Clinical trial NCT03069989
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Tolerability IPF PET imaging Idiopathic Pulmonary Fibrosis Safety Pharmacokinetics Double-blind
Sponsor: GlaxoSmithKline
Start date: 2017-06-13; Completion date: 2018-07-18
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GSK3008348 is being developed as a treatment for IPF. A first-time-in-human study showed that single nebulized doses of 1-3000 micrograms (mcg) GSK3008348 in healthy volunteers were well tolerated, with pharmacokinetic (PK) exposures within the defined limits set in the protocol. The proposed study is a 2-cohort study of single doses, intended to evaluate the safety, tolerability and PK of the drug in participants with IPF not currently treated with pirfenidone or nintedanib, and to obtain preliminary information on target engagement. Cohort 1 will be a 2-period, randomized, double-blind, placebo-controlled group with at least 7 days washout between doses, and follow-up period of up to 7-14 days. Cohort 2 is optional. It will be designed to further explore safety and to provide additional information on the target engagement profile of GSK3008348. The total duration of the study will be up to 62 days.

Detailed description:

Arms: arm 1: Participants will receive a single nebulized dose of GSK3008348 during each of 2 planned dosing periods and up to 3 microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2. arm 2: Participants will receive a single nebulized dose of placebo during each of 2 planned dosing periods and up to 3 microdose of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2. arm 3: Participants will receive a single nebulized dose of GSK3008348 during each of 2 planned dosing periods and up to 3 microdose administrations of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2. arm 4: Participants will receive a single nebulized dose of placebo during each of 2 planned dosing periods and up to 3 microdose of \[18F\]-FBA-A20FMDV2 for the PET scanning in period 2.
Interventions: intervention 1: GSK3008348 intervention 2: Placebo intervention 3: [18F]-FBA-A20FMDV2
Intervention descriptions: intervention 1: Solution for nebulisation. Available as clear colorless to pale yellow colored solution in a 5mL vial with 20 millimeter (mm) stopper and aluminium seal yellow colored solution in a 5mL vial with 20 millimeter (mm) stopper and aluminium seal. intervention 2: Solution for nebulisation. Available as clear colorless to pale yellow colored solution in a 5mL vial with 20mm stopper and aluminium seal. intervention 3: Radio-labeled peptide ligand for PET scan. Available as intravenous (IV) infusion, 20 mL.

Protocol documents:
Prot_000.pdf: 
2016N291965_02
CONFIDENTIAL
GlaxoSmithKline group of companies
204715
1
TITLE PAGE
Protocol Title: A study of single doses to evaluate the safety, tolerability, 
pharmacokinetics and target engagement of nebulised GSK3008348 in idiopathic 
pulmonary fibrosis patients, using positron emission tomography (PET) imaging
Protocol Number: 204715
Protocol Amendment Number: 02
Short Title: Single doses of GSK3008348 in IPF patients using PET imaging
Compound Number:
GSK3008348
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: Please refer to the Study Reference 
Manual
Regulatory Agency Identifying Number(s): 2016-003674-41
Approval Date: 24-JAN-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD
PP


2 0 1 6 N 2 9 1 9 6 5 _ 0 2 
 
2 0 4 7 1 5 
 
3 
 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E 
D O C U M E N T HI S T O R Y 
D o c u m e nt
 D at e
 
A m e n d m e nt  0 2 
2 4-J A N- 2 0 1 8 
A m e n d m e nt  0 1 
0 9- M ar- 2 0 1 7 
Ori gi n al Pr ot oc ol 
0 5- D ec- 2 0 1 7 
 
A me n d me nt 0 2 2 4- J A N- 2 0 1 8 
O ver all R ati o n ale f or t he A me n d me nt:  
T o c orrect t he descri pti o n of t he pri mar y e n d p oi nt a n d pr o vi de f urt her g ui da nce o n t he 
f oll o w u p visit a n d l u n g f u ncti o n re q uire me nts. Ot her t y p o gra p hical err ors ha ve als o bee n 
c orrecte d. 
Secti o n # a n d 
Na me 
Descri pti o n of C ha n ge 
Brief Rati o nale 
Secti o n 1  
S y n o psis: 
O bjecti ves a n d 
E n d p oi nts 
T he w or di n g ‘a n d bl o o d’ has bee n 
re m o ve d fr o m t he pri mar y e n d p oi nt 
pertai ni n g t o t he v ol u me of 
distri b uti o n ( V T ) 
T o pr o vi de clarit y a n d 
c orrect t he defi niti o n of 
t he pri mar y e n d p oi nt 
pertai ni n g t o t he v ol u me 
of distri b uti o n ( V T ).  T he 
V T is ge nerate d usi n g a 
ki netic m o del t hat 
i ncl u des a bl o o d 
c o m part me nt a n d is 
t heref ore i m plicitl y 
c orrecte d f or bl o o d 
v ol u me 
Secti o n 1 
S y n o psis: 
Treat me nt 
Gr o u p a n d 
F oll o w u p 
A d diti o nal w or di n g has bee n i ncl u de d 
i n t he f oll o w u p secti o n f or 
partici pa nts w h o w it h dra w fr o m t he 
st u d y pri or t o t he fi nal d ose 
T o pr o vi de f urt her 
g ui da nce f or partici pa nts 
wit h dra wi n g fr o m t he 
st u d y pri or t o t he fi nal 
d ose 
Secti o n 2 
Sc he d ule of 
Acti vities 
( S o A) 
T he re q uire me nt t o meas ure hei g ht at 
t he f oll o w u p visit has bee n re m o ve d 
A s u bsta ntial c ha n ge i n 
hei g ht is n ot e x pecte d t o 
be o bser ve d o ver a s h ort 
ti me peri o d 
Secti o n 4 
O bjecti ves a n d 
T he w or di n g ‘a n d bl o o d’ has bee n 
re m o ve d fr o m t he pri mar y e n d p oi nt 
T he v ol u me of distri b uti o n 
( VT ) is ge nerate d usi n g a 


2016N291965_02 
 
204715 
 
4 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Endpoints  
Section 10.3.1 
Pharmacodynamic 
Analyses 
 
pertaining to the volume of 
distribution (VT) 
kinetic model that 
includes a blood 
compartment and is 
therefore implicitly 
corrected for blood 
volume 
Section 4 
Objectives and 
Endpoints: 
Exploratory 
The wording ‘with and without 
correction’ has been added and the 
wording ‘corrected’ has been 
removed to describe the standardised 
uptake values [SUV] and VT, for air 
and/or blood volume) 
To correct and provide 
clarity on the standardised 
uptake value (SUV) which 
cannot be readily 
corrected for blood 
volume 
Section 5.2 
Number of 
Participants 
Additional wording on the number of 
participants required to be dosed and 
considered complete when PET data 
at 30min post dose has been collected 
To provide clarity on the 
numbers of participants 
required to meet the 
primary endpoint of: 
Changes in the uptake of 
[18F]-FBA-A20FMDV2 in 
the whole lung at 
approximately 30 min 
post-dose compared to 
pre-dose, as measured by 
PET 
Section 6.4 
Screen Failures 
Re-screened participants should be 
assigned a new participant number 
The following has been removed from 
Section 6.4: 
Rescreened participants should be 
assigned the same participant number 
as for the initial screening 
 
Correction to the protocol 
Section 9.4 Safety 
Assessments 
New wording inserted in Section 
9.4.6 Lung Function Tests 
To provide guidance on 
lung function tests which 
was previously omitted 
from the protocol 
 


2016N291965_02
204715
5
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................14
3.1.
Study Rationale ..........................................................................................14
3.2.
Background ................................................................................................14
3.3.
Benefit/Risk Assessment ............................................................................15
3.3.1.
Risk Assessment .........................................................................16
3.3.2.
Benefit Assessment.....................................................................20
3.3.3.
Overall Benefit:Risk Conclusion...................................................20
4.
OBJECTIVES AND ENDPOINTS...........................................................................20
5.
STUDY DESIGN ....................................................................................................21
5.1.
Overall Design ............................................................................................21
5.1.1.
Cohort 1.......................................................................................21
5.1.2.
Cohort 2.......................................................................................22
5.1.3.
Changes to Cohorts 1 or 2...........................................................23
5.2.
Number of Participants ...............................................................................24
5.3.
Participant and Study Completion...............................................................24
5.4.
Scientific Rationale for Study Design ..........................................................24
5.5.
Dose Justification........................................................................................25
6.
STUDY POPULATION...........................................................................................26
6.1.
Inclusion Criteria.........................................................................................26
6.2.
Exclusion Criteria........................................................................................27
6.3.
Lifestyle Restrictions...................................................................................28
6.3.1.
Meals and Dietary Restrictions ....................................................28
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................28
6.3.3.
Activity .........................................................................................28
6.4.
Screen Failures...........................................................................................29
7.
TREATMENTS.......................................................................................................29
7.1.
Treatments Administered............................................................................29
7.2.
Dose Modification .......................................................................................30
7.3.
Method of Treatment Assignment ...............................................................30
7.4.
Blinding.......................................................................................................30
7.5.
Preparation/Handling/Storage/Accountability..............................................31
7.6.
Treatment Compliance................................................................................32
7.7.
Concomitant Therapy..................................................................................32
7.8.
Treatment after the End of the Study ..........................................................32
8.
DISCONTINUATION CRITERIA.............................................................................33
8.1.
Discontinuation of Study Treatment ............................................................33
8.1.1.
Liver Chemistry Stopping Criteria ................................................33
8.1.2.
QTc Stopping Criteria ..................................................................33


2016N291965_02
204715
6
8.1.3.
Individual Adverse Event Stopping Criteria ..................................34
8.2.
Withdrawal from the Study..........................................................................34
8.3.
Lost to Follow Up........................................................................................35
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
9.1.
Efficacy Assessments.................................................................................36
9.2.
Adverse Events...........................................................................................36
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................36
9.2.2.
Method of Detecting AEs and SAEs.............................................36
9.2.3.
Follow-up of AEs and SAEs.........................................................37
9.2.4.
Regulatory Reporting Requirements for SAEs .............................37
9.2.5.
Cardiovascular and Death Events................................................37
9.2.6.
Pregnancy ...................................................................................37
9.3.
Treatment of Overdose...............................................................................38
9.4.
Safety Assessments ...................................................................................38
9.4.1.
Physical Examinations.................................................................38
9.4.2.
Vital Signs....................................................................................38
9.4.3.
Peripheral capillary oxygen saturation .........................................39
9.4.4.
Electrocardiograms......................................................................39
9.4.5.
Clinical Safety Laboratory Assessments ......................................39
9.5.
Pharmacokinetics .......................................................................................40
9.6.
Positron Emission Tomography (PET)........................................................40
9.7.
Genetics .....................................................................................................41
9.8.
Biomarkers .................................................................................................41
9.9.
Immunogenicity Assessments.....................................................................42
9.10.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................42
10. STATISTICAL CONSIDERATIONS........................................................................42
10.1.
Sample Size Determination ........................................................................42
10.2.
Populations for Analyses ............................................................................43
10.3.
Statistical Analyses.....................................................................................43
10.3.1.
Pharmacodynamic Analyses........................................................43
10.3.2.
Safety Analyses...........................................................................44
10.3.3.
Pharmacokinetic analyses ...........................................................44
10.3.4.
Other Analyses ............................................................................44
10.3.5.
Interim Analyses ..........................................................................44
10.3.5.1.
Interim Analysis for Futility..........................................44
10.3.5.2.
Interim Analysis for Sample Size Re-estimation .........45
11. REFERENCES.......................................................................................................46
12. APPENDICES........................................................................................................48
12.1.
Appendix 1: Abbreviations and Trademarks................................................48
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................51
12.3.
Appendix 3: Study Governance Considerations..........................................52
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................56
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................61
12.6.
Appendix 6: Genetics..................................................................................65


2016N291965_02
204715
7
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................66
12.8.
Appendix 8: Radiation Dose Risk Assessment ...........................................68
12.9.
Appendix 9:  Assessment of the Potential Immunogenicity Risk for 
[18F]-FBA-A20FMDV2 .................................................................................69
12.10. Appendix 10:  Diagram Summarising the Study Decision Making ...............72
12.11. Appendix 11:  Areas Endemic to Foot and Mouth Disease .........................73
12.12. Appendix 12: Protocol Amendment History.................................................74


2016N291965_02
204715
8
1.
SYNOPSIS
Protocol Title: A study of single doses to evaluate the safety, tolerability, 
pharmacokinetics and target engagement of nebulised GSK3008348 in idiopathic 
pulmonary fibrosis patients, using positron emission tomography (PET) imaging
Short Title: Single doses of GSK3008348 in IPF patients using PET imaging
Rationale:  GSK3008348 is a potent and selective inhibitor of the integrin receptor αvβ6, 
and is being developed as a treatment for idiopathic pulmonary fibrosis (IPF).  It has been 
shown to engage αvβ6 integrin and inhibit downstream fibrogenic mechanisms in mouse 
and human lung cells and tissue.  The first-time-in-human study (GSK Document 
Number 2014N201929_01, Study 200262) showed that single nebulised doses of 
1−3,000 µg GSK3008348 in healthy volunteers were well tolerated, with 
pharmacokinetic (PK) exposures within the defined limits set by the protocol.  The 
proposed study is intended to evaluate the safety, tolerability and pharmacokinetics of the 
molecule in patients with IPF not currently treated with pirfenidone or nintedanib, and 
obtain preliminary information on target engagement to support progression to repeat 
dose and proof of mechanism studies.  Target engagement will be measured by positron 
emission tomography (PET) using a radiolabelled αvβ6-specific ligand, [18F]-FBA-
A20FMDV2 (GSK2634673).    
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate target engagement in the lung 
after single nebulised doses of 
GSK3008348 in IPF patients

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the whole lung (assessed as 
the volume of distribution [VT], not corrected 
for air volume) at approximately 30 min 
post-dose compared to pre-dose, as 
measured by PET

To evaluate the safety and tolerability of 
single nebulised doses of GSK3008348 in 
IPF patients

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and pulmonary function tests
Secondary

To evaluate the pharmacokinetic profile of 
single nebulised doses of GSK3008348 in 
IPF patients

Derived pharmacokinetic parameters for 
GSK3008348 including, but not limited to, 
area under the plasma drug concentration 
versus time curve (AUC(0-t), AUC(0-∞)), 
maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration (Tmax), 


2016N291965_02
204715
9
Objective
Endpoint
and terminal half-life (T1/2) following single 
nebulised doses, where data allow

To evaluate duration of target engagement 
after single nebulised doses of 
GSK3008348 in IPF patients

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the lung (assessed as the 
VT) up to 28 h post-dose compared to pre-
dose, as measured by PET
Overall Design:
This is a multi-centre, 2-cohort, study of single doses to investigate the safety, 
tolerability, PK and target engagement of nebulised GSK3008348, in patients with IPF. 
Hospital-based clinical units will recruit and enrol participants; PET imaging will be done 
at a specialist imaging unit.  All participants will be screened up to 30 days before their 
first dose, will have 2 planned dosing periods, and will have a follow-up visit at 7–14 
days post-last dose.  
Cohort 1 will be a randomised, double-blind (sponsor unblind), placebo-controlled group 
of 7 participants, randomised 5:2 to receive 1,000 µg GSK3008348 or placebo.  Safety 
and tolerability will be assessed in dosing period 1, and PET scans in dosing period 2 will 
be used to assess target engagement of GSK3008348.  
After completion of Cohort 1, safety, PET and PK data will be reviewed. 
Cohort 2 is optional, and will be designed to further explore the safety and to provide 
additional information on the target engagement profile of GSK3008348, such that each 
participant has up to 3 PET scans and 2 planned doses of GSK3008348.  
Refer to Figure 1 for a schematic illustrating the study design.
Figure 1
Study Schematic


2016N291965_02
204715
10
Number of Participants:
It is anticipated that up to 21 participants will be randomized. 
Treatment Groups and Duration:
Cohort 1
Cohort 2
Screening
Within 30 days of the first dose.
Dosing 
Period 1
After pre-dose assessments at the 
clinical unit, participants will be 
admitted to the clinical unit the day of 
dosing (Day 1), stay overnight and be 
discharged after 24 h post-dose safety 
and PK assessments (Day 2). 
After pre-dose assessments at the 
clinical unit, participants will attend the 
clinical unit for dosing (Day 1) and stay 
for at least 8 h post-dose for safety and 
PK assessments.  Participants will return 
on Day 2 for 24 h post-dose safety and 
PK assessments.
Washout 
Period
At least 7 days and no more than 28 days between doses.  
Baseline 
PET scan
At least 7 days after the first dose, and no more than 14 days before the first 
post-dose PET.
Dosing 
Period 2
Participants will have pre-dose 
assessments at the clinical unit.  They 
will attend the imaging unit for dosing 
and a 30 min post-dose PET scan, and 
stay for at least 4 h post-dose.  
Participants will return to the imaging 
unit on Day 2 for a 24 h PET scan, and 
safety and PK assessments.
Participants will have pre-dose 
assessments at the clinical unit.  They 
will attend the clinical or imaging unit for 
dosing and will stay for at least 4 h post-
dose.  Participants will have up to 2 
post-dose PET scans on Days 1 or 2, at 
times to be determined after review of 
Cohort 1 data.
Follow-up
At least 7 days and no more than 14 days after the final dose.  If warranted, 
additional follow-up visits may be scheduled.
If a participant withdraws from the study prior to the final dose, the follow up visit 
should occur within 14 days of withdrawal unless a separate timepoint is agreed by 
the principal investigator and medical monitor
Study 
Duration
Up to 62 days
Treatment 
Arms
Participants will receive a single nebulised dose of GSK3008348 or placebo during 
each of 2 planned dosing periods. 
Participants will receive up to 3 microdose administrations of [18F]-FBA-A20FMDV2 
for the PET scanning.  The maximum amount of radioactivity injected during each 
PET scan will be 150 MBq and maximum mass of [18F]-FBA-A20FMDV2 
administered across the 3 administrations will be 100 µg.


2016N291965_02
CONFIDENTIAL
204715
11
2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening
Dosing period 1
Wash-
out
(7-28 
days 
between 
doses)
Dosing
period 2
Follow-
up
(7-14 
days 
post-final 
dose)
Comments
Day ≤-30
Day –11
Day 1
Day 2
Baseline
PET2
Day –11
Day 12
Day 22
1. Visit may take place on Day -1 or on Day 1 before dosing.
2. Visits will take place at imaging unit; all other visits will take 
place at clinical units. 
Informed consent
x
Inclusion and exclusion criteria
x
Demography
x
Medical history 
x
Past and current medical 
conditions  
x
x
Full physical exam including 
height and weight
x
x3
3. Height not required at follow up visit
Brief medical exam
x
x
X4
x
x4
x4
4. Pre-PET scan, per imaging site SOPs; timing may change in 
Cohort 2 depending on PET timing. 
Pregnancy test 
x
x
x5
x5
x5
Pregnancy tests in females, when required, in serum or urine, 
as per site SOPs. 
5. Pre-PET scan; time points may change in Cohort 2 
depending on PET timing.
Hepatitis B and Hepatitis C 
screen 
x
Laboratory assessments 
(include liver chemistries) 
x
x
x6
x
x6
x
6. 24 h post-dose 
12-lead ECG
x
x
x7
x8
x
x9
x8
x
7. 30 min and 2, 4 and 8 h post-dose
8. 24 h post-dose (pre-PET scan in Dosing period 2)
9. Post-PET scan and before leaving imaging unit 
Timings may change in Cohort 2. Vital signs include blood 
pressure, heart rate, respiration rate and temperature.
Vital signs
x
x
x7
x8
x
x9
x8
x
Oxygen saturation monitoring
x
Continuous monitoring from pre-dose to 4 h post-dose. 
Lung function tests (FEV1,FVC)
x
x
x10
x11
x
x
10.
1 h post-dose
11. 24 h post-dose


2016N291965_02
CONFIDENTIAL
204715
12
Procedure
Screening
Dosing period 1
Wash-
out
(7-28 
days 
between 
doses)
Dosing
period 2
Follow-
up
(7-14 
days 
post-final 
dose)
Comments
Day ≤-30
Day –11
Day 1
Day 2
Baseline
PET2
Day –11
Day 12
Day 22
1. Visit may take place on Day -1 or on Day 1 before dosing.
2. Visits will take place at imaging unit; all other visits will take 
place at clinical units. 
DLCO 
x
x
x12
12. 24 h post-dose.
Randomisation
x
GSK3008348 dosing
x
x
All post-dose time points are relative to start of nebulisation
PK blood sample
x
x
x
x
In Dosing period 1, pre-dose, and at 15 and 30 min, 1, 2, 4, 8, 
12, 18 and 24 h after the start of nebulisation.  In Dosing period 
2, pre-dose; on Day 1 at 15 and 30 min, 2 and 4 h post-dose; 
and on Day 2 on arrival and discharge from imaging unit.  
Time points may change in Cohort 2. 
PK urine collection
x
Spot urine sample to be taken from pre-dose void. Total urine 
collection from pre-dose to 8 h post-dose. 
Biomarker blood sample
x13
x14
13. Samples at pre-dose, and at 2 and 8 h post-dose. 
14. Sample at 24 h post-dose.
PET ligand administration & 
PET scan
x15
x16
x17
15. At least 7 days post-first dose, and no more than 14 days 
before next PET scan. 
16. Approx. 30 min (between 20–60 min) post-dose.
17. Approx. 24 h (between 14−28 h) post-dose.  
Timing of post-dose PET scans may change in Cohort 2; 
participants will have a max of 3 PET scans in total.
HRCT
x
Immunogenicity blood sample
x18
x
18. Pre-PET scan.
Genetic sample
x
AE/SAE & CV event review
x
x
x
x
x
x
x
x
Concomitant medication review
x
x
x
x
x
x
x
x
x
ECG: Electrocardiogram, DLCO: Diffusing capacity of the lungs for carbon monoxide, FEV1: Forced expiratory volume in 1 second, FCV: Forced vital capacity, PET: Positron emission 
tomography, HRCT: High resolution computed tomography, AE: Adverse event, SAE : Serious adverse event, CV: Cardiovascular, PK: Pharmacokinetics


2016N291965_02
CONFIDENTIAL
204715
13

The timing and number of planned study assessments, including safety, 
pharmacokinetic, imaging, immunogenicity and biomarker assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The ethics committee will be informed of any 
safety issues that require alteration of the safety monitoring scheme or 
amendment of the information and consent form (ICF).

Acceptable time deviation windows are listed in the Study Reference Manual 
(SRM). 


2016N291965_02
CONFIDENTIAL
204715
14
3.
INTRODUCTION
3.1.
Study Rationale
GSK3008348 is a potent and selective inhibitor of the integrin receptor αvβ6, and is 
being developed as a treatment for idiopathic pulmonary fibrosis (IPF).  It has been 
shown to engage αvβ6 integrin and inhibit downstream fibrogenic mechanisms in mouse 
and human lung cells and tissue.  The first-time-in-human study (GSK Document 
Number 2014N201929_01 Study 200262) showed that single nebulised doses of 
1−3,000 µg GSK3008348 in healthy volunteers were well tolerated, with 
pharmacokinetic (PK) exposures within the defined limits set by the protocol.  The 
proposed study is intended to evaluate the safety, tolerability and PK of the molecule in 
patients with IPF not currently treated with pirfenidone or nintedanib, and obtain 
preliminary information on target engagement to support progression to repeat dose and 
proof of mechanism studies.  Target engagement will be measured by positron emission 
tomography (PET) using a radiolabelled αvβ6-specific ligand, [18F]-FBA-A20FMDV2 
(GSK2634673).    
3.2.
Background
IPF is a form of chronic fibrosing interstitial pneumonia, limited to the lung and 
associated with the histological appearance of usual interstitial pneumonia (UIP) on 
surgical lung biopsy.  The aetiology of IPF is unknown; it progresses in a relentless and 
often insidious manner that may be difficult to detect using parameters such as 
symptomatology, chest radiographic findings, or spirometry alone. Spontaneous 
remissions do not occur, and mean survival ranges from 2 to 4 years (5-year survival 
range, 30 to 50%). 
In the United Kingdom, data from general practice shows that the 12 month prevalence is 
15−18/100,000 person and an incidence of about 5/100,000 person-years.  Approximately 
2,000 new cases of IPF are diagnosed each year in England and Wales
[Navaratnam, 2013]. 
No therapy has been demonstrated to reverse the progression of IPF and it remains a 
major indication for lung transplantation. Two oral therapies are currently marketed for 
IPF, pirfenidone (Roche), the mechanism of action for which is incompletely understood
and nintedanib (Boehringer Ingelheim), a kinase inhibitor. Both of these treatments 
demonstrate a reduction in the rate of decline in lung function (forced vital capacity 
[FVC]) over one year [King, 2014; Richeldi, 2014]. Pirfenidone is associated with 
phototoxicity, and both agents have significant gastrointestinal effects.  In a real-world 
study, treatment with pirfenidone led to discontinuation in approximately one third of 
patients due to adverse events [Hughes, 2016].
The association of transforming growth factor (TGF)activity with fibrosis has been 
established in many disease settings. TGFis secreted in an inactive form, and requires 
activation post-translationally.  Substantial evidence suggests that the v6 integrin 
performs a key TGFactivation function at sites of damaged epithelium [Margadant, 
2010].  Activation of TGFby v6 has been shown to play an important role in lung 


2016N291965_02
CONFIDENTIAL
204715
15
fibrosis: 6 knockout mice are resistant to bleomycin-induced pulmonary fibrosis 
[Munger, 1999] and treatment with an αvβ6 neutralising antibody ameliorates bleomycin 
[Horan, 2008] and radiation-induced pulmonary fibrosis [Puthawala, 2008].
Immunohistochemistry of lung biopsy has shown that αvβ6 is significantly increased in 
the fibrotic areas of the lungs of IPF patients [Horan, 2008].  Expression levels of αvβ6 in 
IPF lungs predict mortality, with highest expression levels in IPF patients who progress 
rapidly [Saini, 2013]. In addition, animal models of pulmonary fibrosis have shown that 
the expression of αvβ6 correlates with the severity of the fibrotic response, and blockade 
of this target reduces the fibrosis [Horan, 2008; Puthawala, 2008]. Inhibition of v6 is 
considered to be advantageous over direct TGFinhibition because v6 expression is 
highly regulated and localised to damaged epithelial sites. Thus, inhibition of integrin-
mediated TGFactivation should minimise the risk of potential side effects caused by 
direct TGFinhibition, e.g. pro-inflammatory responses. 
GSK3008348 is being progressed as a twice-daily small molecule anti-fibrotic medicine,
to be delivered to IPF patients’ lungs by nebulisation. On reaching the peripheral areas of 
the lung, where the fibrosis occurs, GSK3008348 will bind to v6 on the damaged 
epithelium.  Our non-clinical work indicates that binding leads to internalisation of the 
integrin, inhibiting v6-mediated activation of TGFβ. The ability of TGFβ to promote 
collagen production by activated myofibroblasts is thereby limited.  It is hypothesised 
that GSK3008348 will slow or stop the progression of fibrosis, with the potential to 
provide significant benefit to patients in terms of reduction, avoidance or delay of 
symptoms, disability and death.
A 20 amino acid peptide (A20FMDV2), derived from the foot and mouth disease virus
(FMDV2), has been synthesised and shown to bind selectively to v6 (KD =0.22nM). 
The radiolabelled peptide, [18F]-FBA-A20FMDV2, will be used in this study to quantify 
levels of v6 expression and GSK3008348 receptor engagement in the lungs of IPF 
patients.  A single photon emission computed tomography (SPECT) analogue, 
[111In]-FBA-A20FMDV2, has been shown non-clinically to bind specifically to αvβ6 in 
the lungs of mice [John, 2013] and similar results have been obtained using the PET 
ligand in rats [internal GSK data on file].  [18F]-FBA-A20FMDV2 has also been 
administered to humans and shown to provide a signal that allows the distinction between 
IPF patients and healthy participants (GSK Document Number 2013N163906_00 Study 
RES116235). 
3.3.
Benefit/Risk Assessment
Information on the key potential risk associated with GSK3008348 and the strategies to 
mitigate this risk are detailed below in Section 3.3.1.  Further details about the potential 
risks and expected benefits of GSK3008348 may be found in the Investigator’s Brochure
(IB).


2016N291965_02
CONFIDENTIAL
204715
16
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3008348]
Potential local irritancy
Non-clinical:
Upper respiratory tract irritancy was observed in the 4-week 
inhalation toxicity studies in rats and dogs. Principal changes 
included epiglottic cartilage necrosis, regeneration/ 
remodelling at 5850 and 12000 µg/kg/day in rats; and soft 
palate or laryngeal ulcerations in dogs at 3070 and 
8710 µg/kg/day. No Observed Adverse Effect Levels
(NOAELs) were identified at the lowest doses tested (1420 
and 899 µg/kg/day in rats and dogs, respectively).
Lower respiratory tract irritancy was also observed in the 4-
week inhalation toxicity study in dogs. Adverse mixed 
inflammation and alveolar macrophage aggregates were 
observed at 3070 and 8710 µg/kg/day. These findings were 
also present in some animals from the lowest dose tested 
(899 µg/kg/day – the NOAEL), including control. Changes in 
local draining lymph nodes of GSK3008348-treated dogs were 
considered to be a non-adverse secondary response to the 
pulmonary inflammation. 
Non-adverse alveolar macrophage aggregates were seen at a 
low incidence in the lungs of all treated groups and also in 
control males in the 4-week inhalation study in rats. A minor 
test article-related effect could not be entirely discounted in 
female rats. 
In this planned first-time-in-patient study, IPF patients 
will only receive single doses. 
Appropriate inclusion/exclusion criteria (e.g., exclusion 
for current upper or lower respiratory tract infection) will 
be implemented in clinical protocols.
Potential adverse events associated with irritancy (e.g., 
sore throat, cough, dyspnoea, wheezing) are readily 
monitored, and will be monitored during the study. 
Interpretation of these AEs may be compromised in IPF 
patients where cough or dyspnoea may be symptoms 
of their respiratory diseases. Therefore patients’ 
baseline symptoms will be recorded as part of the 
current conditions assessment, and physical 
measurements including respiratory rate and oxygen 
saturation monitoring reviewed, to aid interpretation of 
any new symptoms. It is anticipated that symptoms 
secondary to irritancy will be more acute in nature, 
which will help distinguish from chronic symptoms due 
to IPF.
Symptoms of clinical concern may be investigated 
further in collaboration with an Ear, Nose and Throat


2016N291965_02
CONFIDENTIAL
204715
17
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical:
No symptoms or other clinical findings indicative of upper 
respiratory tract irritancy were observed in the first-time–in-
human study 200262 in healthy volunteers following single 
doses up to 3,000 µg.
(ENT) specialist.
Study Procedures
Participants exposed to 
ionising radiation as a 
consequence of patient’s 
participation in this study. 
The ionising radiation exposure comes from the administered 
radioligand, a high resolution CT (HRCT) for anatomical 
localization and low dose CT scans performed in order to 
correct the PET data for tissue attenuation.  The maximum 
effective dose of ionising radiation that participants in this 
study may be exposed to is 20.9 mSv.  This is equivalent to 
approximately 9 times the average yearly exposure (2.3 mSv) 
from natural background radiation in the United Kingdom.
The additional risk of developing a fatal malignancy as a result 
of these exposures has been estimated as approximately 1 in 
1,000 for an adult in normal health. The reduced life 
expectancy of IPF patients will result in a lower risk for these 
individuals.
Within the UK the guidance set out by International 
Commission on Radiological Protection (ICRP) 62 is generally 
followed in setting research study dose constraints. The level 
of risk may therefore be assumed to broadly fall within the 
ICRP 62 intermediate Category IIb, where the benefit should 
be more directly aimed at the cure or prevention of disease.
The study has been designed to keep the radiation 
dose as low as reasonably practicable whilst obtaining 
images of sufficient quality to meet the objectives.
Male participants < 50 years and female participants 
< 55 years will not be eligible.
To avoid recruitment of radiation worker or serial study 
volunteers, participants who have been exposed to 
ionising radiation in excess of 10mSv above 
background over the previous 3 year period as a result 
of occupational exposure to radiation or as a result of 
research studies are excluded.  Clinically justified 
(therapeutic or diagnostic) exposures are not included 
in the exposure calculation.  Participants are asked 
about any occupational exposure or previous 
participation in research studies at screening so that 
dose estimates can be obtained where necessary.
The study will exclude women of childbearing potential.
The maximal dose of ionising radiation that participants 


2016N291965_02
CONFIDENTIAL
204715
18
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
in this study may be exposed to is outlined in 
Appendix 8. 
Potential risk of 
immunogenicity related to 
A20FMDV2
There is a low theoretical risk that [18F]-FBA-A20FMDV2 may 
be immunogenic in humans. This could potentially lead to 
reduced signal in PET scans from neutralising anti-drug 
antibodies. There is also potential for anaphylactic and other 
immune mediated reactions. Neither of these phenomena has 
been observed in previous administrations of [18F]-FBA-
A20FMDV2 to humans (ongoing GSK Study RES116235).
[Of note, assay for measurement of antibodies to [18F]-FBA-
A20FMDV2 produced positive results in two participants in 
study RES116235. One healthy participant was positive pre-
and post-dosing, and one IPF participant was positive after the 
first scan and negative after the second scan. No clinical 
effects were attributed to effects of antibodies.]
Exclusion of participants with prior exposure to farm 
animals that may harbour FMDV2.
Exclusion of participants from countries where FMDV2 
is endemic.
Short period between repeat PET scans.
Collection of serum samples for measurement of 
antibodies to [18F]-FBA-A20FMDV2.
PET scans performed in an imaging unit with 
immediate access to emergency measures. 
Refer to Appendix 9 for more detail on the 
immunogenicity risk assessment and mitigation.
Potential bystander exposure 
to GSK3008348
Unintended inhalation of GSK3008348 (irritant potential).  
Since clear NOAELs were established in the nonclinical 
toxicity studies (with adequate safety margins) and the 
concentration in the room will be significantly less than direct 
exposure to GSK3008348, the risk for irritancy for bystanders 
is considered to be low.
No events in bystanders were reported in the study in healthy 
volunteers following single doses up to 3,000 µg.
Appropriate precautions will be taken to minimise 
bystander exposure in the study. Nebulised drug 
should not be administered in a confined and/or 
unventilated space. 


2016N291965_02
CONFIDENTIAL
204715
19
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Ensuring sufficient medical 
oversight for safety 
monitoring and transport 
between sites
In dosing period 2 of Cohort 1, the doses will be administered 
to participants in the imaging unit, so that the PET can be 
carried out at approximately 30 minutes post-dose.  However, 
in Cohort 2, there is the option to administer those doses in 
the hospital clinical unit, if required for logistical or safety 
reasons.  In that case, participants would be transported after 
dosing to the imaging site for the PET scans.
In both Cohorts 1 and 2, the first dosing period will be 
conducted in a hospital-based clinical unit, under the 
supervision of a chest physician, with immediate 
access to facilities for the treatment of medical 
emergencies, facilities for stabilizing individuals in an 
acute emergency and ready availability of Intensive 
Care Unit facilities. Following Principal Investigator (PI) 
and GSK medical monitor review of the individual 
safety and tolerability data from the completed first 
dosing period, the patient will continue to the baseline 
PET visit and second dosing period. In the second 
dosing period, the same dose will be administered by 
clinical staff in the imaging unit, alongside an 
appropriately trained research nurse.
If in Cohort 2 doses are to be administered in the 
clinical unit before transporting participants to the 
imaging unit in dosing period 2, patients will be 
observed for at least 4 hours post-dose before being 
transported to the imaging unit.


2016N291965_02
CONFIDENTIAL
204715
20
3.3.2.
Benefit Assessment
Participants will receive single doses of GSK3008348, which is being developed as a 
treatment for IPF.  It is not anticipated that this single dose study will provide any clinical 
benefit to participants.  The results will inform the evaluation of GSK3008348 as a 
treatment for IPF, so participants may contribute to the process of developing new 
therapies for IPF and related conditions.  Participants will be monitored throughout the 
study for any worsening of IPF symptoms or decline in general health.
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with single doses of GSK3008348 
and with study procedures are justified by the anticipated benefits from active treatment
that may be afforded to patients in the future, in developing GSK3008348 as a new 
therapy for IPF.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate target engagement in the 
lung after single nebulised doses of 
GSK3008348 in IPF patients 

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the whole lung (assessed as 
the volume of distribution [VT], not 
corrected for air volume) at approximately 
30 min post-dose compared to pre-dose, 
as measured by PET 

To evaluate the safety and tolerability of 
single nebulised doses of GSK3008348 
in IPF patients

Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG), and pulmonary function tests 
Secondary

To evaluate the pharmacokinetic profile 
of single nebulised doses of 
GSK3008348 in IPF patients 

Derived pharmacokinetic parameters for 
GSK3008348 including, but not limited to, 
area under the plasma drug concentration 
versus time curve (AUC(0-t), AUC(0-∞)), 
maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration 
(Tmax), and terminal half-life (T1/2) following 
single nebulised doses, where data allow 


2016N291965_02
CONFIDENTIAL
204715
21
Objectives
Endpoints

To evaluate duration of target 
engagement after single nebulised 
doses of GSK3008348 in IPF patients

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the lung (assessed as the 
VT) up to 28 h post-dose compared to 
pre-dose, as measured by PET
Exploratory

To explore the pharmacodynamic 
effects of single nebulised doses of 
GSK3008348 in IPF patients using 
additional PET analyses techniques

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the whole lung (assessed 
using standardised uptake values [SUV]
and VT, with and without correction for air 
and/or blood volume) at various time points 
post-dose compared to pre-dose, as 
measured by PET

To explore the spatial distribution of the 
effects of single nebulised doses of 
GSK3008348 in IPF patients and to 
compare it to the spatial distribution of 
disease  

Qualitative assessment of the distribution of 
the uptake of [18F]-FBA-A20FMDV2 in the 
lungs post-dose compared to pre-dose, as 
measured by PET and compared to the 
spatial distribution of disease as indicated 
by HRCT

To explore pharmacodynamic effects of 
GSK3008348 in blood 

Exploratory pharmacodynamic biomarkers 
of the αvβ6/TGFβ mechanism which may 
include but are not limited to: mRNA, 
microRNA and proteins in blood

To explore potential biomarkers of IPF 
disease and/or treatment response

Exploratory biomarkers in blood
5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-centre, 2-cohort, study of single doses to investigate the safety, 
tolerability, PK and target engagement of nebulised GSK3008348, in patients with IPF. 
Hospital-based clinical units will recruit and enrol participants; the PET imaging will be 
done at a specialist imaging unit.  
Participants will be screened up to 30 days before their first dose, and will have a 
follow-up visit at 7–14 days post-last dose.  
Refer to Figure 1 for a schematic illustrating the study design.
5.1.1.
Cohort 1
Cohort 1 will be a randomised, double-blind (sponsor unblind), placebo-controlled group 
of 7 participants, randomised 5:2 to receive 1,000 µg GSK3008348 or placebo.  All 
participants will have 2 planned dosing periods, and receive the same dose in each period.  


2016N291965_02
CONFIDENTIAL
204715
22
Dosing period 1 aims to assess safety and tolerability, and dosing period 2 aims to assess 
target engagement using PET imaging. 
In dosing period 1, participants will be admitted to the clinical unit on the morning of 
Day 1 for pre-dose health assessments and a pharmacogenetic sample; these assessments 
may also take place on Day –1.  On Day 1, they will remain in the clinical unit overnight, 
to enable safety assessments to be carried out for at least 24 h after receiving their 
nebulised dose.  PK and exploratory biomarker samples will also be taken.  Participants 
will then be discharged from the clinical unit. 
There will be a washout of between 7 and 28 days between doses in periods 1 and 2.  
Participants will attend the imaging unit for a baseline PET scan and a high resolution 
computerised tomography (HRCT) scan, at least 7 days after their first dose, and a 
maximum of 14 days before their first post-dose PET scan in dosing period 2.  
In dosing period 2, participants will first attend the clinical unit for pre-dose health 
assessments, on Day 1 or Day −1.  If they pass the health assessments, participants will 
attend the imaging unit for dosing and a PET scan starting approximately 30 min post-
dose (i.e., post the start of nebulisation).  Participants will remain in the imaging unit for 
safety observation for at least 4 h post-dose on Day 1, and then return on Day 2 for a PET 
scan at approximately 24 h post-dose (post the start of nebulisation).  Safety assessments 
and PK sampling will be done throughout those visits.  
Cohort 1 will be considered complete when PET data at 30 min post-dose has been 
collected from 7 participants.  After completion of Cohort 1, blinded safety and PK data 
will be reviewed by a data review team, consisting of the investigators, medical monitor, 
statistician, clinical pharmacokineticist, pharmacovigilance representative, and clinical 
study team members, as appropriate.  The statistician will also perform an unblinded 
review of the PET data. 
5.1.2.
Cohort 2
Cohort 2 is optional, and will proceed only if there is evidence of target engagement at 
30 min post-dose in Cohort 1.  It will be designed to further explore the safety and to 
provide additional information on the target engagement profile of GSK3008348.  
Decisions on whether to proceed with Cohort 2, and on the most informative design for 
Cohort 2, will be based on Cohort 1 data.  Cohort 2 data may be reviewed in-stream and 
the design of Cohort 2 adjusted to maximise the value of the data obtained.  Cohort 2 will 
be designed such that each participant will have up to 3 PET scans and 2 planned doses 
of GSK3008348, and within the logistical limitations of dosing, safety monitoring, PET 
ligand radiochemistry and PET scanning.  For example: 

If there is no evidence of target engagement at 30 min post-dose in Cohort 1, then 
Cohort 2 will not go ahead. 

If the variability in PET measurements is higher than anticipated, participants in 
Cohort 2 may follow the same dosing and scanning regime as in Cohort 1, to 
increase the sample size.


2016N291965_02
CONFIDENTIAL
204715
23

If significant target engagement is observed at 30 min in Cohort 1, but there is no 
evidence of target engagement at 14−28 h, then Cohort 2 may explore time points 
between 30 min and 28 h after a 1,000 µg dose. 

If significant target engagement is observed at 30 min and at 14−28 h, then Cohort 2 
may explore target engagement at time points between 30 min and 28 h after a dose 
lower than 1,000 µg.
A decision-making flowchart is shown in Appendix 10.
Cohort 2 may be open-label, in which case up to 10 participants may receive single doses 
of GSK3008348 in an open-label manner.  If Cohort 1 data suggests that including a 
placebo control would be beneficial, for example for safety reasons, Cohort 2 will be 
carried out in a double-blind (sponsor unblind) fashion, with up to 14 participants 
randomised 5:2 to receive GSK3008348 or placebo. 
The dose level will be 1,000 µg or lower, and may be changed at any time depending on 
previous or emerging data. Participants may receive a lower dose in dosing period 2 
compared to dosing period 1.  The length of post-dose safety monitoring in the clinic will 
be decided based on previous or emerging data, but participants will be monitored for at 
least 8 h post-first dose.  
Participants will have 2 planned dosing periods, both on an outpatient basis, with an 
additional visit for baseline imaging, as follows.

Dosing period 1:  participants will have pre-dose health assessments and a 
pharmacogenetics sample at the clinical unit on the morning of Day 1.  They will 
remain in the clinical unit for at least 8 h after receiving their nebulised dose for 
safety observations, and then return to the clinical unit on Day 2.  Safety assessments 
will be done, and PK and exploratory biomarker samples taken.  

Baseline PET scan and HRCT scan at least 7 days after the first dose, and a maximum 
of 14 days before the first post-dose PET scan. 

Dosing period 2:  participants will attend the clinical unit for health assessments 
before dosing, on Day 1 or Day −1.  If participants pass the health assessments, they 
will attend the imaging unit, have their dose administered, and have up to 2 post-dose 
PET scans.  Alternatively, dosing may take place at the clinical unit before the patient 
is transferred to the imaging unit for their PET scan, depending on the PET scan 
timing; however, the participant must be observed for at least 4 h post-dose without 
changing location.  The timing of the post-dose PET scans will be determined based 
on emerging study data.  Doses will be separated by a washout of between 7 and 
28 days. 
5.1.3.
Changes to Cohorts 1 or 2
Participants in Cohorts 1 and 2 will have 2 planned dosing periods.  However, if a PET 
scan cannot be performed (e.g. because of technical issues, PET ligand synthesis 
radiochemistry failure, or because the participant cannot be scanned for safety reasons), 
participants may repeat the visit or dosing period, and repeat procedures in order to 


2016N291965_02
CONFIDENTIAL
204715
24
obtain a full dataset for each endpoint.  Participants may be administered an additional 
dose of GSK3008348 after a 7-day washout, such that they receive a maximum of 
3 single doses in total during the study.  Participants will not, however, be administered 
an additional dose of [18F]-FBA-A20FMDV2; they will receive a maximum of 3 doses of 
the radiotracer during the study.  
If a participant experiences unexpected and/or potentially serious side effects after their
first or second dose, they will be referred to the clinical site investigator for assessment 
and ongoing care. That may include admission to a clinical bed, if deemed appropriate 
by the investigator, as per routine clinical practice. 
5.2.
Number of Participants
It is anticipated that up to 21 participants will be randomised, as follows. 

Cohort 1 – 7 participants will be randomised. (7 participants will be randomised, 
dosed and considered complete when PET data at 30 min post-dose has been 
collected)

Cohort 2 – up to 10 participants may be randomised if an open-label design is chosen; 
or up to 14 participants may be randomised if a double-blind design is chosen. 
Refer to Section 10.2 for definitions of participants who will be considered evaluable and 
therefore included in the analyses. 
If participants prematurely discontinue the study, additional replacement participants may
be recruited and randomised to the same treatment at the discretion of the Sponsor in 
consultation with the investigator.  Replacement participants will start the study at dosing 
period 1, in order to establish tolerability of the study medication before entering the PET 
scanning dosing period. 
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study, including the baseline PET scan, at least 1 post-dose PET scan, and 
the last follow-up visit.  
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design

Cohort 1 includes a placebo control to allow assessment of safety and tolerability, as 
reporting of adverse events in patients receiving placebo will facilitate the 
differentiation between ‘disease’ and ‘intervention’ adverse events.   

Cohort 1 will be conducted in a double-blind (sponsor unblind) fashion. Safety and 
PK data reviews will be conducted without treatment group assignment or subject 
numbers, so that the investigators and data review team remain blinded. The 


2016N291965_02
CONFIDENTIAL
204715
25
statistician will perform an unblinded review of PET data as part of the pre-planned 
interim analysis, to allow appropriate decision-making.  The sponsor (including the 
medical monitor) may also undertake separate in-stream review of unblinded data to 
help determine the most appropriate response to emerging data.  

The number of patients to be enrolled in Cohort 1 (7 participants) is based on the 
probability of detecting a change in vβ6 internalisation at approximately 30 min
post-dose compared to pre-dose of 6% or greater, as measured by the uptake of [18F]-
FBA-A20FMDV2 in the lungs reported as the volume of distribution [VT]. This
predetermined change is equivalent to approximately half the difference in [18F]-
FBA-A20FMDV2 PET signal observed between healthy volunteers and IPF patients 
in a previous study RES116235. If GSK3008348 cannot achieve that reduction in 
vβ6-associated PET signal and the endpoint variability is as expected, then the study 
will end.

The design for Cohort 2 will be defined following completion of Cohort 1, to ensure 
the most informative doses of GSK3008348 are selected and the PET scans are timed 
appropriately.  Cohort 2 data may be reviewed in-stream and the design of Cohort 2 
adjusted to maximise the value of the data obtained.  The aim is to assess target 
engagement while exposing the smallest possible number of patients to ionising 
radiation from the PET procedure.
5.5.
Dose Justification
The first-time-in-human study 200262 showed that single nebulised doses of 1–3,000 μg 
GSK3008348 were well tolerated in healthy participants, with PK exposures within the 
defined limits set by the protocol.
The 1,000 μg dose was selected for this study as the preliminary geometric mean Cmax
and AUC(inf) observed in healthy volunteers in study 200262 provided 22- and 11-fold 
margins, respectively, over the systemic exposures observed in the most sensitive 
preclinical species (Day 1 exposures from the Rat 1 month good laboratory practice
[GLP] study at the 12000 µg/kg/day dose level; the no effect level for systemic toxicity). 
Additionally, the 1,000 μg dose maintains adequate safety coverage over the NOAEL 
based on the deposited lung dose (36-fold over the rat and 26-fold over the dog, 1 month 
GLP toxicity studies).  The proposed dose therefore allows significant safety margins in 
the event that systemic exposure is greater in IPF patients than in healthy volunteers.
In addition, the observed PK in study 200262 demonstrated peak systemic unbound 
concentrations significantly in excess of the in vitro Kd for GSK3008348. Given that 
GSK3008348 is inhaled, it is reasonable to assume that lung tissue exposures were at 
least as high as those observed in plasma and so are expected to engage with vβ6 to a 
significant extent.


2016N291965_02
CONFIDENTIAL
204715
26
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.
Male participants aged ≥ 50 years, and female participants aged ≥55 years, at the 
time of signing the informed consent.
Type of Participant and Disease Characteristics
2.
Diagnosis of definite or probable IPF as determined by a responsible and 
experienced chest physician and based on established criteria defined by the 
American Thoracic Society/European Respiratory Society Internationale 
Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias 
[Raghu, 2011]. 
3.
Ambulant and capable of attending outpatient visits. 
4.
FVC > 50 % predicted and DLCO > 40 % predicted. 
Weight
5.
Body weight 45 kg and body mass index (BMI) within the range 18.0–35.0 kg/m2
(inclusive).
Sex
6.
Male and female
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this
protocol during the study and for at least 90 days after the follow-up visit, and refrain 
from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and not a woman of childbearing potential (WOCBP) as defined in Appendix 5. 
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.


2016N291965_02
CONFIDENTIAL
204715
27
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
ALT and bilirubin > 1.5x upper limit of normal (ULN; isolated bilirubin > 1.5x ULN 
is acceptable if bilirubin is fractionated and direct bilirubin < 35%).
2.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
3.
QTc > 450 msec, or QTc > 480 msec in participants with Bundle Branch Block. 
4.
Current IPF exacerbation, or upper or lower respiratory tract infection on admission 
to the clinical unit.
5.
History of or suffers from claustrophobia, or unable to lie flat and still on their back 
for up to 2 h in the PET scanner.
6.
Extent of emphysema greater than the extent of fibrotic change on HRCT scan, 
based on investigator judgement.
7.
Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) 
ratio < 0.70 at screening (post-bronchodilator). 
8.
History of sensitivity to the study treatment, or components thereof, or a history of 
drug or other allergy that, in the opinion of the investigators or Medical Monitor, 
contraindicates their participation. 
9.
Any current oro-pharygneal disease or disorders as judged by the investigator. 
Prior/Concomitant Therapy
10. Currently taking pirfenidone or nintedanib, or received pirfenidone or nintedanib 
within 30 days of the first dose of study treatment.
11. Taken, within 7 days or 5 half-lives (whichever is longer) before the first dose of 
study treatment, organic anion transporter (OAT) substrates with a narrow 
therapeutic index (eg methotrexate and tenofovir), vitamins, or dietary or herbal 
supplements, unless in the opinion of the investigator and sponsor the supplement 
will not interfere with the study medication. 
12. Long-term continuous home oxygen therapy (use of oxygen that is only intermittent 
and for symptom relief is acceptable). 
Prior/Concurrent Clinical Study Experience
13. Participation in a clinical trial and receipt of an investigational medicinal product 
within the following time period before the first dose in the current study:  30 days, 
5 half-lives or twice the duration of the biological effect of the investigational 
product (whichever is longer).
14. Exposure to more than 4 new investigational medicinal products within 12 months 
before the first dose. 


2016N291965_02
CONFIDENTIAL
204715
28
Diagnostic assessments
15. Presence of Hepatitis B surface antigen (HBsAg) at screening, or positive 
Hepatitis C antibody test result at screening or within 3 months before the first dose 
of study treatment (Note:  participants with a positive Hepatitis C antibody test 
because of previous, resolved disease can be enrolled if a confirmatory negative 
Hepatitis C RNA test is obtained). 
16. Previous or current exposure to animals that may harbour FMDV2.
17. Previous long term (≥ 3 months) residence in a country where FMDV2 is endemic 
(such as certain areas of Africa, Asia and South America, see Appendix 11). 
18. Where participation in the study would result in loss of blood or blood products in 
excess of 500 mL within 56 days
19. History of drug or alcohol abuse that in the opinion of the investigator affects their 
participation in the study 
Other Exclusions
20. Exposure to ionising radiation in excess of 10 mSv above background over the 
previous 3 year period as a result of occupational exposure or previous participation 
in research studies.  Clinically justified (therapeutic or diagnostic) exposures are not 
included in the exposure calculation.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

During each dosing session, participants will be fasted for 4 hours before dosing. 
Water will be allowed.  The time of the first meal after dosing will be recorded. 
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for at least 
12 hours before the start of dosing until after collection of the final PK sample in that 
period.

During each dosing period, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample in that period. 

Participants who use tobacco products will be instructed that use of nicotine-
containing products will not be permitted while they are in the clinical or imaging 
units. Nicotine patches are allowed.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 72 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).


2016N291965_02
CONFIDENTIAL
204715
29
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized due to failure to meet inclusion/exclusion criteria.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened.  Rescreened participants should be assigned a new participant 
number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment 
Name:
GSK3008348
Placebo
[18F]-FBA-A20FMDV2
Dosage formulation:
Solution for 
nebulisation
Solution for 
nebulisation 
Intravenous (IV)
Formulation 
description:
Formulated at 
250 µg/ml with 5% 
mannitol, citric acid, 
sodium citrate and 
water for injection
5% mannitol, citric 
acid, sodium citrate 
and water for injection
Formulated in 0.9% 
saline
Unit dose 
strength(s)/Dosage 
level(s):
1,000 µg
N/A
Up to 150 MBq of [18F]-
FBA-A20FMDV2 per 
administration; 
≤100 µg total of [18F]-
FBA-A20FMDV2 per 
participant
Route of 
Administration 
Inhaled via 
nebulisation
Inhaled via 
nebulisation
IV
Dosing instructions:
4mL administered by 
nebulisation
4mL administered by 
nebulisation
Intravenous bolus over 
about 30 seconds


2016N291965_02
CONFIDENTIAL
204715
30
Study Treatment 
Name:
GSK3008348
Placebo
[18F]-FBA-A20FMDV2
Physical 
description:
Clear colourless to 
pale yellow coloured 
solution in a 5mL vial 
with 20mm stopper 
and aluminium seal
Clear colourless to 
pale yellow coloured 
solution in a 5mL vial 
with 20mm stopper 
and aluminium seal
IV infusion, 20 mL
Storage conditions:
Refer to SRM
Refer to SRM
N/A
Device:
European Conformity 
mark (CE) marked 
nebuliser
CE marked nebuliser
N/A
7.2.
Dose Modification
The proposed dose for Cohorts 1 and 2 is 1,000 µg GSK3008348. The dose may be 
decreased in Cohort 2 at any time, depending on previous or emerging data.  The decision 
will be made by the data review team based on available preliminary safety, tolerability, 
PK and PET data obtained from preceding participants. The dose will not be increased 
above 1,000 µg. 
7.3.
Method of Treatment Assignment
Participants will be randomised to a subject number in accordance with the randomisation 
schedule generated by GSK Clinical Statistics before the study start, using validated 
internal software (RANDALL NG).  Each participant in Cohort 1 will be randomised 5:2 
to receive either GSK3008348 or placebo.  Participants in Cohort 2 will receive 
GSK3008348 in an open-label manner, unless it is decided that a placebo control would 
be beneficial, in which case participants will be randomised 5:2 to receive either 
GSK3008348 or placebo. 
All participants will be centrally randomised using an Interactive Voice/Web Response 
System (IVRS/IWRS).  Before the study is initiated, the telephone number or log in 
information and directions will be provided to each site.  
Study treatment for both dosing periods will be dispensed by appropriately trained 
pharmacy staff. 
Returned study treatment should not be re-dispensed to the participants. 
7.4.
Blinding
Cohort 1 will be double-blind (sponsor unblind).  Cohort 2 may be open-label, or may be 
double-blind (sponsor unblind) if required.  For double-blind cohorts, the following will 
apply.


2016N291965_02
CONFIDENTIAL
204715
31
An unblinded monitor, if required, and in the event of a Quality Assurance audit, the 
auditors, will be allowed access to unblinded study treatment records at the sites to verify 
that randomisation and dispensing has been done accurately. 
The IVRS/IWRS will be programmed with blind-breaking instructions.  The blind may 
be broken by the investigator or treating physician in the case of an emergency, or if, in 
the opinion of the investigator, it is in the participant’s best interest for the investigator to 
know the study treatment assignment.  The investigator is encouraged to discuss with the 
GSK Medical Monitor or appropriate GSK study personnel before the blind is broken.  If 
GSK is not notified before the blind is broken, they must be notified as soon as possible 
after breaking the blind.  The date and reason that the blind was broken must be recorded 
in the source documentation and electronic case report form (eCRF), as applicable. 
A participant may continue in the study if their treatment assignment is unblinded, at the 
discretion of the Medical Monitor.  If a participant is withdrawn after their treatment code 
is unblinded by the investigator or treating physician, the primary reason for 
discontinuation (the event or condition which led to the unblinding) will be recorded in 
the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in
accordance with local regulations and/or GSK policy.
For an open-label cohort, all participants will be randomised to active study treatment. 
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorised site staff may supply or administer study treatment.  All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access 
limited to the investigator and authorised site staff.

The investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists.  In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.


2016N291965_02
CONFIDENTIAL
204715
32

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance
Participants will be dosed at the sites, and 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. 
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
Participants must not be taking pirfenidone or nintedanib, or must abstain from taking 
pirfenidone or nintedanib within 30 days before their first dose of study treatment until 
completion of the follow-up visit. 
There is an unknown risk of interaction with OAT substrates with a narrow therapeutic 
index (eg methotrexate and tenofovir).  Therefore, participants must abstain from taking 
these agents within 7 days or 5 half-lives (whichever is longer) before their first dose of 
study treatment until completion of the follow-up visit. Participants must also abstain 
from taking vitamins and dietary or herbal supplements for the same period, unless, in the 
opinion of the investigator and sponsor, the supplement will not interfere with the study 
medication. 
Other concomitant medication, including paracetamol at doses of 4 grams/day, is
permitted for use any time during the study.  The Medical Monitor should be contacted if 
there are any questions regarding concomitant or prior therapy.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study.  The investigators are responsible for ensuring that consideration has been given to 
the post-study care of the participant’s medical condition. 


2016N291965_02
CONFIDENTIAL
204715
33
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance). These 
protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant.
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 7.  
8.1.2.
QTc Stopping Criteria
A participant who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec


2016N291965_02
CONFIDENTIAL
204715
34
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period.  
8.1.3.
Individual Adverse Event Stopping Criteria
A participant will be withdrawn from the study if they experience:
1. An SAE that is at least possibly related to the study treatment 
2. An IPF exacerbation, upper or lower respiratory tract infection or other systemic 
infection
3. A clinically significant change in a laboratory value or vital sign
4. Failure to recover from an adverse event
A participant can be discontinued from therapy if the investigator decides that the patient 
should be withdrawn. 
Participants who are withdrawn will complete the follow-up visit, as described in the 
SoA.
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.


2016N291965_02
CONFIDENTIAL
204715
35

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.

Refer to the SoA for data to be collected at follow-up for evaluations that need to be 
completed.
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. 
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. All post-dose time 
points are relevant to the start of nebulisation. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was
performed within the time frame defined in the SoA.


2016N291965_02
CONFIDENTIAL
204715
36

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. 

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
Not applicable. 
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the first dose of study treatment until the follow-up 
visit at the time points specified in the SoA (Section 2).

All AEs will be collected from the first dose of study treatment until the follow-up 
visit at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the first dose of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the eCRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 hours, 
as indicated in Appendix 4. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 


2016N291965_02
CONFIDENTIAL
204715
37
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information eg, 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.
Cardiovascular and Death Events
For any cardiovascular events and all deaths, whether or not they are considered SAEs, 
specific Cardiovascular (CV) and Death sections of the eCRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
dictionary for regulatory activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until the 
follow-up visit.


2016N291965_02
CONFIDENTIAL
204715
38

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK3008348 greater than 1,000 µg within a 24-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
21. Contact the Medical Monitor immediately.
22. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3008348 can no longer be detected systemically (at least 2 days).
23. Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).
24. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
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.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems, and the 
oropharynx. Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, oropharynx, 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

Single readings of temperature, heart rate, respiratory rate, and blood pressure will be 
assessed.


2016N291965_02
CONFIDENTIAL
204715
39

Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.

Vital signs will be measured in a semi-supine position after 5 minutes rest. 
9.4.3.
Peripheral capillary oxygen saturation

Peripheral capillary oxygen saturation (SpO2) levels will be continuously monitored 
with a completely automated device. 
9.4.4.
Electrocardiograms

Triplicate 12-lead ECG will be obtained and recorded in the eCRF as outlined in the 
SoA using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTcF intervals. Refer to Section 8.1.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.
9.4.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. 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 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 2, must be 
conducted in accordance with the SRM and the SoA.

If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF.
9.4.6 Lung Function Tests

Spirometry measurements will be obtained using standard spirometry equipment 
available at sites, to include FEV1 and FVC.

DLCO will be measured according to local procedures.


2016N291965_02
CONFIDENTIAL
204715
40

For calculating % predicted FEV1, FVC and DLCO, the Quanjer 2012 
calculation is to be used.

All subjects will have spirometry and DLCO performed at Screening to assess 
eligibility and at time points as described in the time and events table.

Participants must perform 3 acceptable blows, all within 5% of each other. The 
difference between the highest FEV1 and the second highest should be within 
150 mL. A maximum of 8 attempts can be made for each time point.

Only the highest FEV1 and FVC measurements should be recorded. 

At each time point, measurements of FEV1 and FVC should be compared to 
baseline. Any clinically significant decreases in either measurements compared 
to baseline, as judged by the investigator, will be recorded as an AE.
9.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK3008348 as specified in the SoA.  A maximum of 
5 additional samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. Instructions for 
the collection and handling of biological samples will be provided in the SRM.  The 
actual date and time (24 hour clock time) of each sample will be recorded.

Samples will be used to evaluate the PK of GSK3008348.  Samples collected for 
analyses of GSK3008348 plasma concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study.

Genetic analyses will not be performed on these plasma samples.  Participant 
confidentiality will be maintained. 

Once the plasma has been analyzed for GSK3008348, any remaining plasma may be 
analysed for other compound-related metabolites and the results reported under a 
separate protocol.

Urine samples will be analysed qualitatively for drug-related components and the 
results reported under a separate Platform Technology and Science-Product 
Development and Supply, GlaxoSmithKline study.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.6.
Positron Emission Tomography (PET)
Before each PET scan, participants will have a low dose CT scan to provide data to 
enable correction of the PET data for tissue attenuation.  [18F]-FBA-A20FMVD2 will 
then be injected into a cubital or forearm vein through an intravenous cannula, and 
emission data acquired for up to 90 minutes.  One rest period will be permitted during the 
scan, if required. 


2016N291965_02
CONFIDENTIAL
204715
41
An additional venous cannula in a cubital or forearm vein will be used to collect blood 
samples throughout the PET scan for quantification of the total and unmetabolised [18F]-
FBA-A20FMDV2-related radioactivity in whole blood and plasma.  The data will be 
used to derive an input function for the analysis of emission PET data.  The cannula may 
be flushed with saline to keep it patent, if required; HepSal will not be used.  At the end 
of the scanning day, the cannula will be removed.  
At the baseline visit only, an HRCT scan will also be performed for anatomical 
localisation.
In the event of a problem that prevents the PET scan going ahead after the study 
treatment has been administered, such as a quality control failure of the synthesised 
tracer, the scan may be rescheduled.  An additional dose of study treatment may be 
administered to the participant if required, at the discretion of the investigator and GSK 
Medical Monitor, as described in Section 5.1.3.
9.7.
Genetics
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected from 
participants who have consented to participate in the genetics analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM.
9.8.
Biomarkers
Blood samples will be collected during this study and may be used for the purposes of
measuring novel biomarkers to identify factors that may influence IPF, and/or medically
related conditions, as well as the biological and clinical responses to GSK3008348. If
relevant, this approach will be extended to include the identification of biomarkers
associated with adverse events.  These analyses are exploratory in nature, and will be 
reported separately from the results of the clinical trial. 
Samples will be collected at the timepoints indicated in the SoA. The actual date and
time of each blood sample collection will be recorded. The timing of the collections may
be adjusted on the basis of emerging PK or pharmacodynamic (PD) data from this study 
or other new information in order to ensure optimal evaluation of the endpoints.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological
response associated with IPF or medically related conditions and/or the action of study
treatment may be identified by the potential application of: 

Ribonucleic acid (RNA) transcriptome analysis of blood samples.


2016N291965_02
CONFIDENTIAL
204715
42

Measurement of the levels of a subset of RNA species in blood.

Proteome analysis in plasma and blood samples.

Measurement of the levels of a subset of proteins in plasma and blood samples 
which may include but are not limited to chemokine (C-C  motif) ligand 18 
(CCL18) [Prasse, 2009] and collagen degradation biomarkers [Jenkins, 2015].
Samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to αvβ6, IPF disease processes, pathways associated with 
IPF and/or mechanism of action of GSK3008348.
All samples will be retained for a maximum of 15 years after the last participant
completes the trial.
9.9.
Immunogenicity Assessments
Serum samples will be analysed for the presence of anti-[18F]-FBA-A20FMDV2 
antibodies. Approximately 7 mL of blood will be collected into serum separator (SST) 
tubes (no anti-coagulant) at the timepoints indicated SoA. 
9.10.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
This study is designed to assess the level of receptor engagement as measured by the 
effect of nebulised GSK3008348 on the v6-associated PET signal (VT). The PET data 
from the 5 participants in Cohort 1 receiving GSK3008348 will be used.  This sample 
size has been chosen based on considerations given to: a) the probability of declaring a 
successful study for reductions in v6-associated PET signal deemed to be 
representative of the expected receptor engagement activity, and b) the within-subject 
variability of the PET signal.
The chosen study success criteria is defined as Prob (θ < 0 | Study Data, Prior (θ)) ≥80%, 
where θ is the unknown true logarithm of the ratio of v6-associated PET signal post-
dose / pre-dose in patients receiving GSK3008348, and the prior distribution for θ is non-
informative. Assuming the within-subject standard deviation is as previously observed in 
study RES116235 (within-subject standard deviation following two PET scans was 
estimated to be 0.15, 95% CI [0.099, 0.34]), consideration was given to the probability of 
achieving the study success criteria for a range of true reductions in v6-associated PET 
signal with GSK3008348. In addition, the minimum detectable effect (MDE), i.e., the 
minimum observed reduction in v6-associated PET signal leading to the success 


2016N291965_02
CONFIDENTIAL
204715
43
criteria being achieved, was also derived. In particular, if the true reduction in v6-
associated PET signal is 14% then there is 86% probability of achieving the above 
success criteria, and the MDE is a 6.2% reduction in v6-associated PET signal. 
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All participants
All participants who are screened and for whom a record exists on 
the study database.
Enrolled 
All participants who are screened and enrolled into the study.
Intent-To-Treat (ITT)
All randomised participants who receive at least one dose of study 
treatment. This population will be based on the treatment they 
actually received. 
Per-Protocol
All participants in the ITT population who comply with the protocol 
and that have at least one evaluable PET measurement post 
baseline. 
Pharmacokinetic
All participants in the ITT population receiving active dose for whom 
a pharmacokinetic sample was obtained and analysed. 
10.3.
Statistical Analyses
10.3.1.
Pharmacodynamic Analyses
Endpoint
Statistical Analysis Methods
Volume of 
distribution [VT] in 
whole lung, not 
corrected for air 
volume
The logarithm of the v6-associated PET signal as measured by VT
will be analysed assuming that it follows a normal distribution. The 
mean or median signal level pre- and post-dose, as appropriate 
depending on the posterior distribution, along with the median 
difference post-dose – pre-dose, will be estimated and the 
corresponding 95% credible intervals will be produced. The posterior 
probability that the true difference in the logarithm of v6-associated 
PET signal post-dose vs pre-dose is less than 0 will be calculated. 
Non-informative priors will be used for all the parameters in the 
statistical model.
Secondary
Will be described in the reporting and analysis plan (RAP)
Exploratory
Will be described in the RAP


2016N291965_02
CONFIDENTIAL
204715
44
10.3.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. Safety data will be 
presented in tabular and/or graphical format and summarised descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards.
10.3.3.
Pharmacokinetic analyses
Plasma concentration-time data of GSK3008348 will be displayed in listings, summary 
tables and/or graphically.  Summary data will use nominal/planned sample times, listings 
will display planned and actual times.  Plasma concentration-time data may be used to 
derive PK parameters (such as AUC and Cmax) using standard non-compartmental 
analysis according to current working practices and using Phoenix WNL, or other 
currently validated software.  All calculations of non-compartmental parameters will be 
based on actual sampling times.
Additionally, plasma concentration-time data may be used to derive population PK 
parameters/models using NONMEM or other currently validated software.  Any 
population PK analysis will be presented separately from the main clinical study report 
(CSR).
Statistical analyses of the PK parameter data will be the responsibility of Clinical 
Statistics, GlaxoSmithKline.
10.3.4.
Other Analyses
Exploratory PD and biomarker analyses will be described in the RAP, and will be 
presented separately from the main CSR. 
10.3.5.
Interim Analyses
An interim analysis will be performed for futility or sample size re-estimation based on 
the variability of the PET signal (VT) and the level of receptor engagement at the end of 
Cohort 1 and prior to the start of Cohort 2. The PET data from the 5 participants in 
Cohort 1 receiving GSK3008348 will be used. The logarithm of the v6-associated PET 
signal as measured by VT will be analysed assuming that it follows a normal distribution. 
10.3.5.1.
Interim Analysis for Futility
Assuming that the variability is as anticipated, if the posterior probability Prob (θ < 0 | 
Study Data, Prior (θ)) < 80%, where θ is the unknown true logarithm of the ratio of 
v6-associated PET signal post-dose / pre-dose in patients receiving 1,000 µg
GSK3008348 in Cohort 1, and the prior distribution for θ is non-informative, then the 
study will stop for futility. If the study is stopped at the end of Cohort 1, then Cohort 2 
will not proceed.


2016N291965_02
CONFIDENTIAL
204715
45
10.3.5.2.
Interim Analysis for Sample Size Re-estimation
If the variability in VT is higher than expected, then sample size re-estimation will be 
performed and additional participants receiving 1,000 µg GSK3008348 will be recruited 
into Cohort 2. Sample size re-estimation will be primarily based on the posterior 
predictive distribution of the data given the information collected at the interim, and the 
predictive probability of end-of-study success. This probability will be calculated for a 
range of sample sizes up to a maximum of 10 additional participants receiving 1,000 µg 
GSK3008348 in Cohort 2.
Further details of the interim analysis will be provided in the RAP.


2016N291965_02
CONFIDENTIAL
204715
46
11.
REFERENCES
GSK Document Number 2013N163906_00 Study RES116235. Validation and Dosimetry 
Study of [18F]-FBA-A20FMDV2 PET Ligand for αvβ6 in Healthy Subjects and in the 
Lungs of Idiopathic Pulmonary Fibrosis (iPF) Subjects (PETAL study). Protocol Date 18-
Oct-2013. 
GSK Document Number 2014N201929_01 Study 200262.  A FTIH study with 
GSK3008348 in healthy volunteers and patients with Idiopathic Pulmonary Fibrosis. 
Protocol Date 29-Sep-2015.
Horan G.S, Wood S.,, Ona V., Li D.J., Lukashev M.E., Weinreb P.H. et al. Partial 
inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating 
inflammation. Am. J. Respir. Crit. Care Med. 2008;177:56-65. 
Hughes, G., Toellner, H., Morris, H., Leonard, C., Chaudhuri, N.  Real World 
Experiences:  Pirfenidone and Nintedanib are Effects and Well Tolerated Treatments for 
Idiopathic Pulmonary Fibrosis.  J. Clin. Med.  2016;5:78. 
Jenkins R.G., Simpson J.K., Saini G., Bentley J.H., Russell A.M., Braybrooke R. et al. 
Longitudinal change in collagen degradation biomarkers in idiopathic pulmonar fibrosis: 
an analysis from the prospective, multicentre PROFILE study. The Lancet Respirator 
Medicine. 2015;3:462-472. 
John A.E, Luckett J.C., Tatler A.L., Awais R.O., Desai A. et al. Preclinical SPECT/CT 
imaging of αvβ6 integrins for molecular statification of idiopathic pulmonary fibrosis. J. 
Nucl. Med. 2013;54:2146-2152. 
King T, Bradford W., Castro-Bernardini S., Fagan E., Glaspole I., Glassberg M., et al. 
Effect of design modifications on trial outcomes in idiopathic pulmonary fibrosis (IPF): 
Analysis of data from ASCEND and CAPACITY (CAP). Eur. Respir. J. 2014;44. 
Margadant C, Sonnenberg A.. Integrin-TGF-B crosslink in fibrosis, cancer and wound 
healing. EMBO Rep. 2010;11:97-105. 
Munger J.S., Huang X., Kawakatsu H., Griffiths M.J., Dalton S.L., Wu J., et al. The 
integrin αvβ6 binds and activates latent TGFβ: A mechanism for regulating pulmonary 
inflammation and fibrosis. Cell. 1999;96:319-328. 
Navaratnam V.,. Fogarty AW., Glendening R., McKeever T. and Hubbard RB. The 
increasing secondary care burden of idiopathic pulmonary fibrosis: Hospital admission 
trends in England from 1998 to 2010. Chest. 2013;143:1078-1084. 
Prasse A., Probst C., Bargagli E., Zissel G., Toews G.B., Flaherty K.R., et al. Serum CC-
Chemokine Ligand 18 Concentration Predicts Outcome Idiopathic Pulmonary Fibrosis. 
Am J Respir Crit Care Med. 2009;179:717-723. 


2016N291965_02
CONFIDENTIAL
204715
47
Puthawala K., Hadjiangelis N., Jacoby S.C., Bayongan E., Zhao Z., Yang Z., et al. 
Inhibition of integrin avb6, an activator of latent transforming growth factor-β, prevents 
radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 2008;177:82-90. 
Raghu G., Collard H.R., Egan J.J., Martinez F.J., Behr J., Brown K.K., et al. An Official 
ATS/ERS/JRS/ALAT Statement: Idiopathic Pulonary Fibrosis: Evidence-based 
Guidelines for Diagnosis and Management. Am. J. Respir. Crit Care Med. 2011;183:788-
824. 
Richeldi L., Du Bois R.M., Raghu G., Azuma A., Brown K.K., Costabel U., et al. 
Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New Engl. Med. 
2014;370:2071-2082. 
Saini G., J. Porte, W. Wallace, P. Weinreb, S. Violette T. McKeever and G. Jenkins. 
Imunophenotyping in VATS Lung Biopsy Predicts Prognosis in Idiopathic Pulmonary 
Fibrosis (IPF). 2013:75.


2016N291965_02
CONFIDENTIAL
204715
48
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Transaminase
AUC
Area under the plasma drug concentration versus time curve
AUC(0-t)
Area under the plasma concentration-time curve from zero
(0) hours to time (t)
AUC(0-∞)
Area under the plasma concentration-time curve from zero
(0) hours to infinity (∞)
BMI
Body Mass Index
CCL18
Chemokine (C-C  motif) ligand 18
CE
European Conformity mark 
Cmax
Maximum observed plasma drug concentration
CL
Clearance 
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatinine Phosphokinase
CSR
Clinical Study Report 
CT
Computed Tomography
CV
Cardiovascular 
DLCO
Diffusing capacity of the lungs for carbon monoxide
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ENT
Ear, Nose and Throat
FDA
Food and Drug Administration 
FEV1
Forced Expiratory Volume
FMDV2
Food and Mouth Disease Virus
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety & Pharmacovigilance
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HRCT
High-Resolution Computed Tomography
IB
Investigator Brochure
ICF
Information and consent form 
ICH
International Conference on Harmonisation 
ICRP
International Commission on Radiological Protection
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IP
Investigational Product
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board


2016N291965_02
CONFIDENTIAL
204715
49
ITT
Intent-To-Treat 
IVRS/IWRS
Interactive Voice/Web Response System 
MCH
Mean Cell Haemoglobin
MCV
Mean Cell Volume
MDE
Minimum detectable effect 
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
mm
Millimeter
MM
Medical Monitor
MSDS
Material Safety Data Sheet
mSV
Millisievert
NOAEL
No Observed Adverse Effect Level
OAT
Organic anion transporter
PD
Pharmacodynamic
PET
Positron Emission Tomography
PI
Principal Investigator
PK
Pharmacokinetics
QTc
Corrected QT Interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cells
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SoA
Schedule of Assessments 
SPECT
Single Photon Emission Computed Tomography
SpO2
Peripheral Capillary Oxygen Saturation
SRM
Study Reference Manual
SST
Serum-separator Tube
SUSAR
Suspected Unexpected Serious Adverse Reaction 
SUV
Standardised Uptake Volume
T1/2
Terminal half-life
TGFβ
Transforming Growth Factor Beta
Tmax
Time to maximum concentration
UIP
Usual Interstitial Pneumonia
ULN
Upper Limit of Normal
V
Volume of Distribution (of GSK3008348) 
VT
Volume of Distribution (of PET radioligand) 
WBC
White Blood Cells
WOCBP
Women of childbearing potential


2016N291965_02
CONFIDENTIAL
204715
50
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
HepSal
MedDRA
NONMEM
Phoenix WNL
RANDALL NG


2016N291965_02
CONFIDENTIAL
204715
51
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 1 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 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Total and direct 
bilirubin
Total Protein
Creatinine
Sodium
CPK
Albumin
Glucose 
(non-fasting)
Calcium
Alkaline 
phosphatase
Gamma glutamyl 
transferase 
(gamma GT) 
Aspartate aminotransferase
(AST)
Alanine aminotransferase
(ALT)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

If blood or protein is abnormal, a mid-stream urine sample will be collected 
for further urinalysis, to include microscopy, culture and sensitivities 
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed)2

Serology (hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody; hepatitis C RNA test, if required after a positive antibody test) 
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 7. All events of ALT 3 × 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.


2016N291965_02
CONFIDENTIAL
204715
52
12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (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 substantial amendments to the protocol will require IEC/IRB approval 
before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
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. 


2016N291965_02
CONFIDENTIAL
204715
53

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
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 


2016N291965_02
CONFIDENTIAL
204715
54
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomisation codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
Data Quality Assurance

All participant data relating to the study will be recorded in the eCRF 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 electronically signing the eCRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 

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 eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. 


2016N291965_02
CONFIDENTIAL
204715
55
The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be 
available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


2016N291965_02
CONFIDENTIAL
204715
56
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 


2016N291965_02
CONFIDENTIAL
204715
57
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 


2016N291965_02
CONFIDENTIAL
204715
58
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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 eCRF.

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 eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes 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.


2016N291965_02
CONFIDENTIAL
204715
59
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 IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to  GSK within 24 hours of 
receipt of the information.


2016N291965_02
CONFIDENTIAL
204715
60
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to study treatment (causality) within 72 hours of SAE entry 
into the eCRF. 

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.


2016N291965_02
CONFIDENTIAL
204715
61
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
25. Premenarchal
26. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
27. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
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 


2016N291965_02
CONFIDENTIAL
204715
62
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.
Men must refrain from donating sperm for duration of study and for 90 days after study 
completion.
Female participants
Female participants of childbearing potential are not eligible to participate. 
Table 2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
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. 


2016N291965_02
CONFIDENTIAL
204715
63
Pregnancy Testing

Women should only be included after a negative highly sensitive urine or serum 
pregnancy test 

Additional pregnancy testing will be performed before each PET scan, as required 
locally 
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. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 4. While the investigator is not obligated to actively seek 


2016N291965_02
CONFIDENTIAL
204715
64
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study. 


2016N291965_02
CONFIDENTIAL
204715
65
12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to GSK3008348 or IPF and related 
diseases. They may also be used to develop tests/assays including diagnostic tests) 
related to GSK3008348 (or study treatments of this drug class), and IPF. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis 
of genetic markers throughout the genome [or analysis of the entire genome] (as 
appropriate)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3008348 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3008348 (or study treatments of 
this class) or IPF continues but no longer than 15 years after the last visit of the last 
subject, or other period as per local requirements.


2016N291965_02
CONFIDENTIAL
204715
66
12.7.
Appendix 7: 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 etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT ≥ 3xULN
If ALT ≥ 3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event eCRF, 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

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Blood sample for pharmacokinetic 
(PK) analysis, obtained as soon as 
possible after the event, and within 
36 h of 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 formincluding 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 


2016N291965_02
CONFIDENTIAL
204715
67
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 participants weekly until liver chemistries 
resolve, stabilize or return to within baseline
alcohol intake case report form
If ALT ≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James, 2009]). 
NOTE: not required in China

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 
(excludingstudies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value
stated will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


2016N291965_02
CONFIDENTIAL
204715
68
12.8.
Appendix 8: Radiation Dose Risk Assessment
Participants will be exposed to an additional dose of ionising radiation as a consequence 
of their participation in this study. The ionising radiation exposure from PET and CT 
scanning comes from three sources. A proportion of the radiation exposure comes from 
the administered radioligand ([18F]-FBA-A20FMDV2). The remaining radiation dose 
comes from an HRCT for anatomical localisation (performed once only during the study) 
and low dose CT scans performed in order to correct the PET data for tissue attenuation. 
If the participant needs to be removed from the scanner and repositioned during the PET 
scan than a second low dose CT scan may be performed. The doses chosen for this study 
aim to deliver a minimal radiation exposure, compatible with a good quality PET and CT 
signal. 
Each participant will have up to three PET-CT scans. The effective dose for each 
radioligand administration will be 3.3 mSv based on a conversion factor of 
21.7 Sv/MBq determined from study RES116235 and a maximum administered activity 
of 150 MBq. A low-dose attenuation CT scan of the lung results in an effective dose of 
1.2 mSv. If the participant leaves the scanner during the scan and is repositioned, the CT 
scan will be repeated which would result in a further effective dose of 1.2 mSv. In 
addition, each participant will have one HRCT scan, resulting in an effective dose of 
3.8 mSv. The total effective dose to each participant will therefore be up to 3 x (3.3 + 2.4) 
+ 3.8 = 20.9 mSv. All of this exposure is over and above standard practice.
The total maximum effective dose of 20.9 mSv in this study is equivalent to 
approximately 9 times the average yearly exposure (2.3 mSv) from natural background 
radiation in the United Kingdom. The additional risk of developing a fatal malignancy as 
a result of these exposures has been estimated as approximately 1 in 1,000 for an adult in 
normal health. The reduced life expectancy of IPF patients will result in a lower risk for 
these individuals.
Within the UK the guidance set out by ICRP 62 is generally followed in setting research 
study dose constraints. The level of risk may therefore be assumed to broadly fall within 
the ICRP 62 intermediate Category IIb, where the benefit should be more directly aimed 
at the cure or prevention of disease. 


2016N291965_02
CONFIDENTIAL
204715
69
12.9.
Appendix 9: Assessment of the Potential Immunogenicity 
Risk for [18F]-FBA-A20FMDV2
Immunogenicity is a potential risk for exogenous peptides.  However, we consider the 
risk to be low under the current circumstances where the peptide is synthetic and is not 
administered repeatedly for clinical benefit, but is used as an imaging tracer. 
This potential risk may come from two sources: 
g.
pre-existing antibodies that may arise from prior exposure to the intact virus
h.
induction of a de novo immune response by exposure to the peptide
The risk assessment and management strategy is summarised in Table 3.
Table 3
Summary of the assessment of the immunogenicity risk for [18F]-
FBA-A20FMDV2 in the PETAL Study
Potential risk
Relevant factors and 
comments
Assessment of risk
Risk mitigation /management
Risk level 
Potential risk for pre-
existing antibodies
Previous exposure to 
FMDV may have 
elicited an immune 
response in certain 
individuals that may 
recognise the peptide
FMD is notifiable in 
the UK and the last 
outbreak was in 2007
FMD is endemic in 
certain areas of 
Africa, Asia and 
South America
Participants with prior exposure 
to farm animals are excluded 
from the study. 
Participants resident in 
endemic countries are 
excluded from the study.
Low
Potential risk for 
induction of a de 
novo immune 
response
Route of 
administration
[18F]-FBA-
A20FMDV2 will be 
administered 
intravenously. 
This route is less immunogenic 
than the subcutaneous route. 
Two participants in a previous 
study developed anti-peptide 
antibodies to this tracer but 
neither experienced any clinical 
event.
Low
Number and 
frequency of dosing
[18F]-FBA-
A20FMDV2 will be 
administered 2 or 3 
times to patients with 
IPF 
The 3 doses will be 
administered a maximum of 4  
weeks apart, reducing the 
potential for immune response 
maturation 
Low
Cross-reacting 
antibodies to [18F]-
FBA-A20FMDV2
Anti-[18F]-FBA-
A20FMDV2 
antibodies may 
cross-react with non-
redundant 
endogenous proteins 
and give rise to 
adverse events
Humans are likely to be 
tolerant to sequences 
containing RGD
Development of anti- [18F]-
FBA-A20FMDV2 antibodies 
would require breaking 
tolerance
Low
Physico-chemical 
properties of [18F]-
FBA-A20FMDV2
An effective 
immunogen must 
contain T cell 
epitopes presented in 
the presence of 
adjuvant
[18F]-FBA-A20FMDV2 is 
chemically synthesised and 
there is no elevated concern 
for contaminating host cell 
products with adjuvant 
properties.  
Low


2016N291965_02
CONFIDENTIAL
204715
70
Potential risk
Relevant factors and 
comments
Assessment of risk
Risk mitigation /management
Risk level 
GSK2634673F is 
predicted to contain 
two sequences that 
have binding capacity 
for MHC class II
Aggregation of the peptide is 
minimal
Clinical relevance of in silico
predictions is uncertain, 
however a relevant T cell 
epitope cannot be excluded
In the absence of adjuvant a 
productive immune response is 
very unlikely
Risk mitigation measures
Clinical management
Although the risk of immunogenicity is low, some immune responses can progress to 
hypersensitivity reactions, such as IgE-mediated allergic reactions (anaphylaxis).  The 
impact of such a very rare event would be high. In order to manage this potential risk the 
following measures are in place at the site:

Crash trolleys are available on site

Suitably trained staff are available throughout the study

SOPs have been developed and are current at the site

Direct access to resuscitation teams and intensive care facilities are available 
immediately 
Assay to measure anti-peptide antibodies
Immunogenicity assessment will be performed for serum samples collected as per the 
SoA. Results will be analysed when the study is completed and will be correlated with 
any clinical or imaging observations.
Conclusions
Currently, the evidence suggests that the immunogenicity risk of [18F]-FBA-A20FMDV2, 
a synthetic 20 amino acid peptide, is predicted to be low. Mitigation strategies are 
incorporated into the protocol as described in the table above (such as exclusion of prior 
exposure to FMDV, short period between the 3 doses). In the unlikely event that 
anaphylaxis occurs, appropriate clinical management procedures are available 
immediately.


2016N291965_02
CONFIDENTIAL
204715
71
References
Francis, M. J.,  Fry, C. M., Rowlands, D.J., Brown, F., Bittle, J. L. , Houghten, R. A. , 
and Lerner R. A. Immunological Priming with Synthetic Peptides of Foot-and-Mouth 
Disease Virus. J. gen. Virol. 1985: 66; 2347-2354
Schellekens H. Immunogenicity of Therapeutic Proteins: Clinical Implications and Future 
Prospects. Clinical Therapeutics 2002: 24; 1720-40


2016N291965_02
CONFIDENTIAL
204715
72
12.10.
Appendix 10:  Diagram Summarising the Study Decision 
Making
The data from the 30 min post-dose PET scan will be used to make decisions on the 
design of Cohort 2, assuming Cohort 1 safety data supports proceeding to Cohort 2.  
Figure 2 below illustrates the decision making for the study. 
Figure 2
Diagram illustrating study decision making


2016N291965_02
CONFIDENTIAL
204715
73
12.11.
Appendix 11: Areas Endemic to Foot and Mouth Disease
Figure 3
Global Distribution of Foot and Mouth Disease
Figure 3 shows the geographical distribution of 7 pools of foot and mouth disease viruses 
(FMDV).  Serotype O FMDV is the most widely distributed serotype.  Countries which 
are normally free of the disease (North America, Europe, Russia, Australia and most of 
South America), and are therefore not included in any of the pools shown above, are 
marked in light yellow. 
Reference
Jamal, S. M. & Belsham, G. J. Foot-and-mouth disease: Past, present and future. 
Veterinary Research 44, (2013) 


2016N291965_02
CONFIDENTIAL
204715
74
12.12.
Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 01
Overall Rationale for the Amendment: As part of their review of the clinical trial 
authorisation, the Medicines and Healthcare products Regulatory Agency (MHRA) 
requested a clarification to the emergency unblinding instructions in the protocol. 
Section # 
and Name
Description of Change
Brief Rationale
7.4 Blinding
Clarified that the investigator may break the 
blind for a participant in an emergency, or if it 
is in the participant’s best interest for the 
investigator to know the study treatment 
assignment, whether or not an antidote is 
available, and that the responsibility lies with 
the investigator. The investigator is 
encouraged to discuss with GSK personnel 
before breaking the blind, but if not, may 
inform GSK after the event. 
As requested by the MHRA.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204715
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 204715: A study of single 
doses to evaluate the safety, tolerability, pharmacokinetics 
and target engagement of nebulised GSK3008348 in 
idiopathic pulmonary fibrosis patients, using positron 
emission tomography (PET) imaging. 
Compound Number 
:
GSK3008348
Effective Date 
:
28-JAN-2019
Description:

The purpose of this RAP amendment is to describe the planned analyses and outputs 
for the interim analysis which was conducted on 3rd September 2018. This RAP 
amendment also describes the planned analyses and outputs to be included in the 
Clinical Study Report for Protocol 204715.

This RAP amendment is intended to describe the planned safety, tolerability, 
pharmacokinetics and target engagement analyses required for the study at the end 
of Cohort 1 only. At Interim Analysis and after review of Cohort 1 the study team 
agreed that the study will not progress to Cohort 2, therefore, all analyses pertaining 
to Cohort 2 as specified in the protocol will not be conducted. This RAP amendment 
will be provided to the study team members to convey the content of the Interim 
Analysis (IA) and final Statistical Analysis Complete (SAC) deliverable.

All displays (Tables, Figures & Listings) will use the term 'Subjects'. However, RAP
amendment text will refer to "Participants" in-line with the master RAP template and 
protocol.
Author(s):
Author
Date
 
DD-MMM-YYYY
Principal Statistician (Respiratory, Clinical Statistics)
DD-MMM-YYYY
Manager (Respiratory, Clinical Pharmacology Modelling and 
Simulation (CPMS))
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
204715
2
RAP Team Review and Confirmations (Method: E-mail)
Reviewer
Date
22-JAN-2019
Programming Manager (Respiratory, Clinical Programming)
22-JAN-2019
Clinical Development Manager (Respiratory, Respiratory TAU)
       22-JAN-2019
Director (Experimental Medicine Imaging)
Clinical Statistics & Clinical Programming Line Approvals (Method: Pharma TMF 
eSignature)
Reviewer
Date
Director (Respiratory, Clinical Statistics)
On behalf of 
Statistics Director (Respiratory, 
Clinical Statistics)
24-JAN-2019
28-JAN-2019
Programming Manager (Respiratory, Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
204715
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
1.1.
RAP Amendments ........................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
5.1.
Study Treatment & Sub-group Display Descriptors.....................................15
5.2.
Baseline Definitions ....................................................................................15
5.3.
Multicentre Studies .....................................................................................16
5.4.
Examination of Covariates, Other Strata and Subgroups............................16
5.4.1.
Covariates and Other Strata ........................................................16
5.4.2.
Examination of Subgroups...........................................................17
5.5.
Multiple Comparisons and Multiplicity .........................................................17
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
7.
PHARMACODYNAMIC ANALYSES.......................................................................19
7.1.
Primary Pharmacodynamics Analyses........................................................19
7.1.1.
Endpoint / Variables.....................................................................19
7.1.2.
Summary Measure ......................................................................19
7.1.3.
Population of Interest...................................................................19
7.1.4.
Strategy for Intercurrent (Post-Randomisation) Events ................19
7.1.5.
Statistical Analyses / Methods .....................................................19
7.1.5.1.
Statistical Methodology Specification..........................20
7.2.
Secondary Pharmacodynamic Analyses.....................................................21
7.2.1.
Endpoint / Variables.....................................................................21
7.2.2.
Summary Measure ......................................................................21
7.2.3.
Population of Interest...................................................................21
7.2.4.
Strategy for Intercurrent (Post-Randomisation) Events ................22
7.2.5.
Statistical Analyses / Methods .....................................................22
7.2.5.1.
Statistical Methodology Specification..........................22
7.3.
Exploratory Pharmacodynamic Analyses....................................................22
7.3.1.
Endpoint / Variables.....................................................................23
7.3.2.
Summary Measure ......................................................................23


CONFIDENTIAL
204715
4
7.3.3.
Population of Interest...................................................................23
7.3.4.
Strategy for Intercurrent (Post-Randomisation) Events ................23
7.3.5.
Statistical Analyses / Methods .....................................................24
7.3.5.1.
Statistical Methodology Specification..........................24
8.
SAFETY ANALYSES .............................................................................................25
8.1.
Adverse Events Analyses ...........................................................................25
8.2.
Adverse Events of Special Interest Analyses..............................................25
8.3.
Clinical Laboratory Analyses.......................................................................25
8.4.
Other Safety Analyses ................................................................................25
9.
PHARMACOKINETIC ANALYSES.........................................................................26
9.1.
Primary Pharmacokinetic Analyses.............................................................26
9.1.1.
Endpoint / Variables.....................................................................26
9.1.1.1.
Drug Concentration Measures....................................26
9.1.1.2.
Derived Pharmacokinetic Parameters.........................26
9.1.2.
Summary Measure ......................................................................27
9.1.3.
Population of Interest...................................................................27
9.1.4.
Strategy for Intercurrent (Post-Randomisation) Events ................27
9.1.5.
Statistical Analyses / Methods .....................................................27
9.1.5.1.
Statistical Methodology Specification..........................27
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................28
11. BIOMARKER ANALYSES......................................................................................29
12. PHARMACODYNAMIC INTERIM ANALYSES .......................................................30
12.1.
Pharmacodynamic Interim Analyses...........................................................30
12.1.1.
Endpoint / Variables.....................................................................30
12.1.2.
Summary Measures.....................................................................30
12.1.3.
Population of Interest...................................................................30
12.1.4.
Strategy for Intercurrent (Post-Randomisation) Events ................30
12.1.5.
Statistical Analyses / Methods .....................................................30
12.1.5.1.
Statistical Methodology Specification..........................31
12.1.5.2.
Table Illustrating Study Decision Making Used 
at Interim Analysis ......................................................32
12.1.5.3.
Table Explaining Programming Requirements 
Used at Interim Analysis.............................................34
12.1.5.4.
Figure Illustrating Study Decision Making Used 
at Interim Analysis ......................................................35
12.2.
Model Checking and Diagnostics for Statistical Analyses ...........................35
12.2.1.
General Considerations for Bayesian Analysis ............................35
12.2.1.1.
Prior Distributions .......................................................36
12.2.1.2.
Initial Values...............................................................37
12.2.1.3.
Convergence Diagnostics...........................................37
12.2.2.
General Considerations for All Analyses......................................38
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................40
14. REFERENCES.......................................................................................................41
15. APPENDICES........................................................................................................42


CONFIDENTIAL
204715
5
15.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................42
15.1.1.
Exclusions from Per Protocol Population .....................................42
15.2.
Appendix 2: Schedule of Activities ..............................................................43
15.2.1.
Protocol Defined Schedule of Events...........................................43
15.3.
Appendix 3: Assessment Windows .............................................................45
15.3.1.
Definitions of Assessment Windows for Analyses........................45
15.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................46
15.4.1.
Study Phases ..............................................................................46
15.4.1.1.
Study Phases for Concomitant Medication .................46
15.4.2.
Treatment Emergent Flag for Adverse Events .............................47
15.4.3.
Categorisation of adverse events into Dosing Periods .................48
15.5.
Appendix 5: Data Display Standards & Handling Conventions....................49
15.5.1.
Reporting Process .......................................................................49
15.5.2.
Reporting Standards....................................................................49
15.5.3.
Reporting Standards for Pharmacokinetic....................................50
15.6.
Appendix 6: Derived and Transformed Data ...............................................52
15.6.1.
General........................................................................................52
15.6.2.
Safety ..........................................................................................52
15.6.3.
Pharmacokinetic ..........................................................................53
15.6.4.
Pharmacodynamic.......................................................................53
15.7.
Appendix 7: Reporting Standards for Missing Data.....................................54
15.7.1.
Premature Withdrawals................................................................54
15.7.2.
Handling of Missing Data.............................................................54
15.7.2.1.
Handling of Missing and Partial Dates ........................54
15.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................55
15.8.
Appendix 8: Values of Potential Clinical Importance ...................................56
15.8.1.
Laboratory Values........................................................................56
15.8.2.
ECG.............................................................................................57
15.8.3.
Vital Signs....................................................................................57
15.9.
Appendix 11: Abbreviations & Trade Marks ................................................58
15.9.1.
Abbreviations...............................................................................58
15.9.2.
Trademarks .................................................................................60
15.10. Appendix 12: List of Data Displays..............................................................61
15.10.1. Data Display Numbering..............................................................61
15.10.2. Mock Example Shell Referencing ................................................61
15.10.3. Deliverables.................................................................................61
15.10.4. Study Population Tables..............................................................62
15.10.5. Safety Tables...............................................................................64
15.10.6. Safety Figures .............................................................................68
15.10.7. Pharmacodynamic Tables ...........................................................70
15.10.8. Pharmacodynamic Figures ..........................................................74
15.10.9. Pharmacokinetic Tables...............................................................81
15.10.10.Pharmacokinetic Figures .............................................................82
15.10.11.ICH Listings .................................................................................83
15.10.12.Non-ICH Listings..........................................................................87
15.11. Appendix 13: Example Mock Shells for Data Displays ................................89


CONFIDENTIAL
204715
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) amendment is to describe the 
analyses to be included in the Interim Analysis (IA) and Clinical Study Reports for 
Protocol: 204715
Protocol Revision Chronology:
2016N291965_00
05-DEC-2016
Original
2016N291965_01
09-MAR-2017
As part of their review of the clinical trial
authorisation, the Medicines and Healthcare 
Products Regulatory Agency (MHRA)
requested a clarification to the emergency 
unblinding instructions in the protocol.
2016N291965_02
24-JAN-2018
To correct the description of the primary 
endpoint and provide further guidance on the
follow up visit and lung function requirements. 
Other typographical errors have also been
corrected.
1.1.
RAP Amendments 
The original RAP was finalised prior to the Interim Analysis. At the Interim Analysis it 
was agreed to terminate the study and to not proceed to Cohort 2. This RAP amendment 
was written after the Interim Analysis and prior to final DBF and aims to clarify the 
contents of the SAC outputs.


CONFIDENTIAL
204715
7
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There are no changes or deviations to the originally planned statistical analysis specified 
in the protocol 2016N291965_02 (Dated: 24-JAN-2018). However, the protocol states 
that ‘If the study is stopped at the end of Cohort 1, then Cohort 2 will not proceed’, 
therefore, all analyses pertaining to Cohort 2 will not be conducted.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate target engagement 
in the lung after single 
nebulised doses of 
GSK3008348 in IPF patients

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the whole lung (assessed as the
volume of distribution [VT], not corrected for 
air volume) at approximately 30 min post-dose 
compared to pre-dose, as measured by PET

To evaluate the safety and 
tolerability of single nebulised 
doses of GSK3008348 in IPF 
patients

Adverse events (AE), clinical laboratory values, 
vital signs, electrocardiogram (ECG), and 
pulmonary function tests
Secondary Objectives
Secondary Endpoints

To evaluate the 
pharmacokinetic profile of 
single nebulised doses of 
GSK3008348 in IPF patients

Derived pharmacokinetic parameters for 
GSK3008348 including, but not limited to, area 
under the plasma drug concentration versus 
time curve (AUC(0-t), AUC(0-inf)), maximum 
observed plasma drug concentration (Cmax), 
time to maximum observed plasma drug 
concentration (Tmax), and terminal half-life 
(T1/2) following single nebulised doses, where 
data allow

To evaluate duration of target 
engagement after single 
nebulised doses of 
GSK3008348 in IPF patients

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the lung (assessed as the VT) up 
to 28 h post-dose compared to pre-dose, as 
measured by PET
Exploratory Objectives
Exploratory Endpoints

To explore the 
pharmacodynamic
effects of single nebulised 
doses of GSK3008348 in IPF 
patients using additional PET 
analyses techniques

Changes in the uptake of [18F]-FBA-
A20FMDV2 in the whole lung (assessed using 
standardised uptake values [SUV] and VT, with 
and without correction for air and/or blood 
volume) at various time points post-dose 
compared to pre-dose, as measured by PET

To explore the spatial 
distribution of the effects of 
single nebulised doses of 
GSK3008348 in IPF patients 

Qualitative assessment of the distribution of
the uptake of [18F]-FBA-A20FMDV2 in the
lungs post-dose compared to pre-dose, as
measured by PET and compared to the


CONFIDENTIAL
204715
8
Objectives
Endpoints
and to compare it to the spatial 
distribution of disease
spatial distribution of disease as indicated by 
HRCT

To explore pharmacodynamic 
effects of GSK3008348 in 
blood

Exploratory pharmacodynamic biomarkers
of the αvβ6/TGFβ mechanism which may
include but are not limited to: mRNA,
microRNA and proteins in blood

To explore potential 
biomarkers of IPF disease 
and/or treatment response

Exploratory biomarkers in blood


CONFIDENTIAL
204715
9
2.3.
Study Design
Overview of Study Design and Key Features
Cohort 1 
Design
Features

This is a multi-centre, 2-cohort, study of single doses to investigate 
the safety, tolerability, PK and target engagement of nebulised 
GSK3008348, in patients with IPF.

Cohort 1 will be a randomised, double-blind (sponsor unblind), 
placebo-controlled group of 7 participants, randomised 5:2 to 
receive 1,000 µg GSK3008348 or placebo. After screening (within 
30 days of the first dose), all participants will have 2 dosing periods, 
and receive the same dose in each period as follows:  
o
Dosing period 1:  After pre-dose assessments at the clinical unit, 
participants will be admitted to the clinical unit the day of dosing 
(Day 1), stay overnight and be discharged after 24 h post-dose 
safety and PK assessments (Day 2).
o
Washout period: At least 7 days and no more than 28 days 
between doses.
o
Pre-dose scan: At least 7 days after the first dose, and no more 
than 14 days before the first post-dose PET.
o
Dosing period 2: Participants will have pre-dose assessments at 
the clinical unit. They will attend the imaging unit for dosing
and a 30 min post-dose PET scan and stay for at least 4 h post-
dose. Participants will return to the imaging unit on Day 2 for a 
24 h PET scan, and safety and PK assessments.

Cohort 2 was not conducted. It was optional and would have been
designed to further explore the safety of GSK3008348 and to 
provide additional information on the target engagement profile of 
GSK3008348. Based on Cohort 1 data, the decision was made to 


CONFIDENTIAL
204715
10
Overview of Study Design and Key Features
terminate the study and not continue into cohort 2. 
Dosing

A single nebulised dose in each dosing period
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Cohort 1:

7 IPF patients will be enrolled. More IPF patients may be enrolled 
to achieve a target of 7 evaluable IPF patients.

Subjects in Cohort 1 will be randomised to receive either 1,000 µg 
GSK3008348 or placebo using a 5:2 ratio. 

Interim 
Analysis

An interim analysis to assess safety and tolerability, exposure and 
receptor engagement will occur at the end of Cohort 1. 

For safety assessments in Cohort 1, the review by the study team 
will include data on AEs, ECGs, pulmonary function, clinical 
laboratory values and VS.
2.4.
Statistical Hypotheses / Statistical Analyses
All Parts:

The assessment of the safety and tolerability of single doses of nebulised 
GSK3008348 in this study will not include any formal statistical comparisons.
Cohort 1:

In Cohort 1, the primary comparison of interest is based on the changes in the uptake 
of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the volume of distribution 
[VT], not corrected for air volume) at approximately 30 min post-dose compared to 
pre-dose, as measured by PET.


CONFIDENTIAL
204715
11
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Interim Analyses
Details
Pharmacodynamics
(Cohort 1)

The purpose of the interim analysis at the end of Cohort 1 
was to provide the project team and key GSK stakeholders 
with data on receptor engagement to inform internal 
decision making. There were options to stop the study for 
success or to stop if it was deemed futile to proceed or to 
increase the sample size.

The interim occurred at the end of Cohort 1 when 5 IPF 
subjects receiving GSK3008348 had completed dosing 
period 2 and had a valid baseline and 30 minutes post-dose 
PET scan. 

The primary endpoint for decision-making at the interim 
analysis was the change in the uptake of [18F]-FBA-
A20FMDV2 in the whole lung (assessed as the volume of 
distribution [VT], not corrected for air volume) at 
approximately 30 min post-dose compared to pre-dose, as 
measured by PET

The review occurred on a clean database including the 
PET derived endpoints and the randomisation assignment. 
In addition, in-stream data reviews took place to ensure 
maximum data quality.

At the interim time point the change 30 minutes post-dose 
vs pre-dose in whole lung VT for the 5 active subjects was
analysed. The decision was made to stop the study due to 
success and evidence of receptor engagement, primarily
based on the predefined success criterion, i.e. the posterior 
probability that there was a reduction in uptake of [18F]-
FBA-A20FMDV2 in the whole lung (assessed as the 
volume of distribution [VT], not corrected for air volume) 
at approximately 30 min post-dose compared to pre-dose, 
as measured by PET.

Appropriate data summaries were at the treatment group 
level and individual subject numbers were scrambled so 
treatment allocation was not obvious.  The circulation of 
results was restricted to selected members of the GSK 
project team and key stakeholders. Interim results were
discussed with site investigators following internal review 
at GSK. 
PK

The purpose of the interim PK analysis at the end of 
Cohort 1 was to provide the study team with data on 


CONFIDENTIAL
204715
12
Interim Analyses
Details
(Cohort 1)
systemic exposure to inform dose selection for Cohort 2 
and/or dose selection for future studies and occurred at the 
end of Cohort 1.

PK analysis was performed on the data prior to cleaning. 
Additionally, the analysis was performed using nominal 
times and interim analysis was conducted on data with 
scrambled individual subject numbers. These scrambled 
numbers were different from scrambled numbers for the 
PET endpoint. The critical PK endpoints for assessment 
of systemic exposure were AUC and Cmax. AUC was
assessed as 0-t in the event of insufficient data to 
determine AUC(0-inf). Exposures relative to those observed 
at the NOAEL in toxicology studies were not calculated 
since we were not proceeding to Cohort 2.
Safety
(Cohort 1)

An informal review of safety data occurred at the end of 
Cohort 1. The purpose of this review was to compare 
safety parameters at the pre- and post-dose timepoints 
across both dosing periods and explore any safety signals 
that may have emerged.

The review by the study team included data on AEs,
ECGs, pulmonary function, clinical laboratory values and 
VS.

It was not expected that this review would occur on a 
clean database. No data listings were produced, and no 
statistical analysis was performed on the data.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.


CONFIDENTIAL
204715
13
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses 
Evaluated
All participants

All participants who are screened and for 
whom a record exists on the study database.

Study 
Population
Enrolled

All participants who are screened and 
enrolled into the study.

Note: Screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the 
Enrolled population as they did not enter the 
study.

Study 
Population
Intent-To-Treat 
(ITT)

All randomised participants who receive at 
least one dose of study treatment. This 
population will be based on the treatment 
they actually received.

Note: Any participants who receives a 
treatment randomisation number will be 
considered to have been randomised.

PD

Study 
Population

Safety
Per-Protocol
(PP)

All participants in the ITT population who 
comply with the protocol and that have at 
least one evaluable PET measurement post 
baseline.

Note: Protocol deviations that would exclude 
participants from the PP population are
defined in Section 4.1 (Protocol Deviations) 
and Appendix 1(Protocol Deviation 
Management and Definitions for Per Protocol 
Population).

Note: The ITT set will not be analysed if this 
population is the same as the PP population.

PD
Pharmacokinetic
(PK)

All participants in the Intent-to-Treat
population receiving active dose for whom a 
pharmacokinetic sample was obtained and 
analysed.

Note: Non-quantifiable [NQ] values will be 
considered as non-missing values.

PK
Refer to Appendix 12: List of Data Displays which details the population used for each 
display.


CONFIDENTIAL
204715
14
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.
Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population).
Protocol deviations will be tracked and reviewed by the study team throughout the 
conduct of the study in accordance with the Protocol Deviation Management Plan (Final 
v1.0, Dated: 09-MAR-2017).
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
For the interim analysis, exclusions from the Per-Protocol Population based on the 
criteria detailed in Section 15.1.1 were agreed prior to un-blinding based on review of in-
stream data by the study team.


CONFIDENTIAL
204715
15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
No treatment comparisons between GSK3008348 1000 mcg versus Placebo will be 
conducted.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessment Period
1
2
Baseline Used in Data Display
Dosing 
Period 1 
Day -1 or 
Day 1 
(Pre-
Dose) 
Dosing 
Period 2
Day -1 
or Day 
1 (Pre-
dose)
Dosing 
Period 2, 
Baseline 
scan
(≤2 
Weeks 
Pre-Dose)
Pharmacodynamics
Volume of Distribution (VT), not corrected for air 
volume
X
Volume of Distribution (VT), corrected for air volume
X
Standardised Uptake Values (SUV), not corrected for air 
volume
X
Standardised Uptake Values (SUV), corrected for air 
volume
X
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting
Code
Description
Description
Order in TLF 
A
Placebo
Placebo
1
B
GSK3008348 1000 mcg
GSK3008348 1000 mcg
2


CONFIDENTIAL
204715
16
Parameter
Study Assessment Period
1
2
Baseline Used in Data Display
Dosing 
Period 1 
Day -1 or 
Day 1 
(Pre-
Dose) 
Dosing 
Period 2
Day -1 
or Day 
1 (Pre-
dose)
Dosing 
Period 2, 
Baseline 
scan
(≤2 
Weeks 
Pre-Dose)
Safety
12 Lead ECG
X
X
Vital Signs
X
X
Laboratory Assessments 
X
X
FEV1 and FVC (absolute & % predicted)
X
X
DLCO (absolute & % predicted)
X
For all pharmacodynamics and safety displays, baseline will be labelled ‘Pre-dose’.
If Pre-dose % predicted FVC in Period 2 is missing Pre-dose % predicted FVC in Period 
1 will be used as baseline value instead for PET data analysis.
If Day -1 and Day 1 pre-dose values are missing, screening value for Period 1 will be 
used as baseline. Unless otherwise stated, if baseline data is missing no derivation will be 
performed and baseline will be set to missing.
5.3.
Multicentre Studies
This is a single country, multicentre study and enrolment will be presented by 
investigative site/hospital.
Investigative site/Hospital
Country
University College London Hospital (UCLH)
United Kingdom
Royal Brompton Hospital (RBH)
United Kingdom
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.


CONFIDENTIAL
204715
17
Category
Details
Strata
None
Covariates
Age, Sex, Baseline % Predicted FVC (baseline in Period 2) and Baseline % 
Predicted DLCO (baseline in Period 1).
5.4.2.
Examination of Subgroups
There is no examination of subgroups.
5.5.
Multiple Comparisons and Multiplicity
In Cohort 1, the primary comparison of interest is based on the changes in the uptake of 
[18F]-FBA-A20FMDV2 in the whole lung (assessed as the volume of distribution [VT], 
not corrected for air volume) at approximately 30 min post-dose compared to pre-dose, as 
measured by PET. No treatment comparisons between GSK3008348 1000 mcg versus 
Placebo will be conducted. Therefore, there are no planned adjustments for multiple 
comparisons or multiplicity.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
15.3
Appendix 3: Assessment Windows
15.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
15.5
Appendix 5: Data Display Standards & Handling Conventions
15.6
Appendix 6: Derived and Transformed Data
15.7
Appendix 7: Reporting Standards for Missing Data
15.8
Appendix 8: Values of Potential Clinical Importance


CONFIDENTIAL
204715
18
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Intent-To-Treat (ITT) 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 12: List of Data Displays.


CONFIDENTIAL
204715
19
7.
PHARMACODYNAMIC ANALYSES
7.1.
Primary Pharmacodynamics Analyses
The three PET scans per subject will be denoted as ‘Pre-dose’ (Baseline PET in Period 
2), ‘PET1’ (Period 2, Day 1, 30 minutes PET after dose of GSK3008348, allowable time 
window is 20-60 mins) and ’PET2’ (Period 2, Day 2, 24 hours PET after dose of 
GSK3008348, allowable time window is 14-28 hrs).
7.1.1.
Endpoint / Variables
Change in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the 
volume of distribution [VT], not corrected for air volume) at approximately 30 min post-
dose compared to pre-dose, as measured by PET. VT is implicitly corrected for blood
volume.
7.1.2.
Summary Measure
Ratio (PET1/Pre-dose) in the volume of distribution (VT), not corrected for air volume at 
approximately 30 min post-dose as measured by PET.
7.1.3.
Population of Interest 
The primary pharmacodynamic analyses will be based on the Per-Protocol (PP)
population, unless otherwise specified.
7.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
Several post-randomisations events have been considered e.g. use of rescue medication, 
discontinuation of treatment, treatment switching and death. Due to the short duration of 
the study (and the time at which the pharmacodynamic endpoint is measured; baseline, 
30mins and 14-28hrs post-dose) these post-randomisation events have been deemed to 
have little impact on the endpoint.
Therefore, a treatment policy approach will be adopted hence the actual values of the 
endpoint regardless of whether the intercurrent event has occurred will be analysed.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.


CONFIDENTIAL
204715
20
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

VT (whole lung, not corrected for air volume), at 1000 mcg GSK3008348
Timepoint

The primary timepoint of interest is the 30 minutes post-dose PET scan timepoint.
Model Specification

The distribution of VT will be explored using graphical approaches. It is likely that 
this follows a log-normal distribution in which case the logarithm transformation 
will be applied, and a normal distribution assumed for log (VT).

Only data from those subjects receiving 1,000 mcg GSK3008348 will be included 
in the primary analysis (i.e., no placebo data will be included) in Cohort 1.

The three PET scans per subject will be denoted by Pre-dose (Baseline PET in 
Period 2), PET1 (Period 2, Day 1, 30 minutes PET after dose of GSK3008348, 
allowable time window is 20-60 mins) and PET2 (Period 2, Day 2, 24 hours PET
after dose of GSK3008348, allowable time window is 14-28 hrs).

The mean of the normal distribution will be allowed to vary per post-dose scan 
timepoint by defining the 3-dimensional array parameter ResponsebyVisit as 
follows:
o
ResponsebyVisit[1]  = mean of log (Response) at ‘Pre-dose’
o
ResponsebyVisit[2]  = mean of log (Response) at ‘PET1’
o
ResponsebyVisit[3]  = mean of log (Response) at ‘PET2’

In addition, the following 3 - dimensional array parameter ResponseRatio will also 
be created:
o
ResponseRatio[1] = PET1/Pre-dose
o
ResponseRatio[2] = PET2/Pre-dose
o
ResponseRatio[3] = PET2/PET1

The inclusion of covariates Age, Sex, Baseline % predicted FVC, and Baseline % 
predicted DLCO (baseline from Period 2) will be explored in a sequential manner 
and included in the model if the 95% HPD credible interval for the corresponding 
regression coefficient excludes 0.

This endpoint will be analysed using Bayesian inference assuming non-informative 
priors of the form N(mean=0, SD = 1000) for all regression coefficients in the 
model.

An unstructured 3x3 variance-covariance matrix will be assumed to model the 
dependency between log (VT) in the three PET scans. If the model fails to converge 
then additional structures such as the Toeplitz structure should be explored. Details 
of the prior distributions are presented in Section 12.2.
Model Checking & Diagnostics

Refer to Section 12.2: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Plots of the posterior samples (chains) will be produced for all the parameters in the 
model as listings.

Posterior density plots for VTRatio;


CONFIDENTIAL
204715
21
o
PET1/Pre-dose
o
PET2/Pre-dose
o
PET2/PET1
will be produced.

The adjusted posterior median values of VTRatio (PET1/Pre-dose, PET2/Pre-dose
and PET2/PET1) will be presented in tabular form together with the corresponding 
standard deviations and 95% HPD credible intervals.

Plots of individual subject data for PET1/Pre-dose, PET2/ Pre-dose and 
PET2/PET1 will be superimposed with the adjusted posterior median values of 
PET1/Pre-dose, PET2/Pre-dose and PET2/PET1 respectively. These plots should 
also include the corresponding 95% HPD credible intervals for PET1/Pre-dose, 
PET2/Pre-dose and PET2/PET1. 

The posterior probability that the true ratio PET1/Pre-dose is less than 1 will be 
calculated.
Subgroup Analyses

None
Sensitivity and Supportive Analyses

Following review of the data, additional analyses may be conducted to further 
support the primary statistical analysis, if deemed appropriate. The posterior 
probability that the true ratio PET1/Pre-dose is less than 0.9, 0.8, 0.7 and 0.6, as 
appropriate depending on the observed data, will also be calculated. If the PP and 
ITT populations differ, the same statistical analysis using the ITT population will 
also be conducted.
7.2.
Secondary Pharmacodynamic Analyses
The secondary pharmacodynamic analyses will be conducted in the same manner as the 
primary pharmacodynamic analyses. The only difference is that the timepoint of interest 
is now PET2. The output corresponding to the secondary pharmacodynamic analysis will 
be obtained from the primary pharmacodynamic analysis and corresponds to PET2/Pre-
dose and PET2/PET1.
7.2.1.
Endpoint / Variables
Changes in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the VT) 
up to PET2 post-dose compared to Pre-dose, as measured by PET.
7.2.2.
Summary Measure

Ratio (PET2/Pre-dose) in the volume of distribution (VT), not corrected for air 
volume at 14-28 hrs post-dose as measured by PET.
7.2.3.
Population of Interest 
The secondary pharmacodynamic analyses will be based on the Per Protocol (PP)
population, unless otherwise specified.


CONFIDENTIAL
204715
22
7.2.4.
Strategy for Intercurrent (Post-Randomisation) Events
Treatment policy approach will be adopted hence the actual values of the endpoint 
regardless of whether the intercurrent event has occurred will be analysed as outlined in 
the primary pharmacodynamic analyses.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

VT (whole lung, not corrected for air volume), at 1000 mcg GSK3008348
Timepoint

The secondary timepoint of interest is the PET2.
Model Specification

Similar to the primary pharmacodynamic analyses
Model Checking & Diagnostics

Similar to the primary pharmacodynamic analyses
Model Results Presentation

Similar to the primary pharmacodynamic analyses
Subgroup Analyses

Similar to the primary pharmacodynamic analyses
Sensitivity and Supportive Analyses

Similar to the primary pharmacodynamic analyses
7.3.
Exploratory Pharmacodynamic Analyses
There are four exploratory objectives and associated endpoints as outlined Section 2.2. 
For the exploratory pharmacodynamic analyses, only endpoints associated with the 
following objective will be described in this RAP:

To explore the pharmacodynamic effects of single nebulised doses of GSK3008348 
in IPF patients using additional PET analyses techniques
The following objectives and associated endpoints below will be described separately 
from this RAP:


CONFIDENTIAL
204715
23

To explore the spatial distribution of the effects of single nebulised doses of 
GSK3008348 in IPF patients and to compare it to the spatial distribution of disease

To explore pharmacodynamic effects of GSK3008348 in blood

To explore potential biomarkers of IPF disease and/or treatment response
7.3.1.
Endpoint / Variables

Change in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed using 
standardised uptake values [SUV] and VT, with and without correction for air and/or 
blood volume) at various time points post-dose (PET1 and PET2) compared to pre-
dose (Pre-dose), as measured by PET
7.3.2.
Summary Measure

Ratio (PET1/Pre-dose) in the volume of distribution (VT), whole lung, corrected for 
air volume at approximately 30 mins post-dose as measured by PET.

Ratio (PET2/Pre-dose) in the volume of distribution (VT), whole lung, corrected for 
air volume at 14-28 hrs post-dose as measured by PET.

Ratio (PET2/PET1) in the volume of distribution (VT), whole lung, corrected for air 
volume at approximately 30 mins and 14-28 hrs post-dose as measured by PET.

Ratio (PET1/Pre-dose) in the standardised uptake values (SUV), whole lung, not 
corrected for air volume) at approximately 30 mins post-dose as measured by PET.

Ratio (PET2/Pre-dose) in the standardised uptake values (SUV), whole lung, not 
corrected for air volume at 14-28 hrs post-dose as measured by PET.

Ratio (PET2/PET1) in the standardised uptake values (SUV), whole lung, not 
corrected for air volume at approximately 30 mins and 14-28 hrs post-dose as 
measured by PET.

Ratio (PET1/Pre-dose) in the standardised uptake values (SUV), whole lung, 
corrected for air volume at approximately 30 mins post-dose as measured by PET.

Ratio (PET2/Pre-dose) in the standardised uptake values (SUV), whole lung, 
corrected for air volume at 14-28 hrs post-dose as measured by PET.

Ratio (PET2/PET1) in the standardised uptake values (SUV), whole lung, corrected
for air volume at approximately 30 mins and 14-28 hrs post-dose as measured by 
PET.
7.3.3.
Population of Interest 
The exploratory pharmacodynamic analyses will be based on the Per Protocol (PP) 
population, unless otherwise specified.
7.3.4.
Strategy for Intercurrent (Post-Randomisation) Events
Treatment policy approach will be adopted hence the actual values of the endpoint 
regardless of whether the intercurrent event has occurred will be analysed as outlined in 
the primary pharmacodynamic analyses.


CONFIDENTIAL
204715
24
7.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.3.5.1.
Statistical Methodology Specification
Endpoint / Variables

Volume of distribution (VT), (whole lung, corrected for air volume) at 
approximately 30 mins post-dose as measured by PET.

Volume of distribution (VT), (whole lung, corrected for air volume) at 14-28 hrs
post-dose as measured by PET.

Standardised uptake values (SUV), (whole lung, not corrected for air volume) at 
approximately 30 mins post-dose as measured by PET.

Standardised uptake values (SUV), (whole lung, not corrected for air volume) at 
14-28 hrs post-dose as measured by PET.

Standardised uptake values (SUV), (whole lung, corrected for air volume) at 
approximately 30 mins post-dose as measured by PET.

Standardised uptake values (SUV), (whole lung, corrected for air volume) at 14-28
hrs post-dose as measured by PET.
Timepoints

The exploratory timepoints of interest are PET1 and PET2.
Model Specification

Similar to the primary pharmacodynamic analyses
Model Checking & Diagnostics

Similar to the primary pharmacodynamic analyses
Model Results Presentation

Similar to the primary pharmacodynamic analyses
Subgroup Analyses

None
Sensitivity and Supportive Analyses

Similar to the primary pharmacodynamic analyses


CONFIDENTIAL
204715
25
8.
SAFETY ANALYSES
The safety analyses will be based on the Intent-To-Treat (ITT) population, unless 
otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
8.2.
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. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review by the study team in place at the time of reporting. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
8.3.
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 12: List of Data 
Displays.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs, pulmonary function
and vital signs will be based on GSK Core Data Standards, unless otherwise specified. 
The details of the planned displays are presented in Appendix 12: List of Data Displays.


CONFIDENTIAL
204715
26
9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 15.5.3
Reporting Standards for Pharmacokinetic)
9.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Nominal sampling times may be used during any interim analysis.
Pharmacokinetic parameters listed will be determined from the plasma concentration-
time data, as data permits.
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time 
of the last quantifiable concentration (C(t)) will be calculated using 
the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid.
AUC(0-t)/D
AUC(0-t) corrected for dose 
AUC(0-inf)
Area under the concentration-time curve extrapolated to infinity will 
be calculated as: AUC = AUC(0-t) + C(t) / lambda_z
AUC(0-inf)/D
AUC(0-inf) corrected for dose
Cmax
Maximum observed concentration, determined from the 
concentration-time data.
Tmax
Time to reach Cmax, determined directly from the concentration-time 
data.
Cmax/D
Cmax corrected for dose
Lambda_z[1]
The first order rate constant associated with the terminal (log-linear) 
portion of the concentration-time curve.
Lambda_z_lower
First time point used in computing Lambda_z.
Lambda_z_upper
Last time point used in computing Lambda_z.
#pts
Number of points used in computing Lambda_z.
r-squared
R-squared of Lambda_z computation.
t½
Apparent terminal half-life will be calculated as: t½ = ln2 / 
Lambda_z


CONFIDENTIAL
204715
27
NOTES:

Additional parameters may be included as required.
9.1.2.
Summary Measure
PK treatment comparisons are not planned for this study.
9.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
9.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
In the event of a missing time point, PK parameters will be estimated from the available 
data on that day, unless the missing value compromises the accurate estimate of the 
parameter.
9.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 9.1.1 will be 
summarised by period using descriptive statistics, graphically presented (where 
appropriate) and listed.
9.1.5.1.
Statistical Methodology Specification
No formal statistical modelling will be performed, only descriptive statistics will be 
produced.


CONFIDENTIAL
204715
28
10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
Plasma concentration-time data may be used to derive population PK parameters/models 
using NONMEM or other currently validated software. The timeline for this analysis and 
reporting will be independent of the analysis described in this RAP. In an event that 
GSK3008348 is terminated before these analyses are conducted, they will not be 
reported.


CONFIDENTIAL
204715
29
11.
BIOMARKER ANALYSES
Analyses for exploratory pharmacodynamic biomarkers of the αvβ6/TGFβ mechanism 
which may include but are not limited to: mRNA, microRNA and proteins in blood will 
be independent of the analysis described in this RAP and will be reported separately.


CONFIDENTIAL
204715
30
12.
PHARMACODYNAMIC INTERIM ANALYSES
12.1.
Pharmacodynamic Interim Analyses
The interim analysis for pharmacodynamics in Cohort 1 was based on the Per Protocol 
population.
The interim analysis was conducted in the same manner as the primary pharmacodynamic 
analysis and the primary timepoint of interest was the 30 minutes post-dose scan 
timepoint. The secondary timepoint of interest was the 14-28hrs post dose scan point.
The data was reported to the study team with scrambled individual subject numbers.
12.1.1.
Endpoint / Variables

Change in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the 
volume of distribution [VT], not corrected for air volume) at approximately 30 min 
post-dose compared to pre-dose, as measured by PET.

Change in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the 
volume of distribution [VT], not corrected for air volume) at 14-28hrs post-dose 
compared to pre-dose, as measured by PET.
12.1.2.
Summary Measures

Ratio (PET1/Pre-dose) in the volume of distribution (VT), whole lung, not corrected 
for air volume at approximately 30 mins post-dose as measured by PET.

Ratio (PET2/Pre-dose) in the volume of distribution (VT), whole lung, not corrected 
for air volume at 14-28 hrs post-dose as measured by PET.

Ratio (PET2/PET1) in the volume of distribution (VT), whole lung, not corrected for 
air volume at approximately 30 mins and 14-28 hrs post-dose as measured by PET.
12.1.3.
Population of Interest
The pharmacodynamics interim analyses were based on the Per Protocol (PP) population.
12.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
Treatment policy approach was adopted hence the actual values of the endpoint 
regardless of whether the intercurrent event had occurred were analysed as described for 
the primary pharmacodynamic analyses.
12.1.5.
Statistical Analyses / Methods
Details of the planned displays were provided in Appendix 12: List of Data Displays and 
were based on GSK Data Standards and statistical principles.
Endpoints / variables defined in Section 12.1.1 were summarised using descriptive
statistics, graphically presented (where appropriate) and listed.


CONFIDENTIAL
204715
31
12.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the 
volume of distribution [VT], not corrected for air volume) at approximately 30 min 
post-dose compared to pre-dose, as measured by PET.

Change in the uptake of [18F]-FBA-A20FMDV2 in the whole lung (assessed as the 
volume of distribution [VT], not corrected for air volume) at 14-28hrs post-dose 
compared to pre-dose, as measured by PET.
Timepoints

PET1.

PET2.
Model Specification

Same model specifications as in Section 7.1.5.1 for the primary pharmacodynamics 
analyses
Model Checking & Diagnostics

Same model specifications as in Section 7.1.5.1 for the primary pharmacodynamics 
analyses
Model Results Presentation

Same model specifications as in Section 7.1.5.1 for the primary pharmacodynamics 
analyses
Subgroup Analyses

None
Sensitivity and Supportive Analyses

Same model specifications as in Section 7.1.5.1 for the primary 
pharmacodynamics analyses


CONFIDENTIAL
204715
32
12.1.5.2.
Table Illustrating Study Decision Making Used at Interim Analysis
Interim outcomes from 
204715
Impact on 
development of 
GSK3008348
Traffic lights
Question for cohort 2
Cohort 2 
Cohort 2 -          
Positive data
Cohort- 2 
negative data
1)
No signal, variability as 
expected
Stop development
2)
Signal more variable than 
expected, sample size 
increase required >10
subjects
Failure of PET 
endpoint not '348 
continue to PD 
study (pSMAD2)
N/A
3)
Signal more variable than 
expected, sample size 
increase required <10
subjects
Dependent on 
number 
additional 
subjects required.  
If the number of 
patients can be 
feasibly recruited, 
continue to cohort 
2 to get definitive 
answer.  If it is 
not feasible to 
increase the 
sample size-
failure in 
sensitivity of PET 
endpoint continue 
to PD study 
(pSMAD2)
Can target engagement 
be established in the 
larger cohort?  Is this 
only 10 or less
subjects and can these 
be feasibly recruited?
If Answer to 
both questions 
yes, recruit
additional 
subjects and 
confirm target 
engagement.  
Otherwise 
continue to PD 
study
1) invest API-3 
and repeat dose 
IPF study  
Still no robust 
target 
engagement-
Stop 
development
4)
Signal at 30 minutes, but no
or inconclusive signal at 24 
hours (expected outcome)
Go ahead with 
API-3 and repeat 
dosing studies in 
IPF patients
Is GSK3008348 
suitable for twice daily 
dosing? Can this be 
achieved in a number 
of participants that can 
be feasibly recruited?


CONFIDENTIAL
204715
33
Interim outcomes from
204715
Impact on 
development of 
GSK3008348
Traffic lights
Question for cohort 2
Cohort 2 
Cohort 2 -          
Positive data
Cohort- 2 
negative data
5)
Signal at both 30 mins and 
24 hours
Go ahead with 
API-3 and repeat 
dose study with 
PD assessments
in IPF patients
Investigate whether 
lower doses can be 
used? 
Investigate 
lower doses
Use information to 
inform dose 
selection for 
repeat dosing in 
IPF study
Use 
information to 
inform dose 
selection for 
repeat dosing 
in IPF study


CONFIDENTIAL
204715
34
12.1.5.3.
Table Explaining Programming Requirements Used at Interim Analysis
Study Decision
Description
Statistical Programming
Achieve Study 
Success Criteria 
and
PET Signal is 
Robust
Achieve Study Success 
Criteria 
and
PET Signal is ≥ 5% 
Inhibition
Study Success #1 
= P (log [θ] < 0 | Study Data, 
Prior(θ)) ≥ 80%.
θ = PET1VT/Pre-doseVT and
% Inhibition = (1-PET1VT/Pre-
doseVT)*100
Sample Size Re-
estimation
Include up to 10 active 
additional subjects and 
with each additional 
subject evaluate Study 
Success Rule #2. If this 
rule is not met with 10
additional subjects then 
NO-GO, else Recruit 2nd
Cohort.   
Study Success Rule #1
= P (log [θ] < 0 | Study Data, 
Prior(θ)) ≥ 80%
θ = PET1VT/Pre-doseVT


CONFIDENTIAL
204715
35
12.1.5.4.
Figure Illustrating Study Decision Making Used at Interim Analysis
12.2.
Model Checking and Diagnostics for Statistical Analyses
12.2.1.
General Considerations for Bayesian Analysis

The following points are for guidance and illustration only and do not guarantee a 
successful model convergence. They cannot cover all eventualities and do not remove 
the requirement to do what is best for the specific set of observed data being 
modelled.

Unless otherwise stated, data collected at screening and at unscheduled time points 
will not be included in the statistical analyses, i.e., only planned/scheduled post-
screening data will be included except where screening data is used as baseline. 

All credible intervals reported will be 95% HPD intervals, unless otherwise specified.

After Markov Chain Monte Carlo (MCMC) for Bayesian inference, estimated and 
monitored model parameters (variance components and fixed effects) were compared 
to corresponding estimated parameters from the linear mixed model. Confidence was 
gained if results were similar. Different initial values for fixed effects (but not 


CONFIDENTIAL
204715
36
variance components) were used to assess convergence. Convergence for all the 
parameters in the model needs to be verified

A separate seed for each MCMC chain will be set to ensure reproducibility.
12.2.1.1.
Prior Distributions
Unless otherwise specified, the following will be the default approach to selecting prior 
distributions:

Non-informative priors of the form Normal (0, Var=1E6) will be assigned to each 
fixed-effect parameter in the proposed statistical model.

For repeated measures models, non-informative Inverse-Wishart priors of the 
form IW (υ, Σ) will be assigned for the Variance-Covariance (VC) matrix 
associated with the repeated measures timepoints. The parameter υ represents the 
dimension of VC (number of rows or columns) and the matrix Σ is an identity 
matrix of the same dimension as VC. The unstructured variance covariance 
structure for the repeated measurements will be assumed. In cases of non-
convergence, the Toeplitz structure will be used.
o
If there are issues with these distribution parameters, then Σ may be a 
diagonal matrix that uses best guesses for the residual variance at each 
repeated measure timepoint (or the residual estimate from fitting simple 
models). This only needs to be of the correct order of magnitude.

Non-informative inverse-gamma priors of the form IG(a=2.001, b=0.001) will be 
used for scale parameters (variances). If these parameters do not lead to 
convergence, then choose “a” small and “b” smaller than the expected standard 
deviation.   
It is good practice to ensure that each prior distribution is visualized to ensure it appears 
sensible, i.e., that it allows parameter values that generate clinically plausible response 
values and that it is truly non-informative over the region of the likelihood function 
where the data lies.
Note: 

The Gamma(a,b) density function takes the form
The mean is a/b and the variance is a/b2.

The IG(a,b) density function takes the form


CONFIDENTIAL
204715
37
The mode is b/(a+1), the mean is b/(a-1), if a>1, and the variance is b2/[(a-1)2(a-
2)], if a>2.

There is no requirement to formally report the prior visualisation outputs.
12.2.1.2.
Initial Values
The two MCMC chains should be generated using over-dispersed initial values. To 
achieve this the sample standard deviation of the change from baseline in log(response), 
SD_hat, should be estimated. The two over-dispersed initial values for the parameters 
(ResponsebyVisit) should then be sampled from the following normal distribution N(0, 
SD = 10*SD_hat).
For the remaining model parameters over-dispersed initial values may be drawn at 
random from their respected prior distribution.  If convergence of the Markov chain 
Monte Carlo (MCMC) algorithm is problematic then alternative estimates may be used 
(for example, these could be based on maximum likelihood estimates).
12.2.1.3.
Convergence Diagnostics
To be able to perform Bayesian inference using MCMC simulations the posterior samples 
for all the parameters in the model need to be obtained from the corresponding target 
posterior distribution. To ensure that this is the case the following is a list of convergence 
diagnostics that can be applied for each parameter:
Comparing MCSE vs. posterior standard deviation:

The Monte Carlo Standard Errors (MCSE) should be compared with the standard 
deviation of the posterior distribution (SD) to ensure that only a fraction of the 
posterior variability is due to the simulation, i.e., the ratio MCSE/SD should be as 
small as possible, typically < 0.01.  

Adequate values for the number of MCMC samples / thinning / number of burn-in 
samples should be chosen to ensure that the ratio MCSE/SD for all the parameters 
in the model is < 0.01. 

In addition, if possible, the number of tuning units and maximum number of 
tuning iterations may be increased to find a better proposal distribution for the 
model parameters, which in turn may reduce the MCSE/SD ratio.

Where possible the code should be written to allow the SAS compiler to identify 
and make use of conjugacy, since this can greatly reduce the corresponding 
MCSE/SD ratio.

Models selected with MCSE/SD values > 0.01 would need a brief 
remark/justification added to the CSR to clarify why it was not possible to reach 
the target and why it is believed the subsequent model still has utility from an 
inference perspective.


CONFIDENTIAL
204715
38
Gelman & Rubin diagnostics:

The Gelman & Rubin diagnostic assessment will be used to assess convergence of 
the multiple chains.

The Gelman & Rubin diagnostic is based on running multiple Markov chains, say 
m, each with n draws, with the different chains started at initial values that should 
be overdispersed relative to the target posterior distribution. Thus, the m chains 
yield m possible inferences; to answer the question of whether these inferences 
are similar enough to indicate approximate convergence, Gelman, 1992 suggested
comparing these to the inference made by mixing together the m*n draws from all 
the sequences as follows: the pooled variance across the chains is compared to the 
overall within-chain variance using a ratio, usually called the potential scale 
reduction factor, or
.

Values of 
close to 1 indicate that each of the m sets of n simulated observations 
is close to the target posterior distribution.

Although PROC MCMC in SAS does not provide the Gelman & Rubin , SAS 
has provided a macro, %gelman, for determining the statistic (note that for this to 
work at least two MCMC chains need to be generated, which means that PROC 
MCMC needs to be call as many times as the number of chains, with the different 
starting values). 
Diagnostic plots and visual inspection:

Trace plots of samples versus the simulation index can be used to assess some 
aspects of convergence. The centre of the chain should appear stable with very 
small fluctuations, i.e., the distribution of points should not change as the chain 
progresses and the posterior mean and variance are relatively constant.

Autocorrelation plots provide information on how slow or fast the Markov chain 
converges. If the autocorrelation does not decrease rapidly this means that the 
chain needs to be run for longer to achieve convergence.

Examination of correlation structures between relevant posterior parameters 
should be used to provide information about what potential issues may be and 
also what corrective action(s) may be worthwhile attempting.
Convergence for all the parameters in the model needs to be verified (apart from subject-
specific random effects).
12.2.2.
General Considerations for All Analyses
Model assumptions will be applied, but appropriate adjustments may be made based on 
the data. If there are any departures from the distributional assumptions, alternative 
models will be explored using appropriate transformed data.


CONFIDENTIAL
204715
39
Distributional assumptions underlying the model used for analysis will be examined 
through graphical approaches by assessing the distribution of the residuals against the 
assumed distribution of the response, and by assessing the distribution of the residuals 
against the fitted response values.
Outputs of the residual plots as a check of the normality assumptions of the log(response) 
will be produced.


CONFIDENTIAL
204715
40
13.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
Pharmacodynamic and PK-time data may be used to derive population PKPD 
parameters/models using NONMEM or other currently validated software.  The timeline 
for this analysis and reporting will be independent of the analysis described in this RAP.
In an event that GSK3008348 is terminated before these analyses are conducted, they will 
not be reported.


CONFIDENTIAL
204715
41
14.
REFERENCES
1. GlaxoSmithKline Document No.: 2016N291965_02: A study of single doses to 
evaluate the safety, tolerability, pharmacokinetics and target engagement of 
nebulised GSK3008348 in idiopathic pulmonary fibrosis patients, using positron 
emission tomography (PET) imaging. Effective date: 24-JAN-2018.
2. Gelman, A. and Rubin, D.B. (1992) Inference from Iterative Simulation Using 
Multiple Sequences. Statistical Science, 7, 457-472.


CONFIDENTIAL
204715
42
15.
APPENDICES
15.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
15.1.1.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population.
Number
Protocol Deviation
Full, Case by Case and Partial 
Exclusion [1]
01
Inclusion # 2 – Did not have correct 
diagnosis of definite or probable IPF
Full
02
Inclusion # 4 – Did not have qualifying 
lung function severity (Subjects who do not 
have FVC > 50 % predicted and DLCO > 
40 % predicted).
Full
03
Exclusion # 7 - Forced expiratory volume 
in 1 second (FEV1)/forced vital capacity 
(FVC)
ratio < 0.70 at screening (post-
bronchodilator).
Full
04
PET scan at 30 mins post-dose non-
evaluable 
Full
05
Visit outside of protocol defined window
Case by case
06
Exclusion # 4 – Current IPF exacerbation 
or upper or lower respiratory tract infection 
on admission to the clinical unit.
Partial
07
Exclusion # 10 - Subjects who are currently 
taking Pirfenidone or Nintedanib or who 
have received Pirfenidone or Nintedanib 
within the 30 days prior to the first dosing 
day will be excluded from the study.
Partial
NOTES:
[1] Partial exclusions refer to patients for whom data will be excluded from the Per-Protocol population only 
from the study day at which the deviation takes place onwards. Full exclusions refer to patients for whom 
all the available data will be excluded from the Per-Protocol population. Other protocol deviations not 
listed in this section will be assessed on a case by case basis.


CONFIDENTIAL
204715
43
15.2.
Appendix 2: Schedule of Activities
15.2.1.
Protocol Defined Schedule of Events


CONFIDENTIAL
204715
44


CONFIDENTIAL
204715
45
15.3.
Appendix 3: Assessment Windows
15.3.1.
Definitions of Assessment Windows for Analyses
Analysis Set 
/ Domain
Parameter (if 
applicable)
Target 
timepoin
t
Analysis time deviation 
Window
Analysis 
Timepoint
Earliest
Timepoint
Latest 
Timepoint
ITT/PP
VT
30 mins
20 mins
60 mins
Day 1
ITT/PP
SUV
30 mins
20 mins
60 mins
Day 1
ITT/PP
VT
24 hours
14 hours
28 hours
Day 2
ITT/PP
SUV
24 hours
14 hours
28 hours
Day 2


CONFIDENTIAL
204715
46
15.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
15.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 1
Post-
Treatment
Date > Study Treatment Stop Date + 1
15.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 7 days prior to 
screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: 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.


CONFIDENTIAL
204715
47
15.4.2.
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. 

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop 
Date +1

For studies with greater than one treatment period (e.g., Period 1 
and Period 2), 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 + 1
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.


CONFIDENTIAL
204715
48
15.4.3.
Categorisation of adverse events into Dosing Periods
AEs will be categorised into 4 groups (Dosing Period 1, Dosing Period 1 follow up, 
Dosing Period 2 and Dosing Period 2 follow up) as shown in table below. AEs are 
assigned up to 72 hours for the dosing periods as GSK3008348 will be expected to have 
cleared the systemic circulation by 72 hours [GSK3008348 has a half-life of 8-10 hours
and so 72 hours >5 half-lives]. Any AEs prior to dosing will be listed as screening AEs 
and will not be summarised.
Dosing Period 1 
Start of first dose GSK3008348 to 72 hrs 
post start of dose
Dosing Period 1 Follow up (which will 
include washout and baseline scan)
72 hours post start of first dose of 
GSK3008348 (Period 1) to start of second 
dose of GSK3008348 (Period 2), or end of 
study follow up for subjects that were 
withdrawn before dosing period 2
Dosing Period 2
Start of second dose GSK3008348 to 72 hrs 
post start of second dose
Dosing Period 2 Follow up
72 hours post start of second dose of 
GSK3008348 (Period 2) to end of follow 
up for the study. 


CONFIDENTIAL
204715
49
15.5.
Appendix 5: Data Display Standards & Handling 
Conventions
All displays (Tables, Figures & Listings) will use the term 'Subjects'. However, RAP text 
will refer to "Participants" in-line with the master RAP template and protocol.
15.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area 
Interim
:\arprod\gsk3008348\mid204715\internal_01
HARP Area Dry-
run
:\arprod\gsk3008348\mid204715\data_look_01
HARP Area SAC
:\arprod\gsk3008348\mid204715\final_01
QC Spreadsheet
: \arwork\gsk3008348\mid204715\ internal_01\Documents
QC Spreadsheet
: \arwork\gsk3008348\mid204715\final_01\Documents
QC Spreadsheet
:\arwork\gsk3008348\mid204715\data_look_01\documents
Analysis Datasets 

Analysis datasets were created according to Legacy GSK A&R dataset standards 
(IDSL) for the interim analyses in Cohort 1. The same standards will be used for the 
final analyses.
Generation of RTF Files

RTF files were generated for tables and figures for the IA. In addition, pdf files of the 
plots were generated at IA. Similarly, RTF files for tables and pdf files of the plots 
will be generated at Statistical Analysis Complete (SAC) reporting effort.
15.5.2.
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 in the modular appendices as ICH or non-
ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be 
adopted for reporting of data based on the raw data collected, unless otherwise stated.


CONFIDENTIAL
204715
50

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
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 Principals 7.01 to 7.13.
15.5.3.
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 Standards for the Transfer and Reporting of PK 
Data using HARP.
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. 
NONMEM/Pop 
PK File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical 
Pharmacology Modelling and Simulation function maybe created if 
appropriate.  The data specification and timeline for creation of this 
file will be independent of the analysis described in this RAP. In an 
event that GSK3008348 is terminated before these analyses are 
conducted, this file will not be created.
NONMEM/PK/PD 
File
PK/PD file (CSV format) for the PK/PD analysis by Clinical 
Pharmacology Modelling and Simulation function maybe created, if 


CONFIDENTIAL
204715
51
appropriate. The data specification and timeline for creation of this 
file will be independent of the analysis described in this RAP. In an 
event that GSK3008348 is terminated before these analyses are 
conducted, this file will not be created.
Pharmacokinetic Parameter Derivation
PK Parameter to 
be Derived by 
Programmer
AUC(0-t)/D, AUC(0-inf)/D and Cmax/D
Pharmacokinetic Parameter Data
Is NQ impacted 
PK Parameters 
Rule Being 
Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters.
Descriptive 
Summary 
Statistics, 
Graphical 
Displays and 
Listings
Refer to IDSL PK Display Standards.


CONFIDENTIAL
204715
52
15.6.
Appendix 6: Derived and Transformed Data
15.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.

If there are two values within a time window (as per Section 15.3.1) the value closest 
to the target day for that window will be used. If values are the same distance from 
the target, then the mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-
baseline visit for safety parameters will be counted in both the High and Low 
categories of “Any visit post-baseline” row of related summary tables. This will also 
be applicable to relevant Potential Clinical Importance summary tables.
Study Day

Calculated as the number of days from First Dose Date within a treatment period:
o
Ref Date = Missing              → Study Day = Missing 
o
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date
o
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
15.6.2.
Safety
ECG Parameters
RR Interval

ECGs are machine read, the RR value preceding the measurement QT interval was 
only collected during Imanova visits. Missing RR interval (msec) will not be derived.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) 
and Fridericia’s (QTcF) formulas will be calculated, in msec, depending on the 
availability of other measurements.

If RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 


CONFIDENTIAL
204715
53
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 or replaced with a character value starting with '<x' or '>x' (or 
indicated as less than x or greater than x in the comment field), 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.    

If there is more than one value of a particular parameter for a subject for a visit, the 
scheduled value will be used in summary statistics; all values will be listed.  
15.6.3.
Pharmacokinetic
Dose-Normalised Parameters
AUC(0-t), AUC(0-inf) and Cmax

Derived as: PK parameter/ Inhaled dose (mg)
15.6.4.
Pharmacodynamic 
The VT and SUV are already derived. These endpoints will be further natural log-
transformed. 


CONFIDENTIAL
204715
54
15.7.
Appendix 7: Reporting Standards for Missing Data
15.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion is defined as a subject having reached Last 
Subject Last Visit (LSLV) at the end of Dosing Period 2 in Cohort 1.

Withdrawn subjects will be replaced in the study if they withdraw 
before successful completion of the 30mins PET scan in Dosing 
Period 2 of Cohort 1.

All available data from participants who were withdrawn from the 
study will be listed and all available planned data will be included in 
summary tables and figures, unless otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment 
Windows or will be summarised as withdrawal visits.
15.7.2.
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 using 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.
PK

Adjustments to the derivation of PK parameters where NQ values are 
present in the data will be performed according to how extensive the NQ 
values are and which treatment groups the NQ’s are present in. Refer to 
the Standards for the Handling of NQ impacted PK Parameters 
documentation.
PET

Missing PET measurements will not be imputed.
15.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month 
and year) to be recorded for AE start and end dates; that is, the day of 
the month may be missing. In such a case, the following conventions 
will be applied for calculating the time to onset and the duration of 
the event:
o
Missing Start Day: First of the month will be used unless this 


CONFIDENTIAL
204715
55
Element
Reporting Detail
is before the start date of study treatment; in this case the 
study treatment start date will be used and hence the event is 
considered On-treatment as per Appendix 4: 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 
study treatment stop date will be used.

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.
15.7.2.2.
Handling of Missing Data for Statistical Analysis
For statistical analysis purposes, data will be assumed to be Missing at Random (MAR)
and no imputation will be conducted.


CONFIDENTIAL
204715
56
15.8.
Appendix 8: Values of Potential Clinical Importance
15.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Categor
y
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from 
BL
↓0.075
Haemoglobin 
g/L
Male
180
Female
180
∆from 
BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count 
(WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< 
x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
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
+


CONFIDENTIAL
204715
57
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
U/L
2x ULN ALT
15.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
>450
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline 
QTc
msec
>60
15.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 40
≥ 40
Diastolic Blood Pressure
mmHg
≥ 20
≥ 20
Heart Rate
bpm
≥ 30
≥ 20


CONFIDENTIAL
204715
58
15.9.
Appendix 11: Abbreviations & Trade Marks
15.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the plasma drug concentration versus 
time curve
AUC(0-t)
Area under the plasma concentration-time curve 
from zero (0) hours to time (t)
AUC (0-inf)
Area under the plasma concentration-time curve 
from zero (0) hours (to infinity (inf)
BMI
Body mass index
BQL
Below the quantification limit
CDISC
Clinical Data Interchange Standards Consortium
Cmax
Maximum observed plasma drug concentration 
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CPSR
Clinical Pharmacology Study Report
CPSSO
Clinical Pharmacology Science and Study 
Operations
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
D
Dose
DM
Data Management
DLCO
Diffusing Capacity of the Lungs for Carbon 
Monoxide
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results 
Disclosure Requirements
FEV1
Forced Expiratory Volume in 1 second


CONFIDENTIAL
204715
59
Abbreviation
Description
FVC
Forced Vital Capacity
GCSP
Global Clinical Safety & Pharmacovigilance
GSK
GlaxoSmithKline
µg
Microgram
HPD
Highest Posterior Density 
HR
Heart rate
HRCT
High Resolution Computerised Tomography
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
IPF
Idiopathic Pulmonary Fibrosis
ITT
Intent-To-Treat
z
Terminal phase rate constant
LLQ
Lower limit of quantification
LSLV
Last Subject Last Visit
MCMC
Markov Chain Monte Carlo
MMRM
Mixed Model Repeated Measures
MCSE
Monte Carlo Standard Errors 
msec
Milliseconds
mcg
Microgram
microRNA
Micro Ribonucleic acid
mRNA
Messenger Ribonucleic acid
NONMEM
Nonlinear Mixed Effects Modelling
NQ
Non-quantifiable concentration measured as 
below LLQ
PCI
Potential Clinical Importance 
PCPS
Projects Clinical Platforms and Sciences
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PET
Positron Emission Tomography
PK
Pharmacokinetic
PKPD
Pharmacokinetic Pharmacodynamic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Fridericia’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RandAll NG
RandAll New Generation
RAP
Reporting & Analysis Plan
RAMOS
Randomisation & Medication Ordering System 
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event


CONFIDENTIAL
204715
60
Abbreviation
Description
SAS
Statistical Analysis Software
SI
System Independent 
SD
Standard deviation
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SDTM IG
Standard Data Tabulation Model Implementation 
Guide
SOA
Schedule of Activities
SOP
Standard Operation Procedure
SUV
Standardised Uptake Values 
T
Infusion duration
TA
Therapeutic Area
TAU
Therapeutic Area Unit
TFL
Tables, Figures & Listings 
t OR tlast 
Time of last observed quantifiable concentration
t½
Terminal phase half-life
τ
Dosing interval
tlag
Lag time before observation of drug 
concentrations in sampled matrix
Tmax
Time of occurrence of Cmax
ULQ
Upper limit of quantification 
ULN
Upper limit of normal
UK
United Kingdom
VC
Variance-Covariance 
VS
Vital Signs
VT
Volume of distribution 
WBC
While Blood Cell Count 
15.9.2.
Trademarks
Trademarks 
of 
the 
GlaxoSmithKline 
Group 
of 
Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
SAS
WinNonlin


CONFIDENTIAL
204715
61
15.10.
Appendix 12: List of Data Displays
15.10.1.
Data Display Numbering
All data displays will combine Dosing Period 1 and Dosing Period 2 unless this has been 
explicitly described otherwise or the actual data display requires Dosing Period 1 and 
Dosing Period 2 as separate rows. For the interim analyses subject randomisation 
numbers were scrambled when individual data was shown while for the final analyses 
after breaking study blind actual randomisation numbers will be shown
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.16
N/A
Safety
  2.1 to 2.12
2.1 to 2.4
Pharmacodynamic
3.1 to 3.8
3.1 to 3.8
Pharmacokinetic
4.1 to 4.3
4.1 to 4.4
Section
Listings
ICH Listings
1 to 29
Other Listings
30 to 41
15.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacodynamic 
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming 
Notes’ column as ‘[Non-Standard] + Reference.’
15.10.3.
Deliverables
Delivery [Priority] [1]
Description
IA SAC
Interim Analysis Statistical Analysis Complete
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


CONFIDENTIAL
204715
62
15.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ITT
ES1
Summary of Participant Disposition for the 
Participant Conclusion Record
ICH E3, FDAAA, EudraCT
SAC 
1.2.
ITT
SD1
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment
ICH E3
SAC 
1.3.
ITT
ES4
Summary of Participant Disposition at Each Study 
Epoch
ICH E3
SAC
1.4.
All 
Participants
ES6
Summary of Screening Status and Reasons for 
Screen Failure
Journal Requirements
SAC
1.5.
Enrolled
NS1
Summary of Number of Participants by Country and 
Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.6.
All 
Participants
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Population Analysed
1.7.
All 
Participants
SP1
Summary of Study Populations 
IDSL
SAC


CONFIDENTIAL
204715
63
Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
All 
Participants
SP2
Summary of Exclusions from the Per Protocol
Population
IDSL
SAC
Demographic and Baseline Characteristics
1.9.
PP
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC 
1.10.
PP
DM11
Summary of Age Ranges
EudraCT
SAC 
1.11.
PP
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, 
EudraCT
SAC
1.12.
ITT
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC 
1.13.
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC 
1.14.
Enrolled
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, 
EudraCT
SAC
Prior and Concomitant Medications
1.15.
ITT
MH1 
Summary of Current/Past Medical Conditions
ICH E3 
SAC
1.16.
ITT
CM1
Summary of Concomitant Medications
ICH E3
SAC


CONFIDENTIAL
204715
64
15.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
ITT
AE1 
Summary of All Adverse Events by System 
Organ Class and Preferred Term
ICH E3, Overall and by 
Dosing period (Dosing Period 
1, Dosing Period 1 follow up, 
Dosing Period 2 and Dosing 
Period 2 follow up)
SAC 
2.2.
ITT
AE1            Summary All Drug-Related Adverse Events 
by System Organ Class and Preferred Term
ICH E3, Overall and by 
Dosing period (Dosing Period 
1, Dosing Period 1 follow up, 
Dosing Period 2 and Dosing 
Period 2 follow up)
As 2.1 notes
SAC
Laboratory: Chemistry 


CONFIDENTIAL
204715
65
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
ITT
LB1
Summary of Chemistry Changes from 
Baseline 
ICH E3, By treatment and by 
Dosing period (Period 1, 
Period 2)
Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
SAC
Laboratory: Hematology
2.4.
ITT
LB1
Summary of Hematology Changes from 
Baseline
ICH E3, By treatment and by 
Dosing period (Period 1, 
Period 2)
Includes baseline values.
SAC
Laboratory: Urinalysis
2.5.
ITT
UR3b
Summary of Urinalysis Dipstick Results by 
Planned Timepoint
ICH E3, By treatment and by 
Dosing period (Period 1, 
Period 2)
Includes Baseline values.
SAC
ECG


CONFIDENTIAL
204715
66
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
ITT
EG1
Summary of ECG Findings 
IDSL, By treatment and by 
Dosing period (Period 1, 
Period 2)
As above for Chemistry, using 
ECG findings categories (and 
change from baseline categories, 
if applicable).
SAC
2.7.
ITT
EG2
Summary of Change from Baseline in ECG 
Values by Visit
IDSL, By treatment and by 
Dosing period (Period 1, 
Period 2)
Includes Baseline values.
SAC


CONFIDENTIAL
204715
67
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
2.8.
ITT
VS1
Summary of Change from Baseline in Vital 
Signs
ICH E3, By treatment and by 
Dosing period (Period 1, 
Period 2)
Includes Baseline values.
SAC
Lung Function Tests: (FEV1, % Predicted FEV1, FVC and % Predicted FVC)
2.9.
ITT
PFT1
Summary of Pulmonary Function Test Data
Absolute and % Predicted, by
Visit
SAC
2.10.
ITT
PFT3
Summary of Change from Baseline 
Pulmonary Function Test Data
Absolute and % Predicted, by
Visit
SAC
Diffusing capacity of the lungs for carbon monoxide (DLCO) and % Predicted DLCO
2.11.
ITT
PFT1
Summary of Diffusing Capacity of the 
Lungs for Carbon Monoxide (DLCO).
Absolute and % Predicted, by
Visit 
SAC
2.12.
ITT
PFT3
Summary of Change from Baseline
Diffusing Capacity of the Lungs for Carbon 
Monoxide (DLCO).
Absolute and % Predicted,
SAC


CONFIDENTIAL
204715
68
15.10.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Lung Function Tests (FEV1, % Predicted FEV1, FVC and % Predicted FVC)
2.1.
ITT
PK16a
Individual Patient Profiles 
of Pulmonary Function Test 
Data
Longitudinal patient profile (y axis is the response and 
x axis the Visit). All patients in the same plot. Linear 
Plot only.
By endpoint and Dosing Period, add separate colours 
for GSK3008348 1000mcg or Placebo. 
SAC
2.2.
ITT
PK16a
Individual Patient Profiles 
of Change from Baseline
Pulmonary Function Test 
Data
Longitudinal patient profile (y axis is the response and 
x axis the Visit). All patients in the same plot. Linear 
Plot only.
By endpoint and Dosing Period, add separate colours 
for GSK3008348 1000mcg or Placebo. 
SAC
Diffusing capacity of the lungs for carbon monoxide (DLCO) and % Predicted DLCO
2.3.
ITT
PK16a
Individual Patient Profiles 
of Diffusing Capacity of the 
Lungs for Carbon Monoxide 
(DLCO),
Longitudinal patient profile (y axis is the response and 
x axis the Visit). All patients in the same plot. Linear 
Plot only.
By endpoint and Dosing Period, add separate colours 
for GSK3008348 1000mcg or Placebo. 
SAC


CONFIDENTIAL
204715
69
Safety: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.4.
ITT
PK16a
Individual Patient Profiles 
of Change from Baseline 
Diffusing Capacity of the 
Lungs for Carbon Monoxide 
Changes from Baseline 
(DLCO)
Longitudinal patient profile (y axis is the response and 
x axis the Visit). All patients in the same plot. Linear 
Plot only.
By endpoint and Dosing Period, add separate colours 
for GSK3008348 1000mcg or Placebo. 
SAC


CONFIDENTIAL
204715
70
15.10.7.
Pharmacodynamic Tables
Pharmacodynamic Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Volume of Distribution (VT, mL/cm^3)
3.1.
PP
Non-
Standard
PD_T1
Summary of Volume of Distribution (VT, mL/cm^3) of 
[18F]-FBA-A20FMDV2 not Corrected for Air Volume.
Summary statistics by 
visit
IA SAC, 
SAC
3.2.
PP
Non-
Standard
PD_T2
Summary of Volume of Distribution (VT, mL/cm^3) of 
[18F]-FBA-A20FMDV2 Corrected for Air Volume. 
Summary statistics by 
visit
SAC
3.3.
PP
Non-
Standard
PD_T3
Summary of Statistical Analysis of Volume of 
Distribution (VT, mL/cm^3) of [18F]-FBA-A20FMDV2 
not Corrected for Air Volume (Cohort 1, GSK3008348 
1000mcg).
Excludes placebo 
group
Footnote table with 
details of the model, 
covariates and priors, 
etc. 
IA SAC, 
SAC


CONFIDENTIAL
204715
71
Pharmacodynamic Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4.
PP
Non-
Standard
PD_T4
Summary of Statistical Analysis of Volume of 
Distribution (VT, mL/cm^3) of [18F]-FBA-A20FMDV2 
Corrected for Air Volume (Cohort 1, GSK3008348 
1000mcg).
Excludes placebo 
group
Footnote table with 
‘The covariates: sex, 
age, baseline % 
predicted FVC and 
baseline % predicted 
DLCO were 
independently
considered in the 
model but all were 
removed because the 
HPD CrI includes 0.
SAC


CONFIDENTIAL
204715
72
Pharmacodynamic Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Standardised Uptake Values (SUV, g/mL)
3.5.
PP
Non-
Standard
PD_T1
Summary of Standardised Uptake Values (SUV, g/mL) of 
[18F]-FBA-A20FMDV2 not Corrected for Air Volume.
Summary statistics by 
visit
SAC
3.6.
PP
Non-
Standard
PD_T2
Summary of Standardised Uptake Values (SUV, g/mL) of 
[18F]-FBA-A20FMDV2 Corrected for Air Volume.
Summary statistics by 
visit
SAC
3.7.
PP
Non-
Standard
PD_T3
Summary of Statistical Analysis for Standardised Uptake 
Values (SUV, g/mL) of [18F]-FBA-A20FMDV2 not 
Corrected for Air Volume (Cohort 1, GSK3008348 
1000mcg).
Excludes placebo 
group
Footnote table with; 
‘The covariates: sex, 
age, baseline % 
predicted FVC and 
baseline % predicted 
DLCO were 
independently
considered in the 
model but all were 
removed because the 
HPD CrI includes 0.
SAC


CONFIDENTIAL
204715
73
Pharmacodynamic Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.8.
PP
Non-
Standard
PD_T4
Summary of Statistical Analysis for Standardised Uptake 
Values (SUV, g/mL) of [18F]-FBA-A20FMDV2 
Corrected for Air Volume (Cohort 1, GSK3008348 
1000mcg).
Excludes placebo 
group
Footnote table with; 
‘The covariates: sex, 
age, baseline % 
predicted FVC and 
baseline % predicted 
DLCO were 
independently
considered in the 
model but all were 
removed because the 
HPD CrI includes 0.
SAC


CONFIDENTIAL
204715
74
15.10.8.
Pharmacodynamic Figures
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Volume of Distribution (VT, mL/cm^3)
3.1
PP
Non-
Standard
PD_F1
Plot of Unadjusted Geometric Means 
(95% CI) of Volume of Distribution (VT, 
mL/cm^3) of [18F]-FBA-A20FMDV2 
not Corrected for Air Volume.
Plot for GSK3008348 1000mcg arm only 
with raw data superimposed. Also add raw 
placebo data in different colour on the 
same graph. Placebo subject’s data should 
be jittered on the x axis and with a 
different symbol.   Individual subject 
numbers were scrambled at interim 
analysis only, so treatment allocation was 
not obvious but after unblinding they will 
be unscrambled for final analyses + the 
interim outputs.
Add footnote: 
1. Note: Pre-dose = Baseline PET, PET1= 
20-60 mins and PET2= 14-28 hrs PET
2. Unadjusted Geometric Means (95% CI) 
from GSK3008348 1000mcg arm only.  
IA SAC, 
SAC


CONFIDENTIAL
204715
75
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.2
PP
Non-
Standard
PD_F2
Plot of Adjusted Medians and Adjusted 
Median Ratios of Volume of 
Distribution (VT, mL/cm^3) of [18F]-
FBA-A20FMDV2 not Corrected for Air 
Volume.
Add different colours for GSK3008348 
1000mcg and placebo patients.   Individual 
subject numbers were scrambled at interim 
analysis only, so treatment allocation was 
not obvious but after unblinding they will 
be unscrambled for final analyses + the 
interim outputs.
Add footnote: 
1. Note: Pre-dose = Baseline PET, PET1= 
20-60 mins and PET2= 14-28 hrs PET
2. Unadjusted Geometric Means (95% CI) 
from GSK3008348 1000mcg arm only.  
Footnote added: ‘The covariates: sex, age, 
baseline % predicted FVC and baseline % 
predicted DLCO were independently
considered in the model but all were 
removed because the HPD CrI includes 0’.
IA SAC, 
SAC


CONFIDENTIAL
204715
76
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.3
PP
Non-
Standard
PD_F3
Plot of Unadjusted Geometric Means 
(95% CI) of Volume of Distribution 
(VT, mL/cm^3) of [18F]-FBA-
A20FMDV2 Corrected for Air Volume.
Plot for GSK3008348 1000mcg arm only 
with raw data superimposed. Also add raw 
placebo data in different colour on the 
same graph.  Placebo subject’s data should 
be jittered on the x axis and with a 
different symbol. Individual subject 
numbers were scrambled at interim 
analysis only, so treatment allocation was 
not obvious but after unblinding they will 
be unscrambled for final analyses + the 
interim outputs.
Add footnote: 
1. Note: Pre-dose = Baseline PET, PET1= 
20-60 mins and PET2= 14-28 hrs PET
2. Unadjusted Geometric Means (95% CI) 
from GSK3008348 1000mcg arm only.  
SAC


CONFIDENTIAL
204715
77
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.4
PP
Non-
Standard
PD_F4
Plot of Adjusted Medians and Adjusted 
Median Ratios of Volume of 
Distribution (VT, mL/cm^3) of [18F]-
FBA-A20FMDV2 Corrected for Air 
Volume.
Add different colours for GSK3008348 
1000mcg and placebo patients.  Placebo 
subject’s data should be jittered on the x 
axis and with a different symbol.
Individual subject numbers were 
scrambled at interim analysis only, so 
treatment allocation was not obvious but 
after unblinding they will be unscrambled 
for final analyses + the interim outputs.
Add footnote: 
1. Note: Pre-dose = Baseline PET, PET1= 
20-60 mins and PET2= 14-28 hrs PET
2. Unadjusted Geometric Means (95% CI) 
from GSK3008348 1000mcg arm only.  
Add footnote: ‘The covariates: sex, age, 
baseline % predicted FVC and baseline % 
predicted DLCO were independently
considered in the model but all were 
removed because the HPD CrI includes 0’.
SAC


CONFIDENTIAL
204715
78
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Standardised Uptake Values (SUV, g/mL)
3.5
PP
Non-
Standard
PD_F1
Plot of Unadjusted Geometric Means 
(95% CI) of Standardised Uptake 
Values (SUV, g/mL) of [18F]-FBA-
A20FMDV2 not Corrected for Air 
Volume.
Plot for GSK3008348 1000mcg arm only 
with raw data superimposed. Also add raw 
placebo data in different colour on the 
same graph.  Placebo subject’s data should 
be jittered on the x axis and with a 
different symbol. Individual subject 
numbers were scrambled at interim 
analysis only, so treatment allocation was 
not obvious but after unblinding they will 
be unscrambled for final analyses + the 
interim outputs.
Add footnote: 
1. Note: Pre-dose = Baseline PET, PET1= 
20-60 mins and PET2= 14-28 hrs PET
2. Unadjusted Geometric Means (95% CI) 
from GSK3008348 1000mcg arm only.  
SAC


CONFIDENTIAL
204715
79
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6
PP
Non-
Standard
PD_F2
Plot of Adjusted Medians and Adjusted 
Median Ratios of Standardised Uptake 
Values (SUV, g/mL) of [18F]-FBA-
A20FMDV2 not Corrected for Air 
Volume.
Add different colours for GSK3008348 
1000mcg and placebo patients
Add footnote: ‘The covariates: sex, age, 
baseline % predicted FVC and baseline % 
predicted DLCO were independently
considered in the model but all were 
removed because the HPD CrI includes 0’.
SAC
3.7
PP
Non-
Standard
PD_F3
Plots of Unadjusted Geometric Means 
(95% CI) of Standardised Uptake 
Values (SUV, g/mL) of [18F]-FBA-
A20FMDV2 Corrected for Air Volume.
Plot for GSK3008348 1000mcg arm only
with raw data superimposed. Also add raw 
placebo data in different colour on the 
same graph.  Placebo subject’s data should 
be jittered on the x axis and with a 
different symbol. Individual subject 
numbers were scrambled at interim 
analysis only, so treatment allocation was 
not obvious but after unblinding they will 
be unscrambled for final analyses + the 
interim outputs.
Add footnote: 
1. Note: Pre-dose = Baseline PET, PET1= 
20-60 mins and PET2= 14-28 hrs PET
2. Unadjusted Geometric Means (95% CI) 
from GSK3008348 1000mcg arm only.  
SAC


CONFIDENTIAL
204715
80
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.8
PP
Non-
Standard
PD_F4
Plot of Adjusted Medians and Adjusted 
Median Ratios of Standardised Uptake 
Values (SUV, g/mL) of [18F]-FBA-
A20FMDV2 Corrected for Air Volume.
Add different colours for GSK3008348 
1000mcg and placebo patients 
Add footnote: ‘The covariates: sex, age, 
baseline % predicted FVC and baseline % 
predicted DLCO were independently
considered in the model but all were 
removed because the HPD CrI includes 0’.
SAC


CONFIDENTIAL
204715
81
15.10.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
4.1.
PK
PK01
Summary of Plasma GSK3008348 Pharmacokinetic 
Concentration-Time Data (µg /mL)
By Dosing Period
SAC
PK Derived Parameters
4.2.
PK
PK03
Summary Statistics of Derived Plasma GSK3008348 
Pharmacokinetic Parameters
Parameters with units, 
By Dosing Period
IA SAC, 
SAC
4.3.
PK
PK05
Summary Statistics of Log-Transformed Derived 
Plasma GSK3008348 Pharmacokinetic Parameters
Parameters with units, 
By Dosing Period
SAC


CONFIDENTIAL
204715
82
15.10.10. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Plots
4.1.
PK
PK16a
Individual GSK3008348 Plasma Concentration-Time 
Plot by Subject (Linear and Semi-Log) 
By Dosing Period, both 
periods are on same plot i.e. 1 
graph per subject with 2 
curves (Period 1 and Period 
2)
SAC
4.2.
PK
PK16a
Individual GSK3008348 Plasma Concentration-Time 
Plot (Linear and Semi-Log) 
By Dosing Period. All 
Subjects on the same plot. 
For interim individual subject 
numbers will be scrambled so 
treatment allocation is not 
obvious
IA SAC, 
SAC
Mean / Median Plots
4.3.
PK
PK17
Mean (+ SD) Plasma GSK3008348 Concentration-
Time Plots (Linear and Semi-log) 
By Dosing Period (Replace 
treatment by Dosing Period 
and the two Dosing Periods 
on same plot).
SAC
4.4.
PK
PK18
Median Plasma GSK3008348 Concentration-Time 
Plots Linear and Semi-log) 
By Dosing Period (Replace 
treatment by Dosing Period 
in the plots)
SAC


CONFIDENTIAL
204715
83
15.10.11. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
All 
Participants
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
ITT
ES2 
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
Required for all studies except 
single dose studies.
SAC
4.
ITT
BL1 
Listing of Participants for Whom the Treatment Blind 
was Broken
ICH E3
Blinded studies only.
SAC 
5.
ITT
TA1 
Listing of Planned and Actual Treatments
IDSL
Note: IDSL shell in 
development.
SAC
Protocol Deviations
6.
All 
Participants
DV2
Listing of Important Protocol Deviations 
ICH E3
Listing also includes analysis 
population exclusions.
SAC
7.
All 
Participants
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC


CONFIDENTIAL
204715
84
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
8.
All 
Participants
SP3
Listing of Participants Excluded from Any Population
ICH E3
e.g., participants screened but 
not randomized, participants 
randomized but not treated, 
participants with deviations 
leading to exclusion from per 
protocol population (can be 
separate listing per population).
SAC
Demographic and Baseline Characteristics
9.
ITT
DM2 
Listing of Demographic Characteristics
ICH E3
SAC
10.
Enrolled
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
11.
ITT
CP_CM3 
Listing of Concomitant Medications
IDSL
Note: IDSL shell in 
development. Required for 
ClinPharm studies instead of a 
corresponding table. Not 
required for studies where a 
table is produced.
SAC
Exposure and Treatment Compliance
12.
ITT
EX3 
Listing of Exposure Data
ICH E3
SAC
Adverse Events
13.
ITT
AE8 
Listing of All Adverse Events
ICH E3
SAC


CONFIDENTIAL
204715
85
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
14.
ITT
AE7
Listing of Subject Numbers for Individual Adverse 
Events
ICH E3
SAC
15.
ITT
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
16.
ITT
AE8 
Listing of Fatal & Non-Fatal Serious Adverse Events
ICH E3
Fatal and Non-Fatal SAEs are 
combined into a single listing.
SAC 
17.
ITT
AE8 
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment
ICH E3
SAC 
Hepatobiliary (Liver)
18.
ITT
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
IDSL
SAC 
19.
ITT
SU2
Listing of Substance Use for Participants with Liver 
Stopping Events
IDSL
SAC
All Laboratory
20.
ITT
LB5 
Listing of All Laboratory Data for Participants with Any 
Value Outside Normal Range
Display ALL labs for a subject 
who experienced a value 
Outside Normal Range.
SAC
21.
ITT
LB5 
Listing of Laboratory Values of Potential Clinical 
Importance
IDSL
SAC
22.
ITT
UR2A
Listing of All Urinalysis Results.
IDSL
SAC


CONFIDENTIAL
204715
86
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
23.
ITT
EG3 
Listing of All ECG Values for Participants with Any 
Value of Potential Clinical Importance
Display ALL ECGs for a subject 
who experienced a value of 
potential clinical importance.
SAC
24.
ITT
EG3 
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
25.
ITT
EG5
Listing of All ECG Findings for Participants with an 
Abnormal ECG Finding
IDSL
SAC
26.
ITT
EG5 
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
27.
ITT
VS4 
Listing of All Vital Signs Data for Participants with Any 
Value of Potential Clinical Importance
Display ALL Vital Signs for a 
subject who experienced a 
value of potential clinical 
importance.
SAC
28.
ITT
VS4 
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
Immunogenicity
29.
ITT
IMM1
Listing of Immunogenicity Results
IDSL
SAC


CONFIDENTIAL
204715
87
15.10.12. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Peripheral capillary oxygen saturation (SpO2)
30.
ITT
Non-Standard
SAFE_L1
Listings of Oxygen Saturation Monitoring (SpO2) 
Results
Sorted by subject id
SAC
Forced Expiratory Volume (FEV1) and Forced Vital Capacity (FVC)
31.
ITT
PFT8
Listings of Pulmonary Function Test Data
Sort by subject id and PFT test
SAC
Diffusing capacity of the lungs for carbon monoxide (DLCO)
32.
ITT
PFT8
Listing of Diffusing Capacity of the Lungs for 
Carbon Monoxide (DLCO)
Sort by subject id 
SAC
Pharmacodynamic
33.
ITT
Non-Standard
SAFE_L2
Listing of [18F]-FBA-A20FMDV2 
Administration
SAC
34.
PP
Non-Standard
SAFE_L3
Listing of All PET Data
Sort by subjid
SAC
35.
ITT
Non-Standard
SAFE_L3
Listing of All PET Data
Sort by subjid. This listing includes the 
extra subject with baseline PET data only 
and was not in the PP in listing 34.
SAC
Pharmacokinetic 
36.
ITT
PK07
Listing of Pharmacokinetic Concentration-Time 
Data.
Sort by subjid
SAC
37.
ITT
PK13
Listing of Derived Pharmacokinetic Parameters.
Sort by subjid
SAC


CONFIDENTIAL
204715
88
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
38.
ITT
Non-Standard
SAFE_L4
Listing of the Final Output of the Statistical 
Analysis of Volume of Distribution (VT, 
mL/cm^3) not Corrected for Air Volume of [18F]-
FBA-A20FMDV2 from the Bayesian Analysis 
Model Using PROC MCMC in SAS Assuming 
Non-Informative Prior Distributions.
A dump of the Proc MCMC plots from the 
final Bayesian analysis model, raw SAS 
outputs
Scans will be labelled as ‘Pre-dose, PET1 
and PET2’
IA SAC, 
SAC
39.
ITT
Non-Standard
SAFE_L4
Listing of the Final Output of the Statistical 
Analysis of Volume of Distribution (VT, 
mL/cm^3) Corrected for Air Volume of [18F]-
FBA-A20FMDV2 from the Bayesian Analysis 
Model Using PROC MCMC in SAS Assuming 
Non-Informative Prior Distributions.
A dump of the Proc MCMC plots from the 
final Bayesian analysis model, raw SAS 
outputs
Sort By endpoint as follows;
Scans will be labelled as ‘Pre-dose, PET1 
and PET2’
SAC
40.
ITT
Non-Standard
SAFE_L4
Listing of the Final Output of the Statistical 
Analysis of Standardised Uptake Values (SUV, 
g/mL) not Corrected for Air Volume of [18F]-
FBA-A20FMDV2 from the Bayesian Analysis 
Model Using PROC MCMC in SAS Assuming 
Non-Informative Prior Distributions.
A dump of the Proc MCMC plots from the 
final Bayesian analysis model, raw SAS 
outputs;
Scans will be labelled as ‘Pre-dose, PET1 
and PET2’
SAC
41.
ITT
Non-Standard
SAFE_L4
Listing of the Final Output of the Statistical 
Analysis of Standardised Uptake Values (SUV, 
g/mL) Corrected for Air Volume of [18F]-FBA-
A20FMDV2 from the Bayesian Analysis Model 
Using PROC MCMC in SAS Assuming Non-
Informative Prior Distributions.
A dump of the Proc MCMC plots from the 
final Bayesian analysis model, raw SAS 
outputs;
Scans will be labelled as ‘Pre-dose, PET1 
and PET2’
SAC


CONFIDENTIAL
204715
89
15.11.
Appendix 13: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request.