Clinical trial NCT03359473
Conditions: Cachexia
Keywords: GSK2881078 COPD muscle weakness post-menopausal selective androgen receptor modulator
Sponsor: GlaxoSmithKline
Start date: 2018-02-28; Completion date: 2019-11-19
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Impaired physical function and muscle dysfunction are a major consequence of COPD, which may be associated with increased mortality, poor quality of life and increased health care use. This is a randomized, placebo-controlled, double-blind, parallel group study to evaluate the safety and tolerability of GSK2881078, an SARM over 13 weeks of dosing in older male subjects and post-menopausal female subjects with COPD and muscle weakness. This study will also assess the effect of GSK2881078 on physical strength and function after 13 weeks of treatment. Approximately 100 subjects with COPD and muscle weakness will be randomized into two cohorts of 50 male subjects and 50 female subjects. Within each cohort, subjects will be randomized to receive GSK2881078 or placebo in a ratio of 1:1. All subjects will participate in a standardized home exercise program, which will consist of daily walking, along with several resistance or weight-bearing exercises, such as bicep curls, upright rows, step ups and a sit-to-stand maneuver. The study will consist of a screening/Baseline period of up to 30 days, a 13-week treatment period and a post-treatment follow-up period of 6 weeks.

Detailed description:

Arms: arm 1: Male subjects between the age of 50 and 75 years will be administered GSK2881078 at a dose of 2 mg once daily by the oral route. arm 2: Male subjects between the age of 50 and 75 years will be administered GSK2881078 matching placebo once daily by the oral route. arm 3: Post-menopausal female subjects between the age of 50 and 75 years will be administered GSK2881078 at a dose of 1 mg once daily by the oral route. arm 4: Post-menopausal female subjects between the age of 50 and 75 years will be administered GSK2881078 matching placebo once daily by the oral route.
Interventions: intervention 1: GSK2881078 intervention 2: Matching Placebo
Intervention descriptions: intervention 1: GSK2881078 will be available as capsules for oral administration. GSK2881078 will be administered once daily by the oral route at a dose of 1 mg and 2mg to post-menopausal female subjects and male subjects, respectively. intervention 2: Subjects will be administered two capsules of GSK2881078 matching placebo once daily by the oral route.

Protocol documents:
Prot_001.pdf: 
2014N209767_03 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
200182 
 
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TITLE PAGE 
Protocol Title: 
A randomized, double-blind (sponsor unblind), placebo-controlled, multi-centred phase 
IIa study to evaluate the safety and efficacy of 13 weeks of once daily oral dosing of the 
selective androgen receptor modulator (SARM) GSK2881078 in older men and post 
menopausal women with COPD and muscle weakness, participating in home exercise 
Protocol Number: 200182 Amendment 3 
Short Title: A randomized, double-blind, placebo-controlled study to evaluate the safety 
and efficacy of 13 weeks of the selective androgen receptor modulator (SARM) 
GSK2881078 in COPD 
Compound Number: GSK2881078  
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information Can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Number(s):  
Investigational New Drug (IND) number 125332, EudraCT 2017-001148-37 
Approval Date: 11-OCT-2017 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3 
11-OCT-2017 
Amendment 2 
22-AUG-2017 
Amendment 1 
19-MAY-2017 
Original Protocol 
24-MAR-2017 
 
 
Amendment 3: 11-OCT-2017 
Overall Rationale for the Amendment: This amendment updates the prohibited 
medication list, based on recent results from a study on drug interactions. It also removes 
inspiratory capacity as an endpoint, as well as peak oxygen uptake measurements, during 
the shuttle walk tests to improve participant comfort during the tests and to help 
standardize the tests across multiple sites. There are additional clarifications for 
timepoints. 
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 1 
Synopsis 
Section 4 
Objectives 
and 
Endpoints 
 
Section 2 
Schedule of 
Activities 
Section 
9.2.1.3 
Inspiratory 
Capacity 
 
Section 
10.3.3 
Removal of “Inspiratory 
capacity” as an endpoint and 
removal of reference to IC or 
Inspiratory Capacity  
Equipment required to take these 
measurements during the shuttle walk 
tests is difficult to standardize across 
multiple sites.  


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Section # 
and Name 
Description of Change 
Brief Rationale 
Other 
analyses 
Section 
9.2.3.2 
Shuttle 
Walk Tests 
Removal of reference to peak 
VO2  
Equipment required to take these 
measurements is difficult to 
standardize across multiple sites. 
Section 2 
Schedule of 
Activities 
Addition of footnotes 7 and 8 to 
specify timepoints for activity 
monitor return, as well as 
scheduling of optional MRI. 
Clarification of timepoints for study 
site staff, as well as change in how exit 
interviews are anticipated to be 
conducted. Exit interviews will now be 
conducted by expert interviewers from 
a partner agency rather than trained 
site staff. 
Section 
9.1.3 
Baseline 
(day 1) and 
last dose 
(day 90) 
visits 
Clarification of language for 
scheduling of MRI scans 
Section 
9.2.4 
Patient 
Reported 
Outcome 
Assessments 
Addition of language to specify 
timepoints when CAT, SGRQ, 
PGRS and PGIC will be 
measured. 
Clarification of how exit 
interview will be conducted 
(administered by experienced 
interviewers (by a partner 
agency) instead of by site staff) 
Section 2 
Schedule of 
Activities 
 
Removal of text: “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 IRB/IEC will be informed 
of any safety issues that require 
alteration of the safety 
monitoring scheme or 
amendment of the ICF.” 
This text is intended for phase I 
studies, therefore removed as per latest 
guidance, since addition of timepoints 
for assessments in phase II studies will 
constitute a protocol amendment. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
Section 5.5 
Dose 
Justification 
 
Adjusted drug half-life from 4-7 
to 5-8 days. 
Revision of text so that it now 
reads: 
“Results of drug interaction 
study in healthy volunteers 
conducted with a prototype 
strong CYP3A4 inhibitor 
(itraconazole) showed that 
exposure to GSK2881078 was 
only modestly elevated when co-
administered with a strong 
CYP3A4 inhibitor (AUC(0-∞) 
increased by 60% while Cmax 
decreased by 21%) compared to 
given alone.  Therefore, 
exposure to GSK2881078 is 
expected to be within the safety 
margin at the proposed dose of 1 
mg in women and 2 mg in men if 
a CYP3A4 inhibitor is co-
administered with 
GSK2881078.” 
Information updated based on recent 
results from drug interaction studies 
that revealed much less interaction 
between CYP3A4 inhibitors and GSK 
2881078 in healthy volunteers than 
previously expected from in-vitro data. 
Therefore, there is no reason to 
prohibit CYP3A4 inhibitors. 
Section 6.2 
Exclusion 
Criteria 
Removal of reference to 
administration of strong oral or 
injectable cytochrome P-450 
isoenzyme 3A4 (CYP3A4) 
inhibitors, and removal of 
criteria pertaining to 
consumption of fruit juices that 
are known CYP3A4 inducers 
(exclusion criteria 8 and 
previously numbered 19) 
Section 
6.3.1 
Meal and 
dietary 
restrictions 
Removal of text that stated 
prohibition of “strong inhibitors” 
of CYP3A4, as well as removal 
of dietary requirements relating 
to these. 
Section 7.7 
Removal of text referring to 


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Section # 
and Name 
Description of Change 
Brief Rationale 
Concomitant 
therapy 
strong inhibitors of CYP3A4 
Reiteration of prohibited 
medications that are listed in 
exclusion criterion 9 (drugs 
known to affect muscle mass) 
Section 6.2 
Exclusion 
Criteria 
Clarification of exclusion criteria 
to specify “pulmonary 
rehabilitation exercise program 
outside of inside the home” 
Clarification of language to convey 
intent that a person participating in a 
formal pulmonary rehabilitation 
program, even if at home, would not 
be eligible for the study. 
Section 
9.2.1 
Removal of reference to 
spirometry being measured at 
follow-up visit 
Error in original protocol; revised 
wording in now consistent with the 
SoA. 
Section 9.4 
Treatment 
of overdose 
Modification of definition of 
treatment overdose to any dose 
“above 1.0mg for females and 
2.0mg for males within a 24-
hour period”  
Error in earlier protocol, which stated 
that any dose above 1.0mg would be 
considered an overdose. 
Section  
9.5.4 
Clinical 
Laboratory 
Safety 
Assessments 
Clarification that local 
laboratory tests conducted 
outside of the protocol that are 
clinically significant should be 
recorded in the “relevant section 
of the CRF, e.g. the SAE form.” 
Clarification that there is not a 
separate CRF page for locally 
recorded results, but that these should 
be captured within the relevant CRF 
form. 
Section 
9.5.5 
MRI scans 
Addition of wording: In 
participants who agree to the 
MRI scans, every effort should 
be made to conduct all 
applicable MRI scans (cardiac 
and liver MRI for female 
participants, and additionally a 
prostate MRI for male 
participants). In circumstances 
where it is not feasible to 
continue performing all the MRI 
scans (e.g. patient discomfort), 
the cardiac scan should be 
prioritized over the liver or 
prostate scans. 
Clarify that cardiac MRI scans should 
be prioritized in case consenting study 
participants and/or site staff deem it 
unfeasible to continue to perform all 
relevant MRI scans in the sub-study 
 


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Amendment 2: 22-AUG-2017 
Overall Rationale for the Amendment: This amendment removes the stair climb test as 
a secondary endpoint in the study, as this test could not be standardized across multiple 
sites. The requirements for vitamin D deficiency as an exclusion criteria have been 
removed in response to study feasibility assessments. In addition, reference to an IDMC 
on page 69, which was included in error.  
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 1 
Synopsis 
Section 4 
Objectives 
and 
Endpoints 
Removal of stair climb from 
endpoints table 
Stair climb test could not be standardized 
for 10 steps across multiple sites 
Section 2 
Schedule of 
Activities 
Stair climb test removed from table 
for schedule of activities 
Section 5.4 
Scientific 
rationale for 
study design 
Text modified to read: 
Incremental and endurance shuttle 
walk test, with reference to stair 
climb deleted 
Section 
9.2.3.3 
Stair climb section deleted 
Section 10 
Section 
10.1.1. 
 
Section 
10.1.3 
Section 
10.3.3 
“Stair climb power” deleted 
throughout main text and table 
column titled “Stair climb power” 
 
Section 1 
Synopsis 
Section 4 
Objectives 
and 
Endpoints 
Removal of the “adherence to 
exercise program” secondary 
endpoint from the table in sections 
1 and 4, and addition of following 
wording in exploratory endpoints in 
section 4:  
“Potentially explore adherence to 
Whilst adherence to the home exercise 
program remains of interest, the home 
exercise program is being piloted in this 
study, therefore the dataset can only be 
explored if it is sufficiently complete. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
exercise program (daily physical 
activity and thrice-weekly 
strengthening exercises)” 
Section 2 
Schedule of 
Activities 
Visits numbered (V1, V2, V3, V4, 
V5, V6, V7, V8 and V9)  
Visit labels added to help ease of reference 
for participants and site staff 
Section 2 
Schedule of 
Activities 
‘x’ removed from cell for Day 90 
visit in the row ‘Study treatment 
provided’ 
Error in original protocol; treatment is not 
provided at the end of treatment visit 
Section 2 
Schedule of 
Activities 
Reference to whole body MRI 
removed and replaced with 
‘Cardiac and liver MRI (additionally 
prostate MRI in males)’ 
The whole body MRI is looking specifically 
at the heart, liver and, in males, the 
prostate therefore the wording was 
amended throughout the protocol for clarity. 
Section 3.3.1 
 
Whole body MRI replaced with 
cardiac MRI 
Section 4 
Objectives 
and 
Endpoints 
“Whole body” deleted from 
description of MRI 
Section 9.1.3 
Baseline (day 
1) and last 
dose (day 90) 
visits 
Text modified to read 
“At some study sites, optional 
cardiac, liver and prostate MRI 
scans will be offered to eligible 
participants.” 
Section 9.5.5 
Whole Body 
MRI scan 
“Whole body” deleted from section 
heading 
Reference to “whole body” in main 
text replaced with “cardiac, liver 
and prostate” 
Section 2 
Schedule of 
Activities 
 
Footnote number 2 amended: 
As stated in Section 8.2, if a 
participant decides to withdraw or is 
withdrawn by the responsible 
physician, the reasons for 
withdrawal and the results of any 
relevant tests will be recorded in 
This was reworded to help clarify that only 
the safety assessments at the follow-up 
visit would be conducted in case of 
withdrawal from the study. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
the CRF and the planned safety 
follow-up procedures will be 
performed, where possible. These 
include physical examination, 12-
lead ECG, vitals, blood tests, 
urinalysis and concomitant 
medication review as listed for the 
follow-up visit (V9). 
 
The following text was deleted: 
The leg press should be prioritized 
over other functional assessments. 
 
Safety assessments to be collected 
at follow-up visits in case of study 
discontinuation or withdrawal of 
participants are as follows: physical 
examination, 12-lead ECG, vitals, 
blood tests, urinalysis and 
concomitant medication review as 
listed for the follow-up visit 
Section 5.1 
Overall 
Design 
Text modified with following 
additions: 
“Site staff will supervise 
performance of the initial exercises 
to assess which of the four 
exercises can be prescribed to 
participants, as well as setting the 
baseline intensity for the exercises 
and clarifying instructions from the 
home exercise Application.” 
“Guidance for performing exercises 
and setting goals will be given by 
the home exercise Application from 
the baseline visit onwards, however 
participants will have the 
opportunity to raise any concerns 
they have with site staff.”   
Additional text with clarification on 
supervision of the home exercise program 
was added in response to comments from 
ethics committees. 
Section 6.2 
Exclusion 
The following text was deleted: 
Deficient levels (<20 ng/mL) of 25-
Vitamin D deficiency is likely present in a 
significant portion of our target study 
population, and likely to pose a significant 


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Section # 
and Name 
Description of Change 
Brief Rationale 
Criteria 
Page 31 
OH Vitamin D Total; NOTE: 
Participants with insufficient (20 – 
29 ng/mL) levels may be enrolled. 
barrier to recruitment. Since it should not 
interfere with the study drug mechanism, 
therefore the decision was made to remove.
Section 8.2 
Text added “or an exacerbation that 
requires treatment with oral 
steroids” 
To clarify that any steroid use requires 
participants to withdraw from the study 
Section 12.2 
Appendix 2 
“days” added after 125  
Clarify duration of contraception use – error 
in original protocol 
Section 12.3 
Appendix 3 
Reference to IDMC removed 
Originally included in error, as there is no 
plan to have an IDMC for this study 
 
Amendment 1: 19-MAY-2017 
Overall Rationale for the Amendment: This amendment removes reference to 
measurement of lumbar bone density, as this requires an additional Dual-Energy X-ray 
Absorptiometry (DXA) scan to the ones for measurement of muscle mass, thus reducing 
radiation exposure for subjects. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 3.3.1 
Risk 
assessment 
Remove reference to 
measurement of lumbar bone 
density in the risk mitigation 
strategy for bone effects 
Not required as no longer performing DXA 
scans for measurement of bone density. 
Section 9.2.2.1 
Dual-Energy 
X-ray 
Absorptiometry 
(DXA) 
Remove reference to 
measurement of lumbar bone 
density 
 To remove additional burden on 
study participants in terms of time 
taken to perform an extra scan, as 
well as to reduce radiation 
exposure for subjects. 
 Error in the original protocol 
.   
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ............................................................................................................. 14 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 17 
3. 
INTRODUCTION .................................................................................................... 22 
3.1. 
Study Rationale .......................................................................................... 22 
3.2. 
Background ................................................................................................ 22 
3.3. 
Benefit/Risk Assessment ............................................................................ 23 
3.3.1. 
Risk Assessment ......................................................................... 24 
3.3.2. 
Benefit Assessment ..................................................................... 27 
3.3.3. 
Overall Benefit: Risk Conclusion .................................................. 27 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 27 
5. 
STUDY DESIGN .................................................................................................... 29 
5.1. 
Overall Design ............................................................................................ 29 
5.2. 
Number of Participants ............................................................................... 32 
5.3. 
Participant and Study Completion ............................................................... 32 
5.4. 
Scientific Rationale for Study Design .......................................................... 33 
5.5. 
Dose Justification ........................................................................................ 33 
6. 
STUDY POPULATION ........................................................................................... 34 
6.1. 
Inclusion Criteria ......................................................................................... 34 
6.2. 
Exclusion Criteria ........................................................................................ 35 
6.3. 
Lifestyle Restrictions ................................................................................... 37 
6.3.1. 
Meals and Dietary Restrictions .................................................... 37 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 37 
6.3.3. 
Activity ......................................................................................... 38 
6.4. 
Screen Failures........................................................................................... 38 
7. 
TREATMENTS ....................................................................................................... 38 
7.1. 
Treatments Administered ............................................................................ 38 
7.1.1. 
Medical Devices ........................................................................... 39 
7.2. 
Dose Modification ....................................................................................... 39 
7.3. 
Method of Treatment Assignment ............................................................... 39 
7.4. 
Blinding ....................................................................................................... 40 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 40 
7.6. 
Treatment Compliance ................................................................................ 41 
7.7. 
Concomitant Therapy.................................................................................. 41 
7.8. 
Treatment after the End of the Study .......................................................... 42 
8. 
DISCONTINUATION CRITERIA ............................................................................. 43 
8.1. 
Discontinuation of Study Treatment ............................................................ 43 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 43 
8.1.2. 
QTc Stopping Criteria .................................................................. 44 
8.1.3. 
Temporary Discontinuation .......................................................... 45 
8.1.4. 
Study Treatment Restart or Rechallenge ..................................... 45 


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8.2. 
Withdrawal from the Study .......................................................................... 45 
8.3. 
Lost to Follow Up ........................................................................................ 46 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 46 
9.1. 
Study Procedure ......................................................................................... 47 
9.1.1. 
Screen ......................................................................................... 47 
9.1.2. 
Day -9 and day 80 visits ............................................................... 47 
9.1.3. 
Baseline (day 1) and last dose (day 90) visits .............................. 47 
9.1.4. 
Interim visits ................................................................................. 48 
9.1.5. 
Follow-up visit .............................................................................. 48 
9.2. 
Efficacy Assessments ................................................................................. 48 
9.2.1. 
Pulmonary Function Tests ........................................................... 48 
9.2.1.1. 
Spirometry .................................................................. 48 
9.2.1.2. 
Sniff Nasal Inspiratory Pressure (SNIP) ...................... 48 
9.2.2. 
Lean Mass measures................................................................... 49 
9.2.2.1. 
Dual-Energy X-ray Absorptiometry (DXA) ................... 49 
9.2.3. 
Functional Assessments .............................................................. 49 
9.2.3.1. 
Leg Press ................................................................... 49 
9.2.3.2. 
Shuttle walk tests (Incremental shuttle walk test 
and endurance shuttle walk test) ................................ 49 
9.2.3.3. 
Short Physical Performance Battery (SPPB) .............. 50 
9.2.3.4. 
Handgrip Strength ...................................................... 50 
9.2.4. 
Patient Reported Outcomes Assessments ................................... 50 
9.2.4.1. 
COPD Assessment Test (CAT) .................................. 50 
9.2.4.2. 
St George Respiratory Questionnaire COPD 
(SGRQ-c) ................................................................... 50 
9.2.4.3. 
Patient Global Rating of Severity (PGRS) and 
Patient Global Impression of Change (PGIC) ............. 51 
9.2.4.4. 
Daily PROactive Physical Activity in COPD 
instrument (D-PPAC) .................................................. 51 
9.2.4.5. 
Physical Activity Monitor ............................................. 52 
9.2.4.6. 
Patient Exit Interview .................................................. 52 
9.2.5. 
Home Exercise Program .............................................................. 52 
9.3. 
Adverse Events........................................................................................... 53 
9.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 53 
9.3.2. 
Method of Detecting AEs and SAEs ............................................. 53 
9.3.3. 
Follow-up of AEs and SAEs ......................................................... 54 
9.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 54 
9.3.5. 
Cardiovascular and Death Events ................................................ 54 
9.3.6. 
Pregnancy ................................................................................... 55 
9.4. 
Treatment of Overdose ............................................................................... 55 
9.5. 
Safety Assessments ................................................................................... 55 
9.5.1. 
Physical Examinations ................................................................. 55 
9.5.2. 
Vital Signs .................................................................................... 56 
9.5.3. 
Electrocardiograms ...................................................................... 56 
9.5.4. 
Clinical Safety Laboratory Assessments ...................................... 56 
9.5.5. 
MRI scans (Optional sub-study) ................................................... 57 
9.6. 
Pharmacokinetics ....................................................................................... 57 
9.7. 
Genetics ..................................................................................................... 58 
9.8. 
Biomarkers ................................................................................................. 58 
9.8.1. 
Reproductive Tissue Biomarkers ................................................. 58 


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9.8.2. 
Bone Biomarkers ......................................................................... 59 
9.8.3. 
Exploratory Biomarkers ................................................................ 59 
10. STATISTICAL CONSIDERATIONS ........................................................................ 59 
10.1. 
Sample Size Determination ........................................................................ 60 
10.1.1. 
Sample Size Assumptions ........................................................... 60 
10.1.2. 
Sample Size Sensitivity ................................................................ 62 
10.1.3. 
Sample Size Re-estimation or Adjustment ................................... 62 
10.2. 
Populations for Analyses ............................................................................ 62 
10.3. 
Statistical Analyses ..................................................................................... 62 
10.3.1. 
Efficacy Analyses ......................................................................... 63 
10.3.2. 
Safety Analyses ........................................................................... 64 
10.3.3. 
Other Analyses ............................................................................ 64 
10.3.4. 
Interim Analyses .......................................................................... 64 
11. REFERENCES ....................................................................................................... 66 
12. APPENDICES ........................................................................................................ 69 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 69 
12.2. 
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 71 
12.3. 
Appendix 3: Study Governance Considerations .......................................... 74 
12.4. 
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 78 
12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 81 
12.5.1. 
Definition of Cardiovascular Events ............................................. 86 
12.6. 
Appendix 6: Clinical Laboratory Tests ......................................................... 87 
12.7. 
Appendix 7: Genetics .................................................................................. 89 
 


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1. 
SYNOPSIS 
A randomized, double-blind (sponsor unblind), placebo-controlled, multi-centred phase 
IIa study to evaluate the safety and efficacy of 13 weeks of once daily oral dosing of the 
selective androgen receptor modulator (SARM) GSK2881078 in older men and post 
menopausal women with COPD and muscle weakness, participating in home exercise 
Short Title: A randomized, double-blind, placebo-controlled study to evaluate the safety 
and efficacy of 13 weeks of the selective androgen receptor modulator (SARM) 
GSK2881078 in COPD 
Rationale: 
This study is the third clinical study with administration of GSK2881078 in humans, and 
it will be the first administration to the target population, defined as older men and post-
menopausal female participants (50-75 years of age) with chronic obstructive pulmonary 
disease (COPD) and muscle weakness, participating in home exercise.  This study will 
evaluate the safety and tolerability over 13 weeks of dosing in this population.  This study 
will also evaluate the anabolic effects of GSK2881078 as measured by changes from 
baseline in leg strength, muscle mass, and functional measures. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
Assess the safety and tolerability of 
approximately 13 weeks of dosing of 
GSK2881078 
 
Safety and tolerability of GSK2881078 
as assessed by clinical monitoring of 
blood pressure, heart rate, 
electrocardiogram (ECG) and laboratory 
safety data, as well as reporting of 
adverse events (AEs) 
 Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on leg 
strength in older men and post-
menopausal women with COPD and 
muscle weakness, participating in home 
exercise 
 % change from baseline and change from 
baseline in maximum leg press strength 
following 1 repetition maximum (1- RM) 
Secondary 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on lean 
soft tissue mass  
 
Change from baseline in appendicular, 
and total lean mass as assessed by 
Dual-energy X-ray Absorptiometry (DXA)  


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Objectives 
Endpoints 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on 
exercise capacity 
 
Change from baseline in total Short 
Physical Performance Battery (SPPB) 
score and times for chair rise and 4 m 
gait speed 
 
Change from baseline in Constant Work 
Rate (CWR) duration from endurance 
shuttle walking test  
 
Change from baseline in peak 
performance from incremental shuttle 
walking test 
 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on 
patient reported outcomes, levels of 
physical activity, activities of daily living 
and the patient perspective of efficacy 
 
Change from baseline in COPD 
Assessment Test (CAT)  
 
Change in PROactive endpoints 
(individual components and total score) 
 
Change in physical activity measures as 
assessed via an accelerometer 
 
Patient Global Impression of Change 
 
Patient Global Rating of Severity 
 
Change in St George Respiratory 
Questionnaire-COPD (SGRQ-c) total 
score and domains 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on 
respiratory function 
 
Change from baseline in forced 
expiratory volume in 1 second (FEV1) 
 
Change from baseline in Sniff nasal 
inspiratory pressure (SnIP) 
 
Characterise the population 
pharmacokinetic (PK) profile of 
approximately 13 weeks of dosing of 
GSK2881078 in older men and post-
menopausal women with COPD and 
muscle weakness 
 
Model specific PK parameters of 
GSK2881078 (e.g., oral clearance, oral 
steady-state volume of distribution). 
Additional exploratory analyses related to the primary and secondary endpoints will also 
be performed. 
 
 


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Overall Design: 
This study is a randomized, placebo-controlled, double-blind (sponsor unblind), parallel 
group trial in two equal sized cohorts (male or female) of participants with COPD.  
Following completion of screen assessments, baseline assessments will be conducted in 
eligible participants and, in each cohort, the participants will be randomized 1:1 to 
GSK2881078 or matching placebo. 
Number of Participants: 
At least 100 participants with COPD and muscle weakness will be randomized (25/arm) 
to target approximately 80 evaluable participants (20/arm).  Men and women will be 
recruited into separate cohorts of at least 50 participants each, with each cohort 
containing 1:1 allocation of placebo and GSK2881078.  
Additional participants may be enrolled if the number of participants with exacerbations 
plus the number of participants withdrawn prematurely for other reasons is higher than 
anticipated (approximately 20%), based on differences in observed variability in endpoint 
parameters and the ability to detect a treatment effect at interim. The total sample size 
may be increased by up to 60 participants (approximately 15/arm). Enrolment is not 
expected to exceed approximately 160 total participants. 
Treatment Groups and Duration: 
The study will consist of a screening/baseline period of up to 30 days, a 13-week 
treatment period, and a 6 week (42 days) post-treatment follow-up visit.  Study 
participation, including screening and follow-up, is not expected to exceed 6 months for 
participants in the study. 
Study treatment will consist of two dosing cohorts (Male: placebo or 2.0 mg once daily of 
GSK2881078; Postmenopausal female: placebo or 1.0 mg once daily of GSK2881078).  
All participants will take their first dose of study treatment in the clinic following 
randomization. Participants will be dosed without regards to food intake.  
 


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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Procedure 
Screening  
V1 
(up to 30 
days before 
Day 1) 
 
V2 
Day -9 
Treatment Period (13 weeks) 
 Follow-
up2 
V9 
(42 days 
post last 
dose) 
Notes 
V3 
Baseline 
Day 1 
V4 
Day 
14 
V5 
Day 
28 
V6 
Day 
56 
V7 
Day 
80 
V8 
Last 
dose 
90 
Unscheduled 
visit 1 
 
Visit window (days) 
- 30 to -11 
-11 to 
-7 
-2 to day 
1 
12 - 
16 
24 – 
32 
52- 
60 
76 - 
84 
85 – 
91 
 
126- 140 
There should be an attempt to 
conduct all assessments for a visit 
within a single day3. 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Obtained prior to performing any 
study-related procedures. 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demography/ medical/medication/ 
drug/ alcohol history/ PD disease 
staging 
X 
 
 
 
 
 
 
 
 
 
 
Full physical examination  
X 
 
 
 
 
 
 
 
X 
X 
 
Brief physical exam 
 
 
X 
X 
X 
X 
 
X 
 
 
 
12-lead ECG 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Vital signs 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
HIV, Hepatitis B and C screening 
X 
 
 
 
 
 
 
 
 
 
If test otherwise performed within 3 
months prior to first dose of study 
treatment, testing at screening is 
not required 
Hepatitis C viral RNA PCR  
 
 
 
 
 
 
 
 
X 
 
If evidence of Hepatitis C 
antibodies at screening visit, then 
Hepatitis C viral RNA PCR 
required to exclude active infection. 
This sample is not needed if 
Hepatitis C screening is negative. 


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Procedure 
Screening  
V1 
(up to 30 
days before 
Day 1) 
 
V2 
Day -9 
Treatment Period (13 weeks) 
 Follow-
up2 
V9 
(42 days 
post last 
dose) 
Notes 
V3 
Baseline 
Day 1 
V4 
Day 
14 
V5 
Day 
28 
V6 
Day 
56 
V7 
Day 
80 
V8 
Last 
dose 
90 
Unscheduled 
visit 1 
 
Haematology (Full blood count)/ 
Clinical Chemistry (Creatinine, urea 
and electrolytes, liver function tests, 
glucose)  
X 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Participants should fast overnight 
for at least 8 hours prior to 
collection of these samples.  
HbA1c 
X 
 
 
 
 
 
 
X 
 
 
 
hsCRP, Fibrinogen 
 
 
X 
 
 
 
 
X 
 
X 
 
25-OH Vitamin D Total, 25-OH 
Vitamin D2, 25-OH Vitamin D3 
X 
 
 
 
 
 
 
X 
 
X 
 
Lipid panel 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
Genetic sample 
 
 
X 
 
 
 
 
 
 
 
Obtain after participant is 
randomized. Informed consent to 
obtain the genetics sample must 
be obtained before collecting a 
sample. 
Pharmacokinetic sampling  
 
 
 
X4 
X4,5 
X6 
 
X4 
X 
 
 Times of dose administration for 
the two doses immediately 
preceding a PK sample should be 
accurately recorded. 
Reproductive Tissue Biomarkers  
 
 
X 
 
X 
X 
 
X 
 
X 
 
PSA 
X 
 
X 
 
X 
X 
 
X 
 
X 
For male participants only 
Bone Biomarkers 
 
 
X 
 
 
X 
 
X 
 
X 
 
Exploratory Biomarkers 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
 
 
 
X 
X 
X 
 
DXA 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
Spirometry 
X 
 
X 
 
 
X 
 
X 
 
 
Follow ATS/ ERS guidelines [Celli, 
2004] and Quanjer reference 
equation [Quanjer, 2012].   


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Procedure 
Screening  
V1 
(up to 30 
days before 
Day 1) 
 
V2 
Day -9 
Treatment Period (13 weeks) 
 Follow-
up2 
V9 
(42 days 
post last 
dose) 
Notes 
V3 
Baseline 
Day 1 
V4 
Day 
14 
V5 
Day 
28 
V6 
Day 
56 
V7 
Day 
80 
V8 
Last 
dose 
90 
Unscheduled 
visit 1 
 
Sniff Nasal Inspiratory Pressure 
X 
 
X 
 
 
X 
 
X 
 
 
 
Leg strength 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Handgrip strength 
X 
 
X 
 
 
 
 
X 
 
 
 
Short Physical Performance Battery 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Incremental Shuttle Walk Test 
 
X 
X 
 
 
 
 
X 
 
 
Practice incremental shuttle walk 
test conducted at day -9 
Endurance Shuttle Walk Test 
 
 
X 
 
 
 
 
X 
 
 
 
COPD Assessment Test 
 
 
X 
 
 
X 
 
X 
 
 
 
St George Respiratory 
Questionnaire COPD (SGRQ-c) 
 
 
X 
 
 
 
 
X 
 
 
 
Patient Global Rating of Severity 
 
 
X 
 
 
 
 
X 
 
 
 
Patient Global Impression of Change 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Daily PROactive Physical Activity in 
COPD instrument and Physical 
Activity Monitor 
X 
X7 
 
 
 
X 
X7 
 
 
 
Physical activity monitor dispensed 
at screening, day -9, day 56 and 
day 80 visits. Activity monitor 
should be worn for 7 days at each 
timepoint and returned at the next 
visit. 
Monitored home exercise program 
 
X 
X 
=============== 
X 
 
 
Participants will receive training for 
the exercise program at Day -9, 
and will formally begin exercises 
on day 1 
Patient exit interview 
 
 
 
 
 
 
 
 
 
X 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
All Baseline assessments must be 
obtained prior to randomization.  
Study treatment provided to 
participant 
 
 
X 
 
X 
X 
 
 
 
 
The subject should take their first 
dose of study treatment in the clinic 
after randomization. 


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Procedure 
Screening  
V1 
(up to 30 
days before 
Day 1) 
 
V2 
Day -9 
Treatment Period (13 weeks) 
 Follow-
up2 
V9 
(42 days 
post last 
dose) 
Notes 
V3 
Baseline 
Day 1 
V4 
Day 
14 
V5 
Day 
28 
V6 
Day 
56 
V7 
Day 
80 
V8 
Last 
dose 
90 
Unscheduled 
visit 1 
 
Study treatment  
 
 
X 
================ 
X 
 
 
Participants should dose study 
treatment in the clinic at each clinic 
visit during the treatment period. 
Study treatment accountability by 
study site  
 
 
X 
X 
X 
X 
 
X 
 
 
The required counting of pills by 
site staff to check compliance is 
not considered redispensing the 
study medication. 
AE review 
 
 
X 
============================= 
X 
 
SAE review 
 
 
X 
============================= 
X 
 
Concomitant medication review 
 
 
X 
============================= 
X 
 
Optional sub-study measures 
Cardiac and liver MRI (additionally 
prostate MRI in males) 
 
 
X8 
 
 
 
 
X8 
 
 
MRI is an optional assessment 
undertaken at participating centres 
only. 
 
ECG= Electrocardiogram; HIV= Human Immunodeficiency Virus; PK= Pharmacokinetic; PSA= Prostate Specific Antigen; DXA= Dual-
energy X-ray Absorptiometry; AE= Adverse Event; SAE= Serious Adverse Event. 
1. An unscheduled clinic visit may occur at any time if the investigator believes an unscheduled visit is clinically warranted. 
Individual listed assessments are optional and are performed as needed to follow unresolved findings of clinical concern. Note: 
The “Unscheduled visit” case report form (CRF) form should be completed as soon as possible following the Unscheduled visit. 
2. As stated in Section 8.2, if a participant decides to withdraw or is withdrawn by the responsible physician, the reasons for 
withdrawal and the results of any relevant tests will be recorded in the CRF and the planned safety follow-up procedures will be 
performed, where possible. These include physical examination, 12-lead ECG, vitals, blood tests, urinalysis and concomitant medication 
review as listed for the follow-up visit (V9). 
3. Attempt to conduct all visits within a single day however the baseline (day 1) and last dose (day 90) visits may require subjects to 
visit the study centre on more than one day in order to complete MRI and DXA scans, and possibly other assessments. These 


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scans, and any other assessments, should be conducted within the specified visit window, and prior to randomization at the 
baseline visit. Further details on the suggested order of assessments will be given in the SRM. 
4. Take PK sample prior to dosing in the clinic 
5. Take PK sample 1-4 hours post-dose (sites should try and ensure that a range of times are sampled within this time window for 
different participants, i.e. all PK samples should not be taken at 1 hour post dose or 2 hours post dose). 
6. Take PK sample 5-8 hours post-dose (as above, sites should try and ensure that a range of times are sampled within this time 
window for different participants). 
7. At V3 Baseline Day 1 and V8 Last dose 90, the patients will return the Daily PROactive Physical Activity in COPD Instrument 
and the Physical Activity Monitor to the site.  Patients will not be dispensed the Daily PROactive Physical Activity in COPD 
Instrument and the Physical Activity Monitor at the end of these visits.  
8. All MRI Scans (Cardiac MRI, Liver MRI and, if applicable, Prostate MRI) should preferably be scheduled on the same day. 
Acquisition of the Cardiac MRI should be prioritized above the other two scans if it becomes unfeasible to perform all the MRI 
scans. 
 
The following points must be noted:  
 If assessments are scheduled for the same nominal time, THEN the assessments should occur in the following order: 
i. vital signs 
ii. 12-lead ECG 
iii. blood draws.   
Note: The timing of the assessments should allow the blood draw to occur at the time specified in the SoA 


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3. 
INTRODUCTION 
GSK2881078 belongs to a novel class of non-steroidal, Selective Androgen Receptor 
Modulators (SARMs) and is under investigation by GlaxoSmithKline (GSK) for 
treatment of impaired mobility, disability and functional limitation in older men and post-
menopausal women with muscle weakness associated with Chronic Obstructive 
Pulmonary Disease (COPD). Conditions such as COPD, congestive heart failure, and 
chronic kidney disease can demonstrate significant muscle wasting and associated 
functional impairment, especially in advanced states.  Physical therapy and exercise have 
been shown in these conditions to increase muscle mass and improve physical function.  
The use of the natural steroidal androgen receptor agonist, testosterone, has also been 
shown in these conditions to induce similar benefits, but such use is limited by prostate 
effects and androgenic effects.  A non-steroidal, selective androgen receptor agonist can 
potentially act positively on muscle and bone while not adversely affecting the prostate 
gland in men, or inducing hirsutism or virilization in women. 
3.1. 
Study Rationale 
This study is the third clinical study with administration of GSK2881078 in humans, and 
it will be the first administration to the target population, defined as older men and post-
menopausal female participants (50-75 years of age) with COPD and muscle weakness, 
participating in home exercise.  This study will evaluate the safety and tolerability over 
13 weeks of dosing in this population.  This study will also evaluate the anabolic effects 
of GSK2881078 as measured by changes from baseline in leg strength, muscle mass, and 
functional measures. 
3.2. 
Background 
Impaired physical function and muscle dysfunction are a major consequence of COPD 
and may be associated with increased mortality, poor quality of life, and increased health 
care use. Physical therapy and exercise have been shown to increase muscle mass and 
improve physical function in participants with COPD [Maltais, 2014].  Increased muscle 
mass and improved physical function have also been shown with the natural steroidal 
androgen receptor agonist testosterone in participants with COPD [Atlantis, 2013].  
However, use of testosterone to treat muscle dysfunction in participants with COPD may 
be limited due to adverse effects in both men and women. A non-steroidal, selective 
androgen receptor agonist can potentially act positively on muscle while avoiding 
unwanted effects seen with testosterone (e.g., prostate hypertrophy in men or hirsutism or 
virilization in women). Currently, there are no medications approved by the United States 
Food and Drug Administration (FDA) for the treatment of muscle wasting disorders of 
any aetiology.   
The scientific opportunity for the treatment of muscle-wasting and associated disorders is 
presented through the development of non-steroidal molecules that act via the androgen 
receptor in a cofactor/cellular/tissue-selective manner.  SARMs bind to the androgen 
receptor inducing a unique receptor conformation which allows only certain co-activator 
and co-repressor proteins to interact.  These unique receptor-cofactor ensembles confer 
differential regulation of target genes and other receptor-mediated pathways.  The 


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differential activity allows SARMs to function as potent androgens in target tissues such 
as muscle and bone, but function as antagonists, or partial agonists, in other tissues or 
organs such as the prostate or skin.  Further, an appropriately selective SARM could be 
given to post-menopausal women without inducing hirsutism or virilization, which 
occurs with steroidal androgen receptor modulators. 
While no SARM has been approved for clinical use, there is growing clinical experience 
with this class of compounds.  Enobosarm has been through a series of clinical studies 
and recently finished a Phase 3 program evaluating the efficacy for treatment of muscle 
loss and functional impairment in cancer cachexia [Dalton, 2011; Dobs, 2013]. Although 
the phase 3 study for Enobosarm did not show an improvement in stair climb power (co-
primary endpoint), there appeared to be a consistent effect of enobosarm on muscle mass 
and strength in study participants in phase 2 trials.  An additional SARM, LGD-4033, has 
shown no apparent safety signals and has demonstrated an increase in lean body mass 
(LBM) in repeat dosing in healthy male volunteers [Basaria, 2012].  GSK also has 
clinical experience with SARM compounds, GSK971086 and GSK2849466.  These 
compounds were evaluated in first-time-in-human studies in healthy male volunteers, 
both showing expected effects on biomarkers and no safety signals in studies less than 3 
weeks.  However, both of these compounds were discontinued because of unexpected 
toxicity observed in longer preclinical safety studies. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2881078 is provided in the Investigator’s Brochure (IB). 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK2881078 may be found in the IB. 


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3.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) GSK2881078 
Elevation of Alanine Aminotransferase (ALT) 
and other liver function tests (AST, bilirubin, 
total and direct).   
This has been observed in a variety of SARMs 
and was observed (minimal) in the 14-day and 
13-week rat toxicity studies with administered 
GSK2881078. 
One subject had elevations of Liver Function 
Tests (LFTs) in Phase 1a, but it was unclear if 
this was related to drug. Transient elevations in 
ALT without concomitant changes in bilirubin 
were observed in Phase 1b. 
Monitoring of liver function tests will be in 
place at all clinic visits. This study will use 
follow up procedure that were used in Phase I of 
development of GSK2881078 for participants 
who have met liver stopping criteria, as detailed 
in Section 8.1.1 of this protocol. 
Effects on reproductive organs/tissues: 
Men – testes, epididymis, and prostate gland  
Women – ovaries and uterus 
 
These are recognized effects of SARM 
pharmacology and show recovery on 
discontinuation of dosing. 
Test article-related organ weight and/or 
microscopic changes were observed in the 
gonads and other associated reproductive tissues 
in rat 14-day and 13-week toxicity studies 
administered GSK2881078.  All test article-
related microscopic findings were reversible 
after a 4- or 8- week off dose period.  Test 
article-related effects were observed in male 
mating, fertility, gonadal function, and male-
mediated development in a male rat fertility 
study.  
In phase I studies, all male subjects dosed with 
Males with PSA levels >4.0 ng/mL will be 
excluded. 
Females will be post-menopausal. 
Participants will be monitored at baseline, Day 
28, Day 56, Day 89 and follow-up for changes 
in the following levels: 
 
luteinizing hormone 
 
follicle stimulating hormone 
 
testosterone 
 
free testosterone (calculated) 
 
estradiol 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
GSK2881078 displayed reversible reductions in 
testosterone. No changes in PSA were recorded. 
Reversible reductions in sex hormone binding 
globulin were observed in both men and 
women. There were no clinically significant 
changes in FSH, LH, estradiol or progesterone.  
 
dihydrotestosterone 
 
sex hormone binding globulin 
 
Lowering of High-Density Lipoprotein (HDL) 
levels - A class effect of SARMs 
All subjects dosed with GSK2881078 exhibited 
a reduction in HDL Cholesterol in Phase I 
studies. This reduction exhibited a dose 
response, with evidence of maximal 
pharmacology at a reduction of approximately 
30-40% from baseline. This reduction was 
accompanied by a similar reduction 
proportionally in ApoA1.  In all cases HDL 
Cholesterol returned to baseline on 
discontinuation of dosing.  
Monitoring lipid profiles to confirm decreases 
seen on treatment, and whether lipid parameters 
return to baseline following discontinuation of 
study treatment. Lipid panels will be monitored 
at baseline, Day 56, Day 89 and at follow-up. 
Bone effects 
 
 Minimal trabecular atrophy was observed in 
female rats at all doses in a 13- week toxicity 
study.  This finding was not observed in male 
rats or dogs of either sex after 13 weeks of 
GSK2881078 administration. 
Bone turnover markers will be measured at 
baseline, Day 56, Day 89 and at follow-up. 
Bone biomarkers will include: 
 
procollagen type I N propeptide (s-PINP) 
for formation 
 
C-terminal telopeptide of type I collagen (s-
CTX) 
Anabolic abuse 
Since this compound builds lean body mass, 
there is potential risk for anabolic abuse through 
illicit use of the drug by body builders. 
Use of compound will be restricted to 
participants enrolled in study.  Sites will have in 
place secure storage for compound supply. Sites 
to confirm restricted use of compound by 
enrolled participants at each study visit.  Sites 
will be inspected for secure storage. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Risks to women and foetal risk 
 Risks to women of possible androgenic effects 
from exposure to study compound by handling 
or by seminal exposure.  In pregnant women, 
risk of exposure to compound during period of 
fetal reproductive differentiation. 
Women who are not post-menopausal should 
avoid handling or ingestion of the study 
medication (capsules). Male participants should 
always use condom with female partners of 
childbearing potential. Sites to confirm 
compliance with guidelines by participants at 
each study visit. 
Increase in absolute (not relative) heart weight 
There is a theoretical risk that the anabolic 
effects of GSK2881078 are not only selective 
for striated skeletal muscle, and that there is an 
increase in cardiac muscle size. There are no 
pre-clinical or clinical data to support this risk. 
Cardiac MRI will be carried out on a small 
subset of patients; the scan will be used to 
evaluate changes from baseline in cardiac size, 
structure and function in the treatment arm. 
Study Procedures  
Risk of cardiac angina from incremental or 
endurance shuttle walk exercise tests 
 
There is high incidence of cardiovascular 
comorbidity in COPD; undiagnosed disease may 
manifest during exercise tests 
Physical exam, medical history and baseline 
ECGs 
will 
assess 
cardiovascular 
risk. 
Participants with a history of unstable angina 
will be excluded. Exercise tests will only be 
carried out under the supervision of suitably 
trained study personnel as detailed in the SRM. 
Other  
None 
 
 


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3.3.2. 
Benefit Assessment 
Potential benefits of receiving GSK2881078 include gaining muscle mass, which may 
increase muscle strength and physical function, and may improve glycaemic control.  
Participation in this study will contribute to the process of developing a new therapy in an 
area of unmet need, namely in people with COPD who suffer from muscle weakness.  
Study participants will undergo medical evaluations and assessments associated with 
study procedures, which may be of benefit in identifying or monitoring COPD related 
features, e.g. physical examination, ECGs and laboratory tests can identify individuals at 
risk of cardiac comorbidity. 
3.3.3. 
Overall Benefit: Risk Conclusion 
Based upon review of available data from the FTIH study and the known and possible 
risks of therapy with GSK2881078, the potential therapeutic benefits of the SARM 
GSK2881078 for participants diagnosed with COPD and who suffer from muscle 
weakness warrant further study of the compound.  Therefore, it is appropriate to proceed 
with this Phase II trial with medical supervision as outlined within this protocol. 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
Assess the safety and tolerability of 
approximately 13 weeks of dosing of 
GSK2881078 
 
Safety and tolerability of GSK2881078 as 
assessed by clinical monitoring of blood 
pressure (BP), heart rate, electrocardiogram 
(ECG) and laboratory safety data, as well as 
reporting of adverse events (AEs) 
 Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on leg 
strength in older men and post-
menopausal women with COPD and 
muscle weakness, participating in home 
exercise 
 % change from baseline and change from 
baseline in maximum leg press strength 
following 1 repetition maximum (1- RM) 
Secondary 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on lean 
soft tissue mass  
 
Change from baseline in appendicular, and 
total lean mass as assessed by Dual-energy 
X-ray Absorptiometry (DXA)  


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Objectives 
Endpoints 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on 
exercise capacity 
 
Change from baseline in total Short Physical 
Performance Battery (SPPB) score and 
times for chair rise and 4 m gait speed 
 
Change from baseline in Constant Work 
Rate (CWR) duration from endurance shuttle 
walking test  
 
Change from baseline in peak performance 
from incremental shuttle walking test 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on 
patient reported outcomes, levels of 
physical activity, activities of daily living 
and the patient perspective of efficacy 
 
Change from baseline in COPD Assessment 
Test (CAT)  
 
Change in PROactive endpoints (individual 
components and total score) 
 
Change in physical activity measures as 
assessed via an accelerometer 
 
Patient Global Impression of Change 
 
Patient Global Rating of Severity 
 
Change in St George Respiratory 
Questionnaire-COPD (SGRQ-c) total score 
and domains 
 
Assess the effect of approximately 13 
weeks of dosing of GSK2881078 on 
respiratory function 
 
Change from baseline in forced expiratory 
volume in 1 second (FEV1) 
 
Change from baseline in Sniff nasal 
inspiratory pressure (SnIP) 
 
Characterise the population 
pharmacokinetic (PK) profile of 
approximately 13 weeks of dosing of 
GSK2881078 in older men and post-
menopausal women with COPD and 
muscle weakness 
 
Model specific PK parameters of 
GSK2881078 (e.g., oral clearance, oral 
steady-state volume of distribution). 


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Objectives 
Endpoints 
 
Exploratory 
 
Assess the safety of 13 weeks of dosing 
of GSK2881078 in older men and 
postmenopausal women in a subset of 
up to 15 male and 15 female participants 
with COPD via magnetic resonance 
imaging (MRI) 
 
Changes from baseline in hepatic, prostate 
(males) and cardiac structure and function 
as assessed via MRI. Further exploratory 
analyses may include changes from baseline 
in size of inspiratory muscles and/ or other 
organs. 
 
Conduct semi-structured exit interviews 
 
Gain further insights into the participants’ 
experience with study treatment and their 
participation in the trial. 
 
Assess the effect of 13 weeks of dosing 
of GSK2881078 in older men and 
postmenopausal women on peripheral 
strength 
 
Changes from baseline in handgrip strength 
 
Potentially explore adherence to exercise 
program (daily physical activity and thrice-
weekly strengthening exercises) 
Additional exploratory analyses related to the primary and secondary endpoints will also 
be performed. 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This study is a randomized, placebo-controlled, double-blind (sponsor unblind), parallel 
group, multi-center phase IIa trial in two equal sized cohorts (male or female).  Following 
completion of screen assessments, baseline assessments will be conducted in eligible 
participants and, in each cohort, the participants will be randomized 1:1 to GSK2881078 
or matching placebo. 


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Figure 1 
Study Schematic 
 
This study will assess the effect of GSK2881078 on physical strength and function after 
13 weeks of treatment.  The placebo group will serve as an appropriate control group in 
order to limit evaluation bias in the study endpoints. No suitable active comparator is 
currently available. Both treatment and control groups will be asked to participate in a 
standardized home exercise program. Study treatment will consist of two dosing cohorts 
(Male: placebo or 2.0 mg of GSK2881078; Postmenopausal female: placebo or 1.0 mg of 
GSK2881078).  All participants will take their first dose of study treatment in the clinic 
following randomization, and will continue on a once daily dose for the duration of the 
treatment period.   Participants will be dosed without regards to food intake. All doses 
should be administered in the clinic on study visit days during the treatment period. Time 
of dosing for the 2 doses prior to sample collection should be recorded and PK samples 
should be collected as specified in the SoA (Section 2). 
The study will consist of a screening/baseline period of up to 30 days, a 13-week 
treatment period, and a 6-weeks post-treatment follow-up visit as described in the Time 
and Events table (Section 2 ).  Unscheduled visits may be performed as needed to 
conduct optional assessments required to follow unresolved findings of clinical concern.  
Participants will participate in a screening visit within 30 days prior to randomization and 
baseline assessments.  Prior to randomization, eligible participants will need to have a 
functional muscle deficit as defined by the Short Physical Performance Battery (SPPB) 
inclusion criterion (Section 6.1). Eligible participants will also have physical activity and 
patient reported outcomes (PROs) recorded prior to baseline, and will need to 


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demonstrate compliance with completion of the electronic diaries and wearing the 
activity monitor prior to randomization. 
The selection of individual medications and dosages for the treatment of COPD is 
left to the discretion of the investigator, although it is recommended that treatment 
regimens conform to current, local, national standard of care, and that treatment is 
optimized prior to screening with no further changes to treatment anticipated 
between the randomization visit and the end of the study.  
Eligible participants will be randomized as described above following completion of the 
Baseline assessments.  Participants will be sent home with a 42-day supply of study 
medication.  Participants will be asked to return to the clinical unit on approximately days 
14, 28, 56, 80 and 90 as specified in the SoA (Section 2) Participants will be resupplied 
with study treatment at the Day 28 and 56 visits.   
All visits should be conducted in a single day within the study visit window (Section 2).  
Participants will be provided a meal between completion of fasting labs and start of other 
study assessments. 
All participants will be asked to participate in a home exercise program reflecting usual 
care (e.g. a pulmonary rehabilitation program). The home exercise program will consist 
of daily walking, along with several resistance or weight-bearing exercises, such as bicep 
curls, upright rows, step ups, and a sit-to-stand manoeuvre, as allowed by site staff at 
screening. Site staff will supervise performance of the initial exercises to assess which of 
the four exercises can be prescribed to participants, as well as setting the baseline 
intensity for the exercises and clarifying instructions from the home exercise Application. 
Home exercises will be monitored with the use of a consumer-based activity monitor 
during the activities outside the clinic [Mitchell, 2014].  Guidance for performing 
exercises and setting goals will be given by the home exercise Application from the 
baseline visit onwards, however participants will have the opportunity to raise any 
concerns they have with site staff.  See Study Reference Manual (SRM) for additional 
detail. 
A physical activity monitor will be worn for 7 days at screening for eligible participants,7 
days after the Day -9 visit, for 7 days after the Day 56 visit, and for 7 days following the 
day 80 visit. During those periods, participants will rate their physical activity on a daily 
basis by completing the PROactive eDiary.  In addition, participants will be asked to 
complete additional questionnaires CAT which assesses the impact of COPD on a 
patient’s life, Patient Global Rating of Severity (PGRS), Patient Global Impression of 
Change (PGIC) during scheduled clinic visits as specified in the SoA Time and Events 
table (Section 2).   
Participants will return to the clinic for a follow-up visit 42 days (±7 days) after the final 
dose of study treatment to undergo safety evaluations and final functional assessments.  
In addition, all remaining study medication that was not returned at the last treatment 
visit (i.e., Day 90) will be returned to the clinical unit for final drug accountability.   
The study duration, including screening and follow-up, is not expected to exceed 6 
months for participants in the study. 


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Unblinded data will be reviewed in-stream by the GSK clinical study team and the safety 
review team (SRT). If, at any time, the 2.0 mg dose in men or the 1.0 mg dose in women, 
has a safety signal of clinical concern, treatment will be stopped.    
An interim analysis for the assessment of futility is planned. It is anticipated that a formal 
declaration of futility would not be made before at least 10 participants per group have 
completed dosing and all key study assessments.  However, if at any time it is determined 
that the probability of a successful outcome is sufficiently low, recruitment could be 
stopped. The primary endpoint for assessment of futility is strength. However, the 
decision to continue or stop recruitment will be made by the unblinded GSK clinical 
study team and Safety Review Team (SRT) based on the evaluation of all available 
safety, efficacy, and tolerability data.  Such decisions will be based on the totality of the 
data (including strength, lean mass, function, safety, and tolerability).  See Section 10 for 
more detail. The feasibility of making a decision to stop recruitment based on a futility 
analysis will be dependent on the recruitment rate. Futility will be evaluated separately 
for female and male participants.   
Based on the observed variability and treatment effects at an interim analysis, the sample 
size may be increased to improve the precision of the estimates of treatment effects.  This 
will be evaluated separately for males and females. The sample size may be increased by 
up to 15 subjects/arm. 
5.2. 
Number of Participants 
At least 100 participants with COPD and muscle weakness will be randomized (25/arm) 
to target approximately 80 evaluable participants (20/arm).  Men and women will be 
recruited into separate cohorts of at least 50 participants each, with each cohort 
containing a placebo and GSK2881078 arm. Sample size consideration and assumptions 
are discussed in more detail in Section 10.1.1 . 
Within each cohort, equal numbers of male and female participants will be randomized in 
a 1:1 allocation using a central randomization system to receive one of the planned 
treatment regimens listed below: 
Male participants: Placebo or 2.0 mg GSK2881078  
Female participants: Placebo or 1.0 mg GSK2881078 
Additional participants may be enrolled if the number of participants with exacerbations 
plus the number of participants withdrawn prematurely for other reasons is higher than 
anticipated (approximately 20%), or the precision of the estimates of the treatment effects 
based on the observed variability and treatment effect at an interim analysis. The total 
sample size may be increased by up to 60 participants (approximately 15/arm). 
Enrolment is not expected to exceed approximately 160 total participants. 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if they have completed all phases 
of the study including the follow-up visit. 


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The end of the study is defined as the last participant’s last visit. 
5.4. 
Scientific Rationale for Study Design 
This study is designed as a proof of concept study to evaluate the anabolic potency of 
GSK2881078 using leg strength as the primary endpoint.  This endpoint has been used in 
several studies with testosterone, including dose response studies in men, with a good 
correlation between anabolic potency and change from baseline in leg strength [Bhasin, 
2005].  In addition, functional endpoints, defined as short physical performance battery, 
incremental and endurance shuttle walk, and PRO, are included. The duration of the 
study, 13 weeks, is adequate to reach a near plateau effect in leg strength [Sheffield-
Moore, 2011].   
Based on studies with testosterone [Casaburi, 2004 ; Sheffield-Moore, 2011 ] it is 
estimated that a minimum of 2kg increase in total LBM would be needed to achieve a 
meaningful improvement in leg strength. The amount of muscle mass change required to 
elicit meaningful functional change in humans is unknown. 
5.5. 
Dose Justification 
GSK2881078 has been administered to 154 subjects across two clinical pharmacology 
studies in healthy human volunteers (study 200181 in healthy young men and post-
menopausal women and study 204699 in healthy elderly men and post-menopausal 
women).  PK and pharmacodynamic (PD) of GSK2881078 have been evaluated over the 
range of 0.05 mg to 4.0 mg in men and 0.24 mg to 1.5 mg in women for up to 56 days 
duration. PK data suggests that GSK2881078 has a long half-life in the range of 5-8 days.  
From an efficacy and safety standpoint, significant gains in lean mass from baseline have 
been observed across the dose levels evaluated to date with women showing greater 
sensitivity to the anabolic stimulus than men. Total mean body lean mass accrual in phase 
I studies ranged between 0.43kg and 3.39kg for women and 0.87kg and 1.72kg for men 
across different doses. PD analysis from phase I suggests that a 1.0mg dose in women 
would achieve a total lean mass accrual of approximately 2kg. In males, a plateau 
appeared to have been reached between the 1.5mg and 4mg doses, therefore a dose of 
2.0mg was chosen.  
From a safety coverage standpoint, the exposures as measured by area under the 
concentration-time curve over the dosing interval (AUC[0-τ]) at the 2.0 mg dose in men 
and 1.0 mg dose in postmenopausal women represent <50% of NOAEL established in the 
13-week dog study in both genders, respectively.  The dose limiting toxicity observed in 
the 13-week dog study was at 2 mg/kg/day, the highest dose given.  At 2 mg/kg/day on 
Day 91, mean systemic exposure values were area under the concentration-time curve 
from time zero (pre-dose) to last time of quantifiable concentration within a participant 
across all treatments (AUC0-t) 10.8 µg.h/mL for male dogs and 6.46 µg.h/mL for female 
dogs, and maximum observed concentration (Cmax) 0.778 µg/mL for male dogs and 0.536 
µg/mL for female dogs).  


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GSK2881078 has been generally well tolerated with no SAEs noted.  Adverse events of 
potential clinical significance primarily related to clinical chemistry including elevations 
of liver function tests, HDL cholesterol lowering, and suppression of testosterone and sex 
hormone binding globulin (SHBG). Elevations of liver function tests appeared transient, 
and changes in HDL, testosterone and SHBG were reversible on treatment 
discontinuation. Results of drug interaction study in healthy volunteers conducted with a 
prototype strong CYP3A4 inhibitor (itraconazole) showed that exposure to GSK2881078 
was only modestly elevated when co-administered with a strong CYP3A4 inhibitor 
(AUC(0-∞) increased by 60% while Cmax decreased by 21%) compared to given alone.  
Therefore, exposure to GSK2881078 is expected to be within the safety margin at the 
proposed dose of 1 mg in women and 2 mg in men if a CYP3A4 inhibitor is co-
administered with GSK2881078. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
participant safety. Therefore, adherence to the criteria as specified in the protocol is 
essential. Specific information regarding warnings, precautions, contraindications, AEs, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact participant eligibility is provided in the IB/IB supplement(s). 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
1. Participant must be 50 to 75 years of age inclusive, at the time of signing the 
informed consent. 
2. Male and/or female: 
a. Male participants: 
A male participant with a partner who is a woman of child bearing potential 
(WOCPB) must agree to use contraception as detailed in Appendix 2 of this protocol 
during the treatment period and for at least 5 half-lives of study medication have 
passed after the last ingested dose [125 days, corresponding to time needed to 
eliminate study treatment for both genotoxic and teratogenic study treatments plus an 
additional 90 days (a spermatogenesis cycle) for study treatments with genotoxic 
potential] after the last dose of study treatment and refrain from donating sperm 
during this period. 
b. Female participants:  
A female participant is eligible to participate if she is post-menopausal and not a 
woman of childbearing potential (WOCBP) as defined in Appendix 2. Note: 
Postmenopausal is defined as 12 months of spontaneous amenorrhea [in questionable 


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cases a blood sample with simultaneous follicle stimulating hormone (FSH) levels 
consistent with menopause (refer to laboratory reference ranges for confirmatory 
levels), or be >60 years of age]. 
3. Confirmed diagnosis of COPD in accordance with the ATS/ERS criteria [Celli, 2004] 
with a post-bronchodilator FEV1/ forced vital capacity (FVC) < 0.70 AND 30% ≤ 
FEV1%predicted ≤65% of predicted normal value calculated at Screen using the 
Quanjer reference equation [Quanjer, 2012].   
4. Short Physical Performance Battery (SPPB) with ALL of the following: 
 Timed chair stand score ≥1 AND ≤3 
 No score of “0” on any component of the SPPB (i.e., gait speed, balance, or 
timed chair stand) 
5. Body Mass Index (BMI) within the range 18 - 32kg/ m2 (inclusive), where BMI = 
(weight in kg) / (height in meters)2  
6. Current smokers OR former smokers with a cigarette smoking history of ≥10 pack 
years (1 pack year =20 cigarettes smoked per day for 1 year or equivalent). Former 
smokers are defined as those who have stopped smoking for at least 6 months prior to 
Baseline. 
7. Participants must be able to read and write in the language used for the provided 
electronic diary and be able to operate an electronic device to a level that allows them 
to complete an electronic diary on a daily basis.  
8. Participants participating in a structured exercise program must be willing to convert 
their current exercise program to the home exercise program used in this study. 
9. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participants with a history of myocardial infarction, angina, congestive heart failure 
exacerbation, hospitalization for cardiac aetiology, stroke or transient ischemic attack 
in the past 12 months. 
2. Neurologic, musculoskeletal, osteoarthritis, or any other condition that in the opinion 
of the investigator limits participant’s ability to complete study physical assessments. 
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
4. Participants with a history of cholecystectomy. 
5. Participants with a history of malignancy that is not in complete remission for at least 
2 years or 1 year for non-melanoma skin carcinoma. 
6. Participants with a family history of early onset prostate cancer or familial prostate 
cancer (multiple family members). 


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7. Diseases known to cause malabsorption of protein or energy, such as inflammatory 
bowel disease, celiac disease, pancreatic insufficiency, etc. 
 
Prior/Concomitant Therapy 
8. Current or planned administration of cholestyramine or strong oral or injectable 
cytochrome P-450 isoenzyme 3A4 (CYP3A4) inducers (refer to Section 7.7 for a list 
of prohibited medications). 
9. Current or planned use of any prescription drugs known to affect muscle mass, 
including androgen supplements, anti-androgens (such as LHRH agonists), anti-
estrogens (tamoxifen, etc.), recombinant growth hormone, megesterol, etc.  
10. Use of oral steroids concurrently or within 4 weeks preceding the screening visit. 
 
Prior/Concurrent Clinical Study Experience 
11. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to randomization in the current study:  
30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
 
Diagnostic assessments 
12. Participants with values outside the specified ranges for the following Key Clinical 
Laboratory Tests must be excluded from the study:  
 Renal function: Glomerular Filtration Rate (GFR) <30 (mL/min/1.73 m2) using 
formulae provided in the Study Reference Manual (SRM). Note: Participants 
receiving dialysis are excluded from this study. 
 Metabolic – HbA1c >7.5%.  
 ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%). 
 Haematology – Haemoglobin <10.0 g/dL at screening 
 Prostate Specific Antigen (PSA) >4.0 ng/mL 
 
13. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment. NOTE: 
Participants with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C RNA PCR test is obtained. 
14. QT interval corrected for heart rate by Bazett's formula (QTcB) or QT interval 
corrected for heart rate by Fridericia’s formula (QTcF) >450 msec or QT interval 
corrected for heart rate (QTc) >480 msec in participants with Bundle Branch Block 
based on a single ECG. 
15. A positive test for HIV antibody.  


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Other Exclusions 
16. More than two moderate/severe COPD exacerbations within the past year 
 
Exacerbation is defined as worsening of two or more of the following major 
symptoms: dyspnoea, sputum volume, sputum purulence OR worsening of any 
one major symptom together with at least one of the following additional 
symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever > 
37.5°C without any explained cause, increased cough, increased wheeze. 
 
A moderate exacerbation is defined as an exacerbation that requires treatment 
with antibiotics and/or oral steroids. A severe exacerbation is defined as an event 
that is additionally associated with hospitalization or emergency room visit. 
17. Any moderate/severe COPD exacerbation in the 4 weeks preceding the screening 
visit.  
18. Participants on long term oxygen therapy (LTOT), defined as prescribed continuous 
oxygen use for >14 hours/day.  
19. Clinically diagnosed history of drug or alcohol abuse within 5 years prior to 
randomization. 
20. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation. 
21. Participation in a formal pulmonary rehabilitation exercise program outside or inside 
the home, either currently or completed within the previous 6 months. 
22. For participants who opt to have MRI at participating study sites, there must be no 
contraindications to MRI, for example known claustrophobia or a pacemaker. 
Specific MRI contraindications will be determined by the type of MRI scanner 
available at each site and study personnel should confirm local eligibility 
requirements. 
6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
Over the counter medications or supplements that are known to be strong inducers of 
CYP3A4, such as St John’s Wort, should be discontinued for the duration of the study. 
Except as stated above, participants should continue their regular diet for the duration of 
the study. 
6.3.2. 
Caffeine, Alcohol, and Tobacco 
For each visit, participants will abstain from any alcohol for 24 hours prior to the start of 
the visit until collection of the venous blood sample during each visit. For the duration of 
the study, participants should be encouraged to avoid excessive alcohol intake (defined as 
consumption of more than 1-2 drinks per day in the USA).  


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6.3.3. 
Activity 
Participants should refrain from significant changes in their exercise level (e.g., joining a 
gym), except as instructed by the investigator, for the duration of the study. Participants 
will abstain from strenuous exercise, e.g. running, for 24 hours prior to each blood 
collection for clinical laboratory tests. 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently randomized.  A minimal set of screen information is required 
to ensure transparent reporting of screen failure participants, meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious SAEs. 
Participants are expected to meet study entry criteria when they are randomized.  If a 
participant initially qualifies for the study and their condition changes prior to 
randomization such that they no longer qualify for the study, the participant should be 
considered a screen failure. Participants who experience a moderate/severe exacerbation 
of COPD in the period after the screening visit AND before the baseline visit should be 
considered a run-in failure, however these participants may be eligible for rescreening at 
a later date. Note: Participants who fail screen may be rescreened if, in the opinion of the 
investigator, the participant’s condition was transient and the participant will qualify for 
the study at a later date during the study enrolment period. Participants may be 
rescreened a maximum of two times in total. 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: 
GSK2881078 
Placebo 
Dosage formulation: 
Capsule 
Capsule 
Unit dose strength(s): 
0.5mg, 1.0mg 
N/A 


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Dosage level(s) 
1.0mg for women (2 x 0.5mg 
capsules) once daily 
2.0mg for men (2x 1.0mg 
capsules) once daily 
2 capsules once daily 
Route of Administration  
For oral use only 
For oral use only 
Dosing instructions:  
Take as directed 
Take as directed 
Packaging and Labeling 
Capsules will be provided in 
a bottle. Each bottle will be 
labeled as required per 
country requirement.  
Capsules will be provided in 
a bottle. Each bottle will be 
labeled as required per 
country requirement. 
 
7.1.1. 
Medical Devices 
 
There are no GSK manufactured medical devices (or devices manufactured for GSK 
by a third party) provided for use in this study. 
 
Other medical devices (not manufactured by or for GSK) provided for use in this 
study are the Actigraph physical activity monitor, a consumer pedometer and an 
android tablet which will be used to administer the home exercise program and 
electronic PROs. 
 
Instructions for medical device use are provided in the study reference manual. 
7.2. 
Dose Modification 
Not applicable. 
7.3. 
Method of Treatment Assignment 
Male and post-menopausal female participants who are between 50 and 75 years of age 
and meet all other study entry criteria will be assigned to one of the (Male: placebo or 2.0 
mg of GSK2881078; Postmenopausal female: placebo or 1.0 mg of GSK2881078) in a 
ratio of 1:1 in accordance with the randomization schedule generated under the auspices 
of Clinical Statistics at GSK, prior to the start of the study, using validated software. 
Separate randomizations will be generated for each gender, and the randomisation 
process will assign the container number for study treatment. Each participant will be 
dispensed blinded study treatment with unique container numbers, which will be distinct 
from the randomisation numbers. 
If a participant experiences an exacerbation, then that participant may be replaced upon 
consultation with GSK.  The replacement participant will receive the same treatment as 
the participant being replaced. The random number for the replacement participant will 
be 1000 + the random number for the replaced participant. 


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7.4. 
Blinding 
This will be a double blind (sponsor unblind) study and the following will apply.  
 
The investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious medical 
condition when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the participant as judged by the investigator.  
 
It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment.  
 
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for the 
safety of participants currently in the study.  
 
The date and reason for the unblinding must be fully documented in the CRF  
A participant will be withdrawn if the participant’s 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 CRF. 
 
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.  
 
Members of the GSK study team will be unblinded for in-stream data reviews and 
the interim analyses as appropriate. This may include the study statistician, 
programmers, physician project leader, Muscle Metabolism Discovery Performance 
Unit leader, safety review team and other decision makers. At the time of interim 
analysis, access to the randomization will be restricted to randomization numbers 
that have been assigned at the time of data cut-off. 
7.5. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. Participants should be 
encouraged to store study treatment in a secure environment and follow directions 
for storage on the drug label. 


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3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.  
 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. 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 
 
When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  
 
When participants self-administer study treatment(s) at home, compliance with 
GSK2881078will be assessed through querying the participant during the site visits 
and documented in the source documents and CRF.  A record of the number of 
GSK2881078 tablets dispensed to and taken by each participant must be maintained 
and reconciled with study treatment and compliance records.  Treatment start and 
stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the CRF. 
 
Compliance at each visit will be determined as follows: 
(# dispensed - # returned) x 100 / (# days since last visit) 
 
Participants estimated to have taken less than 80% or more than 120% of study 
treatment capsules at two consecutive visits will be considered noncompliant. All 
attempts should be made to improve the participant’s compliance in taking study 
treatment if the participant is continuing in the study.  
7.7. 
Concomitant Therapy 
Medications and therapies not specifically prohibited by the study are allowed. Study 
participants must be on optimal maintenance therapy for COPD prior to screening, with 
no change in maintenance therapy for at least 4 weeks prior to baseline measurements 
and no anticipated changes between baseline and end of study.  Any medication or 
vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrollment or receives during 
the study must be recorded along with: 
1. reason for use 
2. dates of administration including start and end dates 


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3. dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Use of the following medications with study treatment is prohibited during the study: 
 Cholestyramine 
 Oral steroids 
 Any prescription drugs known to affect muscle mass, including androgen 
supplements, anti-androgens (such as LHRH agonists), anti-estrogens (tamoxifen, 
etc.), recombinant growth hormone, megesterol, etc.  
 
Strong inducers of CYP3A4 such as St John’s Wort, Carbamezapine, Phenytoin and 
Rifampicin. 
Of note, weaker CYP3A4 inducers are allowed. 
A more complete listing of the different classes of CYP3A4 inducers can be found at 
Univ of Indiana School of Pharmacy website 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/ ) or FDA website 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm#classInhibit). 
Although no evidence of lowering of blood glucose has been seen in phase I human 
studies of GSK2881078, improved glycaemic control has been observed with other 
SARMs, e.g. GTx-024, in healthy volunteers. Although the risk of a hypoglycaemic 
event in participants on diabetes treatments and GSK2881078 is considered very low, 
participants who are on medication (either oral medication or insulin) for diabetes should 
be counselled to monitor their blood glucose levels (where applicable) and remain alert 
for hypoglycaemic events. Participants should seek medical advice to adjust their 
diabetes treatment if they have any concerns in conjunction with advice from the 
Investigator and/or the Medical Monitor. 
7.8. 
Treatment after the End of the Study 
Participants will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
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8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
A participant may discontinue treatment if they have a severe exacerbation of COPD 
requiring hospitalization or if they meet liver or QTc stopping criteria. A participant who 
discontinues study treatment should return to the clinic only for the follow-up visit within 
the specified window if possible. Only the safety assessments for the follow-up visit 
(physical examination, 12-lead ECG, vitals, blood tests, urinalysis and concomitant 
medication review) should be conducted in these participants as described in the SoA and 
Section 9.4. 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and 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 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met: 


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Liver Chemistry Stopping and Increased Monitoring Algorithm 
 
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 4 Liver Safety: Required Actions and Follow-up Assessments 
8.1.2. 
QTc Stopping Criteria 
For trial eligibility and discontinuation, ideally the same QT correction formula will be 
used for all participants within a single trial.  However, GSK does recognize that because 
multiple sites from different countries may participate in a single trial, this may not 
always be possible since QT correction formulae pre-programmed by different 
manufacturers within ECG machines tend to vary.  In these situations, the same QT 
correction formula must be used throughout the trial for an individual participant. 
 
The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5-10 minute) recording period.   
A participant who meets either of the bulleted criteria below will be withdrawn from the 
study: 
 
QTc >500 msec OR Uncorrected QT >600 msec 
 
Increase from baseline of QTc >60 msec 
For participants with underlying bundle branch block, follow the discontinuation 
criteria listed below: 
Continue Study Treatment 
Discontinue Study Treatment 
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
Yes
No
*INR value not applicable to subjects on anticoagulants
Plus
Bilirubin ≥ 2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT ≥ 8xULN
ALT ≥ 3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT ≥ 3xULN
but able to 
monitor 
weekly for 
4 weeks
ALT ≥ 3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
ALT ≥ 3xULN
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
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*
5xULN ≤ ALT
< 8xULN
Yes
recheck ALT and bilirubin
2-3 days later and then 
every 2-4 days for 2 weeks;
persists longer than 2 weeks
No
Yes


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Baseline QTc with Bundle Branch Block Discontinuation QTc with Bundle 
Branch Block 
<450 msec 
>500 msec 
450 – 480 msec 
≥530 msec 
 
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed. 
8.1.3. 
Temporary Discontinuation 
Withdrawal of study treatment requires withdrawal from the study.  
8.1.4. 
Study Treatment Restart or Rechallenge 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
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, 
behavioral, compliance or administrative reasons. 
 If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
 If a participant decides to withdraw or is withdrawn by the responsible 
physician, the reasons for withdrawal and the results of any relevant tests will 
be recorded in the CRF and the planned follow-up procedures will be 
performed, where possible.  
 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 the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. Only the 
safety assessments scheduled for the follow-up visit should be conducted in 
these participants as described in the SoA (Section 2). 
 Any participant who experiences a severe COPD exacerbation (i.e., 
associated with hospitalization or emergency room visit) or an exacerbation 
that requires treatment with oral steroids will be permanently discontinued 
from study treatment and should return to the clinic for the follow-up visit 
within the specified window if possible.  Only the safety assessments 
scheduled for the follow-up visit should be conducted in these participants 
as described in the SoA (Section 2 ). 


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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.  
 
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.  
 
Except for the SPPB, procedures conducted as part of the participant’s routine 
clinical management (e.g., blood count) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA. All 
protocol-specified lab samples obtained from Baseline through the end of the study 
must be submitted to the central lab. 
 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. Individual visit blood draws should not exceed 50mls. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples. 


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9.1. 
Study Procedure 
9.1.1. 
Screen 
Participants who meet study inclusion/ exclusion criteria will be provided with a 
computer tablet and physical activity monitor after signing informed consent for the 
study. Participants will complete a “training period” with the Daily PROactive Physical 
Activity in COPD instrument (Section 9.2.4.4) and Physical Activity Monitor (Section 
9.2.4.5) for 1 week after screening, and will return the Actigraph activity monitor at the 
day -9 visit.  
NOTE: If participants do not have results from the screening blood tests available on the 
day of screening, they may still be dispensed a computer tablet and activity monitor 
provided the other study inclusion/exclusion criteria are met; if participants are 
subsequently found to be ineligible, they must return the tablet and monitor to the study 
site as soon as possible and physical activity data from these participants will not be 
collected. 
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening. The following demographic parameters will be captured: year of birth, sex, 
race and ethnicity. Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 6.1. The number of previous exacerbations 
and history of pulmonary rehabilitation must be recorded in the CRF. 
9.1.2. 
Day -9 and day 80 visits 
The purpose of the day -9 and day 80 visits is primarily to collect 7 days of activity data 
from the previous visits (screening and day 56 visits respectively) and to dispense activity 
monitors for the following visit. Activity data and PROactive questionnaire data should 
be downloaded at day -9 and day 80 visits. A fully charged activity monitor and new 7 
day daily PROactive instrument should be dispensed, and this data should be collected at 
baseline (day 1) and last dose (day 90) visits respectively. 
The day -9 visit will also be used to familiarise participants with the home exercise 
training program, and to dispense equipment for home exercises, although participants 
should only begin exercises on day 1. 
A practice incremental shuttle walk test (Section 9.2.3.2) should also be carried out at the 
day -9 visit to familiarise participants with the test prior to baseline.  
9.1.3. 
Baseline (day 1) and last dose (day 90) visits 
Details for efficacy and safety assessments can be found in Section 9.2 and Section 9.5 
respectively. At some study sites, optional cardiac, liver and prostate MRI scans will be 
offered to eligible participants (Section 9.5.5). 
Day 1 and day 90 visits should be conducted within 1 day, but participants may need to 
return on a separate day for the MRI and/or DXA scans, and possibly other assessments. 
The scans, and any other assessments, may be conducted on a separate day within the 


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visit window where it is not feasible to conduct these on the same day. For the baseline 
visit, all assessments should be carried out prior to randomization. The order for 
conducting all study assessments will be specified in the study reference manual (SRM). 
Participants should return the Actigraph activity monitors and completed PROactive 
diary instruments at these visits. At day 90, participants should additionally return 
equipment related to the home exercise program. 
All baseline and day 90 assessment should be conducted in accordance with instructions 
in the SoA and within Section 9. Participants should remain within the unit for 
observation for 1 hour following the first dose. 
9.1.4. 
Interim visits 
All assessments will be performed at the times specified in the SoA and in Section 9.2 
and Section 9.5 . 
9.1.5. 
Follow-up visit 
All assessments will be performed at the times specified in the SoA and in Section 9.2 
and Section 9.5. For participants who have discontinued study treatment, only safety 
assessments as described in Section 9.5  and the SoA should be carried out. 
9.2. 
Efficacy Assessments 
All assessments will be performed at the times specified in the SoA (Section 2) and 
Section 9.1.3. 
9.2.1. 
Pulmonary Function Tests 
9.2.1.1. 
Spirometry 
Spirometry using FEV1 and FVC measurements (FEV% predicted, and FVC% predicted 
and FEV1/FVC will be calculated using the Quanjer reference equation [Quanjer, 2012]) 
will be performed. At least three, and no more than 8 efforts must be performed in order 
to obtain at least three acceptable efforts at one visit. The best of three acceptable efforts 
will be recorded in the CRF. Spirometry assessments should be performed in accordance 
with American Thoracic Society/European Respiratory Society guidelines. Spirometry 
will be performed at screening, baseline, day 56, and day 90. Site-specific training will be 
given at the site initiation visit for all sites to harmonize data collection procedures prior 
to participant recruitment. Assessments should be carried out on the same spirometer and 
by the same site personnel where possible to reduce inter-observer variation. 
9.2.1.2. 
Sniff Nasal Inspiratory Pressure (SNIP) 
Inspiratory muscle strength will be assessed by measuring the maximal SNIP [Kyroussis, 
2002]. A bung size-specific to the participant is placed in the nostril deemed by the 
investigator to be most patent.  The participant is asked to make a maximum voluntary 


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sniff effort via a peak flow meter and the greatest effort from 10 repeat measurements 
will be recorded in the CRF. The sniff meter display is visible to the participants to 
provide feedback. SnIP measurements will be undertaken at screening, baseline, day 56 
and day 90 visits. Site-specific training will be given at the site initiation visit for all sites 
to harmonize data collection procedures prior to participant recruitment. Assessments 
should be carried out by the same site personnel where possible to reduce inter-observer 
variation. 
9.2.2. 
Lean Mass measures 
9.2.2.1. 
Dual-Energy X-ray Absorptiometry (DXA) 
Participants will be asked to lie on a padded platform while a mechanical arm passes over 
their body; the test usually takes approximately 10-30 min.  Output from these scans will 
be used to measure body composition including total body mass, total lean mass and fat 
mass. Appendicular lean mass will be calculated from the regional lean mass 
measurements of the arms and legs. DXA measurements will be undertaken at baseline, 
day 28, 56, 90 and follow-up visits. 
 
9.2.3. 
Functional Assessments 
All functional assessments should be performed as described in the SRM. 
9.2.3.1. 
Leg Press 
Lower extremity strength will be measured as the 1-repetition maximum (1-RM) on a leg 
press device.  
Participants will have a warm up followed by one set of 5-10 repetitions using 40-60% of 
estimated maximum.  Participants will then lift progressively heavier weights in steps, 
with each step separated by an appropriate rest period, until participant cannot complete 
the lift.  The last successfully completed lift will be recorded as the 1-RM [LeBrasseur, 
2008; Travison, 2011]. The same study personnel should perform this test wherever 
possible; site-specific training for this procedure will be given to harmonize data 
collection procedures prior to participant recruitment. Leg press measurements will be 
undertaken at screening, baseline, day 28, day 56, day 90 and follow-up visits. 
9.2.3.2. 
Shuttle walk tests (Incremental shuttle walk test and endurance shuttle 
walk test) 
Participants will perform a practice standard, incremental shuttle walk test on the day -9 
visit. An incremental shuttle walk will be performed at the baseline visit and the day 90 
visit to determine peak work rate.  After a minimum 40 minute rest, participants will 
perform constant work rate testing (endurance shuttle walk test) at 85% of peak work rate 
from the incremental walk test conducted at the baseline visit.  
Tests will be stopped when participants are unable to maintain the walking speed and/or 
are too tired and/or breathless to continue [Singh, 1992]. The total distance walked from 


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the incremental test, duration in seconds from the CWR and percentage change for both 
peak work rate and endurance time should be recorded. 
Site-specific training for this procedure will be given to harmonize data collection 
procedures prior to participant recruitment.  
9.2.3.3. 
Short Physical Performance Battery (SPPB) 
Participants will be assessed for balance, timed rises from a chair, and gait speed, and 
scored according to published guidelines [Guralnik, 1994]. The scores for each 
component and the time in seconds for each component will be recorded. The same study 
personnel should perform this test wherever possible; site-specific training for this 
procedure will be given to harmonize data collection procedures prior to participant 
recruitment. 
Short physical performance battery should be undertaken at screening, baseline, day 28, 
day 56 and day 90 visits. 
9.2.3.4. 
Handgrip Strength 
Handgrip strength of both hands will be measured and recorded using a hand 
dynamometer with participants seated, their shoulders adducted, elbows flexed to 90˚ and 
forearms in a neutral position. Participants will be asked to make a maximal effort to 
squeeze the handle and strength will be recorded to the nearest kilogram. The best of the 
six measurements (three measurements for each hand) will be used for the statistical 
analyses [Puhan, 2013]. 
9.2.4. 
Patient Reported Outcomes Assessments 
9.2.4.1. 
COPD Assessment Test (CAT) 
The CAT (www.CATestonline.org) is a validated, short (8 item), and simple patient 
completed questionnaire which has been developed for use in routine clinical practice to 
measure the general health status of patients with COPD. The CAT is designed to 
measure overall COPD-related health status for the initial assessment and longitudinal 
follow up of COPD patients. When completing the questionnaire, participants complete 
each question by rating their experience on a 6 point scale with anchoring statements, 
ranging from 0 (no impairment) to 5 (maximum impairment) with a total scoring range of 
0 – 40 [Jones, 2009]. The CAT will be completed at baseline, day 56 and day 90. 
9.2.4.2. 
St George Respiratory Questionnaire COPD (SGRQ-c) 
The SGRQ-c (http://www.healthstatus.sgul.ac.uk/SGRQ_download/sgrq-c-manual-april-
2012.pdf) has been developed using COPD data only to measure general health related 
quality of life, and is a validated questionnaire for COPD. It consists of 40 items in total, 
corresponding to 3 individual domains: symptoms, activity and impact, with different 
components carrying a different weighting. The score range is from 0 (no impairment) to 
a theoretical maximum of 3201.9 for the worst possible state of the participant. The 


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minimal clinically important difference for a change in SGRQ-c is 4.0 points [Jones , 
2005].  The SGRQ-c will be completed at baseline and day 90. 
9.2.4.3. 
Patient Global Rating of Severity (PGRS) and Patient Global Impression 
of Change (PGIC) 
The PGRS is a single global question that asks participants to rate how their condition 
impacts their ability to perform physical activity on a five-point scale (none, mildly, 
moderately, severely, very severely). 
Responses to the PGIC question will be on a 7 point Likert scale ranging from much 
better to much worse. 
The PGRS will be completed only at baseline and day 90.  However, the PGIC will be 
completed at day 14, 28, 56, 90 and at the follow up visit.  
9.2.4.4. 
Daily PROactive Physical Activity in COPD instrument (D-PPAC) 
The Daily PROactive instrument is a hybrid outcome assessment tool comprising an 
electronic diary and outputs from a triaxial physical activity monitor (described in 
9.2.4.5)  which has been assessed as compatible with PROactive. The electronic diary 
consists of 7 questions to be completed each evening. The output from the e-diary is 
combined with two summary outputs from the activity monitor to produce the PROactive 
score. 
The PROactive tools were developed by a consortium funded by the European Union 
Innovative Medicines Initiative (IMI) (JU115011) using well accepted methodologies. 
The PROactive consortium included pharmaceutical companies, academic institutions 
and patient organisations from across Europe (www.proactivecopd.com).  Following 
systematic reviews of determinants and outcomes of physical activity [Gimeno-Santos, 
2014] available patient reported measures of activity [Gimeno-Santos, 2011; Williams, 
2012; Frei, 2011] and performance of activity monitors [Van Remoortel, 2012] the 
components of the tool were developed. 
The original activity monitors included in the PROactive trials were chosen based on 
performance in COPD patients across a range of disease severity [Van Remoortel, 2012; 
Rabinovich, 2013].  Activity monitors assessed as compatible for use in the PROactive 
tools are assessed against this standard.  
Development of the electronic diary was patient centred and also involved physician 
interviews [Dobbels, 2014]. The items included in the final diary were finalised using a 
structured, rigorous scientific approach in the item reduction process to select the best 
items and generate the final questionnaire. The psychometric properties of the PROactive 
tool and responsiveness were determined in a program of studies conducted by 
consortium members [unpublished data]. 
The fit of the PROactive tool for this indication and population will be assessed in a 
separate validation exercise and via the exit interviews in this study. 


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9.2.4.5. 
Physical Activity Monitor 
Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity as assessed by airflow limitation, dyspnoea, and 
overall health status [Watz, 2009]. Studies have reported that a low level of daily activity 
in COPD is associated with an increased risk of hospital admissions for acute 
exacerbations of COPD, morbidity and mortality [Bourgeois, 2011; Waschki, 2011]. 
Increased activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].  A recent ECLIPSE sub study in COPD participants 
demonstrated the potential application of physical activity monitors in multicenter 
clinical trials [Waschki, 2012]. 
A clinically validated physical activity monitor (accelerometer) will be used to measure 
levels of activity. The physical activity monitor will be worn for 7 days by the study 
participants at 4 time points during the study to provide the total PROactive score. A 
separate consumer based pedometer will be worn at the wrist throughout the study 
treatment period to count the daily number of steps in conjunction with the home exercise 
program. 
In addition to a period of familiarization with the physical activity monitor after 
screening, there will be 3 assessment periods, including an initial baseline assessment in 
order to provide a reliable estimate of habitual physical activity. Further details will be 
provided in the SRM. 
Physical activity monitors will be shipped from each study site directly to GSK for 
analysis and interpretation or to an independent vendor, contracted by GSK, blinded to 
treatment assignment, who will be responsible for transmitting the data to GSK and 
returning the devices to the sites. 
9.2.4.6. 
Patient Exit Interview 
An exit interview will be administered by experienced interviewers (by a partner agency) 
at the end of the study. The questions included in the interview are designed to more fully 
understand the participant’s experience with the study medication and the study itself. 
Interviewers will  usea semi-structured interview guide and data collection sheet and 
responses will be audio-recorded for purposes of accurate analysis; exit interview data 
will be recorded and reported separately to the main study report.  
9.2.5. 
Home Exercise Program 
A home exercise program will be administered via an application developed by GSK. 
The application gives customised instruction to participants to incrementally increase 
their physical activity (via monitoring step counts) and strength (through a combination 
of strengthening exercises). Exercises are demonstrated on videos in the application as 
well as via written instruction; participants will be further given training on using the 
application by site staff, who will assess their baseline ability to perform all exercises in 
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9.3. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 5. 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or the study (see Section 
8). 
Planned time points for all safety assessments are listed in the SoA (Section 2). 
Additional time points for safety tests (such as vital signs, physical exams and laboratory 
safety tests) may be added during the course of the study based on newly available data to 
ensure appropriate safety monitoring. 
 
9.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
 All SAEs will be collected from start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2). 
 All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2). 
 Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section. 
 All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 5. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available. 
 Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor. 
 The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 5. 
  
9.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  


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Appropriate questions include: 
 
“How are you feeling 
 
“Have you had any (other) medical problems since your last visit/contact?” 
 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
9.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 5. 
 
9.3.4. 
Regulatory Reporting Requirements for SAEs 
 Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study 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 IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
9.3.5. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 5 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV medical 
dictionary for regulatory activities (MedDRA) terms.  The CV information should be 


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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 CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
9.3.6. 
Pregnancy 
 
Female participants of child bearing potential are excluded from this study. 
 
If a pregnancy is reported, the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in 
Appendix 2. 
 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
 
9.4. 
Treatment of Overdose 
For this study, any dose of GSK2881078 greater than 1.0mg for females and 2.0mg for 
males 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/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
9.5. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
9.5.1. 
Physical Examinations 
 A complete physical examination will include, at a minimum, assessments of the 
Skin, Head, Eyes, Ears, Nose, Throat, Thyroid, Cardiovascular, Respiratory, 
Gastrointestinal, Neurological, lymph nodes and extremities. Height and weight 
will also be measured and recorded; height measurements should be undertaken 
without shoes and for weight measurements, participants should remove 
outdoor clothing. 


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 A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen. Other brief 
physical examinations in this study may be conducted at the discretion of the 
Investigator for safety reasons (other than at screening or early 
withdrawal/follow-up). A full physical examination may be performed in lieu of 
a brief examination, at the discretion of the Investigator. 
 Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
9.5.2. 
Vital Signs 
  Skin temperature, pulse rate, respiratory rate, and BP will be assessed. 
 Blood pressure and pulse measurements will be assessed in a seated position 
with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
 Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 BPmeasurements (3 consecutive BP readings will be recorded at intervals of at 
least 1 minute). The average of the 3 BP readings will be recorded on the CRF. 
 
9.5.3. 
Electrocardiograms 
  12-lead ECGs in triplicate will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary. The same ECG machine and 
QTc correction factor should be used for all assessments in an individual 
participant. 
  At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart.  
 
9.5.4. 
Clinical Safety Laboratory Assessments 
 Refer to Appendix 6 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.  
 The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition. 


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 All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 42 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor.  
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
 All protocol-required laboratory assessments, as defined in Appendix 6, must be 
conducted in accordance with the laboratory manual and the SoA. Refer to the 
Laboratory Manual for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.  
 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 (e.g., 
SAE or AE or dose modification), then the results must be recorded in the 
relevant section of the CRF, e.g. the SAE form. 
 
9.5.5. 
MRI scans (Optional sub-study) 
 Pre-specified study sites will offer an optional cardiac, liver and prostate, where 
applicable, MRI to eligible participants. MRI will be undertaken in participants 
who consent at the baseline (day 1) and last dose (day 90) visits. 
 In participants who agree to the MRI scans, every effort should be made to 
conduct all applicable MRI scans (cardiac and liver MRI for female 
participants, and additionally a prostate MRI for male participants). In 
circumstances where it is not feasible to continue performing all the MRI scans 
(e.g. patient discomfort), the cardiac scan should be prioritized over the liver or 
prostate scans. 
 The protocol for the MRI scans can be found in the SRM. 
 The clinical report for the MRI should be reviewed by the investigator, and the 
review, together with any resulting actions, documented and filed in the CRF 
within 2 weeks of the MRI scan.  
 If results from the MRI require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
9.6. 
Pharmacokinetics 
 Blood samples of approximately 2 mL will be collected for measurement of 
plasma concentrations of GSK2881078 as specified in the SoA. Every effort 
should be made to collect samples at times throughout the time window (i.e., 
avoid collections from all subjects at the same time within a window or only at 
the extremes of a window). 


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 Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded in the eCRF.  Times of dose administration for the two doses 
immediately preceding a PK sample should be accurately recorded in the eCRF. 
 Samples will be used to evaluate the PK of study treatment. Samples collected for 
analyses of study treatment 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 parent compound, any remaining 
plasma may be analyzed for other compound-related metabolites and the results 
reported under a separate protocol. 
Drug concentration information that may/would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
9.7. 
Genetics 
A 6 mL blood sample for 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 7 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the Study 
Reference Manual. 
9.8. 
Biomarkers 
 Collection of samples for other biomarker research is also part of this study. 
Blood samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA. 
 Samples will be tested for reproductive tissue biomarkers, bone biomarkers and 
exploratory biomarkers to evaluate their association with the observed clinical 
responses to 2881078. 
 Other samples may be used for research to develop methods, assays, prognostics 
and/or companion diagnostics related to 2881078, COPD and/or sarcopenia, 
pathways associated with disease state, and/or mechanism of action of the study 
treatment. 
9.8.1. 
Reproductive Tissue Biomarkers 
 
luteinizing hormone 


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 
follicle stimulating hormone 
 
total testosterone 
 
free testosterone (calculated) in males and females 
 
estradiol (females) 
 
dihydrotestosterone 
 
sex hormone binding globulin 
 
prostate specific antigen (PSA) males 
9.8.2. 
Bone Biomarkers 
 
procollagen type I N propeptide (s-PINP) 
 
C-terminal telopeptide of type I collagen (s-CTX) 
9.8.3. 
Exploratory Biomarkers 
Blood samples (approximately 10 mL) will be collected at each timepoint indicated in the 
SoA (Section 2), such as proteins related to anabolic effects on muscle.  These samples 
will be analyzed separately. These results will not be reported as part of this study. See 
SRM for further details. 
10. 
STATISTICAL CONSIDERATIONS 
Unblinded data will be reviewed in-stream by the study team. A Bayesian predictive 
approach using a non-informative prior will be used for the assessment of futility of the 
strength endpoint at an interim analysis.  Although strength is the primary endpoint for 
the assessment of futility, the decision to continue or stop recruitment will be based on 
the totality of the data including strength, lean mass, functional endpoints, safety and 
tolerability.  
After study completion, a Bayesian analysis using non-informative priors will be used to 
estimate posterior and posterior predictive distributions, as appropriate, for strength, lean 
mass and the functional endpoints to inform decision making. A multivariate Bayesian 
approach will be employed, data permitting 
 In addition, the effects of GSK2881078 relative to placebo on strength, lean mass and 
functional endpoints (i.e., incremental and endurance shuttle walk tests, and SPPB) will 
be evaluated using an estimation approach where point estimates and associated 90% 
confidence intervals (CI) will be constructed. 
Descriptive statistics will be used to address safety, tolerability, PRO and PK objectives. 
Data for male and female subjects will be analyzed separately. Depending on recruitment 
rates, analysis and reporting may be completed at different times for males and females. 


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10.1. 
Sample Size Determination 
10.1.1. 
Sample Size Assumptions 
The sample size was determined using an estimation approach in order to provide 
sufficient precision for the estimation of the strength endpoint in particular, with 
consideration also given to lean mass and the functional parameters. In addition, the 
influence of the sample size on the estimated posterior probability (true treatment 
difference in change from baseline strength ≥ 9%) was evaluated. An increase in strength 
of 9% or more is of interest because it is consistent with effects observed with 
testosterone treatment [Casaburi, 2004 ; Sheffield-Moore, 2011; Bhasin, 2005 ]. Since 
different doses of GSK2881078 will be administered to males and females, all analyses 
will be conducted separately for each sex. Sample sizes of 10 (interim) and 20 per 
treatment group yield the following precision. 
Primary Endpoint 
 
Change from Baseline 
 
n 
Strength 
 (%)  
Target Effect1 (∆∆)  
 
9  
SD2  
 
10.9  
 
Half-width of 90% CI for ∆∆  
10 
8.45 
20 
5.8  
1∆∆ refers to difference from placebo in change from baseline. Strength  [Casaburi, 2004] 
and data provided by author; [Sheffield-Moore, 2011; Bhasin, 2005]; 2 Strength,  data 
provided by author];   
 
The sample size also supports the evaluation of the posterior probability (assuming a non-
informative prior) that the true treatment difference in change from baseline strength ≥ 
9% as illustrated in the graph below. Note a greater benefit is achieved by increasing the 
sample size from 10 to 20 than from 20 to 30. 


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For the secondary functional endpoints (ISWT, ESWT), it is uncertain what magnitude of 
effect would translate into a meaningful benefit to the participant. Therefore, the target 
effects listed below should be considered exploratory. A range of targets, including those 
indicated below will likely be evaluated. 
Secondary Endpoints 
 
Change from Baseline 
 
 
N 
Total Lean mass 
(kg)  
ISWT (m) 
ESWT (s) 
Target Effect1 (∆∆)  
 
2  
28.5 or 47.5 
132 or 186 
  
 
 
 
 
 
SD2  
 
2.5  
57 
265 
  
 
 
 
 
 
Half-width of 90% CI for 
∆∆  
10 
1.94 
44.2 
206 
20 
1.33  
30.4 
141 
1∆∆ refers to difference from placebo in change from baseline. Lean mass [Casaburi, 
2004] and data provided by author; [Sheffield-Moore, 2011; Bhasin, 2005]; ISWT 
estimated as ½ SD from unpublished GSK data or suggested by [Singh, 2008] ESWT  
estimated as ½ SD from unpublished GSK data or suggested by [Altenburg, 2015]; 2 Lean 
mass, and data provided by author]; ISWT and ESWT from unpublished GSK data 
 


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10.1.2. 
Sample Size Sensitivity 
Sample size sensitivity analyses are described above. 
10.1.3. 
Sample Size Re-estimation or Adjustment 
Based on the observed variability and treatment effects at an interim analysis, the sample 
size may be increased to improve the precision of the estimates of treatment effects and 
the operating characteristics of the end of study decision criteria. Strength, ISWT and 
ESWT will be considered in the sample size evaluation. Males and females will be 
evaluated separately. The sample size may be increased by up to 15 subjects/arm. 
Details of the interim analysis will be described in the Reporting and Analysis Plan 
(RAP). 
10.2. 
Populations for Analyses 
All Participants Population 
The ‘All Participants Population’ is defined as all randomized participants who receive at 
least one dose of study medication. 
Analysis Population 
The ‘Analysis Population’ (AP) is defined as participants in the ‘All Participants’ 
population having baseline and at least one post-baseline assessment of the strength, lean 
mass or functional endpoint.  
Per Protocol Population (PP)  
The ‘Per Protocol Population’ will consist of any AP participants who are compliant with 
protocol-specific criteria and who do not experience an exacerbation during the treatment 
phase of the study. Participants with specified protocol deviations and those failing to 
complete the Week 13 functional assessments will be excluded. The Per Protocol 
population will be used for analysis of strength, lean mass and the functional endpoints. 
Pharmacokinetic (PK) Population 
The ‘PK Population’ is defined as participants in the ‘All Participants’ population for 
whom a PK sample was obtained and analysed for GSK2881078. 
All available data will be used in the analyses as defined in the Populations above. 
Missing values will not be imputed. 
10.3. 
Statistical Analyses 
All analyses will be performed separately for females and males. 


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10.3.1. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Strength 
Change from baseline and percent change from baseline strength will 
be analyzed separately using mixed models repeated 
measures(MMRM) models with effects for treatment, day, treatment 
x day, and baseline strength.  Differences in least squares means 
between the GSK2881078 treated group and placebo will be 
calculated (i.e.; GSK2881078- placebo) along with associated 90% 
CIs. 
The same model will be used at both the interim analysis and at the 
end of the study. The analyses will be performed using all available 
data from participants in both the AP and the Per Protocol 
Population.  The effects of potential predictors of response including, 
but not limited to, baseline vitamin D levels and measures of 
pulmonary function may also be explored. 
At the interim, the posterior predictive distribution for % change 
from baseline strength will be estimated. This distribution will be 
used to estimate the probability that the end of study treatment 
difference will be ≥ 9%. Similarly, at study completion, the posterior 
distribution will be estimated and used to estimate the probability that 
the true treatment difference is ≥ 9%. 
Because % change endpoints often demonstrate a lack of normality, a 
supportive analysis will be performed where log-transformed strength 
is considered the dependent variable and log-transformed baseline the 
covariate using a MMRM model as described above. Differences in 
least squares means between each GSK2881078 treated group and 
placebo (i.e.; GSK2881078- placebo) along with associated 90% CIs 
will be constructed. The point estimates and CIs will be back-
transformed (exponentiated) to provide point estimates and CIs for 
the ratios, GSK2881078 to Placebo. 
Model and distributional assumptions underlying each analysis will 
be assessed by visual inspection of residual plots.  Parameters will be 
log-transformed prior to analysis if necessary to meet assumptions. If 
assumptions are still not met after log-transformation alternative 
methods of analysis will be considered.  
Complete details will be provided in the RAP. Any changes to the 
planned analyses described here will be documented in the study 
RAP and/or the Clinical Study Report. 
Exploratory 
Will be described in the reporting and analysis plan 


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10.3.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Endpoint 
Statistical Analysis Methods 
Primary 
Safety data will be presented in tabular and/or graphical format and 
summarized descriptively according to GSK’s Integrated Data Standards 
Library (IDSL) standards. No formal statistical comparisons will be made 
for the safety data. Complete details will be documented in the RAP. 
Exploratory 
Will be described in the reporting and analysis plan  
 
10.3.3. 
Other Analyses 
Descriptive summaries and graphical displays will be prepared for measures of 
respiratory function (FEV1, SnIP).  
The relationships between changes in lean mass or strength and other endpoints including 
but not limited to functional measures, PROs, and activity measures will be explored.  
A multivariate Bayesian approach using non-informative priors will be employed, data 
permitting, to further explore the relationships between changes in strength and lean mass 
and the functional outcomes (ISWT, ESWT,) and to inform decision making. Details of 
the analysis will be described in the Reporting and Analysis Plan (RAP). 
10.3.4. 
Interim Analyses 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail. 
In-Stream Review 
Safety, tolerability, strength, lean mass, and functional endpoint data will be reviewed by 
the GSK study team on an ongoing basis throughout the study for the purpose of internal 
decision making. These reviews can include individual participant data, summaries by 
treatment group and graphical displays.  GSK staff will be unblinded (See Section 7.3).  
Participants and all site personnel will be blinded to participant randomization. 
Preliminary safety, strength, lean mass, functional endpoint and PK results may be 
reported prior to database freeze for the purposes of safety review by GSK and where 
required by regulatory bodies.  
Interim Analysis 
An interim analysis for the assessment of futility is planned. It is anticipated that a formal 
declaration of futility would not be made before at least 10 participants per group have 
completed dosing and all key study assessments.  However, if at any time it is determined 


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that the probability of a successful outcome is sufficiently low, recruitment could be 
stopped. The primary endpoint for assessment of futility is strength. However, the 
decision to continue or stop recruitment will be made by the unblinded GSK clinical 
study team and SRT based on the evaluation of all available safety, efficacy, and 
tolerability data.  Such decisions will be based on the totality of the data (including 
strength, lean mass, function, safety, and tolerability). The feasibility of making a 
decision to stop recruitment based on a futility analysis will be dependent on the 
recruitment rate. Whether recruitment is suspended for the interim analysis will be 
dependent on the recruitment rate. Assessment of futility will be done separately for 
female and male participants.  A Bayesian predictive approach using a non-informative 
prior will be used to assess the futility of % change from baseline strength at 13 weeks. 
The futility criteria for strength will be based on the posterior predictive probability at the 
interim that the end of study difference in % change from baseline strength between 
GSK2881078 and placebo will achieve a positive outcome (≥9%).  If the predicted 
probability of achieving this positive outcome is too low in the context of all available 
data, then enrolment into the treatment arm(s) or cohort may be stopped.    
Simulations have been conducted to investigate the operating characteristics (statistical 
properties) of different futility criteria across a range of true treatment differences 
between GSK2881078 and placebo.  More details on this procedure will be provided in 
the RAP.  
As described in Section 10.1.3, the sample size may be increased to improve the 
precision of the estimates of treatment effects based on the observed variability and 
treatment effects at an interim analysis. This assessment will be done separately for males 
and females.  


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Basaria S, Collins L, Dillon E, Orwal K, Storer T, Miciek R, et al. The Safety, 
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Bourgeois J, Weston N, Garschick E, Moy M. Daily Step Count Predicts COPD 
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Gimeno-Santos E, Frei A, Dobbels F, Rudell K, Puhan M, et al. Validity of Instruments 
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Rabinovich RA, Louvaris Z, Raste Y, Langer D, Van Remoortel H, et al. Validity of 
Activity Monitors During Daily Life in Patients with COPD. European Respiratory 
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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Analysis Population 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area under concentration-time curve 
AUC(0-t) 
Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a 
participant across all treatments 
AUC(0-tau) 
Area under the concentration-time curve over the dosing 
interval 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CAT 
COPD Assessment Test 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form 
CV 
Cardiovascular 
CWR 
Constant Work Rate 
CYP3A4 
cytochrome P-450 isoenzyme 3A4  
DNA 
Deoxyribonucleic acid 
D-PPAC 
Daily PROactive Physical Activity in COPD 
DXA 
Dual-energy X-ray Absorptiometry 
ECG 
Electrocardiogram 
ESWT 
Endurance shuttle walk test 
FDA 
United States Food and Drug Administration 
FEV1 
The amount of air which can be forcibly exhaled from the 
lungs in the first second of a forced exhalation 
FSH 
Follicle Stimulating Hormone 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GFR 
Glomerular Filtration Rate 
GSK 
GlaxoSmithKline 
HBsAg 
Hepatitis B Surface Antigen 
IB 
Investigator's Brochure 
HDL 
High-Density Lipoprotein (cholesterol) 
HIV 
Human Immunodeficiency Virus 


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ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee 
IMI 
Innovative Medicines Initiative 
IRB 
Institutional Review Board 
ISWT 
Incremental shuttle walk test 
LBM 
Lean Body Mass 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MSDS 
Material Safety Data Sheet 
1-RM 
1-repetition maximum 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PGIC 
Patient Global Impression of Change 
PGRS 
Patient Global Rating of Severity 
PP 
Per Protocol Population 
PRO 
Patient Reported Outcomes 
PSA 
Prostate Specific Antigen 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate by Bazett's formula 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
SARM 
Selective Androgen Receptor Modulator 
SAE 
Serious Adverse Event 
s-CTX 
C-terminal telopeptide of type I collagen  
SNIP 
Sniff Nasal Inspiratory Pressure 
s-PINP 
Procollagen type I N propeptide 
SPPB 
Short Physical Performance Battery 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
ULN 
Upper Limit of Normal (reference range for laboratory) 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Actigraph 
 


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12.2. 
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
 Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Female participants 
Female participants of childbearing potential are not eligible to participate.  
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. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-


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ovulation methods), declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception.  
 Agree to use a male condom plus an additional method of contraception with 
a failure rate of <1% per year as described in Table 1 when having penile-
vaginal intercourse with a woman of childbearing potential  
 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame  
 
Refrain from donating sperm for duration of study and for 4 months from last 
dose 
Table 1 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
 oral 
 intravaginal  
 transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
 injectable  
Highly Effective Methods That Are User Independent  
 Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and
the preferred and usual lifestyle of the participant.)  


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NOTES:  
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.  
b. 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 125 days, corresponding to time needed to eliminate study treatment plus 30 
days for study treatments with genotoxic potential] after the last dose of study treatment  
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment. 
 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
 


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12.3. 
Appendix 3: Study Governance Considerations 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with: 
 Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
 Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/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.  
 Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
 A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
 Participants who are rescreened are required to sign a new ICF. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature. 
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 


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not as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy 408. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
 The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
 The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements.  
 Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 7 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 


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written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor.  
Source Documents 
 Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
 Definition of what constitutes source data can be found in the Trial Master File. 
 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of participants by the investigator 
 
Discontinuation of further study treatment development 


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12.4. 
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments  
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT-absolute 
ALT ≥ 8xULN 
ALT Increase 
ALT ≥ 5xULN persists for ≥2 weeks  
ALT Increase 
ALT ≥ 3xULN persists for ≥4 weeks 
Bilirubin1, 2 
ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) 
INR2 
ALT ≥ 3xULN and INR>1.5, if INR measured 
Cannot Monitor ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT ≥ 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
 Immediately discontinue study treatment  
 Report the event to GSK within 24 hours 
 Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
 Perform liver event follow up assessments  
 Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
 Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted. 
 If restart/rechallenge not allowed per protocol 
 Viral hepatitis serology4 
 Blood sample for pharmacokinetic (PK) 
analysis, obtained within 14 days after 
last dose5 
 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 


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or not granted, permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments  
 
 
MONITORING: 
For bilirubin or INR criteria:  
 Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs 
 Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline  
 A specialist or hepatology consultation is 
recommended 
For All other criteria:  
 Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-72 
hrs  
 Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline 
 Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
 Record alcohol use on the liver event 
alcohol intake case report form 
 
For bilirubin or INR criteria: 
 Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins). 
 Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]).  
 Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody  
5. PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 


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Liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT ≥3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks 
 
 Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety.  
 Subject can continue study treatment 
 Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
 If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
 If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline. 
ALT ≥5xULN and <8xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks 
 Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety.  
 Subject can continue study treatment 
 Subject must return 2-3 days after the initial 
observation and then return every 2-4 days for 
repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, stabilise or 
return to within baseline  
 If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
 If, after 2 weeks of monitoring, ALT <5xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline. 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 


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12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study 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. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE. 
 
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 


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


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f. 
Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
g. Is associated with liver injury and impaired liver function defined as: 
 
ALT ≥ 3xULN and total bilirubin* ≥ 2xULN (>35% direct), or 
 
ALT ≥ 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT ≥ 3xULN 
and total bilirubin ≥ 2xULN, then the event is still to be reported as an SAE. 
h. ** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants.  If INR measurement is obtained, the value is 
to be recorded on the SAE form. 
 
Recording AE and SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
 
The investigator will then record all relevant AE/SAE information in the CRF. 
 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 


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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
 
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 


2014N209767_03 
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85 
 
Follow-up of AE and SAE 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed CRF. 
 
The investigator will submit any updated SAE data to t GSK within 24 hours of 
receipt of the information. 
 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
 
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section). 
 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone. 
 
Contacts for SAE reporting can be found in the study reference manual. 
 
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 or the SAE coordinator. 
 
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 study reference manual. 


2014N209767_03 
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86 
 
12.5.1. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
 
Myocardial infarction/unstable angina 
 
Congestive heart failure 
 
Arrhythmias 
 
Valvulopathy 
 
Pulmonary hypertension 
 
Cerebrovascular events/stroke and transient ischemic attack 
 
Peripheral arterial thromboembolism 
 
Deep venous thrombosis/pulmonary embolism 
 
Revascularization 


2014N209767_03 
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87 
 
12.6. 
Appendix 6: Clinical Laboratory Tests 
 The tests detailed in Table 2 will be performed by the central laboratory, but 
liver chemistry will be assessed both locally and centrally.  
 Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study treatment decision or response 
evaluation, the results must be entered into the CRF. 
 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 2 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
MCHC? 
%Reticulocytes 
 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Fasting glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
 
Phosphorous 
 
Bicarbonate 
 
 
 
 
Routine 
Urinalysis 
 Specific gravity 
 pH, glucose, protein, blood, ketones by dipstick 


2014N209767_03 
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88 
 
Laboratory 
Assessments 
Parameters 
 Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
 Follicle-stimulating hormone (as needed in women of non-childbearing 
potential only) 
 Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) . Note that if second generation Hepatitis C antibody 
positive, a hepatitis C antibody Chiron RIBA immunoblot assay (or other 
third generation immunoassay) should be reflexively performed on the same 
sample to confirm the result.  
Other 
screening, 
baseline and 
post-baseline 
tests 
 25-OH Vitamin D Total, 25-OH Vitamin D2, 25-OH Vitamin D3 
 Hba1c 
 hsCRP 
 Fibrinogen 
 
luteinizing hormone 
 
follicle stimulating hormone 
 
testosterone 
 
free testosterone (calculated) 
 
estradiol (females only) 
 PSA in males 
 
 dihydrotestosterone 
 
sex hormone binding globulin 
 
Lipid panel (total cholesterol, HDL, LDL, triglycerides) 
 
NOTES : 
1. 
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 8.1.1 and Appendix 4 
2. 
PK samples for events or events of special interest will be collected 
3. 
All study-required laboratory assessments will be performed by a central laboratory. 
4. 
The results of each test must be entered into the CRF 


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89 
 
12.7. 
Appendix 7: 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 2881078 or COPD/ sarcopenia and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to 2881078 (or study treatments of this drug class), and COPD/ 
sarcopenia. 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 2881078 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 2881078 (or study treatments of this 
class) or COPD/sarcopenia continues but no longer than 15 years or other period as 
per local requirements. 
 

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200182
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a randomized double-blind 
(sponsor unblind), placebo-controlled, multi-centred phase IIa study 
to evaluate the safety and efficacy of 13 weeks of once daily oral 
dosing of the selective androgen receptor modulator (SARM) 
GSK2881078 in older men and post menopausal women with 
COPD and muscle weakness, participating in home exercise
Compound Number 
:
GSK2881078
Effective Date 
:
09-JAN-2020
Description:

The purpose of this RAP is to describe the planned analyses and output to be included in 
the Clinical Study Report for Protocol 200182 Amendment 3.

This RAP is intended to describe the safety and efficacy analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverables
RAP Author(s):
Author
Associate Statistician (Respiratory, Biostatistics)
Co-Author
Principle Biostatistician, (Parexel)
Copyright 2020 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
200182
2
RAP Team Reviewers (Method: E-mail)
Approver
Date
Clinical Investigation Lead (Discovery Medicine, CPEM)
07-JAN-2020
 
Medical Monitor, Discovery Medicine Lead, Discovery Medicine, 
CPEM
07-JAN-2020
06-JAN-2020
Data Quality Lead (Clinical Data Sciences Canada, RD Projects 
Clinical Platforms & Sciences)
06-JAN-2020
Clinical Program Lead (GCSD)
 
06-JAN-2020
Safety Scientist, Safety and Medical Governance Scientist
Medical Director, Safety and Medical Governance: 
06-JAN-2020
06-JAN-2020
Regulatory Affairs (Global Regulatory Affairs)
06-JAN-2020
Clinical Pharmacologist (Clinical Pharmacology Modelling and 
Simulations)
08-JAN-2020
Patient Centred Outcomes Lead (Value Evidence and Outcomes)
Study Programmer (FPD, Clinical programming)
08-JAN-2020
Clinical Statistics and Clinical Programming Line Approvals:
(Method: Pharma TMF e-signature)
Approver
Date
09-JAN-2020
Statistics Director (FPD, Clinical Statistics)
09-JAN-2020
Programming manager (FPD, Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
200182
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objectives and Endpoints ...................................................................9
2.3.
Study Design ..............................................................................................11
2.4.
Statistical Analyses.....................................................................................12
3.
PLANNED ANALYSES ..........................................................................................13
3.1.
Final Analyses ............................................................................................13
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 .....................................................................................17
5.4.
Examination of Covariates, Other Strata and Subgroups............................17
5.4.1.
Covariates and Other Strata ........................................................17
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.
EFFICACY ANALYSES..........................................................................................20
7.1.
Primary Efficacy Analyses ..........................................................................20
7.1.1.
Summary Measure ......................................................................20
7.1.2.
Endpoint / Variables.....................................................................20
7.1.3.
Population of Interest...................................................................20
7.1.4.
Statistical Analyses / Methods .....................................................20
7.1.4.1.
Statistical Methodology Specification..........................20
7.2.
Secondary Efficacy Analyses......................................................................22
7.2.1.
Endpoint / Variables.....................................................................22
7.2.2.
Summary Measure ......................................................................23
7.2.3.
Population of Interest...................................................................24
7.2.4.
Statistical Analyses / Methods .....................................................24
7.2.4.1.
Statistical Methodology Specification..........................24
7.3.
Exploratory Efficacy Analyses.....................................................................28
7.3.1.
Endpoint / Variables.....................................................................28
7.3.2.
Summary Measure ......................................................................28
7.3.3.
Population of Interest...................................................................28
7.3.4.
Statistical Analyses / Methods .....................................................28
7.3.4.1.
Statistical Methodology Specification..........................28


CONFIDENTIAL
200182
4
7.3.4.2.
Other Analyses...........................................................29
8.
SAFETY ANALYSES .............................................................................................30
8.1.
Adverse Events Analyses ...........................................................................30
8.2.
Adverse Events of Special Interest Analyses..............................................30
8.3.
Clinical Laboratory Analyses.......................................................................30
8.4.
Other Safety Analyses ................................................................................31
9.
PHARMACOKINETIC ANALYSES.........................................................................32
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................32
11. REFERENCES.......................................................................................................33
12. APPENDICES........................................................................................................34
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................34
12.1.1.
Exclusions from Per Protocol Population .....................................34
12.2.
Appendix 2: Schedule of Activities ..............................................................35
12.2.1.
Protocol Defined Schedule of Events...........................................35
12.3.
Appendix 3: Assessment Windows .............................................................40
12.3.1.
Definitions of Assessment Windows for Analyses........................40
12.4.
Appendix 4: Study Phases..........................................................................41
12.4.1.
Study Phases ..............................................................................41
12.4.2.
Study Phases for Concomitant Medication...................................41
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................42
12.5.1.
Reporting Process .......................................................................42
12.5.2.
Reporting Standards....................................................................42
12.6.
Appendix 6: Derived and Transformed Data ...............................................44
12.6.1.
General........................................................................................44
12.6.2.
Efficacy........................................................................................44
12.6.3.
Safety ..........................................................................................47
12.7.
Appendix 7: Reporting Standards for Missing Data.....................................52
12.7.1.
Premature Withdrawals................................................................52
12.7.2.
Handling of Missing Data.............................................................52
12.7.2.1.
Handling of Missing and Partial Dates ........................52
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................53
12.8.1.
Laboratory Values........................................................................53
12.8.2.
ECG.............................................................................................54
12.8.3.
Vital Signs....................................................................................54
12.9.
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................55
12.10. Appendix 10: Abbreviations & Trade Marks ................................................56
12.10.1. Abbreviations...............................................................................56
12.10.2. Trademarks .................................................................................58
12.11. Appendix 11: List of Data Displays..............................................................59
12.11.1. Data Display Numbering..............................................................59
12.11.2. Mock Example Shell Referencing ................................................59
12.11.3. Deliverables.................................................................................59
12.11.4. Study Population Tables..............................................................60
12.11.5. Efficacy Tables ............................................................................62
12.11.6. Efficacy Figures ...........................................................................69


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200182
5
12.11.7. Safety Tables...............................................................................70
12.11.8. Safety Figures .............................................................................75
12.11.9. Pharmacokinetics Tables.............................................................75
12.11.10.ICH Listings .................................................................................76
12.11.11.Non-ICH Listings..........................................................................80
12.12. Appendix 12: Example Mock Shells for Data Displays ................................86


CONFIDENTIAL
200182
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in 
the Clinical Study Report for Protocol.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are outlined in 
Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

An interim analysis for the 
assessment of futility is 
planned (Section 5.1 in the 
protocol). 

Removed all references 
to the interim analysis 

Decided to cancel the 
planned interim analysis,
as per the Note to File 
dated 5March2019

A multivariate Bayesian 
approach using non-
informative priors will be 
employed, data permitting, to 
further explore the 
relationships between changes 
in strength and lean mass and 
the functional outcomes (ISWT, 
ESWT,) and to inform decision 
making. (Section 10.3.3 in the 
protocol)

Multivariate Bayesian 
approach will not be 
planned 

Decision making
endpoints will be 
analysed using a 
univariate Bayesian 
approach and a decision-
making framework 
prospectively defined for 
these endpoints. Any 
multivariate Bayesian 
analyses will be 
considered as post-hoc 
analysis if data 
warranted. 

NA

Analysis of % change 
from baseline in 
appendicular, and total 
lean mass as assessed 
by Dual-energy X-ray 
Absorptiometry (DXA) 
will be planned

To assist clinical team 
review of the secondary 
endpoints

NA

Analysis of % change 
from baseline in 
Constant Work Rate 
(CWR) duration from 
endurance shuttle 
walking test and peak 
performance from 
incremental shuttle 

To assist clinical team 
review of the secondary 
endpoints


CONFIDENTIAL
200182
7
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
walking test will be 
planned

NA

The responder definition 
and analysis between 
treatment groups
(GSK2881078/ Placebo) 
for COPD Assessment 
Test (CAT) and St 
George Respiratory 
Questionnaire-COPD 
(SGRQ-c) will be added

To assist clinical team 
review of the secondary 
endpoints

NA

A Bayesian analysis 
added for the endpoint 
‘times for chair rise’

To assist clinical team 
review of the secondary 
endpoints

Log-transformed leg press 
strength data will be conducted 
as supportive analysis of the 
primary endpoint

Log-transformed leg 
press strength data will 
be analysed only when 
the model assumptions 
are not met, and log-
transformation is 
applicable

Data will only be 
analysed by appropriate 
methods, therefore 
transformations of the 
data prior to analysis will 
only be done if 
applicable.

Log-transformed supportive 
analysis for all the endpoints in 
case of violation of 
assumptions 

Log-transformed data 
will be analysed only 
when the model 
assumptions are not 
met, and log-
transformation is 
applicable

Data will only be 
analysed by appropriate 
methods, therefore 
transformations of the 
data prior to analysis will 
only be done if 
applicable.

Exploratory endpoint: Further 
exploratory analyses may 
include changes from baseline 
in size of inspiratory muscles 
and/ or other organs. 

Will not analysed in this 
RAP

There is no data 
collected

Exploratory endpoint: Gain 
further insights into the 
participants’ experience with 
study treatment and their 
participation in the trial.

Will not analysed in this 
RAP

Exit interview data will be 
reported separately

The ‘Analysis Population’ (AP) 
is defined as participants in the 
‘All Participants’ population 
having baseline and at least 
one post-baseline assessment 
of the strength, lean mass or 
functional endpoint (Section 

The ‘Analysis 
Population’ (AP) is 
defined as participants 
in the ‘All Participants’ 
population having 
baseline and at least 
one post-baseline 

The endpoint PROactive 
scores also added to the 
definition.


CONFIDENTIAL
200182
8
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
10.2 in the protocol).
assessment of the lean 
mass or PROactive 
scores or any of the 
functional endpoints.

The ‘Per Protocol Population’ 
will consist of any AP 
participants who are compliant 
with protocol-specific criteria 
and who do not experience an 
exacerbation during the 
treatment phase of the study. 
Participants with specified 
protocol deviations and those 
failing to complete the Week 13 
functional assessments will be 
excluded (Section 10.2 in the 
protocol).

The ‘Per Protocol 
Population’ will consist 
of any AP participants 
who are compliant with 
protocol-specific criteria 
and who do not 
experience an 
exacerbation during the 
treatment phase of the 
study. Participants with 
specified protocol 
deviations and those 
failing to complete the 
Week 13 functional 
assessments or 
PROactive scores or 
lean mass will be
excluded.

The endpoint PROactive 
scores also added to the 
definition.


CONFIDENTIAL
200182
9
2.2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary Objectives
Primary Endpoints

Assess the safety and tolerability 
of approximately 13 weeks of 
dosing of GSK2881078.

Safety and tolerability of GSK2881078 as assessed 
by clinical monitoring of blood pressure, heart rate, 
electrocardiogram (ECG) and laboratory safety data, 
as well as reporting of adverse events (AEs)

Assess the effect of approximately 
13 weeks of dosing of 
GSK2881078 on leg strength in 
older men and postmenopausal 
women with COPD and muscle 
weakness, participating in home 
exercise.
% change from baseline and change from baseline in 
maximum leg press strength following 1 repetition 
maximum (1- RM)
Secondary Objectives
Secondary Endpoints

Assess the effect of approximately 
13 weeks of dosing of 
GSK2881078 on lean soft tissue 
mass.

Change from baseline in appendicular, and total lean 
mass as assessed by Dual-energy X-ray 
Absorptiometry (DXA).

Assess the effect of approximately 
13 weeks of dosing of 
GSK2881078 on exercise 
capacity.

Change from baseline in total Short Physical 
Performance Battery (SPPB) score and times for 
chair rise and 4 m gait speed.

Change from baseline in Constant Work Rate 
(CWR) duration from endurance shuttle walking 
test. 

Change from baseline in peak performance from 
incremental shuttle walking test.

Assess the effect of approximately 
13 weeks of dosing of 
GSK2881078 on patient reported 
outcomes, levels of physical 
activity, activities of daily living 
and the patient perspective of 
efficacy.

Change from baseline in COPD Assessment Test 
(CAT). 

Change in PROactive endpoints (individual 
components and total score).

Change in physical activity measures as assessed 
via an accelerometer.

Patient Global Impression of Change.

Patient Global Rating of Severity.

Change in St George Respiratory Questionnaire-
COPD (SGRQ-c) total score and domains

Assess the effect of approximately 
13 weeks of dosing of 
GSK2881078 on respiratory 
function.

Change from baseline in forced expiratory volume in 
1 second (FEV1)

Change from baseline in Sniff nasal inspiratory 
pressure (SnIP).


CONFIDENTIAL
200182
10
Objectives
Endpoints

Characterise the population 
pharmacokinetic (PK) profile of 
approximately 13 weeks of dosing 
of GSK2881078 in older men and 
post-menopausal women with 
COPD and muscle weakness.

Model specific PK parameters of GSK2881078 
(e.g., oral clearance, oral steady-state volume of 
distribution).
Exploratory Objectives
Endpoints                                

Assess the safety of 13 weeks of 
dosing of GSK2881078 in older 
men and postmenopausal women 
in a subset of up to 15 male and 
15 female participants with COPD 
via magnetic resonance imaging 
(MRI).

Changes from baseline in hepatic, prostate (males) 
and cardiac structure and function as assessed via 
MRI. Further exploratory analyses may include 
changes from baseline in size of inspiratory muscles 
and/ or other organs.

Conduct semi-structured exit 
interviews.

Gain further insights into the participants’ 
experience with study treatment and their 
participation in the trial.

Assess the effect of 13 weeks of 
dosing of GSK2881078 in older 
men and postmenopausal women 
on peripheral strength.

Changes from baseline in handgrip strength.

Potentially explore adherence to exercise program 
(daily physical activity and thrice-weekly 
strengthening exercises).


CONFIDENTIAL
200182
11
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

This study is a randomized, placebo-controlled, double-blind (sponsor unblind), 
parallel group, multi-centre phase IIa trial in two equal sized cohorts (male or 
female). Following completion of screen assessments, baseline assessments 
will be conducted in eligible participants and, in each cohort, the participants 
will be randomized 1:1 to GSK2881078 or matching placebo.

This study will assess the effect of GSK2881078 on physical strength and 
function after 13 weeks of treatment. The placebo group will serve as an 
appropriate control group to limit evaluation bias in the study endpoints. No 
suitable active comparator is currently available. Both treatment and control 
groups will be asked to participate in a standardized home exercise program.
Dosing
Study treatment will consist of two dosing cohorts (Male: placebo or 2.0 mg of 
GSK2881078; Postmenopausal female: placebo or 1.0 mg of GSK2881078).
Dosing levels: 1.0 mg for women (2 x 0.5mg capsules) once daily
2.0 mg for men (2x 1.0mg capsules) once daily
Placebo: 2 capsules once daily
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment
Male and post-menopausal female participants who are between 50 and 75 
years of age and meet all other study entry criteria will be assigned to one of 
the treatments (Male: placebo or 2.0 mg of GSK2881078; Postmenopausal 
female: placebo or 1.0 mg of GSK2881078) in a ratio of 1:1 in accordance with 
the randomization schedule.


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Overview of Study Design and Key Features
Interim 
Analysis
No interim analysis is planned for the study (See Note to File dated 
5March2019)
2.4.
Statistical Analyses
Change from baseline and percent change from baseline in maximum leg press strength following 
1- RM will be analyzed separately using mixed models repeated measures (MMRM) models with 
effects for treatment, day, treatment x day, and baseline strength. Differences in least squares 
means between the GSK2881078 treated group and placebo treated group will be calculated (i.e.; 
GSK2881078 - placebo) along with associated 90% CIs. The analysis will be done separately for 
each gender.
The analyses will be performed using all available data from participants in both the analysis 
population and the Per Protocol Population. The effects of potential predictors of response 
including baseline BMI and percent predicted FEV1 will be explored.
Additionally, a Bayesian approach using a non-informative prior will be conducted to estimate the 
posterior distribution and to estimate the probability that the true treatment difference of % change 
from baseline strength at week 13 (Day90) is ≥ 9%. Additional threshold values and timepoints will 
also be presented for all decision-making endpoints including other key secondary endpoints.
Model and distributional assumptions underlying each analysis will be assessed and the details 
can be found at Appendix 9. 
Safety data will be presented in tabular and/or graphical format and summarized descriptively 
according to GSK’s Integrated Data Standards Library (IDSL) standards. No formal statistical 
comparisons will be made for the safety data.
Sample size estimations and explorations into sample size sensitivity are given in Section 10.1 of 
the protocol.


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3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the following 
sequential steps:
1.
All participants have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final database release
(DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All participants who were screened for eligibility 
and allocated a subject number.

Screened subjects
Enrolled 

All participants who passed screening and entered 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 
All Participants

The ‘All Participants Population’ is defined as all 
randomized participants who receive at least one dose 
of study medication.

This population will be based on the treatment the 
participant was randomized to.

Study Population
Safety 

The ‘Safety Population’ is defined as all randomized 
participants who receive at least one dose of study 
medication.

This population will be based on the treatment the 
participant received.

Safety
Analysis (AP)

The ‘Analysis Population’ (AP) is defined as 
participants in the ‘All Participants’ population having 
baseline and at least one post-baseline assessment of 
the lean mass or PROactive scores or any of the 
functional endpoints.

This population will be based on the treatment the 
participant was randomized to. The functional 
endpoints include leg press strength, peak 
performance from Incremental shuttle walking test,
Constant Work Rate (CWR) duration from
endurance shuttle walking test, total SPPB score 
and handgrip strength.

Efficacy


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Population
Definition / Criteria
Analyses Evaluated
Per Protocol

The ‘Per Protocol Population’ will consist of any AP 
participants who are compliant with protocol-specific 
criteria and who do not experience an exacerbation 
during the treatment phase of the study. Participants 
with specified protocol deviations and those failing to 
complete any of the Week 13 functional assessments
or PROactive scores or lean mass will be excluded. 
This population will be based on the treatment the 
participant was randomized to.  Further details will be 
given in Section 12.1.1.

Efficacy (Strength, 
SGRQ, PROactive 
Constant Work 
Rate (CWR) 
duration from 
endurance shuttle 
walking test and 
time for repeated 
chair rise)
Pharmacokinetic
(PK)

The ‘PK Population’ is defined as participants in the 
‘All Participants’ population for whom a PK sample was 
obtained and analysed for GSK2881078.

PK
1.
Refer to Appendix 11: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion criteria, 
conduct of the trial, patient management or patient assessment) will be summarised and listed.
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 by the study team throughout the conduct of the study in 
accordance with the ‘Protocol Deviation Specification version 6.0 dated 28 Nov 2019
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. It will not be possible to identify whether
subjects received a different treatment to the one they were randomised to until post 
unblinding, hence this protocol deviation will be identified after unblinding the database.
o A blinded data review meetings (BDRM) will be handled before the final database release 
(DBR)
o This dataset will be the basis for the summaries and listings of protocol deviations.
A listing of all inclusion/exclusion criteria deviations will also be provided. This listing will be based 
on data as recorded on the inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
The analysis and summary will be separately analysed by gender. All graphical displays will 
present results for males and females on separate pages. Sex will be either a subtitle or 
subheading (“by” variable) on these displays.
For each efficacy analysis table, the results for female will displayed first and then repeated for 
male; for other tables, the summary will be presented in the order of female and male. Listings will 
be sorted by gender.
Treatment Group Descriptions
Treatment Group
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
PTM GSK2881078 1.0mg
Placebo
1 - Female
B
GSK2881078 1.0 mg
GSK2881078 1.0 mg
2- Female
C
PTM GSK2881078 2.0mg
Placebo
1 - Male
D
GSK2881078 2.0 mg
GSK2881078 2.0 mg
2- Male
Treatment comparisons will be displayed as follows using the descriptors as specified and 
separated by gender:
Female: GSK2881078 1.0 mg vs Placebo
Male: GSK2881078 2.0 mg vs Placebo
5.2.
Baseline Definitions
Parameter
Study Assessments Considered as 
Baseline
Baseline Used in 
Data Display
Screening
Day -9
Day 1 (Pre-Dose)
Efficacy
Leg Strength
X
X
whichever is latest*
Incremental Shuttle Walk Test
X
X
whichever is higher
Endurance Shuttle Walk Test
X
Day 1
Dual-energy X-ray Absorptiometry
(DXA)
X
Day 1
Short Physical Performance 
Battery (SPPB)
X
X
whichever is latest*
COPD Assessment Test (CAT)
X
Day 1
Patient Global Rating of Severity 
(PGRS)
X
Day 1
St George Respiratory 
X
Day 1


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Parameter
Study Assessments Considered as 
Baseline
Baseline Used in 
Data Display
Screening
Day -9
Day 1 (Pre-Dose)
Questionnaire COPD (SGRQ-c)
PROactive Physical Activity
X
X
See detail below**
Spirometry
X
X
whichever is latest*
Sniff Nasal Inspiratory Pressure 
(SnIP)
X
X
whichever is latest*
Safety
Vital Signs
X
X
whichever is latest*
12-lead ECG
X
X
whichever is latest*
Haematology 
X
X
whichever is latest*
Clinical Chemistry
X
X
whichever is latest*
Urinalysis
X
X
whichever is latest*
hsCRP, Fibrinogen
X
Day 1
Lipid panel
X
X
whichever is latest*
PSA
X
X
whichever is latest*
HbA1c 
X
screening
Exploratory
Cardiac and liver MRI
X
Day 1
Handgrip strength
X
X
whichever is latest*
Reproductive Tissue Biomarkers
X
Day 1
Bone Biomarkers
X
Day 1
***Exploratory Biomarkers
X
Day 1
***Monitored home exercise 
program
X
X
whichever is latest*
*Baseline value will be the latest pre-dose assessment with a non-missing value, including those 
from unscheduled visits. If time is not collected, Day 1 assessments are assumed to be taken prior 
to first dose and used as baseline.
**Baseline will be the average of the data collected from the 7-day period after Day -9 device 
dispense.
***Exploratory Biomarkers and home exercise program will be analysed separately and will not be 
reported as part of this study Statistical Analysis Complete reporting.
Unless otherwise stated, if baseline data is missing no derivation will be performed and baseline 
will be set to missing.


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5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigative site. There is no 
analysis planned by center/investigative site.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates which will be used in descriptive summaries and statistical analyses., 
including the primary analysis are described in the table below. Additional covariates percent 
predicted FEV1 and baseline BMI will be explored as a sensitivity analysis for the primary endpoint 
of the leg press strength only.
Category
Details
Covariates
Treatment, Day, Treatment x Day and Baseline 
Exploratory covariates
Percent Predicted FEV1 and Baseline BMI
5.4.2.
Examination of Subgroups
There is no subgroup analysis planned for this RAP, however, males and females will be analysed 
separately since they have a different dose level.
5.5.
Multiple Comparisons and Multiplicity
The primary comparison of interests is the change from baseline and percent change from baseline 
in maximum leg press strength following 1 repetition maximum (1- RM). The key endpoint used for 
decision making purpose will be the percent change from baseline in maximum leg press strength.
This analysis will be conducted separately for each gender and the two analyses will be considered 
co-primary (i.e. both must be considered a success for the study to be successful), therefore no 
multiplicity adjustment is required. There will be no multiplicity adjustments for multiple endpoints or
multiple timepoints or multiple treatment comparisons. Analyses of other efficacy endpoints will not 
be subject to any multiplicity adjustment.
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
12.3
Appendix 3: Assessment Windows
12.4
Appendix 4: Study Phases 
12.5
Appendix 5: Data Display Standards & Handling Conventions
12.6
Appendix 6: Derived and Transformed Data
12.7
Appendix 7: Reporting Standards for Missing Data
12.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be mainly based on the All Participants 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 11: List of Data Displays.
Table 2 provides an overview of the planned study population analyses, with full details of data 
displays being presented in Appendix 11: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Display’s Generated
Table
Listing
Randomisation
Randomisation
Y [1]
Subject Disposition
Subjects Enrolled by Country and Site ID [6]
Y
Y
History of Rescreened Subjects [2]
Y
Reasons for Screen Failure [2]
Y
Y
Subjects for Whom the Treatment Blind was Broken
Y
Subject Disposition
Y
Y
Study Visit Dates  
Y
Populations Analysed
Study Populations [2]
Y
Y
Protocol deviations
Important Protocol Deviations
Y
Y
Deviations leading to exclusion from PP
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Demography
Demographic Characteristics [3]
Y
Y
Summary of Age Ranges [6]
Y
Race & Racial Combinations [4]
Y 
Y
Disease Staging
Y
Medical Conditions, Concomitant Medications 
Medical Conditions (Current and Past)
Y 
Y


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Exacerbation History
Y
Alcohol History
Y
History of Tobacco Use
Y
Change of Smoking Status During the Study
Y
Concomitant Medications
Y
Y 
HIV, Hepatitis B and C screening (Hepatitis C viral RNA 
PCR if Hepatitis C screening is positive)
Y
Other 
IP Compliance [5]
Y
Y
NOTES:

Y = Display Generated, T = Tables, L = Listings, IP = Investigational Product
1.
One listing of subjects randomised but not treated.
2.
Screened population.
3.
Age, sex, age group, ethnicity, race, weight, height, body surface area, percent predicted FEV1 and BMI (kg/m^2)
needs to be summarized. 
4.
The five-high level FDA race categories and designated Asian subcategories will be summarised along with all 
combinations of high-level categories which exist in the data. A by-subject listing of race will also be produced.
5.
Dispensation information (dates, number of tablets dispensed, returned, taken and lost, compliance percentage, 
duration of treatment and treatment cumulative dose also will be included).
6.
Enrolled population 


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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Summary Measure
The adjusted mean treatment difference for change and percent change from baseline in maximum 
leg press strength will be presented at Days 28, 56 and 90.
7.1.2.
Endpoint / Variables
The primary endpoints are change from baseline and percent change from baseline in maximum 
leg press strength following 1 repetition maximum (1- RM). The key endpoint used for decision 
making purpose will be the percent change from baseline in maximum leg press strength.
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the Analysis population. A supportive efficacy 
analyses will be based on the Per Protocol population.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and will be 
based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be summarised using 
descriptive statistics, graphically presented (where appropriate) and listed.
7.1.4.1.
Statistical Methodology Specification
Endpoints / Variables

% change from baseline and change from baseline in maximum leg press strength (Kg) 
following 1 repetition maximum (1- RM) at Days 28, 56 and 90.
Model Specification

Change from baseline and percent change from baseline strength will be analyzed separately 
using mixed models repeated measures (MMRM) adjusted for treatment, day, treatment x day, 
and baseline strength, with day as the repeated factor. 

Data falling into the analysis windows for day 28, day 56 and day 90 will be included in the 
model

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

In the event that this model fails to converge, the model will be re-fitted with other covariance 
structures such as compound symmetry and one which gives the least Akaike's Information 
Criteria (AIC) from the fitted model will be used as the covariance structure.

The analysis will be conducted separately by gender 


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
If there are any departures from the distributional assumptions for change or percentage 
change from baseline, the change of log-transformed data at post- baseline from log baseline 
will be the response variable, adjusted for treatment, log-transformed baseline strength, day 
and the interaction of treatment and day, with day as the repeated factor. The sensitivity 
analysis for the change from baseline and percentage change from baseline are the same.
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

For change and percent change from baseline, adjusted means, corresponding standard error 
of means (SEs) and 90% confidence intervals will be presented for each treatment by day, 
together with estimated treatment differences (GSK2881078 – Placebo) and the corresponding 
90% confidence intervals and p-value by day for both Analysis and Per Protocol population. 

A line plot of the adjusted mean of change (and percentage change) from baseline as well as 
the 90% confidence interval over time (day) for each treatment from the MMRM model will be 
provided for the analysis population.  
Log-transformed data results presentation

The estimated coefficients of the MMRM model will be transformed back (exponential 
transform). 

For each treatment, adjusted ratio of the post baseline value to the baseline value and 
corresponding 90% confidence intervals will be presented by day. 

The adjusted treatment ratio of the ratio (postbaseline value/baseline value) between the two 
treatments with the corresponding 90% confidence interval be presented by day.  

The plot of adjusted ratio of the post baseline value to the baseline value and its 90% 
confidence interval over time (day) for each treatment arm will be presented for the analysis 
population
Supportive Statistical Analysis - Bayesian

% change from baseline in maximum leg press strength following 1 repetition maximum (1-
RM) at Days 28, 56 and 90 will be estimated by Bayesian analysis and separately by gender.

The posterior probability of treatment difference greater than 4% points, less than 9% points 
and greater than or equal to 9% points for each visit separately by gender.
Model Specification

Create indicator variables for the categorical effect: Treatment (GSK2881078 vs. Placebo) 
and Day (day28, day56 and day90). 
For treatment, if treatment=placebo, then drug=0; if treatment=GSK2881078, then drug=1;

Construct a linear model for each day(visit) in order to model within-subject observation 
covariance structures by multivariate normal (MVN) distribution in the MCMC procedure. For 
subject i on treatment j at Day k, the model can be written as: 
  PCHijk=β0 + β1 drug + β2 baseline + βd Dayk + βdk drug* Dayk +εijk       εijk ~ N(0, σ2);
where PCH refers to percentage change from baseline and Dayk for k=1, 2, 3 represent days 
28, 56 and 90, respectively, and are indicator variables, which are intrinsically formed within 


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PROC MCMC from the design matrix. The last element, Day3, is excluded by setting it to 0 in 
the PARMS statement.

(β1+ βd1), (β1+ βd2), are the estimated treatment differences (GSK2881078 vs. Placebo) at 
Day 28, Day 56 respectively. β1 is the estimated treatment difference (GSK2881078 vs. 
placebo) at Day 90

Reformat the input data in the way that all repeated measurements from a subject are in one 
row 

Set seed=123456 with the simulation size of 500000, 5000 burn-in iterations. The simulation 
size and number of burn-in iterations could be updated during the convergence check.

The non-informative priors (normal (0, var=1e6)) will be used for the regression parameters 

The 3-dimension inverse wishart scale matrix will be used as the prior of the covariance 
matrix. The degrees of freedom will be 3 and the positive definite scale matrix will be an 
identity matrix.

Multivariate normal (MVN) distribution will be specified to model all repeated measurements

Count the proportion at Day90 where β1 greater than 4% points, less than 9% points and 
greater or equal to 9% points respectively from the posterior probability distribution simulation.

Similarly, Count the proportion at Day28 and Day56 where (β1+ βd1), (β1+ βd2) are separately
greater than 4% points, less than 9% points and greater or equal to 9% points respectively 
from the posterior probability distribution.

For calculating the posterior adjusted least square mean and corresponding difference, use 
the coefficient of L-matrix of the covariates from the MMRM analysis mentioned in Section 
7.1.4.1
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

n, posterior adjusted least square mean and 90% highest posterior density (HPD) interval, the 
adjusted treatment difference and its 90% HPD credible interval and standard deviation for the 
posterior adjusted least square mean and difference.

The treatment difference (GSK2881078 – Placebo) for the percentage change from baseline at 
each visit (Day 28, Day 56 and Day 90) > 4 percentage points, <9 percentage points and ≥ 9
percentage points will be reported based upon the simulation results from the posterior 
probability model.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
The secondary endpoints are:

Change and % change from baseline in appendicular, and total lean mass as assessed by 
Dual-energy X-ray Absorptiometry (DXA).

Change from baseline in total Short Physical Performance Battery (SPPB) score, times for 
chair rise and 4 m gait speed.


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
Change and % change from baseline in Constant Work Rate (CWR) duration from 
endurance shuttle walking test. 

Change and % change from baseline in peak performance from incremental shuttle 
walking test.

Change in PROactive endpoints (individual components (difficulty and amount score) and 
total score).

Change from baseline in COPD Assessment Test (CAT).

Responder of COPD Assessment Test (CAT). 

Change in St George Respiratory Questionnaire (SGRQ) total score and domain scores 
derived from SGRQ-c raw score.

Responder of St George Respiratory Questionnaire (SGRQ) defined by the total score.

Change from baseline in forced expiratory volume in 1 second (FEV1).

Patient Global Impression of Change (PGIC).

Patient Global Rating of Severity (PGRS).

Change from baseline in Sniff nasal inspiratory pressure (SnIP).

Change in physical activity measures as assessed via an accelerometer.
7.2.2.
Summary Measure
The adjusted mean treatment differences (GSK2881078 – Placebo) for the following endpoints will 
be presented:

Change and % change from baseline in appendicular, and total lean mass as assessed by 
Dual-energy X-ray Absorptiometry (DXA) at Days 28, 56 and 90.

Change from baseline in total Short Physical Performance Battery (SPPB) score, times for 
chair rise and 4 m gait speed at Days 28, 56 and 90. 

Change and % change from baseline in Constant Work Rate (CWR) duration from 
endurance shuttle walking test at Day 90.

Change and % change from baseline in peak performance from incremental shuttle 
walking test at Day 90.

Change from baseline in PROactive endpoints at Days 56 and 90. (individual components 
and total score).

Change from baseline in COPD Assessment Test (CAT) score at Days 56 and 90. 

Change from baseline in St George Respiratory Questionnaire (SGRQ) total score and 
domain scores derived from SGRQ-c raw scores at Days 90.
The responder analysis between GSK2881078 and Placebo (GSK2881078/ Placebo) for the 
following endpoints will be explored 

Odds ratio between treatment groups for the COPD Assessment Test (CAT) responder at 
Days 56 and 90. 

Odds ratio between treatment groups for the St George Respiratory Questionnaire 
(SGRQ) responder defined by the total score derived from SGRQ-c raw scores at Days 90.
The descriptive summaries will be reported for the following endpoints 

Change from baseline in forced expiratory volume in 1 second (FEV1).


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
Frequency and percentages of Patient Global Impression of Change (PGIC) responses.

Frequency and percentages of Patient Global Rating of Severity (PGRS) responses.

Change from baseline in Sniff nasal inspiratory pressure (SnIP).

Change in physical activity measures as assessed via an accelerometer.
7.2.3.
Population of Interest 
The secondary efficacy analyses will be based on the Analysis Population. The decision-making
endpoints PROactive endpoint, SGRQ, SPPB (time for repeated chair rise endpoint) and constant 
work rate (CWR) duration from endurance shuttle walking test will be also analysed based on the 
Per Protocol population.
7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and will be 
based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be summarised using 
descriptive statistics, graphically presented (where appropriate) and listed.
7.2.4.1.
Statistical Methodology Specification
Secondary Efficacy Endpoint / Variables – Multiple Post-baseline Visit

Change and % change from baseline in appendicular, and total lean mass as assessed by 
Dual-energy X-ray Absorptiometry (DXA) at Days 28, 56 and 90.

Change from baseline in total Short Physical Performance Battery (SPPB) score, **time for 
repeated chair rise and 4 m gait speed at Days 28, 56 and 90.

Change from baseline (Day 1) in *PROactive endpoints (individual components (difficulty and 
amount score) and **total score) at Days 56 and 90.

Change from baseline in COPD Assessment Test (CAT) score at Days 56 and 90. 
*A physical activity monitor will be worn for 7 days after the Day -9 visit (Day 1), for 7 days after the Day 
56 visit (Day 56), and for 7 days following the day 80 visit (Day 90).
**Bayesian analysis will be performed only for the endpoints change from baseline of PROactive total 
scores and change from baseline in the time for repeated chair rise. The posterior probability of 
treatment difference greater than 3 points and less than 6 points for PROactive total scores and greater 
than 1.3 seconds and less than 1.7 seconds for time for repeated chair rise will be estimated for each 
visit separately by gender.
Model Specification

Treatment difference (GSK2881078 – placebo) at each visit on change from baseline or 
percentage change from baseline (as appropriate) will be analysed using mixed models 
repeated measures (MMRM) models as what was described for the primary efficacy endpoint 
in Section 7.1.4.1. The analyses will be based on the analysis population for all endpoints 
additionally the endpoints PROactive and SPPB will be analysed for per-protocol population as 
well.

If there are any departures from the distributional assumptions for change or percentage 
change from baseline, the change of log-transformed data at post- baseline from log baseline 
will be the response variable, adjusted for treatment, log-transformed baseline value, day and 


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the interaction of treatment and day, with day as the repeated factor.

A Bayesian approach will also be employed for the change from baseline in PROactive weekly 
total score and time for repeated chair rise to estimate the treatment difference in the change 
from baseline for analysis population, following the similar procedures described in Section 
7.1.4.1. for the primary efficacy endpoint analysis. For calculating the posterior adjusted least 
square mean and corresponding difference, use the coefficient of L-matrix of the covariates 
from the corresponding frequentist MMRM analysis.
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

For change and percent change from baseline, adjusted means and corresponding standard 
error of means (SEs) and 90% confidence intervals will be presented for each treatment by 
gender and then by time, together with estimated treatment differences (GSK2881078 –
Placebo) and the corresponding 90% confidence intervals for MMRM estimation.

In case of the violation of assumptions in MMRM analysis, adjusted mean for ratio to baseline 
and 90% confidence intervals will be presented for each treatment by gender and then by time, 
together with adjusted treatment ratio of the ratio (postbaseline value/baseline value) between 
the two treatments with the corresponding 90% confidence interval be presented by day.

A line plot of the adjusted mean change from baseline or percentage change from baseline (as 
appropriate) as well as 90% confidence intervals over time (day) for each treatment by gender 
from the MMRM model will be provided for the analysis population. In case of violation of 
assumption in MMRM analysis, the adjusted mean for ratio to baseline and corresponding 90% 
confidence interval will be plotted.          

For the Bayesian analysis, n, posterior adjusted least square mean and 90% highest posterior 
density (HPD) interval, the adjusted treatment difference and its 90% HPD credible interval and 
standard deviation for the posterior adjusted least square mean and difference will be reported 
along with the estimated probabilities.    

For the Bayesian analysis for PROactive weekly total score, the probability of treatment 
difference (GSK2881078-placebo) greater than 3 points and less than 6 points will be 
estimated through the simulations of the posterior probability distribution. Similarly, for the 
Bayesian analysis for time for repeated chair rise, the probability of treatment difference 
(GSK2881078-placebo) greater than 1.3 seconds and less than 1.7 seconds will be estimated 
through the simulations of the posterior probability distribution.
Secondary Efficacy Endpoint / Variables – Categorical Variable

Odds ratio of COPD Assessment Test (CAT) responder at Days 56 and 90. 

Odds ratio of St George Respiratory Questionnaire (SGRQ) responder derived by the total 
score at Days 90.
Model Results Presentation

The number of responders, odds ratio and associated 90% exact confidence intervals between 
treatment groups (GSK2881078 vs. placebo) will be reported for CAT and SGRQ responder 
analysis by gender.


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Secondary Efficacy Endpoint / Variables – Single Post-baseline Visit

Change and % change from baseline in Constant Work Rate (CWR) duration* from endurance 
shuttle walking test at Day 90.

Change and % change from baseline in peak performance from incremental shuttle walking 
test at Day 90.

Change from baseline in St George Respiratory Questionnaire (SGRQ) total score* and 
domain scores derived from SGRQ-c raw scores at Days 90.
*Bayesian analysis will be performed only for the endpoints change from baseline of Constant Work 
Rate (CWR) duration and change from baseline of SGRQ total score. The posterior probability of 
treatment difference greater than 36 seconds and less than 48 seconds for Constant Work Rate (CWR) 
duration and greater than 2 points and less than 4 points SGRQ total score will be estimated.
Model Specification

Treatment difference (GSK2881078 – placebo) in the change from baseline and percentage 
change from baseline at Day 90 will be analysed using ANCOVA where baseline and 
treatment will be included as the independent variables in the model. Each gender will be 
analysed separately. The analyses will be based on the analysis population for the endpoints 
CWR duration, peak performance from incremental shuttle walking test and SGRQ total score
additionally the endpoints CWR duration and SGRQ total score will be analysed for per-
protocol population as well.

If there are any departures from the distributional assumptions, the change of log-transformed 
data at post- baseline from log baseline will be the response variable, adjusted for treatment, 
and log-transformed baseline value.

A Bayesian approach will also be conducted to estimate the treatment difference in the change 
from baseline at Day 90 for CWR duration and change from baseline SGRQ total score for the 
analysis population, following the similar procedures described in Section 7.1.4.1. for the 
primary efficacy endpoint analysis with the model being constructed as below:

Create indicator variables for the categorical effect: Treatment (GSK2881078 vs. Placebo). 
For treatment, if treatment=placebo, then drug=0; if treatment=GSK2881078, then drug=1;

For subject i on treatment j, the model can be written as: 
                  CHij=β0 + β1 drug + β2 base+ +εij 
where CH refers to the change from baseline at Day 90; base means baseline assessment; 
drug=0 when treatment is placebo and drug=1 for GSK2881078 treatment; εij ~ N(0, σ2);
β1 is the estimated treatment difference (GSK2881078 vs. placebo) at Day 90; 

Set seed=123456 with the simulation size of 200000 and 5000 burn-in iterations; the sample 
size and the number of burn-in iterations could be updated during the convergence check.

The non-informative priors (normal (0, var=1e6)) will be used for the regression parameters 
β0, β1, and β2. and the prior for variance σ2 will be the inverse gamma (0.01, scale=0.01)

For calculating the posterior adjusted least square mean and corresponding difference, use 
the coefficient of L-matrix of the covariates from the corresponding ANCOVA analysis 
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.


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Model Results Presentation

For change and percent change from baseline, adjusted means and corresponding standard 
error of means (SEs) and 90% confidence intervals will be presented for each treatment at Day 
90, together with estimated treatment differences (GSK2881078 – Placebo) and the 
corresponding 90% confidence intervals through ANCOVA model.

In case of the violation of assumptions in ANCOVA analysis, adjusted mean for ratio to 
baseline and 90% confidence intervals will be presented for each treatment by gender, 
together with adjusted treatment ratio of the ratio (postbaseline value/baseline value) between 
the two treatments with the corresponding 90% confidence interval be presented.

For the Bayesian analysis, n, posterior adjusted least square mean and 90% highest posterior 
density (HPD) interval, the adjusted treatment difference and its 90% HPD credible interval and 
standard deviation for the posterior adjusted least square mean and difference will be reported 
along with the estimated probabilities.    

For the Bayesian analysis for CWR duration, the probability of treatment difference 
(GSK2881078-placebo) greater than 36 seconds and less than 48 seconds will be estimated 
through the simulations of the posterior probability distribution. Similarly, for the Bayesian 
analysis for SGRQ total score, the probability of treatment difference (GSK2881078-placebo) 
greater than 2 points and less than 4 points will be estimated through the simulations of the 
posterior probability distribution.
Secondary Efficacy Endpoint / Variables – Descriptive Summary

Forced expiratory volume in 1 second (FEV1) at Days 1, 56 and 90.

Patient Global Impression of Change (PGIC) at Days 14, 28, 56 and 90.

Patient Global Rating of Severity (PGRS) at Days 1 and 90.

Sniff nasal inspiratory pressure (SnIP) at Days 1, 56 and 90.

Physical activity measures as assessed via an accelerometer at Days 1, 56 and 80.
Summary Results Presentation
Baseline, each postbaseline visit and change from baseline, will be descriptively summarized by 
treatment group for endpoints: weekly average steps, vector magnitude unit/wear time and 
moderate/vigorous activity duration measures via an accelerometer. The number of subjects with 
the eligible days i.e. wear duration more than 8 hours for at least 4 days, the average eligible days 
for those subjects and average wear duration (minutes) during the eligible days will be 
summarized.
Baseline, each postbaseline visit and change from baseline, will be descriptively summarized by 
treatment group for original FEV1 (L) and percentage predicted FEV1 and maximum SnlP.
In addition, a box plot will be prepared for the change from baseline for FEV1 and SnIP at the post-
baseline visits.
For the categorical endpoints, PGRS and PGIC, the count and percentage will be summarized by 
category and treatment for each visit separately by gender.


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7.3.
Exploratory Efficacy Analyses
7.3.1.
Endpoint / Variables
The exploratory endpoints that will be analysed are:
Changes from baseline in handgrip strength.
7.3.2.
Summary Measure
Descriptive summary of baseline assessments, post-baseline assessments and change from 
baseline for handgrip strength.
Changes from baseline in size of inspiratory muscles and/or other organs will not be analyzed in 
this report because there is no data collected. In addition, exit interview data will be reported 
separately, thus the analysis of the endpoint ‘Gain further insights into the participants’ experience 
with study treatment and their participation in the trial’ will not be performed in this RAP. The 
adherence to the exercise program (daily physical activity and thrice-weekly strengthening 
exercises) will not be explored in this RAP. 
7.3.3.
Population of Interest 
The exploratory efficacy analyses will be based on the Analysis population, unless otherwise 
specified.
7.3.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and will be 
based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be summarised using 
descriptive statistics, graphically presented (where appropriate) and listed.
7.3.4.1.
Statistical Methodology Specification
Endpoint / Variables

Changes from baseline in handgrip strength.
Summary Results Presentation

The handgrip strength of left hand and right hand will be separately summarized for baseline, 
Day 90 and change from baseline at Day 90 by treatment for each gender separately


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7.3.4.2.
Other Analyses

An exploratory analysis will be performed on the analysis population to identify how the 
change from baseline of PROactive total and domain scores changes over the responses 
of PGIC questionnaire. This relationship between PGIC levels and change from baseline in 
PROactive total and domains scores will be explored by a descriptive summary table for 
the visits Day 56 and 90. This comparison will be by gender (males, females and overall 
(male + female)) and not with respect to treatment. Along with the seven levels of PGIC, 
the pooled categories “Much worse and Worse” and “Better and Much Better” will also be 
summarized.

A sensitivity analysis has to be performed to identify the influence of center 
 on the 
primary analysis. The primary analysis of percentage change from baseline for leg press 
has to perform by removing the subjects recruited from the center 
for the analysis 
population. This is the analysis supporting the SPOOS ((Significant Payments of Other 
Sorts) impact analysis. 
Plots to be generated in R-shiny App
Shiny is an open R package from RStudio, which provides a web application framework to create 
interactive web applications (visualization) called “Shiny apps”. Shiny combines the computational 
power of R with the interactivity of the modern web. Shiny web apps can be deployed locally or on 
the web through tools such as RStudio Connect. 
The below mentioned plots will be generated in the R-shiny app at SAC. These displays will then
be sent for clinical review. From the generated plots only the clinically important ones will be 
identified and added to the CSR and will be considered post hoc analyses. These plots will be 
generated for the analysis population.

Absolute, Change and percent change from baseline in the leg press strength and change 
from baseline in constant work rate (CWR) duration from endurance shuttle walking test 
and peak performance from incremental shuttle walking test versus baseline SPPB 
categories will be plotted (box-plot) by treatment group for each gender separately. The 
box-plots for both the treatment groups will be presented in one plot for one gender; then 
repeat for the other gender. 

The relationship between absolute, change and percent change from baseline at Day 90 in 
the leg press strength , change from baseline in constant work rate (CWR) duration from 
endurance shuttle walking test at Day 90  and peak performance from incremental shuttle 
walking test at Day 90 versus baseline PROactive scores for all the domains score as well 
as the baseline average daily steps via an accelerometer will be explored by the scattered
plots by treatment group for each gender. Baseline scores will be the x-axis and absolute 
or change from baseline or percent from baseline at Day 90 in the leg press strength and 
shuttle walk tests separately will be the y-axis 

Mean absolute, change from baseline and percentage change from baseline in leg press 
strength, change from baseline in appendicular and total lean mass, constant work rate 
(CWR) duration from endurance shuttle walking test, peak performance from incremental 
shuttle walking test, total SPPB score, hand grip, SGRQ (all domains) and PROactive (all 
domains)  will be plotted by treatment group for each gender, where descriptive mean for 
absolute, change from baseline and percentage change from baseline for the respective 
endpoints will be the Y-axis in each plot and X-axis will be the visits.
PPD
PPD


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8.
SAFETY ANALYSES
The safety analyses will be based on the safety population and actual treatment group, unless 
otherwise specified. Data for male and female subjects will be analysed separately.
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 AE text recorded in the eCRF will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA version 22.0) and will be 
reported using the primary System Organ Class (SOC) and Preferred Term (PT). Results will be 
displayed irrespective of treatment phase  in the order of decreasing frequency, both across SOC 
and within SOC. The details of the planned displays are provided in Appendix 11: List of Data 
Displays.
For those displays with maximum intensity, if AEs are reported more than once by a subject, the 
most severe intensity will be included. An adverse event will be considered as a common adverse 
event if it occurs in more than one patient in either gender.
8.2.
Adverse Events of Special Interest Analyses
The table in Section 12.6.3 (“Safety”) presents the Adverse Events of Special Interest (AESI) and 
the groups of terms that they comprise. AESI which are not standardized MedDRA queries (SMQs) 
comprise a selection of PTs defined by GSK. The final list of AESIs, and the PTs that contribute to 
each of the AESIs, will be provided by Safety and Medical Governance (SMG), using the MedDRA 
version current at the time of reporting. This list will be finalized prior to unblinding the database. 
Changes to the MedDRA dictionary may occur between the start of the study and the time of 
reporting. Furthermore, emerging data from on-going studies may highlight additional AESI. 
Therefore, the list of AESI, and the terms included for each AESI, will be based on the safety 
review team (SRT) agreements in place at the time of reporting. The details of the planned displays 
are provided in Appendix 11: List of Data Displays.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Haematology
laboratory tests, Urinalysis, Lipids and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
A line plot of the mean change from baseline (latest pre-dose value including unscheduled visits)
as well as +/- standard error over time (day) for each treatment by gender will be plotted for below 
mentioned sex hormones and metabolic analytes.      
Sex / Reproductive Hormones
Testosterone, Free Testosterone, Sex hormone-binding globulin (SHBG), Follicle-stimulating 
hormone (FSH), Luteinizing hormone (LH) and Prostate specific antigen (PSA).


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Metabolic Analytes
Total Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglyceride, Glucose and HbA1c.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be based on
GSK Core Data Standards, unless otherwise specified. The details of the planned displays are 
presented in Appendix 11: List of Data Displays.
A listing of changes from baseline in hepatic, prostate (males) and cardiac structure and function 
assessed via MRI scan will be presented as an exploratory analysis. 
Biomarkers will be summarized descriptively. The reproductive tissue biomarkers and bone 
markers to summarize are given below.
Reproductive Tissue Biomarkers
Luteinizing hormone, Follicle stimulating hormone, Total testosterone, Free testosterone 
(calculated) in males and female, Estradiol (females), Dihydrotestosterone, Sex hormone binding 
globulin and Prostate specific antigen (PSA) (males).
Bone Biomarkers
Procollagen type I N propeptide (s-PINP) and C-terminal telopeptide of type I collagen (s-CTX).


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9.
PHARMACOKINETIC ANALYSES
PK concentration related summaries will be presented. No PK parameters will be derived in this 
RAP. The PK parameters for the Study will be derived as a part of Population Pharmacokinetic 
(POPPK) analyses. The POPPK RAP will include the detailed population PK analysis and resulting 
derived PK parameters including Cmax and AUC over dosing interval. 
9.1.
Secondary Pharmacokinetic Analyses
9.1.1.
Summary Measure
Pharmacokinetic concentration data will be presented in graphical and tabular form and will be 
summarized descriptively by gender.
9.1.2.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic population, unless 
otherwise specified.
9.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and will be 
based on GSK Data Standards and statistical principles.
9.1.3.1.
Statistical Methodology Specification
Plasma concentration time data will be descriptively summarized by the 3 sampling intervals (pre
dose, 1-4h interval and 5-8 h intervals) by visit and also listed by treatment group for each gender. 
10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
A population PK analysis will be conducted on the final data. The timeline for these analyses will be 
independent of the analysis described in this RAP. To support this analysis a NONMEM-specific 
data file will be generated, the analysis approach and specifications are detailed in the POP PK 
Data Analysis Plan by CPMS.
To support this analysis two NONMEM-specific data files will be generated by S&P using pre-
defined formatted datasets provided by CPMS. The first formatted dataset will focus on the PK 
data and all relevant covariates. The second dataset will contain the time dependent efficacy and 
safety endpoints.  


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11.
REFERENCES
Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS, et al. Standards for the diagnosis and 
treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Resp J 2004 23: 
932-946
IMI PROACTIVE IN COPD DAILY AND CLINICAL INSTRUMENTS D-PPAC and C-PPAC USER 
GIDE (14June2016)
Jones, PW and Forde Y (2016). St. Georges Respiratory Questionnaire for COPD Patients 
Manual, version 1.3.
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL et al. Multi-ethnic reference values for 
spirometry for the 3-95 year age range: the global lung function 2012 equations. Eur Resp J. 2012; 
40: 1324-1343


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12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
The criteria for subject exclusion from the Per Protocol population are based on ‘the Protocol 
Deviation Specification version 2.0-31August 2018’. Refer to the latest version of the rules 
document prior to finalisation of the per protocol population.
The following criteria define the protocol deviations Potential protocol deviations leading to 
exclusion from PP population will be reviewed by the study team to confirm that they meet these 
criteria.  This review will occur before the clinical database has been frozen for analysis. Note: 
None of the protocol deviations need the data unblinding to take the decision whether the subject 
data to be excluded from analysis or not. So, the protocol deviation meeting post unblinding won’t 
be conducted.
A subject meeting any of the following criteria will be excluded from the Per Protocol population:
Number
Exclusion Description
01
Inclusion #1 – Subject not 50-75 years of age inclusive
02
Inclusion #3 – Did not have Confirmed Diagnosis of COPD
03
Inclusion #4 – SPPB: Score of “0” on any component of the SPPB or Timed Chair Stand 
Score is < 1 and > 3
04
Inclusion #5 – BMI not within 18-32 kg/m2 (inclusive)
05
Inclusion #6 – not current smokers or former smokers with a cigarette smoking history of 
<10 pack years
06
Exclusion #1-7 – Prohibited Medical Conditions
07
Exclusion #8-10 – Prohibited Treatments
08
Exclusion #11 – Prohibited Prior/Current Clinical Study Experience
09
Exclusion #12-13 – Key laboratory tests out of range
10
Exclusion #14 – ECG values above ranges (QTc > 480, QTcB/F > 450)
11
Exclusion #15 – Positive HIV antibody test
12
Any other deviations from inclusion/exclusion criteria which could impact the efficacy 
assessment.
13
Experience an exacerbation, which needed treatment with steroids during the treatment 
phase of the study
14
Not completing the Day 80 PROactive endpoint, Week 13 (Day 90) lean mass and all of the 
functional assessments (leg press strength, peak performance from Incremental shuttle 
walking test, Constant Work Rate (CWR) duration from endurance shuttle walking test, total 
SPPB score and handgrip strength).
15
Permanent discontinuation of the treatment during the study treatment period (This check 
must will be performed by Statistics and Programming).


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12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
Procedure
Screening 
V1
(up to 30 
days before 
Day 1)
V2
Day -9
Treatment Period (13 weeks)
Follow-
up2
V9
(42 days 
post last 
dose)
Notes
V3
Baseline 
Day 1
V4
Day 
14
V5
Day 
28
V6
Day 
56
V7
Day 
80
V8
Last 
dose 
90
Unscheduled 
visit 1
Visit window (days)
- 30 to -11
-11 to 
-7
-2 to day 
1
12 -
16
24 –
32
52-
60
76 -
84
85 –
91
126- 140
There should be an 
attempt 
to 
conduct 
all 
assessments for a visit within a 
single day3.
Informed consent
X
Obtained prior to performing any 
study-related procedures.
Inclusion and exclusion criteria
X
Demography/ medical/medication/ 
drug/ alcohol history/ PD disease 
staging
X
Full physical examination 
X
X
X
Brief physical exam
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
HIV, Hepatitis B and C screening
X
If test otherwise performed within 3 
months prior to first dose of study 
treatment, testing at screening is 
not required


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Procedure
Screening 
V1
(up to 30 
days before 
Day 1)
V2
Day -9
Treatment Period (13 weeks)
Follow-
up2
V9
(42 days 
post last 
dose)
Notes
V3
Baseline 
Day 1
V4
Day 
14
V5
Day 
28
V6
Day 
56
V7
Day 
80
V8
Last 
dose 
90
Unscheduled 
visit 1
Hepatitis C viral RNA PCR 
X
If evidence of Hepatitis C 
antibodies at screening visit, then 
Hepatitis C viral RNA PCR 
required to exclude active infection. 
This sample is not needed if 
Hepatitis C screening is negative.
Haematology (Full blood count)/ 
Clinical Chemistry (Creatinine, urea 
and electrolytes, liver function tests, 
glucose) 
X
X
X
X
X
X
X
X
Participants should fast overnight 
for at least 8 hours prior to 
collection of these samples. 
HbA1c
X
X
hsCRP, Fibrinogen
X
X
X
25-OH Vitamin D Total, 25-OH 
Vitamin D2, 25-OH Vitamin D3
X
X
X
Lipid panel
X
X
X
X
X
X
X
Genetic sample
X
Obtain after participant is 
randomized. Informed consent to 
obtain the genetics sample must 
be obtained before collecting a 
sample.
Pharmacokinetic sampling
X4
X4,5
X6
X4
X
Times of dose administration for 
the two doses immediately 
preceding a PK sample should be 
accurately recorded.
Reproductive Tissue Biomarkers 
X
X
X
X
X
PSA
X
X
X
X
X
X
For male participants only
Bone Biomarkers
X
X
X
X


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Procedure
Screening 
V1
(up to 30 
days before 
Day 1)
V2
Day -9
Treatment Period (13 weeks)
Follow-
up2
V9
(42 days 
post last 
dose)
Notes
V3
Baseline 
Day 1
V4
Day 
14
V5
Day 
28
V6
Day 
56
V7
Day 
80
V8
Last 
dose 
90
Unscheduled 
visit 1
Exploratory Biomarkers
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
DXA
X
X
X
X
X
X
Spirometry
X
X
X
X
Follow ATS/ ERS guidelines [Celli, 
2004] and Quanjer reference 
equation [Quanjer, 2012].  
Sniff Nasal Inspiratory Pressure
X
X
X
X
Leg strength
X
X
X
X
X
X
Handgrip strength
X
X
X
Short Physical Performance Battery
X
X
X
X
X
X
Incremental Shuttle Walk Test
X
X
X
Practice incremental shuttle walk 
test conducted at day -9
Endurance Shuttle Walk Test
X
X
COPD Assessment Test
X
X
X
St George Respiratory 
Questionnaire COPD (SGRQ-c)
X
X
Patient Global Rating of Severity
X
X
Patient Global Impression of Change
X
X
X
X
X
Daily PROactive Physical Activity in 
COPD instrument and Physical 
Activity Monitor
X
X7
X
X7
Physical activity monitor dispensed 
at screening, day -9, day 56 and 
day 80 visits. Activity monitor 
should be worn for 7 days at each 
timepoint and returned at the next 
visit.
Monitored home exercise program
X
X
===============
X
Participants will receive training for 
the exercise program at Day -9, 
and will formally begin exercises 
on day 1
Patient exit interview
X


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Procedure
Screening 
V1
(up to 30 
days before 
Day 1)
V2
Day -9
Treatment Period (13 weeks)
Follow-
up2
V9
(42 days 
post last 
dose)
Notes
V3
Baseline 
Day 1
V4
Day 
14
V5
Day 
28
V6
Day 
56
V7
Day 
80
V8
Last 
dose 
90
Unscheduled 
visit 1
Randomization 
X
All Baseline assessments must be 
obtained prior to randomization. 
Study treatment provided to 
participant
X
X
X
The subject should take their first 
dose of study treatment in the clinic 
after randomization.
Study treatment 
X
================
X
Participants should dose study 
treatment in the clinic at each clinic 
visit during the treatment period.
Study treatment accountability by 
study site 
X
X
X
X
X
The required counting of pills by 
site staff to check compliance is 
not considered redispensing the 
study medication.
AE review
X
=============================
X
SAE review
X
=============================
X
Concomitant medication review
X
=============================
X
Optional sub-study measures
Cardiac and liver MRI (additionally 
prostate MRI in males)
X8
X8
MRI is an optional assessment 
undertaken at participating centres 
only.
ECG= Electrocardiogram; HIV= Human Immunodeficiency Virus; PK= Pharmacokinetic; PSA= Prostate Specific Antigen; DXA= Dual-energy X-ray 
Absorptiometry; AE= Adverse Event; SAE= Serious Adverse Event.
1.
An unscheduled clinic visit may occur at any time if the investigator believes an unscheduled visit is clinically warranted. Individual listed 
assessments are optional and are performed as needed to follow unresolved findings of clinical concern. Note: The “Unscheduled visit” case 
report form (CRF) form should be completed as soon as possible following the Unscheduled visit.


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2.
As stated in Section 8.2 , if a participant decides to withdraw or is withdrawn by the responsible physician, the reasons for withdrawal and the 
results of any relevant tests will be recorded in the CRF and the planned safety follow-up procedures will be performed, where possible. These 
include physical examination, 12-lead ECG, vitals, blood tests, urinalysis and concomitant medication review as listed for the follow-up visit (V9).
3.
Attempt to conduct all visits within a single day however the baseline (day 1) and last dose (day 90) visits may require subjects to visit the study 
centre on more than one day in order to complete MRI and DXA scans, and possibly other assessments. These scans, and any other 
assessments, should be conducted within the specified visit window, and prior to randomization at the baseline visit. Further details on the 
suggested order of assessments will be given in the SRM.
4.
Take PK sample prior to dosing in the clinic
5.
Take PK sample 1-4 hours post-dose (sites should try and ensure that a range of times are sampled within this time window for different 
participants, i.e. all PK samples should not be taken at 1 hour post dose or 2 hours post dose).
6.
Take PK sample 5-8 hours post-dose (as above, sites should try and ensure that a range of times are sampled within this time window for 
different participants).
7.
At V3 Baseline Day 1 and V8 Last dose 90, the patients will return the Daily PROactive Physical Activity in COPD Instrument and the Physical 
Activity Monitor to the site. Patients will not be dispensed the Daily PROactive Physical Activity in COPD Instrument and the Physical Activity 
Monitor at the end of these visits.
8.
All MRI Scans (Cardiac MRI, Liver MRI and, if applicable, Prostate MRI) should preferably be scheduled on the same day. Acquisition of the 
Cardiac MRI should be prioritized above the other two scans if it becomes unfeasible to perform all the MRI scan.
The following points must be noted: 
If assessments are scheduled for the same nominal time, THEN the assessments should occur in the following order:
i. vital signs
ii.12-lead ECG
iii. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the time specified in the SoA.


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12.3.
Appendix 3: Assessment Windows
12.3.1.
Definitions of Assessment Windows for Analyses
Analysis 
Set / 
Domain
Parameter    
(if 
applicable)
Protocol Window
Target 
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
All
All
Day -30
Day -11
Day -
30 to -
11
Day -60
Day -12
Screening/Visit 
1
All
All
Day -11
Day -7
Day -9
Day -11
Day -5
Visit 2
All
All
Day -2
Day 1
Day 1
Day -4
Day 1
Visit 3, Day 1
All
All
Day 12
Day 16
Day 14
Day 10
Day 18
Visit 4, Day 14
All
All
Day 24
Day 32
Day 28
Day 22
Day 34
Visit 5, Day 28
All
All
Day 52
Day 60
Day 56
Day 50
Day 62
Visit 6, Day 56
All
All
Day 76
Day 84
Day 80
Day 76
Day 84
Visit 7, Day 80
All
All
Day 85
Day 91
Day 90
Day 85
Day 97
Visit 8, Day 90
All
All
Day 126
Day 140
Day 
132
Day 126
Day 140
Follow-Up, Day 
132

For scheduled visits the analysis visit would equal the nominal visit irrespective of the 
assessment date and irrespective of whether that date falls in the visit window.

Only unscheduled visits are slotted according to the table above and this slotting algorithm 
will be applicable for both efficacy and safety domains.

After slotting of Un-scheduled visits, if there are multiple assessments at a planned time-
point, then the value closest to the target day for that window will be considered. If the
multiple assessments are equidistant from the target day, then mean of the assessments 
will be considered.

For any time post baseline and baseline (if the definition of baseline is the latest pre-dose 
visit) all assessments are used irrespective of whether they fall into visit windows or not.


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12.4.
Appendix 4: Study Phases 
12.4.1.
Study Phases 
Only Concomitant Medication will be reported by treatment phases and all other displays will be 
irrespective of the phases.
12.4.2.
Study Phases for Concomitant Medication 
Definition
Treatment Phase
Pre-Treatment
On-Treatment*
Subject did not take study treatment (e.g., screening failures) AND 
concomitant medication stop date >= date of Screening
Y
Concomitant medication start date < treatment start date AND (date of 
Screening <= concomitant medication stop date <treatment start date)
Y
Concomitant medication start date < (treatment start date or screening 
Date) and the variable that defines the status of Concomitant medication 
end with respect to reference time -period is ("BEFORE”) 
Y
Concomitant medication start date < treatment start date AND the 
variable that defines the status of Concomitant medication end with 
respect to reference time -period is ("AFTER", “DURING”, 
“DURING/AFTER”, “ONGOING”)
Y
Y
Concomitant medication start date < treatment start date AND 
(treatment start date < concomitant medication stop date <= treatment 
stop date)
Y
Y
(Concomitant medication start date < treatment start date) AND 
(concomitant medication stop date > treatment stop date)
Y
Y
Treatment start date <= concomitant medication start date 
Y
*On-Treatment phase includes both On-Treatment and Post-Treatment concomitant medications.


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12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Reporting Process
Software

The currently supported versions of SAS software (Version 9.2 or higher).
Reporting Area
HARP Server
: us1salx00259
HARP Compound
: \ARPROD\GSK2881078\mid200182\
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & AdaM IG 
Version 1.0.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented as SDTM.
Generation of RTF Files

RTF files will be generated for each reporting effort.
12.5.2.
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
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF except for the parameters 
specified below.
Domain
DP for Mean
Leg Press (Last Successful Lift 1-Rep Max (kg))
1 DP
Appendicular Lean Mass (kg) & Total Lean Mass (kg)
3 DP
PRO parameters & SGRQ parameters
2 DP
Total Score for SPPB
1 DP
CAT
1 DP
Time for the Fastest Walk (sec) & Time Repeated Chair Stand 
Test (sec)
3 DP


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Incremental Shuttle Walking test - Maximum Distance Walked 
(m)
1 DP
CWR - Exercise Duration (sec)
1 DP

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.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will be assigned to a study visit using the assessment windows defined in 
Section 12.3. After slotting of Un-scheduled visits, if there are multiple assessments at a planned 
time-point, then the value closest to the target day for that window will be used. If its equidistant 
from the target day, then mean of the assessments will be used in summary and figures. Listing will 
show both the planned and un-scheduled assessments.

Data summaries will only report visits that are planned assessment time points for each parameter 
(according to the T&E table) which can include the unscheduled visits if slotted.

All unscheduled visits will be included in listings.

Unscheduled visits can be included in the derivation of any time post baseline visits and baseline if 
the definition of baseline is the latest pre-dose visit (See Section 5.2).
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.


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12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements (not in case of visit slotting) 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 12.3.1) 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:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
Note that Treatment Start Date is considered as Study Day 1.
Post-baseline

Post-baseline refers to the combined time periods of On-treatment and Post-treatment.
Change from Baseline
= Post-baseline -Baseline
Ratio to Baseline
= exp (log (Post-baseline) -log (Baseline))
Percent Change from Baseline
= 100*(Post-baseline – Baseline)/Baseline
Treatment compliance
= 100 * (Total Amount Taken/ (Treatment duration in days* 2))
    Total Amount Taken = Total tablets dispensed – Total tablets returned – Total tablets lost.
12.6.2.
Efficacy
Secondary Efficacy endpoints
Peak performance from incremental shuttle walking test

‘Maximum distance walked’ collected from incremental shuttle walk test in CRF
Constant Work Rate (CWR) duration from endurance shuttle walking test

‘Exercise duration time (seconds)’ collected from endurance shuttle walk test in CRF
St George Respiratory Questionnaire (SGRQ) total score and domains

The total score and three component scores (Symptoms, Activity and Impacts) will be derived from St 
George Respiratory Questionnaire- COPD (SGRQ- c) raw scores based upon the score manual (ST 


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Secondary Efficacy endpoints
GEORGE’S RESPIRATORY QUESTIONNAIRE FOR COPD PATIENTS (SGRQ-C) Version No.1.3 
March 2016)

First, sum the weights for all items with a positive response:
Symptoms component consists of all the questions (question 1 -7) in Part 1. The weights for Questions 
1-7 are summed. A single response is required to each item. If multiple responses are given to an item, 
the weights for the multiple positive responses should be averaged then added to the sum.
Activity component is calculated from the summed weights for the positive responses to items 
questions 9 and 12 in Part 2 of the questionnaire.
Impacts component is calculated from questions 8, 10, 11, 13, 14 in Part 2 of the questionnaire. The
weights for all positive responses to items in Questions 10, 11, 13 are summed together
with the responses to the single item that should have been checked (ticked) in Questions 8 and 14. In 
the case of multiple responses to either of these items, the average weight for the item should be 
calculated.
Total score is calculated by summing the weight to all the positive responses in each component.

Then, calculate the score:
The score for each component is calculated separately by dividing the summed weights by the 
maximum possible weight for that component and expressing the results as a percentage:
Sum of maximum possible weights for each component and Total:
Symptoms:    566.2     Impact:  1652.8
Activity:          982.9    Total:       3201.9

Last, converting SGRQ-c scores to be comparable to SGRQ:
The adjustment is:
Symptoms:  SGRQ score = (SGRQ-C x 0.99) + 0.94 units
Activity: SGRQ score = (SGRQ-C x 0.87) +7.01 units
Impacts: SGRQ score = (SGRQ-C x 0.88) +2.18 units
Total: SGRQ score = (SGRQ-C x 0.90) + 3.10 units

Handling of missing items
A Total score can be calculated in the presence of missing data, but only if the domains meet their 
‘missing items’ rules (see below). If one domain exceeds its permitted number of missed items, then a 
total score cannot be calculated.
Symptoms: The Symptoms component will tolerate a maximum of 1 missed item. The weight for the 
missed item is subtracted from the total possible weight for the Symptoms component (566.2) and from 
the Total weight (3201.9) and then calculate the score.
Activity: The Activity component will tolerate a maximum of 3 missed items. The weight for the missed 
item (s) is subtracted from the total possible weight for the Activity component (982.9) and from the 
Total weight (3201.9) and then calculate the score.
Impacts: The Impacts component will tolerate a maximum of 5 missed items. The weight for the missed 
item (s) is subtracted from the total possible weight for the Impacts component (1652.8) and from the 
Total weight (3201.9) and then calculate the score.

Responder is defined as ‘Yes’ when the total score at a post-baseline visit decreases by 4 or more from 
baseline total score, otherwise, non-responder.


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Secondary Efficacy endpoints
Total Short Physical Performance Battery (SPPB) score and times for chair rise and 4 m gait 
speed

Total SPPB score, ‘Time for five stands done successfully’ collected for chair and ‘time for fastest walk 
for 4 m gait test’ collected from CRF will be used, respectively

SPPB at baseline will be categorized as below:
      SPPB 10-12 points fit patient, normal 
      SPPB 8-9 points pre-frail patient 
      SPPB ≤ 7 points frail patient
COPD Assessment Test (CAT)

Total score of 8 questions will be used

Responder is defined as ‘Yes’ when the total score at a post-baseline visit decreases by 2 or more from 
baseline total score, otherwise, non-responder.

If one or more of the 8 questions are missing the total score and the responder will be missing.
PROactive endpoints (individual components (Difficulty and Amount) and total score)

The PROactive instrument (IMI PROACTIVE IN COPD DAILY AND CLINICAL INSTRUMENTS D-
PPAC and C-PPAC 2016 (Use D-PPAC for the calculation of scores)) combines a PRO questionnaire 
and an activity monitor to measure physical activity in COPD patients. It is 9-item daily assessments
covering 2 different domains (amount and difficulty) designed for electronic administration. The ‘amount’ 
domain is covered by 2 items (questions - amount of walking outside and chores outside) and by 2 
activity monitor outputs (vector magnitude units per minute (VMU/min) and steps/day). The ‘difficulty’ 
domain is covered by 5 items (questions). 

The scores for activity monitor outputs, step counts and VMU’s is assigned based on the 5 level
categories they are falling in (see the table below).
Scores
VMU/min
Steps/day

Calculation of daily score for each domain (amount, difficulty) and total score:
First, domains are scored by simple adding items, which, the values are 0-17 for ‘amount’ and 0-20 for 
‘difficulty’. The raw scores are then scaled to a score ranging from 0 to 100, based on Table 1 in the 
guidance (see Reference)
The ‘total score’ is obtained calculating the average between two domains. This score has the same 
scale of two individual domains, from 0 to 100.
PROactive scores for a day cannot be calculated if the subjects missed any of the 9 items in any day.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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Secondary Efficacy endpoints

Calculation of the weekly score for each domain (amount, difficulty) and total score:
The average of the daily scores during a 7-day period will be the weekly score separately for each 
domain (amount, difficulty) and total score.

Score eligibility:
Adequate physical activity data are considered for days where more than eight hours of wearing time is 
available. The activity monitor measurement days used should be concurrent with the questionnaire.
At least four days with ≥ 8 hours of wearing time of activity monitor data are required for the 
measurements to be valid for a weekly average. These four days should be in the same week (7 days 
from the first day of assessments), do not need to be consecutive, and could cover weekdays or 
weekend days without distinction.
Physical Activity Measures 

At least four days with ≥ 8 hours of wearing time of activity monitor data are required for the 
measurements to be valid for a weekly average. These four days should be in the same week (7 days 
from the first day of assessments), do not need to be consecutive, and could cover weekdays or 
weekend days without distinction. Then calculate the average by dividing total with number of days.

The physical activity measures weekly average steps, weekly average vector magnitude unit/wear time 
and weekly average moderate/vigorous activity duration have the same derivation.

The number of subjects included: The count of subject in each visit who has wear time more than 8 
hours for at least 4 days in a week. 

Average number of days included per subject: This the average number of days with wear duration 
more than 8 hours for at least 4 days in each visit.

Average number of minutes included per subject: This the average wear duration in minutes for those 
subjects with more than 8 hours of wear duration for at least 4 days in a week for each visit.
12.6.3.
Safety
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1
The number of days exposure therefore does not take into account dose interruptions.

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

Actual amount taken (number of tablets) = Total tablets dispensed – Total tablets returned – Total 
tablets lost.

Females will take 1 mg everyday (2*0.5mg tables) and males will take 2 mg (2*1mg). So, the actual 
dose (mg) taken will be the same as actual amount taken for males and for females it will be actual 
amount taken divided by 2.

The cumulative actual dose (mg) will be the sum of the actual doses taken.
Adverse Events
Onset Time Since 
1st Dose (Days)
If Treatment Start Datetime ≤ AE Onset Datetime , then AE Onset Datetime -
Treatment Start Datetime +1
If time part is missing in any of the Datetime, then use the Treatment Start date and AE 


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Extent of Exposure
Onset date in calculation and missing otherwise.
Duration (Days) 
AE Resolution Datetime – AE Onset Datetime + 1
If time part is missing in any of the Datetime, then use the AE Resolution date and AE 
Onset date in calculation and missing otherwise.
Drug-related
If the question ‘is there a reasonable possibility that AE may have been caused by the 
Study Treatment’ is marked ‘YES’ on CRF or is missing. 
MRI 

Body Surface Area (BSA) (m2) =0.007184 * Weight (kg)0.425 * Height (cm)0.725

Left Ventricular End Systolic Volume Index (LVESVi)=

Left Ventricular End Diastolic Volume Index (LVEDVi)=
Adverse Events
Adverse Events of Special Interest (AESI))
The following table presents the AESI. AESI which are not SMQs are made up of a selection of preferred 
terms (PTs) defined by GSK. The complete list of AESI, including the PTs which contribute to each of the 
AESI will be provided by Safety and Medical Governance using the MedDRA version current at the time of 
reporting. 
AESI
Group of terms (MedDRA SMQ, HLT or individual PTs)
Drug related hepatic 
disorders
Drug related hepatic disorders – comprehensive search (SMQ)
Reproductive organ 
effects, male
Prostatic neoplasms and hypertrophy HLT plus selected preferred terms:
Prostatic specific antigen abnormal
Prostatic specific antigen increased
Reproductive organ 
effects, female
Female gonadal function disorders HLT (includes PT of Hirsutism and Virilism)
Virilism in females
Hirsutism PT, Virilism PT, Acnes HLT, Dysphonia PT
Dyslipidaemia
Dyslipidaemia SMQ
Bone effects
Osteoporosis/osteopenia (SMQ),
Plus, selected Fracture PTs (57 terms)
MedDRA PT
PT Code
Ankle fracture
10002544
Bone decalcification
10070817
Bone disorder
10005956
Bone fragmentation
10064211
Clavicle fracture
10009245
Comminuted fracture
10052614
Complicated fracture
10010149
Compression fracture
10010214


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Epiphyseal fracture
10053962
Facial bones fracture
10016042
Fibula fracture
10016667
Foot fracture
10016970
Fracture delayed union
10017081
Fracture displacement
10053206
Fracture reduction
10057609
Fractured coccyx
10049164
Fractured skull depressed
10017310
Greenstick fracture
10018720
Hand fracture
10019114
Humerus fracture
10020462
Impacted fracture
10066386
Internal fixation of spine
10069749
Jaw fracture
10023149
Lower limb fracture
10061599
Open fracture
10030527
Osteocalcin decreased
10050940
Osteonecrosis
10031264
Osteonecrosis of jaw
10064658
Patella fracture
10034122
Scapula fracture
10039579
Skeletal injury
10061363
Skull fracture
10061365
Skull fractured base
10040960
Sternal fracture
10042015
Stress fracture
10042212
Tibia fracture
10043827
Torus fracture
10066094
Traumatic fracture
10049514
Ulna fracture
10045375
Upper limb fracture
10061394
Vertebral wedging
10065317
Atypical fracture
10072395
Avulsion fracture
10066184
Chance fracture
10073162
Limb fracture
10074551
Osteochondral fracture
10073853
Periprosthetic fracture
10069135
Spinal fusion fracture
10074807
Fracture malunion
10017085
Fracture nonunion
10017088
Craniofacial fracture
10077603
Spinal flattening
10077756
Bone metabolism biochemical marker
increased
10078949
Subchondral insufficiency fracture 
10079864


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Maisonneuve fracture
10081343
Degenerative bone disease
10081730
Internal fixation of fracture
10022576
Cardiovascular effects
See the table below.
Hypersensitivity
Hypersensitivity (SMQ) narrow, Angioedema (SMQ) narrow, Anaphylactic reaction 
(SMQ) narrow
Hostility/aggression
Hostility/aggression (SMQ)
Sexual desire 
disorders
Sexual desire disorders HLT
Embolic and 
thrombotic events
Embolic and thrombotic events (SMQ)
Cardiovascular effects AESI
AESI 
AESI Subgroup
Sub-SMQ
Scope
Cardiovascular 
effects
Cardiac arrhythmia
Arrhythmia related investigations, 
signs and symptoms (SMQ)
Broad
Bradyarrhythmia terms, nonspecific 
(SMQ)
Broad
Conduction defects (SMQ)
Broad
Disorders of sinus node function 
(SMQ)
Broad
Cardiac arrhythmia terms, 
nonspecific (SMQ)
Broad
Supraventricular tachyarrhythmias 
(SMQ)
Broad
Tachyarrhythmia terms, nonspecific 
(SMQ)
Broad
Ventricular tachyarrhythmias (SMQ)
Broad
Cardiac failure (SMQ)
Broad
Ischaemic heart 
disease (SMQ)
Broad
Hypertension (SMQ)
Broad
Central nervous 
system haemorrhages 
and cerebrovascular 
conditions (SMQ)
Broad
Cardiomyopathy 
(SMQ)
Narrow
ECG Parameters
General

The summary should be based on average value of triplicate ECG readings obtained over a brief 
recording period (missing readings will not be counted).
Eligibility Criteria 

The QT values at screening will be using for the eligibility checking of subjects.


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ECG Parameters
Stopping Criteria
A subject who meet either of the bulleted criteria below will be withdrawn from the study:

QT interval corrected for heart rate by Bazett's formula (QTcB) or QT interval corrected for heart 
rate by Fridericia’s formula (QTcF) >450 msec 

QT interval corrected for heart rate (QTc) >480 msec in participants with Bundle Branch Block 
based on a single ECG. 
Laboratory Parameters
General

All clinical laboratory tests will be based on central laboratory assessments only. If a laboratory value 
which is expected to have a numeric value for summary purposes, has a non-detectable level reported 
in the database, where the numeric value is missing, but typically a character value starting with ‘<x’ or 
‘>x’ (or indicated as less than x or greater than x in the comment field) is present, the number of 
significant digits in the observed values will be used to determine how much to add or subtract in order 
to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digits  =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
Laboratory Toxicity Grade

Toxicities will be based on FDA guidance ‘Common Terminology Criteria for adverse events v4.03 
(CTCAE) defined by NCI-CTEP (National Cancer Institute – Cancer Therapy Evaluation Program).

When summarising toxicity grades for such parameters, they will be categorised as to whether they are 
above or below the normal range.
Parameter
Below Normal Range
Above Normal Range
Fasted glucose
Hypoglycaemia
Hyperglycaemia
Sodium
Hyponatremia
Hypernatremia
Potassium
Hypokalemia
Hyperkalemia
Calcium
Hypocalcemia
Hypercalcemia
Hepatitis Status

Hepatitis B and C will be determined using antibody (IgM or IgG) at the screening or within 3 months 
prior to first dose of study treatment. If there is evidence of Hepatitis C antibodies at the screening visit, 
then Hepatitis C viral RNA PCR is required to exclude active infection. This sample is not needed if 
Hepatitis C screening is negative

Antibody (IgM or IgG) status with ‘BORDERLINE’ or ‘REACTIVE’ will be considered Positive

A subject will be considered positive for hepatitis B virus (HBV) if they have a positive surface antigen 
(HBsAg) during screening. Subjects positive for HBV are not allowed to enter the study
COPD Exacerbation Event Count

The total number of exacerbation events is determined by summing the number of times there is a non-
missing “Date of Onset” on the exacerbation CRF page” for a subject

The number of exacerbating patients refers to the count of the unique patient in the COPD 
Exacerbation CRF data. In other words, it is the total number of patients who experience one or more 
exacerbations defied in the first bullet.


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12.7.
Appendix 7: Reporting Standards for Missing Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as subjects who 
completed all visits of the study including the follow-up visit.

Withdrawn subjects may be replaced in the study.

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 assigned to a planned visit or an unscheduled visit and will be 
slotted as per Appendix 3: Assessment Windows.
12.7.2.
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 by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.7.2.1.
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 is before the start 
date of study treatment; in this case the study treatment start date will be used.
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.


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12.8.
Appendix 8: Values of Potential Clinical Importance
12.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< 
x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
(Female & Male)
0.075
Haemoglobin 
g/L
Male
180
Female
180
∆from BL 
(Female & Male)
25
Lymphocytes
x109/ L
0.8
Neutrophil Count
x109/ L
1.5
Platelet Count 
x109/ L
100
550
White Blood 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
µmol/L
∆from BL
44.2
Glucose
mmol/L
3
9
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2 (Bicarbonate)
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
>=3xULN
AST/SGOT 
U/L
High
>=2xULN
Alkaline phosphatase
U/L
High
>=2xULN
T Bilirubin 
µmol/L
High
>=1.5ULN
T. Bilirubin + ALT
µmol/L
High
>=1.5ULN T. Bilirubin
+
U/L
>=3xULN ALT


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12.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
N/A
> 500
Uncorrected QT
msec
N/A
> 600
Change from Baseline
Increase from Baseline QTc
msec
N/A
> 60
12.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
<85
>160
Diastolic Blood Pressure
mmHg
<45
>100
Pulse Rate
Beats/min
<40
>110
Respiratory Rate
breaths/min
N/A
>20
Temperature (skin)
°C
N/A
>38


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12.9.
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses
Analysis
     Mixed Model Repeated Measure (MMRM)

Distributional assumptions underlying the model used for analysis will be examined by
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.
Analysis
     Bayesian Analysis

Non-informative prior should be plotted to make sure it is truly non-informative.

Adequate values for the number of MCMC samples / thinning / number of burn-in
samples should be chosen to ensure that the ratio Monte Carlo Standard Errors (MCSE) and 
standard deviation of the posterior distribution for all the parameters in the model as small as 
possible, typically close to 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.

The Geweke diagnostic test checks whether the mean estimates have converged by 
comparing means from the early and latter part of the Markov chain using a z score t-test. 
Large absolute values of the z-score statistic indicate rejection of the null hypothesis of no 
difference between the mean estimates obtained from the early and latter parts of the chain.

The convergence diagnostics for all parameters in the Bayesian analysis will be visually 
checked by the trace plots.

If the trace plots show apparent trend or the autocorrelation plots show significant positive or 
negative autocorrelation, number of iterations will be increased or reparameterization might be 
explored.
Analysis
Analysis of covariance (ANCOVA)

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.


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12.10.
Appendix 10: Abbreviations & Trade Marks
12.10.1.
Abbreviations
Abbreviation
Description
1-RM
1 repetition maximum
AP
Analysis Population
A&R
Analysis and Reporting 
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
BDRM
Blinded data review meeting
BP
Blood Pressure
BS
Biostatistics
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CPMS
Clinical Pharmacology Modelling & Simulation
CRF
Case report form
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CV
Cardiovascular
CVA
Cerebrovascular event stroke 
CWR
Constant Work Rate
DAP
Data Analysis Plan
DBF
Database Freeze
DBR
Database Release
DM
Data management
DOB
Date of Birth
DP
Decimal Places
DVT
Deep vein thrombosis 
DXA
Dual-energy X-ray Absorptiometry
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FSH
Follicle-stimulating hormone
GSK
GlaxoSmithKline
HR
Heart rate
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System


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Abbreviation
Description
IP
Investigational Product
LH
Luteinizing hormone
LVEF
Left ventricular ejection fraction
MMRM
Mixed Model Repeated Measures
MRI
Magnetic Resonance Imaging
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PE
Pulmonary embolism 
PGIC
Patient Global Impression of Change
PGRS
Patient Global Rating of Severity
PSA
Prostate specific antigen
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcB
Bazett’s QT Interval Corrected for Heart Rate
QTcF
Frederica’s QT Interval Corrected for Heart Rate
RAMOS
Randomization & Medication Ordering System 
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SARM
Selective Androgen Receptor Modulator
SD
Standard deviation
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SE
Standard error
SGRQ
St George Respiratory Questionnaire
SGRQ-c
St George Respiratory Questionnaire-COPD
SMG
Safety and Medical Governance
SnIP
Sniff Nasal Inspiratory Pressure
SOP
Standard Operation Procedure
SPPB
Short Physical Performance Battery
SRT
Safety Review Team
SHBG
Sex hormone-binding globulin
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TIA
Transient ischemic attack 
FEV1
Forced Expiratory Volume in 1 second
SnIP
Sniff Nasal Inspiratory Pressure


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12.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
None


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12.11.
Appendix 11: List of Data Displays
12.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.13
Efficacy
2.1 to 2.47
2.1 to 2.9
Safety
3.1 to 3.36
3.1 to 3.4
PK
4.1
Section
Listings
ICH Listings
1 to 34
Other Listings
35 to 89
12.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up displays 
provided in Appendix 12: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.11.3.
Deliverables
Delivery 
Description
SAC
Final Statistical Analysis Complete


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12.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All 
Participants
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record
ICH E3, FDAAA, EudraCT
SAC 
1.2.
All 
Participants
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC 
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC 
1.4.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.5.
All 
Participants
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Population Analysed
1.6.
Screened 
SP1 
Summary of Study Populations 
IDSL
Headline 
Results & SAC 
1.7.
All 
Participants
SP2
Summary of Exclusions from the Per Protocol Population
IDSL
SAC
Demographic and Baseline Characteristics
  1.8.
All 
Participants
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Footnote: Age is imputed when full date 
of birth is not provided.
Headline 
Results & SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.9.
Enrolled
DM11
Summary of Age Ranges
EudraCT
Footnote: Age is imputed when full date 
of birth is not provided.
SAC
1.10.
All 
Participants
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
Prior and Concomitant Medications
1.11.
All 
Participants
MH4
Summary of Medical Conditions
ICH E3 
SAC 
1.12.
All 
Participants
CM1
Summary of Concomitant Medications
ICH E3
Note: On-Treatment phase includes 
both On-Treatment and Post-Treatment 
concomitant medications.
SAC 
Exposure
1.13.
Safety
EX1
Summary of Extent of Exposure to Investigational Product
ICH E3
SAC


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12.11.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Efficacy
2.1.
Analysis
EFF_T1
Analysis of Percent Change from Baseline in Leg Press Strength
(%) by Visit - Repeated Measure Mixed Model
Headline 
Results & SAC
2.2.
Per Protocol
EFF_T1
Analysis of Percent Change from Baseline in Leg Press Strength
(%) by Visit - Repeated Measure Mixed Model
SAC 
2.3.
Analysis
EFF_T1
Analysis of Change from Baseline in Leg Press Strength (kg) by 
Visit - Repeated Measure Mixed Model
SAC 
2.4.
Per Protocol
EFF_T1
Analysis of Change from Baseline in Leg Press Strength (kg) by 
Visit- Repeated Measure Mixed Model
SAC 
2.5.
Analysis
EFF_T2
Bayesian Analysis of Percentage Change from Baseline in Leg 
Press Strength (%) by Visit
Headline 
Results & SAC
2.6.
Analysis 
EFF_T3
Descriptive Summary of Change and Percent Change from 
Baseline in Leg Press Strength by Visit
Summarize the data for change from 
baseline, percentage change from 
baseline and ratio to baseline along 
with the data at each visit for 
parameters Last Successful Lift 1-Rep 
Max (kg), Number of Successful Lifts 
and Starting Lift Weight (kg).
Headline 
Results & SAC


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2.7.
Per Protocol
EFF_T3
Descriptive Summary of Change and Percent Change from 
Baseline in Leg Press Strength by Visit
Summarize the data for change from 
baseline, percentage change from 
baseline and ratio to baseline along 
with the data at each visit for 
parameters Last Successful Lift 1-Rep 
Max (kg), Number of Successful Lifts 
and Starting Lift Weight (kg).
SAC
2.8.
Analysis
EFF_T1
Analysis of Percent Change from Baseline in Leg Press Strength
(%) by Visit - Repeated Measure Mixed Model with Exploratory 
Covariate
Add the exploratory covariates 
predicted FEV1 and BMI at baseline in 
the same model for Table 2.1.
Update the shell footnote by adding the 
exploratory covariates 
SAC
Secondary Efficacy
2.9.
Analysis
EFF_T1
Analysis of Change from Baseline in Appendicular (kg), and 
Total Lean Mass (kg) as Assessed by Dual-energy X-ray 
Absorptiometry by Visit - Repeated Measure Mixed Model
Similar shell as EFF_T1, add a by line 
for Parameter under the Sex 
p-value is not required
Headline 
Results & SAC
2.10.
Analysis
EFF_T1
Analysis of Percent Change from Baseline in Appendicular (%), 
and Total Lean Mass (%) as Assessed by Dual-energy X-ray 
Absorptiometry by Visit - Repeated Measure Mixed Model
Similar shell as EFF_T1, add a by line 
for Parameter under the Sex
p-value is not required
SAC 
2.11.
Analysis 
EFF_T3
Descriptive Summary of Change and Percent Change from 
Baseline in Appendicular and Total Lean Mass as Assessed by 
Dual-energy X-ray Absorptiometry by Visit
Summarize the data for change from 
baseline, percentage change from 
baseline and ratio to baseline along 
with the data at each visit
Headline 
Results & SAC
2.12.
Analysis
EFF_T1
Analysis of Change from Baseline in PROactive Total Score, 
Difficulty and Amount Scores by Visit- Repeated Measure Mixed 
Model
Similar shell as EFF_T1, add a by line 
for Parameter under the Sex
p-value is not required
Headline 
Results & SAC


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2.13.
Per Protocol
EFF_T1
Analysis of Change from Baseline in PROactive Total Score, 
Difficulty and Amount Scores by Visit- Repeated Measure Mixed 
Model
Similar shell as EFF_T1, add a by line 
for Parameter under the Sex
p-value is not required
SAC
2.14.
Analysis
EFF_T2
Bayesian Analysis of Change from Baseline in PROactive Total 
Score by Visit
Headline 
Results & SAC
2.15.
Analysis 
EFF_T3
Descriptive Summary of Change from Baseline in PROactive 
Total Score, Difficulty and Amount Scores by Visit
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
Headline 
Results & SAC
2.16.
Per Protocol
EFF_T3
Descriptive Summary of Change from Baseline in PROactive 
Total Score, Difficulty and Amounts Scores by Visit
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
SAC
2.17.
Analysis
EFF_T1
Analysis of Change from Baseline in COPD Assessment Test 
(CAT) score by Visit- Repeated Measure Mixed Model
Similar shell as EFF_T1, p-value is not 
required
SAC 
2.18.
Analysis 
EFF_T6
Responder Analysis of COPD Assessment Test 
(CAT) 
SAC
2.19.
Analysis
EFF_T3
Descriptive Summary of Change from Baseline in COPD 
Assessment Test (CAT) score by Visit
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
SAC
2.20.
Analysis
EFF_T7
Analysis of Change from Baseline in St George Respiratory 
Questionnaire (SGRQ) Total Score and Domains Score at Day 
90 - ANCOVA Model
Headline 
Results & SAC
2.21.
Per Protocol
EFF_T7
Analysis of Change from Baseline in St George Respiratory 
Questionnaire (SGRQ) Total Score and Domains Score at Day 
90 – ANCOVA Model
SAC
2.22.
Analysis
EFF_T6
Responder Analysis of St George Respiratory Questionnaire 
(SGRQ) 
SAC
2.23.
Analysis
EFF_T2
Bayesian Analysis of Change from Baseline in St George 
Respiratory Questionnaire (SGRQ) Total Score at Day 90
Same as EFF_T2, remove the visit 
column
Headline 
Results & SAC


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2.24.
Analysis
EFF_T3
Descriptive Summary of Change from Baseline in St George 
Respiratory Questionnaire (SGRQ) Total Score and Domains 
Scores by Visit
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
Headline 
Results & SAC
2.25.
Per Protocol
EFF_T3
Descriptive Summary of Change from Baseline in St George 
Respiratory Questionnaire (SGRQ) Total Score and Domains 
Scores by Visit
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
SAC
2.26.
Analysis
EFF_T1
Analysis of Change from baseline in total Short Physical 
Performance Battery (SPPB) score and times for chair rise (sec)
and 4 m gait speed (sec) by Visit - Repeated Measure Mixed 
Model
Similar shell as EFF_T1, add a by line 
for Parameter under the Sex
p-value is not required
Headline 
Results & SAC
2.27.
Per Protocol
EFF_T1
Analysis of Change from baseline in total Short Physical 
Performance Battery (SPPB) score and times for chair rise (sec)
and 4 m gait speed (sec) by Visit - Repeated Measure Mixed 
Model
Similar shell as EFF_T1, add a by line 
for Parameter under the Sex
p-value is not required
SAC 
2.28.
Analysis
EFF_T2
Bayesian Analysis of Change from Baseline in Times for chair 
rise (sec) by Visit
Headline 
Results & SAC
2.29.
Analysis
EFF_T3
Descriptive Summary of Change from baseline in total Short 
Physical Performance Battery (SPPB) score and times for chair 
rise and 4 m gait speed by Visit 
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
Headline 
Results & SAC
2.30.
Per Protocol
EFF_T3
Descriptive Summary of Change from baseline in total Short 
Physical Performance Battery (SPPB) score and times for chair 
rise and 4 m gait speed by Visit 
Summarize the data for change from 
baseline and ratio to baseline along 
with the data at each visit
SAC
2.31.
Analysis
EFF_T7
Analysis of Change from Baseline in Constant Work Rate 
(CWR) Duration (sec) from Endurance Shuttle Walking Test at 
Day 90 – ANCOVA model
Similar shell as EFF_T7, remove the 
column ‘Parameter’
Headline 
Results & SAC
2.32.
Per Protocol
EFF_T7
Analysis of Change from Baseline in Constant Work Rate 
(CWR) Duration (sec) from Endurance Shuttle Walking Test at
Day 90 – ANCOVA model
Similar shell as EFF_T7, remove the 
column ‘Parameter’
SAC


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2.33.
Analysis
EFF_T7
Analysis of Percent Change from Baseline in Constant Work 
Rate (CWR) Duration (%) from Endurance Shuttle Walking Test 
at Day 90 – ANCOVA model
Similar shell as EFF_T7, remove the 
column ‘Parameter’
Update footnote [1] as “[1] Lsmeans of 
percent change from baseline for each 
treatment group as well as the 
difference of lsmeans of percent 
change from baseline is estimated from 
ANCOVA model with baseline score as 
the covariate adjusting for the 
treatment. In case of violation of the 
assumptions, the same model is fitted 
with log of ratio to baseline and 
replacing the covariate baseline with 
log baseline. ”
SAC
2.34.
Analysis
EFF_T2
Bayesian Analysis of Change from Baseline in Constant Work 
Rate (CWR) Duration (sec) from Endurance Shuttle Walking 
Test at Day 90
Same as EFF_T2, remove the visit 
column
Headline 
Results & SAC
2.35.
Analysis
EFF_T3
Descriptive Summary of Change and Percent Change from 
Baseline in Constant Work Rate (CWR) Duration from 
Endurance Shuttle Walking Test by Visit
Summarize the data for change from 
baseline, percentage change from 
baseline and ratio to baseline along 
with the data at each visit
Headline 
Results & SAC
2.36.
Per Protocol
EFF_T3
Descriptive Summary of Change and Percent Change from 
Baseline in Constant Work Rate (CWR) Duration from 
Endurance Shuttle Walking Test by Visit
Summarize the data for change from 
baseline, percentage change from 
baseline and ratio to baseline along 
with the data at each visit
SAC
2.37.
Analysis
EFF_T7
Analysis of Change from Baseline in Peak Performance from 
Incremental Shuttle Walking Test at Day 90 – ANCOVA Model
Similar shell as EFF_T7, remove the 
column ‘Parameter’
SAC 


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2.38.
Analysis
EFF_T7
Analysis of Percent Change from Baseline in Peak Performance 
from Incremental Shuttle Walking Test (%) at Day 90 –
ANCOVA Model
Similar shell as EFF_T7, remove the 
column ‘Parameter’
Update footnote [1] as “[1] Lsmeans of 
percent change from baseline for each 
treatment group as well as the 
difference of lsmeans of percent 
change from baseline is estimated from 
ANCOVA model with baseline score as 
the covariate adjusting for the 
treatment. In case of violation of the 
assumptions, the same model is fitted 
with log of ratio to baseline and 
replacing the covariate baseline with 
log baseline. ”
SAC
2.39.
Analysis
EFF_T3
Descriptive Summary of Change and Percent Change from 
Baseline in Peak Performance from Incremental Shuttle Walking 
Test by Visit
Summarize the data for change from 
baseline, percentage change from 
baseline and ratio to baseline along 
with the data at each visit.
Update footnote as “Note: When there 
are multiple pre-dose assessments, the 
highest non-missing pre-dose 
assessment from day -9 and day 1 is 
identified and captured as "Baseline 
(Derived)" visit”
SAC
2.40.
Analysis
EFF_T3
Descriptive Summary of Change from Baseline in Physical 
Activity Measures as Assessed via an Accelerometer.
SAC 
2.41.
Analysis
EFF_T8
Descriptive Summary of Patient Global Impression of Change
SAC 
2.42.
Analysis
EFF_T10
Descriptive Summary of Patient Global Rating of Severity.
SAC 
2.43.
Analysis
EFF_T3
Descriptive Summary of Change from Baseline in FEV1 (L) by 
Visit
This table will include both FEV1 (L)
and Percent Predicted FEV1.
SAC


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2.44.
Analysis
EFF_T3
Descriptive Summary of Change from Baseline in Sniff Nasal 
Inspiratory Pressure (SnIP) by Visit
SAC 
Exploratory
2.45.
Analysis
EFF_T3
Descriptive Summary of Change from Baseline in Handgrip 
strength
First left hand, then right hand
SAC 
2.46.
Analysis
EFF_T5
Descriptive Summary of Change from Baseline in PROactive 
total and domains scores in different levels of PGIC
SAC
2.47.
Analysis
EFF_T4
Analysis of Change from Baseline in Leg Press Strength (kg) by 
Visit excluding the site 
 (Impact analysis) - Repeated 
Measure Mixed Model
Fit the model for Table 2.3 by excluding 
the site 
.
SAC
PPD
PPD


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12.11.6.
Efficacy Figures
Efficacy: Figures
No.
Populati
on
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Leg Strength
2.1
Analysis
EFF_F1
Line Plot of Adjusted Mean (90% CI) Change from Baseline in 
Leg Press Strength (kg) Over Time – Repeated Measure 
Mixed Model
Separately for each gender
Use the same footnote about model 
specification as in the corresponding 
analysis table
SAC 
2.2
Analysis
EFF_F1
Line Plot of Adjusted Mean (90% CI) Percent Change from 
Baseline in Leg Press Strength (%) Over Time – Repeated 
Measure Mixed Model
Separately for each gender 
Use the same footnote about model 
specification as in the corresponding 
analysis table
SAC 
Lean Mass
2.3
Analysis 
EFF_F1
Line Plot of Adjusted Mean (90% CI) Change from Baseline in 
Appendicular Lean Mass (kg) and Total Lean Mass (kg) as 
Assessed by Dual-energy X-ray Absorptiometry Over Time –
Repeated Measure Mixed Model
Separately for each gender by parameter
Use the same footnote about model 
specification as in the corresponding 
analysis table
SAC 
Functional Tests
2.4
Analysis 
EFF_F1
Line Plot of Adjusted Mean (90% CI) Change from Baseline in 
PROactive Total Score, Difficulty and Amount Scores Over 
Time - Repeated Measure Mixed Model
Separately for each gender by parameter
Use the same footnote about model 
specification as in the corresponding 
analysis table
SAC 
2.5
Analysis 
EFF_F1
Line Plot of Adjusted Mean (90% CI) Change from Baseline in 
COPD Assessment Test (CAT) score Over Time - Repeated 
Measure Mixed Model
Separately for each gender
Use the same footnote about model 
specification as in the corresponding 
analysis table
SAC 


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2.6
Analysis 
EFF_F1
Line Plot of Adjusted Mean (90% CI) Change from Baseline in 
total Short Physical Performance Battery (SPPB) score and 
times for chair rise (sec) and 4 m gait speed (sec) – Repeated 
Measure Mixed Model
Separately for each gender by parameter
Use the same footnote about model 
specification as in the corresponding 
analysis table
SAC
Exploratory Variable
2.7
Analysis 
LB9
Box Plot: Change from Baseline in FEV1 (L)
Separately for each gender, X-axis is 
visit, Y-axis is change from baseline in 
FEV1 values; 
SAC 
2.8
Analysis 
LB9
Box Plot: Change from Baseline in Sniff Nasal Inspiratory
Pressure (Snip)
Separately for each gender, X-axis is 
visit, Y-axis is change from baseline in 
Snip values;
SAC 
2.9
Analysis
EFF_F1
Descriptive Mean Change from Baseline in Average Daily 
Steps over Time
SAC
12.11.7.
Safety Tables
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
Headline 
Results & SAC
3.2.
Safety
AE5A
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity
For AEs reported more than once by a 
subject, the most severe intensity will 
be included.
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.3.
Safety
AE3
Summary of Common Adverse Events by Overall Frequency
ICH E3
Note: Common adverse event is 
defined as events occurring more than 
one in either gender.
SAC 
3.4.
Safety
AE3
Summary of Common Severe Adverse Events by Overall 
Frequency
ICH E3
Note: Common adverse event is 
defined as events occurring more than 
one in either gender.
SAC 
3.5.
Safety
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term.
ICH E3
SAC 
3.6.
Safety
AE15
Summary of Common Non-serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences)
FDAAA, EudraCT
Note: Common adverse event is 
defined as events occurring more than 
one in either gender.
SAC 
3.7.
Safety
AE3
Summary of Common Drug-Related Severe Adverse Events by 
Overall Frequency
ICH E3
Note: Common adverse event is 
defined as events occurring more than 
one in either gender.
SAC 
Serious and Other Significant Adverse Events
3.8.
Safety
AE3
Summary of Fatal Serious Adverse Events
SAC 
3.9.
Safety
AE3
Summary of Drug-Related Fatal Serious Adverse Events
SAC 
3.10.
Safety
AE3
Summary of Serious Adverse Events by System Organ Class
SAC 
3.11.
Safety
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class
FDAAA, EudraCT
SAC 


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.12.
Safety 
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
3.13.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term 
IDSL
SAC
Special Interest AEs
3.14.
Safety
AE3
Summary of Adverse Events of Special Interest
IDSL – To display by page for CV 
events and Liver events
Headline 
Results & SAC
Laboratory: Chemistry 
3.15.
Safety
LB1
Summary of Chemistry Changes from Baseline by Visit
ICH E3
SAC 
3.16.
Safety
LB16
Summary of Chemistry Results by Maximum Grade Increases 
Post-baseline Relative to Baseline
ICH E3
SAC 
3.17.
Safety
LB4
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
IDSL
SAC
Laboratory: Haematology
3.18.
Safety
LB1
Summary of Haematology Changes from Baseline
ICH E3
SAC 
3.19.
Safety
LB16
Summary of Haematology Results by Maximum Grade 
Increases Post-baseline Relative to Baseline
ICH E3
SAC 
3.20.
Safety
LB4
Summary of Haematology Shifts from Baseline Relative to 
Normal Range
IDSL
SAC
Laboratory: Urinalysis
3.21.
Safety
LB1
Summary of Urine Concentration Changes from Baseline
ICH E3
SAC 


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.22.
Safety
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3 Including glucose, protein, 
blood
SAC 
3.23.
Safety
LB4
Summary of Urinalysis Shifts from Baseline Relative to Normal 
Range
IDSL
SAC
Laboratory: Hepatobiliary (Liver)
3.24.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC 
Laboratory: Other
3.25.
Safety
LB1
Summary of Sex/Reproductive Hormones
Summarize Testosterone, Free 
Testosterone, Sex hormone-binding 
globulin (SHBG), Follicle-stimulating 
hormone (FSH), Luteinizing hormone 
(LH) and Prostate specific antigen 
(PSA).
SAC 
3.26.
Safety
LB1
Summary of Lipid Panel 
SAC 
3.27.
Safety
LB1
Summary of hsCRP, Fibrinogen
SAC
ECG
3.28.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC 
3.29.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IDSL
SAC 
3.30.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC 
3.31.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IDSL
SAC 
Vital Signs


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.32.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC 
3.33.
Safety
VS7
Summary of Worst Case Vital Signs Results Relative to Normal 
Range /Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline
IDSL
SAC 
Biomarkers
3.34.
Safety
LB1
Summary of Change from Baseline in Bone Biomarkers
SAC 
3.35.
Safety
LB1
Summary of Change from Baseline in Reproductive Tissue 
Biomarkers
SAC 
COPD Events
3.36.
Safety
SAFE_T1
Summary of COPD Events
SAC


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12.11.8.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT
IDSL
SAC 
3.2.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin
IDSL
SAC 
3.3.
Safety
EFF_F1
Line Plot of Change from Baseline in Sex/reproductive 
Hormones Over Time 
Each hormone per page 
SAC 
3.4.
Safety
EFF_F1
Line Plot of Change from Baseline in Metabolic factors Over 
Time
Each factor per page
SAC 
12.11.9.
Pharmacokinetics Tables
Pharmacokinetics: Table
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1
PK
PK01
Summary of Plasma Concentration Time data     
SAC


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12.11.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC 
2.
All 
Participants
ES2 
Listing of Reasons for Study Withdrawal          
ICH E3
SAC 
3.
All 
Participants
SD2
Listing of Reasons for Study Treatment Discontinuation  
ICH E3
SAC 
4.
All 
Participants
BL1 
Listing of Participants for Whom the Treatment Blind was Broken
ICH E3
SAC 
5.
Enrolled 
TA1 / CP_RD1x
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6.
All 
Participants
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC 
7.
All 
Participants
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC 
8.
All 
Participants
POP_L4
Listing of Protocol Deviations leading to Exclusion from the Per-
Protocol Population
SAC 
Populations Analysed
9.
All 
Participants
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
10.
All 
Participants
DM2 
Listing of Demographic Characteristics
ICH E3
Footnote: Age is imputed when full date 
of birth is not provided.
SAC 
11.
All 
Participants
DM9 
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
12.
All 
Participants
CP_CM3 
Listing of Concomitant Medications
IDSL
Note: On-Treatment phase includes 
both On-Treatment and Post-Treatment 
concomitant medications.
SAC
Exposure and Treatment Compliance
13.
All 
Participants
EX3 
Listing of Investigational Product Exposure Data
ICH E3
SAC 
Adverse Events
14.
Safety
AE8CPa
Listing of All Adverse Events
ICH E3
SAC 
15.
Safety
AE8
Listing of Drug-Related Adverse Events
SAC 
16.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC 
Serious and Other Significant Adverse Events
17.
Safety
AE8CPa 
Listing of Fatal Serious Adverse Events
ICH E3
SAC 
18.
Safety
AE8
Listing of Drug-Related Fatal Serious Adverse Events
SAC 
19.
Safety
AE8 
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC 
20.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC 


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
21.
Safety
AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC 
Hepatobiliary (Liver)
22.
All 
Participants
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IDSL
SAC
23.
All 
Participants
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL only subjects have such events
SAC 
24.
All 
Participants
LIVER 5
Listing of Liver Monitoring/Stopping Event Reporting
IDSL only subjects have such events
SAC 
All Laboratory
25.
Safety
LB5A
Listing of Clinical Chemistry Laboratory Data 
ICH E3
SAC 
26.
Safety
LB5A
Listing of Haematology Laboratory Data 
ICH E3
SAC 
27.
Safety
LB14
Listing of Clinical Chemistry Laboratory Data with Character 
Results
IDSL
SAC 
28.
Safety
LB14
Listing of Clinical Haematology Data with Character Results
IDSL
SAC 
29.
Safety
LB5A
Listing of All Urine Analysis Data
ICH E3
SAC
ECG
30.
Safety
EG3 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC 
31.
Safety
EG5 
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Findings
IDSL
SAC 
32.
Safety 
EG3
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC 


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
33.
Safety
VS4
Listing of All Vital Signs for Subjects with Any Value of Potential 
Clinical Importance
IDSL
SAC 
34.
Safety
VS4 
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC


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12.11.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
35.
Enrolled
POP_L1
Listing of Subject Recruitment by Country and Site Number
SAC 
36.
Screened
ES9
Listing of Subject Who were Rescreened
SAC 
37.
All 
Participants
POP_L2
Listing of Visit Dates
SAC 
38.
Screened
POP_L3
Listing of Study Population
SAC 
39.
All 
Participants
POP_L5
Listing of Disease Stage and Exacerbation History
SAC 
40.
All 
Participants
MH2
Listing of Current and Past Medical Conditions at Baseline
SAC
41.
All 
Participants
POP_L6
Listing of Alcohol History and Tobacco Use/Smoking History
SAC 
42.
All 
Participants
POP_L7
Listing of Smoking Status Change during the Study
SAC
43.
All 
Participants
POP_L8
Listing of HIV and Hepatitis Test Results 
SAC 
44.
Safety
POP_L9
Listing of Investigational Product Accountability 
SAC 


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Safety
45.
Safety
SAFE_L1
Listing of COPD Exacerbation Log
SAC 
46.
Safety
SAFE_L2
Listing of Hepatic, Prostate and Cardiac Structure assessed via 
MRI
SAC
47.
Safety
SAFE_L3
Listing of Change from baseline of Lipids and Sex hormones
List the sex hormones Testosterone, 
Free Testosterone, Sex hormone-
binding globulin (SHBG), Follicle-
stimulating hormone (FSH), Luteinizing 
hormone (LH) and Prostate specific 
antigen (PSA).
SAC
Primary Efficacy
48.
Analysis
EFF_L1
Listing of leg Press Strength (kg) Results
SAC 
Secondary Efficacy
49.
Analysis
EFF_L2
Listing of Appendicular (kg), and Total Lean Mass (kg) as 
Assessed by Dual-energy X-ray Absorptiometry (DXA)
SAC 
50.
Analysis
EFF_L3
Listing of PROactive Endpoints 
Total score, difficulty and amount 
scores will be displayed
SAC 
51.
Analysis
EFF_L4
Listing of Total Short Physical Performance Battery (SPPB) 
Score and Times for Chair Rise (sec) and 4 m Gait Speed (sec) 
Results
SAC 
52.
Analysis
EFF_L5
Listing of Constant Work Rate (CWR) Duration (sec) from 
Endurance Shuttle Walking Test
SAC 
53.
Analysis
EFF_L6
Listing of Peak Performance from Incremental Shuttle Walking 
Test
SAC 
54.
Analysis
EFF_L7
Listing of COPD Assessment Test (CAT)
SAC 
55.
Analysis
EFF_L8
Listing of Patient Global Impression of Change
SAC 
56.
Analysis
EFF_L9
Listing of Patient Global Rating of Severity
SAC 


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57.
Analysis
EFF_L10
Listing of St George Respiratory Questionnaire (SGRQ) Results
Total score, impact, symptoms and 
activity domain scores derived by 
SGRQ-c raw scores
SAC 
58.
Analysis
EFF_L11
Listing of Spirometry Results
SAC 
59.
Analysis
EFF_L12
Listing of Sniff Nasal Inspiratory Pressure (SnIP)
SAC 
60.
Analysis
EFF_L13
Listing of Physical Activity Measures Assessed via an 
Accelerometer.
SAC
Exploratory
61.
Analysis
EFF_L14
Listing of Handgrip strength
SAC 
Pharmacokinetics
62.
PK
PK07
Listing of Plasma Pharmacokinetic Concentration time data
SAC
Supportive SAS Listing
63.
Analysis
Supportive SAS Listing for the Analysis of Percent Change from 
Baseline in Leg Press Strength (%) by Visit - Repeated Measure 
Mixed Model
SAC
64.
Per Protocol
Supportive SAS Listing for Analysis of Percent Change from 
Baseline in Leg Press Strength (%) by Visit - Repeated Measure 
Mixed Model
SAC 
65.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
Leg Press Strength (kg) by Visit - Repeated Measure Mixed 
Model
SAC 
66.
Per Protocol
Supportive SAS Listing for Analysis of Change from Baseline in 
Leg Press Strength (kg) by Visit- Repeated Measure Mixed 
Model
SAC 
67.
Analysis
Supportive SAS Listing for Bayesian Analysis of Percentage 
Change from Baseline in Leg Press Strength (%) by Visit
SAC 


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68.
Analysis
Supportive SAS Listing for Analysis of Percent Change from 
Baseline in Leg Press Strength (%) by Visit - Repeated Measure 
Mixed Model with Exploratory Covariates
SAC
69.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
Appendicular (kg), and Total Lean Mass (kg) as Assessed by 
Dual-energy X-ray Absorptiometry by Visit - Repeated Measure 
Mixed Model
SAC
70.
Analysis
Supportive SAS Listing for Analysis of Percent Change from 
Baseline in Appendicular (%), and Total Lean Mass (%) as 
Assessed by Dual-energy X-ray Absorptiometry by Visit -
Repeated Measure Mixed Model
SAC
71.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
PROactive Total Score, Difficulty and Amount Scores by Visit-
Repeated Measure Mixed Model
SAC
72.
Per Protocol
Supportive SAS Listing for Analysis of Change from Baseline in 
PROactive Total Score, Difficulty and Amount Scores by Visit-
Repeated Measure Mixed Model
SAC
73.
Analysis
Supportive SAS Listing for Bayesian Analysis of Change from 
Baseline in PROactive Total Score, Difficulty and Amount Score
by Visit
SAC
74.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
COPD Assessment Test (CAT) score by Visit- Repeated 
Measure Mixed Model
SAC
75.
Analysis 
Supportive SAS Listing for Responder Analysis of COPD 
Assessment Test (CAT) 
SAC
76.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
St George Respiratory Questionnaire (SGRQ) Total Score and 
Domains Score at Day 90 - ANCOVA
SAC


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77.
Per Protocol
Supportive SAS Listing for Analysis of Change from Baseline in 
St George Respiratory Questionnaire (SGRQ) Total Score and 
Domains Score at Day 90 – ANCOVA
SAC
78.
Analysis
Supportive SAS Listing for Responder Analysis of St George 
Respiratory Questionnaire (SGRQ) 
SAC
79.
Analysis
Supportive SAS Listing for Bayesian Analysis of Change from 
Baseline in St George Respiratory Questionnaire (SGRQ) Total 
Score at Day 90
SAC
80.
Analysis
Supportive SAS Listing for Analysis of Change from baseline in 
total Short Physical Performance Battery (SPPB) score and 
times for chair rise (sec) and 4 m gait speed (sec) by Visit -
Repeated Measure Mixed Model
SAC
81.
Per Protocol
Supportive SAS Listing for Analysis of Change from baseline in 
total Short Physical Performance Battery (SPPB) score and 
times for chair rise (sec) and 4 m gait speed (sec) by Visit -
Repeated Measure Mixed Model
SAC
82.
Analysis
Supportive SAS Listing for Bayesian Analysis of Change from 
Baseline in Times for chair rise (sec) by Visit
SAC
83.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
Constant Work Rate (CWR) Duration (sec) from Endurance 
Shuttle Walking Test at Day 90 – ANCOVA model
SAC
84.
Per Protocol
Supportive SAS Listing for Analysis of Change from Baseline in 
Constant Work Rate (CWR) Duration (sec) from Endurance 
Shuttle Walking Test at Day 90 – ANCOVA model
SAC
85.
Analysis
Supportive SAS Listing for Analysis of Percent Change from 
Baseline in Constant Work Rate (CWR) Duration (%) from 
Endurance Shuttle Walking Test at Day 90 – ANCOVA model
SAC


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86.
Analysis
Supportive SAS Listing for Bayesian Analysis of Change from 
Baseline in Constant Work Rate (CWR) Duration (sec) from 
Endurance Shuttle Walking Test at Day 90
SAC
87.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
Peak Performance from Incremental Shuttle Walking Test at 
Day 90 – ANCOVA
SAC
88.
Analysis 
Supportive SAS Listing for Analysis of Percent Change from 
Baseline in Peak Performance from Incremental Shuttle Walking 
Test (%) at Day 90 - ANCOVA
SAC
89.
Analysis
Supportive SAS Listing for Analysis of Change from Baseline in 
Leg Press Strength (kg) by Visit excluding the site 
 
(Impact analysis) - Repeated Measure Mixed Model
SAC
PPD


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12.12.
Appendix 12: Example Mock Shells for Data Displays
STUDY POPULATION 
Listings 
Example : POP_L1
Protocol: xxxxxxx                                                                               Page 1 of 1
Population: Screened
Listing xx
Listing of Subjects Recruitment by Country and Site Number
  Sex: Female
Country
Site Id./
Investigator Name
Unique Subject Id
Randomization 
Number
Assigned Treatment
Treatment 
Start Date
xxx
xx
xxx
DDMMMYXXX
xxx
xx
DDMMMYXXX
Programming note: continue with Sex= Male


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Example : POP_L2
Protocol: XXXXXXX                                                                             Page 1 of x
Population: All Participants
Listing xx
Listing of Visit Dates
Country: xxxxx
Centre ID: xxxxxx
Investigator: AAAAAA
Sex
Unique
Subject 
Id.
Treatment
Nominal CRF 
Visit
Visit Start 
Date
Visit End Date Analysis Visit 
[1]
Study Day
F
xxxxx
GSK2881078 Screening
DDMMMYYYY
DDMMMYYYY
Screening
-18
Day 1/Visit 3 DDMMMYYYY
DDMMMYYYY
Day 1
 1
Visit 4
DDMMMYYYY
DDMMMYYYY
Visit 4
xx
Visit 5
DDMMMYYYY
DDMMMYYYY
Visit 5
xx
Unscheduled
DDMMMYYYY
DDMMMYYYY
Visit 6
xx
DDMMMYYYY
DDMMMYYYY
Visit 7
xx
...
xxxxx
Placebo 
Screening
DDMMMYYYY
DDMMMYYYY
Screening
-29
Day 1
DDMMMYYYY
DDMMMYYYY
Day 1
-1
...
[1] Analysis Visit is the slotted visits and it is derived by applying the slotting algorithm to Visit Start Date.
Programmer’s note: repeat for each site within country, then repeat for each country.


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Example : POP_L3
Protocol: XXXXXXX                                                                             Page 1 of x
Population: Screened
Listing xx
Listing of Study Populations
Sex: Female
Treatment: None
Site 
Id./Investi
gator 
Id./Investi
gator Name
Randomized
All 
Participants
Analysis
Per-
Protocol
Safety
xxxxx/xxx
No
No
No
No
No
xxxxx/xxx
No
No
No
No
No
xxxxx/xxx
No
No
No
No
No
...
Sex: Female
Treatment: GSK2881078
Site 
Id./Investi
gator 
Id./Investi
gator Name
Randomized
All 
Participants 
Analysis
Per-
Protocol
Safety
xxxxx/xxx
Yes
Yes
Yes
Yes
Yes
xxxxx/xxx
Yes
Yes
Yes
No
No
xxxxx/xxx
Yes
No
No
No
No
...


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Treatment: Placebo
...
Programmer’s note: Include all analysis populations specified in RAP and give its definition as a footnote.
Example : POP_L4
Protocol: xxxxxxx                                                                               Page 1 of 1
Population: All Participants
Listing xx
Listing of Protocol Deviations Leading to Exclusion from the Per-Protocol Population
Sex: Female
Treatment: GSK2881078
Inv.
Unique
Subj.
Age
Protocol Deviations
Deviation Start 
Date/ 
Day
xxxxx
xxx
xx
xxxxxxxxxxxxxxxxxxxx
DDMMMYXXX/
XXX
xxx
xx
xxxxxxxxxxxxxxxxxxxx
DDMMMYXXX/
XXX
...
...


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Example : POP_L5
Protocol: XXXXXXX                                                                             Page 1 of x
Population: All Participants
Listing xx
Listing of Disease Stage and Exacerbation History
Sex: Female
Treatment: GSK2881078
Site Id./  
Unique 
Subject 
Id.
Disease 
Initial 
Diag. Date
Age
(yrs)
Exacerbation History
(Number of Exacerbations in the last 12 Months)
Without 
Corticosteroids 
and/or 
Antibiotics
Need 
Corticosteroids 
and/or 
Antibiotics
Required 
Hospitalised
Period Prior to 
Visit [1]
xxx/xxx
DDMMMYYYY
xx
xx
xx
xxxx
xx
xxx/xxx
DDMMMYYYY
xx
xxx
DDMMMYYYY
xx
xxx
DDMMMYYYY
xx
xxx
DDMMMYYYY
xx
[1] Period Prior to Visit is the Evaluation Interval considered while collecting Exacerbation history.


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Example : POP_L6
Protocol: XXXXXXX                                                                             Page 1 of x
Population: All Participants
Listing xx
Listing of Alcohol and Tobacco Use/Smoking History
Sex: Female
Treatment: GSK2881078
Site 
Id./Uniq
ue 
Subject 
Id
Alcohol
Tobacco Use and Smoking History
Assessment 
Date
Alcohol 
History/# 
Unit Per 
Week
Tobacco 
Smoking 
History
Last Smoke 
Date
Smokeless
Tobacco
Use History
Number of 
Cigarettes 
per Day
Years 
Smoking 
Tobacco
Pack 
Year
xxx/xxx
DDMMMYYYY
xx/xx
Smoked
DDMMMYYYY
Current 
User
xxxx
xx
xxx/xxx
DDMMMYYYY
xx


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Example : POP_L8
Protocol: XXXXXXX                                                                             Page 1 of x
Population: All Participants
Listing xx
Listing of HIV and Hepatitis Test Results
Sex: Female
Treatment: GSK2881078
Site 
Id./Uniqu
e Subject 
Id.
Sample Date
Age
(yrs)
HIV Test 
Results/[1]
Hepatitis B Test 
Result
Hepatitis C Test 
Result/RBA PCR [2]
xxx/
DDMMMYYYY
xx
Negative
Non-Reactive
Non-Reactive
xxx
DDMMMYYYY
xx
Non-Reactive
Reactive
xxx/
DDMMMYYYY
xx
Non-Reactive
Non-Reactive
xxx
DDMMMYYYY
xx
Non-Reactive
Non-Reactive
xxx
DDMMMYYYY
xx
Non-Reactive
Non-Reactive
    [1] only when HIV test is reactive;
    [2] only when Hepatitis C test is reactive


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Example : POP_L9
Protocol: XXXXXXX                                                                             Page 1 of x
Population: Safety
Listing xx
Listing of Investigational Product Accountability
Sex: Female
Treatment: GSK2881078
Site 
Id.
Unique 
Subject 
Id.
Compliance
Percentage
Date IP
Dispensed/
Study Day
Date IP
Returned
/
Study 
Day
Tablets
Dispensed
Tablets
Returned
Amoun
t
Taken
Number 
of 
Tables 
Lost 
Container
Number
xxxxx
xxxx
xx
DDMMMYYYY/
xx
DDMMMYYY
Y/
xx
xx
xx
xx
xx
xxxxxx
xx
xx
xx
xx
xxxxxx
xx
DDMMMYYYY/
xx
DDMMMYYY
Y/
xx
xx
xx
xx
xx
xxxxxx
xx
xx
xx
xx
Xxxxxx
Note : Treatment compliance = 100 * (Total Amount Taken/ (Actual treatment duration in days* frequency)).


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EFFICACY
Tables 
Example : EFF_T1
Protocol: XXXXXXX                                                                              Page 1 of 1
Population: XXXXXXX
                                                 Table xx
               xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
             
  Sex: Female                                                  
                                                                                             
                                                               Placebo                      GSK2881078
  Visit                                                       (N=xxx)                     (N=xxx)
  --------------------------------------------------------------------------------------------------------
  Visit X,  n
                                                xxx                         xxx
  Day X     Adjusted Mean [1] (SE)                           x.xxx (x.xxx)              x.xxx (x.xxx)
            90% C.I.                                       (x.xxx, x.xxx)             (x.xxx, x.xxx)
  
            GSK2881078 vs. Placebo
            Difference [2]                                                               x.xxx
            90% C.I.                                                                   (x.xxx, x.xxx)      
            p-value                                                                       xxx
[1] Estimates were calculated from a repeated measures model including the following covariates: Treatment, Day, 
Treatment* Day and baseline xxxxxx, with Day as the repeated factor. In case of violation of the assumptions, the 
same model is fitted with log of ratio to baseline and replacing the covariate baseline xxxxx with log baseline 
xxxxx. The correlation matrix for within-subject errors used is unstructured.
[2] GSK2881078-Placebo.


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Programming note: Please repeat for Sex: Male.
Programming note: Update the footnotes with the appropriate endpoints and covariate as per RAP.
If data has been log-transformed, then use the following shell:
Protocol: XXXXXXX                                                                              Page 1 of 1
Population: XXXXXX 
                                                 Table EFF_T1
                  xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
  Sex: Female                                                  
                                                                                                 
                                                             Placebo                      GSK2881078
  Visit                                                     (N=xxx)                     (N=xxx)
  --------------------------------------------------------------------------------------------------------
  Visit X,   n
                                               xxx                         xxx
  Day X      Model-Adjusted Geometric Mean for            xx.xx (x.xxx, x.xxx)       xx.xx (x.xxx, x.xxx)    
             Ratio to Baseline (90% CI)[1]                                 
  
             Adjusted Treatment Ratio of                                         xx.xx (x.xxx, x.xxx)
             Geometric Means (90% CI)[2]                                                      
             p-value                                                                        xxxx
             
[1] Estimates were calculated from a repeated measures model including the following covariates: Treatment, Day, 
Treatment* Day and baseline xxxxxx, with Day as the repeated factor. In case of violation of the assumptions, the 


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same model is fitted with log of ratio to baseline and replacing the covariate baseline xxxxx with log baseline 
xxxxx. The correlation matrix for within-subject errors used is unstructured.
[2] GSK2881078 ratio to Placebo.
Programming note: Please repeat for Sex: Male.
Programming note: Update the footnotes with the appropriate endpoints and covariate as per RAP.
Example : EFF_T2
Protocol: XXXXXXX                                                                              Page 1 of 1
Population: XXXXXXX
                                                 Table xx
               xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
             
  Sex: Female                                                  
  
                                                              Placebo                      GSK2881078
  Visit                                                      (N=xxx)                     (N=xxx)
  --------------------------------------------------------------------------------------------------------
  Visit X,  n
                                                xxx                         xxx
  Day X     Posterior Adjusted Mean (SD)[1]                   x.xxx (x.xxx)               x.xxx (x.xxx)
            90% HPD Credible Interval                          (x.xxx, x.xxx)             (x.xxx, x.xxx)
  
            GSK2881078 vs. Placebo
            Posterior adjusted mean for                                                    x.xxx
            treatment difference [SD][2]
            90% HPD Credible Interval                                                   (x.xxx, x.xxx)  
            Posterior probability treatment                                                x.xxx
            difference >=x% 
            Posterior probability treatment                                                x.xxx
            difference >x% 
            Posterior probability treatment                                                x.xxx
            difference <x%                                                              
                                                             


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[1] Estimates were calculated from a Bayesian repeated measures model including the following covariates: Treatment,
Day, Treatment* Day and baseline xxxxxx, with Day as the repeated factor. 
[2] GSK2881078-Placebo.
Note: HPD - Highest Posterior Density.
Programming note: Please repeat for Sex: Male.
Programming note: Update the footnotes with the appropriate endpoints and covariate as per RAP. Add the 
probabilities x% based on the domain.
Example : EFF_T3
Protocol: XXXX                                                                                Page 1 of 1
Population: XXXXXX
                                                 Table XX
                     xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
                                        
Parameter: xxxxxxxxxxxxxxxxxxx
                                                        Female                          Male
                                            ------------------------------ ------------------------------
                                                                            
                                            Placebo        GSK2881078             Placebo        GSK2881078
  Visit                         Statistics (N=20)        (N=22)           (N=24)        (N=22)
  -------------------------------------------------------------------------------------------------------
  Baseline                       n           xx           xx               xx             xx
                                 Mean       xxx.x         xxx.x            xxx.x         xxx.x
                                 SD          xx.xx         xx.xx            xx.xx          xx.xx
                                 Median      xx.x         xxx.x            xxx.x          xxx.x
                                 Min.        xx            xx               xx            xxx
                                 Max.       xxx           xxx              xxx            xxx
  Visit X, Day X                 n           xx           xx               xx             xx
                                 Mean       xxx.x         xxx.x            xxx.x          xxx.x
                                 SD          xx.xx         xx.xx            xx.xx          xx.xx
                                 Median      xx.x         xxx.x            xxx.x          xxx.x
                                 Min.        xx            xx               xx            xxx
                                 Max.       xxx           xxx              xxx            xxx


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  Change from Baseline at Visit  n           xx           xx               xx             xx
  X, Day X                       Mean       xxx.x         xxx.x            xxx.x          xxx.x
                                 SD          xx.xx         xx.xx            xx.xx          xx.xx
                                 Median      xx.x         xxx.x            xxx.x          xxx.x
                                 Min.        xx            xx               xx            xxx
                                 Max.       xxx           xxx              xxx            xxx
(a)Note: When there are multiple pre-dose assessments, the latest non-missing pre-dose assessment is identified and 
captured as "Baseline (Derived)" visit.
(b)Note: "Visit X, Day X" is considered as Baseline.
Programming note: Repeat for other visits and summarize its change from baseline, percent change from baseline and 
ratio to baseline whereever applicable Programming note: If the baseline is a derived visit add the footnote (a) 
else if it is a single visit add footnote (b)
Example : EFF_T4
Protocol: XXXXXXX                                                                              Page 1 of 1
Population: XXXXXXX
Table xx
Analysis of Change from Baseline in Leg Press Strength (kg) by Visit excluding the site 
 (Impact analysis) -
Repeated Measure Mixed Model
             
  Sex: Female                                                  
                                                                                             
                                                               Placebo                      GSK2881078
  Visit                                                       (N=xxx)                     (N=xxx)
  --------------------------------------------------------------------------------------------------------
  Visit X,  n
                                                xxx                         xxx
  Day X     n1
                                                xxx                         xxx
            Adjusted Mean [1] (SE)                           x.xxx (x.xxx)              x.xxx (x.xxx)
            90% C.I.                                       (x.xxx, x.xxx)             (x.xxx, x.xxx)
  
            GSK2881078 vs. Placebo
            Difference [2]                                                               x.xxx
            90% C.I.                                                                   (x.xxx, x.xxx)      
            p-value                                                                         xxx
PPD


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[1] Estimates were calculated from a repeated measures model including the following covariates: Treatment, Day, 
Treatment* Day and baseline leg strength with Day as the repeated factor. In case of violation of the assumptions, 
the same model is fitted with log of ratio to baseline and replacing the covariate baseline leg strength with log 
baseline leg strength. The correlation matrix for within-subject errors used is unstructured.
[2] GSK2881078-Placebo.
Note: n1 indicates the number of analysable subjects excluding the site 
.
Programming note: Please repeat for Sex: Male.
Programming note: Update the footnotes with the appropriate endpoints and covariate as per RAP.
PPD


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Example : EFF_T5
Protocol: xxxxxxx                                                                              Page 1 of 1
Population: Analysis 
Table XX
Analysis of Change from Baseline in PROactive total and domains scores in different levels of PGIC
Parameter: XXXXXXXXXXX
Visit
PGIC Level
Statistics
Males
(N=XXX)
Females
(N=XXX)
Overall 
(Males + Females)
(N=XXX)
Visit X, 
Much Better
n
xx
xx
Xx
Day X
Mean
xx.xx
xx.xx
xx.xx
SD
xx.xxx
xx.xxx
xx.xxx
Median
xx.xx
xx.xx
xx.xx
Min. 
xx.x, xx.x
xx.x, xx.x
xx.x, xx.x
Max.
xx.x, xx.x
xx.x, xx.x
xx.x, xx.x
Better
n
xx
xx
Xx
Mean
xx.xx
xx.xx
xx.xx
SD
xx.xxx
xx.xxx
xx.xxx
Median
xx.xx
xx.xx
xx.xx
Min. 
xx.x, xx.x
xx.x, xx.x
xx.x, xx.x
Max.
xx.x, xx.x
xx.x, xx.x
xx.x, xx.x


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Programming Note: Continue with all PGIC Levels and add levels ‘Much Worse and Worse’ and ‘Better and Much Better’ 
to the existing levels of PGIC.  Repeat for Day 90 and Parameters of PROactive Scores.
Example : EFF_T6
Protocol: XXXXXXX                                                                              Page 1 of 1
Population: Analysis 
                                                 Table XX
                       xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Sex: Female
Visit
Treatment
N
Responder Rate
n1/n (%)
Odds Ratio (90% 
C.I.)
Visit X, Day 
X
GSK2881078
xx
xx/xx (xx.x%)
x.xxx (x.xxx, x.xxx)
Placebo
xx
xx/xx (xx.x%)
Note: A subject is defined as a responder when the total score at a post-baseline visit decreases
XX or more from baseline total score.
Note: n1 is the number of responders in each treatment group and the percentages are calculated
using n.
Note: The confidence interval for odds ratio (GSK2881078/Placebo) is calculated using the Exact method.
Programming note: continue for the next visit and repeat for Sex: Male.


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Example : EFF_T7
Protocol: XXXXXXX                                                                              Page 1 of 1
Population: XXXXXXX
                                                 Table XX
              xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
             
  Sex: Female                                                  
                                                                                             
                                                               Placebo                      GSK2881078
  Parameter                                                    (N=xxx)                     (N=xxx)
  --------------------------------------------------------------------------------------------------------
  xxxxxxxx  n
                                                xxx                         xxx
            Adjusted Mean [1] (SE)                           x.xxx (x.xxx)              x.xxx (x.xxx)
            90% C.I.                                       (x.xxx, x.xxx)             (x.xxx, x.xxx)
  
            GSK2881078 vs. Placebo
            Difference [2]                                                               x.xxx
            90% C.I.                                                                   (x.xxx, x.xxx)      
[1] Lsmeans of change from baseline for each treatment group as well as the difference of lsmeans of
change from baseline is estimated from ANCOVA model with baseline score as the covariate adjusting


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for the treatment. In case of violation of the assumptions, the same model is fitted with log of ratio to 
baseline and replacing the covariate baseline with log baseline. 
[2] GSK2881078-Placebo.
Example : EFF_T8
Protocol: XXXXXXXX                                                                                  Page 1 of x
Population: Analysis 
Table xx
Descriptive Summary of Patient Global Impression of Change 
Sex: Female
Visit
Treatment
N
n
PGIC Category
Much Worse
Worse
Slightly 
Worse
No Change
Slightly 
Better
Better
Much 
Better
Day 14
GSK2881078
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Placebo
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Day 28
GSK2881078
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Placebo
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
…..
Note: The percentages have been calculated based on n.
Programming note: Continue with Visit= Day 56, Day 90 and then repeat for Sex: Male


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Example : EFF_T9
Protocol: XXXXXXXX                                                                                  Page 1 of x
Population: Analysis 
Table XX
Descriptive Summary of Patient Global Rating of Severity 
Sex: Female
Treatment: Placebo
Analysis 
Visit
N
n
PGRS Category
None
Mild
Moderate
Severe
Very Severe
Baseline
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Day 90
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx
xx
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
…..
Programming note: repeat for Sex: Male


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Figures 
Example : EFF_F1
Protocol: XXXXXXX                                                                                  Page 1 of x
Population: XXXXXXXX
Figure xx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
GSK
Placebo


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Listings
Example : EFF_L1
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing XX
                                        Listing of Leg Press Strength (kg) Results
Sex: Female
Treatment: XXXXX
Site Id/
Unique 
Subject Id
Visit / 
Analysis 
Visit
Assessment
Date/Day
Parameter
Leg Press 
Performed?
(if no, 
provide 
reason)
Assessment
Value
Change/Percent 
Change from 
Baseline
Unscheduled / 
Visit X Day 
DDMMMYYYY/1
Number of 
Successful 
Lifts
Yes
xx 
xxxx / xxx.x
No
Starting 
Lift 
Weight 
(Unit)
Yes
xx (xxx)
xxxx / xxx.x
Last 
Successful 
Lift 1-RM 
(Unit)
No
Note: Baseline value will be the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.
Programming note: Sorted by treatment, Center, Subject, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”


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Example : EFF_L2
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
         Listing of Appendicular (kg), and Total Lean Mass (kg) as Assessed by Dual-energy X-ray Absorptiometry 
(DXA)
Sex: Female
Treatment: XXXXXXXXXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assessment
Date/Day
Appendicular Lean Mass
Total Lean Mass
Assessment
(Unit)
Change from 
Baseline 
(Unit)
Assessment 
(Unit)
Change from 
Baseline
(Unit)
xxxx/xxxx
Day 1 / 
Baseline
DDMMMYYYY/1
xx (xxx)
xx (xxx)
Unscheduled 
/ Visit X 
Day X
xx (xxx)
xx (xxx)
xxxx / xxx.x
                      
Note: "Visit 3, Day 1" is considered as Baseline.
Programming note: Sorted by treatment, Center, Subject, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”


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Example : EFF_L3
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
                                         Listing of PROactive Endpoints
Sex: Female
Treatment: XXXX
Site Id/
Unique 
Subject Id
Analysis Visit
Individual Component Score
Total Score
Amount
/Change from 
Baseline
Difficulty /Change 
from Baseline
Assessment 
Change from 
Baseline
xxxx/xxxx
Baseline
xx 
xx 
xx 
Visit X Day X
xx /xxx
xx /xxx
xx
xxxx
                      
Note: "Visit 3, Day 1" is considered as baseline and is calculated as average of the data collected from the 7-day 
period after  Day -9 device dispense.
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”


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Programming note: Sorted by treatment, Center, Subject,Visit and continue for SEX: Male
Example : EFF_L4
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Total Short Physical Performance Battery (SPPB) Score and Times for Chair Rise (sec) and 4 m Gait Speed 
(Sec) Results
Sex: Female
Treatment: XXXX
Site 
Id/
Unique 
Subjec
t Id
Visit / 
Analysis 
Visit
SPPB  
Perfo
rmed? 
Assessment
Date/Day
Balance 
Tests
Gait Speed Tests
Chair Stand Test
SPPB 
Total 
Score
Total 
Balance 
Score
Gait 
Test 
Perfo
rmed?
Walking 
Aids
Time 
for the 
Fastest 
Walk 
(Unit)
4 
Meter 
Walk 
Test 
Score
Five 
Successful 
Stand Time 
(unit)
Repeated 
Chair 
Test 
Score
xxxx/x
xxx
Baseline
Yes
DDMMMYYYY/1
xx
Yes
xxxx
xx(xx)
xx
xx (xxx)
xx (xxx)
xxxx
No
Unschedu
led / 
Visit X 
Day X
Yes
xxxx
                      
Note: Baseline value will be the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.
Programming note: Sorted by treatment, Center, Subject, Visit and continue for SEX: Male


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Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L5
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Constant Work Rate (CWR) Duration (sec) from Endurance Shuttle Walking Test
Sex: Female
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assesment 
Date/Day
Endurance
Time 
(seconds)
Distance 
Walked 
(meters)
Reason for 
Stopping 
Test
Endurance 
Time Change 
from Baseline 
Day 
1/Baseline
DDMMMYYYY
xx
xx
xxxxx
Unscheduled 
/ Visit X 
Day X
DDMMMYYYY
xx
xx
xxxxx
xxxx
                      


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Note: "Visit 3, Day 1" is considered as Baseline.
Programming note: Sorted by treatment, Center, Subject, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L6
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Peak Performance from Incremental Shuttle Walking Test 
Sex: Female
Treatment: XXXXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assesment 
Date/Day
Maximum 
Distance Walked 
(meters)
Speed 
(km/hr)
Endurance
Walking 
Speed 
Level
Reason for 
Stopping 
Test
Max Walked 
Distance 
Change from 
Baseline 
Day -9
DDMMMYYYY
xxx
xx
xx
xxxxx
Day 1 / 
Baseline
Reason for 
Stopping 
Test
Unscheduled 
/ Visit X 
Day X
DDMMMYYYY
xxxx 
                      


CONFIDENTIAL
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Note: When there are multiple pre-dose assessments, the highest non-missing pre-dose assessment from day -9 and day 
1 is identified and captured as "Baseline (Derived)" visit.
Programming note: Sorted by treatment, Center, Subject, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L7
Protocol: XXXXXXX
Page 1 of 1
Population: Analysis
Listing xx
Listing of COPD Assessment Test (CAT) 
Sex: Female
Treatment: XXXXXX
Individual Question Score
Total 
Score/Chang 
from Baseline
Site 
Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assesment 
Date/Day
1
2
3
4
5
6
7
8
xxxxxx/
xxxxxx
Xx
DDMMMYYYY Xx
xx
xx
xx
xx
xx
xx
xx
xxxxxx/
xxxxxx
Unscheduled 
/  Day xx
DDMMMYYYY


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Note: 1="Frequency of Cough", 2="Amount of Phlegm in My Chest", 3="Tightness in Chest",
4="Breathless Walking Upstairs", 5="Limited Doing Home Activities", 6="Confident Leaving Home",
7="Sleeping Soundly", 8="Amount of Energy".
Note: "Visit 3, Day 1" is considered as Baseline.
Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L8
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Patient Global Impression of Change
Sex: Female
Treatment: XXXXXX    
Site 
Id/
Unique 
Subject 
Id
Assessment 
Date/Day
Visit / 
Analysis 
Visit
Much Worse
Worse
Slightly 
Worse
No Change
Slightly 
Better
Better
Much 
Better
DDMMMYYYY 
/14
Visit x 
/ Visit 
X Day X
No
No
No
No
Yes
No
No
DDMMMYYYY/1
xx
                      
Programming note: Sorted by treatment, Center,Subjects, Visit and continue for SEX: Male
PGIC Category


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Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L9
Protocol: XXXXXXXX                                                                                  Page 1 of x
Population: Analysis 
Listing xx
Listing of Patient Global Rating of Severity (PGRS) 
Sex: Female
Treatmet: XXXXX
Site Id/
Unique 
Subject Id
Assessment 
Date/Day
Visit / 
Analysis 
Visit
PGRS Category
None
Mild
Moderate
Severe
Very Severe
Xxxx/xxxx
Baseline 
/ Visit 
X Day X
Yes
…..


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Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L10
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of St. George Respiratory Questionnaire (SGRQ) Results
Sex: Female
Treamtment: XXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assessment
Date/Day
Individual Domain Score
Total Score
Symptoms
/Change from 
Baseline
Activity 
/Change from 
Baseline
Impacts/Change 
from Baseline
Assessment 
Change 
from 
Baseline
xxxx/xxxx
Baseline 
/ Visit X 
Day X
DDMMMYYYY/1
xx 
xx 
xx 
xx 
xxxx
Unschedul
ed / 
Visit X 
DDMMMYYYY/1
xx /xxx
xx /xxx
xx /xxx
xx
xxxx


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Day X
     
                 
Note: "Visit 3, Day 1" is considered as Baseline.
Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L11
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Spirometry Results
Sex: Female
Treatment: XXXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assesment  
Date/Day
FEV1 
(L)
Predicted 
FEV1 (L)
Percent 
Predicted 
FEV1 (%)
FVC 
(L)
Predicted 
FVC (L)
Percent 
Predicted
FVC (%)
FEV1/FVC
xxxx/xxxx
Screening/
Baseline 
DDMMMYYYY:hh:mm/-
xx
xx
xx
xx
xx
xxxxx
xx
xx.x
Day 
1/Visit X 
Day X
DDMMMYYYY:hh:mm/1
xx
xx
xx
xx
xxxxx
xx
xxx.x


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Note: Baseline value will be the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male
Example : EFF_L12
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Sniff Nasal Inspiratory Pressure (SNIP)
Sex: Female
Treatment: XXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assesment 
Datetime/Day
Maximum 
SnIP
Maximum SnIP 
Change from 
Baseline
xxxx/xxxx
Screening/
Baseline  
DDMMMYYYY:hh:mm/-xx
xx.x
Unscheduled DDMMMYYYY:hh:mm/1
xxx.x


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/ Visit X 
Day X
                     
                     
Note: Baseline value will be the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.
Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L13
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
Listing of Handgrip Strength
Sex: Female
Treatment: XXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assessment
Date/Day
Left or 
Right
Performed?
(No,reason) 
Reading 1
Reading 2
Reading 3
Average of 
3 Readings
xxxxxxx
Day 
1/Baseline
DDMMMYYYY 
/-xx
xx
xx
xx
xx
xxxxx
xx


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Unsheduled 
/ Visit X 
Day X
DDMMMYYYY 
/1
xx
xx
xx
xx
xxxxx
xx
  
Note: Baseline value will be the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.
Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Example : EFF_L14
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Analysis
Listing xx
                          Listing of Physical Activity Measures Assessed via an Accelerometer
Sex: Female
Treatment: XXXX
Site Id/
Unique 
Subject Id
Analysis Visit
Weekly average 
steps
Weekly Average 
Wear duration
Number of 
days with 
wear 
duration 
Weekly 
Average 
Vector 
magnitude 
Weekly Average 
Moderate/vigorous 
activity duration


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more than 
8 h
unit/wear 
time
xxxx/xxxx
Baseline
xx 
xx 
Xx
xx 
Visit X Day X
xx /xxx
xx /xxx
xx
xx
xxxx
                      
Note: "Visit 3, Day 1" is considered as baseline and is calculated as average of the data collected from the 7-day 
period after  Day -9 device dispense.
Programming note: Use assessment datetime instead of date if time collected and update the label as “Assessment
Datetime/Day”
Programming note: Sorted by treatment, Center, Subject,Visit and continue for SEX: Male
SAFETY
Tables
Example: SAFE_T1
Protocol: 200182                                                                                 Page 1 of 1
Population: Safety


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                                                 Table xx
                                           Summary of COPD Events
                                                  Female                             Male
                                     --------------------------------  --------------------------------
                                                    
                                     Placebo         GSK2881078        Total     Placebo        GSK2881078        
Total
                                     (N=xx)         (N=xx)               (N=xx)         (N=xx)     
    ---------------------------------------------------------------------------------------------------
    Number of events in total          x (x%)        x (x%)       x       x (x%)            x (x%)     x   
         Number of exacerbating patients        x (x%)        x (x%)       x       x (x%)            x (x%)     x   


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Listings 
Example: SAFE_L1
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Safety
Listing xx
Listing of COPD Exacerbation Log
Sex: Female
Treatment: XXXX
Site 
Id./    
Unique 
Subject 
Id.
Onset 
Date/Day/
Resolution
Date
Outcome
Primary 
Cause 
(Other, 
Specify)
1
2
3
4
5
6
7
8
DDMMMYYYY 
/xx/DDMMYYYY
xx
Other, xxx
No
No
No
No
No
No
No
xxxx
DDMMMYYYY/1
xx
xx
Yes, 
xxxx
                      
Note: 1= withdrawn due to the exacerbation, 2=corticosteroids taken for this exacerbation, 3=antibiotics taken for 
this exacerbation, 4= hospitalized due to this exacerbation, 5=visited the emergency room, 6=intubated for this 
exacerbation, 7=medication taken for this exacerbation, 8=adverse event reference identifier
Programming note: If medications is taken, show the reference identifier; Sorted by treatment, Center, Subjects and 
continue for SEX: Male


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Example: SAFE_L2
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Safety
Listing xx
                     Listing of Hepatic, Prostate and Cardiac Structure assessed via MRI
Sex: Female 
Treatment: XXXX
Site Id/
Unique 
Subject 
Id
Visit / 
Analysis 
Visit
Assessment
Date/Day
Liver 
Volume 
(Unit)
Spleen 
Volume 
(Unit)
Prostate 
Volume 
(Unit)
Left 
Ventricular
Volume 
(Unit) 
Left 
Ventricular
Ejection
Fraction
Left 
Ventricular 
End 
Diastolic 
Volume 
Index/ Left 
Ventricular 
End 
Systolic 
Volume 
Index
xxxx/xxxx
Day 
1/Baseline
DDMMMYYYY 
/1
xx
xx
xxxxx
xx
xx.x
xx
Unsheduled 
/ Visit X 
Day X
DDMMMYYYY 
/xx
xx
xx
xxxxx
xx
xxx.x
xx
                      
Note: "Visit 3, Day 1"  is considered as Baseline.
Programming note: Sorted by treatment, Center, Subjects, Visit and continue for SEX: Male


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Example : SAFE_L3
Protocol: XXXXXX                                                                                  Page 1 of x
Population: Safety
Listing xx
                     Listing of Change from baseline of Lipids and Sex hormones
Sex: Female
Treatment: XXXX
Site Id/
Unique 
Subject 
Id
Test 
(Units)
Visit / 
Analysis 
Visit
Assesment 
Datetime/Day
Analysis 
Value
Change from 
Baseline
xxxx/xxxx
PSA
Screening/
Baseline  
DDMMMYYYY:hh:mm/-xx
xx.x
Unscheduled 
/ Visit X 
Day X
DDMMMYYYY:hh:mm/1
xxx.x
xxxx
                     
Note: The baseline value will be the latest pre-dose assessment between Screening and Day 1 with a non-missing 
value, including those from unscheduled visits.