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
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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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.
 
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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.
 
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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)
 
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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. 
 
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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
 
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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
 
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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
 
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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. 
 
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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)
 
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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
 
 
 
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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
 
 
 
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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 
 
 
 
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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).
 
 
 
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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.
 
 
 
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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.
 
 
 
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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).
 
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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 
 
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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).
 
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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
 
 
 
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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).
 
 
 
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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.
 
 
 
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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).
 
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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.  
 
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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 
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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, 
 
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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: 
 
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
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.
 
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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.
 
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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 
 
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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.
 
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
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:
 
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
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.  
 
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
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.
 
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
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 
 
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
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. 
 
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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.
 
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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).
 
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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. 
 
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
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.
 
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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.
 
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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.
 
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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 
 
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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.
 
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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. 
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D’Alonzo E, et al. Survival in Patients with Primary Pulmonary Hypertension. Annals of 
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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 
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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 
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of GSK2586881 in subjects with acute lung injury. Report Date 07-Oct-2015. 
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Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM,et.al. Prevention of 
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Simonneau, M.D. Treatment of Pulmonary Arterial Hypertension, The New England 
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Johnson JA, Hemnes AR, Perrien DS, et al. Cytoskeletal defects in Bmpr2-associated 
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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.
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Intravenous Epoprostenol Infusion in Primary Pulmonary Hypertension. Journal of the 
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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-
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Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J et al. Hydrolysis of biological 
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of Biological Chemistry. 2002; 277, 14838–14843.
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determines plasma clearance of angiotensin-(1–7). Hypertension.1998; 32(3):496–502.
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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
 
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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
 
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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
 
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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
 
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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.
 
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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. 
 
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
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.
 
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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.
 
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
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
 
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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 
 
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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 
 
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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, 
 
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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.
 
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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.
 
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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.
 
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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 
 
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
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.
 
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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.
 
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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 
 
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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 
 
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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
 
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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.
 
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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
 
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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 
 
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