Clinical trial NCT03315559
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: GSK2269557 Pharmacokinetics Radiolabel Healthy Excretion Bioavailability
Sponsor: GlaxoSmithKline
Start date: 2017-11-14; Completion date: 2017-12-22
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
GSK2269557 is being developed as an anti-inflammatory agent for the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory lung diseases such as asthma. This study is designed to investigate the recovery, excretion, and pharmacokinetics (PK) of (14 Carbon \[C\])-GSK2269557 administered as a single intravenous (IV) dose (concomitant with an inhaled non-radiolabelled dose) and as a single oral dose in 6 healthy male subjects. Subjects will receive \[14C\] radiolabelled GSK2269557 administered as IV infusion, with a nonradiolabelled dose of GSK2269557 via dry powder inhaler (DPI) in treatment period 1 and a single dose of \[14C\]-GSK2269557, administered as an oral solution in treatment period 2. There will be a washout period of at least 14 days after inhaled and IV dosing before subjects takes part in treatment period 2. The IV microtracer dose of GSK2269557 will be administered concomitant to an inhaled non-radiolabelled dose to ensure that the pharmacokinetics represent a clinically relevant dose. The total study duration will be up to 11 weeks, including a screening visit, 2 treatment periods and a follow-up visit.

Detailed description:

Arms: arm 1: Eligible subjects will receive IV infusion of \[14C\] radiolabelled GSK2269557 with a single dose of 10 micrograms (µg) administered as single microtracer, concomitantly with an inhaled nonradiolabelled 1000 µg dose of GSK2269557. There will be a washout of at least 14 days after inhaled and IV dosing before subjects receive treatment 2. arm 2: Eligible subjects will receive \[14C\]-GSK2269557 with a single dose of 800 µg, administered as an oral solution.
Interventions: intervention 1: [14C]-GSK2269557 IV infusion intervention 2: GSK2269557 via DPI intervention 3: [14C]-GSK2269557 oral solution
Intervention descriptions: intervention 1: The \[14C\]-GSK2269557 solution will be available in dosing strength of 10 µg, administered as single dose IV infusion over 15 minutes. It will be prepared by dissolving a hemisuccinate salt (GSK2269557T) in normal saline. intervention 2: GSK2269557 DPI will be available with dosing strength of 1000 µg, administered as oral inhalation intended to inhale twice. It will be prepared by blending GSK2269557 hemisuccinate salt (GSK2269557H) with lactose and magnesium stearate. intervention 3: The \[14C\]-GSK2269557 solution will be available with dosing strength of 800 µg, administered as single dose orally. It will be prepared by dissolving \[14C\]-GSK2269557 hemisuccinate salt (GSK2269557T) in water.

Protocol documents:
Prot_000.pdf: 
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GlaxoSmithKline group of companies 
 
 
 
1 
 
TITLE PAGE 
Protocol Title: An open-label study in healthy male subjects, to determine the excretion 
balance and pharmacokinetics of [14C]-GSK2269557, administered as a single 
intravenous microtracer (concomitant with an inhaled non-radiolabelled dose) and a 
single oral dose. 
Protocol Number: 206764 Amendment 01 
Short Title: Absorption & elimination of radiolabelled GSK2269557 
Compound Number: GSK2269557 
 
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 2017-002347-16 
Approval Date: 30-OCT-2017 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment1 
30-Oct-2017 
Original Protocol 
09-Aug-2017 
 
Amendment 1 30-OCT-2017 
Overall Rationale for the Amendment:  
Protocol Amendment 1 was put in place to: 
• Respond to comments from the Regulatory Authority: Medicines and Healthcare 
Products Regulatory Authoring. 
• Reflect an update to the Investigator’s Brochure (IB) published since approval of 
the original protocol. 
A description of changes and rationale are provided in the table below.  The previous 
protocol version text is shown with strikethrough revision marks denoting removed text; 
bold text denotes new text that has been added in this amendment. 
Section #  
and Name 
Description of Change 
Brief Rationale 
6.2. 
Exclusion 
Criteria 
Addition of exclusion criteria 26: 
Known sensitivity to any of the study treatments, or 
components thereof (including lactose and magnesium 
stearate [MgSt]), or drug or other allergy that, in the opinion of 
the investigator or medical monitor, contraindicates 
participation in the study. 
MHRA request 
8.1.3.  Other 
study 
stopping 
criteria 
 
A participant will be discontinued from the study if they experience a 
serious adverse event and/or unacceptable adverse events, as 
determined by the investigator and/or medical monitor.  Every 
effort should be made to complete safety follow-up procedures 
after a participant is discontinued from study drug. 
MHRA request 
5.5.1. 
GSK2269557 
Dose  
For more detailed information on the clinical pharmacokinetics, see 
the GSK2269557 IB [GlaxoSmithKline Document Number 
2012N141231_06 2012-N141231_07]. and the Supplement to 
GSK2269557 IB [GlaxoSmithKline Document Number 
2017N324691_00]. 
(References to Investigator’s Brochure also updated in Section 3). 
New Investigator’s 
Brochure (version 8) 
published on 22 Sep 
2017. 
9.4.2. Vital 
Signs 
For time points where vital signs are collected in triplicate, only 
systolic and diastolic blood pressure, and pulse rate should be 
repeated.  There should be at least a 2 minute interval between 
readings.   
Clarification of vital sign 
parameters required to 
be measured in 
triplicate. 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ............................................................................................................... 7 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 10 
3. 
INTRODUCTION .................................................................................................... 15 
3.1. 
Study Rationale .......................................................................................... 15 
3.2. 
Background ................................................................................................ 15 
3.3. 
Benefit/Risk Assessment ............................................................................ 16 
3.3.1. 
Risk Assessment ......................................................................... 17 
3.3.2. 
Benefit Assessment ..................................................................... 21 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 21 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 21 
5. 
STUDY DESIGN .................................................................................................... 22 
5.1. 
Overall Design ............................................................................................ 22 
5.1.1. 
Screening Period ......................................................................... 23 
5.1.2. 
Study Periods .............................................................................. 23 
5.1.3. 
Follow-up ..................................................................................... 24 
5.2. 
Number of Participants ............................................................................... 25 
5.3. 
Participant and Study Completion ............................................................... 25 
5.4. 
Scientific Rationale for Study Design .......................................................... 25 
5.5. 
Dose Justification ........................................................................................ 25 
5.5.1. 
GSK2269557 Dose ...................................................................... 25 
5.5.2. 
Radiolabel Dose .......................................................................... 27 
6. 
STUDY POPULATION ........................................................................................... 27 
6.1. 
Inclusion Criteria ......................................................................................... 27 
6.2. 
Exclusion Criteria ........................................................................................ 28 
6.3. 
Lifestyle Restrictions ................................................................................... 30 
6.3.1. 
Meals and Dietary Restrictions .................................................... 30 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 30 
6.3.3. 
Activity ......................................................................................... 31 
6.4. 
Screen Failures........................................................................................... 31 
7. 
TREATMENTS ....................................................................................................... 31 
7.1. 
Treatments Administered ............................................................................ 32 
7.2. 
Dose Modification ....................................................................................... 33 
7.3. 
Method of Treatment Assignment ............................................................... 33 
7.4. 
Blinding ....................................................................................................... 33 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 33 
7.6. 
Treatment Compliance ................................................................................ 33 
7.7. 
Concomitant Therapy.................................................................................. 34 
7.8. 
Treatment after the End of the Study .......................................................... 34 
8. 
DISCONTINUATION CRITERIA ............................................................................. 35 
8.1. 
Discontinuation of Study Treatment ............................................................ 35 


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8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 35 
8.1.2. 
QTc Stopping Criteria .................................................................. 35 
8.1.3. 
Other study stopping criteria ........................................................ 36 
8.1.4. 
Temporary Discontinuation .......................................................... 36 
8.2. 
Withdrawal from the Study .......................................................................... 36 
8.3. 
Lost to Follow Up ........................................................................................ 36 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 37 
9.1. 
Efficacy Assessments ................................................................................. 38 
9.2. 
Adverse Events........................................................................................... 38 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 38 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 39 
9.2.3. 
Follow-up of AEs and SAEs ......................................................... 39 
9.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 39 
9.2.5. 
Pregnancy ................................................................................... 39 
9.3. 
Treatment of Overdose ............................................................................... 39 
9.4. 
Safety Assessments ................................................................................... 40 
9.4.1. 
Physical Examinations ................................................................. 40 
9.4.2. 
Vital Signs .................................................................................... 40 
9.4.3. 
Electrocardiograms ...................................................................... 41 
9.4.4. 
Clinical Safety Laboratory Assessments ...................................... 41 
9.4.5. 
Local Tolerability .......................................................................... 42 
9.5. 
Pharmacokinetics ....................................................................................... 42 
9.5.1. 
Blood Sample Collection .............................................................. 42 
9.5.2. 
Urine Sample Collection .............................................................. 42 
9.5.3. 
Faecal Sample Collection ............................................................ 43 
9.5.4. 
Bile Collection .............................................................................. 43 
9.5.5. 
Sample Analysis .......................................................................... 43 
9.6. 
Pharmacodynamics .................................................................................... 44 
9.7. 
Genetics ..................................................................................................... 44 
9.8. 
Biomarkers ................................................................................................. 44 
10. STATISTICAL CONSIDERATIONS ........................................................................ 44 
10.1. 
Sample Size Determination ........................................................................ 44 
10.2. 
Populations for Analyses ............................................................................ 44 
10.3. 
Statistical Analyses ..................................................................................... 45 
10.3.1. 
Pharmacokinetic Analyses ........................................................... 45 
10.3.2. 
Metabolite profiling ....................................................................... 46 
10.3.3. 
Safety Analyses ........................................................................... 46 
11. REFERENCES ....................................................................................................... 47 
12. APPENDICES ........................................................................................................ 48 
12.1. 
Appendix 1:  Abbreviations and Trademarks ............................................... 48 
12.2. 
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 51 
12.3. 
Appendix 3: Study Governance Considerations .......................................... 53 
12.4. 
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 57 
12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 59 


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12.6. 
Appendix 6: Clinical Laboratory Tests ......................................................... 64 
12.7. 
Appendix 7: Protocol Amendment History ................................................... 66 
 


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1. 
SYNOPSIS 
Protocol Title: An open-label study in healthy male subjects, to determine the excretion 
balance and pharmacokinetics of [14C]-GSK2269557, administered as a single 
intravenous microtracer (concomitant with an inhaled non-radiolabelled dose) and a 
single oral dose. 
Short Title:  Absorption & elimination of radiolabelled GSK2269557 
Rationale: GSK2269557 is a potent and highly selective PI3K-delta inhibitor, being 
developed as an anti-inflammatory agent for the treatment of COPD and other 
inflammatory lung diseases.  The pharmacokinetics, absorption, distribution and 
metabolism of GSK2269557 have been studied in animals, in vitro, and in previous 
clinical studies; however, the elimination routes, intravenous pharmacokinetics and 
metabolic pathways of GSK2269557 have not been fully elucidated in humans.  This 
open-label study in 6 healthy male participants will assess the excretion balance of the 
treatment, intravenous clearance and volume of distribution, and estimate its inhaled and 
oral bioavailability.  Participants will receive [14C] radiolabelled GSK2269557, 
administered as a single microtracer by IV infusion (concomitant with an inhaled non-
radiolabelled dose of GSK2269557), and a single dose of [14C]-GSK2269557, 
administered as an oral solution.  Samples from this study will also be used to 
characterise and where possible quantify the metabolites of GSK2269557 in plasma, 
urine, faeces and duodenal bile.   
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
• To determine total radioactivity (drug related 
material) in plasma following a single IV 
microtracer of [14C]-GSK2269557 
(concomitant with an inhaled non-
radiolabelled GSK2269557 dose) and a 
single oral dose of [14C]-GSK2269557. 
• AUC (0-inf), AUC (0–t), Cmax, tmax, t1/2 of 
total drug-related material (radioactivity) in 
plasma. 
 
• To determine the rate and extent of 
excretion of total radioactivity in urine and 
faeces and the total recovery of radioactivity 
following a single IV microtracer of [14C]-
GSK2269557 (concomitant with an inhaled 
non-radiolabelled dose) and a single oral 
dose of [14C]-GSK2269557. 
• Urinary and faecal cumulative excretion as 
a percentage of the total radioactive dose 
administered over time. 


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Objective 
Endpoint 
Secondary 
• To determine parent GSK2269557 
concentration in plasma following a single 
IV microtracer of [14C]-GSK2269557 
concomitant with an inhaled non-
radiolabelled GSK2269557 dose and a 
single oral dose of [14C]-GSK2269557. 
• AUC(0-inf), AUC(0–t), Cmax, tmax, and t1/2 
of parent GSK2269557 and 
[14C]-GSK22695571 in plasma.  
• Volume and clearance of parent 
[14C]-GSK22695571 after IV dose only.   
• To estimate the absolute bioavailability of 
GSK2269557 following inhaled and oral 
administration.  
• Oral and inhaled F (absolute bioavailability). 
• To evaluate the safety and tolerability of 
GSK2269557 after single IV, oral and 
inhaled doses in healthy participants. 
• Incidence of adverse events. 
• Laboratory safety, electrocardiogram (ECG) 
and vital signs parameters. 
Exploratory  
• To generate samples that will be used to 
characterise the metabolic profile of 
GSK2269557 in plasma, urine, faeces, and 
duodenal bile (following IV dose only), 
following a single IV microtracer of 
[14C]-GSK2269557 (concomitant with an 
inhaled non-radiolabelled dose) and a 
single oral dose of [14C]-GSK2269557 
(these analytical investigations will be 
conducted and the results reported under a 
separate Platform Technology Services 
(PTS) In vitro/In vivo Translation (IVIVT), 
GlaxoSmithKline protocol). 
• Characterisation and quantification of 
metabolites in plasma, urine, faeces, and 
duodenal bile (these analytical 
investigations will be conducted and the 
results reported in a separate GSK PTS 
IVIVT protocol). 
1 For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 
describes the parent GSK2269557 concentration derived via analysis by liquid chromatography (LC) + 
Accelerator Mass Spectrometry (AMS), whereas GSK2269557 describes the parent GSK2269557 
concentration derived via liquid chromatography-tandem mass spectrometry (LC/MS). 
 
Overall Design:  This is an open-label, single centre, non-randomised, 2-period 
single-sequence crossover, mass balance study to investigate the recovery, excretion, and 
pharmacokinetics (PK) of [14C]-GSK2269557 administered as a single IV dose 
(concomitant with an inhaled non-radiolabelled dose) and a single oral dose, in healthy 
male participants. 
Number of Participants:  6 healthy male participants.  


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Treatment Groups and Duration:  Each participant will participate in the study for up 
to 11 weeks, and will have a screening visit, 2 treatment periods, and a follow-up visit.  
In each treatment period, participants will be resident in the unit from the morning before 
Day 1 (Day –1).    
On Day 1 of treatment period 1, after an overnight fast of at least 8 h, each participant 
will take 1000 µg non-radiolabelled GSK2269557 by inhalation. Within 5 min after the 
inhalation, participants will receive 10 µg [14C]-GSK2269557 (approximately 22.2 kBq; 
0.6 µCi) by IV infusion over 15 min.   Following dosing, blood, duodenal bile, urine and 
faecal samples will be collected up to 168 h after dosing (Day 8).  Participants will be 
discharged on Day 8 after completion of the 168-h post-IV dosing sample collection.  
There will be a washout of at least 14 days after inhaled and IV dosing before participants 
take the oral dose of [14C]-GSK2269557 in treatment period 2. 
On Day 1 of treatment period 2, after an overnight fast of at least 8 h, each participant 
will take 800 µg [14C] -GSK2269557 (approximately 1850 kBq; 50 µCi) as an oral 
solution.  Following dosing, blood, urine and faecal samples will be collected for a 
minimum of 168 h (up to Day 8), but could be up to 336 h (Day 15) or longer after 
dosing, depending on the amount of radioactivity excreted by each participant.  Liquid 
scintillation counting (LSC) will be performed daily on 24-h urine collections and 24-h 
faecal homogenates after Day 6 (at 144 h and 168 h from dosing).     
• If less than 1% of the dose is excreted in each 24-h period on Day 6 (120-144 h) and 
Day 7 (144-168 h) for a given participant, that participant may be discharged as early 
as Day 8 (after the LSC results are available), and no further samples will be 
collected.   
• If excretion is higher than 1%, or if the results are inconclusive, in each 24-h period 
on Day 6 (120-144 h) and Day 7 (144-168 h) for a given participant, the participant 
will remain at the unit, and urine and faecal collections will continue at 24-h intervals, 
for up to 7 days (until the morning of Day 15).  If less than 1% of the dose is excreted 
in any of the 24-h periods between Day 7 and Day 15, that participant will be 
discharged.  All remaining participants will be discharged from the unit on Day 15.   
• In the unlikely event that excretion is still higher than 1% upon discharge on Day 15, 
the participants will continue to collect faecal samples only, at home, at 24-h 
intervals.  Samples will be returned to the unit every 2–3 days for analysis.    
Bile samples will be collected after the IV microtracer only, using Entero-Test string 
sampling of duodenal bile (subject to commercial availability).   
Plasma samples will be prepared (from collected blood samples) to measure parent drug 
(GSK2269557, [14C]-GSK2269557) and total radiolabelled drug-related material.  Urine 
and faecal samples will be collected to measure total radiolabelled drug-related material.  
Samples of plasma, urine, bile and faeces will also be transferred to a separate study to 
characterise and, where possible, quantify metabolites in those matrices. 
Safety data will include AE reporting, 12-lead ECG, vital signs, and laboratory safety 
tests. 


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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Schedule of activities for Treatment Period 1 
Procedure 
Screening 
Treatment Period 1 (IV and inhaled dosing) 
Day 
–30 to –1 
−1 
1 
2 
3 
4 
5 
6 
7 
8 
Pre-
dose 
Post- dose 
0–16 h 
24 h 
48 h 
72 h 
96 h 
120 h 
144 h 
168 h 
Admission to Unit 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from Unit 
 
 
 
 
 
 
 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Full Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
Brief Physical Exam 
 
X 
 
 
 
 
 
 
 
 
X 
Inhaler training1 
 
X 
 
 
 
 
 
 
 
 
 
Medical/medication/drug/alcohol history 
X 
 
 
 
 
 
 
 
 
 
 
HIV, Hep B and Hep C screen 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol and cotinine tests, and urine drugs of 
abuse2 
X 
X 
 
 
 
 
 
 
 
 
 
Laboratory safety tests 
X 
X 
X 
 
X 
 
 
 
 
 
X 
12-lead ECG3 
X  
X  
X  
X 
X 
 
 
 
 
 
X 
Vital signs (HR and BP)3 
X  
X  
X  
X 
X 
 
 
 
 
 
X 
Inhaled dose  
 
 
X 
 
 
 
 
 
 
 
IV infusion 
 
 
 
X4 
 
 
 
 
 
 
 
Local tolerability assessment5 
 
 
 
X 
X 
X 
 
 
 
 
 
Blood samples for background radiation, total 
radioactivity, [14C]-GSK2269557 analysis and cold 
GSK2269557 analysis6 
X7 
X7 
X7,8 
X 
X 
X 
X 
X 
 
 
X 


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Procedure 
Screening 
Treatment Period 1 (IV and inhaled dosing) 
Day 
–30 to –1 
−1 
1 
2 
3 
4 
5 
6 
7 
8 
Pre-
dose 
Post- dose 
0–16 h 
24 h 
48 h 
72 h 
96 h 
120 h 
144 h 
168 h 
Blood samples for metabolite profiling 
 
 
X8 
X9 
 
 
 
 
 
 
 
Urine collection10,11 
 
 
X  
X  
X 
X 
X 
X 
X 
X 
X 
Faecal collection12,13 
 
 
X13 
X  
X 
X 
X 
X 
X 
X 
X 
Entero-Test14 
 
 
 
 
 
 
 
 
 
Meals15 
 
 
 
X 
 
 
 
 
 
 
 
AE/concomitant medication review16 
 
 
1. 
Training conducted by reviewing the Patient Information Leaflet with the participant. Additional training may be conducted at the discretion of the 
investigator. 
2. 
Breath test will be performed to check alcohol consumption. Both CO breath tests and urine cotinine tests will be performed to check smoking state. 
3. 
Triplicate measurements will be taken at screening and pre-dose on Day 1; single measurements will be taken at 6 h post-dose on Day 1 and at all other time 
points.  Mean of triplicate measurements to be used as baseline.  
4. 
IV infusion to begin as soon as possible (but within 5 min) after the start of the inhaled dose. 
5. 
Local tolerability assessment for injection site reactions will be performed immediately after the end of dosing on Day 1 at 6 and 12 h, and on Days 2 and 3. 
6. 
Sampling times relative to the start of the IV infusion.  Blood samples for total radioactivity, [14C]-GSK2269557 analysis and cold GSK2269557 analysis will 
be taken:  pre-dose and at 0h (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 h 
after the start of infusion. 
7. 
Background radiation sample taken at screening, Day –1 and pre-dose only.   
8. 
An additional pre-dose blood sample may be taken from 1 participant for preparation of a plasma shipment control (details provided in the SRM).  
9. 
Blood samples for plasma metabolite profiling will be collected at 0.5 h and 4 h after the start of the IV infusion. 
10. 
An aliquot from each urine collection will be taken for metabolic profiling (separate study). 
11. 
Sampling times relative to the start of the IV infusion.  Urine will be collected at pre-dose, 0-6 h, 6-24 h then over 24 h collection periods as follows: 24-48 h, 
48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h.   
12. 
An aliquot from each homogenised faecal collection will be taken for metabolic profiling (separate study). 
13. 
Sampling times relative to the start of IV infusion.  The pre-dose faecal collection sample can be collected up to 24 h pre-dose. Afterward faeces will be 
collected over 24 h collection periods as follows: 0-24 h, 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168h. 
14. 
Entero-Test string device will be swallowed at approximately 3.5 h pre-dose (start of inhaled dose) while participants are in a fasted state and the string 
removed at about 2.5 h post-dose on Day 1. At about 0.5 h post-dose (i.e. 2 hours before string withdrawal) a food cue will be used to stimulate gall bladder 
emptying). 


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15. 
Meal times are 30 min, 4 h and 10 h post dose on Day 1.  On all other days, meals will be served at the standard times for the unit.  
16. 
AEs and SAEs will be collected from the signing of the ICF until the follow-up visit. However, any SAEs related to study participation or a GSK concomitant 
medication will be recorded from the time a participant consents to participate in the study and until the final follow-up visit contact. 


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Schedule of activities for treatment period 2 
Procedure 
Treatment Period 2 (Oral dosing) 
Follow-up 
Day  
(7-14 days 
post-last 
dose)2,3  
 -1 
11 
2 
3 
4 
5 
6 
7 
8 
  
Pre-
dose 
Post-dose 
0-16 h 
24 h 
48 h 
72 h 
96 h 
120 h 
144 h 
168 h 
  
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
Discharge from Unit2,3 
  
  
  
  
  
  
  
  
  
X 
  
Drugs of abuse 
X 
  
  
  
  
  
  
  
  
  
  
Alcohol and cotinine tests4 
X 
  
  
  
  
  
  
  
  
  
  
Brief Physical Exam 
  
X 
  
  
  
  
  
  
  
  
X 
Laboratory safety tests 
X 
X 
  
X 
  
  
  
  
  
X 
X 
12-lead ECG 
X 
X 
X5 
X 
  
  
  
  
  
X  
X  
Vital signs (HR and BP) 
X 
X 
X5 
X 
  
  
  
  
  
X  
X  
Oral dose 
  
X 
  
  
  
  
  
  
  
  
Blood samples for total 
radioactivity, 
[14C]-GSK2269557 analysis and 
cold GSK2269557 analysis 
  
X6 
X 
X 
X 
X 
X 
  
  
X 
  
Blood samples for metabolite 
profiling 
 
X 
X7 
X 
 
 
 
 
 
 
 
Urine collection8,9 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Faecal collection10,11 
  
X11 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
Meals13 
  
  
X 
  
  
  
  
  
  
  
  


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Procedure 
Treatment Period 2 (Oral dosing) 
Follow-up 
Day  
(7-14 days 
post-last 
dose)2,3  
 -1 
11 
2 
3 
4 
5 
6 
7 
8 
  
Pre-
dose 
Post-dose 
0-16 h 
24 h 
48 h 
72 h 
96 h 
120 h 
144 h 
168 h 
  
AE/concomitant medication 
review14 
  
 
 
1. There will be a washout of at least 14 days between dosing in treatment period 1 and 2. 
 
 
 
 
 
 
 
 
2. If less than 1% of the dose is excreted in each 24 h period on Day 6 (120-144 h) and Day 7 (144-168 h) for a given participant, the participant may be discharged 
as early as Day 8 (after the LSC results are available), and no further samples (apart from for laboratory safety tests) will be collected.  Follow-up procedures 
may be done at discharge and procedures scheduled for Day 8 and follow up will only be done once.  
3. If excretion is higher than 1%, or if the results are inconclusive in each 24-h period on Day 6 (120-144 h) and Day 7 (144-168 h) for a given participant, that 
participant will remain at the unit, and urine and faecal collections will continue at 24-h intervals, for up to 7 days (until the morning of Day 15), until excretion 
is less than 1%.  All remaining participants will be discharged from the unit on Day 15.  Follow-up procedures may be done at discharge.  In the unlikely event 
that excretion is still higher than 1% upon discharge on Day 15, participants will continue to collect faecal samples only, at home, at 24-h intervals.  Samples 
collected at home will be returned to the clinic every 2-3 days. 
 
 
 
4. Breath test will be performed to check alcohol consumption. Both CO breath tests and urine cotinine tests will be performed to check smoking state. 
 
5. Vital signs and ECG will be taken 6 h post dose.  
 
 
 
 
 
 
6. Sampling times relative to the oral dose.  Blood samples for total radioactivity, [14C]-GSK2269557 analysis and cold GSK2269557 analysis will be taken:  pre-
dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose. 
7. Blood samples for plasma metabolite profiling will be collected at 2 h and 6 h post-[14C]-GSK2269557oral dose. 
 
 
 
 
 
8. An aliquot from each urine collection will be taken for metabolic profiling (separate study). 
 
 
 
 
 
 
 
9. Urine will be collected at pre-dose, at 0-6 h, 6-24 h then over 24 h collection periods as follows: 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h. 
10. An aliquot from each faecal collection will be taken for metabolic profiling (separate study).  
 
 
 
 
 
 
 
11. The pre-dose faecal sample can be collected up to 24 h pre-dose. Afterward faeces will be collected over 24 h collection periods as follows: 0-24 h, 24-48 h, 48-
72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h.  
 
 
 
 
 
 
 
 
 
 
12. If dose excretion is still higher than 1% after day 15 the participants will continue to collect faecal samples only, at home, at 24-h intervals until excretion is less 
than 1%. 
13. Meal times are 4h and 10h post dose on Day 1.  On all other days, meals will be served at the standard times for the unit.  
 
 
 
 
14. AEs and SAEs will be collected from the signing of the ICF until the follow-up visit. However, any SAEs related to study participation or a GSK concomitant 
medication will be recorded from the time a participant consents to participate in the study and until the final follow-up visit contact. 
 


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3. 
INTRODUCTION 
3.1. 
Study Rationale 
This open-label study in 6 healthy male participants will assess the excretion balance of 
GSK2269557 in humans, using [14C]-radiolabelled drug substance administered orally 
and as an intravenous (IV) infusion.  [14C]-GSK2269557 administered by IV infusion 
will be a microtracer; therefore, it will be administered concomitantly to an inhaled 
non-radiolabelled dose.  This will be done in order to ensure that the pharmacokinetics 
represent a clinically relevant dose.  The study will also provide an assessment of the 
bioavailability of GSK2269557 following oral and inhaled administration. 
The pharmacokinetics, absorption, distribution and metabolism of GSK2269557 have 
been investigated through a series of IV, oral, intratracheal or inhaled studies in animals, 
and in in vitro studies using unlabelled GSK2269557.  Only preliminary data are 
available so far for in human pharmacokinetics. GSK2269557 has been administered to 
humans in several clinical trials all via the inhalation route across a range of doses up to 
3200 mcg twice daily for 7 Days in healthy volunteers and up to 1000 mcg once daily for 
84 Days to exacerbating chronic obstructive pulmonary disease (COPD) patients.  
Definitive absorption, distribution, metabolism and excretion (ADME) characteristics 
derived from this study will provide important understanding of GSK2269557 in human 
including routes of elimination and metabolic pathways. 
 
This study will use the Entero-Test (Entero-Test: HDC Corp., Mountain View, CA; or 
alternative source subject to commercial availability) for sampling of duodenal bile to 
conduct qualitative assessment of drug metabolites in this matrix in order to characterise 
biliary elimination pathways.   
Samples from this study will also be used to characterise, where possible, and quantify 
the metabolites of GSK2269557 in plasma, urine, faeces and duodenal bile. 
3.2. 
Background 
GSK2269557 is a potent and highly selective inhaled phosphoinositide 3-kinase (PI3K)-
delta (δ) inhibitor, being developed as an anti-inflammatory agent for the treatment of 
COPD and other inflammatory lung disease such as asthma.  PI3Kδ is a member of the 
Class IA family of PI3Ks, that converts the membrane phospholipid phosphatidylinositol 
4,5-biphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3).  PIP3 is a 
second messenger in many cellular processes including cell growth, differentiation and 
migration.  
PI3Kδ has specific roles in mediating antigen receptor and cytokine signalling in T-cells, 
mast cells and B-cells PI3Kδ is thought to play an important part in various epithelial 
responses relevant for the development of COPD and asthma. 
COPD is an umbrella term for the two disease processes: chronic bronchitis and 
emphysema.  COPD invariably has a degree of both, though one phenotype/process may 
predominate in any individual.  Inflammation has been linked to the pathogenesis of 
COPD.  Tobacco smoke or other irritants activate epithelial cells and macrophages to 


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release inflammatory mediators, such as chemokines, that attract neutrophils and T-cells 
to the lungs.  Both neutrophil and T-cell are targets of PI3Kδ inhibitors.   
Chronic inflammation in the lung is also linked to the pathogenesis of asthma.  
Inflammation in asthma is associated with a T-cell response to allergens in the lung, with 
Th2 cytokines driving the differentiation, survival and function of the major effector cells 
involved in the allergic cascade.  Th2 cells also play an essential role in the increased 
production of allergen-specific Immunoglobulin E (IgE) by B-cells.  IgE mediates type I 
hypersensitivity allergic responses and the orchestration of local chronic allergic 
inflammation.  Therefore, suppression of the Th2 drive in the lung has the potential to be 
disease modifying in asthma patients.  GSK2269557 has been shown in vivo to 
potentially block T-cell activation in the lung, via reducing the production of pro-
inflammatory Th2 cytokines interleukin (IL)-13, IL4 and IL-5, thus preventing 
recruitment of inflammatory cells to the lung. 
As a PI3Kδ inhibitor, GSK2269557 has the potential to inhibit the major cell types 
responsible for the inflammation associated with both COPD and asthma.  GSK2269557 
has already been administered as a nebulised solution and dry powder formulation in 
single and repeated doses to humans and has been well tolerated across the range of doses 
used.  A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2269557 is provided in the Investigator’s Brochure [ GlaxoSmithKline Document 
Number 2012N141231_07].  
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2269557 may be found in the Investigator’s 
Brochure[ GlaxoSmithKline Document Number 2012N141231_07]. Section 3.3.1 
outlines the risk assessment and mitigation strategy for this protocol:


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3.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product [e.g. GSK2269557] 
Radioactivity exposure risk 
([14C]-GSK2269557) 
The total effective dose associated with IV and oral 
administrations of [14C]-GSK2269557 is 0.75 mSv.  That 
effective dose is within the lower end of WHO 
recommendation (0.5 to 5 mSv) for Category II projects, 
which is considered to be within dose limits for members 
of the public.  The total effective dose is also below the 
GlaxoSmithKline Global Safety Board level of radiation 
which would require specific additional justification and 
exemption (10 mSv). 
Participants will be monitored for recovery of 
radioactivity throughout the study. 
 
Bronchospasm 
Can potentially occur with any inhaled treatment. 
All doses of study treatment will be administered 
in the clinical pharmacology unit in the presence 
of trained clinical staff.  
Treatment with a short-acting inhaled 
bronchodilator will be available. GSK2269557 
should be discontinued immediately, the 
participant assessed and, if necessary, an 
alternative therapy instituted as deemed 
appropriate by the investigator or the attending 
physician. Participants will be withdrawn from the 
study. 
 
 
 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Mucosal irritancy 
Detected in 13 week toxicology study in the dog. 
Participants will be regularly monitored for AEs. 
No evidence of mucosal irritancy has been seen 
so far in clinical studies. 
Exposure to GSK2269557 
The total systemic exposure of GSK2269557 from the 
combined IV microtracer (10 μg) and inhaled dose 
(1000 μg) is predicted to be below the systemic exposure 
from the highest dose of GSK2269557 tested in previous 
human studies (a single inhaled nebulised dose of 
6400 μg).  The oral dose to be tested is 800 µg.  Overall 
GSK2269557 has been well tolerated in previous clinical 
studies and has an acceptable safety profile.  The most 
commonly observed AEs have been cough and 
headache. 
In addition to taking samples for pharmacokinetic 
analysis of GSK2269557, pharmacodynamic 
markers of GSK2269557 will be monitored: HR 
and QTc measurements will be taken, 
haematology and clinical chemistry will be 
monitored as part of the panel of laboratory 
safety tests. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Procedures  
Intravenous Dosing – Pain at the 
injection site 
GSK2269557 has not previously been administered by IV 
infusion in humans.  Doses of 12 µg/kg, 360 µg/kg and 
1200 µg/kg of GSK2269557, dissolved in a 5% dextrose 
in water solution, were given as a 1 hour IV infusion 
(5 mL/kg/hr dosing volume) to male rats, in a rat 
cardiovascular study.  No irritancy at site of injection has 
been reported for the study.  
• Participants will be monitored for signs of 
pain at the injection site.  Paracetamol or 
Acetaminophen, at doses of ≤ 2 g/day can 
be taken if required.  
Entero-Test for bile collection risk 
 
The use of the Entero-Test has been approved by the 
European regulatory authorities (ISO 9001 and CE Mark 
Certification; European Union Medical Devices Directive 
(MDD)).   
• Streaks of blood on the string due to local irritation 
have been infrequently noted.  
• Rarely, a patient will be unable to swallow the 
capsule because of gagging or will vomit after doing 
so.   
• Gagging upon retrieval of the string can occur. 
• On a few occasions, an entire string has been 
swallowed without ill effects and passes out from the 
body in the faeces.   
• The string will be securely taped in place 
(to the cheek of each individual) during the 
collection time to minimise risk of 
swallowing the entire string.   
• Any participant incapable of swallowing the 
string will be allowed to participate in the 
study without duodenal bile collection.  
 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Population 
Post-inhalation cough immediately 
following inhalation of study 
treatment (GSK2269557) 
Treatment-related, mild and moderate cough (preferred 
term) were reported as adverse events (AEs), immediately 
after dosing, in previous studies of GSK2269557 
conducted in both healthy participants and exacerbating 
COPD patients.  Additional details are provided in the 
Investigator’s Brochure [ GlaxoSmithKline Document 
Number 2012N141231_07]. 
In this study, healthy participants will receive a 
single inhaled dose during treatment period 1.   
Participants will be in the presence of clinical 
staff during their 7-day post-dose residence at 
the clinical pharmacology unit and will be 
regularly monitored for AEs. 
Inclusion of volunteers >30 years 
and <55 years (inclusive) 
Justification of the use of healthy volunteers below the 
age of 50 years is required in accordance with the 
guidelines of the Administration of Radioactive 
Substances Advisory Committee and the Association of 
the British Pharmaceutical Industry, as well as GSK 
internal policies.  In this study, healthy male volunteers 
between 30 and 55 years will be enrolled.  This is 
acceptable, because the total effective dose of this study 
is considered to be within variations in natural background 
radiation with a minimal risk. 
Not applicable. 
 


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3.3.2. 
Benefit Assessment 
Healthy participants in this study will receive no direct medical benefit.  However, they 
may benefit from the knowledge that they are contributing to the process of developing a 
new treatment in an area of unmet need.  They might also benefit from the thorough 
medical assessments they receive during the course of the study. 
3.3.3. 
Overall Benefit:Risk Conclusion 
It is considered acceptable to conduct this study in healthy participants, because whilst 
they will receive no direct medical benefit, the risks from the study treatment and 
procedures are minimal.  The study will be conducted in a fully equipped clinical 
pharmacology unit with access to hospital emergency facilities. 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To determine total radioactivity (drug related 
material) in plasma following a single IV 
microtracer of [14C]-GSK2269557 
(concomitant with an inhaled non-
radiolabelled GSK2269557 dose) and a 
single oral dose of [14C]-GSK2269557. 
• AUC(0-inf), AUC(0–t), Cmax, tmax, t1/2 of 
total drug-related material (radioactivity) in 
plasma. 
 
• To determine the rate and extent of 
excretion of total radioactivity in urine and 
faeces and the total recovery of radioactivity 
following a single IV microtracer of 
[14C]-GSK2269557 (concomitant with an 
inhaled non-radiolabelled dose) and a 
single oral dose of [14C]-GSK2269557. 
• Urinary and faecal cumulative excretion as 
a percentage of the total radioactive dose 
administered over time. 
Secondary 
• To determine parent GSK2269557 
concentration in plasma following a single 
IV microtracer of [14C]-GSK2269557 
(concomitant with an inhaled 
non-radiolabelled GSK2269557 dose) and a 
single oral dose of [14C]-GSK2269557. 
• AUC(0-inf), AUC(0–t), Cmax, tmax, and t1/2 
of parent GSK2269557 and 
[14C]-GSK22695571 in plasma.  
• Volume and clearance of parent 
[14C]-GSK2269557 1 after IV dose only.   
• To estimate the absolute bioavailability of 
GSK2269557 following inhaled and oral 
administration. 
• Oral and inhaled F (absolute bioavailability). 


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Objectives 
Endpoints 
• To evaluate the safety and tolerability of 
GSK2269557 after single IV, oral and 
inhaled doses in healthy participants. 
• Incidence of adverse events 
• Laboratory safety, electrocardiogram (ECG) 
and vital signs parameters. 
Exploratory 
• To generate samples that will be used to 
characterise the metabolic profile of 
GSK2269557 in plasma, urine, faeces, and 
duodenal bile (following IV dose only), 
following a single IV microtracer of 
[14C]-GSK2269557 (concomitant with an 
inhaled non-radiolabelled dose) and a 
single oral dose of [14C]-GSK2269557 
(these analytical investigations will be 
conducted and the results reported under a 
separate Platform Technology Services 
(PTS) In vitro/In vivo Translation (IVIVT), 
GlaxoSmithKline protocol). 
• Characterisation and quantification of 
metabolites in plasma, urine, faeces, and 
duodenal bile (these analytical 
investigations will be conducted and the 
results reported in a separate GSK PTS 
IVIVT protocol). 
 
1 For measured concentrations of GSK2269557 in blood plasma, the nomenclature 
[14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by 
LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via 
LC/MS. 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is an open-label, single centre, non-randomised, 2-period, single-sequence 
crossover, mass balance study to investigate the recovery, excretion, and 
pharmacokinetics of [14C]-GSK2269557 administered as a single IV dose (concomitant 
with an inhaled non-radiolabelled dose) and a single oral dose, in healthy male 
participants. 
Each participant will participate in the study for up to 11 weeks, and will have a 
screening visit, 2 treatment periods, and a follow up visit (see Figure 1).  If excretion is 
higher than 1%, or if the results are inconclusive, upon discharge on Day 15 (if 
participants haven’t been discharged before then), participants will continue to collect 
faecal samples only, at home, at 24-h intervals which will be returned to the clinic every 
2-3 days. 
 
 


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Figure 1 
Study design schematic. 
 
5.1.1. 
Screening Period 
Participants must be screened within 30 days before the first dose, and must meet all 
eligibility criteria.   
5.1.2. 
Study Periods 
The study will be divided into treatment periods 1 (concomitant IV and inhaled dosing) 
and 2 (oral dosing).  In each treatment period, participants will be resident in the unit 
from the afternoon before Day 1 (Day –1).  
On Day 1 of treatment period 1, after an overnight fast of at least 8 h, each participant 
will take 1000 µg non-radiolabelled GSK2269557 by inhalation.  Within 5 min after the 
inhalation, participants will receive 10 µg [14C]-GSK2269557 (approximately 22.2 kBq; 
0.6 µCi) by IV infusion over 15 min.  Following dosing, blood, duodenal bile, urine and 
faecal samples will be collected up to 168 h after dosing (Day 8).   
Participants will be discharged on Day 8 after completion of the 168-h post-IV dosing 
sample collection.  There will be a washout of at least 14 days after inhaled and IV 
dosing before participants take the oral dose of GSK2269557 in treatment period 2. 
On Day 1 of treatment period 2, after an overnight fast of at least 8 h, each participant 
will take 800 µg [14C]-GSK2269557 (50 µCi or 1850 kBq) as an oral solution.  Following 
dosing, blood, urine and faecal samples will be collected for a minimum of 168 h (up to 
Day 8), but could be up to 336 h (Day 15) or longer after dosing, depending on the 
amount of radioactivity excreted by each participant.  Liquid scintillation counting (LSC) 
will be performed daily on 24 h urine collections and 24 h faecal homogenates after 
Day 6 (at 144 h and 168 h from dosing).   


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• If less than 1% of the dose is excreted in each 24-h period on Day 6 (120–144 h) and 
Day 7 (144–168 h) for a given participant, that participant may be discharged as early 
as Day 8 (after the LSC results are available), and no further samples will be 
collected.   
• If excretion is higher than 1%, or if the results are inconclusive in each 24-h period on 
Day 6 (120-144h) and Day 7 (144-168h) for a given participant, the participant will 
remain at the unit, and urine and faecal collections will continue at 24-h intervals, for 
up to 7 days (until the morning of Day 15).  If less than 1% of the dose is excreted in 
any of the 24-h periods between Day 7 and Day 15, that participant will be 
discharged.  All remaining participants will be discharged from the unit on Day 15.   
• In the unlikely event that excretion is still higher than 1% upon discharge on Day 15, 
the participants will continue to collect faecal samples only, at home, at 24-h 
intervals.  Samples will be returned to the unit every 2–3 days for analysis.    
The Entero-Test to measure duodenal bile will be used (subject to commercial 
availability) only for Treatment 1 (IV dosing).  The Entero-Test will be inserted about 3.5 
h before the start of the IV infusion while participants are in a fasted state, and it will be 
removed about 2.5 h after the end of the IV infusion.  About 0.5 h after the end of the IV 
infusion (2 h before string withdrawal) a food cue will be used to stimulate gall bladder 
emptying. 
Plasma samples will be prepared (from collected blood samples) to measure parent drug 
(GSK2269557, [14C]-GSK2269557) and total radiolabelled drug-related material.  Urine 
and faecal samples will be collected to measure total radiolabelled drug-related material.  
Samples of plasma, urine, bile and faeces will also be transferred to a separate study to 
characterise and, where possible, quantify metabolites in those matrices. 
Safety data will include AE reporting, 12-lead ECG, vital signs, and laboratory safety 
tests. 
5.1.3. 
Follow-up 
Follow-up procedures will be done 7–14 days after the last dose, and can be done on the 
day of discharge or at a separate visit.  
The follow-up period may be extended if: 
(i) 
radioactivity excretion is still higher than 1% 
(ii) 
a participant has an unresolved AE at the follow-up visit, which, in the opinion of 
the investigator, merits further follow-up;  
(iii) 
new information becomes available that supports an extended follow-up period. 
The investigator will decide on the nature of the extended follow-up.  For example, 
participants may have a telephone follow-up at which they are asked about AEs, or 
participants may be asked to attend extra outpatient visits for additional monitoring of 
blood levels or, and for extra safety tests.  The extra safety tests might include tests that 
are not described in this protocol.  The investigator reserves the right, during or after the 
study, to repeat safety tests or to do any extra safety tests that are in the best interest of 
the participants.  Those extra tests may or may not be described in this protocol. 


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5.2. 
Number of Participants 
Six healthy male participants will be enrolled.  Refer to Section 10.1 for details on 
sample size determination. 
If participants prematurely discontinue the study, additional replacement participants may 
be enrolled at the discretion of the sponsor and in consultation with the investigator. 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he has completed all phases of 
the study including the last visit.  
The end of the study is defined as the date of the last visit of the last participant in the 
study for the last participant in the trial. 
5.4. 
Scientific Rationale for Study Design 
In this study, a single IV microtracer of [14C]-GSK2269557 (concomitant with an inhaled 
non-radiolabelled dose) and a single oral dose of [14C]-GSK2269557, will be 
administered. 
It is not technically possible to administer a radiolabelled inhaled dose of GSK2269557; 
therefore oral and IV doses will be used as surrogates.  Oral administration is a surrogate 
for the swallowed portion of an inhaled dose. IV administration is a surrogate for the 
exposure resulting from the portion of the inhaled dose being absorbed into the systemic 
circulation.  As an IV microtracer is being used, it will be administered concomitant to an 
inhaled non-radiolabelled dose, to ensure that the pharmacokinetics represent a clinically 
relevant dose.   
Metabolic elimination pathways will be characterised after the IV dose to include the 
planned collection of duodenal bile.  Complexities in human faecal sample analysis such 
as extraction, stability in the gastrointestinal (GI) tract, and endogenous contamination 
are minimised through assessment of the metabolic profile in duodenal bile. 
5.5. 
Dose Justification 
5.5.1. 
GSK2269557 Dose 
This study will test single doses of GSK2269557, administered via different routes to 
healthy volunteers, in order to characterise the ADME properties of GSK2269557 in 
human.  GSK2269557 is being developed for inhaled delivery and has been administered 
via inhalation at higher doses (6400 µg via nebulisation) than those proposed in this study 
(1000 µg).  GSK2269557 has also been administered via inhalation, using the Diskus 
device, as a repeated dose of 1000 µg for 84 days to patients experiencing an 
exacerbation of COPD (study 116678).  The inhaled dose of 1000 µg proposed in this 
study has been chosen to match the clinical material (device and formulation) for phase 
2b and beyond, and to give a sufficient single dose to aid quantification of analytes.  


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The intravenous and oral dose routes have not previously been tested in humans, although 
testing has been conducted in pre-clinical studies.  One of the purposes of the intravenous 
data is to define plasma pharmacokinetics and, in particular, central clearance rate from 
plasma.  The proposed intravenous dose of 10 µg (given over a 15 minute infusion) 
represents less than 0.2% of the highest dose tested in humans (6400 µg) and is therefore 
expected to be well within the exposures generated previously.  This includes the 
concomitant cold inhaled dose at 1000 µg.  Due to absorption or first passes clearance 
effects; the oral dose of 800 µg is not expected to achieve systemic exposures close to 
those of an equivalent inhaled dose.  However, based on previous data generated in 
humans using charcoal block (study 201544), exposure via this route is expected.  In this 
study, approximately 23% of the systemic exposure of an inhaled 200 µg dose was 
attributable to the orally absorbed drug.  
Table 1 shows the approximate estimates for exposures to participants following both 
treatment periods 1 and 2 using pharmacokinetic information obtained to date using a 
range of assumptions as detailed in the table.  Systemic exposure multiples have been 
calculated based on both pre-clinical data and clinical experience with GSK2269557. 
Table 1 
Approximate estimates for exposures to participants 
Period/Regimen 
Parameter1 
Exposure Margin 
Pre-clinical2 
Clinical3 
1 = 1000 µg 
Inhaled + 10 µg IV 
Cmax (ng/mL) 
13 
2 
AUC0−24h (ng.h/mL) 
19 
6 
2 = 800 µg Oral 
Cmax (ng/mL) 
94 
11 
AUC0−24h (ng.h/mL) 
78 
23 
1. 
Using the geometric mean measured exposed individual based on study 201544 (200 µg top 
dose Day 1) to generate (linear extrapolation including an increase of 1.71 fold for Cmax and 
1.54-fold on AUC due to formulation differences) the exposure for a 1000 µg Inhaled dose 
concomitant with a 10 mcg intravenous dose (15 min infusion) (intravenous dose exposures 
assume 1% of inhaled exposure as worst case) based on a single dose period 1 and following 
a single oral dose of 800 µg in period 2 (assuming 60:40 lung to oral deposition using study 
data from 201544 and charcoal block and linear extrapolation). Cmax and AUC0-24h of 3.5 
ng/mL and 14.7 ng.h/mL for Period 1 and a Cmax and AUC0-24h of 0.47 ng/mL and 3.7 
ng.h/mL for Period 2 respectively. 
2. 
Based on the no observed adverse event level (NOAEL) derived from the rat 3 month 
toxicology study R29876 with a Cmax and AUC of 43.7 ng/mL and 286 ng.h/mL respectively. 
3. 
Based on the highest achieved geometric mean value derived from reported trials to date of 5.3 
ng/mL and 85 ng.h/mL based on exposure on Day 7 following repeat daily single doses (study 
PII115117). 
 
For more detailed information on the clinical pharmacokinetics, see the GSK2269557 IB 
[GlaxoSmithKline Document Number 2012N141231_07]. 


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5.5.2. 
Radiolabel Dose 
The effective dose of radiolabelled drug administered in human mass balance studies is 
calculated from data on the distribution and elimination of the radioactive drug in in vivo 
experiments.  The calculations have taken into account the nature of the isotope, the 
concentration of radioactivity in individual tissues/organs and the residence or 
elimination half-life of the radioactivity from those tissues/organs.  Following oral 
administration of [14C]-GSK2269557 the effective radioactive dose was calculated as 4 x 
10-10 Sv/Bq which corresponds to 0.4 mSv/MBq (0.0148 mSv/µCi). 
In this study each participant will be administered 1850 kBq (50 µCi) of radioactivity by 
the oral route.  Each participant will also receive a small amount of radioactivity as a 
microtracer intravenous dose administered concomitantly with an inhaled administration: 
22.2 kBq (0.6 µCi) – approximately 1/80th the oral radioactive dose. 
By summing the radioactive doses (~1873 kBq) and, conservatively, using the effective 
radioactive dose calculated following oral administration (0.4 mSv/MBq), each 
participant will be exposed to an effective radioactive dose of 0.75 mSv.  On this basis, 
the effective radioactive dose would be at the lower end of WHO category II (0.5 - 5 mSv 
– within dose limits for members of the public) and within International Commission on 
Radiological Protection (ICRP) category IIa (0.1 - 1 mSv – minor risk).  
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment 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 30 to 55 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Participants who are overtly healthy as determined by the investigator or medically 
qualified designee based on a medical evaluation including medical history, physical 
examination, vital signs, laboratory tests, and cardiac monitoring.  A participant with 
a clinical abnormality or laboratory parameter(s) which is/are not specifically listed 
in the inclusion or exclusion criteria, outside the reference range for the population 
being studied may be included only if the investigator agrees and documents that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures. 
3. A history of regular bowel movements (averaging one or more bowel movements per 
day). 


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Weight 
4. Body weight ≥ 50 kg and body mass index (BMI) within the range 19.0–31.0 kg/m2 
(inclusive). 
Sex 
5. Male. 
6. Participants with female partners of child bearing potential must agree to use 
contraception as detailed in Appendix 2 of this protocol during the treatment period, 
from the time of first dose of study medication until follow-up, and refrain from 
donating sperm during this period. 
Informed Consent 
7. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (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. Alanine aminotransferase (ALT) > 1.5xULN. 
2. Bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin < 35%). 
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
4. Mean QTCF  > 450 msec. 
5. Any clinically relevant abnormality identified at the screening medical assessment 
(physical examination/medical history), clinical laboratory tests, or 12-lead ECG. 
6. A pre-existing condition(s) interfering with normal GI anatomy or motility, including 
constipation, malabsorption or other GI dysfunction which may interfere with the 
absorption, distribution, metabolism or elimination of the study drug.  Participants 
with a history of cholecystectomy must be excluded. 
7. At screening, a supine or semi-supine blood pressure (BP) that is persistently higher 
(triplicate measurements at least 2 min apart) than 140/90 millimetres of mercury 
(mmHg). 
8. At screening, a supine or semi-supine mean HR outside the range 40–90 beats per 
minute (BPM). 
9. Participant is mentally or legally incapacitated. 
10. A history of respiratory disease (e.g. history of asthma) in the last 10 years. 


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Prior/Concomitant Therapy 
11. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the first dose 
of study medication, unless in the opinion of the investigator and GSK Medical 
Monitor the medication will not interfere with the study procedures or compromise 
participant safety. 
12. Need of Paracetamol or Acetaminophen, at doses of > 2 g/day.  Other concomitant 
medication may be considered on a case by case basis by the GSK Medical Monitor.   
Prior/Concurrent Clinical Study Experience 
13. The participant has participated in a clinical trial and has received an investigational 
product (IP) within 3 months before their first dose in the current study.  
14. Participation in a clinical trial involving administration of 14C-labelled compound(s) 
within the last 12 months.  A participants’ previous effective dose will be reviewed 
by the medical investigator to ensure there is no risk of contamination/carryover into 
the current study. 
Diagnostic assessments 
15. Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test 
result at screening. 
NOTE: Subjects 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. 
16. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment. 
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing. 
17. A positive test for Human Immunodeficiency Virus (HIV) antibody 
18. A positive pre-study drug/alcohol screen.   
19. Exposure to more than four new chemical entities within 12 months before the 
participant’s first dose. 
20. Participants have received a total body radiation dose of greater than 5.0 mSv (upper 
limit of WHO category II) or exposure to significant radiation (e.g. serial x-ray or 
computed tomography [CT] scans, barium meal etc) in the 12 months before this 
study. 
21. An occupation which requires monitoring for radiation exposure, nuclear medicine 
procedures or excessive x-rays within the past 12 months. 
22. Participation in the study would result in donation of blood or blood products in 
excess of 500 mL within a 90 day period. 


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23. Unwillingness or known inability to follow the procedures outlined in the protocol, 
including the use of the Enterotest capsule. 
Other Exclusions 
24. History of regular alcohol consumption within 6 months of the study, defined as an 
average weekly intake of >21 units.  One unit is equivalent to 8 g of alcohol:  a half-
pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.  
25. Urinary cotinine levels indicative of smoking; current smoker; or ex-smokers who 
(a) gave up less than 6 months ago or (b) who have a history of more than 10 pack-
years. 
Pack-years  = 
 cigarettes per day x number of years smoked.  
20 
26. Known sensitivity to any of the study treatments, or components thereof (including 
lactose and magnesium stearate [MgSt]), or drug or other allergy that, in the opinion 
of the investigator or medical monitor, contraindicates participation in the study. 
6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
• 
Participants will not be allowed to consume red wine, Seville oranges, grapefruit or 
grapefruit juice, pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 
7 days before the first dose of study medication until after their final visit. 
• 
Adequate hydration should be encouraged to help facilitate stool sample production.  
If needed, participants may consume prunes or prune juice to facilitate stool samples.   
• 
Participants should fast (no food or drink, except water) for at least 5 h before 
laboratory safety tests. 
• 
Participants should fast (no food or drink, except water) for at least 8 h before dosing 
and for about 4 h after dosing (with the exception of a food stimulus given to 
stimulate gall bladder emptying for bile collection at 0.5 h after the start of the IV 
infusion – Treatment 1).  Standard meals will be given at all other times.   
6.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks and chocolate) for 24 hours before the start of dosing 
until collection of the final pharmacokinetic sample during each session.  
• 
During each dosing session, participants will abstain from alcohol for 24 hours (7 
days for red wine, see Section 6.3.1) before the start of dosing until collection of the 
final pharmacokinetic sample during each session.  At all other times during the 
study (i.e. between screening and the post-study follow-up contact), participants will 
drink no more than 3 units of alcohol daily. 
• 
Only non-smokers will be enrolled into the study. 


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6.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise from screening and until their final 
follow-up visit.  Participants may participate in light recreational activities during 
studies (eg, watching television, reading). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered 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 set of screen failure information 
is required including demography, screen failure details, eligibility criteria, protocol 
deviations and any serious adverse events (SAEs) (as detailed in Section 9.2). 
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 as for the initial screening. 
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. 


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7.1. 
Treatments Administered 
Study treatment 
Study Treatment 
Name: 
[14C]-GSK2269557 
solution for IV infusion 
GSK2269557 Ellipta DPI 
[14C]-GSK2269557  
oral solution 
Dosage 
formulation: 
 
[14C]-GSK2269557 
hemisuccinate salt 
(GSK2269557T) in normal 
saline 
GSK2269557 hemisuccinate 
salt (GSK2269557H) 
blended with lactose and 
magnesium stearate1packed 
in foil blisters 
[14C]-GSK2269557 
hemisuccinate salt 
(GSK2269557T) in 
water 
Unit dose 
strength(s)/ 
Dosage level(s): 
10 µg 
[14C]-GSK2269557  
(<0.5 µCi) in 10 mL 
500 µg GSK2269557 per 
inhalation / 1000 µg dose 
800 µg  
[14C]-GSK2269557 
(approximately 50 µCi) 
in 10 mL 
Route of 
Administration:  
IV infusion 
Oral Inhalation 
Oral 
Dosing 
instructions: 
 
Non-sterile powder is to be 
dissolved aseptically in 
0.9% sodium chloride v/w to 
a concentration of 1 µg/mL 
free base equivalent.  IV 
solution is prepared by 
sterile filtration.  20 mL will 
be withdrawn into Individual 
labelled participant specific 
60 mL syringes. Only 10 mL 
of IV solution, equivalent to 
10 µg GSK2269557 is then 
administered intravenously 
as a single dose over 15 
minutes, as soon as 
possible (within 5 minutes) 
after the start of the inhaled 
dose 
Inhale TWICE from this 
Inhaler, as directed. 
Non-sterile powder is to 
be dissolved in sterile 
water to a concentration 
of 80 µg/mL.  10 mL of 
the solution, equivalent 
to 800 µg, is then 
administered as a 
single oral dose.  
Participants can have 
up to 250 mL water to 
wash the dose down 
Packaging and 
Labelling 
.   
Labelled drug substance 
will be provided in High 
Density Polyethylene 
(HDPE) containers with 
polypropylene closure to 
the site pharmacy. 
Study Treatment will be 
provided in a foil overwrap. 
Each foil overwrap will be 
labelled as required per 
country requirement. 
Labelled drug 
substance will be 
provided in HDPE 
containers with 
polypropylene closure 
to the site pharmacy. 
Manufacturer 
GSK 
GSK 
GSK 
Device: 
 
ELLIPTA™ inhaler 
 
1. Magnesium stearate 0.4% w/w of total drug product 
For more information on the preparation of the oral and IV dosing solutions, please refer 
to the Study Reference Manual (SRM). 


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7.2. 
Dose Modification 
Not applicable 
7.3. 
Method of Treatment Assignment 
This is an open-label study and all the participants will be assigned to each of the 
following treatments in a non-randomized manner.  All participants will receive 
Treatment 1 (IV infusion [concomitant with an inhaled dose]) first, and Treatment 2 (oral 
dose) second. 
7.4. 
Blinding 
This will be an open-label study. 
7.5. 
Preparation/Handling/Storage/Accountability 
1. A description of the methods and materials required for preparation of 
[14C]-GSK2269557 solution for IV infusion and oral administration is provided in 
the SRM and will be accompanied by a Quality Agreement. 
A description of the storage and handling requirements for GSK2269557 inhalers is 
provided in the SRM. 
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. 
2. 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. 
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
treatment are provided in the SRM.  
5. Precaution will be taken to avoid direct contact with the study treatment.  A 
Material Safety Data Sheet (MSDS) describing occupational hazards and 
recommended handling precautions will be provided to the investigator.  In the 
case of unintentional occupational exposure, notify the monitor, Medical Monitor 
and/or GSK study contact. 
7.6. 
Treatment Compliance 
• 
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.  


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• 
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 of 
each 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.  For the oral dose, study site personnel will 
examine each participant’s mouth to ensure that the study treatment was ingested. 
• 
[14C]-GSK2269557 will be intravenously administered to participants at the site.  
Administration will be documented in the source documents and reported in the case 
report form (CRF). 
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 
enrolment 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. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study.  
All inhibitors and inducers of the Cytochrome P450 pathway are prohibited (please refer 
to the SRM).   
All inhibitors of P-glycoprotein are prohibited (please refer to the SRM). 
Paracetamol or Acetaminophen, at doses of ≤ 2 g/day is permitted.  Other concomitant 
medication may be considered on a case by case basis by the GSK Medical Monitor.   
7.8. 
Treatment after the End of the Study 
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation. 


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8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
8.1.1. 
Liver Chemistry Stopping Criteria 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met: 
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 4. 
8.1.2. 
QTc Stopping Criteria 
• 
The QTcF should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief recording period (less than 4 minutes).  If 
an ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief 
period (e.g. 5 to 10 minutes), then use the averaged QTCF value of the 3 ECGs to 
determine whether the participant should be discontinued from the study. 
• 
A participant who meets either bulleted criterion below will be withdrawn from the 
study. 
• QTCF > 500 msec 
• Change from baseline:  QTCF > 60 msec 


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See the schedule of assessments (SoA) (Section 2) for data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that need to be 
completed. 
8.1.3. 
Other study stopping criteria 
A participant will be discontinued from the study if they experience a serious adverse 
event and/or unacceptable adverse events, as determined by the investigator and/or 
medical monitor.  Every effort should be made to complete safety follow-up procedures 
after a participant is discontinued from study drug. 
The study will be halted if there is a SAE or 2 severe AEs, considered to be at least 
possibly related to the investigational medicinal product (IMP).  If following an internal 
safety review, it is appropriate to restart the trial, a substantial amendment will be 
submitted to the Medicines and Healthcare Regulatory Authority (MHRA) and Research 
Ethics Committee (REC).  The trial will not restart until the amendment has been 
approved by the MHRA and REC. 
8.1.4. 
Temporary Discontinuation 
A participant withdrawn from the study treatment will no longer continue in the trial. 
8.2. 
Withdrawal from the Study  
• 
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. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• 
The investigator will ask withdrawn participants to consent to a follow-up 
examination, to check that they have come to no harm as a result of taking part in the 
trial.  Provided that participants agree, they will undergo, at withdrawal from the 
trial, the medical examination and other tests and procedures planned for the follow-
up visit.  The investigator will record in the CRF the results of follow-up 
examination of withdrawn participants, if they give their consent for that. 
• 
Refer to the SoA (Section 2) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed, provided the participant gives consent. 
8.3. 
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.  


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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/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 (i.e., 
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 following points must be noted:  
• 
If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order: 
1. 12-lead ECG 
2. vital signs 
3. blood draws.   
Note:  The timing of the assessments should allow the blood draw to occur at the 
exact nominal time. 


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• 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF.  
• 
No more than 533 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required. 
9.1. 
Efficacy Assessments 
There will be no efficacy assessments for this study.  
9.2. 
Adverse Events 
Planned time points for all safety assessments are listed in the SoA (Section 2).  
Additional time points for safety tests (such as vital signs, physical exams and laboratory 
safety tests) may be added during the course of the study based on newly available data to 
ensure appropriate safety monitoring. 
The definitions of an AE or SAE can be found in Appendix 5. 
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 treatment (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 signing of the ICF 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 immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 5.  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 5. 


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9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  
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 (as defined in Section 3.3.1), will be 
followed until the event is resolved, stabilized, otherwise explained, or the participant is 
lost to follow-up (as defined in Section 8.3).  Further information on follow-up 
procedures is given in Appendix 5. 
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 e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
9.2.5. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be 
collected after the start of study treatment and until follow up. 
• 
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 2. 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
9.3. 
Treatment of Overdose 
For this study, any dose of GSK2269557 greater than 2000 µg within a 24-hour time 
period will be considered an overdose.  For [14C]-GSK2269557, an intravenous dose of 


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100 µg or an oral dose of 4000 µg within a 24-hour time period will be considered an 
overdose. 
GSK does not recommend specific treatment for an overdose.  The Investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose, the Investigator (or the treating physician) should: 
• 
Contact the Medical Monitor immediately. 
Closely monitor the participant for AE/SAE and laboratory abnormalities until [14C]-
GSK2269557 can no longer be detected systemically (at least 14 days). 
Obtain a plasma sample for PK analysis within 14 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis). 
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. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 2). 
9.4.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
head, eyes, ears, nose, throat, thyroid and skin, as well as the cardiovascular, 
respiratory, gastrointestinal and neurological systems.  Height and weight will 
also be measured and recorded. 
• 
A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
9.4.2. 
Vital Signs 
• 
Vital signs will be measured in a supine or semi-supine position after 5 minutes 
rest and will include temperature, systolic and diastolic blood pressure, and 
pulse and respiratory rate. 
• 
For time points where vital signs are collected in triplicate, only systolic and 
diastolic blood pressure, and pulse rate should be repeated.  There should be at 
least a 2 minute interval between readings. 


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• 
Baseline will be defined as the mean of the 3 pre-dose measurements taken on 
Day 1 (Treatment 1). 
9.4.3. 
Electrocardiograms 
• 
12-lead ECGs will be measured in a supine or semi-supine position after 5 
minutes rest. 
• 
12-lead ECGs will be obtained at each time point during the study, as outlined in 
the SoA (see Section 2).  This will be performed using an ECG machine that 
automatically calculates the heart rate and measures PR interval, QRS duration, 
QT, and QTcB or QTcF intervals.  Refer to Section 8.1.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary. 
• 
At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart.  The full set of triplicates should be completed in less than 
4 minutes. 
• 
Baseline will be defined as the mean of the 3 pre-dose measurements taken on 
Day 1 (Treatment 1). 
9.4.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 6 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the 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 7 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 aetiology should be identified and the sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 6 must be 
conducted in accordance with the laboratory manual/SRM and the SoA.  


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9.4.5. 
Local Tolerability 
Local tolerability at the infusion site will be assessed during treatment period 1, at time 
points outlined in the SoA (Section 2).  Light pressure will be applied at the injection site 
and record any pain, tenderness, erythema and induration. 
Pain and tenderness will be assessed according to the following scale:  
• 
none  
nothing 
• 
mild  
easily tolerated 
• 
moderate 
interferes with daily activities 
• 
severe 
prevents normal everyday activities or sleep. 
Erythema and induration will be measured using a ruler, or a template supplied by the 
sponsor. 
9.5. 
Pharmacokinetics 
Background radioactivity samples (3 samples during period 1) are taken to provide 
confidence in the determination of endogenous radiocarbon content in the plasma of the 
participants, and in the processing of those samples to avoid contamination with 
extraneous radiocarbon. 
9.5.1. 
Blood Sample Collection 
Blood samples for plasma total radioactivity, [14C]-GSK2269557, GSK2269557 plasma 
concentrations, and metabolite profiling will be collected into ethylenediaminetetraacetic 
acid (EDTA) tubes at the time points indicated in the SoA (Section 2).   
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.   
Processing, storage and shipping procedures are provided in the SRM.  
Plasma samples for metabolite profiling will be analysed under a separate GSK Platform 
Technology Services (PTS) IVIVT protocol.  The results of these analyses will be 
reported separately. 
9.5.2. 
Urine Sample Collection 
Urine samples to measure total radioactivity excreted in urine and for metabolite profiling 
(to be conducted in a separate study) will be collected over the time periods specified in 
the SoA (Section 2).  All participants will be asked to void their bladders before study 
treatment administration.  A blank urine sample will be collected pre-dose.  The weight 
of urine collected during each collection interval will be recorded in the CRF.  Further 


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details of urine sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
9.5.3. 
Faecal Sample Collection 
Faecal samples to measure total radioactivity excreted in faeces and for metabolite 
profiling (to be conducted in a separate study) will be collected over the time periods 
specified in the SoA.  A faecal sample will be collected from each participant before 
dosing (the pre-dose sample can be collected up to 48 h before dosing).  The weight of 
faeces collected during each collection interval will be recorded in the CRF.  Further 
details of faecal sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
9.5.4. 
Bile Collection 
Bile samples for analysis of metabolites (to be conducted in a separate GSK PTS IVIVT 
protocol) will be collected (subject to commercial availability) via the Entero-Test over 
the time periods specified in the SoA (Section 2).  The Entero-Test comprises a gelatine 
capsule which contains 90 cm or 140 cm of nylon string attached to a 1 g steel weight.  
One end of the string is attached to the outside of the mouth before swallowing the 
capsule, so that it can still be retrieved.  The gelatine capsule dissolves in the stomach 
whilst the string and weight continue to the duodenum via peristalsis.  Following a food 
cue to stimulate gall bladder emptying the string is withdrawn.  On withdrawal of the 
string through the mouth the steel weight separates from the string at the pyloric sphincter 
and is excreted in the faeces.  Once the string has been removed from the participant it 
will be frozen and shipped for metabolite profiling (to be conducted in a separate study).  
Full details of the Entero-Test sample collection, processing, storage and shipping 
procedures are provided in the SRM. 
9.5.5. 
Sample Analysis 
Total radioactivity measurements in urine samples and faecal homogenates will be 
determined by LSC at Covance Laboratory (Harrogate, UK) or by accelerator mass 
spectrometry (AMS) at Xceleron, as appropriate.  Total radioactivity measurements from 
plasma derived from blood will be analysed, as appropriate, by LSC and if required 
AMS, at GSK, as detailed in the SRM.   
[14C]-GSK2269557 and GSK2269557 plasma concentrations will be analysed, as 
appropriate, at GSK, as detailed in the SRM. 
Plasma prepared from blood and aliquots of urine and faecal homogenates will be 
analysed under a separate GSK protocol for metabolite profiling investigations.  
Duodenal bile samples collected via the Entero-Test will similarly be analysed under a 
separate GSK protocol.  The results of these analyses will be reported separately. 
Analysis of all samples (plasma, urine, faeces, and duodenal bile) will be performed 
under the control of PTS IVIVT, GlaxoSmithKline, the details of which will be included 
in the SRM.  Raw data will be archived at the bioanalytical site (detailed in the SRM). 


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Analysis of the PK data collected is explained in details in Section 10.3.1. 
9.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
9.7. 
Genetics 
Genetics are not evaluated in this study. 
9.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample Size Determination 
No formal sample size calculation has been performed for this study.  The primary 
objective of the study is to gain a better understanding of the compound’s excretory and 
metabolic profile and 4-6 participants are deemed sufficient for this purpose (Penner, 
2009).  6 participants will be enrolled into the study in order to achieve at least 4 
completed participants. 
10.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
All Participants Enrolled 
(APE) Population 
All participants for whom a record exists on the study database; 
includes both screened participants and participants who are not 
screened but sign the ICF. 
Safety Population 
Participants in the APE Population who receive at least one dose of 
study treatment. Participants will be analysed according to the 
treatment they actually received. 
The Safety Population will be used for all safety summaries. 
PK Population 
Participants in the APE Population who receive at least one dose of 
study treatment and for whom a PK sample was obtained and 
analysed. Participants will be analysed according to the treatment 
they actually received. 
The PK Population will be used for all PK summaries. 
 


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10.3. 
Statistical Analyses 
Interim analyses may be conducted to provide preliminary results on plasma PK 
parameters, see the Reporting and Analysis Plan (RAP) for further details. 
10.3.1. 
Pharmacokinetic Analyses 
Plasma GSK2269557 concentration-time data will be listed for each participant and 
summarised by treatment and planned sampling time.  [14C]-GSK2269557 and 
radioactivity concentrations in plasma will be reported similarly.  Individual participant, 
mean, and median plasma GSK2269557, [14C]-GSK2269557 and total radioactivity 
concentration-time profiles will be plotted for each treatment on both a linear and semi-
log scale.  
Pharmacokinetic analysis will be performed by or under the direct auspices of Clinical 
Pharmacology Modelling & Simulation, GSK.  Plasma GSK2269557, [14C] 
-GSK2269557 and total radioactivity concentration-time data will be analysed by non-
compartmental methods with WinNonlin Version 6.3 or above.  Calculations will be 
based on the actual sampling times recorded during the study.  From the plasma 
concentration-time data the following pharmacokinetic parameters will be determined, 
for GSK2269557, [14C]-GSK2269557 and total radioactivity, as data permits:  maximum 
observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma 
concentration-time curve [AUC(0-t) and AUC(0-inf)], terminal phase rate constant (λz), 
and apparent terminal phase half-life (t½) following inhaled, oral and IV dosing.  
Additionally, volume and clearance will be derived following IV dosing.  These 
parameters will be summarised descriptively. 
Absolute bioavailability will be estimated for the inhaled and oral doses for each 
participant and will be summarised. 
Derivation of the urine and faecal radioactivity parameters will be the responsibility of 
the IVIVT department within GSK.  The following parameters will be determined from 
the urine and faecal radiolabelled drug-related material (radioactivity) data, and will be 
listed and summarised by treatment: 
• 
Absolute amount excreted and percentage excreted in urine (Ae[urine] and 
Fe%[urine]) within each collection period and cumulative urinary recovery and 
fraction excreted over the total collection period. 
• 
Absolute amount excreted and percentage excreted in faeces (Ae[faecal] and 
Fe%[faecal]) with each collection period and cumulative faecal recovery and fraction 
excreted over the total collection period and cumulatively over the collection period. 
• 
Total excretion (sum of urine and faecal excretion), Ae [total] and Fe% [total] will be 
calculated by collection interval for each participant.  
The urine, faecal and total radioactivity parameters will be listed, summarised and 
plotted.  


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All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.  Production of the summaries, listings and figures of the plasma, 
urine and faeces data will be performed under the direct auspices of Clinical Statistics, 
GSK. 
Further details regarding the tables, figures and listings to be produced for the study 
report will be given in the Reporting and Analysis Plan (RAP). 
10.3.2. 
Metabolite profiling 
The metabolic profiling/structural characterisation aspect of this work will be performed 
by GSK under a separate IVIVT protocol and reported separately. 
10.3.3. 
Safety Analyses 
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards.  Further details will be given 
in the RAP. 
 
 


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11. 
REFERENCES 
GlaxoSmithKline Document Number 2012N141231_07. GSK2269557 Investigator's 
Brochure. Date 22 Sep 2017.  
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. 
Penner N, Klunk L, Prakash C.  Human radiolabelled mass balance studies:  Objectives, 
utilities and limitations. Biopharm. Drug Dispos. 2009;30:185-203. 


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12. 
APPENDICES 
12.1. 
Appendix 1:  Abbreviations and Trademarks 
Abbreviations 
ADME 
Absorption Distribution Metabolism Excretion  
AE 
Adverse Event 
ALT 
Alanine aminotransferase (SGPT) 
AMS 
Accelerator Mass Spectrometry 
APE 
All Participants Enrolled 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under concentration-time curve 
AUC(0- inf) 
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a participant across all 
treatments 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
Beat Per Minute 
Bq 
Becquerel 
C 
Carbon 
Ci 
Curie 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum observed concentration  
CO 
Carbon Monoxide 
CO2 
Carbon dioxide 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CT 
Computed Tomography 
δ 
Delta 
DMPK 
Drug Metabolism and Pharmacokinetics 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
F 
Absolute bioavailability 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
h 
Hour(s) 
HDPE 
High Density Polyethylene 
HPLC 
High-performance liquid chromatography 


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Abbreviations 
HBsAg 
Hepatitis B surface antigen 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HMR 
Hammersmith Medicines Research 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ICRP 
International Commission on Radiological Protection 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgM 
Immunoglobulin M 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIVT 
In vitro/In vivo Translation 
kBq 
Kilo Becquerel 
Kg 
Kilogram 
λz 
Terminal phase rate constant 
L 
Litre 
LDH 
Lactate dehydrogenase 
LSC 
Liquid Scintillating Counting 
µCi 
Micro Curie 
µg 
Microgram 
µSv 
Micro Sievert 
m 
Meter 
MBq 
Megabecquerel 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MDD 
Medical Devices Directive 
MgSt 
Magnesium stearate 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
mL 
Millilitre 
mmHg 
Millimetre of mercury 
MSDS 
Material Safety Data Sheet 
msec 
Milliseconds 
mSv 
Millisievert 
nCi 
Nano Curie 
NOAEL 
No-observed-adverse-effect-level 
PI3K 
Phosphoinositide 3-kinases 


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Abbreviations 
PIP2 
Phosphatidylinositol 4,5-biphosphate 
PIP3 
Phosphatidylinositol 3,4,5-trisphosphate 
PK 
Pharmacokinetic 
PTS 
Platform Technology Services 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
RBC 
Red blood cells 
REC 
Research Ethics Committee 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event(s) 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SoA 
Schedule of activities 
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
Sv 
Sievert 
t½ 
Terminal phase half-life 
tmax 
Time of occurrence of Cmax 
ULN 
Upper limit of normal 
WBC 
White blood cells 
WHO 
World Health Organisation 
WOCBP 
Woman of child bearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
DISKUS 
 
Entero-Test 
ELLIPTA  
 
WinNonlin 
 


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12.2. 
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information 
Contraception Guidance 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
• Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 2, when having 
penile-vaginal intercourse with a woman of childbearing potential  
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame; 
• 
In addition male participants must refrain from donating sperm for duration of 
study. 
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 ovulationb  
• 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 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 


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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.  
b. 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least the duration of the study. 
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study.  This applies only to participants who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
 


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12.3. 
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 (eg, 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.  
• 
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 


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guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
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 multicentre studies only in their entirety and not as individual 
site data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 


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have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate. 
• 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed 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 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 ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/equivalent summary unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed 
during the retention period without the written approval of the sponsor.  No records 
may be transferred to another location or party without written notification to the 
sponsor.  
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF 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. 


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• 
Definition of what constitutes source data will be documented in a source data 
agreement. 
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: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event aetiology (in alignment with the FDA premarketing clinical 
liver safety guidance).  They are described in Table 3. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Table 3 
Phase I liver chemistry stopping criteria and required follow up 
assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
 
ALT-absolute 
 
ALT≥3xULN 
If  ALT≥3xULN  AND bilirubin1,2 ≥ 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments following Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below) 
MONITORING: 
If ALT≥3xULN AND bilirubin ≥ 2xULN  or INR 
>1.5 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• Viral hepatitis serology3 
• Blood sample for pharmacokinetic (PK) 
analysis, obtained 48 h post last dose4 
• Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin≥2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 
If ALT≥3xULN AND bilirubin ≥ 2xULN  or 


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Liver Chemistry Stopping Criteria – Liver Stopping Event 
• A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 
• Monitor participantss weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
INR >1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James, 2009]. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT ≥ 3xULN and bilirubin ≥ 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. 
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and INR>1.5, 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. Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
4. 
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  


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12.5. 
Appendix 5: 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 fulfils 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. 
g. Is associated with liver injury and impaired liver function defined as: 
• 
ALT ≥ 3xULN and total bilirubin* ≥ 2xULN (>35% direct), or 
• 
ALT ≥ 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT ≥ 3xULN 
and total bilirubin ≥ 2xULN, then the event is still to be reported as an SAE.  
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form. 
Refer to Appendix 4 for the required liver chemistry follow-up instructions. 
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, 
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. 


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• 
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. 
 
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-


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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 Paper CRF 
• 
The SAE CRF should be transmitted to the SAE coordinator by e-mail. 
• 
In rare circumstances and in the absence of other options, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
 


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12.6. 
Appendix 6: Clinical Laboratory Tests 
• 
The tests detailed in Table 4 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 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 4 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
White blood cells (WBC) 
count with Differential: 
Red blood cell (RBC) 
Count 
Mean corpuscular 
volume (MCV) 
Neutrophils 
Hemoglobin 
Mean corpuscular 
haemoglobin (MCH) 
Lymphocytes 
Hematocrit 
Mean corpuscular 
haemoglobin 
concentration (MCHC) 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
Clinical 
Chemistry1  
Urea 
Potassium Aspartate 
aminotransferase (AST) 
(serum glutamic-
oxaloacetic 
transaminase) (SGOT) 
Triglycerides 
Creatinine 
Sodium 
ALT (Serum glutamic 
pyruvic transaminase) 
(SGPT) 
Total bilirubin 
Glucose, fasting  
Calcium 
Alkaline phosphatase 
Total Protein 
Uric Acid  
Chloride 
Gamma GT 
Albumin 
 
Phosphate Cholesterol 
Globulin 
Routine 
Urinalysis 
• dipstick test:  protein, blood, ketones, glucose, bilirubin, 
urobilinogen, leukocyte esterase, specific gravity, nitrites, pH; 
• Microscopic examination (if leukocyte esterase, nitrites, blood or 
protein is abnormal) 
Other 
Screening 
Tests 
• HIV 
• Hepatitis B (HBsAg) 
• Hepatitis C (Hep C antibody) 
• Alcohol, cotinine and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 


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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 8.1.1 and Appendix 4 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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12.7. 
Appendix 7: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
206764
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for an open-label study in 
healthy male subjects, to determine the excretion balance and 
pharmacokinetics of [14C]-GSK2269557, administered as a 
single intravenous microtracer (concomitant with an inhaled 
non-radiolabelled dose) and a single oral dose
Compound Number 
:
GSK2269557
Effective Date 
:
09-JAN-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 206764.

This RAP is intended to describe the safety and pharmacokinetic analyses required 
for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Study Statistician (Clinical Statistics)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
206764
2
RAP Team Approvals:
Approver
Date
Approval Method
03-JAN-2018
email
Data Manager (Data Management)
05-JAN-2018
email
Manager (Clinical Pharmacology)
04-JAN-2018
email
Clinical Research Scientist (Clinical Sciences)
04-JAN-2018
email
Clinical Development Scientist (Clinical 
Development)
Clinical Development Director (Clinical 
Development)
03-JAN-2018
email
08-JAN-2018
email
Manager (Clinical Programming)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
09-JAN-2018
email
Director (Clinical Statistics)
09-JAN-2018
email
Manager (Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses / Statistical Analyses .................................................7
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................8
4.1.
Protocol Deviations.......................................................................................8
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Baseline Definitions ....................................................................................10
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................10
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Study Population Analyses........................................12
7.
SAFETY ANALYSES .............................................................................................13
7.1.
Adverse Events Analyses ...........................................................................13
7.2.
Adverse Events of Special Interest Analyses..............................................13
7.3.
Clinical Laboratory Analyses.......................................................................13
7.4.
Other Safety Analyses ................................................................................13
8.
PHARMACOKINETIC ANALYSES.........................................................................14
8.1.
Endpoint / Variables....................................................................................14
8.1.1.
Drug Concentration Measures .....................................................14
8.1.2.
Derived Pharmacokinetic Parameters..........................................14
8.2.
Primary Pharmacokinetic Analyses.............................................................20
8.2.1.
Endpoint / Variables.....................................................................20
8.2.1.1.
Drug Concentration Measures....................................20
8.2.1.2.
Derived Pharmacokinetic Parameters.........................20
8.2.2.
Summary Measure ......................................................................20
8.2.3.
Population of Interest...................................................................20
8.2.4.
Statistical Analyses / Methods .....................................................20
8.3.
Secondary Pharmacokinetic Analyses........................................................20
8.3.1.
Endpoint / Variables.....................................................................20
8.3.1.1.
Drug Concentration Measures....................................20
8.3.1.2.
Derived Pharmacokinetic Parameters.........................21
8.3.2.
Summary Measure ......................................................................21
8.3.3.
Population of Interest...................................................................21
8.3.4.
Statistical Analyses / Methods .....................................................21


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8.3.4.1.
Statistical Methodology Specification..........................21
9.
EXPLORATORY ANALYSES.................................................................................23
10. REFERENCES.......................................................................................................24
11. APPENDICES........................................................................................................25
11.1.
Appendix 1: Protocol Deviation Management .............................................25
11.2.
Appendix 2: Schedule of Activities ..............................................................26
11.2.1.
Protocol Defined Schedule of Events...........................................26
11.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................30
11.3.1.
Study Phases ..............................................................................30
11.3.1.1.
Study Phases for Concomitant Medication .................30
11.3.2.
Treatment Emergent Flag for Adverse Events .............................31
11.4.
Appendix 4: Data Display Standards & Handling Conventions....................32
11.4.1.
Reporting Process .......................................................................32
11.4.2.
Reporting Standards....................................................................32
11.4.3.
Reporting Standards for Pharmacokinetic....................................33
11.5.
Appendix 5: Derived and Transformed Data ...............................................34
11.5.1.
General........................................................................................34
11.5.2.
Study Population..........................................................................34
11.5.3.
Safety ..........................................................................................35
11.6.
Appendix 6: Reporting Standards for Missing Data.....................................36
11.6.1.
Premature Withdrawals................................................................36
11.6.2.
Handling of Missing Data.............................................................36
11.6.2.1.
Handling of Missing and Partial Dates ........................36
11.7.
Appendix 7: Values of Potential Clinical Importance ...................................38
11.7.1.
Laboratory Values........................................................................38
11.7.2.
ECG.............................................................................................39
11.7.3.
Vital Signs....................................................................................39
11.8.
Appendix 8: Abbreviations & Trade Marks ..................................................40
11.8.1.
Abbreviations...............................................................................40
11.8.2.
Trademarks .................................................................................41
11.9.
Appendix 9: List of Data Displays ...............................................................42
11.9.1.
Data Display Numbering..............................................................42
11.9.2.
Mock Example Shell Referencing ................................................42
11.9.3.
Deliverables.................................................................................42
11.9.4.
Study Population Tables..............................................................43
11.9.5.
Pharmacokinetic Tables...............................................................44
11.9.6.
Pharmacokinetic Figures .............................................................49
11.9.7.
Safety Tables...............................................................................56
11.9.8.
ICH Listings .................................................................................58
11.9.9.
Non-ICH Listings..........................................................................61
11.10. Appendix 10: Example Mock Shells for Data Displays ................................63


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2017N324843_00
09-AUG-2017
Original
2017N324843_01
30-OCT-2017
Protocol Amendment 1 was put in place to:

Respond to comments from the Regulatory Authority: 
Medicines and Healthcare Products Regulatory 
Authoring.

Reflect an update to the Investigator’s Brochure (IB) 
published since approval of the original protocol.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 1 [(Dated: 30/Oct/2017)], however additional PK 
parameters have been requested.
2.2.
Study Objective(s) and Endpoint(s)
Objective
Endpoint
Primary

To determine total radioactivity (drug related 
material) in plasma following a single IV 
microtracer of [14C]-GSK2269557 
(concomitant with an inhaled non-
radiolabelled GSK2269557 dose) and a 
single oral dose of [14C]-GSK2269557.

AUC (0-inf), AUC (0–t), Cmax, tmax, t1/2 of 
total drug-related material (radioactivity) in 
plasma.

To determine the rate and extent of 
excretion of total radioactivity in urine and 
faeces and the total recovery of radioactivity 
following a single IV microtracer of [14C]-
GSK2269557 (concomitant with an inhaled 
non-radiolabelled dose) and a single oral 
dose of [14C]-GSK2269557.

Urinary and faecal cumulative excretion as 
a percentage of the total radioactive dose 
administered over time.


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Objective
Endpoint
Secondary

To determine parent GSK2269557 
concentration in plasma following a single 
IV microtracer of [14C]-GSK2269557 
concomitant with an inhaled non-
radiolabelled GSK2269557 dose and a 
single oral dose of [14C]-GSK2269557.

AUC(0-inf), AUC(0–t), Cmax, tmax, and t1/2 
of parent GSK2269557 and 
[14C]-GSK22695571 in plasma. 

Volume and clearance of parent 
[14C]-GSK22695571 after IV dose only.  

To estimate the absolute bioavailability of 
GSK2269557 following inhaled and oral 
administration. 

Oral and inhaled F (absolute bioavailability).

To evaluate the safety and tolerability of 
GSK2269557 after single IV, oral and 
inhaled doses in healthy participants.

Incidence of adverse events.

Laboratory safety, electrocardiogram (ECG)
and vital signs parameters.
Exploratory 

To generate samples that will be used to 
characterise the metabolic profile of 
GSK2269557 in plasma, urine, faeces, and 
duodenal bile (following IV dose only), 
following a single IV microtracer of 
[14C]-GSK2269557 (concomitant with an 
inhaled non-radiolabelled dose) and a 
single oral dose of [14C]-GSK2269557 
(these analytical investigations will be 
conducted and the results reported under a 
separate Platform Technology Services 
(PTS) In vitro/In vivo Translation (IVIVT), 
GlaxoSmithKline protocol).

Characterisation and quantification of 
metabolites in plasma, urine, faeces, and 
duodenal bile (these analytical 
investigations will be conducted and the 
results reported in a separate GSK PTS 
IVIVT protocol).
1.
For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes 
the parent GSK2269557 concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass 
Spectrometry (AMS), whereas GSK2269557 describes the parent GSK2269557 concentration derived via liquid 
chromatography-tandem mass spectrometry (LC/MS).
Note: the above table is as presented in the protocol amendment, subsequently additional PK parameters have been 
requested including: plasma AUC(0-24) and %AUCex for parent GSK2269557 and total radioactivity analytes; plasma 
ML(iv), ML(po), Fg, EH, Fabs; parent GSK2269557/ total radioactivity ratios for the plasma PK parameters Cmax, 
AUC(0-t), AUC(0-24) and AUC(0-∞); and CLr derivations are described in Section 8.


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

open-label

single centre

non-randomised

2-period single-sequence crossover

mass balance study 

approximately 6 healthy male participants will be enrolled

there will be a washout period of at least 14 days between doses
Dosing

The investigational drug is nemiralisib (GSK2269557). Each subject will 
receive a 10 µg radiolabelled version of GSK2269557 ([14C]-GSK2269557) 
microtracer administered by IV infusion, concomitant with an inhaled non-
radiolabelled 1000 µg dose of GSK2269557, in period 1 and a single 800 µg 
dose of [14C]-GSK2269557 administered as an oral dose in period 2.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

This is an open label, non-randomised, 2-period single-sequence crossover 
study.

All subjects will receive [14C]-GSK2269557 administered as a single IV dose 
(concomitant with an inhaled non-radiolabelled dose) at period 1 followed by 
[14C]-GSK2269557 administered as a single oral dose at period 2
2.4.
Statistical Hypotheses / Statistical Analyses

No formal hypotheses will be tested or treatment comparisons performed. Data will 
be summarised using descriptive methods only.


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3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
Note: pharmacokinetic concentration and pharmacokinetic parameter raw file 
generation start after GSK DBF – take approx. 18 working days after DBF. All other 
datasets available at DBF.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Enrolled (APE) 
Population

All participants for whom a record exists on the 
study database; includes both screened 
participants and participants who are not screened 
but sign the informed consent form (ICF).

Screen Failure
Safety Population

Participants in the APE Population who receive at 
least one dose of study treatment. 

Participants will be analysed according to the 
treatment they actually received

Study Population

Safety
Pharmacokinetic 
(PK) Population

Participants in the APE Population who receive at 
least one dose of study treatment and for whom a 
PK sample was obtained and analysed.

Participants will be analysed according to the 
treatment they actually received

PK
Refer to Appendix 9: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.


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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the pCRF.
The study endpoints will be reported using the populations detailed in Section 4 of this 
document regardless of whether the subjects deviate from the protocol.
If there are subjects with protocol deviations that may potentially impact the PK 
endpoints, exploratory sensitivity summaries may be considered. If further summaries of 
the data are produced, they will be detailed in the clinical study report.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Data Displays for Reporting [1]
Code
Description
Description
Order [2]
A
GSK2269557 1000 mcg Inhaled + 
[14C]-GSK2269557 10 mcg IV
557 IH + 14C-557 IV
1
B
[14C]-GSK2269557 800 mcg Oral
14C-557 ORAL
2
NOTES:
1.
The following footnote will be presented on each display:
557 IH + 14C-557 IV = Intravenous radiolabelled 10 mcg GSK2269557 co-administered with inhaled 1000 
mcg GSK2269557; 14C-557 ORAL = 800 mcg radiolabelled GSK2269557 administered orally
2.
Order represents treatments being presented in TFL, as appropriate
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. Baseline definitions defined in the table are applicable to each 
“period” for this crossover study.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
12-Lead ECG
X
X
X
Day 1 (Pre Dose)
Vital Signs
X
X
X
Day 1 (Pre Dose)
Haematology 
X
X
X
Day 1 (Pre Dose)
Clinical Chemistry
X
X
X
Day 1 (Pre Dose)
Liver Function
X
X
X
Day 1 (Pre Dose)
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. The mean of triplicate measurements at any given time 
point will be used as the value for that time point unless otherwise stated.
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:


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Section
Component
11.3
Appendix 3 Study Phases and Treatment Emergent Adverse Events
11.4
Appendix 4 Data Display Standards & Handling Conventions
11.5
Appendix 5 Derived and Transformed Data
11.6
Appendix 6 Reporting Standards for Missing Data
11.7
Appendix 7 Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 9 List of Data Displays.


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7.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 9 List of Data Displays.
7.2.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. The details of the planned displays are provided in Appendix 9 List of 
Data Displays.
7.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 9 List of Data 
Displays.
7.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 9 List of Data Displays.


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8.
PHARMACOKINETIC ANALYSES
The plasma pharmacokinetic concentrations will have different nomenclatures dependent 
on the method of measuring. For measured concentrations of GSK2269557 in blood 
plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 
concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass 
Spectrometry (AMS), whereas GSK2269557 describes the parent GSK2269557 
concentration derived via liquid chromatography-tandem mass spectrometry (LC/MS). It
is expected that, for period 1, the radiolabelled iv dose will be measured using LC+AMS 
and will be labelled “[14C]-GSK2269557”, the non-radiolabelled inhaled dose will be 
measured using LC/MS and will be labelled “GSK2269557”. For period 2, the 
radiolabelled oral dose will be measured using LC/MS and will be labelled 
“GSK2269557”. For each period the total radioactivity will be measured by AMS and 
will be labelled “Total Radioactivity”. However, these methods may be adapted if 
necessary.
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Clinical Pharmacology Science and Study 
Operations (CPSSO), GlaxoSmithKline. 
Derivation of plasma pharmacokinetic parameters for [14C]-GSK2269557, total 
radioactivity and GSK2269557 will be performed by, or under the direct auspices of, 
Clinical Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline.
Derivation of urine/faeces total radioactivity parameters will be performed by, or under 
the direct auspices of Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS IVIVT, 
GlaxoSmithKline.
8.1.
Endpoint / Variables
8.1.1.
Drug Concentration Measures
Refer to Appendix 4 Data Display Standards & Handling Conventions (Section 11.4.3
Reporting Standards for Pharmacokinetic)
8.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. 
Pharmacokinetic parameters listed in Table 1 will be determined from the plasma 
concentration-time data, as data permits, for each subject, analyte (total radioactivity, 
GSK2269557 and [14C]-GSK2269557) and treatment period unless otherwise stated.
Pharmacokinetic parameters listed in Table 2 will be determined from the urine and 
faeces concentration-time data, as data permits, for each collection interval, subject and 
treatment period unless otherwise stated.


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Table 1
Derived Plasma Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-24)
Area under the concentration-time curve from time zero to 24 hours post dose (C(t)) will 
be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) will be calculated 
as:
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
CL(iv)
Total iv clearance will be calculated as:
CL(iv)=Dose(iv)/AUC(0-∞)
Treatment period 1, analyte [14C]-GSK2269557 only where Dose(iv) is the actual iv dose 
calculated as [weight of full syringe (g) minus syringe weight after dose (g)] multiplied by 
nominal concentration (µg/g)
CLr
If Plasma AUC(0-∞) is calculable then
CLr= Cumulative Ae[urine] for treatment period 1/Plasma AUC(0-∞)
If Plasma AUC(0-∞) is not calculable then 
CLr= Cumulative Ae[urine] for treatment period 1/Plasma AUC(0-t)
Where cumulative Ae from excretion data for treatment period 1 and AUC from NCA PK 
analysis of Treatment period 1, analyte [14C]-GSK2269557 only.
V(c)
Treatment period 1, analyte [14C]-GSK2269557 only.
Where Dose(IV) is the radiometric dose as described in Table 1. 
V(dss)
Treatment period 1, analyte [14C]-GSK2269557 only.
Where AUMC is the area under the moment curve and Dose(IV) is the radiometric dose 
as described in Table 1. 


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Parameter
Parameter Description
ML(iv)
Metabolite load following intravenous administration is calculated as:
Treatment period 1 only
ML(po)
Metabolite load following oral administration is calculated as:
Treatment period 2 only.
Note: GSK2269557 AUC(0-∞) may be updated depending on the sample analysis 
conducted but refers to the parent GSK2269557 from oral dose.
Fg
Fraction metabolised by gut wall as a fraction of the oral dose will be calculated as 
follows:
Fg= 1 –(ML(po)–ML(iv))
EH
Hepatic extraction ratio is calculated (Davis, B et al, 1993) as follows:
EH  = CL(iv)/1450 mL/min
Fabs
Fraction absorbed following an oral dose is calculated as follows:
Dose(IV)
Radiometric IV dose will be calculated by Covance
Dose(oral) 
Radiometric Oral dose will be calculated by Covance
Dose(inhaled)
Nominal inhaled dose 
Oral F (0-∞)
Oral absolute bioavailability based on AUC(0-∞) calculated as:
Per subject.
Note: Radiometric dose will be used for oral and iv as described in Table 1.
GSK2269557 AUC(0-∞)(oral) may be updated depending on the sample analysis 


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Parameter
Parameter Description
conducted but refers to the parent GSK2269557 from oral dose.
Inhaled F (0-∞)
Inhaled absolute bioavailability based on AUC(0-∞) calculated as
Per subject.
Note: Radiometric dose will be used for oral and iv as described in Table 1.
Oral F (0-t)
Oral absolute bioavailability based on AUC(0-t) calculated as:
   
Per subject.
Note: Radiometric dose will be used for oral and iv as described in Table 1. .
GSK2269557 AUC(0-∞)(oral) may be updated depending on the sample analysis 
conducted but refers to the parent GSK2269557 from oral dose.
Inhaled F (0-t)
Inhaled absolute bioavailability based on AUC(0-t) calculated as
Per subject.
Note: Radiometric dose will be used for oral and iv as described in Table 1.
GSK2269557 
/Total radioactivity 
ratio for Cmax, 
Cmax Ratio = Exp { [loge(GSK2269557 Cmax] - [loge(Total radioactivity Cmax]}
Per subject for radiolabelled oral dose. GSK2269557 may be updated depending on the 
sample analysis conducted but refers to the parent GSK2269557 from oral dose
GSK2269557 
/Total radioactivity 
ratio for AUC(0-inf)
AUC(0-inf) Ratio = Exp { [loge(GSK2269557 AUC(0-inf)] - [loge(Total radioactivity 
AUC(0-inf)] } 
Per subject for radiolabelled oral dose. GSK2269557 may be updated depending on the 
sample analysis conducted but refers to the parent GSK2269557 from oral dose
GSK2269557 
/Total radioactivity 
AUC(0-t) Ratio = Exp { [loge(GSK2269557 AUC(0-t)] - [loge(Total  radioactivity AUC(0-
t)] } 


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Parameter
Parameter Description
ratio for AUC(0-t)
Per subject for radiolabelled oral dose. GSK2269557 may be updated depending on the 
sample analysis conducted but refers to the parent GSK2269557 from oral dose
[14C]-GSK2269557 
/Total radioactivity 
ratio for Cmax, 
Cmax Ratio = Exp { [loge([14C]-GSK2269557 Cmax] - [loge(Total radioactivity Cmax]}
Per subject for radiolabelled IV dose.
[14C]-GSK2269557 
/Total radioactivity 
ratio for AUC(0-inf)
AUC(0-inf) Ratio = Exp { [loge([14C]-GSK2269557 AUC(0-inf)] - [loge(Total radioactivity 
AUC(0-inf)] } 
Per subject for radiolabelled IV dose.
[14C]-GSK2269557 
/Total radioactivity 
ratio for AUC(0-t)
AUC(0-t) Ratio = Exp { [loge([14C]-GSK2269557 AUC(0-t)] - [loge(Total  radioactivity 
AUC(0-t)] } 
Per subject for radiolabelled IV dose.
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.

The 10 PK parameters AUC(0-t), AUC(0-24), AUC(0-inf), AUCex, Cmax, tmax, t1/2, CL, Vdss and Vc will be derived 
from phoenix and sent to S&P. The radiometric IV and oral dose will be calculated by Covance and sent to S&P. 
Additional parameters will be derived by S&P including CLr, ML(iv), ML(po), Fg, EH, Fabs, F and the treatment ratios
Table 2
Derived Urine and Faeces Pharmacokinetic Parameters
Parameter
Parameter Description
Ae[urine]
Total radioactivity recovered in the urine (Ae[urine]) calculated for each collection interval
per subject and treatment period as:
Ae[urine]= (concentration in urine sample x collected sample weight) 
for each urine collection interval, eg 0-6, 6-24, 24-48, etc.
Cumulative 
Ae[urine]
Cumulative total radioactivity recovered in the urine (Cumulative Ae[urine]) calculated for 
each cumulative collection interval per subject and treatment period as:
Cumulative Ae[urine]= summation of Ae[urine]
for each urine collection within the cumulative urine collection interval, eg 0-24, 0-48, etc.
Fe%[urine]
% of total dose excreted as total radioactivity (Fe%[urine]) for each collection interval per
subject and treatment period, will be estimated as:
Fe%[urine]=(Ae[urine]) for each collection period)/Dose*100.
Where the dose is the radiolabelled [14C]-GSK2269557, that is in period 1 radiometric iv 
dose, in period 2 radiometric oral dose
Cumulative 
Fe%[urine]
Cumulative % of total dose excreted as total radioactivity (Cumulative Fe%[urine]) for each 
cumulative collection interval per subject and treatment period, will be estimated as:
Cumulative Fe%[urine]=summation of Fe%[urine]
for each urine collection within the cumulative urine collection interval, eg 0-24, 0-48, etc.


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Parameter
Parameter Description
Ae[faeces]
Total radioactivity recovered in the faeces (Ae[faeces]) calculated for each collection 
interval per subject and treatment period as
Ae[faeces] = (concentration in faecal homogenate aliquot analysed x weight of 
homogenate aliquot analysed) x (total homogenate weight / collected sample weight)
for each faecal collection interval, eg 0-24, 24-48, etc
Cumulative 
Ae[faeces]
Cumulative total radioactivity recovered in the faeces (Cumulative Ae[faeces]) calculated 
for each cumulative collection interval per subject and treatment period as
Cumulative Ae[faeces]= summation of Ae[faeces]
for each faecal collection within the cumulative faecal collection interval, eg 0-24, 0-48, etc
Fe%[faeces]
% of total dose excreted as total radioactivity (Fe%[faeces]) for each collection interval per 
subject and treatment period will be estimated as:
Fe%[faeces] =(Ae[faeces] for each collection period)/Dose*100.
Where the dose is the radiolabelled [14C]-GSK2269557, that is in period 1 radiometric iv 
dose, in period 2 radiometric oral dose
Cumulative 
Fe%[ faeces]
Cumulative % of total dose excreted as total radioactivity (Cumulative Fe%[ faeces]) for 
each cumulative collection interval per subject and treatment period will be estimated as:
Cumulative Fe%[faeces]=summation of Fe%[faeces]
for each faecal collection within the cumulative faecal collection interval, eg 0-24, 0-48, etc.
Ae[total]
Total radioactivity recovered in total excretion (sum of urine and faecal excretion), Ae[total] 
will be estimates by collection interval for each subject and treatment period as:
Ae[total]=Ae[urine]+ Ae[faeces]
Cumulative 
Ae[total]
Total radioactivity recovered in total excretion (sum of urine and faecal excretion), 
cumulative Ae[total] will be estimates by cumulative collection interval per subject and 
treatment period as:
Cumulative Ae[total]= summation of Ae[total] 
for each total excretion collection within the cumulative total excretion collection interval, eg 
0-24, 0-48, etc
Fe%[total]
% of total dose excreted as total radioactivity (Fe%[ total]) for each collection period will be 
estimated for each subject and treatment period as:
Fe%[total]= Fe%[urine]+ Fe%[faeces]
Cumulative
Fe%[total]
Cumulative % of total dose excreted as total radioactivity (Cumulative Fe%[ total]) for each 
cumulative collection period will be estimated for each subject and treatment period as:
Cumulative Fe%[total]= Cumulative Fe%[urine]+ Cumulative Fe%[faeces]
for each total excretion collection within the cumulative total excretion collection interval, eg 
0-24, 0-48, etc
NOTES:

Additional parameters may be included as required.


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8.2.
Primary Pharmacokinetic Analyses
8.2.1.
Endpoint / Variables
8.2.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3
Reporting Standards for Pharmacokinetic)
8.2.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated as described in Section 8.1.2. 
8.2.2.
Summary Measure
A primary objective is to determine total radioactivity (drug related material) in plasma 
following a single IV microtracer of [14C]-GSK2269557 (concomitant with an inhaled 
non-radiolabelled GSK2269557 dose) and a single oral dose of [14C]-GSK2269557. To 
assess this, the plasma PK parameters: AUC (0-inf), AUC (0–t), AUC (0–24), %AUCex, 
Cmax, tmax, t1/2 of total drug-related material (radioactivity) will be summarised and 
listed.
The additional primary objective is to determine the rate and extent of excretion of total 
radioactivity in urine and faeces and the total recovery of radioactivity following a single 
IV microtracer of [14C]-GSK2269557 (concomitant with an inhaled non-radiolabelled 
dose) and a single oral dose of [14C]-GSK2269557. To assess this, the PK parameters:
Ae and Fe% will be summarised and listed for urine faeces and total (Urine + Faeces).
8.2.3.
Population of Interest
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic”
population, unless otherwise specified.
8.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9 List of Data Displays and will 
be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.3.
Secondary Pharmacokinetic Analyses
8.3.1.
Endpoint / Variables
8.3.1.1.
Drug Concentration Measures
Refer to Appendix 4 Data Display Standards & Handling Conventions (Section 11.4.3
Reporting Standards for Pharmacokinetic)


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8.3.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated as described in Section 8.1.2. 
8.3.2.
Summary Measure
A secondary objective is to determine parent GSK2269557 concentration in plasma 
following a single IV microtracer of [14C]-GSK2269557 (concomitant with an inhaled 
non-radiolabelled GSK2269557 dose) and a single oral dose of [14C]-GSK2269557. To 
assess this, the plasma PK parameters: AUC (0-inf), AUC (0–t), AUC (0–24), %AUCex, 
Cmax, tmax, t1/2 of parent GSK2269557 ([14C]-GSK2269557 and GSK2269557) will 
be summarised and listed and the volume (Vdss and Vc) and clearance of parent 
GSK2269557 ([14C]-GSK2269557) after IV dose only will be summarised and listed.
Another secondary objective is to estimate the absolute bioavailability of GSK2269557 
following inhaled and oral administration. To assess this, the oral and inhaled 
bioavailability (F) will be summarised and listed.
To assess metabolism, the plasma PK parameters: ML(iv), ML(po), Fg, EH, Fabs will be 
summarised and listed. To assess exposure and metabolite ratio in humans, the ratio of 
Parent GSK2269557/total radioactivity will be calculated for the plasma PK parameters: 
Cmax, AUC(0-t), AUC(0-24) and AUC(0-∞), results will be summarised, listed and 
statistical analyses will be conducted as described in Section 8.3.4.1. To assess renal 
clearance, the PK CLr will be summarised and listed if bioanalysis can quantify parent 
GSK2269557 in urine collection intervals (i.e. if Ae is quantifiable for collection
intervals).
8.3.3.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic
population, unless otherwise specified.
8.3.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9 List of Data Displays and will 
be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.3.4.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles).
Endpoint / Variables

Parent GSK2269557/Total radioactivity ratio for Cmax, AUC(0-t), AUC(0-24) and AUC(0-∞)
Model Specification
NOTE: The description below describes the current thinking of how to analyse these endpoints.  The 


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proposed models will be assessed, and if not appropriate alternative models could be used.
[14C]-GSK2269557/ Total radioactivity ratio for Cmax, AUC(0-t), AUC(0-24) and AUC(0-∞) - Period 1 IV 
Dose
Following sample analyses the Parent GSK2269557 for the IV dose is likely to be presented as [14C]-
GSK2269557 depending on the method, this is in addition to the Parent GSK2269557 for the inhaled dose 
and the total radioactivity. Analysis has been described for the [14C]-GSK2269557 analyte however may be 
adapted if alternate sample analysis is conducted.
For each period, following loge-transformation of plasma pharmacokinetic parameters of [14C]-GSK2269557 
(from period 1 IV dose) and total radioactivity (from period 1 IV dose), AUC(0-∞), AUC(0-24), AUC(0-t) and 
Cmax will be separately analysed using a mixed effects model fitting a fixed effect term for analytes ([14C]-
GSK2269557 (from period 1 IV dose) and total radioactivity (from period 1 IV dose)) and a random effect for 
subject. The Kenward & Roger (KR) degrees of freedom approach will be used. Point estimates for the 
mean difference between the [14C]-GSK2269557 and total radioactivity analytes, and associated 95% 
confidence interval will be constructed using the residual variance. 
GSK2269557/ Total radioactivity ratio for Cmax, AUC(0-t), AUC(0-24) and AUC(0-∞) - Period 2 oral dose
Following sample analyses the Parent GSK2269557 will be presented as either GSK2269557 or [14C]-
GSK2269557 depending on the method, in addition to total radioactivity. Analysis has been described for 
parent GSK2269557 analyte and should be adapted to the appropriate analyte as appropriate. 
For each period, following loge-transformation of plasma pharmacokinetic parameters of Parent 
GSK2269557 (from period 2 oral dose) and total radioactivity (from period 2 oral dose), AUC(0-∞), AUC(0-
24), AUC(0-t) and Cmax will be separately analysed using a mixed effects model fitting a fixed effect term 
for analytes (Parent GSK2269557 (from period 2 oral dose) and total radioactivity (from period 2 oral dose)) 
and a random effect for subject. The Kenward & Roger (KR) degrees of freedom approach will be used. 
Point estimates for the mean difference between the Parent GSK2269557 and total radioactivity analytes, 
and associated 95% confidence interval will be constructed using the residual variance. 
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments may be made based on the data

The Kenward and Roger method for approximating the denominator degrees of freedom and correcting 
for bias in the estimated variance-covariance of the fixed effects will be used.

Normality assumptions underlying the model used for analysis will be examined by obtaining a normal 
probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking the 
normality assumption and constant variance assumption of the model respectively) to gain confidence 
that the model assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative models will be explored 
using appropriate transformed data
Model Results Presentation

Point estimates for the mean difference between the Parent GSK2269557 and total radioactivity 
analytes, and associated 95% confidence interval will be constructed using the residual variance. The 
point estimate and confidence interval will then be exponentially back-transformed to obtain point 
estimates and associated 95% confidence interval for the ratio Parent GSK2269557/total radioactivity. 
These will be presented in a tabular form.
Sensitivity Analyses

Data will be reviewed and if there are deviation that may affect the PK results, sensitivity analyses may
be conducted as appropriate which may include excluding individual time points or excluding individual 
subjects as appropriate.


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9.
EXPLORATORY ANALYSES
As outlined in the protocol, there is an exploratory endpoint of characterisation and 
quantification of metabolites in plasma, urine, faeces, and duodenal bile. These analytical 
investigations may be conducted by GSK PTS IVIVT and the results reported in a 
separate GSK PTS IVIVT report.


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10.
REFERENCES
Davis,B and Morris,T. Physiological Parameters in Laboratory Animals and Humans. 
Pharmaceutical ResearchVol10.No.7.1093-1095.1993.
PKOne and relevant information on Standards for the Transfer and Reporting of PK Data 
using HARP available within IDSL standards, 2008.
Protocol Deviation Management Plan for an open-label study in healthy male subjects, to 
determine the excretion balance and pharmacokinetics of [14C]-GSK2269557, 
administered as a single intravenous microtracer (concomitant with an inhaled non-
radiolabelled dose) and a single oral dose, 2017


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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management

As detailed in Section 4.1, Protocol deviations will be tracked by the study team 
throughout the conduct of the study in accordance with the Protocol Deviation 
Management Plan and a listing and summary of important Protocol Deviations will be 
provided. 

A Per Protocol Population is not being defined for this study. However additional 
exploratory sensitivity summaries may be considered, if there are protocol deviations 
that may affect the primary PK endpoints. Any additional sensitivity summaries will 
be documented in the CSR.


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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Schedule of activities for Treatment Period 1
Procedure
Screening
Treatment Period 1 (IV and inhaled dosing)
Day
–30 to –1

1
2
3
4
5
6
7
8
Pre-
dose
Post- dose 
0–16 h
24 h
48 h
72 h
96 h
120 h
144 h
168 h
Admission to Unit
X
Informed Consent
X
Discharge from Unit
X
Demographics
X
Full Physical Exam
X
Brief Physical Exam
X
X
Inhaler training1
X
Medical/medication/drug/alcohol history
X
HIV, Hep B and Hep C screen
X
Alcohol and cotinine tests, and urine drugs of 
abuse2
X
X
Laboratory safety tests
X
X
X
X
X
12-lead ECG3
X 
X 
X
X
X
X
Vital signs (HR and BP)3
X 
X 
X
X
X
X
Inhaled dose
X
IV infusion
X4
Local tolerability assessment5
X
X
X
Blood samples for background radiation, total 
radioactivity, [14C]-GSK2269557 analysis and cold 
GSK2269557 analysis6
X7
X7
X7,8
X
X
X
X
X
X
Blood samples for metabolite profiling
X8
X9
Urine collection10,11
X 
X
X
X
X
X
X
X
X
Faecal collection12,13
X13
X
X
X
X
X
X
X
X
Entero-Test14
Meals15
X


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Procedure
Screening
Treatment Period 1 (IV and inhaled dosing)
Day
–30 to –1

1
2
3
4
5
6
7
8
Pre-
dose
Post- dose 
0–16 h
24 h
48 h
72 h
96 h
120 h
144 h
168 h
AE/concomitant medication review16
1.
Training conducted by reviewing the Patient Information Leaflet with the participant. Additional training may be conducted at the discretion of the 
investigator.
2.
Breath test will be performed to check alcohol consumption. Both CO breath tests and urine cotinine tests will be performed to check smoking state.
3.
Triplicate measurements will be taken at screening and pre-dose on Day 1; single measurements will be taken at 6 h post-dose on Day 1 and at all other time 
points.  Mean of triplicate measurements to be used as baseline. 
4.
IV infusion to begin as soon as possible (but within 5 min) after the start of the inhaled dose.
5.
Local tolerability assessment for injection site reactions will be performed immediately after the end of dosing on Day 1 at 6 and 12 h, and on Days 2 and 3.
6.
Sampling times relative to the start of the IV infusion.  Blood samples for total radioactivity, [14C]-GSK2269557 analysis and cold GSK2269557 analysis will 
be taken:  pre-dose and at 0h (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 h 
after the start of infusion.
7.
Background radiation sample taken at screening, Day –1 and pre-dose only.  
8.
An additional pre-dose blood sample may be taken from 1 participant for preparation of a plasma shipment control (details provided in the SRM). 
9.
Blood samples for plasma metabolite profiling will be collected at 0.5 h and 4 h after the start of the IV infusion.
10.
An aliquot from each urine collection will be taken for metabolic profiling (separate study).
11.
Sampling times relative to the start of the IV infusion.  Urine will be collected at pre-dose, 0-6 h, 6-24 h then over 24 h collection periods as follows: 24-48 h, 
48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h.  
12.
An aliquot from each homogenised faecal collection will be taken for metabolic profiling (separate study).
13.
Sampling times relative to the start of IV infusion The pre-dose faecal collection sample can be collected up to 24 h pre-dose. Afterward faeces will be 
collected over 24 h collection periods as follows: 0-24 h, 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168h.
14.
Entero-Test string device will be swallowed at approximately 3.5 h pre-dose (start of inhaled dose) while participants are in a fasted state and the string 
removed at about 2.5 h post-dose on Day 1. At about 0.5 h post-dose (i.e. 2 hours before string withdrawal) a food cue will be used to stimulate gall bladder 
emptying).
15.
Meal times are 30 min, 4 h and 10 h post dose on Day 1.  On all other days, meals will be served at the standard times for the unit. 
16.
AEs and SAEs will be collected from the signing of the ICF until the follow-up visit. However, any SAEs related to study participation or a GSK concomitant 
medication will be recorded from the time a participant consents to participate in the study and until the final follow-up visit contact.


 
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Schedule of activities for treatment period 2 
Procedure 
Treatment Period 2 (Oral dosing) 
Follow-up 
Day  
(7-14 days 
post-last dose)2,3 
 -1 
11 
2 
3 
4 
5 
6 
7 
8 
  
Pre-dose 
Post-dose 
0-16 h 
24 h 
48 h 
72 h 
96 h 
120 h 
144 h 
168 h 
  
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
Discharge from Unit2,3 
  
  
  
  
  
  
  
  
  
X 
  
Drugs of abuse 
X 
  
  
  
  
  
  
  
  
  
  
Alcohol and cotinine tests4 
X 
  
  
  
  
  
  
  
  
  
  
Brief Physical Exam 
  
X 
  
  
  
  
  
  
  
  
X 
Laboratory safety tests 
X 
X 
  
X 
  
  
  
  
  
X 
X 
12-lead ECG 
X 
X 
X5 
X 
  
  
  
  
  
X  
X  
Vital signs (HR and BP) 
X 
X 
X5 
X 
  
  
  
  
  
X  
X  
Oral dose 
  
X 
  
  
  
  
  
  
  
  
Blood samples for total 
radioactivity, [14C]-GSK2269557 
analysis and cold GSK2269557 
analysis 
  
X6 
X 
X 
X 
X 
X 
  
  
X 
  
Blood samples for metabolite 
profiling 
 
X 
X7 
X 
 
 
 
 
 
 
 
Urine collection8,9 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Faecal collection10,11 
  
X11 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
Meals13 
  
  
X 
  
  
  
  
  
  
  
  
AE/concomitant medication 
review14 
  


 
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1. There will be a washout of at least 14 days between dosing in treatment period 1 and 2. 
2. If less than 1% of the dose is excreted in each 24 h period on Day 6 (120-144 h) and Day 7 (144-168 h) for a given participant, the participant may be 
discharged as early as Day 8 (after the LSC results are available), and no further samples (apart from for laboratory safety tests) will be collected.  Follow-up 
procedures may be done at discharge and procedures scheduled for Day 8 and follow up will only be done once.  
3. If excretion is higher than 1%, or if the results are inconclusive in each 24-h period on Day 6 (120-144 h) and Day 7 (144-168 h) for a given participant, that 
participant will remain at the unit, and urine and faecal collections will continue at 24-h intervals, for up to 7 days (until the morning of Day 15), until 
excretion is less than 1%.  All remaining participants will be discharged from the unit on Day 15.  Follow-up procedures may be done at discharge.  In the 
unlikely event that excretion is still higher than 1% upon discharge on Day 15, participants will continue to collect faecal samples only, at home, at 24-h 
intervals.  Samples collected at home will be returned to the clinic every 2-3 days. 
4. Breath test will be performed to check alcohol consumption. Both CO breath tests and urine cotinine tests will be performed to check smoking state. 
5. Vital signs and ECG will be taken 6 h post dose. 
6. Sampling times relative to the oral dose.  Blood samples for total radioactivity, [14C]-GSK2269557 analysis and cold GSK2269557 analysis will be taken:  
pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose. 
7. Blood samples for plasma metabolite profiling will be collected at 2 h and 6 h post-[14C]-GSK2269557oral dose. 
8. An aliquot from each urine collection will be taken for metabolic profiling (separate study). 
9. Urine will be collected at pre-dose, at 0-6 h, 6-24 h then over 24 h collection periods as follows: 24-48 h, 48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h. 
10. An aliquot from each faecal collection will be taken for metabolic profiling (separate study). 
11. The pre-dose faecal sample can be collected up to 24 h pre-dose. Afterward faeces will be collected over 24 h collection periods as follows: 0-24 h, 24-48 h, 
48-72 h, 72-96 h, 96-120 h, 120-144 h, 144-168 h. 
12. If dose excretion is still higher than 1% after day 15 the participants will continue to collect faecal samples only, at home, at 24-h intervals until excretion is 
less than 1%. 
13. Meal times are 4h and 10h post dose on Day 1.  On all other days, meals will be served at the standard times for the unit. 
14. AEs and SAEs will be collected from the signing of the ICF until the follow-up visit. However, any SAEs related to study participation or a GSK 
concomitant medication will be recorded from the time a participant consents to participate in the study and until the final follow-up visit contact. 
 


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11.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
11.3.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start and/or stop time/date of the study treatment within the period (for period 1 the 
inhaled and IV dose, for period 2 the oral dose).
These treatment phases are already defined in the Time and Event table in Appendix 2
Schedule of Activities (Section 11.2).
Treatment Phase
Definition
Pre-Treatment 
Date/Time ≤ Study Treatment Start Date/Time
On-Treatment
Study Treatment Start Date/Time < Date/Time ≤ Study Treatment Stop Date/Time
Post-Treatment
Date/Time > Study Treatment Stop Date /Time
11.3.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


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11.3.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date plus washout.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 14 
days.

For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. For the initial period the logic would be as above. For the later 
period the logic would use the treatment dates associated with the later period:

Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date 
+14 days.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.


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11.4.
Appendix 4: Data Display Standards & Handling 
Conventions
11.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SAL00175
HARP Compound
: GSK2269557
HARP Study
: mid206764
Analysis Datasets 

Analysis datasets will be created according to Clinical Data Interchange Standards Consortium (CDISC) 
standards. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent.
Generation of RTF Files

RTF files will be generated for summary tables. 
11.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

All data will be reported according to the actual treatment the subject received unless otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the pCRF.

The reported precision from non pCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 


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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.
11.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
PKOne. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
Plasma PK 
Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: CLr, ML(iv), 
ML(po), Fg, EH, Fabs, F(Oral, (0-t)), F(Oral, (0-∞)), F(inhaled, (0-t)), F (inhaled, (0-
∞))  and the Parent GSK2269557/ Total Radioactivity ratio for Cmax, AUC(0-t), 
AUC(0-24) and AUC(0-∞).
note: Parent GSK2269557/ Total Radioactivity ratios will be either GSK2269557/ 
Total Radioactivity or [14C]-GSK2269557/ Total Radioactivity depending on the 
method of sample analyses and are of interest for the radiolabelled IV and oral 
dose.
Urine and Faeces
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: cumulative Ae,
Fe% and cumulative Fe%.
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
No. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to PKOne


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11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
General
Multiple Measurements at One Analysis Time Point

Triplicate measures of 12-lead ECG and vital signs (HR and BP) will be taken at screening and pre 
dose for period 1. The mean of the measurements will be calculated and used in any derivation of 
summary statistics but if listed all data will be presented.

There are no other scheduled multiple measurements however, if multiple measurements are recorded 
at a given time point the following process will be followed:
[1] Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.
[2] If there are two values within a time window (as per Section 11.2) the value closest to the 
target day for that window will be used. If values are the same distance from the target 
then the mean will be taken.
[3] Subjects having both High and Low values for Normal Ranges at any post-baseline visits 
for safety parameters will be counted in both the High and Low categories of “Any visit 
post-baseline” row of related summary tables. This will also be applicable to relevant 
Potential Clinical Importance summary tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
11.5.2.
Study Population
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’. 
o
The year of the birth date will be captured in the pCRF
Age will then be derived as the integer value of [(DoB- date of Screening)/365.25]

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m) 2]
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated.

Planned Treatment Duration is defined as 1 day in period 1 and 1 day in period 2. 
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  


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Study Population
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
11.5.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcF is machine read, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the pCRF, corrected QT intervals by Fridericia’s (QTcF) formulas will be 
calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcF will be derived as: 
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
This imputation should be performed on the raw data before the conversion of units in CDISC studies to 
ensure correct imputation of missing data.


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11.6.
Appendix 6: Reporting Standards for Missing Data
11.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one who has 
completed all phases of the study including the last visit. 

If participants prematurely discontinue the study, additional replacement participants 
may be enrolled at the discretion of the sponsor and in consultation with the 
investigator

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
Liver 
Chemistry 
Stopping 
Criteria

Study treatment will be stopped for a subject if the following liver chemistry
stopping criteria is met:
o
ALT ≥ 3 x ULN; or
o
ALT ≥ 3 X ULN and total bilirubin ≥ 2 x ULN (> 35% direct bilirubin); or
o
ALT ≥ 3 x ULN and INR > 1.5 (INR is not a Protocol requirement)
Note: Refer to Appendix 4 of Protocol for details of the required assessments if a subject 
meets the above criteria.
QTc 
Stopping 
Criteria

A subject who meets either bulleted criterion below will be withdrawn from the study:
o
QTcF > 500 msec
o
Change from baseline: QTcF > 60 msec
11.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The pCRF allows for the possibility of partial dates (i.e., only month and/or year) to be 
recorded for AE start and end dates; that is, the day or the month of the date may be 
missing. 

Any fully or partially missing dates for adverse events will be raised to data 
management for resolution before DBR.


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Element
Reporting Detail

If fully or partially missing dates are available following DBF, the following conventions 
will be applied for calculating the time to onset and the duration of the event:
Partially Missing Dates:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the latest study treatment start date will be 
used and hence the event is considered On-treatment as per Appendix 3 Study 
Phases and Treatment Emergent Adverse Events.
o
Missing Start Month: January will be used unless this is before the start date of 
study treatment; in this case the month of the latest study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 3 Study 
Phases and Treatment Emergent Adverse Events.
o
Missing Start Year: Current year will be used unless this is before the start date of 
study treatment; in this case the year of the latest study treatment start date will be 
used and hence the event is considered On-treatment as per Appendix 3 Study 
Phases and Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the latest study treatment stop date will be 
used. 
o
Missing Stop Month: December will be used, unless this is after the stop date of 
study treatment; in this case the latest month of study treatment stop date will be 
used.
o
Missing Stop Year: Current year will be used, unless this is after the stop date of 
study treatment; in this case the latest year of study treatment stop date will be 
used.
Fully Missing Dates:
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haematocrit 
Ratio of 1
Male
0.54
∆from BL
↓0.075
Haemoglobin 
g/L
Male
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
White Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
mmol/L
30
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
1.3 x ULN
Creatinine
mmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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11.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
≤ 450
Absolute PR Interval
msec
< 120
< 220
Absolute QRS Interval
msec
≤ 120
Absolute Ventricular rate
beats/min
<35
>100
Change from Baseline
Increase from Baseline QTc
msec
> 60
11.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 90
≤ 140
Diastolic Blood Pressure
mmHg
≥ 40
≤ 90
Heart Rate
bpm
≥ 40
≤ 90
Respiration rate
breaths/min
≥ 8
≤ 20
Oral Temperature
ºC
≥ 35.5
≤ 37.8
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Systolic Blood Pressure
mmHg
≥ 40
≥ 40
Diastolic Blood Pressure
mmHg
≥ 20
≥ 20
Heart Rate
bpm
≥ 30
≥ 30


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11.8.
Appendix 8: Abbreviations & Trade Marks
11.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
pCRF
Paper Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model


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Abbreviation
Description
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
11.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
SAS
WinNonlin


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11.9.
Appendix 9: List of Data Displays
11.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.11
N/A
Pharmacokinetic
2.1 to 2.20
2.1 to 2.17
Safety
3.1 to 3.11
N/A
Section
Listings
ICH Listings
1 to 30
Other Listings
31 to 46
11.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
N/A
N/A
N/A
Pharmacokinetic
N/A
N/A
N/A
Safety
N/A
N/A
SAFE_L1
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
11.9.3.
Deliverables
Delivery
Description
SAC
Final Statistical Analysis Complete


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11.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.1.
Safety
ES1A
Summary of Participant Disposition for the Participant
Conclusion Record
ICH E3, FDAAA, EudraCT
SAC
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC
1.3.
Safety
ES4
Summary of Participant Disposition at Each Study Epoch
ICH E3
SAC
1.4.
APE
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
1.6.
Safety
IE2
Summary of Inclusion/Exclusion Criteria Deviations
SAC
Population Analysed
1.7.
Safety
SP1 
Summary of Study Populations 
IDSL
SAC
Demographic and Baseline Characteristics
1.8.
Safety
DM3
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC
1.9.
Safety
DM11
Summary of Age Ranges
EudraCT
SAC
1.10.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Prior and Concomitant Medications
1.11.
Safety
CM1
Summary of Concomitant Medications
ICH E3
SAC
11.9.5.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Plasma
2.1.
PK
PK01
Summary of Plasma Total Radioactivity Concentrations by Treatment 
and Time
Include un transformed concentrations
SAC
2.2.
PK
Refer to 
Programming 
Notes
Summary of Log Transformed Plasma Total Radioactivity 
Concentrations by Treatment and Time
Include log transformed concentrations
use standard macro for sumstatsinrows 
for log transformed variable, present 
similar to example shell PK01 but 
present geometric mean and SD (Log) 
rather than mean and SD respectively.
SAC
2.3.
PK
PK03
Summary of Derived Plasma Total Radioactivity PK Parameters by 
Treatment
Include columns for parameter, period, 
treatment, N, n, arithmetic mean, 95% 
CI of arithmetic mean, standard 
deviation (SD), median, minimum and 
maximum.
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.4.
PK
PK05
Summary of Log-Transformed Derived Plasma Total Radioactivity PK 
Parameters by Treatment
Include columns for parameter, period, 
treatment, N, n, geometric mean, 95% 
CI of geometric mean, standard 
deviation (SD) of logged data, median, 
minimum, maximum and between 
subject geometric coefficient of 
variation (CVb (%)).
Refer to Section 11.4.3 for parameters 
that should be log transformed
refer to 
gsk2269557/pii115119/part_a/drivers/t_
pk_sum_log (Table 4.3)
SAC
2.5.
PK
PK01
Summary of Plasma [14C]-GSK2269557 Concentrations by Treatment 
and Time
Include un transformed concentrations
SAC
2.6.
PK
Refer to 
Programming 
Notes
Summary of Log Transformed Plasma [14C]-GSK2269557 
Concentrations by Treatment and Time
Include log transformed concentrations 
use standard macro for sumstatsinrows 
for log transformed variable, present 
similar to example shell PK01 but 
present geometric mean and SD (Log) 
rather than mean and SD respectively.
SAC
2.7.
PK
PK03
Summary of Derived Plasma [14C]-GSK2269557 PK Parameters by 
Treatment
Include columns for parameter, period, 
treatment, N, n, arithmetic mean, 95% 
CI of arithmetic mean, standard 
deviation (SD), median, minimum and 
maximum.
In addition to standard [14C]-
GSK2269557 pk parameters include 
Clearance (CL(iv) and CLr) and volume 
(Vdss and Vc).
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.8.
PK
PK05
Summary of Log-Transformed Derived Plasma [14C]-GSK2269557 PK 
Parameters by Treatment
Include columns for parameter, period, 
treatment, N, n, geometric mean, 95% 
CI of geometric mean, standard 
deviation (SD) of logged data, median, 
minimum, maximum and between 
subject geometric coefficient of 
variation (CVb (%)).
Refer to Section 11.4.3 for parameters 
that should be log transformed. In 
addition to standard [14C]-
GSK2269557 pk parameters include 
Clearance (CL(iv) and CLr) and volume 
(Vdss and Vc).
refer to 
gsk2269557/pii115119/part_a/drivers/t_
pk_sum_log (Table 4.3)
SAC
2.9.
PK
PK01
Summary of Plasma GSK2269557 Concentrations by Treatment and 
Time
Include un transformed concentrations
SAC
2.10.
PK
Refer to 
Programming 
Notes
Summary of Log Transformed Plasma GSK2269557 Concentrations by 
Treatment and Time
Include log transformed concentrations 
use standard macro for sumstatsinrows 
for log transformed variable, present 
similar to example shell PK01 but 
present geometric mean and SD (Log) 
rather than mean and SD respectively.
SAC
2.11.
PK
PK03
Summary of Derived Plasma GSK2269557 PK Parameters by 
Treatment
Include columns for parameter, period, 
treatment, N, n, arithmetic mean, 95% 
CI of arithmetic mean, standard 
deviation (SD), median, minimum and 
maximum.
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.12.
PK
PK05
Summary of Log-Transformed Derived Plasma GSK2269557 PK 
Parameters by Treatment
Include columns for parameter, period, 
treatment, N, n, geometric mean, 95% 
CI of geometric mean, standard 
deviation (SD) of logged data, median, 
minimum, maximum and between 
subject geometric coefficient of 
variation (CVb (%)).
Refer to Section 11.4.3 for parameters 
that should be log transformed
refer to 
gsk2269557/pii115119/part_a/drivers/t_
pk_sum_log (Table 4.3)
SAC
2.13.
PK
PK06
Summary of Oral and Inhaled Absolute Bioavailability
Refer to Section 11.4.3 for parameters 
that should be log transformed.
Include PK Parameters: Inhaled F (0-
∞), Inhaled F (0-t), Oral F (0-∞) and 
Oral F (0-t), Dose(Inhaled), Dose(iv) 
and Dose(Oral).
Note: Dose(iv) and Dose(Oral) is 
radiometric dose, Dose(Inhaled) is 
nominal
SAC
2.14.
PK
PK06
Summary of Metabolic, Hepatic Extraction and Absorption Parameters
Refer to Section 11.4.3 for parameters 
that should be log transformed.
Include PK Parameters: ML(iv), ML(po), 
Fg, EH and Fabs
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.15.
PK
[Non-Standard] 
Refer to 
Programming 
notes
Summary of Parent GSK2269557/Total Radioactivity Ratio for Cmax, 
AUC(0-24), AUC(0-∞) and AUC(0-t)
Include columns for: period, parent 
GSK2269557/total radioactivity ratio 
(GSK2269557/total radioactivity or 14C-
GSK2269557/ total radioactivity), 
parameter (Cmax, AUC(0-24), AUC(0-
∞) or AUC(0-t)), geometric mean for 
ratio, SD(log), 95% CI, median, 
minimum, maximum and between 
subject geometric coefficient of 
variation (CVb (%)).
SAC
2.16.
PK
[Non-Standard] 
Refer to 
Programming 
notes
Summary of Statistical Analyses for Parent GSK2269557/Total 
Radioactivity Ratio for Cmax, AUC(0-24),  AUC(0-∞) and AUC(0-t)
Include columns for: period, parent 
GSK2269557/total radioactivity ratio 
(GSK2269557/total radioactivity or 14C-
GSK2269557/ total radioactivity), 
parameter (Cmax, AUC(0-24), AUC(0-
∞) or AUC(0-t)), estimate for ratio, 
SD(log) and 95% CI
SAC
Urine/Faeces
2.17.
PK
PK02
Summary of Urinary and Faecal –Total Radioactivity Pharmacokinetic 
Parameters (Amount Excreted) by Treatment and Time
Include Ae(urine), Ae(faeces) and 
Ae(total).
SAC
2.18.
PK
PK02
Summary of Urinary and Faecal –Total Radioactivity Pharmacokinetic 
Parameters (Cumulative Amount Excreted) by Treatment and Time
Include cumulative Ae(urine), 
Cumulative Ae(faeces) and Cumulative 
Ae(total).
SAC
2.19.
PK
PK02
Summary of Urinary and Faecal –Total Radioactivity Pharmacokinetic 
Parameters (% of Dose Excreted) by Treatment and Time
Include Fe%(urine), Fe%(faeces) and 
Fe%(total).
SAC
2.20.
PK
PK02
Summary of Urinary and Faecal –Total Radioactivity Pharmacokinetic 
Parameters (Cumulative % of Dose Excreted) by Treatment and Time
Include cumulative Fe%(urine), 
Cumulative Fe%(faeces) and 
Cumulative Fe%(total).
SAC


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11.9.6.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Plasma
2.1.
PK
PK16a
Individual Subject Plasma Total Radioactivity-time Plot (Linear and 
Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
N (likely 6) lines for each treatment with 
legend to identify subjects
Time = Planned time post dose (h)
Include the LLOQ as a reference line 
and footnote
refer to 
GSK961081/mid201003/final/f_pk_21 
(Table 2.1)
SAC
2.2.
PK
PK19
Arithmetic Mean (+SD) Plasma Total Radioactivity-time Plot (Linear 
and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to GSK961081/ mid201003/ final/ 
f_pk_22 (Table 2.2)
SAC
2.3.
PK
PK20
Median (Range) Plasma Total Radioactivity-time Plot (Linear and 
Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to GSK961081/ mid201003/ final/ 
f_pk_23 (Table 2.3)
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.4.
PK
PK16a
Individual Subject Plasma [14C]-GSK2269557 Concentration-time Plot 
(Linear and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
N (likely 6) lines for each treatment with 
legend to identify subjects
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to 
GSK961081/mid201003/final/f_pk_21
SAC
2.5.
PK
PK19
Arithmetic Mean (+SD) Plasma [14C]-GSK2269557 Concentration-time 
Plot (Linear and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to GSK961081/ mid201003/ final/ 
f_pk_22
SAC
2.6.
PK
PK20
Median (Range) Plasma [14C]-GSK2269557 Concentration-time Plot 
(Linear and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to GSK961081/ mid201003/ final/ 
f_pk_23
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.7.
PK
PK16a
Individual Subject Plasma GSK2269557 Concentration-time Plot 
(Linear and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
N (likely 6) lines for each treatment with 
legend to identify subjects
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to 
GSK961081/mid201003/final/f_pk_21
SAC
2.8.
PK
PK19
Arithmetic Mean (+SD) Plasma GSK2269557 Concentration-time Plot 
(Linear and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
Time = Planned time post dose (h)
Include the LLOQ as a reference line 
and footnote
refer to GSK961081/ mid201003/ final/ 
f_pk_22
SAC
2.9.
PK
PK20
Median (Range) Plasma GSK2269557 Concentration-time Plot (Linear 
and Semi-log) by Treatment
Linear and log plot on same page. 
Separate page per treatment. 
Time = Planned time post dose (h) 
Include the LLOQ as a reference line 
and footnote
refer to GSK961081/ mid201003/ final/ 
f_pk_23
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Urine and Faeces
2.10.
PK
PK_F4
Individual Subject Absolute –Total Radioactivity Recovered (Amount 
Excreted) for Urine, Faeces and Total Excretion by Time and
Treatment
Ae(urine), Ae(faeces), Ae(total).
Linear scale only. 
Separate page per subject and 
treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_210
SAC
2.11.
PK
PK_F5
Arithmetic Mean Absolute –Total Radioactivity Recovered (Amount 
Excreted) for Urine, Faeces and Total Excretion by Time and
Treatment
Ae(urine), Ae(faeces), Ae(total).
Linear scale only. Separate page per 
Treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_212
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.12.
PK
PK_F4
Individual Subject Cumulative –Total Radioactivity Recovered 
(Cumulative Amount Excreted) for Urine, Faeces and Total Excretion 
by Time and Treatment
Cumulative Ae(urine), Cumulative 
Ae(faeces), Cumulative Ae(total).
Linear scale only. 
Separate page per subject and 
treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_210
SAC
2.13.
PK
PK_F5
Arithmetic Mean Cumulative –Total Radioactivity Recovered 
(Cumulative Amount Excreted) for Urine, Faeces and Total Excretion 
by Time and Treatment
Cumulative Ae(urine), Cumulative 
Ae(faeces), Cumulative Ae(total).
Linear scale only. Separate page per 
Treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_212
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.14.
PK
PK_F4
Individual Subject Absolute –Total Radioactivity Recovered (% of 
Dose) for Urine, Faeces and Total Excretion by Time and Treatment
Fe%(urine), Fe%(faeces), Fe%(total).
Linear scale only. 
Separate page per subject and 
treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_210
SAC
2.15.
PK
PK_F5
Arithmetic Mean Absolute –Total Radioactivity Recovered (% of Dose) 
for Urine, Faeces and Total Excretion by Time and Treatment
Fe%(urine), Fe%(faeces), Fe%(total).
Linear scale only. Separate page per 
Treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_212
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.16.
PK
PK_F4
Individual Subject Cumulative –Total Radioactivity Recovered 
(Cumulative % of Dose) for Urine, Faeces and Total Excretion by Time 
and Treatment
Cumulative Fe%(urine), Cumulative 
Fe%(faeces), Cumulative Fe%(total).
Linear scale only. 
Separate page per subject and 
treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_210
SAC
2.17.
PK
PK_F5
Arithmetic Mean Cumulative –Total Radioactivity Recovered 
(Cumulative % of Dose) for Urine, Faeces and Total Excretion by Time 
and Treatment
Cumulative Fe%(urine), Cumulative
Fe%(faeces), Cumulative Fe%(total).
Linear scale only. Separate page per 
Treatment. 3 lines per plot with legend 
to identify Urine Faeces and Total 
Excretion
Time = actual mid-point of collection
post dose (h).
refer to GSK961081/ mid201003/ final/ 
f_pk_212
SAC


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11.9.7.
Safety Tables
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
Adverse Events (AEs)
3.1.
Safety
AE1CP 
Summary of All Adverse Events by System Organ Class and Preferred 
Term
ICH E3
SAC
3.2.
Safety
AE1CP
Summary All Drug-Related Adverse Events
ICH E3
SAC
Serious and Other Significant Adverse Events
3.3.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
SAC
3.4.
Safety
AE1CP
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Treatment or Withdrawal from Study
IDSL
SAC
Laboratory: Chemistry 
3.5.
Safety
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
SAC
Laboratory: Hematology
3.6.
Safety
LB1
Summary of Hematology Changes from Baseline
ICH E3
SAC
Laboratory: Urinalysis
3.7.
Safety
LB1
Summary of Urine Concentration Changes from Baseline
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
3.8.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
ECG
3.9.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC
3.10.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC
Vital Signs
3.11.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC


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11.9.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.
APE
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
APE
ES9
Listing of Subjects Who Were Rescreened
SAC
3.
Safety
ES3
Listing of Reasons for Study Withdrawal
ICH E3
SAC
4.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3.
SAC
5.
Safety
CP_TA2
Listing of Planned and Actual Treatments
IDSL
non randomised study so do not say 
“randomised” use “Planned” instead
SAC
Protocol Deviations
6.
Safety
DV2A
Listing of Important Protocol Deviations
ICH E3
SAC
7.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC
Populations Analysed
8.
APE
SP3a
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
9.
Safety
DM4
Listing of Demographic Characteristics
ICH E3
SAC
10.
Safety
DM10
Listing of Race
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
Prior and Concomitant Medications
11.
Safety
CP_CM4
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
12.
Safety
EX4
Listing of Exposure Data
ICH E3
SAC
Adverse Events
13.
Safety
AE9CP
Listing of All Adverse Events
ICH E3
SAC
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
16.
Safety
AE9CPa
Listing of Serious Adverse Events
ICH E3
Include fatal and non fatal
SAC
17.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
18.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
Include fatal and non fatal
SAC
Hepatobiliary (Liver)
19.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IDSL
SAC
20.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping Events
IDSL
SAC


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ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
All Laboratory
21.
Safety
LB6
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
SAC
22.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance
SAC
23.
Safety
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
24.
Safety
UR2B
Listing of Urinalysis Data for Participants with Any Value of Potential 
Clinical Importance
ICH E3
SAC
ECG
25.
Safety
CP_EG4
Listing of All ECG Values for Participants with Any Value of Potential 
Clinical Importance
IDSL
SAC
26.
Safety
CP_EG4
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
27.
Safety
CP_EG6
Listing of All ECG Findings for Participants with an Abnormal ECG 
Finding
IDSL
SAC
28.
Safety
CP_EG6
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
29.
Safety
VS5
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
30.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC


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11.9.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Plasma PK
31.
PK
PK08
Listing of Plasma Total Radioactivity-Time Data
SAC
32.
PK
PK14
Listing of Derived Plasma Total Radioactivity Pharmacokinetic 
Parameters
SAC
33.
PK
PK08
Listing of Plasma [14C]-GSK2269557 Concentration-Time Data
SAC
34.
PK
PK14
Listing of Derived Plasma [14C]-GSK2269557 Pharmacokinetic 
Parameters
In addition to standard [14C]-GSK2269557 
pk parameters include Clearance (CL(iv) and 
CLr) and volume (Vdss and Vc).
SAC
35.
PK
PK08
Listing of Plasma GSK2269557 Concentration-Time Data
SAC
36.
PK
PK14
Listing of Derived Plasma GSK2269557 Pharmacokinetic Parameters
SAC
37.
PK
PK14
Listing of Oral and Inhaled Absolute Bioavailability
Include PK Parameters: Inhaled F (0-∞), 
Inhaled F (0-t), Oral F (0-∞) and Oral F (0-t), 
Dose(Inhaled), Dose(iv) and Dose(Oral).
Note: Dose(iv) and Dose(Oral) is radiometric 
dose, Dose(Inhaled) is nominal
SAC
38.
PK
PK14
Listing of Metabolic, Hepatic Extraction and Absorption Parameters
Include PK Parameters: ML(iv), ML(po), Fg, 
EH and Fabs
SAC
39.
PK
PK15
Listing of Individual Subject Parent GSK2269557/Total Radioactivity 
Ratio for Cmax, AUC(0-∞), AUC(0-24) and AUC(0-t)
SAC


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Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Urine and Faeces PK
40.
PK
[Non-Standard] 
Refer to 
programming 
notes
Listing of Urinary and Faecal Total Radioactivity Parameters (Amount 
Excreted) by Time
Ae(urine), Ae(faeces), Ae(total) and 
cumulative Ae(urine), cumulative Ae(faeces), 
cumulative Ae(total)
refer to GSK961081/ mid201003/ final/ 
l_pk_ae (listing 35)
SAC
41.
PK
[Non-Standard] 
Refer to 
programming 
notes
Listing of Urinary and Faecal Total Radioactivity Parameters (% 
Excreted) by Time
Fe%(urine), Fe%(faeces), Fe%(total) and 
cumulative Fe%(urine), cumulative 
Fe%(faeces), cumulative Fe%(total)
refer to GSK961081/ mid201003/ final/ 
l_pk_fe (listing 36)
SAC
Liver Monitoring
42.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC
43.
Safety
LIVER7
Listing of Liver Biopsy Details
SAC
44.
Safety
LIVER8
Listing of Liver Imaging Details
SAC
45.
Safety
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria Post-
Baseline
SAC
Entero-Test
46.
Safety
[Non-Standard] 
SAFE_L1
Listing of Entero-Test Administration and Removal
SAC


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11.10.
Appendix 10: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request