2586881 IV infusion. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. arm 4: Eligible subjects will receive single dose of 0.8 mg/kg of GSK2586881 IV infusion. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.

Interventions: intervention 1: GSK2586881
Intervention descriptions: intervention 1: GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.

Protocol document:
Prot_000.pdf: 
2016N290015_04
CONFIDENTIAL
GlaxoSmithKline group of companies
206246
1
TITLE PAGE
Protocol Title: An Open-label, Dose-escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of GSK2586881 
in Participants with Pulmonary Arterial Hypertension
Protocol Number: 206246 / Amendment 4
Short Title: Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of 
GSK2586881 in Participants with Pulmonary Arterial Hypertension
Compound Number:
GSK2586881
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
Regulatory Agency Identifying Number(s): EudraCT 2017-000212-41, IND 132281
Approval Date: 10-JUL-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N405280_00


 
2019N405280_00
PPD
PPD


2016N290015_04
CONFIDENTIAL
206246
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 4
10-Jul-2018
2016N290015_04
Amendment 3
01-Dec-2017
2016N290015_03
Amendment 2
07-Nov-2017
2016N290015_02
Amendment 1
03-May-2017
2016N290015_01
Original Protocol
04-Apr-2017
2016N290015_00
Amendment 4
10-JUL-2018
Overall Rationale for the Amendment:
This is a substantial amendment with changes to the inclusion and exclusion criteria 
to more accurately reflect the patient population.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
4
Section # and 
Name
Description of Change
*Bolded text indicates newly added text, and 
strikethrough indicates deleted text.
Brief Rationale
6.1 Inclusion 
Criteria #3
The following change was made:  
Idiopathic pulmonary arterial hypertension 
(IPAH), hereditary pulmonary arterial 
hypertension (HPAH), or PAH associated 
with collagen vascular disease, repaired 
congenital heart disease, or appetite 
suppressant use.
PAH associated with repaired 
congenital heart disease was 
removed as this differs clinically 
from other forms of PAH.
6.1 Inclusion 
Criteria #5
The following change was made:
Hemodynamically stable on background 
therapy with no evidence of uncontrolled
right heart failure (historic data), as 
determined by the investigator.
This change clarifies that 
participants with uncontrolled 
right heart failure must be 
excluded. However, participants 
with controlled right heart failure 
can be included as determined 
by the investigator. 
6.1 Inclusion 
Criteria #6 and 
9.4 Six-minute
walk test
The following change was made:     
Six minute walk (6MW) distance, as 
performed at screening or within 6 months
prior to screening, of ≥100 meters and < 
450 ≤ 500 meters.
Six-minute walk maximum 
distance was increased to 500
meters to allow participants to 
be included that meet all other 
criteria.
6.1 Inclusion 
Criteria #10
The following change was made:
Body weight <90 ≤ 100 kg and body mass 
index (BMI) within the range 18-30 35
kg/m2 (inclusive).
Maximum BMI was increased to 
35 to more accurately reflect the 
range observed in the patient 
population.
6.2 Exclusion 
criteria #4
The following change was made:
Complex repaired and unrepaired 
congenital heart disease.
This change clarifies that both 
complex repaired and 
unrepaired congenital heart 
disease will be excluded from 
the study.
6.2 Exclusion 
criteria #9
The following change was made:
Estimated glomerular-filtration-rate (eGFR) 
< 60 45 mL/min/1.73m2.
eGFR rate was reduced to 
45ml/min/1.73m2 to more 
accurately reflect the range 
observed in the patient 
population.
12.2 Appendix 2: 
Clinical 
Laboratory 
Tests
The following change was made:
Activated Prothrombin time (PT)
aPTT 
Q2 confirmed the assay they 
use is activated prothrombin 
time (aPTT)
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
5
Section # and 
Name
Description of Change
*Bolded text indicates newly added text, and 
strikethrough indicates deleted text.
Brief Rationale
12.2 Appendix 2: 
Clinical 
Laboratory 
Tests
The following change was made:
Local laboratory results are only required 
in the event that the central laboratory 
results are not available in time for either 
study treatment administration and/or 
response evaluation. If a local sample is 
required, it is important that the sample for 
central analysis is obtained at the same 
time. Additionally, if the local laboratory 
results are used to make either a study 
treatment decision or response evaluation, 
the results must be entered into the CRF.
This change allows sites to use 
local labs, if necessary;
however, it ensures samples are 
always collected and analysed 
centrally. 
12.5 Appendix 5: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Pregnancy testing, with a high sensitivity 
test will be performed using the test kit 
provided by the central laboratory /and 
approved by the sponsor and in 
accordance with instructions provided in its 
package insert.
This change gives flexibility for 
sites to use local labs for 
pregnancy testing. 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................17
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................19
3.3.1.
Risk Assessment .........................................................................20
3.3.2.
Benefit Assessment.....................................................................23
3.3.3.
Overall Benefit:Risk Conclusion...................................................23
4.
OBJECTIVES AND ENDPOINTS...........................................................................23
5.
STUDY DESIGN ....................................................................................................24
5.1.
Overall Design ............................................................................................24
5.2.
Number of Participants ...............................................................................24
5.3.
Participant and Study Completion...............................................................25
5.4.
Scientific Rationale for Study Design ..........................................................25
5.5.
Dose Justification........................................................................................25
6.
STUDY POPULATION...........................................................................................26
6.1.
Inclusion Criteria.........................................................................................26
6.2.
Exclusion Criteria........................................................................................27
6.3.
Lifestyle Restrictions...................................................................................29
6.3.1.
Caffeine, Alcohol, and Tobacco ...................................................29
6.3.2.
Activity .........................................................................................29
6.3.3.
Contraception Requirements .......................................................29
6.4.
Screen Failures...........................................................................................29
7.
TREATMENTS.......................................................................................................30
7.1.
Treatments Administered............................................................................30
7.2.
Dose Modification .......................................................................................30
7.3.
Method of Treatment Assignment ...............................................................31
7.4.
Blinding.......................................................................................................31
7.5.
Preparation/Handling/Storage/Accountability..............................................31
7.6.
Treatment Compliance................................................................................32
7.7.
Concomitant Therapy..................................................................................32
7.8.
Treatment after the End of the Study ..........................................................33
8.
DISCONTINUATION CRITERIA.............................................................................33
8.1.
Liver Chemistry Monitoring .........................................................................33
8.2.
QTc Monitoring Criteria...............................................................................33
8.3.
Withdrawal from the Study..........................................................................34
8.4.
Lost to Follow Up........................................................................................34
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
7
9.1.
Pharmacodynamics ....................................................................................35
9.1.1.
Hemodynamics............................................................................35
9.2.
Adverse Events...........................................................................................36
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................36
9.2.2.
Method of Detecting AEs and SAEs.............................................36
9.2.3.
Follow-up of AEs and SAEs.........................................................37
9.2.4.
Regulatory Reporting Requirements for SAEs .............................37
9.2.5.
Cardiovascular and Death Events................................................37
9.2.6.
Pregnancy ...................................................................................38
9.3.
Treatment of Overdose...............................................................................38
9.4.
Six-Minute Walk Test..................................................................................38
9.5.
Safety Assessments ...................................................................................38
9.5.1.
Physical Examinations.................................................................39
9.5.2.
Vital Signs....................................................................................39
9.5.3.
Pulse Oximetry ............................................................................39
9.5.4.
Electrocardiograms......................................................................39
9.5.5.
Telemetry.....................................................................................39
9.5.6.
Clinical Safety Laboratory Assessments ......................................39
9.6.
Pharmacokinetics .......................................................................................40
9.7.
Immunogenicity Assessments.....................................................................41
9.8.
Biomarkers .................................................................................................41
9.9.
Genetics .....................................................................................................41
10. STATISTICAL CONSIDERATIONS........................................................................42
10.1.
Sample Size Determination ........................................................................42
10.2.
Populations for Analyses ............................................................................42
10.3.
Statistical Analyses.....................................................................................42
10.3.1.
Pharmacodynamic and Safety Analyses......................................43
10.3.2.
Pharmacokinetic and Pharmacokinetic-Pharmacodynamic 
Analyses......................................................................................43
10.3.3.
Interim Analyses ..........................................................................44
11. REFERENCES.......................................................................................................45
12. APPENDICES........................................................................................................47
12.1.
Appendix 1: Abbreviations and Trademarks................................................47
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................50
12.3.
Appendix 3: Study Governance Considerations..........................................52
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................56
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................61
12.6.
Appendix 6: Genetics..................................................................................64
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................65
12.8.
Appendix 8: Protocol Amendment History...................................................68
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
8
1.
SYNOPSIS
Protocol Title: An Open-label, Dose-escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of GSK2586881 
in Participants with Pulmonary Arterial Hypertension
Short Title: Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of 
GSK2586881 in Participants with Pulmonary Arterial Hypertension
Rationale:
GSK2586881 is a purified intravenous (IV) formulation of soluble recombinant human 
Angiotensin Converting Enzyme (rhACE2) that is being investigated as a potential 
treatment for Pulmonary Arterial Hypertension (PAH).
Angiotensin converting enzyme type 2 (ACE2) is a type I, membrane-bound 
carboxypeptidase that inactivates Angiotensin II (Ang II) by cleaving it to produce 
Ang(1-7).  Ang II is a key effector peptide of the Renin-Angiotensin-System (RAS) that 
can exert deleterious effects on the pulmonary vasculature resulting in vasoconstriction, 
proliferation and inflammation, all of which contribute to PAH development. Conversely
Ang(1-7) has shown vasodilatory, anti-proliferative and anti-inflammatory properties by 
signalling through the Mas receptor and recombinant ACE2 has proven effective in 
blocking or treating established PAH in several rodent models.
ACE2 hydrolyses a number of other biological peptides, including converting Ang I to 
Ang(1-9) and removing the C-terminal residue from the bradykinin metabolites [des-
Arg9]-bradykinin and lys[des-Arg9]-bradykinin . 
GSK2586881 has been tested in healthy subjects and mechanically ventilated patients 
with Acute Respiratory Distress Syndrome (ARDS) and has been shown to be well 
tolerated with the rapid modulation of RAS peptides. This will be the first 
GlaxoSmithKline (GSK) study to test the safety and preliminary effects on pulmonary 
hemodynamics of GSK2586881 in participants with PAH.
A detailed description of the biology, pharmacology, efficacy, and safety of 
GSK2586881 is provided in the Investigator’s Brochure (IB).
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate changes in the pulmonary 
hemodynamics after single IV doses of 
GSK2586881 administered to participants 
with PAH receiving background PAH 
therapy.

Change from baseline in pulmonary 
vascular resistance (PVR), cardiac output 
(CO) and mean pulmonary artery pressure
(mPAP), as data permit
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
9
Objectives
Endpoints
Secondary

To evaluate the safety and tolerability of 
single IV doses of GSK2586881 
administered to participants with PAH 
receiving background PAH therapy.

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), pulse oximetry and 
immunogenicity.

To evaluate the effect of single IV doses of 
GSK2586881 on RAS peptide responses 
in participants with PAH receiving 
background PAH therapy.

Change from baseline of pulmonary wedge 
and systemic RAS peptides (e.g. Ang II, 
Ang(1-7), Ang(1-5), and AngII/Ang(1-7) 
ratio).

To evaluate the effect on biomarkers of 
disease activity after single IV doses of 
GSK2586881 administered to participants 
with PAH receiving background PAH 
therapy.

To evaluate the pharmacokinetics (PK) of 
GSK2586881 after single IV doses of 
GSK2586881 in participants with PAH 
receiving background PAH therapy.

Change from baseline in NT pro-BNP, NO 
and cardiac troponin I.

Plasma concentrations of GSK2586881 
and derived PK parameters.
Overall Design:
This is a Phase IIa, open-label, dose-escalation, single dose study in participants with 
PAH (as defined in the eligibility criteria) whose symptoms have been clinically stable 
for 8 weeks prior to enrolment and who have had no change in PAH-specific therapy in 
the 12 weeks prior to enrolment.
Number of Participants:
The total number of participants recruited will be determined through an ongoing review 
of the safety, tolerability, PK and PD data with a minimum of 4 participants recruited per
cohort. There will be 4 cohorts.  At the end of each cohort a dose escalation meeting will 
occur and a decision will be made whether to dose escalate.  
A maximum of 27 participants will complete dosing and critical assessments in this 
study.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same dose level at the discretion of the Sponsor in 
consultation with the investigator.
Treatment Groups and Duration:
The study will comprise of 4 separate cohorts. Participants will be administered a single 
dose at the following planned doses: 0.1, 0.2, 0.4, or 0.8mg/kg. 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
10
Dose escalation will occur after a minimum of 4 participants have been dosed per cohort 
and review of safety, tolerability, PK and hemodynamic data up to 24h post dose has 
taken place. Dose escalation will continue up to a maximum dose of 0.8mg/kg. 
Cohort sizes may vary with a minimum of 4 participants per cohort. Additional 
participants may be enrolled to expand a dosing cohort to further evaluate findings at a 
given dose level.
It is anticipated that the total duration of participation in the study will be up to a 
maximum of 59 days from screening to the last study visit.
Study Design
0.1mg/kg
0.8mg/kg
0.4mg/kg
0.2mg/kg
Single Dose
(minimum 4 participants per cohort)
*
*
*
* dose escalation meeting (review of safety, PK and hemodynamic data)
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
11
2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening 
(up to 28 
days before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Informed consent
X
Genetics consent
X
Genetics consent is 
Optional
Inclusion and exclusion 
criteria
X
Recheck clinical 
status before 
randomization and/or 
1st dose of study 
medication
Demography
X
Full physical examination 
including height and 
weight
X
Medical history (includes 
substance usage and 
family history of premature 
CV disease)
X
Substances: drugs, 
alcohol, tobacco and 
caffeine
Past and current medical 
conditions  
X
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
12
Procedure
Screening 
(up to 28 
days before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Serum OR urine 
pregnancy test (WOCBP 
only)
X
X
X
FSH and estradiol test 
(postmenopausal females 
only as needed)
X
Human Immunodeficiency 
Virus (HIV), Hepatitis B 
and C screening
X
If test performed 
within 3 months prior 
to first dose of study
treatment, testing at 
screening is not 
required
Functional classification
X
6 Minute Walk Distance
X3
Admission
X
Participants may be 
admitted the day 
before dosing to 
enable completion of 
required pre-dose 
time point
assessments.
Brief physical
X
X
Study Treatment
X
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
13
Procedure
Screening 
(up to 28 
days before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Vital Signs
X
X
X
X
X
X
X
X
X
Vital signs will be 
measured after 5 
minutes supine at all 
time points.
Triplicate blood 
pressure (BP) will be 
taken at screening
only.
Pulse Oximetry (SpO2)
X
X
X
X
X
X
X
X
X
Pulse oximetry will 
be measured and 
recorded with each 
blood pressure 
assessment
Laboratory assessments 
(include liver chemistries, 
haematology panel and 
coagulation panel)
X
X
X
X
Urinalysis
X
X
12-lead ECG
X
X
X
X
X
Triplicate will be 
performed at 
Screening and Pre-
dose 
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
14
Procedure
Screening 
(up to 28 
days before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Telemetry
-------------------------------------------------------------------------------------
Monitoring to start 
30min prior to 
treatment 
administration and 
continue throughout 
the study until 24h 
after dosing
Right heart catheter 
Insertion
-------------------------------------------------------------------------------
RHC inserted prior to 
dose and removed 
after the 4h 
hemodynamic 
measurement
Blood sample for 
biomarkers of disease 
activity
X
X
X
X
Blood sample for Nitric 
Oxide 
X
X
X
X
Blood sample for PK
X
X
X
X
X
X
X
X
Blood sample for 
immunogenicity
X
X
X
Additional visits may 
be required. (see 
Section 9.7 for 
details).
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
15
Procedure
Screening 
(up to 28 
days before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Blood sample for renin-
angiotensin system
biomarkers
X
X
X
X
X
X
X
X
X
Blood sample for 
pulmonary wedge RAS 
biomarkers
X
X
X
X
Hemodynamic 
measurements
X
X
X
X
Genetic sample
X
Can be taken any 
time after consent 
has been signed. 
Only required once 
and
is optional.
Discharge
X
AE review
==========================================================
X
SAE review
X
===========================================================
X
Concomitant medication 
review4
X
X
X
1.
Pre-dose measurements may be taken any time after admission up until dosing.
2.
Procedures will be completed immediately after dosing has completed.
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
16
3.
If the six minute walk(6MW) has been performed in the last 6 months, and participant has been stable on current medications then there is no need to repeat.  Historical data will 
be databased.
4.
Concomitant medications for the 30 days prior (8 weeks prior for PAH medications) will be reviewed/recorded at screening to evaluate eligibility and changes will be recorded 
throughout the study.
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
17
3.
INTRODUCTION
While considerable advances have been made in treatment, PAH continues to be a 
serious, life shortening disease. PAH is characterised by impedance to blood flow 
through the pulmonary vasculature that occurs as a consequence of enhanced pulmonary 
vasoconstriction, small pulmonary arteriole remodelling, and loss of vessel 
compliance/distensibility due to perivascular fibrosis [Maron, 2013; Crosswhite, 2014]. 
Severe pulmonary hypertension leads to right ventricular overload and right-sided heart 
failure.
GSK2586881 is a purified intravenous formulation of soluble rhACE2 that is being 
investigated clinically as a potential treatment for PAH.  ACE2 is a type I, membrane-
bound carboxypeptidase that inactivates Ang II by cleaving it to produce Ang (1-7).  Ang 
II is a key effector peptide of the RAS that can exert deleterious effects on the pulmonary 
vasculature resulting in vasoconstriction, inflammation, proliferation and structural 
remodelling, all of which contribute to PAH development (Lipworth, 1994, Cheng, 2005, 
Schiffrin, 2003).  Conversely Ang (1-7) signals through the Mas receptor and has shown 
vasodilatory, anti-inflammatory and anti-proliferative properties in experimental models 
(Clarke, 2011).  Vasodilation induced by Ang (1-7) has been attributed to the activation 
of endothelial nitric oxide synthase (eNOS) and the release of nitric oxide (NO) 
(Sampaio, 2007). The mechanism of action of ACE2 and the downstream consequences 
are thus distinct from ACE inhibitors and angiotensin receptor blockers (Figure 1).
Systemic and pulmonary Ang II levels have been reported to be increased in patients with 
idiopathic (I)PAH and are associated with increased pulmonary vascular remodelling (De 
Man, 2012) while serum ACE2 levels are reported to be decreased in patients with 
congenital heart disease-associated PAH, and correlate with mPAP (Dai, 2013). The 
presence of autoantibodies to ACE2 have also been reported in the serum of patients 
with autoimmune disease with constrictive vasculopathies, PAH or persistent digital 
ischemia and correlate with reduced ACE2 activity (Takahashi, 2010). Taken together 
these studies suggest ACE2 activity may be impaired in PAH patients and 
administration of exogenous ACE2 may be beneficial. This is supported in rodent 
models of PAH where recombinant ACE2 has proven effective in blocking or treating 
established PAH in several rodent models, including in BMPR2-mutation related PAH 
and pulmonary artery banding (Johnson, 2011; Johnson, 2012).
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
18
Figure 1
Renin-Angiotensin System
Angiotensinogen
Angiotensin I (1-10)
Angiotensin II(1-8)
Angiotensin (1-9)
Angiotensin (1-7)
Renin
ACE 1
Aldosterone
Vascular leak
Vasoconstriction
Pro-inflammatory
Pro-fibrotic/apoptotic
Sodium/water retention
ACE 1
ACE 2
ACE 2
Reduced vascular leak
Vasodilatation
Anti-inflammatory
Anti-proliferation/apoptotic
3.1.
Study Rationale
GSK2586881 is a purified intravenous formulation of soluble rhACE2 that is being 
investigated as a potential treatment for PAH. GSK2586881 has been tested in healthy 
subjects (Haschke, 2013) and mechanically ventilated patients with Acute Respiratory 
Distress Syndrome (ARDS) (GSK study ACE114622; GSK Document Number
2014N217963_00) and has been shown to be well tolerated with the rapid modulation of 
RAS peptides. This will be the first GSK study to test the safety and preliminary 
hemodynamic effects of GSK2586881 in participants with PAH.
3.2.
Background
PAH is defined as mPAP >25 mmHg at rest and a mean pulmonary wedge pressure of 
≤15 mmHg (Galie, 2009). Patients may present with shortness of breath, swelling, 
fatigue, chest pain, and in advanced cases syncope. Women of childbearing age are most 
commonly affected, although PAH has been reported in children and older adults. 
Untreated PAH eventually leads to right sided heart failure and death. PAH is a 
progressive disease, and mortality and morbidity remain high in spite of recent 
improvements in therapy.
The development of PAH is associated with connective tissue disease, liver disease, HIV 
infection, use of appetite suppressants, congenital systemic-to-pulmonary shunts (e.g., 
atrial septal defect), and portal hypertension.  PAH may also occur with no known cause, 
in which case it is considered primary or idiopathic PAH (IPAH), and as an inherited 
disease, referred to as heritable PAH (HPAH). IPAH is a devastating disease which if 
untreated has a median life expectancy of 2.8 years (D’Alonzo, 1991).  Outcome for PAH 
associated with other disorders such as scleroderma is even worse.
At the histologic level, all forms of PAH are characterized by marked structural 
remodeling of small pulmonary arteries (<100µ in diameter); specifically, vascular 
smooth muscle cell proliferation (medial hyperplasia), intimal fibrosis and hyperplasia, 
and in situ microthrombosis.  In advanced disease, plexiform lesions, likely a disordered 
attempt at neovascularization, have been identified. These changes in the small 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
19
pulmonary arteries lead to narrowing and obliteration of the vessel lumen, increased 
resistance to blood flow, and increased strain on the right ventricle. The molecular 
mechanisms underlying this vasculopathy remain poorly understood.
Management strategies for PAH include prevention of microthrombosis using 
anticoagulants such as warfarin and promoting vasodilation and regression of muscular 
hypertrophy and intimal fibrosis using endothelin receptor antagonists and 
phosphodiesterase (PDE) 5 inhibitors (Humbert, 2004).  In severe disease or in cases of 
treatment failure with oral therapy, prostanoids (inhaled, subcutaneous, or intravenous) 
are used. In selected patients who are not responsive to medical therapy, lung transplant 
is an option. Despite improvement in medical therapy, only two-thirds of patients are 
alive 3 years after treatment with the most effective therapy available for PAH, 
continuous intravenous epoprostenol (Sitbon, 2002). The current therapeutic options 
remain unsatisfactory, and there remains an urgent need for novel therapies.
A detailed description of the biology, pharmacology, efficacy, and safety of 
GSK2586881 is provided in the IB (GSK Document Number 2010N108777_03 and GSK 
Document Number 2016N300457_00)
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK2586881 may be found in the IB (GSK Document
Number 2010N108777_03).
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
20
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2586881
Unknown potential for  adverse 
hemodynamic effects in patients with 
PAH
Pre-Clinical:
Pharmacology studies in rats showed additive reduction in BP
when GSK2586881 at single daily dose of 1 mg/kg was given 
with an angiotensin type 1 receptor blocker or an ACE 
inhibitor.
Clinical: 
No adverse hemodynamic or BP effects noted in the first time 
in humans (FTIH) healthy volunteer study (APN01-1-01).
No acute adverse hemodynamic effects related to study drug 
administration or considered significantly different from those 
expected of patients with ARDS in study ACE114622.
Participants will be monitored including 
frequent vital signs.
Participants will be excluded if concomitant 
therapy includes the use of an ACE inhibitor 
or angiotensin receptor blocker within 14 
days prior to dosing.
Potential Cardiovascular(CV) Effects
Pre-Clinical:
In the cynomolgus monkey study, twice daily administration of 
10.4 mg/kg (20.8mg/kg/day, highest dose given) for 12 
consecutive days resulted in a waveform abnormality in a 
single female (n=12) which was 6 premature ventricular 
complexes(PVCs) including an episode of non-sustained 
ventricular tachycardia (NSVT) consisting of 3 consecutive 
PVCs (triplet).  Timing of the NSVT was 2 to 3 hours following 
the first daily dose while subsequent PVCs occurred at a 
Participants will be monitored including 
telemetry
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
21
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
similar time point after the second daily dose.  There was no 
evidence of QT prolongation or anatomical changes in the 
heart.
Clinical:
No adverse effects on ECG were seen in the FTIH study 
(APN01-1-01).
In study ACE114622 in ARDS, no clinically significant effects 
on ECG that were considered related to study drug were 
observed.
Potential for Immunogenicity
Clinical:
There was no induction of an immune response to rhACE2 in 
any of the treated subjects up to 28 days after last 
administration in the FTIH healthy volunteer study (APN01-1-
01) or in ARDS patients (ACE114622).
Participants will have routine monitoring of 
any immunological response that may occur.
Unknown risk of teratogenicity
Pre-Clinical:
Reproductive toxicology studies have not yet been performed 
with GSK2586881. A review of the literature suggests that 
ACE2 is present in organs of fetal mice late in gestation, and 
in the placentae of rats, guinea-pigs and humans.  Some of 
the changes noted in the PD and toxicity studies with ACE2 
are similar to those reported with an ACE inhibitor.  In 
addition, the older ACE inhibitors are known to be teratogenic 
in humans.
Pregnancy testing at screening and prior to 
dosing.
Information on contraception post study will 
be provided in the informed consent form 
(ICF).
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
22
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Potential for Rash
Clinical:
In study ACE114622, rash was reported more frequently in 
subjects receiving GSK2586881, although only one event was 
considered drug-related.
Participants will be monitored for rash in the 
clinical trials.
Study Procedures
Pulmonary arterial catheterization
(PAC)
More common risks of PAC placement include: bruising at the 
site of the PAC insertion, excessive bleeding, vein injury or 
tear or pneumothorax.  Less common complications include: 
thrombosis, infection, hypotension, arrhythmia, cardiac 
tamponade or pulmonary artery rupture.
Insertion of catheter performed by 
experienced physicians, continuous 
monitoring of participants during procedure 
per site standard operating procedures
(SOPs).
Exposure to ionzing radiation
Catheter placement may be confirmed by chest X-ray or 
fluoroscopy, as clinically indicated. Both chest X-ray and 
fluoroscopy are assumed to increase the risk of cancer or 
heritable effects due to radiation exposure. Radiation 
exposure from chest X-ray is minimal (0.02mSv). Radiation 
exposure from fluoroscopy used to confirm placement of the 
catheter is dependent on the equipment and duration of the 
procedure. The dose will typically be around 2mSv but may
range from 2-5mSv. The additional risk of developing a fatal 
malignancy (cancer) as a result of these exposures has been 
estimated as between 1 in 10,000 and 1 in 2000 for an adult in 
normal health.
Negative pregnancy testing prior to 
procedure. Minimize fluoroscopy time; lead 
shielding per site SOPs.  Maximum exposure 
will not exceed 10mSv to confirm placement 
of the catheter.
 
 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
23
3.3.2.
Benefit Assessment

All participants will undergo a thorough medical assessment during the study, 
including ECG, vital signs monitoring, and physical examinations. Monitoring for 
worsening of their disease will also take place.

Participants may benefit from the knowledge that they are contributing to the process 
of developing a new treatment in an area of unmet need, even if not directly 
beneficial for them.
3.3.3.
Overall Benefit:Risk Conclusion
In clinical trials completed to date GSK2586881 has been well-tolerated and most AEs 
were mild to moderate in intensity.  The most commonly observed AE in critically ill 
patients has been hypokalemia that occurred with equal frequency following 
administration of GSK2586881 and placebo.  Hypernatremia, rash, dysphagia and 
pneumonia occurred more frequently in subjects receiving GSK2586881 in study 
ACE114622 (GSK Document Number 2014N217963_00). There have been no treatment 
related clinically significant changes in vital signs or ECG at any dose of GSK2586881. 
Taking into account the measures taken to minimize risks to participants in this study, the 
potential risks identified in association with GSK2586881 are justified by the anticipated 
benefits that may be afforded to participants with PAH.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate changes in the pulmonary 
hemodynamics after single IV doses of 
GSK2586881 administered to participants 
with PAH receiving background PAH 
therapy.

Change from baseline in pulmonary 
vascular resistance (PVR), cardiac output 
(CO) and mean pulmonary artery pressure
(mPAP), as data permit
Secondary

To evaluate the safety and tolerability of 
single IV doses of GSK2586881 
administered to participants with PAH 
receiving background PAH therapy.

Adverse events (AE), clinical laboratory 
values, vital signs, ECG, pulse oximetry 
and immunogenicity.

To evaluate the effect of single IV doses of 
GSK2586881 on RAS peptide responses 
in participants with PAH receiving 
background PAH therapy.

Change from baseline of pulmonary wedge 
and systemic RAS peptides (e.g. Ang II, 
Ang(1-7), Ang(1-5), and AngII/Ang (1-7) 
ratio).
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
24
Objectives
Endpoints

To evaluate the effect on biomarkers of 
disease activity after single IV doses of 
GSK2586881 administered to participants 
with PAH receiving background PAH 
therapy. 

Change from baseline in NT pro-BNP, NO 
and cardiac troponin I.

To evaluate the pharmacokinetics of 
GSK2586881 after single IV doses of 
GSK2586881 in participants with PAH 
receiving background PAH therapy.

Plasma concentrations of GSK2586881 
and derived PK parameters.
Exploratory

To evaluate PK/PD relationships after 
single IV doses of GSK2586881.

Pulmonary wedge RAS peptides, and/or
pulmonary vascular hemodynamic 
measurements compared with PK 
exposure.

To evaluate pharmacogenetics(PGx). 

Evaluate I/D polymorphisms in the 
Angiotensin Converting Enzyme (ACE) 
gene and analyze the impact on Ang II 
(and possibly other RAS peptides), and 
responses to GSK2586881 administration.
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IIa, open-label, dose-escalation study in participants with PAH (as 
defined in the eligibility criteria) whose symptoms have been clinically stable for 8 weeks 
prior to enrolment and who have had no change in PAH-specific therapy in the 12 weeks 
prior to enrolment. Eligible participants will undergo baseline assessments before 
receiving a single dose of GSK2586881.
It is anticipated that the total duration of participation in the study will be up to a 
maximum of 59 days from screening to last study visit.
5.2.
Number of Participants
The total number of participants recruited will be determined through an ongoing review 
of the safety, tolerability, PK and PD data with a minimum of 4 participants recruited per 
cohort. There will be 4 cohorts. At the end of each cohort a dose escalation meeting will 
occur and a decision will be made whether to dose escalate.  
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
25
Once dose escalation is complete additional participants may be recruited to further 
evaluate findings at a given dose level. A maximum of 27 participants will complete 
dosing and critical assessments in this study.
Evaluable participants are defined in Section 10.2.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same dose level at the discretion of the Sponsor in 
consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow up visit and the last scheduled procedure shown 
in the Schedule of Activities.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
The lack of a placebo arm is justified in that the primary goals of this study are to 
understand the initial hemodynamic effects, safety and tolerability of GSK2586881 in a 
small number of participants with PAH. 
Due to the open label design it is accepted that there may be potential bias in AE 
reporting, this will be taken into account when interpreting the study results.
5.5.
Dose Justification
GSK2586881 has been studied in 21 healthy subjects as single, intravenous doses over 30 
minutes from 0.1 mg/kg to 1.2 mg/kg, and in repeated daily doses for up to six days of 
0.4 mg/kg once a day.  In addition, ARDS patients have received four doses of 
GSK2586881: 0.1 mg/kg, 0.2 mg.kg, 0.4 mg/kg and 0.8 mg/kg over a 24 hour period 
(n=5) or 0.4 mg/kg BID for 3 days (n=19). 
A preliminary population PK model for GSK2586881 has been derived from data 
obtained in healthy subjects and ARDS patients and showed that the systemic PK profile 
was adequately described by a two-compartment first order elimination model and that 
the PK profile was independent of population (healthy subjects or ARDS patients).  
Decreases in Ang II levels occurred rapidly after GSK2586881 administration with Ang
II concentrations maximally or near maximally reduced at the first sampling time of 5 
minutes post-dose; consistent with maximal plasma concentrations of GSK2586881. The 
PK/PD response (the relationship between ACE2 and Ang II) in healthy subjects and 
ARDS patients appeared to be best described with a single direct Emax model after 
accounting for differences in baseline Ang II concentrations between healthy subjects and 
ARDS patients.  The observation of no significant delay between GSK2586881 
concentration and effect is in line with its mechanism of action as an enzyme on a 
substrate.  
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
26
Based on the preliminary population PK/PD model described above, it is predicted that 
following a single dose of ≥0.2 mg/kg, Ang II concentrations will on average be reduced 
below participant baseline levels for at least 24 hours post-dose (assuming Ang II levels 
in PAH participants is consistent with levels reported in ARDS participants in GSK study 
ACE114622 (GSK Document Number 2014N217963_00).  The 0.8mg/kg dose has been 
selected to investigate the safety and tolerability dose range for GSK2586881 in this 
patient population.
In an investigator-sponsored study (NCT01884051) GSK2586881 has been studied in 3
PAH patients as a single, intravenous dose at 0.2 mg/kg, and in 2 patients at 0.4mg/kg.  
There were no SAEs and no dose limiting toxicities were observed. 
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be between 18-75 years of age (inclusive), at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Documented diagnosis of PAH, defined as mPAP > 25 mmHg and PWP ≤15 
mmHg.
3.
Idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial 
hypertension (HPAH), or PAH associated with collagen vascular disease, or appetite 
suppressant use. 
Note: Those with portopulmonary hypertension or pulmonary veno-occlusive 
diseas (PVOD) are not eligible for the study
4.
World Health Organization (WHO) functional class I, II, or III, stable for at least 8 
weeks prior to enrollment.
5.
Hemodynamically stable on background therapy with no evidence of uncontrolled 
right heart failure (historic data), as determined by the investigator. 
6.
Six minute walk (6MW) distance, as performed at screening or within 6 months prior 
to screening, of ≥100 meters and ≤ 500 meters.
7.
Mean BP of >60 mmHg
8.
Receiving stable doses of one or more medications that are approved for treatment of 
PAH, including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
27
and/or prostanoids/prostacyclin receptor agonists, for a minimum of 12 consecutive 
weeks before enrollment. 
NOTE: Anticoagulant therapy can be adjusted according to target INR
9.
Diuretic dose stable for 8 weeks.
Weight
10. Body weight ≤100 kg and body mass index (BMI) within the range 18-35 kg/m2
(inclusive).
Sex
11. Male and/or female (following confirmation of negative pregnancy test for 
WOCBP).  Women who are pregnant or breastfeeding are excluded.
Informed Consent
12. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History of systemic hypotension, defined as systolic BP <90 mmHg and/or diastolic 
BP <50 mmHg.
2.
Hospitalization for PAH associated deterioration in the previous 6 months. 
3.
Any additional medical condition, serious intercurrent illness, or other extenuating 
circumstance that, in the opinion of the Investigator, may significantly interfere with 
study compliance, including all prescribed evaluations and follow-up activities. 
Concurrent disease or condition that may interfere with study participation or safety 
include bleeding disorders, arrhythmia, organ transplant, organ failure, current 
neoplasm, poorly controlled diabetes mellitus, and serious neurological disorders.
4.
Complex repaired and unrepaired congenital heart disease.
5.
Subjects with Eisenmenger physiology.
6.
Alanine transferase (ALT) >2x upper limit of normal (ULN).
7.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
8.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
9.
Estimated glomerular-filtration-rate (eGFR) <45mL/min/1.73m2.
10. QTc >480 msec or QTc > 500 msec in participants with bundle branch block.
NOTES: 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
28

The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read.
The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In 
other words, several different formulas cannot be used to calculate the QTc for an 
individual participant and then the lowest QTc value used to include or 
discontinue the participant from the trial.
11. Any bleeding concerns as evidenced by INR >1.5 (in participants not receiving 
anticoagulation therapy) or platelet count <80,000.
12. Hb <10 g/dL
Prior/Concomitant Therapy
13. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or Medical Monitor, contraindicates 
participation in the study.
14. Any use of an ACE inhibitor, angiotensin receptor blocker, or renin inhibitors within 
14 days prior to dosing.  Therapy can be stopped to enable inclusion if deemed safe 
by the participant’s treating physician.
Prior/Concurrent Clinical Study Experience
15. Use of any investigational product (IP) or device within 30 days prior to dosing, or 
known requirement for any investigational agent prior to completion of all scheduled 
study assessments.
Diagnostic assessments
16. Positive HIV antibody test.
17. Presence of Hepatitis B surface antigen (HBsAg) at screening. 
18. Positive Hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved 
disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic 
acid (RNA) test is obtained.
19. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.
NOTE: Test is optional and participants with negative Hepatitis C antibody test 
are not required to also undergo Hepatitis C RNA testing.
Other Exclusions
20. Participation in the study would result in loss of blood or blood products in excess of 
300mL within 65 days.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
29
21. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
22. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening
23. Unable to refrain from smoking during the in-house treatment period.
6.3.
Lifestyle Restrictions
6.3.1.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing products 
(eg, coffee, tea, cola drinks, and chocolate) for 2 hours before the start of dosing.

Participants will abstain from alcohol for 24 hours before the start of dosing until 
after collection of the final PK and/or PD sample. 

Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches) will not be permitted while they are 
in the clinical unit.
6.3.2.
Activity

Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).
6.3.3.
Contraception Requirements
Specific requirements for contraception can be found in Appendix 5 and will be provided 
in the informed consent form (ICF).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. 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, and any serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Rescreened participants should be assigned a new participant 
number.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
30
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment Name:
GSK2586881
Dosage formulation:
Clear, colorless liquid
Unit dose strength(s)/Dosage level(s):
Unit dose strength: 5 mg/mL
Up to 0.8mg/kg
Route of Administration 
IV 
Dosing instructions:
IV push over 3-5 minutes
Packaging and Labeling
Study Treatment will be provided in 
frozen vials. Each vial will be labeled as 
required per country requirement.
Manufacturer
Polymun/GSK
7.2.
Dose Modification
The study will comprise of 4 separate cohorts.  Participants will be administered a single 
dose of one of the following planned doses: 0.1, 0.2, 0.4, or 0.8mg/kg. 
Dose escalation will occur after a minimum of 4 participants have been dosed per cohort 
and review of safety, tolerability, PK and hemodynamic data up to 24h post dose has 
taken place. Dose escalation will continue up to a maximum dose of 0.8mg/kg. 
Cohort sizes may vary with a minimum of 4 participants per cohort. Additional 
participants may be enrolled to expand a dosing cohort to further evaluate findings at a 
given dose level.
If a subject experiences a dose limiting toxicity (DLT) that is considered at least possibly 
related to study drug, dosing of additional participants will be halted and a full safety 
review will be performed to confirm causality.  If 2 participants in any cohort experience 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
31
a DLT considered at least possibly related to study drug, the maximum tolerated dose 
(MTD) has been exceeded.
Dose limiting toxicities are defined as toxicities that, due to their severity or duration, are 
considered unacceptable, and limit further dose escalation.  Examples of DLT’s include,
but are not limited to:

Severe headache unrelieved by nonsteroidal anti-inflammatory drugs (NSAIDS)

Nausea/Vomiting

Hypotension as defined by mean arterial pressure <60mmHg or a drop in systolic 
BP of 25%
7.3.
Method of Treatment Assignment
As this is an open label study, participants will be assigned to the ongoing treatment 
group at that time.
Study using 
IWRS
All participants will be assigned to a treatment group using an 
Interactive Web Response System (IWRS). Before the study starts, 
the log in information & directions for the IWRS will be provided to 
each site.
Study treatment will be dispensed at the study visits summarized in 
SOA.
7.4.
Blinding
Open-label using 
IWRS
This is an open-label study; however, the specific dose level to be 
taken by a participant will be assigned using an IWRS to aid 
cohort management. The site will contact the IWRS prior to the 
start of study treatment administration for each participant. The 
site will record the treatment assignment on the applicable case 
report form (CRF), if required. 
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
32

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
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.
7.6.
Treatment Compliance

GSK2586881 will be intravenously administered to participants at the site.  
Administration will be documented in the source documents and reported in the 
CRF.

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time 
(start and end time of infusion) of the dose administered in the clinic will be recorded 
in the source documents.  The dose of study treatment 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 treatment.  
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
No medications will be prohibited except for those listed below:
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
33

ACE inhibitors, angiotensin receptor blockers, and renin inhibitors will be 
discontinued at least 14 days prior to dosing until 72 hours post dose.
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Other concomitant medication may be considered on a case-by-case
basis by the investigator in consultation with the Medical Monitor if required.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participants medical condition, whether or not GSK is providing specific
post-study treatment.
8.
DISCONTINUATION CRITERIA
There are no treatment discontinuation criteria as this is a single dose study. 
8.1.
Liver Chemistry Monitoring
Liver chemistry monitoring criteria have been designed to assure participant safety and 
evaluate liver event etiology, (in alignment with the Food and Drug Administration(FDA)
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7.
8.2.
QTc Monitoring Criteria
There are no treatment discontinuation criteria as this is a single dose study, however the 
following criteria described below still apply. 

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
34

The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5-10 minute) recording period.  
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will receive additional monitoring as appropriate:

QTc > 530 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
8.3.
Withdrawal from the Study
Participants who withdraw from the study after treatment will still be required to 
complete both follow-up visits as detailed in the SoA.

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.  This applies to withdrawal 
from the genetic substudy.

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.  This applies to withdrawal from the genetic substudy.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

If a participant is withdrawn from the study every effort must be made to 
complete the follow-up assessments detailed in the SoA within 7-14 days of last 
dose and the Day 28 follow-up assessments.
8.4.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she 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.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
35

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

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 (eg, 
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 300mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Pharmacodynamics
9.1.1.
Hemodynamics
Pulmonary arterial catheters will be placed in all participants enrolled. Participants will 
consent to have the catheter inserted for the purposes of the study. Catheter placement 
may be confirmed by chest X-ray or fluoroscopy, as clinically indicated.  All effort will 
be made to minimize radiation exposure time.
Variables that will be recorded from the right heart catheterization, as data permit, 
include: 

right atrial pressure

pulmonary artery systolic and diastolic pressure

mean pulmonary artery pressure

pulmonary wedge pressure

cardiac output and index measured by thermodilution 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
36

pulmonary vascular resistance (PVR)

pulmonary artery oxygen saturation (PAsat)
The clinical sites will use their SOPs for the insertion, maintenance and removal of the 
catheter.  The catheter will be removed following completion of the “4 hour post-dose” 
catheter measurements and sample collections. The participant will then be monitored for 
a minimum of 20 hours or until discharge.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any 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 treatment or the study, 
or that caused the participant to discontinue the study (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4. 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 in former study 
participants. 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 treatment or study 
participation, the investigator must promptly notify the sponsor.

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 4.
9.2.2.
Method of Detecting AEs and SAEs
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. 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
37
9.2.3.
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 8.4). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
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 treatment 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 treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/ 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 (eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any CV events and all deaths, whether or not they are considered SAEs, specific CV
and Death sections of the CRF will be required to be completed. These sections include 
questions regarding CV (including sudden cardiac death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV medical 
dictionary for regulatory activities (MedDRA) terms. The CV information should be 
recorded in the specific CV section of the CRF within one week of receipt of a CV Event 
data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
38
9.2.6.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 1 week
after dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK2586881 greater than 1.2mg/kg will be considered an 
overdose.
Sponsor 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 until 
GSK2586881 can no longer be detected systemically (at least 3 days post last dose).
3.
Obtain a plasma sample for PK analysis as described in the SoA (Section 2).  PK 
assessments may be continued beyond 24 hours 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.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Six-Minute Walk Test
Six minute walk (6MW) distance, as performed at screening or within 6 months prior to 
screening. The subject is asked to walk along a prescribed path (typically 30 meters long) 
as far as possible during a 6-minute interval. The subject may walk at whatever pace is 
comfortable, with the goal of walking the longest distance possible. The subject may rest 
as needed.  The subject will need to walk a minimum distance of 100 meters and 
maximum distance of ≤500 meters to meet study inclusion criteria. The distance walked 
will be entered into the CRF.
9.5.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
39
9.5.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, CV, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded (at screening only).

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, CV system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.5.2.
Vital Signs

Pulse rate, respiratory rate, and BP will be assessed.

Blood pressure and pulse measurements will be assessed (supine) with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones). At screening there will be 1 pulse and 3 BP
measurements (3 consecutive BP readings will be recorded at intervals of at 
least 1 minute). The average of the 3 BP readings will be recorded on the CRF.
9.5.3.
Pulse Oximetry

Oxygen saturation will be measured by pulse oximetry after the subject has been 
at rest for at least 5 minutes.
9.5.4.
Electrocardiograms

12-lead ECG will be obtained using an ECG machine that automatically 
calculates the HR and measures PR, QRS, QT, and QTc intervals. Refer to 
Section 8.2 for QTc monitoring criteria and additional QTc readings that may be 
necessary.

Triplicate ECG are required at screening and predose. At these time points, 3
individual ECG tracings should be obtained as closely as possible in succession, 
but no more than 2 minutes apart. 
9.5.5.
Telemetry

Telemetry will be measured continuously as detailed in the SoA (Section 2).

Only AE and SAE data related to telemetry will be databased.
9.5.6.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 2) for the timing and frequency. 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
40

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 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 
during participation in the study or within 3 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology 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.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.6.
Pharmacokinetics
Whole blood samples will be collected for measurement of plasma concentrations of 
GSK2586881 as specified in the SoA (Section 2). The actual date and time (24-hour 
clock time) of each sample will be recorded.
Additional sample time points may be added during the study if warranted and agreed 
upon between the investigator and the sponsor, however, the maximum allowed blood 
volume will not be exceeded. 
Samples collected for analyses of GSK2586881 plasma concentration may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the study.
Once the plasma has been analyzed for GSK2586881 any remaining plasma may be 
analyzed for other compound-related metabolites and the results reported under a 
separate protocol.
Details of blood sample collection (including volume to be collected), processing, storage 
and shipping procedures are provided in the lab manual.
Plasma analysis will be performed under the control of GSK, the details of which will be 
included in the lab manual.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
41
9.7.
Immunogenicity Assessments
Whole blood samples will be collected for measurement of immunogenicity assessments 
as specified in the SoA (Section 2). 
Additional visits at 12, 24, and 36 weeks post-dose (and less frequently thereafter), to 
obtain immunogenicity samples may be required in the unlikely event that subjects 
develop a clinically relevant immunoglobulin response to the drug as described in the lab 
manual.
Details of immunogenicity blood sample collection (including volume to be collected), 
processing, storage and shipping procedures are provided in the lab manual.
9.8.
Biomarkers
The following samples for biomarker research will be collected from all participants in 
this study as specified in the SoA (Section 2):

RAS peptides Ang II, Ang (1-7) and Ang (1-5) and other vasoctive peptides in 
the RAS and bradykinin cascade, and Nitric Oxide may be analyzed from 
plasma as data permit.

Biomarkers of disease activity: NT pro-BNP, and cardiac troponin I may be 
analyzed from serum as data permit.
Additional sample time points may be added during the study if warranted and agreed 
between the investigator and the sponsor, however the maximum allowed blood volume 
will not be exceeded.
In addition, with the participant’s consent, samples will be stored and may be used to 
investigate additional biomarkers thought to play a role in PAH disease progression or to
evaluate their association with observed clinical responses to GSK2586881.
Samples may also be used for research to develop methods or support identification of 
prognostic/diagnostic biomarkers associated with clinical outcomes in PAH and related 
diseases.
Details of blood sample collection (including volume to be collected), processing, storage 
and shipping procedures are provided in the lab manual.
9.9.
Genetics
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected from 
participants who have consented to participate in the genetics analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
42
Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in SRM. 
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
The sample size chosen is not based on statistical considerations.  
The design of the study is deemed acceptable under the anticipated safety profile, given 
previous clinical experience with GSK2586881. 
If additional participants/cohorts are enrolled to allow for evaluation of additional dose 
levels the proposed analysis approach(s) would be modified accordingly. 
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF
Safety
All participants who take at least 1 dose of study treatment. 
Participants will be analyzed according to the treatment they actually 
received.
Evaluable
All participants who are in the Safety population who complete all 
Day 1 assessments (including up to 24 hours post dose) and were 
not deemed to have had major protocol deviations (as defined within 
the PDMP)
PK Population
Subjects in the ‘Safety’ population for whom a PK sample was 
obtained and analysed.  PK population will be the population for 
reporting PK data.
10.3.
Statistical Analyses
Limited subject level data/information from a GSK supported study (NCT01884051) is 
available at doses of 0.2 mg/kg and 0.4 mg/kg.  This data may be used as supportive only 
in reference to basic comparisons of safety, PK and PD with the current study.  This 
previous study data will not be incorporated into statistical analyses associated with the 
current study.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
43
10.3.1.
Pharmacodynamic and Safety Analyses
Endpoint
Statistical Analysis Methods
Primary

Descriptive Summaries, Figures and Listings of Change from 
Baseline PVR, CO and mPAP by planned timepoints. 

If data permit, linear regression of Dose vs Change from Baseline 
PVR, CO and/or mPAP at 4 hours (endpoints loge transformed if 
necessary).
Secondary

Descriptive Summaries, Figures and Listings. 

Simple figures (e.g. scatterplots and/or scatterplot matrix plots) 
exploring correlation between key PD endpoints (e.g. RAS peptides) 
and the Primary endpoints (PVR, CO and mPAP).

All safety analyses will be performed on the Safety Population
Exploratory
Will be described in the RAP.  Note that exploratory genetic analyses, should 
they occur will be detailed in a separate RAP.
10.3.2.
Pharmacokinetic and Pharmacokinetic-Pharmacodynamic
Analyses
Pharmacokinetics analysis will be performed by, or under direct auspices of the Clinical 
PK Modeling & Simulation department within GSK.  Plasma GSK2586881 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin V6.3 or greater.  Calculations will be based on the actual sampling times 
recorded during the study. 
From the plasma concentration-time data, the following PK 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) and area under 
the concentration-time curve from time zero (pre-dose) extrapolated to infinite time 
[AUC(0-∞)], the last observed quantifiable concentration (Clast), time of the last 
quantifiable concentration (tlast), plasma clearance (CL), volume of distribution (VD) and 
apparent terminal phase half-life (t1/2).  Other PK parameters may also be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All PK data will be stored in the Archives, GSK
Pharmaceuticals, research and development (R&D). 
A population PK analysis may be conducted.  In addition the GSK2586881 plasma 
concentration-time data may be merged with historical data and analysed as part of a 
population PK meta-analysis. Further details will be provided in the RAP. If data permit, 
potential association between systemic exposure of GSK2586881 and identified 
biomarker (e.g. Ang II, Ang(1-7), Ang(1-5)), and/or clinical related endpoints 
(pulmonary vascular hemodynamic) may be studied.  In addition the PK/PD data may be 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
44
merged with historical data and analysed as part of a population PK/PD (biomarker) 
meta-analysis. Further details will be provided in the RAP. Population PK and PK/PD 
exploratory analyses may be presented separately to the CSR.
10.3.3.
Interim Analyses
Safety, PK and pulmonary hemodynamic data will be reviewed after 4 subjects have 
completed dosing in each cohort prior to dosing at the next level. A linear regression 
model may be fitted to the (log transformed, if necessary) Change from Baseline at 4h 
PVR, CO and/or mPAP data from the first three cohorts (Dose Vs baseline adjusted 
response); and the slope parameter estimated along with the (extrapolated) mean response 
for the planned 4th dose of 0.8mg/kg. This will be used in addition to safety, PK and other 
PD data, to aid the team in decision making with regards to additional subject recruitment 
at an optimum dose level(s).
The RAP will describe the planned interim analyses in greater detail.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
45
11.
REFERENCES
Cheng ZJ, Vapaatalo H, Mervaala E. Angiotensin II and vascular inflammation. Medical 
Science Monitor. 2005; 11:194–205.
Clarke NE and Turner AJ. Angiotensin-Converting Enzyme 2: The First 
Decade.International Journal of Hypertension. 2011; doi:10.1155/2012/307315
Crosswhite P, Sun Z. Molecular Mechanisms of Pulmonary Arterial Remodeling. 
Molecular Medicine.2014; 20(1): 191–201.
D’Alonzo E, et al. Survival in Patients with Primary Pulmonary Hypertension. Annals of 
Internal Medicine. 1991;15(5):343-349
Dai HL, Guo Y, Guang XF, Xiao ZC, Zhang M, Yin XL. The changes of serum 
angiotensin-converting enzyme 2 in patients with pulmonary arterial hypertension due to 
congenital heart disease. Cardiology. 2013;124(4):208-12.
De Man F, Tu, Handoko, et al. Dysregulated Renin-Angiotensin-Aldesterone System 
Contributes to Pulmonary Arterial Hypertension. American Journal of Respiratory and 
Critical Care Medicines. 2012;186(8):780-9
Galie N, et al. Guildines for the diagnosis and treatment of pulmonary hypertension. 
European Respiratory Journal. 2009; 34(6):1219-63
GlaxoSmithKline Document Number 2010N108777_03 Study ID 
GSK2586881.Investigator's Brochure for GSK2586881 (formerly known as APN01)– A 
Soluble Recombinant Human Angiotensin Converting Enzyme 2 (rhACE2). Report Date 
18-Sep-2015
GlaxoSmithKline Document Number 2014N217963_00 Study ID ACE114622. A two 
part study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics 
of GSK2586881 in subjects with acute lung injury. Report Date 07-Oct-2015. 
GlaxoSmithKline Document Number 2016N300457_00 Supplement to GSK2586881 
Investigator’s Brochure. Version 2.  Report Date 07-Oct-2016.
Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM,et.al. Prevention of 
angiotensin induced cardiac remodeling by angiotensin-(1–7). American Journal of 
Physiology. Heart and Circulatory Physiology. 2007;292(2):H736–H742.
Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, et al. 
Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting 
enzyme 2 in healthy human subjects. Clinical Pharmacokinetics. 2013 Sep;52(9):783-92.
Humbert 2004 Marc Humbert, M.D., Ph.D., Olivier Sitbon, M.D., and Gérald 
Simonneau, M.D. Treatment of Pulmonary Arterial Hypertension, The New England 
Journal of Medicine.  2004;351:1425-36.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
46
Johnson JA, Hemnes AR, Perrien DS, et al. Cytoskeletal defects in Bmpr2-associated 
pulmonary arterial hypertension. American Journal of Physiology-Lung 
Cellular and Molecular Physiology. 2012;302:L474-84
Johnson JA, West J, Maynard KB, Hemnes AR. ACE2 improves right ventricular 
function in a pressure overload model. PLoS One. 2011;6(6):e20828
Lipworth BJ, Dagg KD. Vasoconstrictor effects of angiotensin II on the pulmonary 
vascular bed. Chest. 1994; 105(5):1360–1364.
Maron BA, Loscalzo J. Pulmonary hypertension: pathophysiology and signaling 
pathways. Handbook of Experimental Pharmacology. 2013;218:31-58.
Sampaio WO, Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. 
Angiotensin-(1–7) through receptor Mas mediates endothelial nitric oxide synthase 
activation via Akt-dependent pathways. Hypertension 2007;49(1):185–192.
Schiffrin EL, Touyz RM. Inflammation and vascular hypertrophy induced by angiotensin 
II: role of NADPH oxidase-derived reactive oxygen species independently of blood 
pressure elevation? Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23:707–
709. 
Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et.al. Long-Term 
Intravenous Epoprostenol Infusion in Primary Pulmonary Hypertension. Journal of the 
American College of Cardiology. 2002;40(4)
Takahashi Y, Haga S, Ishizaka Y, Mimori A. Autoantibodies to angiotensin-converting 
enzyme 2 in patients with connective tissue diseases. Arthritis Research & Therapy.
2010;12(3):R85
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G & Turner AJ. A human homolog 
of angiotensin-converting enzyme. Cloning and functional expression as a captopril-
insensitive carboxypeptidase. The Journal of Biological Chemistry. 2000; 275, 33238–
33243.
Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J et al. Hydrolysis of biological 
peptides by human angiotensin-converting enzyme-related carboxypeptidase. The Journal 
of Biological Chemistry. 2002; 277, 14838–14843.
Yamada K, Iyer SN, Chappell MC, Ganten D, Ferrario CM. Converting enzyme 
determines plasma clearance of angiotensin-(1–7). Hypertension.1998; 32(3):496–502.
Zhang F, Hu Y, Xu Q, Ye S. Different effects of angiotensin II and angiotensin-(1–7) on 
vascular smooth muscle cell proliferation and migration. PLoS ONE. 2010;5(8):e12323.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
47
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
ABBREVIATIONS
2D
Two-dimensional
6MW
Six minute walk
ACE2
Angiotensin converting enzyme type 2
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
Ang II
Angiotensin II
ARDS
Acute respiratory distress syndrome
AST
Aspartate aminotransferase (SGOT)
aPTT
Activated prothrombin time
AUC(0-)
Area under the plasma concentration-time curve 
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments
BID
Bi-Daily
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CIOMS
Council for International Organizations of Medical Sciences
Clast
Last observed quantifiable concentration
CL
Plasma clearance 
Cmax
Maximum observed plasma concentration 
CO
Cardiac output
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase
CRF
Case Report Form
CRM
Continual reassessment model
CSR
Clinical study report
CV
Cardiovascular 
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular-filtration-rate
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
GCP
Good Clinical Practice
GFR
Glomerular-filtration-rate
GSK
GlaxoSmithKline
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
48
HB
hemoglobin
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability
HIV
Human Immunodeficiency Virus
HPAH
Heritable PAH
HPLC
High performance liquid chromatography
HR
Heart rate
HRT
Hormone replacement therapy 
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICF
Informed Consent Form 
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IPAH
Idiopathic PAH
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
Interactive Web Response System
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mPAP
Mean pulmonary arterial pressure
MSDS
Material Safety Data Sheet
MTD
Maximal tolerated dose 
NO
Nitric oxide
NSAIDS
Nonsteroidal anti-inflammatory drugs
NSVT
Non-sustained ventricular tachycardia
PAC
Pulmonary arterial catheterization
PAH
Pulmonary Arterial Hypertension
PAP
Pulmonary arterial pressure
PAsat
Pulmonary artery saturation
PCW
Pulmonary capillary wedge
PD
Pharmacodynamic
PDE
Phosphodiesterase
PDMP
Protocol Deviation Management Plan 
PGx
Pharmacogenetics
PK
Pharmacokinetic
PT
Prothrombin time
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
49
PVC
Premature Ventricular Complexes
PVR
Pulmonary vascular resistance
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
R&D
Research and development 
RAP
Reporting and Analysis Plan
RAS
Renin-Angiotensin System
RBC
Red blood cells
rhACE2
Recombinant human angiotensin converting enzyme type 2
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SaO2
Oxygen saturations
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOA
Schedule of Activities 
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
t½
Terminal phase half-life
tlast
Time of last quantifiable concentration
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
VD
Volume of distribution
WHO
World Health Organization
WOCBP
Women of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
WinNonlin
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
50
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 1 will be performed by the central laboratory. 

If a local sample is required, it is important that the sample for central analysis is 
obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 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 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
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
Glucose 
Calcium
Alkaline phosphatase
International normalized 
ratio (INR)
Activated Prothrombin 
time (PT)
aPTT
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, Microscopic examination 
(only if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
51
Laboratory 
Assessments
Parameters

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis C 
RNA and hepatitis C virus antibody)
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 8.1 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.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
52
12.3.
Appendix 3: Study Governance Considerations
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 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/IEC

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
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.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
53

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

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.
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/her 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. 

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.
Publication Policy

The results of this study may be published or 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 multicenter 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.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
54
Dissemination of Clinical Study Data

This study will be registered and study information from this protocol will be 
posted on publicly available clinical trial registers before enrolment of study 
participants begins.

The results summary of this study will be posted to the GSK Clinical Study 
Register and other publicly available clinical trial registers within 8 months of the 
primary study completion date.

A manuscript reporting the study results will be submitted to a peer reviewed 
journal within 18 months of the last participant’s last visit. 
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 (eg, 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. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

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 after study completion 
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. 
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.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
55

Data reported on the CRF or entered in the 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.
Study and Site Closure
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 
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 treatment development
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
56
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.

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 treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, 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 treatment 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 
treatment 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 (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
57
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.
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 (eg, 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:
a.
Results in death
b.
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.
c.
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.
d.
Results in persistent 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 (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
58
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.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, 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, 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
59
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 sufficiently 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.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 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 treatment 
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.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
60
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.
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 for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

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 medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in SRM.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
61
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
No specific contraception is required of males as the likelihood of study drug distribution
in semen is low.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 2 from screening up to 3 days following treatment with study drug.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
62
Table 2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Pregnancy Testing

WOCBP should only be included after a negative highly sensitive urine or serum
pregnancy test 

Additional pregnancy testing should be performed as specified in the SoA during the 
treatment period.

Pregnancy testing will be performed when pregnancy is otherwise suspected 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
63

Pregnancy testing, with a high sensitivity test will be performed using the test kit in 
accordance with instructions provided in its package insert 
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Section 12.4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating will be withdrawn 
from the study.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
64
12.6.
Appendix 6: Genetics
There are no reported genetic mutations in ACE2 that have been associated with the 
development of PAH. However, genetic studies of a common insertion/deletion (I/D) 
polymorphism within the ACE gene appears to explain much of the variance observed in 
ACE enzyme expression levels, with the D allele conferring higher ACE and Ang II 
levels in tissue and serum (Marshall, 2002).  Numerous studies report genetic mutations
in ACE and association with various forms of pulmonary hypertension. For example, in 
male subjects, but not in the female subjects, the ACE DD genotype was negatively 
associated with electrocardiographic evidence of right ventricular hypertrophy (van 
Suylen, 1999), and pulmonary hypertension evoked by exercise challenge in patients with 
Chronic Obstructive Pulmonary Disease (COPD) (Kanazawa, 2000) plus others.
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples may be used for research related to [GSK2586881] or [PAH] and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to GSK2586881 and PAH and related diseases. Genetic research may 
consist of the analysis of the entire genome.

DNA samples may be analyzed if it is hypothesized that this may help further 
understanding of the clinical data.  Analysis could include, but not be limited to, 
evaluation of the impact of I/D polymorphisms in the Angiotensin Converting 
Enzyme (ACE) gene on RAS peptides, and responses to GSK2586881 
administration.

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2586881 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2586881 (or study treatments of 
this class) or PAH continues but no longer than 15 years or other period as per local 
requirements.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
65
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
There are no criteria for study discontinuation as this is a single dose study; however if 
any of the criteria for liver events (as described in the table below) are met, then the 
monitoring and follow-up assessments are required as described.
Phase II liver chemistry increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology 
Phase II liver chemistry additional monitoring criteria and required follow up 
assessments 
Liver Chemistry Additional Monitoring Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
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 chemistry event follow up 
assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for 
pharmacokinetic (PK) analysis (within 
24 hours) after last dose

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
66
liver event follow up assessments within  24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
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 (CRF) 
page 
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in 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 
pages.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
67
Phase II liver chemistry increased monitoring criteria 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Kanazawa H, Okamoto T, Hirata K, Yoshikawa J.  Deletion Polymorphisms in the 
Angiotensin Converting Enzyme Gene Are Associated with Pulmonary Hypertension 
Evoked by Exercise Challenge in Patients with Chronic Obstructive Pulmonary Disease. 
American Journal of Respiratory and Criticial Care Medicine. 2000; 162: 1235- 1238
Marshall RP, Webb S, Bellingan GJ et al. Angiotensin Converting Enzyme 
Insertion/Deletion Polymorphism Is Associated with Susceptibility and Outcome in 
Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care 
Medicine. 2002; 166: 646-650
van Suylen RJ,  Wouters EF, Pennings HJ et al. The DD Genotype of the Angiotensin 
Converting Enzyme Gene Is Negatively Associated with Right Ventricular Hypertrophy 
In Male Patients with Chronic Obstructive Pulmonary Disease. American Journal of 
Respiratory and Critical Care Medicine. 1999; 156: 1791-1795
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
68
12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 3
01-Dec-2017
Overall Rationale for the Amendment
This is a substantial amendment to enable characterisation of the response at a 
lower starting level of 0.1mg/kg GSK2586881.
Section # and 
Name
Description of Change
Brief Rationale
Throughout
Top (maximum) dose reduced from 
1.2mg/kg to 0.8mg/kg.
1.2mg/kg dose removed to 
enable investigation of a 
0.1mg/kg group without 
increasing the size of the study.
1. Synopsis
and
7.2 Dose 
Modification
Planned doses changed from 0.2, 0.4, 0.8 
and 1.2mg/kg to 0.1, 0.2, 0.4 and 
0.8mg/kg.
To enable characterisation of 
the dose response at 0.1mg/kg.
1. Synopsis
Study design schematic.
Changed to reflect new planned 
dose cohorts.
1. Synopsis
and
5.2 Number of 
Participants 
Additional participants can be recruited 
into a cohort prior to completion of all dose 
escalation.
Changed to allow the total 
number of participants recruited 
per cohort to be determined 
through an ongoing review of 
the safety, tolerability, PK and 
PD data prior to dose escalation.
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
69
Amendment 2
07-Nov-2017
Overall Rationale for the Amendment:
This is a non-substantial amendment to clarify the target population to be enrolled, the 
changes to the inclusion and exclusion criteria are listed in the table below.  In addition, 
an upper limit for the 6MW was added, the evaluable population was changed, and the 
proposed linear regression analysis was expanded. 
Section # and 
Name
Description of Change
Brief Rationale
Throughout
Transpulmonary RAS biomarkers was 
changed to pulmonary wedge RAS.
Transpulmonary is the position 
the sample is taken however a 
more appropriate way of 
describing this sample is 
pulmonary wedge RAS.
2. Schedule of 
Activities
Notes were added for genetic consent and 
genetic sample
Notes were added to ensure the 
timing and consent process are 
clear for the genetic sample.
6.1 Inclusion 
Criteria
A maximum distance of 450 meters was 
added for the Six minute walk (6MW) 
distance.
To confine the participant 
population to WHO functional 
class I, II, and III subjects.
6.2 Exclusion 
Criteria
Added renin inhibitors as restricted 
concomitant medication.
Renin inhibitors may potentially 
reduce Ang I and subsequently 
Ang II levels which is the target 
of ACE2 so by excluding them 
patients have a better chance of 
having elevated Ang II.
10.2 Population 
for Analysis 
Evaluable population was changed from 
participants that completed day 7 and 14 
follow ups to include participants that 
complete day 1.
To ensure participants lost to 
follow up will still be included in 
the evaluable population.
10.3.1 and 10.3.3 
Statistical 
Analysis 
Proposed linear regression analysis 
expanded to include other primary 
endpoints CO and mPAP if data permit 
(Section 10.3.1 and Section 10.3.3).
Expanded to assess additional 
hemodynamic measurements 
(primary endpoints) in relation to 
dose of GSK2586881
 
2019N405280_00


2016N290015_04
CONFIDENTIAL
206246
70
Amendment 1
03-May-2017
Overall Rationale for the Amendment: The protocol was amended to include the risk 
of exposure to ionizing radiation that was previously omitted and update information on 
participant rescreening numbers. 
Section # and 
Name
Description of Change
Brief Rationale
3.3.1 Risk 
Assessment 
Risk of exposure to ionizing 
radiation was added
Some participants will be exposed to 
ionizing radiation as part of the right heart 
catheterization, therefore the risk was 
added. 
9.1.1 
Hemodynamics
The procedure of confirming the 
right heart catheter placement by 
chest X-ray or fluoroscopy was 
added.
Procedure was added to ensure clear 
understanding. 
6.4 Screen 
Failures
Rescreened participants should be 
assigned a new participant 
number.
Due to a change in eCRF system 
rescreened participants will be assigned a 
new number. 
12.4 Appendix 
4
Added SAE Reporting to GSK via 
Paper CRF
Missing from original protocol 
 
2019N405280_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
206246
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Open-label, Dose-escalation 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of Single Doses of GSK2586881 in 
Participants with Pulmonary Arterial Hypertension
Compound Number 
:
GSK2586881
Effective Date 
:
15-FEB-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 206246.

This RAP is intended to describe the safety, pharmacodynamic and pharmacokinetic 
analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Interim Analyses and Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval 
Method
Principal Statistician (Respiratory, Clinical Statistics)
07-FEB-2018
Pharma 
TMF
Manager (Respiratory, Clinical Pharmacology)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N405280_00
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
206246
2
RAP Team Approvals:
Approver
Date
Approval 
Method
07-FEB-2018
Pharma TMF
Director, Discovery Medicine (Respiratory TAU)
09-FEB-2018
Pharma TMF
GSK Fellow, Translational Pharmacology 
Manager (Respiratory TAU)
14-FEB-2018
Pharma TMF
SERM Director (GCSP)
09-FEB-2018
Pharma TMF
Translational Pharmacology Manager 
(Respiratory TAU)
07-FEB-2018
Pharma TMF
Principal Clinical Research Scientist (CPSSO)
07-FEB-2018
Pharma TMF
Principal Data Manager (CPSSO)
14-FEB-2018
Pharma TMF
Programming Manager (Clinical Programming)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
08-FEB-2018
Pharma TMF
Director (Respiratory, Clinical Statistics)
15-FEB-2018
Email
Director (Clinical Programming)
 
2019N405280_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
206246
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................12
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
6.2.
Concomitant Medications for PAH ..............................................................14
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................15
7.1.
Primary Analyses........................................................................................15
7.1.1.
Endpoint / Variables.....................................................................15
7.1.2.
Summary Measure ......................................................................15
7.1.3.
Population of Interest...................................................................15
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................15
7.1.5.
Statistical Analyses / Methods .....................................................16
7.1.5.1.
Statistical Methodology Specification..........................16
7.2.
Secondary Analyses ...................................................................................18
7.2.1.
Endpoint / Variables.....................................................................18
7.2.2.
Summary Measure ......................................................................18
7.2.3.
Population of Interest...................................................................18
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................18
7.2.5.
Statistical Analyses / Methods .....................................................19
8.
SAFETY ANALYSES .............................................................................................20
8.1.
Adverse Events Analyses ...........................................................................20
8.2.
Clinical Laboratory Analyses.......................................................................20
8.3.
Other Safety Analyses ................................................................................20
9.
PHARMACOKINETIC ANALYSES.........................................................................21
9.1.
Pharmacokinetic Analyses..........................................................................21
 
2019N405280_00


CONFIDENTIAL
206246
4
9.1.1.
Endpoint / Variables.....................................................................21
9.1.1.1.
Drug Concentration Measures....................................21
9.1.1.2.
Derived Pharmacokinetic Parameters.........................21
9.1.2.
Population of Interest...................................................................22
9.1.3.
Statistical Analyses / Methods .....................................................22
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................23
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................24
12. REFERENCES.......................................................................................................25
13. APPENDICES........................................................................................................26
13.1.
Appendix 1: Protocol Deviation Management and Definitions for 
Evaluable Population ..................................................................................26
13.1.1.
Exclusions from Evaluable Population .........................................26
13.2.
Appendix 2: Schedule of Activities ..............................................................27
13.2.1.
Protocol Defined Schedule of Events...........................................27
13.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................32
13.3.1.
Study Phases ..............................................................................32
13.3.1.1.
Study Phases for Concomitant Medication .................32
13.4.
Appendix 4: Data Display Standards & Handling Conventions....................33
13.4.1.
Reporting Process .......................................................................33
13.4.2.
Reporting Standards....................................................................33
13.4.3.
Reporting Standards for Pharmacokinetic....................................34
13.5.
Appendix 5: Derived and Transformed Data ...............................................35
13.5.1.
General........................................................................................35
13.5.2.
Study Population..........................................................................35
13.5.3.
Pharmacodynamic and Biomarker ...............................................36
13.6.
Appendix 6: Reporting Standards for Missing Data.....................................38
13.6.1.
Premature Withdrawals................................................................38
13.6.2.
Handling of Missing Data.............................................................38
13.6.2.1.
Handling of Missing and Partial Dates ........................39
13.7.
Appendix 7: Values of Potential Clinical Importance ...................................40
13.7.1.
Laboratory Values........................................................................40
13.7.2.
ECG.............................................................................................41
13.7.3.
Vital Signs....................................................................................41
13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses ......................42
13.8.1.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................42
13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................45
13.9.1.
Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................45
13.10. Appendix 10: Abbreviations & Trade Marks ................................................64
13.10.1. Abbreviations...............................................................................64
13.10.2. Trademarks .................................................................................65
13.11. Appendix 11: List of Data Displays..............................................................66
13.11.1. Data Display Numbering..............................................................66
13.11.2. Mock Example Shell Referencing ................................................66
13.11.3. Deliverables.................................................................................66
13.11.4. Study Population Tables..............................................................67
 
2019N405280_00


CONFIDENTIAL
206246
5
13.11.5. Safety Tables...............................................................................69
13.11.6. Safety Figures .............................................................................71
13.11.7. Pharmacokinetic Tables...............................................................73
13.11.8. Pharmacokinetic Figures .............................................................74
13.11.9. Pharmacodynamic and Biomarker Tables....................................75
13.11.10.Pharmacodynamic and Biomarker Figures ..................................79
13.11.11.Pharmacokinetic / Pharmacodynamic and Biomarker 
Figures ........................................................................................86
13.11.12.ICH Listings .................................................................................89
13.11.13.Non-ICH Listings..........................................................................91
13.12. Appendix 13: Example Mock Shells for Data Displays ................................93
 
2019N405280_00


CONFIDENTIAL
206246
6
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:
Revision Chronology:
2016N290015_00
04/APR/2017
Original
2016N290015_01
03/MAY/2017
Amendment 1
2016N290015_02
07/NOV/2017
Amendment 2
2016N290015_03
01/DEC/2017
Amendment 3
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
To support internal decision making, some additional analyses have been included to 
output posterior probabilities for the primary hemodynamic measurements and also for 
Cardiac Index (CI) in relation to change from baseline (ratio to baseline).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate changes in the pulmonary 
hemodynamics after single IV doses of 
GSK2586881 administered to 
participants with PAH receiving 
background PAH therapy.

Change from baseline in pulmonary vascular 
resistance (PVR), cardiac output (CO) and 
mean pulmonary artery pressure (mPAP), as 
data permit
Secondary Objectives
Secondary Endpoints

To evaluate the safety and tolerability 
of single IV doses of GSK2586881 
administered to participants with PAH 
receiving background PAH therapy.

Adverse events (AE), clinical laboratory
values, vital signs, electrocardiogram
(ECG), pulse oximetry and immunogenicity.

To evaluate the effect of single IV 
doses of GSK2586881 on RAS peptide 
concentrations in participants with PAH 
receiving background PAH therapy.

Change from baseline of pulmonary wedge 
and systemic RAS peptides
(e.g. Ang II, Ang(1-7), Ang(1-5) and
AngII/Ang(1-7) ratio) (a)

To evaluate the effect on biomarkers of 
disease activity after single IV doses of 
GSK2586881 administered to 
participants with PAH receiving 
background PAH therapy.

Change from baseline in NT pro-BNP, NO and 
cardiac troponin I.

To evaluate the pharmacokinetics (PK) 
of GSK2586881 after single IV doses 
of GSK2586881 in participants with 
PAH receiving background PAH 

Plasma concentrations of GSK2586881 and 
derived PK parameters.
 
2019N405280_00


CONFIDENTIAL
206246
7
Objectives
Endpoints
therapy.
Exploratory Objectives
Exploratory Endpoints

To evaluate PK/PD relationships after
single IV doses of GSK2586881

RAS peptides (systemic and pulmonary 
wedge) and/or pulmonary vascular
hemodynamic measurements compared with 
PK exposure. (b)

To evaluate pharmacogenetics (PGx).

Evaluate I/D polymorphisms in the Angiotensin 
Converting Enzyme (ACE) gene and analyze 
the impact on Ang II (and possibly other RAS 
peptides), and responses to GSK2586881 
administration.
(a) Note for reporting the terms ‘venous (systemic) RAS peptides’ and ‘pulmonary wedge RAS peptides’ will be 
presented to clearly distinguish between the systemic venous sampling and the arterial venous pulmonary 
wedge sampling.
(b) Note this endpoint has been updated slightly from the current protocol amendment which states “Pulmonary 
wedge RAS peptides, and/or pulmonary vascular hemodynamic measurements compared with PK exposure” 
to clarify that both venous (systemic) and pulmonary wedge RAS data will be evaluated.
 
2019N405280_00


CONFIDENTIAL
206246
8
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Open-label, phase IIa, dose-escalation study in participants with PAH (as 
defined in the eligibility criteria) whose symptoms have been clinically stable for 
8 weeks prior to enrolment and who have had no change in PAH-specific 
therapy in the 12 weeks prior to enrolment.
Dosing

Single dose
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Each participant will be assigned to a single dose at one dose level as shown 
above
Interim 
Analysis

Review of Safety, PK and hemodynamics after 4 subjects have completed 
each dose level
2.4.
Statistical Hypotheses / Statistical Analyses
There are no statistical hypotheses for this study.  Data will be presented descriptively
with supportive posterior probabilities for selected hemodynamic endpoints in relation to 
changes from baseline (ratio to baseline).
 
2019N405280_00


CONFIDENTIAL
206246
9
3.
PLANNED ANALYSES
3.1.
Interim Analyses
The planned dose levels for the study are 0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg and 0.8
mg/kg.  Each cohort will recruit a minimum of 4 subjects to a dose level.  After the final 
participant has completed dosing within a given cohort and data are available, a dose 
escalation meeting will take place.  If additional participants are added to a particular 
dose level, a further meeting may be held to review the additional data.
The study review team may include the following (or delegates as appropriate): Clinical 
Statistics, CPMS, GCSP, CIL, OSL, Medical Monitor and DQL.  Other functions may be 
invited as required.  The data will be used to support the decision to move to the next 
dose level as planned.  Decisions made at each meeting in relation to a given dose, will 
be documented in the CPSR.  For dose escalation decision making, the data to be 
reviewed will be preliminary safety, PK and hemodynamics.  RAS peptide data, if 
available, will also be reviewed in stream.
Prior to each dose escalation meeting, unblinded safety data for this open-label study will 
be made available to the study team via listings from Inform and Q2 Results Viewer.   In 
addition, CPMS will obtain the interim unblinded PK concentration data from SMS2000 
via HARP according to current working practices.  If any process changes occur which 
affect the way in which SMS2000 data is obtained during the study, then the applicable 
process at the time will be followed and any changes in processes between dose 
escalations will be documented.    Descriptive tabular summaries (geometric mean, 
CV(%), median and range) for PK parameters and graphical presentation of PK 
concentration data will be produced, as appropriate, based on nominal times.
Preliminary hemodynamic data for the primary endpoints PVR, CO, mPAP and also 
Cardiac Index (CI) will be summarised descriptively by the Statistics and Programming
team (S&P).  Summary statistics and a data listing will be produced by endpoint, for each 
dose escalation review.  In addition, a graphic will be produced for each endpoint, 
displaying all subjects within the given dose group, by timepoint (i.e. overlaid time 
profiles for each subject).
To support internal team decision making (particularly around the lower doses of 0.1 
mg/kg and 0.2 mg/kg), a Bayesian analysis of change from baseline (ratio to baseline) in 
PVR, CO, mPAP and CI will be performed and posterior probabilities produced (see 
Section 7.1.5).  Only analyses carried out at the final reporting effort, once all dose 
groups have completed, will be included in the CPSR.  In addition, for the hemodynamic 
parameters and available RAS data, individual participant profiles may be presented 
alongside profiles from a previous investigator led study (NCT01884051) for visual 
comparison.
A summary of the dose escalation meetings is provided in the table below.  The steps 
below assume no changes to the planned doses, however, there is flexibility to 
adapt/change a dose if required during the study and the format of the dose escalations 
below would be modified to accommodate any dose changes.  In addition, flexibility is 
 
2019N405280_00


CONFIDENTIAL
206246
10
allowed within the study to recruit additional participants to a previous cohort (post dose 
escalation review) if a need for further data is required.  Any additional participants 
would be summarised as part of the final (all dose groups) reporting.
Dose Escalation [DE] Level
Data to be Reviewed/Output after a minimum of 
4 participants have completed

Review of Dose Level 1: 0.1 mg/kg 
(planned)

DE[1]

Safety: Via Q2 Results Viewer and Inform

PK: CPMS to use SMS2000 data based on 
nominal times and generate summaries, and 
graphs.

PD (PVR, CO, mPAP & CI): S&P will generate 
a summary table, listing and individual subject 
graphic (all subjects on one graph) for each 
endpoint based on SI data provided by Data 
Management via HARP.  Outputs may be 
produced using PC SAS or HARP.

Posterior probabilities (PVR, CO, mPAP & CI).

Review of RAS data (if available or post dose 
escalation meeting).

Review of Dose Level 2: 0.2 mg/kg 
(planned)

DE[2]

Safety: Via Q2 Results Viewer and Inform

PK: CPMS to use SMS2000 data based on
nominal times and generate summaries, and 
graphs.

PD (PVR, CO, mPAP & CI): S&P will generate 
a summary table, listing and individual subject 
graphic (all subjects on one graph) for each 
endpoint based on SI data provided by Data 
Management via HARP. Outputs may be 
produced using PC SAS or HARP.

Posterior probabilities (PVR, CO, mPAP & CI).

Review of RAS data (if available or post dose 
escalation meeting)

Review of Dose Level 3: 0.4 mg/kg 
(planned)

DE[3]

Safety: Via Q2 Results Viewer and Inform

PK: CPMS to use SMS2000 data based on 
nominal times and generate summaries, and 
graphs.

PD (PVR, CO, mPAP & CI): S&P will generate 
a summary table, listing and individual subject 
graphic (all subjects on one graph) for each 
endpoint based on SI data provided by Data 
Management via HARP.  Outputs may be 
produced using PC SAS or HARP.

Posterior probabilities (PVR, CO, mPAP & CI).

Review of RAS data (if available or post dose 
escalation meeting)

Final Reporting (SAC)

Data for all dose levels including the planned 
4th dose of 0.8 mg/kg will be summarised in the 
final reporting.
 
2019N405280_00


CONFIDENTIAL
206246
11
3.2.
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 (the study is open-
label but randomisation numbers are still generated for each cohort). 
4.
Randomization codes have been distributed according to RandAll NG procedures
(the study is open-label but a Randall dataset is still generated)
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses 
Evaluated
Enrolled
All participants who sign the ICF
Screening 
summaries
Safety
All participants who take at least 1 dose of study treatment.  Participants 
will be analysed according to the treatment they actually received.
Study Population
& Safety
Evaluable
Evaluable:  All participants who are in the Safety population who 
complete all Day 1 assessments (including up to 24 hours post dose)
and were not deemed to have had major protocol deviations (as defined 
within the PDMP)
PD
Pharmac-
okinetic
Subjects in the ‘Safety’ population for whom a pharmacokinetic sample 
was obtained and analysed.
PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
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.
o Data will be reviewed prior to freezing the database to ensure all important deviations 
and deviations which may lead to exclusion from the analysis are captured and 
categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol deviations.
o A separate 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.
 
2019N405280_00


CONFIDENTIAL
206246
12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting
Code
Description
Description
Order in TLF
A
Dose 1
GSK2586881 i.v. 0.1 mg/kg
1
B
Dose 2
GSK2586881 i.v. 0.2 mg/kg
2
C
Dose 3
GSK2586881 i.v. 0.4 mg/kg
3
D
Dose 4
GSK2586881 i.v. 0.8 mg/kg
4
NOTES: Order represents treatments being presented in TFL, as appropriate.
As this is a small study, for graphical representation, each participant may be assigned a 
unique combination of plotting symbol / line style / colour based on the attribute map 
facility using SAS SG procedures.  The GSK statistician will provide further details to 
the study team.  The unique characterisation will apply to all graphics of by subject data.  
In the case that an alternative statistical package is used, every effort will be made to 
apply a unique set of graphical characterisations for subjects.
In addition, for graphics summarising data by dose group, colours/symbols for each dose 
group will be made consistent throughout.  For example: 
GSK2586881 i.v. 0.1 mg/kg - blue diamond
GSK2586881 i.v. 0.2 mg/kg - red square
GSK2586881 i.v. 0.4 mg/kg - green circle
GSK2586881 i.v. 0.8 mg/kg - black star.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) 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 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered As 
Baseline
Baseline Used in Data 
Display
Screening
Day 1 (Pre-Dose)
Safety
Labs
X
X
Day 1
ECGs
X [1]
X [1]
Day 1 [1]
Vital Signs
X [1]
X
Day 1
Pulse Oximetry
X
X
Day 1
Immunogenicity
X
Day 1
 
2019N405280_00


CONFIDENTIAL
206246
13
Parameter
Study Assessments Considered As 
Baseline
Baseline Used in Data 
Display
Screening
Day 1 (Pre-Dose)
Biomarkers/Pharmacodynamic
RAS peptides, disease activity 
biomarkers
X
Day 1
Hemodynamics (e.g., PVR, CO, mPAP
& CI)
X
Day 1
[1] Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the 
value for that time point.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
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
13.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
13.4
Appendix 4: Data Display Standards & Handling Conventions
13.5
Appendix 5: Derived and Transformed Data
13.6
Appendix 6: Reporting Standards for Missing Data
13.7
Appendix 7: Values of Potential Clinical Importance
 
2019N405280_00


CONFIDENTIAL
206246
14
6.
STUDY POPULATION ANALYSES
6.1.
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, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Data collected for functional class, 6-minute walking distance and PAH underlying cause 
will also be summarised.  Details of the planned displays are presented in Appendix 11: 
List of Data Displays.
6.2.
Concomitant Medications for PAH
PAH medications (reason for medication) will be reviewed by the medical monitor.  Two 
reviews will be planned; one prior to DBF to enable pre-programming and a final review 
on receipt of final concomitant medication data at DBF.  An intermediate review will 
take place if required.  A spreadsheet of the databased concomitant medications will be 
generated by S&P for review by the medical monitor, who will add a flag to records that 
are relevant to PAH.  S&P will then use the spreadsheet when creating the derived A&R 
CMANAL dataset to include the flagged records for use within the corresponding output.
In addition, to support the programming of PCI ranges for International Normalized Ratio 
(INR), Prothrombin time (PT) and PTT (see Section 13.7.1) medications of Heparin or 
Warfarin will need to be confirmed per participant by review of related concomitant 
medication terms. This will require non-standard coding for the programming of PCI 
ranges.
 
2019N405280_00


CONFIDENTIAL
206246
15
7.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
7.1.
Primary Analyses
7.1.1.
Endpoint / Variables
The primary endpoints are hemodynamic measurements of:

Pulmonary Vascular Resistance (PVR)

Cardiac Output (CO)

Mean Pulmonary Artery Pressure (mPAP)
Additional hemodynamic endpoints are:

Right Atrial Pressure

Pulmonary Artery Systolic Pressure

Pulmonary Artery Diastolic Pressure

Pulmonary Capillary Wedge Pressure

Cardiac Index (CI)

Pulmonary Artery Oxygen Saturation
7.1.2.
Summary Measure
Absolute and change from baseline will be the summary measures of interest for 
hemodynamic endpoints.  Hemodynamic measurements will also be log transformed to 
aid further analysis and therefore the change from baseline geometric means at each post-
dose timepoint, will represent a percentage increase/decrease from baseline (presented as 
a ratio to baseline).  
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the Evaluable population, unless 
otherwise specified.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Hemodynamic data will be collected according to the timepoints referenced in Appendix 
2: Schedule of Activities.  Missing data will not be replaced.
The Evaluable population defined in Section 4, utilises patients who complete all Day 1 
assessments.  If a consistent pattern of withdrawals prior to the completion of Day 1 is 
noted (for example, sensitivity to the catheter causing it to be removed early) which 
causes a lower than expected Evaluable population, then additional reviews of available 
data for those not included in the Evaluable population may take place.
 
2019N405280_00


CONFIDENTIAL
206246
16
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
A Bayesian analysis will be conducted by dose group and timepoint displaying posterior 
probabilities as detailed in Section 7.1.5.1.  
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

PVR, CO, mPAP and CI
Model Specification

The description below describes the current thinking of how to analyse this endpoint.  The 
proposed model will be assessed, and if not appropriate alternative models could be used.  
Reasons for and a full description of alternative modeling/analysis methods used would be fully 
documented in the CPSR.

Separate Bayesian repeated measures mixed effect models (one model per endpoint) will be 
used to assess changes from baseline for dose group and post-treatment timepoint 
combinations.  Individual patient data will be log-transformed prior to analysis and change from 
baseline (CFB) calculated on transformed data. The Baseline values (BS) used in the model 
should also have been log-transformed prior to their use. 
Note: The modeling described below should be appropriately modified for the 1st interim 
analysis (e.g. to remove terms involving dose).
Response: CFB = BS*Time + Time + Dose + Dose*Time
Fixed effects: (class) Time [3 levels, 1H, 2H and 4H], Dose level [either 0.1, 0.2, 0.4 or 0.8 
mg/kg as appropriate to the timing of the <interim> analysis].
Fixed effects: (continuous): Baseline value (on the Ln scale)
Repeated measures on Time, Subject=Subject, Unstructured Variance Co-Variance (VCV)
matrix (3x3)
Appropriate combinations of the fitted model parameters will be used to obtain posterior 
distributions (one per planned comparison). The planned comparisons are the equivalent of the 
LSMeans for each timepoint within each dose level (on a back transformed scale their 
interpretation is the fold change c.f. baseline).

Non-informative priors should be assumed for all model parameters. Therefore, unless there is 
a large proportion of missing data, the posterior probabilities may be obtained by fitting the 
proposed model using SAS PROC MIXED and extracting the appropriate pieces of 
information. 

However, if PROC MCMC is used then the default prior for each fixed effect model parameter
should be Normal~(Mean=0, Var=1E6). The default prior for the VCV matrix would be an 
Inverse-Wishart with parameters k and S (where S = (k – p - 1) * R and p = dimension of the 
 
2019N405280_00


CONFIDENTIAL
206246
17
VCV matrix). Under this framework R can be thought of as a best guess for the VCV of the 
endpoint being modelled. Care should be taken in the choice of k and R for each endpoint. The 
default should set k = 5 (p + 2) and R should be set to the following for each endpoint, in order 
to obtain the value of S to put into the inverse-Wishart prior:
CO (L/min)
CI (L/Min/m**2)
PVR (Wood units)
mPAP (mmHg)








005
.0
014
.0
017
.0
014
.0
064
.0
096
.0
017
.0
096
.0
160
.0








005
.0
014
.0
017
.0
014
.0
064
.0
096
.0
017
.0
096
.0
160
.0






030
.0
111
.0
070
.0
111
.0
544
.0
204
.0
070
.0
204
.0
323
.0






018
.0
017
.0
007
.0
017
.0
039
.0
031
.0
007
.0
031
.0
031
.0
These values of R were obtained from a historical study (GSK ID 204696) and unit conversion 
may be required to match this study.
(Note: depending on the software used and parameterization the above may need to be 
adjusted to use a Wishart instead of the inverse-Wishart). 
Given the small sample sizes in this study the above priors may be more informative/influential
than intended. An optional sanity check may be made by comparing the observed sample VCV 
matrix to the prior. If there are large discrepancies alternative priors may be 
attempted/evaluated as part of sensitivity analyses (and the output from the most appropriate 
model reported in the CPSR along with a brief justification/discussion on any switched priors). 
For example R may be replaced by the observed sample VCV matrix (on the log transformed 
scale) once the study data are available.

Posterior medians and 95% credible intervals will be presented for each posterior distribution.  
<As stated previously estimates will be back-transformed so that the difference from baseline 
represents a ratio.>

The posterior distributions will be used to produce several probability statements, presented in 
tabular format.  This will include but are not limited to:

PVR, the probability of any % reduction from baseline (<0%), <-20% and <-30% 
(equivalent to <1, <0.8 and <0.7 in terms of a ratio from baseline)

CI, the probability of any % increase from baseline (>0%), >20% and >30% (equivalent to 
>1, >1.2 and >1.3 in terms of a ratio from baseline)

CO probability of >0% increase (or >1 in terms of a ratio from baseline)

mPAP probability of <0% (or <1 in terms of a ratio from baseline)
Model Checking & Diagnostics

Assumptions regarding normality will apply if the analysis is conducted using proc mixed.  
Should major violations occur (caveat being that the sample sizes will be small) then a non-
parametric Wilcoxon signed rank test may be considered.  
Model Results Presentation

A summary table will be produced for each endpoint by dose group and timepoint, displaying 
medians and 95% credible intervals for the change from baseline (ratio to baseline) endpoints 
along with the posterior probabilities as described above.
 
2019N405280_00


CONFIDENTIAL
206246
18
7.2.
Secondary Analyses
7.2.1.
Endpoint / Variables
The secondary biomarker endpoints are:
Venous (systemic) RAS Peptides:

Ang II

Ang(1-7)

Ang(1-5)

Ang II / Ang(1-7)
Pulmonary Wedge RAS Peptides:

Ang II

Ang(1-7)

Ang(1-5)

Ang II / Ang(1-7)
Disease Activity Biomarkers:

NT pro-BNP

Serum NO

Cardiac troponin I
7.2.2.
Summary Measure
Absolute and change from baseline will be the summary measures of interest for RAS 
Peptides and Disease Activity Biomarkers. As a log-transformed summary for 
biomarkers will be included, the change from baseline geometric means will represent a 
percentage increase/decrease from baseline (presented as a ratio to baseline).
7.2.3.
Population of Interest
The secondary analyses will be based on the Evaluable population, unless otherwise 
specified.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
Venous (systemic) RAS peptide data will be collected at timepoints in line with the PK.  
Pulmonary wedge RAS peptides will be collected in line with hemodynamic data pre-
dose to 4 hours post dose.   Disease activity biomarkers will be collected at timepoints up 
to 24 hours.  For details on data collection timepoints, refer to Appendix 2: Schedule of 
Activities.   Missing data will not be replaced but data recorded as NQ will be imputed 
based on details given in Appendix 6: Reporting Standards for Missing Data.
 
2019N405280_00


CONFIDENTIAL
206246
19
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
2019N405280_00


CONFIDENTIAL
206246
20
8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays.
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
8.3.
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. The details of the 
planned displays are presented in Appendix 11: List of Data Displays.
For systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR), in 
addition to standard tables and listings, the change from baseline over time by dose group
will displayed graphically along with individual subject profiles.
 
2019N405280_00


CONFIDENTIAL
206246
21
9.
PHARMACOKINETIC ANALYSES
9.1.
Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 13.4.3
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 Pro. For the final reporting effort (see Section 3.1 for interim details of 
pharmacokinetic analyses), 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
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
Cmax
Maximum observed concentration, determined directly from the concentration-time 
data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
Clast
Last observed quantifiable concentration
tlast
Time of the last observed quantifiable concentration
CL
Plasma clearance
V
Volume of distribution
Lambda_z
The first order rate constant associated with the terminal (log-linear) portion of the 
concentration-time curve.
Lambda_z_lower
First time point used in computing Lambda_z.
Lambda_z_upper
Last time point used in computing Lambda_z.
#pts
Number of points used in computing Lambda_z.
r-squared
R-squared of Lambda_z computation.

Additional parameters may be included as required

Lambda_z is the terminal phase rate constant
 
2019N405280_00


CONFIDENTIAL
206246
22
9.1.2.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
9.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
2019N405280_00


CONFIDENTIAL
206246
23
10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
A population PK analysis, to characterize the population pharmacokinetics of 
GSK2586881 administered IV in participants with PAH, may be conducted, if 
appropriate. To support this analysis, a NONMEM-specific data file will be generated, 
the specifications of which are provided in Appendix 8: Population Pharmacokinetic 
(PopPK) Analyses. Specific details of the analysis, which may be part of a population PK 
meta-analysis with historical data, will be appropriately documented in a separate RAP 
and report which will be written by, or under the direct auspices of, Clinical 
Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline, as required. The 
timeline for these analyses will be independent of the analysis described in this RAP.
 
2019N405280_00


CONFIDENTIAL
206246
24
11.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
The primary goal of these exploratory analyses are to investigate the pharmacokinetic / 
pharmacodynamic relationship(s) of GSK2586881 administered IV in participants with 
PAH.  Graphics of RAS Peptides vs PK concentrations and hemodynamic endpoints vs 
PK concentrations using the PK population, unless otherwise specified, will be initially 
used to assess any potential relationships. If data permit, the potential association 
between systemic exposure of GSK2586881 and RAS peptides (Ang II, Ang(1-7), 
Ang(1-5) and AngII/Ang(1-7) from both venous (systemic) and pulmonary wedge
sampling) and clinical endpoints (e.g., PVR, CO, mPAP and CI) may be studied.  To 
support any analyses that is required based on the initial graphical assessment,
NONMEM-specific data files will be generated, the specifications of which are provided 
in Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses. Specific details of any 
PK/PD analysis, which may be part of a population PK meta-analysis with historical data, 
will be appropriately documented in a separate RAP and report which will be written by, 
or under the direct auspices of, Clinical Pharmacology Modelling and Simulation 
(CPMS), GlaxoSmithKline, as required. The timeline for these analyses will be 
independent of the analysis described in this RAP.
 
2019N405280_00


CONFIDENTIAL
206246
25
12.
REFERENCES
Not Applicable
 
2019N405280_00


CONFIDENTIAL
206246
26
13.
APPENDICES
13.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Evaluable Population
13.1.1.
Exclusions from Evaluable Population
Subjects with major/important protocol deviations will be excluded from Evaluable 
Population.  The Protocol Deviation Management Plan (PDMP) will be used to determine 
major/important protocol deviations that will lead to exclusion from the Evaluable 
Population.
 
2019N405280_00


CONFIDENTIAL
206246
27
13.2.
Appendix 2: Schedule of Activities
13.2.1.
Protocol Defined Schedule of Events
Procedure
Screening 
(up to 28 
days 
before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Informed consent
X
Genetics consent
X
Inclusion and exclusion 
criteria
X
Recheck clinical 
status before 
randomization 
and/or 1st dose of 
study medication
Demography
X
Full physical examination 
including height and 
weight
X
Medical history (includes 
substance usage and 
family history of 
premature CV disease)
X
Substances: drugs, 
alcohol, tobacco 
and caffeine
Past and current medical 
conditions  
X
 
 
 
2019N405280_00


CONFIDENTIAL
206246
28
Procedure
Screening 
(up to 28 
days 
before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Serum OR urine 
pregnancy test (WOCBP 
only)
X
X
X
FSH and estradiol test 
(postmenopausal 
females only as needed)
X
Human 
Immunodeficiency Virus
(HIV), Hepatitis B and C 
screening
X
If test performed 
within 3 months 
prior to first dose of 
study treatment, 
testing at screening 
is not required
Functional classification
X
6 Minute Walk Distance
X3
Admission
X
Participants may be 
admitted the day 
before dosing to 
enable completion 
of required pre-dose 
time point 
assessments.
Brief physical
X
X
Study Treatment
X
 
 
 
2019N405280_00


CONFIDENTIAL
206246
29
Procedure
Screening 
(up to 28 
days 
before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Vital Signs
X
X
X
X
X
X
X
X
X
Vital signs will be 
measured after 5
minutes supine at 
all time points.
Triplicate blood 
pressure (BP) will 
be taken at 
screening only.
Pulse Oximetry (SpO2)
X
X
X
X
X
X
X
X
X
Pulse oximetry will 
be measured and 
recorded with each 
blood pressure 
assessment
Laboratory assessments 
(include liver chemistries, 
haematology panel and
coagulation panel)
X
X
X
X
Urinalysis
X
X
12-lead ECG
X
X
X
X
X
Triplicate will be 
performed at 
Screening and Pre-
dose 
 
 
 
2019N405280_00


CONFIDENTIAL
206246
30
Procedure
Screening 
(up to 28 
days 
before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Telemetry
-------------------------------------------------------------------------------------
Monitoring to start 
30min prior to 
treatment 
administration and 
continue throughout 
the study until 24h 
after dosing
Right heart catheter 
Insertion
-------------------------------------------------------------------------------
RHC inserted prior 
to dose and 
removed after the 
4h hemodynamic 
measurement
Blood sample for 
biomarkers of disease 
activity
X
X
X
X
Blood sample for Nitric 
Oxide 
X
X
X
X
Blood sample for PK
X
X
X
X
X
X
X
X
Blood sample for 
immunogenicity
X
X
X
 
 
 
2019N405280_00


CONFIDENTIAL
206246
31
Procedure
Screening 
(up to 28 
days 
before 
dosing)
Treatment Period
Follow-
up
Day 7-
14 
Follow-
upDay 
28 3 
days
Notes
Pre-
dose1
0h
0.08h
(5 
min)2
0.5h
1h
2h
4h
8h
24h
Blood sample for renin-
angiotensin system  
biomarkers
X
X
X
X
X
X
X
X
X
Blood sample for 
transpulmonary RAS 
biomarkers
X
X
X
X
Hemodynamic 
measurements
X
X
X
X
Genetic sample
X
Can be taken any 
time after consent
Discharge
X
AE review
==========================================================
X
SAE review
X
===========================================================
X
Concomitant medication 
review4
X
X
X
1.
Pre-dose measurements may be taken any time after admission up until dosing.
2.
Procedures will be completed immediately after dosing has completed.
3.
If the six minute walk(6MW) has been performed in the last 6 months, and participant has been stable on current medications then there is no need to repeat.  Historical data will 
be databased.
4.
Concomitant medications for the 30 days prior (8 weeks prior for PAH medications) will be reviewed/recorded at screening to evaluate eligibility and changes will be recorded 
throughout the study.
 
 
 
2019N405280_00


CONFIDENTIAL
206246
32
13.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
13.3.1.
Study Phases
This is a single dose study.  Assessments and events will be classified according to time 
of occurrence relative to the start date and time of the study treatment. 
Treatment State
Definition
Pre-Treatment
AE Start Date / Time < Study Treatment Start Date / Time
This will apply to all subjects enrolled into the study, including those who were not 
assigned to a dose (screen failures).  For screening failures, any SAEs will be 
captured in the relevant listing.  For dosed subjects included in the Safety population, 
these events will be captured in summary listings with treatment group=’Pre-
Treatment’.
On-Treatment 
Study Treatment Start Date / Time  ≤ AE Start Date / Time ≤ Follow-up (Day 7-14) 
Date
Post-Treatment
AE Start Date > Follow-Up (Day 7-14) Date
There shouldn’t be any instances of this.  Subjects return for a follow-up visit between 
Days 7 and 14 and AEs/SAEs prior to this will be recorded.  Subjects then return for a 
Day 28 follow-up but AEs/SAEs will not be recorded.
Onset Time Since 
1st Dose 
(Days/Hours/Mins)
If Study Treatment Start Date / Time ≤ AE Start Date / Time 
= AE Start Date / Time – Study Treatment Start Date / Time + 1 (min)
Missing otherwise.
A calculation to assess the time since the single dose up until the start time of the AE.  
Example:
If Dose was administered at 08:00am 01OCT2017 and AE started at 09:10am 
01OCT2017, then onset time since first dose would be 0d 1h 11m.
Duration 
(Days/Hours/Mins) 
AE Resolution Date /Time – AE Onset Date / Time + 1 (min)
Example:
AE started at 08:00am and resolved at 08:30am on the same day, then duration would 
be 0d 0h 31m
Drug-related
If relationship is marked ‘YES’ on Inform OR value is missing.
13.3.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 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.
 
2019N405280_00


CONFIDENTIAL
206246
33
13.4.
Appendix 4: Data Display Standards & Handling 
Conventions
13.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: \\UK1SALX00175.corpnet2.com\ARENV\
HARP Compound
: \ARPROD\GSK2586881\206246\Internal_01
: \ARPROD\GSK2586881\206246\Internal_02
: \ARPROD\GSK2586881\206246\Internal_03
: \ARPROD\GSK2586881\206246\Internal_04
: \ARPROD\GSK2586881\206246\Final_01
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will be generated for the final reporting effort.
13.4.2.
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 

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

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.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
 
2019N405280_00


CONFIDENTIAL
206246
34
Unscheduled Visits

Unscheduled visits will not be included in summary tables and figures.

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, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
13.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
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
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: For standard PK outputs concentration values will be imputed as per 
GUI_51487 for descriptive summary statistics/analysis and summarized graphical 
displays only. 
For PK/PD graphics only which are generated by S&P, ½ LLQ can be used for NQ 
PK data to coincide with methods used for Biomarker data (see Section 13.6.2).  
Variables relating to different imputation methods for PK data will be available 
within the derived A&R PKCNC dataset. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 13.8.1 Population Pharmacokinetic (PopPK) Dataset 
Specification.
NONMEM/PK/PD 
File
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology Modelling 
and Simulation function will be created according to the data specification detailed 
in Section 13.9.1 Pharmacokinetic/Pharmacodynamic Dataset Specification.
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to [Standards for Handling NQ Impacted PK Parameters].
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.  The following PK parameters will not 
included in summary tables: Lambda_z, lambda_z_lower, lambda_z_upper, 
#pts, R squared
 
2019N405280_00


CONFIDENTIAL
206246
35
13.5.
Appendix 5: Derived and Transformed Data
13.5.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken.

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 First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
13.5.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
 
2019N405280_00


CONFIDENTIAL
206246
36
13.5.3.
Pharmacodynamic and Biomarker
Pharmacodynamic
Pulmonary Hemodynamics
Pulmonary Vascular Resistance (PVR)                 [All endpoints will be provided in SI datasets]
Cardiac Output (CO)
Mean Pulmonary Artery Pressure (mPAP)
Cardiac Index (CI)
Right Atrial Pressure
Pulmonary Artery Systolic Pressure
Pulmonary Artery Diastolic Pressure
Pulmonary Capillary Wedge Pressure
Pulmonary Artery Oxygen Saturation
Variance stabilising transformations (e.g. taking natural logarithms of the observed responses) may 
be implemented on a per endpoint basis, if deemed necessary by the study statistician. If 
transformations are used the results will be reported on the back-transformed response scales.
When assessing change from baseline, the individual timepoint values will be log-transformed prior 
to calculating a change from baseline difference (in log transformed values).  Back transformation 
and summaries of the geometric mean and 95% CI of the back-transformed change from baseline 
calculations will represent percentage increase/decrease from baseline (presented as a ratio to 
baseline).
Biomarker
RAS Peptides
RAS Venous (systemic) Samples: 

Ang II, Ang(1-5), Ang(1-7) will be provided in SI datasets

Ang II / Ang(1-7) ratio will be derived in A&R datasets
RAS Pulmonary Wedge Samples:

Ang II, Ang(1-5), Ang(1-7) will be provided in SI datasets

Ang II / Ang(1-7) ratio will be derived in A&R datasets
Disease Activity Biomarkers
NT Pro-BNP, NO and Cardiac Troponin I will be provided in SI datasets
For biomarkers, variance stabilising transformations (e.g. taking natural logarithms of the observed 
responses) may be implemented on a per endpoint basis, if deemed necessary by the study 
statistician. If transformations are used the results will be reported on the back-transformed 
response scales.
When assessing change from baseline, the individual timepoint values will be log-transformed prior 
to calculating a change from baseline difference (in log transformed values).  Back transformation 
and summaries of the geometric mean and 95% CI of the back-transformed change from baseline 
calculations will represent percentage increase/decrease from baseline.
 
2019N405280_00


CONFIDENTIAL
206246
37
Pharmacodynamic
Source of Biomarker Data
Biomarker 
Category
Analyte
Sample
Method
Lab
Matrix
Total 
samples 
expected per 
subject
RAS 
Peptides1
Ang II
Venous
LC/MS
Q2
Plasma
9
Ang (1-5)
Venous
LC/MS
Q2
Plasma
9
Ang (1-7)
Venous
LC/MS
Q2
Plasma
9
RAS 
Peptides2
Ang II
Pulmonary 
Wedge
LC/MS
Q2
Plasma
4
Ang (1-5)
Pulmonary 
Wedge
LC/MS
Q2
Plasma
4
Ang (1-7)
Pulmonary 
Wedge
LC/MS
Q2
Plasma
4
Disease 
Biomarkers3
NT pro-BNP 
Venous
Elisa
Q2
Serum
4
Nitric Oxide
Venous
Chemical 
Method
Q2
Plasma
4
Cardiac 
troponin I
Venous
Elisa
Q2
Serum
4
NOTES :
1.  Sampling times: Pre-dose, End of Infusion, 0.5h, 1h, 2h, 4h, 8h, 24h, follow-up day 7-14
2.  Sampling times: Pre-dose, 1h, 2h and 4h
3.  Sampling times: Pre-dose, 2h, 4h and 24h
 
2019N405280_00


CONFIDENTIAL
206246
38
13.6.
Appendix 6: Reporting Standards for Missing Data
13.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as a participant 
who has completed all phases of the study including the follow up visit and the last 
scheduled procedure

Withdrawn subjects may be replaced in the study at the discretion of the sponsor.

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.
13.6.2.
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.
Biomarkers

Any values below the Lower Limit of Quantification (LLQ) will be assigned a 
value of ½ LLQ for display purposes in Figures and for computation of summary 
statistics. Any values above the Upper Limit of Quantification (ULQ) will be 
assigned to the ULQ for display purposes in Figures and for computation of 
summary statistics. If multiple LLQ and /or ULQ values are available per assay 
(for example if multiple runs with different standard curves are utilised) then the 
LLQ and/or ULQ value used for the above imputation shall be the minimum of 
the available LLQs and/or the maximum of the ULQs. 

If the number of LLQ (and/or ULQ) values is large for an individual biomarker 
then alternative analysis strategies may be required. “Large” is hard to define 
prospectively and may depend upon the dataset in question but a general rule 
of thumb is if >30% of values are LLQ and/or ULQ. If “large” numbers of LLQ 
and/or ULQ values are observed methodologies to summarise and analyse the 
responses similar to those detailed in “Standards for the Handling of NQ 
impacted PK Parameters” (Respiratory DB and CPMS - 14th December 2009) 
may be employed. Any such methodology will be documented in the statistical 
contributions to the clinical study report.
 
2019N405280_00


CONFIDENTIAL
206246
39
For the derivation of the pulmonary wedge and venous (systemic) AngII / Ang(1-7) ratios, the
following will apply:
Flags
Numerator (ANGII)
BLQ
Data
ALQ
Missing
Denominator (ANG1-7)
BLQ
(1/2 LLQ of ANGII) / 
(1/2 LLQ of Ang(1-7))
ANGII / 
(1/2 LLQ of Ang(1-
7))
(ULQ of ANGII) / 
(1/2 LLQ of Ang(1-7))
Missing
Data
(1/2 LLQ of ANGII) / 
Ang(1-7)
ANGII / Ang(1-7)
(ULQ of ANGII) / 
Ang(1-7)
Missing
ALQ
(1/2 LLQ of ANGII) / 
(ULQ of Ang(1-7))
ANGII / 
(ULQ of Ang(1-7))
(ULQ of ANGII) / 
(ULQ of Ang(1-7))
Missing
Missing
Missing
Missing
Missing
Missing
LLQ / ULQ = Lower / Upper Limit of Quantification, BLQ / ALQ = Below / Above Limit of Quantification
Note:  The status of the numerator and denominator should be stored within derived datasets so 
they can be used in subsequent Summary Tables to display the amount of imputation necessary.
In addition, to support the PK/PD file to be generated (see Section 13.9.1), which will 
include the AngII/Ang(1-7) ratio, a variable will be included based on non-imputed data 
i.e., for this variable, the ratio will only be calculated if both AngII and Ang(1-7) have 
non-missing numeric values, otherwise the ratio will be set to missing.
13.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

Missing or partial dates of AEs will not be allowed in this study.
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.
 
2019N405280_00


CONFIDENTIAL
206246
40
13.7.
Appendix 7: Values of Potential Clinical Importance
13.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
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
RBC Count
TI/L
0.93 x LLN
1.07 x ULN
MCV
FL
0.25 x LLN
2 x ULN
MCH
PG
0.85 x LLN
1.1 x ULN
%Reticulocytes
%
0.5 x LLN
5 x ULN
Monocytes
x109/ L
0.25 x LLN
2 x ULN
Eosinophils
x109/ L
0
2 x ULN
Basophils
x109/ L
0
5 x ULN
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
↑ 1.3 x ULN
Creatinine
mmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
BUN
mmol/L
0.7x
1.6x
Direct Bilirubin
umol/L
1.5x ULN
Total Protein
G/L
1.25x
International normalized ratio 
(INR)
On Warfarin
4 x 
Not on Warfarin
1.5 x
Prothrombin time (PT)
sec
On Warfarin
4 x ULN
Not on Warfarin
1.2 x ULN
 
2019N405280_00


CONFIDENTIAL
206246
41
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
PTT
Sec
On Heparin
4 x ULN
Not on Heparin
1.2 x ULN
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
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT
Direct Bilirubin
1.5 x ULN
13.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
≥ 500
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 60
13.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 90
> 150
Diastolic Blood Pressure
mmHg
< 50
> 100
Heart Rate
bpm
< 35
> 130
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
 
2019N405280_00


CONFIDENTIAL
206246
42
13.8.
Appendix 8: Population Pharmacokinetic (PopPK) Analyses
13.8.1.
Population Pharmacokinetic (PopPK) Dataset Specification
The PME compliant file structure is a space-delimited file with each row containing the 
following columns of information.
Variable 
short 
name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric or 
text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric or 
text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnot
es
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg)*WT
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
h
Time during which total dose infused. 
(Time at end of infusion – Time of start 
infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment 
Identifier 
Decimal
-
DGRP = 0.1 for 0.1 mg/kg treatment
DGRP = 0.2 for 0.2 mg/kg treatment
DGRP = 0.4 for 0.4 mg/kg treatment
DGRP = 0.8 for 0.8 mg/kg treatment
PART
Study Part
Integer 
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric or 
text) N= Day N, Actual Study Day
CTIM
Clock Time of Event
HH:MM:SS
-
Clock Time of Event  
DATE
Date of Record
(DD/MM/YY
YY)
-
Date of Record 
TRLD
Actual time relative 
to LAST dose
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
DV
Dependent Variable 
Decimal 
pg/mL
When LABL=5, observed GSK2586881 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0
 
2019N405280_00


CONFIDENTIAL
206246
43
Variable 
short 
name
Assessment 
description
Format
Unit
Valid Values / Format
MDV
Missing Data 
Variable
Integer
-
Either ‘0’ if DV value present or 1 if DV 
value is non-quantifiable (NQ) or LABL 
= 1, 2, 3 or 4 
MDV1
Missing data 
variable
Integer
-
Either ‘0’ if LABL=5 or ‘1’ if LABL= 1, 2, 
3 or 4
TYPE
F-Flag
Integer
-
If MDV1 = ‘1’ then TYPE =’0’,
If DV value present (but not NQ)
TYPE= ‘1’ 
If DV value NQTYPE = ‘2’
LLQ
Lower Limit of
quantification
Integer
pg/mL
Lower limit of quantification for specific 
analyte SMS dataset (PCLLQ)
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  OBSERVATION event: 
CMT =1, specifies compartment from 
which observation is obtained.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give age at 
last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as weight 
divided by height squared
EVID
Event 
Indentifcation data 
item
Integer
-
Flag indicating whether LABL contains 
dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
44
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
5
Observed concentration record for GSK2586881 at time specified by TRLD; 
excludes NA, IS and NR, includes non-quantifiable (NQ) data
pg/mL
 
2019N405280_00


CONFIDENTIAL
206246
45
13.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
13.9.1.
Pharmacokinetic / Pharmacodynamic Dataset Specification
Specification for ANG II Venous (Systemic) [Proposed dataset name PKPDAIIV]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric 
or text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric 
or text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
h
Time during which total dose 
infused. (Time at end of infusion –
Time of start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier Decimal
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric 
or text) N= Day N, Actual Study 
Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
to LAST dose
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BLII
AngII concentration 
record
Decimal
Baseline value (pre-dose value) 
from venous (systemic) RAS 
sampling
 
2019N405280_00


CONFIDENTIAL
206246
46
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
DV
AngII concentration 
record
Decimal
When LABL=6, observed AngII 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0, from 
venous (systemic) RAS sampling
MDV
Missing data 
variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value 
or LABL= 1, 2, 3, or 4
MDV1
Missing data 
variable
Integer
-
‘1’ if LABL= 1, 2, 3 or 4
“0” when LABL=6
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If DV value present (but not NQ) 
TYPE= ‘1’ 
If DV value NQ TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event: 
CMT=3 for DV (ANGII) observation 
event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give 
age at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as 
weight divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
47
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
6
Observed venous (systemic) sample ANGII record (concentration or ratio) 
at time specified by TRLD; excludes NA, IS and NR, includes non-
quantifiable (NQ) data
Specification for ANG II Pulmonary Wedge [proposed dataset name PKPDAIIP]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric or 
text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric or 
text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
h
Time during which total dose infused. 
(Time at end of infusion – Time of 
start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier 
Decimal
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric or 
text) N= Day N, Actual Study Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
 
2019N405280_00


CONFIDENTIAL
206246
48
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
to LAST dose
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BLII
AngII concentration 
record
Decimal
Baseline value (pre-dose value) from 
pulmonary wedge RAS sampling
DV
AngII concentration 
record
Decimal
When LABL=11, observed AngII 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0, from 
pulmonary wedge RAS sampling
MDV
Missing data variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value or 
LABL= 1, 2, 3, or 4
MDV1
Missing data variable
Integer
-
‘1’ if LABL= 1, 2, 3 or 4
“0” when LABL=11
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If DV value present (but not NQ) 
TYPE= ‘1’ 
If DV value NQ TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event: 
CMT=3 for DV (ANGII) observation 
event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give age 
at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as 
weight divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
49
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
11
Observed pulmonary wedge sample ANGII record (concentration or ratio) 
at time specified by TRLD; excludes NA, IS and NR, includes non-
quantifiable (NQ) data
Specification for ANG(1-5) Venous (Systemic) [proposed dataset name PKPDA15V]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric or 
text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric or 
text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
H
Time during which total dose infused. 
(Time at end of infusion – Time of 
start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier 
Decimal
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric or 
text) N= Day N, Actual Study Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
 
2019N405280_00


CONFIDENTIAL
206246
50
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
to LAST dose
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BL15
Ang1-5 
concentration record
Decimal
Baseline value, from venous 
(systemic) RAS sampling
DV
AngI1-5 
concentration record
Decimal
When LABL=7, observed Ang1-5 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0, from venous 
(systemic) RAS sampling
MDV
Missing data variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value or 
LABL=1, 2, 3 or 4 
MDV1
Missing data variable
Integer
-
‘1’ if LABL=1, 2, 3 or 4 
“0” when LABL=7
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If DV value present (but not NQ) 
TYPE= ‘1’ 
If DV value NQ TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event CMT=4 for 
ANG1-5 observation event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give age 
at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as 
weight divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
51
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
7
Observed venous (systemic) sampling ANG15 record (concentration or 
ratio) at time specified by TRLD; excludes NA, IS and NR, includes non-
quantifiable (NQ) data
Specification for ANG(1-5) Pulmonary Wedge [proposed dataset name PKPDA15P]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric 
or text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric 
or text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
H
Time during which total dose 
infused. (Time at end of infusion –
Time of start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier Decimal
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric 
or text) N= Day N, Actual Study 
Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
 
2019N405280_00


CONFIDENTIAL
206246
52
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
TRLD
Actual time relative 
to LAST dose
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BL15
Ang1-5 
concentration 
record
Decimal
Baseline value, from pulmonary 
wedge RAS sampling
DV
AngI1-5 
concentration 
record
Decimal
When LABL=12, observed Ang1-5 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0, from 
pulmonary wedge RAS sampling
MDV
Missing data 
variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value 
or LABL=1, 2, 3 or 4 
MDV1
Missing data 
variable
Integer
-
‘1’ if LABL=1, 2, 3 or 4 
“0” when LABL=12
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If DV value present (but not NQ) 
TYPE= ‘1’ 
If DV value NQ TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event CMT=4 for 
ANG1-5 observation event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give 
age at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as 
weight divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
53
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
12
Observed pulmonary wedge sampling ANG15 record (concentration or 
ratio) at time specified by TRLD; excludes NA, IS and NR, includes non-
quantifiable (NQ) data
Specification for ANG(1-7) Venous (Systemic) [proposed dataset name PKPDA17V]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric or 
text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric or 
text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type of 
assessment in that 
record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
H
Time during which total dose infused. 
(Time at end of infusion – Time of 
start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier 
Decimal 
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric or 
text) N= Day N, Actual Study Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
 
2019N405280_00


CONFIDENTIAL
206246
54
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
to LAST dose
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BL17
Ang1-7 concentration 
record
Decimal
Baseline value, from venous 
(systemic) RAS sampling
DV 
Ang1-7 concentration 
record
Decimal
When LABL=8, observed Ang1-7 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0, from venous 
(systemic) RAS sampling
MDV
Missing data variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value or 
LABL=1, 2, 3 or 4 
MDV1
Missing data variable
Integer
-
‘1’ if LABL=1, 2, 3 or 4  
“0” when LABL=8
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If ANG1-7 value present (but not NQ) 
TYPE= ‘1’ 
If ANG1-7 value NQ TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event: 
CMT=5 for ANG1-7 observation 
event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give age 
at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as weight 
divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
55
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
8
Observed venous (systemic) sampling ANG17 record (concentration or 
ratio) at time specified by TRLD; excludes NA, IS and NR, includes non-
quantifiable (NQ) data
Specification for ANG(1-7) Pulmonary Wedge [proposed dataset name PKPDA17P]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric or 
text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric or 
text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type of 
assessment in that 
record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
H
Time during which total dose infused. 
(Time at end of infusion – Time of 
start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier 
Decimal 
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric or 
text) N= Day N, Actual Study Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
 
2019N405280_00


CONFIDENTIAL
206246
56
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
to LAST dose
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BL17
Ang1-7 concentration 
record
Decimal
Baseline value, from pulmonary 
wedge RAS sampling
DV 
Ang1-7 concentration 
record
Decimal
When LABL=13, observed Ang1-7 
concentration at time specified by 
TRLD.  When LABL= 1, 2, 3 or 4 
(dosing record), DV=0, from 
pulmonary wedge RAS sampling
MDV
Missing data variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value or 
LABL=1, 2, 3 or 4 
MDV1
Missing data variable
Integer
-
‘1’ if LABL=1, 2, 3 or 4  
“0” when LABL=13
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If ANG1-7 value present (but not NQ) 
TYPE= ‘1’ 
If ANG1-7 value NQTYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event: 
CMT=5 for ANG1-7 observation 
event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give age 
at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as weight 
divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
 
2019N405280_00


CONFIDENTIAL
206246
57
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
13
Observed pulmonary wedge sampling ANG17 record (concentration or 
ratio) at time specified by TRLD; excludes NA, IS and NR, includes non-
quantifiable (NQ) data
Specification for ANGII/ANG(1-7) Venous (Systemic) [proposed dataset name 
PKPDARTV]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric 
or text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric 
or text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
H
Time during which total dose 
infused. (Time at end of infusion –
Time of start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier 
Decimal 
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric 
or text) N= Day N, Actual Study 
Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
 
2019N405280_00


CONFIDENTIAL
206246
58
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
to LAST dose
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BLRT
AngII/Ang1-7 ratio 
concentration 
record
Decimal
Baseline value, from venous 
(systemic) RAS sampling
Refer to Section 13.6.2 for details 
of data to include.
DV 
AngII/Ang1-7 ratio 
concentration 
record
Decimal
When LABL=10, observed 
AngII/Ang1-7 ratio at time specified 
by TRLD.  When LABL= 1, 2, 3 or 
4 (dosing record), DV=0, from 
venous (systemic) RAS sampling
Refer to Section 13.6.2 for details 
of data to include.
MDV
Missing data 
variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value 
or missing value or LABL=1, 2, 3 or 
4 
MDV1
Missing data 
variable
Integer
-
‘1’ if LABL=1, 2, 3 or 4  
“0” when LABL=10
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If ANGII/ANG1-7 value present (but 
not NQ) TYPE= ‘1’ 
If ANGII/ANG1-7 value NQ (or 
missing) TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event: 
CMT=6 for ANGII/ANG1-7 
observation event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give 
age at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as 
 
2019N405280_00


CONFIDENTIAL
206246
59
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
weight divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
10
Observed venous (systemic) sampling ANGII/ANG17 record (ratio) at time 
specified by TRLD; excludes NA, IS and NR, includes non-quantifiable 
(NQ) data
Specification for ANGII/ANG(1-7) Pulmonary Wedge [proposed dataset name 
PKPDARTP]
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric 
or text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric 
or text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
that record
Integer
See 
footnotes
See footnotes
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
H
Time during which total dose 
infused. (Time at end of infusion –
Time of start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
 
2019N405280_00


CONFIDENTIAL
206246
60
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
DGRP
Treatment Identifier 
Decimal 
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric 
or text) N= Day N, Actual Study 
Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
to LAST dose
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BLRT
AngII/Ang1-7 ratio 
concentration 
record
Decimal
Baseline value, from pulmonary 
wedge RAS sampling
Refer to Section 13.6.2 for details 
of data to include.
DV 
AngII/Ang1-7 ratio 
concentration 
record
Decimal
When LABL=14, observed 
AngII/Ang1-7 ratio at time specified 
by TRLD.  When LABL= 1, 2, 3 or 
4 (dosing record), DV=0, from 
pulmonary wedge RAS sampling
Refer to Section 13.6.2 for details 
of data to include.
MDV
Missing data 
variable
Integer
-
Either ‘0’ if DV value present or 1 if 
DV is non-quantifiable (NQ) value 
or missing value or LABL=1, 2, 3 or 
4 
MDV1
Missing data 
variable
Integer
-
‘1’ if LABL=1, 2, 3 or 4  
“0” when LABL=14
TYPE
F-Flag
Integer
-
If MDV1= ‘1’ then TYPE =’0’,
If ANGII/ANG1-7 value present (but 
not NQ) TYPE= ‘1’ 
If ANGII/ANG1-7 value NQ (or 
missing) TYPE = ‘2’
CMT
Compartment data 
item
Integer
-
DOSE event: CMT=1, specifies the 
compartment into which DOSE is 
introduced.  
OBSERVATION event: 
CMT=6 for ANGII/ ANG1-7 
observation event.
AGE
Age 
Decimal
Yrs
Integer. Age in years at time of 
screening rounded down to give 
age at last birthday.
WT
Weight 
Decimal
Kg
Weight in kilograms at time of 
 
2019N405280_00


CONFIDENTIAL
206246
61
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
screening.
HT
Height 
Decimal
Cm
Height in centimetres at time of 
screening.
SEX
Subject gender
Integer
-
Integer. One of the following -
1 = male
2 = female
ETHN
Subject ethnicity
Integer
-
Integer.  Code as CRF
RACE
Subject race
Integer
-
Integer.  Code as CRF
BMI
Body mass index
Decimal
kg/m^2
body mass index calculated as 
weight divided by height squared
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
Assessments captured in the LABL variable
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
14
Observed pulmonary wedge sampling ANGII/ANG17 record (ratio) at time 
specified by TRLD; excludes NA, IS and NR, includes non-quantifiable 
(NQ) data
Specification for PVR/CO/mPAP/CI
The PME compliant file structure is a space-delimited file with each row containing the 
following columns of information. Data from all treatments will be included. 
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
C
Data Identifier
Integer
-
0
STUD
Protocol Number
Integer
-
206246
DRUG
Name of Drug
Integer
-
Maximum 10 characters (numeric 
or text). 2586881
SUBJ
Subject identifier in 
study
Integer
-
Maximum 10 characters (numeric 
or text). Different identifier for each 
subject
CENT
Study centre 
identifier
Integer
-
LABL
Indicator field 
describing the type 
of assessment in 
Integer
See 
footnotes
See footnotes
 
2019N405280_00


CONFIDENTIAL
206246
62
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
that record
AMT
Dose of 
GSK2586881
Decimal
Mg
Amount of drug given = Total 
GSK2586881 dose (mg/kg) * WT.  
AMT=0 when LABL=0
For dosing events: total dose of 
GSK2586881 taken
For concentration events: 0
INF
Infusion Time
Decimal
h
Time during which total dose 
infused. (Time at end of infusion –
Time of start infusion)
RATE
Rate of Infusion
Decimal
Mg/h
Rate of infusion (AMT/INF)
DGRP
Treatment Identifier Decimal 
-
DGRP=0.1 for 0.1 mg/kg treatment
DGRP=0.2 for 0.2 mg/kg treatment
DGRP=0.4 for 0.4 mg/kg treatment
DGRP=0.8 for 0.8 mg/kg treatment
PART
Study Part
Varchar
-
1=Study Period 1
DAY
Study day
Integer
-
Maximum 10 characters (numeric 
or text) N= Day N, Actual Study 
Day
CTIM
Clock time of Dose 
or measurement
HH:MM:SS
-
DATE
Date of record
DD/MM/YYY
TRLD
Actual time relative 
to LAST dose
Decimal
Hours
When LABL = 1, 2, 3, or 4 TRLD is 
Time (Hours) since start of LAST 
infusion. For pre-dose sample, 
TRLD=0 
BLPVR
PVR
Decimal
mmHg
Baseline Value
PVR
PVR
Decimal
mmHg
When LABL=9, PVR at time 
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), PVR=0
PVRFLD
PVR ratio to 
baseline (fold 
change)
Decimal
-
When LABL=9, PVRFLD fold 
change at time specified by TRLD.  
When LABL= 1, 2, 3 or 4 (dosing 
record), PVRFLD=0
PVRCHG
PVR change from 
baseline
Decimal
mmHg
When LABL=9, PVRCHG at time 
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), 
PVRCHG=0
BLCO
Cardiac Output
Decimal
L/min
Baseline Value
CO
Cardiac Output
Decimal
L/min
When LABL=9, CO at time 
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), DV=0 
CO=0
COFLD
Cardiac Output 
ratio to baseline 
(fold change)
Decimal
-
When LABL=9, COFLD fold 
change at time specified by TRLD.  
When LABL= 1, 2, 3 or 4 (dosing 
record), DV=0 COFLD=0
COCHG
Cardiac Output 
Decimal
L/min
When LABL=9, COCHG at time 
 
2019N405280_00


CONFIDENTIAL
206246
63
Variable 
short name
Assessment 
description
Format
Unit
Valid Values / Format
change from 
baseline
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), DV=0 
COCHG=0
BLCI
Cardiac Index
Decimal
L/min/m2
Baseline Value
CI
Cardiac Index
Decimal
L/min/m2
When LABL=9, CI at time specified 
by TRLD.  When LABL= 1, 2, 3 or 
4 (dosing record), DV=0 CI=0
CIFLD
Cardiac Index ratio 
to baseline (fold 
change)
Decimal
-
When LABL=9, CIFLD fold change 
at time specified by TRLD.  When 
LABL=1, 2, 3 or 4 (dosing record), 
DV=0 CIFLD=0.
CICHG
Cardiac Index 
change from 
baseline
Decimal
L/min/m2
When LABL=9, CICHG at time 
specified by TRLD.  When 
LABL=1, 2, 3 or 4 (dosing record), 
DV=0 CICHG=0.
BLMPAP
mPAP
Decimal
mmHg
Baseline Value
MPAP
mPAP
Decimal
mmHg
When LABL=9, mPAP at time 
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), DV=0 
mPAP=0
MPAPFLD
mPAP ratio to 
baseline (fold 
change)
Decimal
-
When LABL=9, mPAPFLD at time 
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), DV=0 
mPAPFLD=0
MPAPCHG
mPAP change from 
baseline
Decimal
mmHg
When LABL=9, mPAPCHG at time 
specified by TRLD.  When LABL= 
1, 2, 3 or 4 (dosing record), DV=0 
mPAPCHG=0
EVID
Event Identification 
data item
Integer
-
Flag indicating whether LABL 
contains dosing admin info or drug 
concentration data.
Valid values are -
1 – each dosing record for subject
0 - for all other records
Label
Description
Units
1
Dosing records for 0.1 mg/Kg GSK2586881
2
Dosing records for 0.2 mg/Kg GSK2586881
3
Dosing records for 0.4 mg/Kg GSK2586881
4
Dosing records for 0.8 mg/Kg GSK2586881
9
Observed hemodynamic record at time specified by TRLD; excludes NA, IS 
and NR, includes non-quantifiable (NQ) data
 
2019N405280_00


CONFIDENTIAL
206246
64
13.10.
Appendix 10: Abbreviations & Trade Marks
13.10.1.
Abbreviations
Abbreviation
Description
ACE2
Angiotensin converting enzyme type 2
AE
Adverse Event
Ang
Angiotensin
A&R
Analysis and Reporting 
AUC(0-t)
Area under the concentration time curve from time zero to the time of 
the last quantifiable concentration
AUC(0-∞)
Area under the concentration time curve extrapolated to infinity
CI
Cardiac Index
CI
Confidence Interval
CIL
Clinical Investigative Lead
CL
Clearance
Clast
Last observed quantifiable concentration
Cmax
Maximum observed plasma concentration
CO
Cardiac Output
CPMS
Clinical Pharmacology Modelling & Simulation
CPSR
Clinical Pharmacology Study Report
CS
Clinical Statistics
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
DQL
Data Quality Lead
eCRF
Electronic Case Record Form
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonisation
ICF
Informed Consent Form
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
IV
Intravenous
GUI
Guidance
mmHg
Millimeter of Mercury
mPAP
Mean Pulmonary Artery Pressure
NO
Nitric Oxide
NT-proBNP
N-terminal pro-brain natriuretic peptide
OSL
Operational Study Lead
PAH
Pulmonary Arterial Hypertension
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
 
2019N405280_00


CONFIDENTIAL
206246
65
Abbreviation
Description
PK
Pharmacokinetic
PT
Preferred Term
PVR
Pulmonary Vascular Resistance
QC
Quality Control
QTcF
Friderica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RAS
Renin-Angiotensin-System
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SD
Standard Deviation
SOC
System Organ Class
SOP
Standard Operation Procedure
S&P
Statistics and Programming
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
Tlast
Time of the last observed quantifiable concentration
Tmax
Time to reach Cmax
T1/2
Apparent terminal half-life
V
Volume of distribution
13.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
RANDALL NG
SAS
WinNonlin
 
2019N405280_00


CONFIDENTIAL
206246
66
13.11.
Appendix 11: List of Data Displays
13.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Population Pharmacokinetic (PopPK)
5.1 to 5.n
5.1 to 5.n
Pharmacodynamic and / or Biomarker
6.1 to 6.n
6.1 to 6.n
Pharmacokinetic / Pharmacodynamic
7.1 to 7.n
7.1 to 7.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
13.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_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.’
13.11.3.
Deliverables
Delivery
Description
DE [1]
Dose Escalation Dose 1 (Responsibility of GSK)
DE [2]
Dose Escalation Dose 2 (Responsibility of GSK)
DE [3]
Dose Escalation Dose 3 (Responsibility of GSK)
SAC / 
SAC(GSK)
Final Statistical Analysis Complete /
Final Statistical Analysis Complete (Responsibility of GSK)
 
2019N405280_00


CONFIDENTIAL
206246
67
13.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1
Summary of Participant Disposition for the Participant
Conclusion Record
ICH E3, FDAAA, EudraCT
SAC
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.3.
Safety
NS1
Summary of Number of Participants by Country and Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Population Analysed
1.5.
Safety
SP1
Summary of Study Populations 
IDSL
SAC
Demographic and Baseline Characteristics
1.6.
Safety
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC
1.7.
Safety
DM11
Summary of Age Ranges
EudraCT
SAC
1.8.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.9.
Safety
POP_T1
Summary of Baseline Characteristics
Include Functional Class (I, II, III) 
(frequencies) and 6MWD (summary 
stats) and PAH underlying causes
(frequencies) by dose group and overall
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
68
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.10.
Safety
MH1
Summary of Past Medical Conditions
ICH E3 
SAC
1.11.
Safety
MH1
Summary of Current Medical Conditions
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC
1.12.
Safety
CM1
Summary of Concomitant Medications
ICH E3
SAC
1.13.
Safety
CM1
Summary of Concomitant Medications for PAH
Will be based on a spreadsheet review 
by the medical monitor to flag those 
records within the conmed dataset that 
were applicable to PAH.  This flag will 
be read in and merged when creating 
the CMANAL dataset.  One review prior 
to DBF for pre-programming and a final 
review (quick turnaround) at DBF.
SAC
Exposure and Treatment Compliance
1.14.
Safety
EX3
Listing of Exposure to Study Treatment
ICH E3
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
69
13.11.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
SAC
3.2.
Safety
AE1CP
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term/by Overall Frequency
ICH E3
.
SAC
Serious and Other Significant Adverse Events
3.3.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
SAC
ECG
3.4.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC
3.5.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC
3.6.
Safety
CP_EG11
Frequency of ECG Values by Pre-Specified PCI Categories
Categories as per PCI details in Section 
13.7.2
SAC
3.7.
Safety
CP_EG12
Frequency of Change from Baseline ECG Values by Pre-
Specified PCI Categories
Categories as per PCI details in Section 
13.7.2
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
70
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.8.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC
Pulse Oximetry
3.9.
Safety
VS1
Summary of Oxygen Saturation
Collected at same timepoints as vital 
signs (but no triplicates at pre-dose)
SAC
Immunogenicity
3.10.
Safety
IMM1
Summary of Positive Immunogenicity Results
Results will be categorised by visit (Day 
7, Day 28) and dose group within the 
table.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
71
13.11.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
SAF_F1
Summary of Change from Baseline (95% CI) in Systolic Blood 
Pressure by Dose Group
Data from VITALS dataset.  See 
example, x-axis will be post-dose 
timepoint with each dose group mean 
95% CI plotted (dose groups offset)
Include a horizontal dashed grey line at 
zero.
Please use symbols as indicated in 
Section 5.1
SAC
3.2.
Safety
SAF_F1
Summary of Change from Baseline (95% CI) in Diastolic Blood 
Pressure by Dose Group
Data from VITALS dataset.  See 
example, x-axis will be post-dose 
timepoint with each dose group mean 
95% CI plotted (dose groups offset)
Include a horizontal dashed grey line at 
zero.
Please use symbols as indicated in 
Section 5.1
SAC
3.3.
Safety
SAF_F1
Summary of Change from Baseline (95% CI) in Heart Rate by 
Dose Group
Data from VITALS dataset.  See 
example:  x-axis will be post-dose 
timepoint with each dose group mean 
95% CI plotted (dose groups offset)
Include a horizontal dashed grey line at 
zero.
Please use symbols as indicated in 
Section 5.1
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
72
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4.
Safety
SAF_F2
Summary of Individual Systolic Blood Pressure by Dose Group
Data from VITALS dataset. See 
example:  One plot per dose group, 
with all subject profiles on each dose 
group plot, 4 pages per output
SAC
3.5.
Safety
SAF_F2
Summary of Individual Diastolic Blood Pressure by Dose Group
Data from VITALS dataset. See 
example:  One plot per dose group, 
with all subject profiles on each dose 
group plot, 4 pages per output
SAC
3.6.
Safety
SAF_F2
Summary of Individual Heart Rate by Dose Group
Data from VITALS dataset. See 
example:  One plot per dose group, 
with all subject profiles on each dose 
group plot, 4 pages per output
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
73
13.11.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
4.1.
PK
PKCT1 (PK01)
Summary of GSK2586881 Pharmacokinetic Concentration-Time 
Data (ng/mL)
By dose group
SAC
PK Parameter Data
4.2.
PK
PKPT1 (PK03)
Summary Statistics of Derived Plasma GSK2586881 
Pharmacokinetic Parameters
By dose group.
See Section 9.1.1.2 for full list of 
parameters to be expected
SAC
4.3.
PK
PKPT3 (PK05)
Summary Statistics of Log-Transformed Derived Plasma 
GSK2586881 Pharmacokinetic Parameters
By dose group. 
See Section 9.1.1.2 for full list of 
parameters to be expected (Tmax, 
lambda_x variables, #pts and R2 not 
included)
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
74
13.11.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
4.1.
PK
PKCF1P 
(PK16a)
Individual GSK2586881 Plasma Concentration–Time Plots 
(Linear and Semi-log)
By Subject plots
SAC
4.2.
PK
PKCF6 (PK24)
Individual GSK2586881 Plasma Concentration–Time Plot
(Linear and Semi-log)
Page by dose group, all subjects on 
a plot for each dose group
SAC
4.3.
PK
PKCF2 (PK17)
Mean Plasma GSK2586881 Concentration-Time Plot (Linear 
and Semi-Log)
Include a legend for dose groups
SAC
4.4.
PK
PKCF3 (PK18)
Median Plasma GSK2586881 Concentration-Time Plot
Include a legend for dose groups
SAC
4.5.
PK
(PK28)
Plot of Individual (+Geometric Mean and 95% CIs) GSK2586881 
Cmax versus Dose
SAC
4.6.
PK
(PK28)
Plot of Individual (+Geometric Mean and 95% CIs) GSK2586881 
AUC(0-t) versus Dose
SAC
4.7.
PK
(PK28)
Plot of Individual (+Geometric Mean and 95% CIs) GSK2586881 
AUC(0-inf) versus Dose
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
75
13.11.9.
Pharmacodynamic and Biomarker Tables
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Hemodynamics
6.1.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Pulmonary Hemodynamics 
(Absolute)
Interim Tables
Include PVR, CO mPAP & CI only for dose group being 
assessed at the time (can be indicated in the title ‘Dose Group = 
xx mg/kg’)
Provide second page with geometric means etc (from log-
transformation)
SAC Table
By dose group and endpoint (x9 PVR, CO, mPAP, Right Atrial 
Pressure etc).  n[1] in mock not required for Hemodynamic 
endpoints.
Log-transformed summary to be included as a second page for 
each parameter (see mock).  Timepoints are Pre-dose, 1h, 2h 
and 4h.
DE[1], 
DE[2], 
DE[3] & 
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
76
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.2.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Change from Baseline in 
Pulmonary Hemodynamics
Interim Tables
Include PVR, CO mPAP & CI only for dose group being 
assessed at the time (can be indicated in the title ‘Dose Group = 
xx mg/kg’)
Provide second page with geometric means etc (from log-
transformation)
SAC Table
By dose group and endpoint (x9 PVR, CO, mPAP, Right Atrial 
Pressure etc).  Pre-dose excluded. n[1] in mock not required for 
Hemodynamic endpoints.
Log-transformed summary to be included as a second page for
each parameter (see mock). Timepoints are 1h, 2h and 4h.
DE[1], 
DE[2], 
DE[3] & 
SAC
6.3.
Evaluable
PD_T3
Summary of Statistical Analysis of PVR, 
CO, mPAP and CI
Interim Tables
Utilising Bayesian version of repeated measures mixed effect 
modelling results for dose group(s) of interest at the time.  
Posterior probabilities to be included, see Section 7.1.5.1.
SAC table
As above, with consideration to all dose groups, discuss with 
team to ensure probabilities of interest are displayed as further 
probabilities may be required in addition to those quoted in 
Section 7.1.5.1.
DE[1], 
DE[2],
DE[3],
SAC (GSK)
 
 
 
2019N405280_00


CONFIDENTIAL
206246
77
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
RAS
6.4.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Venous (Systemic) RAS 
Peptides (Absolute Data)
By dose group and analyte.  
Log-transformed summary to be included as a second page for 
each parameter. To include AngII, Ang(1-7), Ang(1-5).
Timepoints are Pre-dose, 0.5h, 1h, 2h, 4h, 8h, 24h and Day(7-
14) FU
SAC
6.5.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Pulmonary Wedge RAS 
Peptides (Absolute Data)
By dose group and analyte.  
Log-transformed summary to be included as a second page for 
each parameter. To include Ang II, Ang(1-7), Ang(1-5).
Timepoints are Pre-dose, 1h, 2h and 4h only.
SAC
6.6.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Change from Baseline in 
Venous (Systemic) RAS Peptides
By dose group and analyte.  
Log-transformed summary to be included as a second page for 
each parameter. To include AngII, Ang(1-7), Ang(1-5).
Timepoints are 0.5h, 1h, 2h, 4h, 8h, 24h and Day(7-14) FU
SAC
6.7.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Change from Baseline in 
Pulmonary Wedge RAS Peptides
By dose group and analyte.  
Log-transformed summary to be included as a second page for 
each parameter. To include Ang II, Ang(1-7), Ang(1-5).
Timepoints are 1h, 2h and 4h only.
SAC
6.8.
Evaluable
PD_T2
Summary of Venous (Systemic) RAS 
AngII/Ang(1-7) Ratio
By dose group.  
Log-transformed summary to be included as a second page.
Timepoints are Pre-dose, 0.5h, 1h, 2h, 4h, 8h, 24h and Day(7-
14) FU
SAC
6.9.
Evaluable
PD_T2
Summary of Pulmonary Wedge RAS 
AngII/Ang(1-7) Ratio
By dose group.  
Log-transformed summary to be included as a second page.
Timepoints are Pre-dose, 1h, 2h, 4h
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
78
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Biomarkers
6.10.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Disease Activity 
Biomarkers (Absolute Data)
By dose group and analyte.  
Log-transformed summary to be included as a second page for 
each parameter. 
To include NT pro-BNP, serum NO, cardiac tropinin I.  
Timepoints are Pre-dose, 2h, 4h and 24h only.
SAC
6.11.
Evaluable
PD_T1 (or 
modify PFT1 & 
PFT2)
Summary of Change from Baseline in 
Disease Activity Biomarkers
By dose group and analyte.  
Log-transformed summary to be included as a second page for 
each parameter. To include NT pro-BNP, serum NO, cardiac 
tropinin I.  Timepoints are 2h, 4h and 24h only.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
79
13.11.10. Pharmacodynamic and Biomarker Figures
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Hemodynamics
6.1.
Evaluable
PD_F3a
Individual Subject Profiles of Pulmonary 
Hemodynamics (Absolute) 
Interim Plots:
All subjects on one plot.  Page by endpoint CO, PVR, 
mPAP and CI.
Include ‘Dose Group = XX’ within title
Include a second page (similar for PD_F7) that 
displays the dose group profiles from 206246 side by 
side with the data from previous ISS study – for each 
parameter
SAC Plots
All subjects on one plot.  One page per dose group.  
Page also by endpoint CO, PVR, mPAP and CI only. 
Include a second page with log10 axes.
DE[1], DE[2], 
DE[3]
& SAC
6.2.
Evaluable
PD_F1
Summary of Pulmonary Hemodynamics 
(Absolute)
X-axis will be timepoints Pre-dose, 1h, 2h, 4h. Y-axis 
will be mean endpoint including 95% CI, by treatment 
groups (add to legend).  Offset doses at each 
timepoint.
Page by endpoint CO, PVR, mPAP and CI only
Present geometric means and 95% CIs on second 
page.
Please use symbols as indicated in Section 5.1
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
80
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.3.
Evaluable
PD_F2
Summary of Change from Baseline in 
Pulmonary Hemodynamics
X-axis will be timepoints 1h, 2h, 4h. Y-axis will be 
mean endpoint including 95% CI, by treatment groups 
(add to legend).  Offset doses at each timepoint.
Page by endpoint CO, PVR, mPAP and CI only
Present geometric means and 95% CIs on second 
page.
Please use symbols as indicated in Section 5.1
SAC
6.4.
Evaluable
PD_F4
Linear Regression Plots for Post-dose
Changes from Baseline vs Dose in PVR, CO, 
mPAP and CI
To include data from all dose groups (similar to 
PD_F4 but with data points plotted for 0.8 mg/kg 
also).  One page per timepoint (1h, 2h and 4h)
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
81
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
RAS Biomarkers
6.5.
Evaluable
PD_F3b
Individual Subject Profiles of Venous 
(Systemic) RAS Biomarkers
Interim Plots (as required based on data 
availability)
All subjects on one plot, one page per dose group 
and endpoint.  
Include a second page (similar to PD_F8) that 
displays the dose group profiles from 206246 side by 
side with the data from previous ISS study – primarily 
for AngII and Ang(1-7).
SAC Plot
All subjects on one plot, one page per dose group.  
AngII x 4 pages, Ang(1-5) x 4 pages, Ang(1-7) x 4 
pages.
Timepoints are Pre-dose, 0.5h, 1h, 2h, 4h, 8h, 24h 
and Day(7-14) FU
Include a second page with log10 axes for each 
endpoint/dose group
DE[1], DE[2], 
DE[3]
& SAC
6.6.
Evaluable
PD_F3b
Individual Subject profiles of Pulmonary 
Wedge RAS Biomarkers
All subjects on one plot, one page per dose group: 
Ang II x 4 pages, Ang(1-5) x 4 pages, Ang(1-7) x 4 
pages, Ang II/Ang(1-7) x 4 pages.
Timepoints are Pre-dose, 1h, 2h and 4h only.
Include a second page with log10 axes for each 
endpoint/dose group.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
82
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.7.
Evaluable
PD_F1
Summary of Venous (Systemic) RAS 
Biomarkers (Absolute)
X-axis will be timepoints Pre-dose, 0.08h, 0.5h, 1h, 
2h, 4h, 8h, 24h, FU7-14. Y-axis will be geometric
mean RAS including 95% CI, by dose groups (add to 
legend).  One page per endpoint (4 x RAS 
endpoints).
Presenting geometric means from log-transformed 
data (see matching table).
Include AngII, Ang(1-7), Ang(1-5) and AngII/Ang(1-
7)
Please use symbols as indicated in Section 5.1
SAC
6.8.
Evaluable
PD_F1
Summary of Pulmonary Wedge RAS 
Biomarkers (Absolute)
X-axis will be timepoints Pre-dose, 1h, 2h, 4h. Y-axis 
will be geometric RAS including 95% CI, by dose 
groups (add to legend).  One page per endpoint (4 x 
RAS endpoints).
Presenting geometric means from log-transformed 
data (see matching table).
Include AngII, Ang(1-7), Ang(1-5) and AngII/Ang(1-
7)
Please use symbols as indicated in Section 5.1
SAC
6.9.
Evaluable
PD_F5
Correlation plot for Venous (Systemic) RAS 
Biomarkers
Scatter plot of Ang II vs Ang(1-7) on page 1, Ang II vs 
Ang(1-5) on page 2 and Ang(1-5) vs Ang(1-7) on 
page 3. Venous RAS timepoints.  
To be plotted on log-log scales.
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
83
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.10.
Evaluable
PD_F5
Correlation plot for Pulmonary Wedge RAS 
Biomarkers
Scatter plot of Ang II vs Ang(1-7) on page 1, Ang II vs 
Ang(1-5) on page 2 and Ang(1-5) vs Ang(1-7) on 
page 3. Pulmonary wedge RAS timepoints.  
To be plotted on log-log scales.
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
Disease Activity Biomarkers
6.11.
Evaluable
PD_F1
Summary of Disease Activity Biomarkers 
(Absolute)
X-axis will be timepoints Pre-dose, 2h, 4h, 24h.  Y-
axis will be geometric mean endpoint including 95% 
CI, by treatment groups (add to legend).  One page 
per endpoint (3 x endpoints)
Presenting geometric means from log-transformed 
data (see matching table).
Please use symbols as indicated in Section 5.1
SAC
6.12.
Evaluable
PD_F3b
Individual Subject profiles of Disease Activity 
Biomarkers 
All subjects on one plot, one page per dose group: 
NT pro-BNP x 4, NO x 4 and cardiac troponin I x 4 
pages.
Include a second page with log10 axes for each 
endpoint/dose group.
SAC
RAS Biomarkers vs Hemodynamics
6.13.
Evaluable
PD_F6
Scatter Plot (log-log) of Venous (Systemic) 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs PVR
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on PVR.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
84
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.14.
Evaluable
PD_F6
Scatter Plot (log-log) of Venous (Systemic) 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs CO
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on CO.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
6.15.
Evaluable
PD_F6
Scatter Plot (Semi-log) of Venous (Systemic) 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs mPAP
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on mPAP.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
6.16.
Evaluable
PD_F6
Scatter Plot (log-log) of Venous (Systemic) 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs CI
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on CI.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
6.17.
Evaluable
PD_F6
Scatter Plot (Semi-log) of Pulmonary Wedge 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs PVR
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on PVR.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
85
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.18.
Evaluable
PD_F6
Scatter Plot (Semi-log) of Pulmonary Wedge 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs CO
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on CO.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
6.19.
Evaluable
PD_F6
Scatter Plot (Semi-log) of Pulmonary Wedge 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs mPAP
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on mPAP.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
6.20.
Evaluable
PD_F6
Scatter Plot (Semi-log) of Pulmonary Wedge 
RAS Peptides (Ang II, Ang(1-5) and Ang(1-7)) 
vs CI
3 pages, 1 for each RAS, 4 dose groups on each 
page, dose/timepoint indicated in legend.  Timepoints 
of interest based on CI.  
Log-log axes
Please provide clear dose/timepoint labels within the 
legend, mock-up is basic example only.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
86
13.11.11. Pharmacokinetic / Pharmacodynamic and Biomarker Figures
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK / RAS Peptides
7.1.
PK
PK_F1
Scatter plot (Log-log) of PK Concentration vs 
Venous (Systemic) Ang II, Ang(1-5), Ang(1-7)
and AngII/Ang(1-7)
Scatter plot of PK conc vs Ang II on page 1, PK 
conc vs Ang(1-5) on page 2, PK conc vs Ang(1-7) 
on page 3 and PK conc vs AngII/Ang(1-7) on page 
4. Timepoints of interest based on PK.  
To be plotted on log-log scales.
Please provide clear dose/timepoint labels within 
the legend, mock-up is basic example only.
Note: For PK/PD plots only, PK concentration data 
recorded as NQ can be imputed following the same 
method for biomarker data i.e., replace with ½ LLQ.  
The imputed variable for PK should be available in 
the PKCNC dataset.  See Section 13.4.3  
Footnote to include: ‘Note: Values below Lower 
Limit of Quantification (LLQ) replaced with ½ LLQ. 
LLQ for PK concentration = xx ng/mL, LLQ for AngII 
= xx pg/mL, LLQ for Ang(1-5) = xx pg/mL and LLQ 
for Ang(1-7) = xx pg/mL.’
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
87
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
7.2.
PK
PK_F1
Scatter plot (Log-log) of PK Concentration vs 
Pulmonary Wedge Ang II, Ang(1-5), Ang(1-7) 
and AngII/Ang(1-7)
Scatter plot of PK conc vs Ang II on page 1, PK 
conc vs Ang(1-5) on page 2,  PK conc vs Ang(1-7) 
on page 3 and PK conc vs AngII/Ang(1-7) on page 
4. Timepoints of interest based on Pulmonary 
Wedge RAS.  
To be plotted on log-log scales.
Please provide clear dose/timepoint labels within 
the legend, mock-up is basic example only.
Note: For PK/PD plots only, PK concentration data 
recorded as NQ can be imputed following the same 
method for biomarker data i.e., replace with ½ LLQ.  
The imputed variable for PK should be available in 
the PKCNC dataset.  See Section 13.4.3  
Footnote to include: ‘Note: Values below Lower 
Limit of Quantification (LLQ) replaced with ½ LLQ. 
LLQ for PK concentration = xx ng/mL, LLQ for AngII 
= xx pg/mL, LLQ for Ang(1-5) = xx pg/mL and LLQ 
for Ang(1-7) = xx pg/mL.’
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
88
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
7.3.
PK
PK_F1
Scatter Plot (Log-log) of PK Concentration vs 
PVR, CO, mPAP and CI
Scatter plot of PK conc vs PVR on page 1, PK conc 
vs CO on page 2, PK conc vs mPAP on page 3
and PK conc vs CI on page 4. Timepoints of interest 
based on hemodynamics.  
To be plotted on log-log scales.
Please provide clear dose/timepoint labels within 
the legend, mock-up is basic example only.
Note: For PK/PD plots only, PK concentration data 
recorded as NQ can be imputed following the same 
method for biomarker data i.e., replace with ½ LLQ.  
The imputed variable for PK should be available in 
the PKCNC dataset.  See Section 13.4.3.  
Footnote to include: ‘Note: Values below Lower 
Limit of Quantification (LLQ) replaced with ½ LLQ. 
LLQ for PK concentration = xx ng/mL.’
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
89
13.11.12. 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
Journal Guidelines
SAC
2.
Safety
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
Safety
TA1
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
4.
Safety
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
5.
Safety
IE3
Listing of Participants with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC
Populations Analysed
6.
Safety
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
7.
Safety
DM2
Listing of Demographic Characteristics
ICH E3
SAC
8.
Safety
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
9.
Safety
CP_CM3
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
10.
Safety
EX3
Listing of Exposure Data
ICH E3
SAC
Adverse Events
11.
Safety
AE8CP
Listing of All Adverse Events
ICH E3
SAC
12.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
90
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
13.
Safety
AE8CPa
Listing of Serious Adverse Events
ICH E3
SAC
14.
Safety
AECP8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
All Laboratory
15.
Safety
LB5
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance/Outside Normal Range
ICH E3
SAC
16.
Safety
LB5
Listing of Laboratory Values of Potential Clinical Importance
SAC
ECG
17.
Safety
EG3/CP_EG3
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
18.
Safety
EG3/CP_EG3
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
19.
Safety
EG5/CP_EG5
Listing of All ECG Findings for Participants with an Abnormal ECG 
Finding
IDSL
SAC
20.
Safety
EG5/CP_EG5
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
21.
Safety
VS4
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
22.
Safety
VS4
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
91
13.11.13. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Baseline Characteristics
23.
Safety
POP_L1
Listing of Baseline Characteristics
SAC
Pharmacodynamic
24.
Safety
PD_L2
Listing of Hemodynamic Endpoints
Interim Listings:
Produce for relevant dose group.  Include % change from baseline
(presented as a ratio to baseline based on back-transformed data)
SAC Listing:
Produce for all dose groups.  Include % change from baseline 
(presented as a ratio to baseline based on back-transformed data)
DE[1], 
DE[2]. 
DE[3] 
& SAC
25.
Safety
PFT8
Listing of Oxygen Saturation
Follow PFT8 IDSL format, replacing last 4 columns with Oxygen 
Saturation endpoint.
SAC
Biomarkers
26.
Safety
PD_L1
Listing of Venous (Systemic) RAS 
Peptides 
See non-standard example PD_L1.  To include AngII, Ang(1-5) and 
Ang(1-7)
SAC
27.
Safety
PD_L1
Listing of Pulmonary Wedge RAS 
Peptides
See non-standard example PD_L1 (4 timepoints only) 
To include AngII, Ang(1-5) and Ang(1-7)
SAC
28.
Safety
PD_L1
Listing of Disease Biomarkers
See non-standard example PD_L1 (4 timepoints only)
SAC
Immunogenicity
29.
Safety
IMM2
Listing of Immunogenicity
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
92
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK
30.
PK
PKCL1P
(PK07)
Listing of GSK2586881 Plasma 
Pharmacokinetic Concentration–
Time Data
SAC
31.
PK
PKPL1P
(PK13)
Listing of Derived GSK2586881 
Plasma Pharmacokinetic 
Parameters
See Section 9.1.1.2 for list of parameters.  To include lambda_z and 
the additionally the first point, last point and number of points used 
in the determination of lambda_z for listings and R squared.
SAC
 
 
 
2019N405280_00


CONFIDENTIAL
206246
93
13.12.
Appendix 13: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
 
 
2019N405280_00