Clinical trial NCT03235726
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: bystander inhalation powder monodose device COPD pharmacokinetics safety Healthy CCI15106 tolerability
Sponsor: GlaxoSmithKline
Start date: 2017-07-13; Completion date: 2018-06-19
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This single and repeat increasing dose study will collect information on safety, tolerability and drug levels in the body of the CCI15106 inhalation powder. The study will also look at the level of CCI15106 that will be released into the air and may be found in the blood of the people standing around the person inhaling it (bystanders). This is a two-part study in which Part 1 will enroll healthy subjects and look at environmental and bystander exposure and Part 2 will enroll subjects with moderate COPD. Approximately 36 healthy subjects and approximately 22 subjects with COPD will be randomized in this study for dosing. The total study duration will be 82 days for Cohort A Part 1; 75 days for Cohort B Part 1 and Cohort C Part 1; 77 days for Cohort A Part 2; and 90 days for Cohort B Part 2.

Detailed description:

Arms: arm 1: 60 milligrams (mg) single dose of CCI15106 will be administered by inhalation route on Day 1; 120 mg single dose will be administered on Day 3; and then 30 mg dose will be administered twice daily (BID) on Days 6-19 to healthy subjects. arm 2: 60 mg single dose of placebo will be administered by inhalation route on Day 1; 120 mg single dose will be administered on Day 3; and then 30 mg dose will be administered BID on Days 6-19 to healthy subjects. arm 3: 60 mg of CCI15106 BID will be administered by inhalation route for 14 days to healthy subjects. arm 4: 60 mg of placebo BID will be administered by inhalation route for 14 days to healthy subjects. arm 5: Healthy subjects will be enrolled to follow bystander exposure and will be studied concomitantly with Cohort B. arm 6: 60 mg single dose of CCI15106 will be administered by inhalation route to subjects with COPD. arm 7: 60 mg single dose of placebo will be administered by inhalation route to subjects with COPD. arm 8: 60 mg BID dose of CCI15106 will be administered by inhalation route for 14 days to subjects with COPD. arm 9: 60 mg BID dose of placebo will be administered by inhalation route for 14 days to subjects with COPD.
Interventions: intervention 1: CCI15106 intervention 2: Placebo
Intervention descriptions: intervention 1: One capsule (single dose or repeat dose) of 30 mg of CCI15106 will be administered to healthy subjects and subjects with COPD via inhalation route using Monodose RS01 device. The morning dose will be taken in fasting state and for repeat dose; the evening dose will be taken at least 2 hours after food. intervention 2: One capsule of placebo will be administered to healthy subjects and subjects with COPD via inhalation route using Monodose RS01 device. The morning dose will be taken in fasting state and for repeat dose; the evening dose will be taken at least 2 hours after food.

Protocol documents:
Prot_000.pdf: 
2016N290366_00
CONFIDENTIAL
GlaxoSmithKline group of companies
205822
1
TITLE PAGE
Protocol Title: A double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study to investigate the safety, tolerability, and 
pharmacokinetics of CCI15106 inhalation powder in healthy participants and participants 
with moderate chronic obstructive pulmonary disease (COPD) including evaluation of
environmental and healthy by-stander exposure levels during dosing.
Protocol Number: 205822
Short Title: Study of safety and drug levels of CCI15106 inhalation powder in healthy 
adults and adults with moderate chronic obstructive pulmonary disease.  Study of 
CCI15106 levels in people standing near the person inhaling the drug.
Compound Number:
CCI15106
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT  2017-001070-42
Approval Date: 20-APR-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2016N290366_00
CONFIDENTIAL
205822
3
TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................18
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................20
3.3.1.
Risk Assessment .........................................................................21
3.3.2.
Benefit Assessment.....................................................................28
3.3.3.
Overall Benefit:Risk Conclusion...................................................28
4.
OBJECTIVES AND ENDPOINTS...........................................................................29
5.
STUDY DESIGN ....................................................................................................30
5.1.
Overall Design ............................................................................................30
5.2.
Number of Participants ...............................................................................34
5.3.
Participant and Study Completion...............................................................34
5.4.
Scientific Rationale for Study Design ..........................................................34
5.5.
Dose Justification........................................................................................35
6.
STUDY POPULATION...........................................................................................37
6.1.
Inclusion Criteria.........................................................................................37
6.1.1.
Inclusion Criteria for Healthy Participants and Bystanders...........37
6.1.2.
Inclusion Criteria for Participants with COPD...............................38
6.2.
Exclusion Criteria........................................................................................39
6.2.1.
Exclusion Criteria for Healthy Participants and Bystanders..........39
6.2.2.
Exclusion Criteria for Participants with COPD..............................41
6.3.
Lifestyle Restrictions...................................................................................44
6.3.1.
Meals and Dietary Restrictions ....................................................44
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................45
6.3.3.
Activity .........................................................................................45
6.4.
Screen Failures...........................................................................................45
7.
TREATMENTS.......................................................................................................45
7.1.
Treatments Administered............................................................................46
7.1.1.
Medical Devices...........................................................................47
7.2.
Dose Modification .......................................................................................47
7.3.
Method of Treatment Assignment ...............................................................48
7.4.
Blinding.......................................................................................................48
7.5.
Preparation/Handling/Storage/Accountability..............................................49
7.6.
Treatment Compliance................................................................................51
7.7.
Concomitant Therapy..................................................................................52
7.7.1.
Permitted Medications and Non-Drug Therapies..........................52
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................52
7.8.
Treatment after the End of the Study ..........................................................53
8.
DISCONTINUATION CRITERIA.............................................................................53
8.1.
Discontinuation of Study Treatment ............................................................53


2016N290366_00
CONFIDENTIAL
205822
4
8.1.1.
Liver Chemistry Stopping Criteria ................................................53
8.1.2.
QTc Stopping Criteria ..................................................................54
8.1.3.
Other Stopping Criteria ................................................................54
8.1.4.
Rechallenge.................................................................................55
8.2.
Withdrawal from the Study..........................................................................55
8.3.
Lost to Follow Up........................................................................................56
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................56
9.1.
Efficacy Assessments.................................................................................57
9.2.
Adverse Events...........................................................................................57
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................57
9.2.2.
Method of Detecting AEs and SAEs.............................................58
9.2.3.
Follow-up of AEs and SAEs.........................................................58
9.2.4.
Regulatory Reporting Requirements for SAEs .............................58
9.2.5.
Cardiovascular and Death Events................................................58
9.2.6.
Pregnancy ...................................................................................59
9.2.7.
Medical Device Incidents (Including Malfunctions).......................59
9.2.7.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................59
9.2.7.2.
Follow-up of Medical Device Incidents........................59
9.2.7.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................60
9.2.7.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................60
9.3.
Treatment of Overdose...............................................................................60
9.4.
Safety Assessments ...................................................................................60
9.4.1.
Screening Assessments ..............................................................61
9.4.2.
Physical Examinations.................................................................61
9.4.3.
Vital Signs....................................................................................61
9.4.4.
Electrocardiograms......................................................................62
9.4.5.
Spirometry ...................................................................................62
9.4.6.
Capillary pCO2 ............................................................................62
9.4.7.
Clinical Safety Laboratory Assessments ......................................62
9.4.8.
Environmental and Bystander Exposure Evaluation.....................63
9.4.8.1.
Air Monitoring .............................................................63
9.4.8.2.
Bystander Monitoring..................................................64
9.5.
Pharmacokinetics .......................................................................................65
9.5.1.
Blood Sample Collection..............................................................65
9.5.2.
BAL Sample Collection ................................................................65
9.5.3.
Urea Blood Sample......................................................................65
9.5.4.
Sample Analysis ..........................................................................65
9.6.
Pharmacodynamics ....................................................................................66
9.7.
Genetics .....................................................................................................66
9.8.
Biomarkers .................................................................................................66
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................66
10. STATISTICAL CONSIDERATIONS........................................................................66
10.1.
Sample Size Determination ........................................................................66
10.1.1.
Sample Size Sensitivity................................................................67
10.1.2.
Sample Size Re-estimation or Adjustment...................................67


2016N290366_00
CONFIDENTIAL
205822
5
10.2.
Populations for Analyses ............................................................................67
10.3.
Statistical Analyses.....................................................................................68
10.3.1.
Safety Analyses...........................................................................69
10.3.2.
Pharmacokinetic Analyses...........................................................69
10.3.3.
Bystander and Environmental exposure Analyses .......................70
10.3.4.
Interim Analyses ..........................................................................70
11. REFERENCES.......................................................................................................71
12. APPENDICES........................................................................................................74
12.1.
Appendix 1: Abbreviations and Trademarks................................................74
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................76
12.3.
Appendix 3: Study Governance Considerations..........................................78
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................82
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................89
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................92
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................94


2016N290366_00
CONFIDENTIAL
205822
6
1.
SYNOPSIS
Protocol Title: A double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study to investigate the safety, tolerability, and 
pharmacokinetics of CCI15106 inhalation powder in healthy participants and participants 
with moderate chronic obstructive pulmonary disease (COPD).  A concomitant study to 
evaluate environmental and healthy bystander exposure levels during dosing.
Short Title: Study of safety and drug levels of CCI15106 inhalation powder in healthy 
adults and adults with moderate chronic obstructive pulmonary disease.  Study of 
CCI15106 levels in people standing near the person inhaling the drug.
Rationale:
This study is the first administration of CCI15106 inhalation powder hard capsules 
(CCI15106:polyvinyl alcohol 99:1 w/w 0.9x1 m cylinder shape crystalline particles
presented in capsules, from here on referred to as CCI15106-IP) to humans. This study 
will evaluate the safety, tolerability, and lung and systemic pharmacokinetics (PK) of
CCI15106-IP delivered using Monodose RS01 device in healthy participants and in 
participants with moderate COPD.  
The intention of this study is to provide sufficient confidence in the safety of the 
molecule delivered by inhalation to inform progression to further repeat dose and proof 
of concept studies.
A different formulation of CCI15106 (CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 
m pollen shape particles) has been previously administered to humans in the first time 
in human study (FTiH) 202031.  
Marketed CCI15106 is classified as teratogenic and is contra-indicated in women who are 
pregnant and in male partners of pregnant women and it is important to understand 
whether bystanders may be exposed to CCI15106 when it is used by patients in a dry 
powder, inhaled form.  This study will evaluate the levels of CCI15106 in room air and in 
the plasma of bystanders.  The study aims to replicate the real-life scenarios of dosing as 
close as possible.  Real-life scenarios may include dosing of multiple patients in a single 
room in a nursing home or dosing of a single patient at home.  A realistic worst-case 
scenario for bystanders is dosing of multiple patients in a standard size room in a nursing 
home.  


2016N290366_00
CONFIDENTIAL
205822
7
Objectives and Endpoints:
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
CCI15106-IP following single and repeat 
escalating doses in healthy participants and 
participants with moderate COPD.

To determine systemic PK of CCI15106
following single and repeat escalating doses 
of CCI15106-IP in healthy participants and 
participants with moderate COPD.

To evaluate potential inhalation exposure of 
bystanders to airborne CCI15106 during 
self-administered dosing of participants.

To evaluate the distribution and persistence 
of airborne CCI15106 in room air post-
dosing.

Adverse events (AEs), clinical laboratory, 
electrocardiogram (ECG), telemetry, 
spirometry, and vital signs assessments.

Derived systemic PK parameters of 
CCI15106: Single dose: area under the 
curve (AUC) from time zero to the time of 
last quantifiable concentration (AUC[0-last]),
concentration at maximum (Cmax), time of 
maximum concentration (tmax), AUC from 
time zero to infinity (AUC[0-]) elimination 
half-life (t1/2), clearance (CL/F), as data 
permit.
Repeat dose: AUC from time zero to end of 
dosing interval (AUC[0-]) (=12 hours [h] 
for twice daily dose regimen), Cmax, tmax,
elimination half-life (t1/2) as data permit.

Concentration of CCI15106 in plasma of 
bystanders 15-20 minutes (min) after dosing
(at predicted tmax) and amount of 
CCI15106 accumulated on filters fitted on 
bystander over 15 min after dosing.

Amount of CC15106 in room air assessed 
by measuring amount of CCI15106 
accumulated over 20 and 60 min intervals 
during and immediately post-dosing on 
filters fitted on stationary pumps placed in
the room.
Secondary

To determine the concentration of 
CCI15106 in the lung of healthy participants 
and participants with moderate COPD
following repeat dosing of CCI15106-IP.

To investigate the performance of the 
Monodose RS01 device for the 
administration of CCI15106-IP in healthy 
participants and participants with moderate 
COPD.

Concentrations of CCI15106 in lung 
epithelial lining fluid (ELF) assessed by 
bronchoalveolar lavage.  

Device safety and performance parameters, 
including medical device incidents reporting, 
as well as systemic PK and lung CCI15106 
concentrations.


2016N290366_00
CONFIDENTIAL
205822
8
Overall Design:
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, 
single and repeat escalating dose study.  Investigator and participants will be blinded to 
treatment type (active or placebo), but will know what dose of the medication is being 
administered.  Part 1 will investigate single and repeat ascending doses in healthy 
participants and investigate environmental and bystander exposure.  Part 2 will evaluate 
single and repeat dose in participants with moderate COPD.  Participants may only be 
enrolled in one study part and randomized to one cohort per the randomization schedule.
Study schematic is presented below:


2016N290366_00
CONFIDENTIAL
205822
9
Number of Participants:
Approximately 36 healthy participants and approximately 22 participants with COPD 
will be randomized in this study for dosing.  
Treatment Groups and Duration:
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106-
IP or Placebo with 3:1 ratio.  In Cohort B Part 1 and Cohort B Part 2, participants will be 
randomized with 6:1 ratio.   Cohort C Part 1 will not be randomized or dosed, but each 
bystander participant will be assigned to a dosing participant.  Screening visit will occur 
within 30 days of dosing for cohorts in Part 1 and within 45 days of dosing for cohorts in 
Part 2.  Doses administered and treatment duration for participants in each specific cohort 
will be as defined in the study schematic above. Participants will return for the follow-up 
visit approximately 30 days after discharge.
The total study duration will be approximately 82 days for Cohort A Part 1; 
approximately 75 days for Cohort B Part 1 and Cohort C Part 1; approximately 77 days 
for Cohort A Part 2; and approximately 90 days for Cohort B Part 2.
2.
SCHEDULE OF ACTIVITIES (SOA)
If assessments are scheduled for the same nominal time, THEN the assessments should 
occur in the following order pre-dose:
1.
Telemetry start
2.
spirometry
3.
12-lead electrocardiogram (ECG)
4.
vital signs
5.
blood draws
  
and in the following order post-dose:
1.
12-lead ECG
2.
vital signs
3.
blood draws
4.
spirometry
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, or others assessments may be altered during the course of the 
study based on newly available data (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring. 


2016N290366_00
CONFIDENTIAL
205822
10

Any change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GlaxoSmithKline (GSK) study team member and then archived in the 
study sponsor and site study files, but this will not constitute a protocol 
amendment. 

The institutional review board (IRB)/independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 


2016N290366_00
CONFIDENTIAL
205822
11
Screening and follow-up procedures for all cohorts
Procedure
Screening, 30 
days before D1 for 
Part 1 or 45 days 
before D1 for Part 
21
Follow up
302 days after the 
last dosing day
Notes
Informed consent
X
1.
Screening assessments can be performed over multiple screening visits
2.
If test otherwise performed within 3 months prior to first dose of study treatment, testing 
at screening is not required
3.
To be drawn fasting (for at least 8 h)
4.
To be administered to participants with COPD only, 15-30 minutes prior to spirometry
5.
To be done at screening for participants with COPD only, following salbutamol dosing
6.
To be performed in the bronchoalveolar lavage (BAL) cohorts only to confirm participant 
eligibility
7.
To be performed in the BAL cohorts only to confirm participant eligibility.  Can be done 
pre-dose on Day -1 instead, if required
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including 
height and weight, oral examination 
X
Brief physical examination, oral 
examination
X
Medical history (includes substance 
usage  and Family history of 
premature CV disease)
X
Substance testing (drugs, alcohol)
X
Assessment of child-bearing potential 
for females
X
Serum pregnancy test in women
X
X
Human immunodeficiency virus (HIV), 
Hepatitis B (Hep B) and Hepatitis C
(Hep C) screen2
X
Haematology, clinical chemistry and 
urinalysis (include liver chemistries)3
X
X
Salbutamol administration4
X
Spirometry5
X
12-lead ECG and vital signs
X
X
Coagulation parameters6
X
Capillary pCO27
X
PK blood sample
X
AE review 
X
SAE review
X
X
Concomitant medication review
X
X


2016N290366_00
CONFIDENTIAL
205822
12
Schedule for Cohort A Part 1
Procedure
Treatment Period, Days
-1
11
2
31
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Inclusion and exclusion criteria
X
Brief physical examination, oral 
examination
X
X
Substance testing (drugs, alcohol, tobacco)
X
Inhaler device training2
X
Serum pregnancy test in women
X
Admittance to clinic
X
Randomization
X3
Discharge
X4
Haematology, clinical chem and urinalysis 
(include liver chem)5
X
X
X
X
X
Spirometry
X1
X1
X6
X7
X7
X7
X6
Telemetry (starting 30 min pre-morning 
dose and continuous at least 4h post-
morning dose)
X1
X1
X
X
X
12-lead ECG and vital signs
XX
X
X1
X1
X8
X8
X8
X8
X8
X8
X8
X8
CCI15106-IP or placebo treatment, device 
incident assessment
X1
X1
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
PK blood sample10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE review
========================================================================================
SAE review
=============================================================================================
Concomitant medication review
=============================================================================================
1.
Single dose days.  Follow schedule for Day 1 of Part 2 Cohort A
2.
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion.  
3.
Can be performed on Day 1 prior to dosing
4.
After all procedures and assessments are complete
5.
To be drawn fasting (for at least 8 h)
6.
To be performed at the following timepoints in the mornings only: pre-dose, and 0.25, 0.5, 1, 4 h post-dose 
7.
To be performed at the following timepoints in the mornings only: pre-dose and 4 h post-dose
8.
ECG and vital signs to be obtained 2 h after the morning dose


2016N290366_00
CONFIDENTIAL
205822
13
9.
BID
10.
PK samples on days 1, 3, 6, and 19 will be collected at the following timepoints:  pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 h.  On day 2, one sample in the morning (24h 
post day 1 dose). On days 4 and 5, one sample on each morning (24h and 48h post day 3 dose). On days 6 and 19, the evening dose will be given after 12 h post-dose 
sample is collected.  On all other days, PK sample will be collected once, before the morning dose (if on dosing days).


2016N290366_00
CONFIDENTIAL
205822
14
Schedule for Cohort A Part 2 (and all other single dose administrations)
Procedure
Treatment Period, Days (D) and hours (h)
D-1
D1
D2
Pre-
dose
0h
0.25h
0.5h
0.75h
1h
2h
4h
6h
8h
10h
12h
24h
Inclusion and exclusion criteria
X
Brief physical examination, oral examination
X
X
Substance testing (drugs, alcohol)
X
Serum pregnancy test in women
X
Admittance to clinic
X
Inhaler device training1
X
Randomization
X2
Discharge
X3
Haematology, clinical chem and urinalysis (include liver chem)4
X
X
Spirometry
X5
X6
X
X6
X6
Telemetry
30 min pre-dose and continuous until at least 4 h 
post-dose
12-lead ECG and vital signs
XXX
X
X
X
X
X
X
CCI15106-IP or placebo treatment
X
PK blood sample7
X
X
X
X
X
X
X
X
X
X
X
X
AE review
=================================================================
SAE review
==============================================================================
Concomitant medication review
==============================================================================
1.
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion
2.
Can be performed on Day 1 prior to dosing
3.
After all assessments are completed
4.
To be drawn fasting (for at least 8 h)
5.
To be performed within 15 to 60 minutes pre-dose
6.
To be performed after ECG, VS and PK blood draw are obtained
7.
Additional PK collection time points may be added to better characterize the PK profile


2016N290366_00
CONFIDENTIAL
205822
15
Repeat dose schedule to be followed for repeat dose cohorts in Parts 1 and 2 (other than Cohort A Part 1)
Procedure
Treatment Period, Days 
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Inclusion and exclusion criteria
X
Brief physical examination, oral examination
X
X
Substance testing (drugs, alcohol, tobacco1)
X
Inhaler device training2
X
Serum pregnancy test in women
X
Admittance to clinic
X
Randomization
X3
Discharge
X4
Dosing procedure training with bystanders
X5
Haematology, clinical chem and urinalysis (include liver chem)6
X
X
X
Spirometry
X7
X8
X8
X8
X7
Telemetry (starting 30 min pre-morning dose and continuous at 
least 4h post-morning dose)
X
X
X9
12-lead ECG and vital signs10
XXX
X
X
X
X
X
X
X11
X11
CCI15106-IP or placebo treatment BID, device incident 
assessment BID12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample13
X
X
X
X
X
X
X
X
X
BAL
X14
Urea blood sample
X15
AE review
=================================================================
SAE review
==============================================================================
Concomitant medication review
==============================================================================
1.
Tobacco test to be performed only in healthy participants 
2.
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion.  
3.
Can be performed on Day 1 prior to dosing
4.
After all procedures and assessments are complete
5.
To be done only in Cohort(s) where bystanders are present.  Can be performed on Day -1 instead, if desired. Other time-points may be added per investigators discretion.
6.
To be drawn fasting (for at least 8 h)
7.
To be performed at the following timepoints in the mornings only: pre-dose, and 0.25 (in participants with COPD only), 0.5, 1, 4 h post-dose 
8.
To be performed at the following timepoints in the mornings only: pre-dose and 4 h post-dose


2016N290366_00
CONFIDENTIAL
205822
16
9.
Telemetry may be performed on Days 11 or 12 instead, not to coincide with the BAL procedure.
10. ECG and vital signs to be obtained 2 h after the morning dose
11. When BAL is performed, vital signs and ECG will be performed before and after the procedure and oxygen saturation will be measured continuously. 
12. For cohort with bystanders, BID doses may have 1.5 h window.
13. PK samples on days 1 and 14 will be collected at the following timepoints:  pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 h.  The evening dose will be given after 12 h post-dose 
sample is collected.  On all other days, PK sample will be collected once, before the morning dose.  When BAL is performed, one additional PK sample will be collected after 
dosing immediately prior to bronchoscopy
14. Done once during these four days, as soon as possible (within 1 h) after the first dose of the day
15. To be collected immediately before bronchoscopy


2016N290366_00
CONFIDENTIAL
205822
17
Schedule for Cohort C Part 1 (bystanders and air monitoring), to be executed concomitantly with Cohort B
Part 1
Procedure
Treatment Period, Days 
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Inclusion and exclusion criteria
X
Brief physical examination, oral examination
X
X
Substance testing (drugs, alcohol, tobacco)
X
Serum pregnancy test in women
X
Admittance to clinic
X
Discharge
X1
Training2
X
Haematology, clinical chem and urinalysis (include liver chem)3
X
X
X
Exposure to dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample
X4
X4
X4
X
Stationary pump air monitoring5
X
X
X
Personal exposure pump monitoring6
X
X
X
12-lead ECG and vital signs
XXX
X7
X7
X7
X7
X7
X7
X7
X7
AE review
=================================================================
SAE review
=================================================================================
Concomitant medication review
=================================================================================
1.
After all procedures and assessments are complete
2.
Day -1 training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion
3.
To be drawn fasting (for at least 8 h)
4.
PK samples will be collected pre-dose and 15 min after the dosing participant takes their first daily dose.  In addition, on days 7 and 14, one sample on each day will be collected 
before the dosing participant takes the first daily dose. On day 15, one sample will be collected before discharge.
5.
Samples of air to be collected for 20 and 60 min during and after the first morning dose
6.
Samples of air to be collected for 15 min during and after the first morning dose
7.
ECG and vital signs to be obtained 2 h after the exposure to morning dose


2016N290366_00
CONFIDENTIAL
205822
18
3.
INTRODUCTION
3.1.
Study Rationale
This study is the first administration of CCI15106-IP (CCI15106:polyvinyl alcohol 99:1
w/w 0.9x1 m cylinder shape crystalline particles produced using Liquidia’s Particle 
Replication In Non-wetting Templates [PRINT] technology) to humans. The study will 
evaluate the safety, tolerability, and lung and systemic pharmacokinetics (PK) of single 
and repeat ascending doses of CCI15106-IP delivered by inhalation in healthy 
participants and in participants with moderate chronic obstructive pulmonary disease 
(COPD).  The study will use a Monodose RS01 device for drug delivery by inhalation.
A different formulation of CCI15106 (CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 
m pollen shape particles) has been previously administered to humans in the first time 
in human study (FTiH) 202031.  That formulation was referred to as CCI15106 capsules 
for inhalation (CCI15106-CFI).
The intention of this study is to provide sufficient information regarding the safety of the 
molecule to inform progression to further repeat dose and proof of concept studies. The 
dose range proposed in this study is based on a starting dose previously investigated with 
the different formulation in the FTiH and escalating to a dose not to exceed the the no 
observed adverse effect level (NOAEL) in the most sensitive species (Section 5.5).
The other intention of this study is to investigate the level of CCI15106 that will be 
released into the air and may be found in the blood of the bystanders around participants 
inhaling CCI15106-IP.
3.2.
Background
CCI15106 is ribavirin, which is a generic, broad spectrum nucleoside antiviral, 
discovered in the early 1970s, with both clinical and nonclinical data available, which 
is approved and used for oral administration in the treatment of chronic hepatitis C 
virus.  It is also approved for respiratory syncytial virus (RSV) bronchiolitis by 
pulmonary inhalation in paediatric patients.  CCI15106 is active versus RSV, human 
metapneumovirus, parainfluenza, influenza, adenovirus, and human rhinovirus (HRV), 
although HRV is 4-15-fold less susceptible than the others (GlaxoSmithKline 
Document Number 2015N249287_00). Based upon published data coronaviruses 
could also be susceptible without co-administration of interferon [Kurai, 2013, 
Morgenstern, 2005].  CCI15106 is not considered to be the active form, rather it is 
actively transported into target organs/cells and converted to ribavirin triphosphate 
(RTP) believed to be the active form against the viruses [Thomas, 2012]. The major 
limitation of the use of CCI15106 is hemolytic anemia due to accumulation of RTP in 
red blood cells and teratogenicity.   
Liquidia’s Particle Replication In Non-wetting Templates (PRINT) technology uses 
lithographic etching processes to produce particles with highly defined size and shape. 
CCI15106 plus the excipient, polyvinyl alcohol, are combined in a ratio of 99:1 w:w
using Liquidia’s technology to produce CCI15106-IP, a highly dispersible powder of 
uniform 0.9x1 m cylinder shape particles which has afforded a 24-fold increase in lung 


2016N290366_00
CONFIDENTIAL
205822
19
concentration at maximum (Cmax) relative to micronised CCI15106:Lactose formulation 
in a solid dose inhaled rat PK study (GlaxoSmithKline Document Number 
2015N242219_00 [N20691-39]). The size and uniformity of the Liquidia particles 
provides an opportunity to improve the efficiency of CCI15106 administration to the lung 
while limiting systemic exposure that has the potential to limit hemolytic anemia and 
teratogenicity. 
Acute exacerbations of COPD are a significant cause of morbidity and mortality 
[Vestbo, 2013; Kurai, 2013]. Multiple studies show that viral and/or bacterial 
respiratory infections are the most commonly associated triggers of COPD 
exacerbations.  Respiratory viruses are detected in 20-60% of acute exacerbations of 
COPD [Kurai, 2013].
High efficiency lung delivery of broad spectrum CCI15106-containing engineered 
particles will establish an antiviral state in the lung.  This has the potential to prevent the 
establishment or spread of the virus in the lower respiratory tract from the upper 
respiratory tract and/or increase the viral clearance translating to prevention of an 
exacerbation or a decrease in exacerbation severity and/or duration.
CCI15106 has been previously administered to humans in a different formulation, 
CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 m pollen shape PRINT particles
(CCI15106 capsules for inhalation, referred to as CCI15106-CFI).  Forty eight healthy 
participants have been administered a single dose of that formulation in one FTiH study 
202031 and 12 participants received placebo.  This study was planned as a double-blind 
(sponsor unblind), randomized, placebo-controlled, single and repeat escalating dose 
study to investigate the safety, tolerability, and pharmacokinetics of CCI15106-CFI in 
healthy participants and participants with moderate chronic obstructive pulmonary 
disease (COPD).  In the single dose part of the study, CCI15106-CFI was administered 
by inhalation using Modified Air Inlet Rotahaler device at doses of 7.5 mg, 15 mg, 30 
mg, and 60 mg.  Overall, no clinically meaningful changes in vital signs or 
electrocardiograms (ECGs) were observed.  There were no serious adverse events (SAEs)
reported.  Of the 60 subjects in the study, 25 reported adverse events (AEs) and 12 
reported possibly drug-related AEs.  The most common AEs were headache and cough 
(11 and 3 subjects, respectively).  The comprehensive review conducted after single dose 
cohorts revealed acceptable safety profile, but lung epithelial lining fluid (ELF) levels of 
CCI15106 measured with 30 or 60 mg dose were below the levels predicted by pre-
clinical evaluations and the increase in dose from 30 to 60 mg did not appear to result in a 
substantial increase in the lung concentration.  Development of the CCI15106-CFI 
formulation was terminated before dosing repeat dose or COPD cohorts as a new
formulation (CCI15106-IP) was developed that has higher ratio of active pharmaceutical 
ingredient to inactive ingredients per unit of powder and allows achieving the same dose 
in 1 capsule instead of 4. This is expected to lead to a higher lung ELF Cmax. The 
decision to terminate was not based on safety data.   
Marketed formulations of CCI15106 are classified as teratogenic and is contra-indicated 
in women who are pregnant and in male partners of pregnant women.  Currently 
approved aerosolised forms of CCI15106 are recommended to be administered in a 
negative pressure environment [Virazole USPI 2013].  It is important to understand 
whether bystanders may be exposed to CCI15106 when it is used by patients in a dry 


2016N290366_00
CONFIDENTIAL
205822
20
powder, inhaled form.  The most likely route of exposure of bystanders will be through 
inhalation of powder released during dosing. The study aims to replicate the real-life 
scenarios of dosing as close as possible.  Real-life scenarios may include dosing of 
multiple patients in a single room in a nursing home or dosing of a single patient at home.  
A realistic worst-case scenario is dosing of multiple patients in a standard size room in a 
nursing home.  
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of CCI15106 may be found in the Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 2015N250735_00].  Information 
specific to the approved formulations of CCI15106 can be found in the labels for oral 
CCI15106 approved for the treatment of hepatitis C and CCI15106 nebulizer approved 
for the treatment of respiratory syncytial infections in children [Rebetol SPC 2009; 
Virazole USPI 2013].  
Based on pre-clinical safety assessment studies summarized in the IB and the clinical 
experience with CCI15106-CFI, as well as oral and inhaled (nebulised) CCI15106, the 
following clinical parameters will be monitored throughout the study in order to better 
characterize the safety and tolerability of CCI15106-IP (Section 3.3.1).  Refer to SoA,
Section 2, for the timing of all clinical assessments.


2016N290366_00
CONFIDENTIAL
205822
21
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product, CCI15106-IP
Teratogenicity and embryocidal effects
CCI15106 showed embryocidal and teratogenic effects in animals.  The no 
observed adverse effect level (NOAEL) in oral embryofetal development 
studies in rats and rabbits was 0.3 mg/kg/day, considerably lower than the 
maximum proposed inhaled clinical dose of 120 mg/day CCI15106 (0.02-
fold to 0.05-fold based on mg/m2).  In addition, human seminal fluid contains 
2-fold higher concentrations of CCI15106 compared to serum.  There are 
limited data from the use of CCI15106 in pregnant women (5 cases of 
measles-pneumonia and 1 case of influenza-pneumonia)) [Virazole SPC, 
2014]. Four pregnancies were completed and resulted in the birth of healthy 
children. A further 7 cases are known in which nurses administered Virazole 
dry substance during pregnancy (n=6) or just before conception (n=1). In 6 
cases, healthy children were born. In one case, a chromosomal 
translocation was reported with mild developmental delay [Virazole SPC, 
2014].
Women of child-bearing potential and male partners of 
women who are pregnant or breastfeeding will be 
excluded.  Effective contraception for female partners of 
male participants will be required up to 7 months post 
study.  
Any pregnancies that occur during the study or up to 7 
months post study will be reported by the investigator to 
the pregnancy registry.  
The informed consent form will describe these reproductive 
risks, as well as the risk to female partners of male 
participants.
Systemic exposure for the target clinical dose of CCI15106 
is expected to be lower than exposure for currently 
available oral and nebulized CCI15106.  The maximum 
inhaled total daily single dose of CCI15106 in Protocol 
205822 will be 120 mg and the maximum inhaled multiple 
daily doses will be 60 mg twice daily (BID).  These 
proposed maximum clinical doses are significantly lower 
than the currently approved doses of CCI15106 (800-1400
mg for Copegus and Rebetol and 6 g for inhaled Virazole).
Mutagenicity
CCI15106 is clastogenic in vitro and in vivo but is Ames negative.  The 
pattern of genotoxicity is consistent with that reported for other nucleoside 
analogues.  Point of departure modelling (an accepted method of risk 
assessment for nucleoside analogues) indicates a negligible genotoxic 
concern.  CCI15106 was not tumorigenic in lifetime rodent studies at doses 
up to 75 mg/kg/day in the mouse and 40 mg/kg/day in the rat (3-fold the 
The data indicate a negligible genotoxic concern, which is 
mitigated by the lower expected systemic and lung 
exposure compared with currently available oral and 
nebulized CCI15106 and shorter duration of clinical 
treatment (14 days).  The maximum inhaled single total 
daily dose of 120 mg or multiple total daily doses of 60 mg 


2016N290366_00
CONFIDENTIAL
205822
22
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
maximum proposed inhaled clinical dose of CCI15106-IP based on mg/m2), 
or in the transgenic p53() mouse model at doses of up to 300 mg/kg/day.
BID for Protocol 205822 are significantly lower than the 
currently approved doses of CCI15106 (800-1400mg for 
Copegus and Rebetol and 6 g for inhaled Virazole).
Increased exposure in participants with 
severe renal impairment 
As CCI15106/ribavirin is substantially excreted by the kidneys, exposure 
may be increased in those with pre-existing renal impairment
CCI15106 is contraindicated in patients with chronic renal failure, patients 
with creatinine clearance < 50mL/min, and/or on hemodialysis [Rebetol
SPC, 2009] However, the Copegus labels allow dose modifications for 
patients with CrCl <50 mL/min [Copegus USPI, 2015; Copegus SPC, 2015].
The maximum inhaled single total daily dose of 120 mg or 
multiple total daily doses of 60 mg BID proposed for 
Protocol 205822 are significantly lower than the currently 
approved doses of CCI15106 (800-1400mg for Copegus 
and Rebetol and 6 g for inhaled Virazole).
COPD patients with impaired renal function (eGFR <30 
cc/min, using CKD-EPI equation) will be excluded and 
renal function will be monitored.
Pulmonary effects
GSK’s formulations:
In toxicity studies conducted by GSK, no adverse pulmonary toxicity was 
observed following administration of either CCI15106:trehalose:trileucine 
particles or CCI15106-IP in GSK studies of 28 day duration at dose levels of 
32.5 mg/kg in rat or 34.2 mg/kg in dog.  The deposited lung doses at the 
NOAELs on the 28 day studies using CCI15106-IP were estimated 6- to 8-
fold higher than in human at the maximum proposed clinical administration 
of CCI15106-IP of 120 mg/day (conservatively assuming 100% human lung
deposition). Adverse lung pathology (including neutrophilic inflammatory 
cell infiltrates) and unscheduled deaths were observed in rats in a 14 day 
inhaled tolerability study with CCI15106-IP at an estimated dose of 68.7 
mg/kg.  Rat deaths and lung pathology have been reported during oral and 
inhalation toxicology programs for approved/marketed formulations of 
CCI15106 at systemic exposures and inhalation dose levels similar or less 
than those delivered in this study.
As CCI15106-IP is dry powder, it has a reduced risk of acute lung effects
compared to low osmolarity nebulised solution.  No bronchospasms were 
observed in the FTIH study 202031; however there were occurrences of 
non-serious cough and dyspnoea.  Maximal amounts of powder 
administered were higher in the FTIH study than those planned for the 
Repeat dosing will be evaluated in healthy participants in 
this study prior to dosing in participants with COPD.  
Patients with poorly controlled COPD will be excluded (see 
Section 6.2.2).  Lung function will be monitored with 
frequent spirometry and physical examinations will be 
conducted.  If they become medically necessary, short-
acting bronchodilators may be administered as needed by 
the clinical staff.  Oxygen and resuscitation measures will 
be available in the unit in the event they would be needed.
The trial is to be conducted in a dedicated phase I unit with 
supplementary (Medicines & Healthcare Products 
Regulatory Agency) accreditation and experience in the 
conduct of Phase I studies.


2016N290366_00
CONFIDENTIAL
205822
23
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
current study. 
Labels of approved formulations:
Virazole SPC (13 November 2014) includes the following:

Sudden deterioration in pulmonary function associated with 
aerosolized CCI15106/ ribavirin has been observed in children, 
and significant deterioration in pulmonary function has been 
observed in patients with asthma and chronic obstructive 
pulmonary disease (COPD)  during CCI15106/ribavirin treatment.

Bronchospasm has been reported following CCI15106/ribavirin 
use by patients with COPD and asthma.
Pulmonary adverse reactions reported in clinical studies or in postmarketing 
use of aerosolized CCI15106/ribavirin include bacterial pneumonia, 
pneumothorax, laryngitis, pharyngitis, dyspnoea, cough, hypo- and 
hyperventilation, apnoea, and bronchospasm.
Haemolytic anaemia
The primary toxicity of approved formulations of CCI15106 is haemolytic 
anemia, which was observed in 10% of oral CCI15106 plus interferon 
alpha2b combination-treated participants and occurs within 1 to 2 weeks of 
start of therapy [Rebetol USPI, 2015].  Haemolytic anemia associated with 
CCI15106 may result in worsening of cardiac disease that has led to fatal 
and nonfatal myocardial infarction.  CCI15106 is known to accumulate in the 
red blood cells and may cause hemolysis, which may result in increased uric 
acid [De Franceschi, 2000].  Anemia has been shown to occur frequently 
with experimental oral and intravenous CCI15106 in humans [Virazole USPI, 
2013].  Haemolytic anaemia is monitorable and reversible with reduction / 
cessation of treatment [Rebetol USPI, 2015].
GSK formulations:
In toxicity studies conducted by GSK, mild anaemia was seen in 4 week 
studies following inhalation administration of CCI15106:trehalose:trileucine 
particles (rat and dog) or CCI15106-IP (rat only).  
Participants will be monitored regularly with complete 
blood counts and hematocrit, as per SoA (Section 2).  
Participants with hemoglobinopathies will be excluded. 
Due to the short dose and duration and the red blood cell 
count monitoring in place, laboratory monitoring for 
hemolysis is not warranted in this study.  Participants will 
have an ECG assessment prior to and during the study.  
Cardiac monitoring, including assessment of blood 
pressure and heart rate, along with 12-lead 
electrocardiograms (ECGs) will be performed, per protocol.  
If cardiac status deteriorates on therapy, study medication
should be suspended and/or discontinued.  


2016N290366_00
CONFIDENTIAL
205822
24
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiac effects
GSK formulations:
Heart toxicity was not observed in definitive 4 week toxicity studies in rats 
and dogs following inhalation administration of 
CCI15106:trehalose:trileucine particles or CCI15106-IP.  Minimal 
lymphocytic/mononuclear or mixed inflammatory cell infiltrate in the 
myocardium was observed following inhalation administrations of 68.7 
mg/kg/day as CCI15106-IP at higher dose levels during a 14 day tolerability 
study (AUC0-24h was 5-fold higher than the human AUC0-24h estimated at 120 
mg CCI15106-IP).  These findings were also observed following oral and 
inhalation administrations of approved/marketed formulations of CCI15106-
IP and do not, therefore, present at a greater risk compared to 
marketed/approved CCI15106 formulations which are approved for 
administration at higher inhaled and oral dose levels/ systemic exposures 
and administered for longer treatment durations than those proposed for 
CCI15106-IP. 
There were no cardiac events reported in the FTIH study of CCI15106-CFI.
The following cardiovascular adverse reactions have been reported in 
clinical studies and in the postmarketing setting of CCI15106, which 
included severely ill infants with life-threatening underlying disease:  cardiac 
arrest, hypotension, bradycardia, and digitalis toxicity [Virazole USPI, 2013].  
Bigeminy, bradycardia, and tachycardia, have been described in patients 
with underlying cardiac disease.
Participants will have ECG prior to dosing and will be 
assessed prior to and during therapy by 12-lead ECG and 
telemetry.  If cardiac status deteriorates on therapy, study 
medication should be suspended and/or discontinued.  
Participants with uncontrolled or unstable cardiac diseases 
will be excluded.
Photosensitization
Photosensitivity reaction has been reported commonly in clinical trials and in 
the postmarketing setting for CCI15106 [Rebetol SPC, 2009].  Photoallergic 
reaction with CCI15106 has been described in the literature [Stryjek-
Kaminska, 1999].
Physical examination to include skin exams will be 
performed and documented as per SoA (Section 2).  Any 
findings suggesting photosensitivity reaction will be 
promptly addressed according to appropriate standard of 
care and followed up for resolution.
Oral erosions
Ulcerative stomatitis, stomatitis, mouth ulceration are undesirable effects 
associated with CCI15106 [Rebetol SPC, 2009].  Nasal erosions were 
Physical examination to include oral exam will be 
performed and documented as per SoA (Section 2).  Any 


2016N290366_00
CONFIDENTIAL
205822
25
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
observed in the squamous epithelium of the nasal turbinates of a proportion 
of dogs (but not rats) receiving the high dose (25.1 mg/kg/day) following 
administration of CCI15106-CFI and ≥16.3 mg/kg following administration 
CCI15106-IP for 4 weeks.  These effects were considered non adverse and 
unlikely to be clinically relevant since CCI15106  will be administered to 
humans by oral inhalation, compared with oro-nasal administration (over 60 
minutes) in the dog study, thereby minimising the potential for nasal 
exposure.  Histopathological findings in rats included epithelial changes in 
the larynx (squamous metaplasia) in animals given the control article and 
CCI15106 formulation over 4 weeks. These changes were low in incidence 
and severity and showed full recovery following completion of the off-dose 
period. The findings were consistent with low grade non-specific irritation 
and, being an adaptive change of low severity, are considered non-adverse 
[Kaufmann, 2009] and a poor predictor of irritancy in humans given that the 
rat larynx is known to be particularly sensitive to inhaled irritants [Lewis, 
1991].
findings suggesting oral erosion will be promptly 
addressed according to appropriate standard of care and 
followed up for resolution.
Testicular toxicity
Testicular toxicity:  Testicular toxicity was seen in mice treated orally with 
CCI15106 for 3 to 6 months at doses of 15 mg/kg/day and [Rebetol SPC, 
2009].  Recovery occurred within one or two spermatogenic cycles.  No 
stage specific or cell specific abnormalities of spermatogenesis were 
observed in GSK studies which were conducted on the testes of rats 
(CCI15106:trehalose:trileucine particles and CCI15106-IP) and dogs 
(CCI15106-IP only) during definitive 4 week inhalation toxicity studies.
Given the shorter duration of clinical treatment (14 days) 
and lower expected exposure compared with currently 
available oral and nebulized CCI15106, the risk of 
testicular toxicity is considered to be low.  


2016N290366_00
CONFIDENTIAL
205822
26
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures 
BAL procedure
BAL requires bronchoscopy and sedation.  Bronchoscopy can be performed 
safely on an outpatient basis [Du Rand, 2013], however, serious 
complications occurred in 1.1% of patients, including mortality in 0.02% of 
patients in a retrospective series (n=20,986 patients).  Common adverse 
events reported with bronchoscopy, included tachycardia/bradycardia, major 
and minor bleeding, bronchospasm, laryngospasm, cough, dyspnea, sore 
throat, apnea, seizure, desaturation, pneumothorax, and pulmonary edema.
BAL will be performed by an experienced pulmonologist in 
dedicated bronchoscopy suite with close monitoring in 
recovery area post procedure.
Other
Bystander exposure, including healthcare 
workers 
Detectible levels of CCI15196-IP may be present in the immediate inhalation
area during routine care activities.
Labels of approved formulations:
The Virazole patient information leaflet (last revision August 2014) states the 
following:

Virazole is to be administered in a hospital setting only, by a 
doctor or a nurse.

The nebuliser through which Virazole is given should be turned off 
5 to 10 minutes before visitors see the patient to minimise 
unnecessary exposure to Virazole.

Pregnant women, women who are trying to become pregnant, and 
sexually active men should avoid exposure to Virazole, because 
the risk of harm to an unborn baby is unknown.  Breast-feeding 
women are also to avoid exposure to Virazole.
Postmarketing surveillance of CCI15106 has revealed reports of adverse 
events in individuals providing direct care to infants receiving aerosolized 
CCI15106 [Virazole USPI 2013].  The most common signs and symptoms 
were headache, conjunctivitis, rhinitis, nausea, rash, dizziness, pharyngitis, 
Levels in air and in bystanders will be assessed.
Whenever study participants are dosed outside the 
negative pressure room, all hospital personnel will be 
asked to leave the room and will not re-enter until 15 min 
after dosing.    
Pregnant women or women of child-bearing potential will
be warned of the potential risks. 
Training on the potential health hazard will be provided to 
study personnel, including protective equipment, 
monitoring, and waste disposal. 
No women of child-bearing potential will be enrolled as 
participants or as bystanders.


2016N290366_00
CONFIDENTIAL
205822
27
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and lacrimation.  Several cases of bronchospasm and/or chest pain have 
been reported, usually in individuals with reactive airways disease. Seven 
cases are known in which nurses administered Virazole dry substance 
during pregnancy (n=6) or just before conception (n=1). In 6 cases, healthy 
children were born. In one case, a chromosomal translocation was reported 
with mild developmental delay.
Exposure risk for additional medications administered in the study (Salbutamol):
See package leaflet (https://www.medicines.org.uk/emc/PIL.22837.latest.pdf).


2016N290366_00
CONFIDENTIAL
205822
28
3.3.2.
Benefit Assessment
As this Phase I study is being conducted to assess the safety and PK in healthy 
participants and participants with COPD, there is no direct clinical benefit to study 
participants. Participation in this study may contribute to the process of developing new 
therapies in an area of unmet need.
3.3.3.
Overall Benefit:Risk Conclusion
CCI15106 is an approved product as an oral agent in combination with interferon or 
(pegylated and non-pegylated) for chronic hepatitis C in patients 3 years of age and older 
with compensated liver disease (Copegus, Rebetol), and is approved in the nebulised 
form for use in infants and young children with severe respiratory syncytial virus 
infections (Virazole). CCI15106-CFI has been administered to healthy participants in 
single doses up to 60 mg with acceptable safety and tolerability profile.  The risk of 
adverse effects is minimized for the population being investigated in the proposed study 
by careful selection of participants for the study, the relatively short duration of exposure, 
and the extent of safety monitoring incorporated into the study.  The highest dose planned 
in this study (single dose of 120 mg or multiple doses of 60 mg BID) is significantly 
lower than the currently approved doses of CCI15106 (800-1400 mg for Copegus and 
Rebetol and 6 g for aerosolized Virazole).  The risk to study staff will be managed by 
occupational precautions.


2016N290366_00
CONFIDENTIAL
205822
29
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
CCI15106-IP following single and repeat 
escalating doses in healthy participants and 
participants with moderate COPD.

To determine systemic PK of CCI15106
following single and repeat escalating doses 
of CCI15106-IP in healthy participants and 
participants with moderate COPD.

To evaluate potential inhalation exposure of 
bystanders to airborne CCI15106 during 
self-administered dosing of participants.

To evaluate the distribution and 
persistence of airborne CCI15106 in room 
air post-dosing.

Adverse events (AEs), clinical laboratory, 
electrocardiogram (ECG), telemetry, 
spirometry, and vital signs assessments.

Derived systemic PK parameters of 
CCI15106: Single dose: area under the 
curve (AUC) from time zero to the time of 
last quantifiable concentration (AUC[0-last]),
concentration at maximum (Cmax), time of 
maximum concentration (tmax), AUC from 
time zero to infinity (AUC[0-]) elimination 
half-life (t1/2), clearance (CL/F), as data 
permit.
Repeat dose: AUC from time zero to end of 
dosing interval (AUC[0-]) (=12 hours [h] 
for twice daily dose regimen), Cmax, tmax,
elimination half-life (t1/2) as data permit.

Concentration of CCI15106 in plasma of 
bystanders 15-20 minutes (min) after dosing 
(at predicted tmax) and amount of 
CCI15106 accumulated on filters fitted on 
bystander over 15 min after dosing.

Amount of CC15106 in room air assessed 
by measuring amount of CCI15106 
accumulated over 20 and 60 min intervals 
during and immediately post-dosing on 
filters fitted on stationary pumps placed in
the room.
Secondary

To determine the concentration of 
CCI15106 in the lung of healthy participants 
and participants with moderate COPD
following repeat dosing of CCI15106-IP.

To investigate the performance of the
Monodose RS01 device for the 
administration of CCI15106-IP in healthy 
participants and participants with moderate 
COPD.

Concentrations of CCI15106 in lung 
epithelial lining fluid (ELF) assessed by
bronchoalveolar lavage (BAL).

Device safety and performance parameters, 
including medical device incidents reporting, 
as well as systemic PK and lung CCI15106 
concentrations.


2016N290366_00
CONFIDENTIAL
205822
30
Objectives
Endpoints
Tertiary/Exploratory 

To assess dose proportionality of 
CCI15106-IP versus systemic PK 
parameters.

To explore the relationship of drug exposure 
to safety and tolerability parameters after 
single and repeat escalating doses of 
CCI15106-IP in healthy participants and 
participants with moderate COPD.

To extrapolate study outcomes to a realistic
worst case real-life scenario of dosing 
multiple patients in a single room in a 
nursing home.

Comparisons of doses administered and 
systemic PK parameters of CCI15106: 
AUC(0-24) or AUC(0-) and Cmax.

The dose or plasma exposure parameters 
for CCI15106 and the relationship of these 
to safety and tolerability parameters, as 
data permit.

Comparison of the study room with a 
potential nursing home room, including 
room dimensions, patient density, 
ventilation (air change rates per hour)
5.
STUDY DESIGN
5.1.
Overall Design
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, 
single and repeat escalating dose study.  Investigator and participants will be blinded to 
treatment type (active or placebo), but will know what dose of the medication is being 
administered.  Part 1 will investigate single and repeat ascending doses in healthy 
participants and investigate environmental and bystander exposure.  Part 2 will evaluate 
single and repeat dose in participants with moderate COPD.  Participants may only be 
enrolled in one study part and randomized to one cohort per the randomization schedule.


2016N290366_00
CONFIDENTIAL
205822
31
Study schematic is presented below:


2016N290366_00
CONFIDENTIAL
205822
32
The following reviews will be conducted during the study progression:

In Part 1, Cohort B dosing can begin only after review of safety/tolerability and PK 
of all dosing in Part 1 Cohort A (see Section 7.2 for composition of the review 
team).    

In Part2, Cohort A dosing can begin only after review of safety/tolerability for a 
single dose administration of 60 and 120 mg in all participants in Part 1 Cohort A
(see Section 7.2 for composition of the review team).  

In Part 2, Cohort B dosing can begin only after the comprehensive review of all data 
obtained in Part 1, including safety and systemic PK and lung PK, if available (see 
Section 7.2 for composition of the review team) and after review of 
safety/tolerability of Part 2 Cohort A.    

Environmental and bystander exposure review may be conducted at any time after 
the data are collected.  Until this review is completed and exposure found 
acceptable, all subsequent cohorts will be dosed in the negative pressure 
environment. 

The planned doses may be modified, repeated or cancelled based upon 
safety/tolerability/ and/or PK from preceding cohorts (See Section 7.2 for more 
information). Single doses will not exceed 120 mg and repeat doses 60 mg BID.

The planned dose frequency or duration may be modified based on emerging 
safety/tolerability and PK data from previous cohorts.  The total daily dose will not 
exceed 120 mg.

The number of cohorts may be reduced or expanded if needed.

All participants in Part 1 Cohort B and in Part 2 Cohort B (60 mg BID dose for both 
Cohorts) will undergo BAL once during the study on days 10, 11, 12, or 13 after the 
first (morning) dose.  Based on the lung ELF concentrations of CCI15106 observed, 
additional double-blinded, single-blinded or open-label repeat dose cohort(s) may be 
added at a dose not to exceed 120 mg daily.  The total number of participants will 
not exceed that specified in Section 5.2.


2016N290366_00
CONFIDENTIAL
205822
33

BAL may be used in the additional cohorts to obtain a more accurate estimation of 
the dose to lung exposure ratio and provide data for future dose predictions.  
There will be approximately 3 cohorts of healthy participants in this study and 
approximately 2 cohorts of participants with moderate COPD.  Participants in the dosing 
cohorts will be randomized to receive either CCI15106-IP or matching Liquidia particles
without the active ingredient (lactose:polyvinyl alcohol 98:2 w/w 0.9x1 m cylinder 
shape amorphous particles, referred to as placebo).  Participants in Cohort C will be 
assigned to participants in Cohort B on a one to one basis for the entire duration of the 
study.
Screening visit will occur within 30 days of dosing for cohorts in Part 1 and within 45 
days of dosing for cohorts in Part 2.  
For Cohort A Part 1, 60 mg single dose will be administered on Day 1; 120 mg single 
dose will be administered on Day 3; and then 30 mg dose will be administered BID on
Days 6-19.  Participants will report to the unit on Day -1 for assessments and 
randomization (randomization can also be done on Day 1, prior to dosing). Participants 
will be dosed the following morning on Day 1 followed by post-dose assessments. Blood 
for PK assessments will be collected for the next 48 hours (h).  On Day 3 (after collection 
of 48 h PK time point), participants will receive a single dose of 120 mg followed by 
post-dose assessments and PK assessments for the next 72 h.  Repeat dosing will begin
on the morning of Day 6 (after collection of 72 h PK time point) and will continue for 
14 days BID.  Participants will remain in the unit for additional 2 days until 72 h PK 
timepoint is collected.  Dosing frequency and duration may be adjusted based on 
emerging safety and tolerability data. 
For Cohort B Part 1, Repeat Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing). Dosing will begin on the
morning of Day 1 and continue for 14 days BID.  Dosing frequency and duration may be 
adjusted based on emerging safety and tolerability data. BAL procedure will be 
performed as soon as possible (within 1 h) after the first (morning) dose on one of the 
following days: 10, 11, 12, or 13. Participants will be discharged on Day 15 following
completion of all post-dose assessments after the last dose, or later if additional PK 
collection or other assessments are required.  Participants will return for the follow-up 
visit approximately 30 days after discharge.
For Cohort C Part 1, 14 healthy participants will be enrolled to evaluate bystander 
exposure and will follow Cohort C Part 1 SoA.  Bystanders and air exposure will be 
evaluated concomitantly with Cohort B Part 1.  Bystanders will report to the unit on Day 
-1 and will remain for all 14 days of dosing of Cohort B.  They will be positioned in the 
room with the dosing participants for every dose taken, as described in Section 9.4.8.  Air 
sampling and bystander PK evaluation will be conducted on days 1, 7, and 14 as 
described in Section 9.4.8.  Bystanders will be discharged on Day 15 following 
completion of all post-dose assessments after the last dose.  Bystanders will return for the 
follow-up visit approximately 30 days after discharge.
For Cohort A Part 2, Single Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 


2016N290366_00
CONFIDENTIAL
205822
34
(randomization can also be done on Day 1, prior to dosing).  They will be dosed the 
following morning on Day 1 followed by post-dose assessments. Participants will be 
discharged following completion of the post-dose assessments the next day (Day 2).  
They will return for the follow-up visit approximately 30 days after discharge.
For Cohort B Part 2, Repeat Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing). Dosing will begin on the
morning of Day 1 and continue for 14 days BID.  Dosing frequency and duration may be 
adjusted based on emerging safety and tolerability data. BAL procedure will be 
performed as soon as possible (within 1 h) after the first (morning) dose on one of the 
following days: 10, 11, 12, or 13.  Participants will be discharged on Day 15 following
completion of all post-dose assessments after the last dose, or later if additional PK 
collection or other assessments are required.  Participants will return for the follow-up 
visit approximately 30 days after discharge.  
The total study duration will be approximately 82 days for Cohort A Part 1;
approximately 75 days for Cohort B Part 1 and Cohort C Part 1; approximately 77 days 
for Cohort A Part 2; and approximately 90 days for Cohort B Part 2.  
5.2.
Number of Participants
Approximately 36 healthy participants and approximately 22 participants with COPD 
will be randomized in this study for dosing.  
Evaluable participants will be defined in the Reporting and Analysis Plan (RAP).
Additional participants or cohorts may be enrolled to allow for evaluation of additional 
dose levels or to increase numbers on prior doses or to increase the number of bystanders. 
The total number of participants in this study will not exceed 86 and the total number of 
cohorts will not exceed 7, including the bystander cohort(s).
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
Participants and all site personnel, with the exception of the study pharmacist or 
designee, will be blinded to participant randomization throughout the study.  The GSK
study team participating in the dose escalation meetings will review blinded data and will 
be un-blinded on a need to know basis only if necessary to facilitate review of the safety, 


2016N290366_00
CONFIDENTIAL
205822
35
tolerability and PK data as appropriate in real time to inform dose escalation decisions.  
The GSK study team or personnel at any contract research organization that may be 
involved in data management or in statistics and programming will not reveal the 
treatment assignments to the site personnel or participants. 
In repeat dosing cohorts, CCI15106-IP will be administered for 14 days to mimic the 
expected duration of treatment in target patient populations. 
Inclusion of Bronchoscopy
BAL will be performed on 14 healthy participants (Cohort B Part 1) and 14 participants 
with COPD (Cohort B Part 2) to evaluate levels of CCI15106 in the ELF.  BAL will be 
performed once, as soon as possible (within 1h) after the first (morning) dose.  This will 
allow assessment of CCI15106 levels at around tmax in the ELF.  The timing of BAL in 
Part 2 Cohort B may be adjusted based on BAL results obtained in Part 1.  Available 
models [Weber, 2017] predict that the level of CCI15106 in the bronchoalveolar fluid
following 14 days of 60 mg BID dosing may be achieved above 200 M around Tmax
which is above the EC50 for all respiratory viruses including HRV and expected to 
prevent or minimise the migration of an upper respiratory tract viral infection to the lower 
respiratory tract. These data will enable a more accurate estimation of the dose to lung 
exposure ratio and provide valuable information for future dose predictions. 
Inclusion of Participants with COPD Cohort
Due to potential exposure differences as a function of COPD-induced lung damage, 
participants with moderate COPD will be included to aid in dose selection for the future 
proof of concept studies in participants with COPD.  This cohort will also help obtain
some safety and tolerability data in this patient population prior to a wider administration 
in the Proof of Concept study.
Inclusion of Bystander Cohort
Due to known teratogenic potential of CCI15106, we need to evaluate how much of it 
gets into the environment around the dosing participant to ensure that no potentially 
pregnant bystanders are put at-risk due to secondary exposure.  Participants dosed in the 
Cohort used to evaluate environmental and bystander exposure will be dosed outside a 
negative pressure enclosure.  All other participants will be dosed inside the enclosure.  
When participants dose outside the enclosure, all personnel will leave the room and not 
re-enter until 15 min after dosing.  During this time, participants will be observed through 
a window in the door.
5.5.
Dose Justification
The dose proposed for Part 1 Cohort A is based on the data from 202031 where 
CCI15106-CFI up to 60 mg single dose has been evaluated, and no SAEs or severe AEs 
were observed, as well as the investigation of the four week toxicity and toxicokinetics in 
rats and dogs in which the NOAEL was determined [GSK Document Number 
2017N312240_00 and GSK Document Number 2017N312247_00].


2016N290366_00
CONFIDENTIAL
205822
36
Table 1 below shows the safety margins in terms of lung and systemic exposure with 
respect to the NOAEL obtained from the pre-clinical studies, and the folder cover with 
respect to the systemic exposure following oral administration of the marketed dose 
(1200 mg/day) in humans for the doses proposed in this study. These data indicated 
reasonable safety margins for Cohort A in Parts 1 and 2, where single dose of CCI15106-
IP will be administered.
The selection of appropriate dose for Part 1 Cohort B will be performed upon 
consideration of available safety, tolerability and systemic PK data from Part 1 cohort A. 
The review data set for this selection will, at minimum, consist of: any adverse events, 
liver function test results, vital signs, ECG, spirometry data, and laboratory findings, and 
any available systemic PK results. 
The selection of appropriate dose for Part 2 Cohort A will be performed upon 
consideration of available safety and tolerability data following the single doses (60 and 
120 mg) in all participants in Cohort A of Part 1.
The selection of appropriate dose for Part 2 Cohort B will be performed upon 
consideration of available safety, tolerability, systemic PK and lung concentration data 
from Part 1 Cohort B.
The dose level in any cohort may be titrated up or down based on emerging safety, 
tolerability, and systemic PK and lung data where available.  The maximum dose will not 
exceed 120 mg per day.
Table 1
Prediction of Human Systemic and Lung Exposure and Safety 
Margins of CCI15106
Dose 
Frequency
Proposed 
human 
dose per 
day (mg) 
Human 
Lung 
Dose 
(mg/g)
Lung 
Safety 
Margin 
(Rats)
Lung 
Safety 
Margin 
(Dogs)
Human 
Systemic 
expoure         
AUC(0-24) 
(ng.h/mL) *
Systemic 
Safety 
Margin 
(Rats)
Systemic 
Safety 
Margin 
(Dogs)
Systemic 
Safety 
Margin 
(human 
Oral 
Ribavirin)
Assume 100% lung deposition in humans
SD
60
0.06
12
16
SD
120
0.12
6
8
Assume 59% lung deposition in humans
SD
60
0.04
20
26
552
17
40
92
SD
120
0.07
10
13
1104
8
20
46
BD**
30
0.04
20
26
3080
3
7
16
BD
60
0.07
10
13
6150
2
4
8
Assumptions:
human: body weight 70 kg, lung weight 1000 g; 100% or 59% inhaled dose into lungs are assumed
59% was predicted from the MPPD for lung deposition of the device
rat: mean body weight 0.244kg, mean lung weight 1.145 g, 10% inhaled dose into lungs;
dog: mean body weight 8 kg, mean lung weight 73.1 g, 25% inhaled dose into lungs.


2016N290366_00
CONFIDENTIAL
205822
37
Rat NOAEL dose = 32.5 mg/kg, AUC=9.34 g.h/mL (whole study means)
Dog NOAEL dose = 34.2 mg/kg, AUC=22.2 g.h/mL (whole study means)
Human oral AUC(0-24) =2xAUC0-12=50.722 g.h/mL (Steady state) [Copegus USPI, 2015]
* human systemic AUC(0-24) is predicted from a mechanistic model [Weber, 2017]
** BD - twice daily dosing; AUC(0-24) on Day 14 
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
6.1.1.
Inclusion Criteria for Healthy Participants and Bystanders
Participants are eligible to be included in the study only if all of the following criteria 
apply.  Rescreening is allowed only if approved by the Medical Monitor.
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
3.
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator (in 
consultation with the Medical Monitor if required) decide and document that the
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.  
Weight
4.
Body weight 50 kg for males and 45 kg for females and body mass index (BMI) 
within the range 19 to 31 kg/m2 (inclusive) for males and 17 to 31 kg/m2 (inclusive)
for females.
Sex
5.
Male OR Female
a.
Male participants:
A male participant with female partner of child bearing potential must agree to use 
contraception as detailed in Appendix 5 of this protocol during the treatment period 
and for at least 7 months after the last dose of study treatment and refrain from 
donating sperm during this period.


2016N290366_00
CONFIDENTIAL
205822
38
b.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in 
Appendix 5.  
Informed Consent
6.
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.
6.1.2.
Inclusion Criteria for Participants with COPD
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 40 to 75 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Diagnosed with moderate COPD (GOLD class II) by a qualified physician as defined 
by the GOLD guidelines (http://www.goldcopd.org/).
3.
The participant has spirometry at screening, conducted 15-30 minutes after 
administration of 400 microgram (g) salbutamol via metered dose inhaler showing:

post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% and 
<80% predicted normal [Quanjer, 2012] and

post-bronchodilator FEV1/ forced vital capacity (FVC)<0.7, where FEV1 is 
forced expiratory volume in 1 second and FVC is forced vital capacity. 
4.
Participant is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).
5.
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor if required agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Weight
6.
Body weight ≥ 45 kg and BMI within the range 17 – 32 kg/m2 (inclusive).


2016N290366_00
CONFIDENTIAL
205822
39
Sex
7.
Male OR Female
a. Male participants:
A male participant with female partner of child bearing potential must agree to use 
contraception as detailed in Appendix 5 of this protocol during the treatment period 
and for at least 7 months 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 not pregnant (see Appendix 5),
not breastfeeding, and not a WOCBP as defined in Appendix 5.  
Informed Consent
8.
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
6.2.1.
Exclusion Criteria for Healthy Participants and Bystanders
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
4.
QTc > 450 msec
NOTES:

The QTc is the QT interval corrected for heart rate (HR) according to 
Fridericia’s formula (QTcF), machine-read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial.

For purposes of data analysis, QTcF will be used as specified in the RAP.


2016N290366_00
CONFIDENTIAL
205822
40
5.
Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<40 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcF interval 
>450 msec
6.
Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, 
metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions 
that, in the opinion of the investigator may place the participant at an unacceptable 
risk as a participant in this trial or may interfere with the absorption, distribution, 
metabolism or excretion of drugs.
Prior/Concomitant Therapy
7.
Past or intended use of over-the-counter or prescription medication (including herbal 
medications) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is longer) prior to dosing until completion of the follow-up 
visit, unless in the opinion of the Investigator and sponsor the medication will not 
interfere with the study.  Specific medications listed in Section 7.7 may be allowed.
Prior/Concurrent Clinical Study Experience
8.
Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 month period.
9.
Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
10. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
Diagnostic assessments
11. Hemoglobin (Hgb) below the lower level of the normal range with one repeat testing 
allowed, or known hemoglobinopathies.
12. Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, and erythema multiforme.
13. Presence of Hepatitis B surface antigen (HBsAg) at screening, Positive Hepatitis C 
antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment


2016N290366_00
CONFIDENTIAL
205822
41
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
15. Positive pre-study drug/alcohol screen
16. Positive HIV antibody test
17. Regular use of known drugs of abuse
Other Exclusions
18. Male partners of women who are pregnant or lactating
19. Regular alcohol consumption within 3 months prior to the study defined as: 

an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits. 
20. Breath test indicative of smoking at day -1.
21. History of sensitivity to any of the study medications, including CCI15106 or 
components thereof and, for cohorts that will undergo BAL, those that may be used in 
association with the BAL procedure or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.
22. For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage 
including hypercapnia >50 mm Hg, abnormal blood coagulation parameters, known 
or suspected intolerance of medications necessary for bronchoscopy, refractory 
hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial 
infarction.
23. Documented lactose allergy/intolerance for dosing cohorts.
6.2.2.
Exclusion Criteria for Participants with COPD
1.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
4.
QTc > 450 msec or QTc > 480 msec in participants with Bundle Branch Block
NOTES:

The QTc is the QT interval corrected for HR according to Fridericia’s formula 
(QTcF), machine-read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 


2016N290366_00
CONFIDENTIAL
205822
42
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial.

For purposes of data analysis, QTcF will be used as specified in the RAP.
5.
Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<40 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcF interval 
>450 msec
6.
Participant has poorly controlled COPD, defined as the occurrence of either of the 
following:

Acute worsening of COPD requiring use of antibiotics or systemic 
corticosteroids in the 6 weeks prior to screening visit OR

More than 2 exacerbations of COPD requiring treatment with oral steroids in 
the preceding year or hospitalization for the treatment of COPD within 3 
months of screening or more than twice during the preceding year.
7.
History of an upper or lower respiratory tract infection requiring antibiotics in the 4 
weeks prior to screening
8.
Participant has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the Investigator, compromise the safety of the participant or 
affect the interpretation of the results. 
9.
Unstable or uncontrolled cardiac disease.
10. Participants who have past or current medical conditions or diseases that are not well 
controlled and, which as judged by the Investigator, may affect participant safety or 
influence the outcome of the study.  (Note: Patients with adequately treated and well 
controlled concurrent medical conditions (e.g. hypertension) ARE permitted to be 
entered into the study).
Prior/Concomitant Therapy
11. Participants are not allowed to take oral corticosteroids from 4 weeks prior to 
screening and for the duration of the study.
12. Participants taking medications for any chronic conditions have to be on stable doses 
for 4 weeks prior to screening and until after completion of the treatment period.  
This includes COPD maintenance therapies (e.g. inhaled corticosteroids, long-acting 
beta-agonists, long-acting muscarinic agonists).
13. Didanosine and azathioprine are not allowed.
14. Use of short-acting inhaled bronchodilators is allowed, but participants must be able 
to discontinue their medications several times during the study as described in 
Section 7.7.


2016N290366_00
CONFIDENTIAL
205822
43
15. Use of long-acting bronchodilators is allowed, but participants must be able to 
modify the schedule of their medications twice during the study as defined in 
Section 7.7.
Prior/Concurrent Clinical Study Experience
16. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
17. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
18. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
Diagnostic assessments
19. Impaired renal function (eGFR <30 cc/min, using CKD-EPI equation).
20. Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, and erythema multiforme.
21. Hgb below the lower level of the normal range with one repeat testing allowed or 
known hemoglobinopathies.
22. Presence of Hepatitis B surface antigen (HBsAg) at screening, Positive Hepatitis C 
antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
23. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
24. Positive pre-study drug/alcohol screen
25. Positive human immunodeficiency virus (HIV) antibody test
26. Regular use of known drugs of abuse
Other Exclusions
27. Male partners of women who are pregnant or lactating
28. Regular alcohol consumption within 3 months prior to the study defined as: 

an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits. 
29. Unable to refrain from smoking for 2 h prior to dosing and until all assessments are 
complete for 4 h after dosing and also for 1 h prior to any vital signs and ECG 
assessments.


2016N290366_00
CONFIDENTIAL
205822
44
30. History of sensitivity to any of the study medications, including CCI15106 or 
components thereof and, for cohorts that will undergo BAL, those that may be used in 
association with the BAL procedure or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.
31. For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage 
including hypercapnia >50 mm Hg, abnormal blood coagulation parameters, known 
or suspected intolerance of medications necessary for bronchoscopy, refractory 
hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial 
infarction.
32. Documented lactose allergy/intolerance.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants will be allowed soft drinks without caffeine starting from 2 h after 
dosing, including both AM and PM doses.  Standardized meals will be provided 
while the participant is confined to the clinical research unit, as outlined below.

Participants will report to the clinic fasting (for at least 8 h) for screening visit, Day -
1 of treatment periods and for follow-up visit.

At all mealtimes, food will be served only after completion of protocol specified 
procedures scheduled at or around the same time.

The morning dose of the CCI15106-IP will be given after fasting (for at least 8 h).  
The evening dose of the CCI15106-IP will be given at least 2 h after food.  The 
doses will be approximately 12 h apart.  For the first dose for any participant in the 
study, water should not be allowed for 2 h prior to dosing.  For all other doses, water 
will be allowed freely.

Participants should not eat for 2 h after dose administration for the single dose 
cohorts and after the first dose of the multiple dose cohorts.

Breakfast will not be provided on the mornings of the BAL, however a snack is 
permitted on this day after the end of the procedure, as long as it does not interfere 
with any study related procedures.

All other meals and snacks may be provided as per the clinics schedule.  Should a 
mealtime interfere with a study procedure such as BAL, the investigator in 
consultation with the sponsor, may modify the meal times to ensure safety of the 
participants.  Also, the fasting requirements may be modified or removed at any time 
during the study at the discretion of the sponsor in consultation with the investigator.


2016N290366_00
CONFIDENTIAL
205822
45
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 h 
prior to the start of dosing until the participants leave the clinical unit. 

During each dosing session, participants will abstain from alcohol for 24 h prior to 
the start of dosing until the participants leave the clinical unit. 

For healthy participants, use of tobacco products is not allowed from screening until 
after participants leave the clinical unit.

Participants with COPD who use tobacco products will be instructed that use of 
nicotine-containing products (including nicotine patches) will not be permitted while 
they are in the Clinical Unit.  Participants with COPD will be escorted by staff for 
smoking breaks except during the period for 2 h prior to dosing and until all 
assessments are complete for 4 h after dosing.
6.3.3.
Activity

Participants will abstain from strenuous exercise from screening until follow-up visit.
Participants may participate in light recreational activities during studies (eg, 
watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study may be rescreened
only upon approval of Medical Monitor.  Rescreened participants should be assigned a 
different screening 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.


2016N290366_00
CONFIDENTIAL
205822
46
7.1.
Treatments Administered
Study Treatment 
Name:
CCI15106-IP
Placebo
Dosage formulation:
1 capsule
1 capsule
Unit dose 
strength(s)/Dosage 
level(s):
30 mg of CCI15106
As 30.3 mg of CCI15106: 
polyvinyl alcohol 99:1 w/w 
PRINT 0.9x1 m cylinder
shape crystalline particles
30.3 mg of lactose: polyvinyl 
alcohol 98:2 w/w PRINT 0.9x1 m 
cylinder shape amorphous 
particles
Route of 
Administration 
By inhalation
By inhalation
Dosing instructions:
Each inhalation will follow 
instructions provided with 
the device.  The number of 
inhalations will depend on 
the dose.
The morning dose to be 
taken fasting (at least 8 h).  
For repeat dose cohorts, the 
evening dose to be taken at 
least 2 h after food.
For repeat dose cohort(s) 
with bystander exposure 
monitoring, a 1.5 h window 
is allowed.
Each inhalation will follow 
instructions provided with the 
device.  The number of inhalations 
will depend on the dose.
The morning dose to be taken 
fasting (at least 8 h).  For repeat 
dose cohorts, the evening dose to 
be taken at least 2 h after food.
For repeat dose cohorts with 
bystander exposure monitoring, a 
1.5 h window is allowed.
Packaging and 
Labeling
Study Treatment will be 
provided in a HDPE (high 
density polyethylene) bottle. 
Each bottle contains 2 
capsules and a desiccant 
canister.  Each bottle is 
overwrapped in a foil pouch 
containing a desiccant 
sachet. Each bottle and 
each pouch will be labelled 
as required per country 
requirement.
Study Treatment will be provided 
in a HDPE bottle. Each bottle 
contains 2 capsules and a 
desiccant canister.  Each bottle is 
overwrapped in a foil pouch 
containing a desiccant sachet. 
Each bottle and each pouch will
be labelled as required per 
country requirement.
Device
Monodose RS01
Monodose RS01
Manufacturer
Plastiape S.p.A.
Plastiape S.p.A.


2016N290366_00
CONFIDENTIAL
205822
47
7.1.1.
Medical Devices

The GSK manufactured medical devices (or devices manufactured for GSK by a
third party) provided for use in this study are Monodose RS01.

Instructions for medical device use are provided in the Study Reference Manual 
(SRM).

GSK medical device incidents, including those resulting from malfunctions of the
device, must be detected, documented, and reported by the investigator throughout 
the study (see Section 9.2).
7.2.
Dose Modification

This protocol allows some alteration from the currently outlined dosing schedule.  
The maximum daily dose administered will not exceed 120 mg per day either as a 
single dose or as 60 mg BID.

The decision to proceed to Part 1 Cohort B will be made by the GSK Study Team
comprised at a minimum of the team leader, medical monitor, Global Clinical Safety 
and Pharmacovigilance scientist or physician (Clinical Pharmacokineticist, 
Statistician and Preclinical Safety Assessment as necessary), and the Investigator or 
delegate based on safety and tolerability data obtained in all participants at the prior 
dose levels in Part 1.  The actual doses to be administered may be adjusted based on 
safety, tolerability, and preliminary PK data if appropriate, at previous dose levels; 
these dose adjustments may involve either an increase or a decrease in the planned 
dose.  The highest dose in the study will not exceed 120 mg per day either as a single 
dose or as 60 mg BID.

The decision to proceed to participants with COPD will be made by the GSK Study 
Team comprised at a minimum of the team leader, medical monitor, Global Clinical 
Safety and Pharmacovigilance scientist or physician (Clinical Pharmacokineticist, 
Statistician and Preclinical Safety Assessment as necessary), and the Investigator or 
delegate based on safety and tolerability data obtained after single dosing completes 
in healthy participants in Part 1 Cohort A.  

The actual doses to be administered may be adjusted based on safety, tolerability, 
and preliminary PK data if appropriate, at previous dose levels; these dose 
adjustments may involve either an increase or a decrease in the planned dose.  

The dosing schedule may also be adjusted to expand a dosing cohort to further 
evaluate safety and PK findings at a given dose level, or to add cohorts to evaluate 
additional dose levels.  The study procedures for these additional participant(s) or 
cohort(s) will be the same as that described for other study participants.


2016N290366_00
CONFIDENTIAL
205822
48
7.3.
Method of Treatment Assignment
No treatment assignment will be performed for bystander cohort(s).
For all other cohorts, participants will be centrally randomized using an Interactive Web 
Response System.
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106-
IP or Placebo with 3:1 ratio.  In Cohort B Part 1 and Cohort B Part 2, participants will be 
randomized with 6:1 ratio. 
Study treatment will be dispensed at all times indicated in the SoA (Section 2).
7.4.
Blinding
This will be a double-blind (sponsor unblinded) study.  The GSK study team participating 
in the dose escalation meetings will be blinded to the participant’s treatment assignment 
and will be un-blinded only if necessary to facilitate review of the safety, tolerability and 
PK data as appropriate in real time to inform dose escalation decisions.
However, the study team performing the analyses to support dose escalation decisions 
will be unblinded to allow accurate assessment of the data, including the study 
pharmacokineticists, statisticians, programmers and data managers, who will have access 
to the randomization codes for analysis purposes. If additional contract research 
organizations are involved in data analysis or in statistical analysis and programming, the 
same will apply to their staff as well.
Participants will be randomized to receive study treatment.  Investigators will remain 
blinded to each participant’s assigned study treatment throughout the course of the study.  
In order to maintain this blind, an otherwise uninvolved 3rd party will be responsible for 
the reconstitution and dispensation of all study treatment and will ensure that there are no 
differences in time taken to dispense following randomization.
This 3rd party will instruct the participant to avoid discussing the taste, dosing frequency, 
or packaging of the study treatment with the investigator or with other participants.
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to un-blinded study treatment records at the site(s) to verify that 
randomization/dispensing has been done accurately.
Additional double-blinded, single-blinded or open-label repeat dose cohort(s) may be 
added at a dose not to exceed 120 mg daily.  

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. 

Investigators have direct access to the participant’s individual study treatment. 


2016N290366_00
CONFIDENTIAL
205822
49

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. 

The date and reason for the unblinding must be fully documented.
A participant may continue in the study if that participant’s treatment assignment is 
unblinded, upon discussion with the medical monitor.  
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.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.

Capsules should be kept refrigerated (2-8°C) in their sealed packaging, protected 
from moisture. 

Monodose RS01 devices will be supplied in bulk.  After use, the devices will be 
placed in a plastic bag, and the bag will be labelled with the participant number, day 
of dosing, and date.  Devices will be disposed of at site after reconciliation is verified 
by study monitor.

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).  

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM or equivalent. 

Precaution will be taken to avoid direct contact with the study treatment.  No women 
of child-bearing potential will administer study treatment.  Staff administering the 
study treatment will wear protective gown and gloves.  A Material Safety Data Sheet  
describing occupational hazards and recommended handling precautions will be 
provided to the investigator.  In the case of unintentional occupational exposure 
notify the monitor, Medical Monitor and/or GSK study contact.


2016N290366_00
CONFIDENTIAL
205822
50
Dosing Procedure for Cohorts not Used for Environmental Exposure 
Monitoring

Participants will inhale the dose from the Monodose RS01 device inside a negative 
pressure room or enclosure.

The investigator/designee will remove the capsule from the bottle and load it into the 
Monodose RS01 device one at a time in a safety cabinet.  One device will be used per 
capsule.  The investigator/designee will be trained to load the capsule into the device
and pierce the capsule ready for inhalation (empty capsules will be used for training).

The participant will inhale the dose, and staff will observe participant doing it.  Staff 
will be trained to listen for a rattle that the device makes during successful dosing.  
After dosing, the Monodose RS01 device will be placed in a plastic bag, and the bag 
will be labelled with the participant number, day of dosing, and date.

The participant will be trained to use a “fast and deep” inspiration technique per 
inhalation, to achieve rapidly consecutive maximal inhalations (empty capsules will 
be used for training).  This will ensure optimal and consistent treatment delivery.  For 
participants, the training session will be on either Day -1 or on Day 1, prior to 
administration of the first dose.  Subsequent assessment of Monodose RS01 device
technique, and repeat device training where deemed necessary by the 
investigator/designee, will take place immediately before administration of each dose. 
Dosing Procedure for Cohorts Used for Environmental Exposure 
Monitoring

Participants will inhale the dose from the Monodose RS01 device in a room 
designated for dosing. All investigators/designees will leave the room and observe 
dosing participants and bystanders through a glass in the door.  Only participants 
inhaling the dose and designated bystanders are allowed in the room during inhalation 
of the dose.

The bystander will remove the capsule from the bottle and load it into the Monodose 
RS01 device one at a time.  One device will be used per dose (2 capsules in this 
cohort).  The bystander will be trained to load the capsule into the device and pierce 
the capsule ready for inhalation (empty capsules will be used for training).    

The bystander will pass loaded and charged device to the dosing participant.

The participant will inhale the dose, and staff will observe participant doing it through 
a glass in the door.  The bystander will be trained to listen for a rattle that the device 
makes during successful dosing.  After dosing, the participant will pass the device 
back to the bystander.

The bystander will open the device, remove the capsule and place it on the table 
between the dosing participant and the bystander.  The bystander will then load the 
second capsule into the same device, pierce the capsule and pass the loaded device
back to the dosing participant.

The participant will inhale the second dose, the bystander will listen for a rattle that 
the device makes during successful dosing and staff will observe participant doing it 


2016N290366_00
CONFIDENTIAL
205822
51
through a glass in the door.  After dosing, the participant will pass the device back to 
the bystander.

The bystander will open the device, remove the second capsule, and place the open 
device with both capsules on the table between the dosing participant and the 
bystander. 

The bystander and participant will remain seated around the table for 15 min.  After 
this time, the bystander will place the Monodose RS01 device and both used capsules
into the plastic bag labelled with the participant number, day of dosing, and date.  
After that is done, bystander and participant can leave the room.  The bystander will 
need to wash their hands prior to leaving the room.

The participant will be trained to use a “fast and deep” inspiration technique per 
inhalation, to achieve rapidly consecutive maximal inhalations (empty capsules will 
be used for training).  This will ensure optimal and consistent treatment delivery.  For 
participants and bystanders, the training session will be on either Day -1 or on Day 1, 
prior to administration of the first dose.  Subsequent assessment of Monodose RS01
device technique, and repeat device training where deemed necessary by the 
investigator/designee, will take place immediately before administration of each dose. 
7.6.
Treatment Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff. 
The participants 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.  
If failure of the capsule actuation is suspected (i.e. due to failure to pierce the capsule 
during device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose.  If dosing failure is suspected 
for any other reason, the participant may have to be excluded after consultation with the 
Medical Monitor.
The Monodose RS01 devices will be under the supervision of the study organisers at all 
times during the clinical trial. 


2016N290366_00
CONFIDENTIAL
205822
52
7.7.
Concomitant Therapy
7.7.1.
Permitted Medications and Non-Drug Therapies
Paracetamol or Acetaminophen, at doses of ≤2 grams/day is permitted.
Medications associated with the BAL procedure are permitted, but these medications are 
to be disclosed to the Sponsor prior to dosing any participants.
Participants with COPD taking medications for any chronic conditions have to be on 
stable doses for 4 weeks prior to screening and until after completion of the treatment 
period.
Salbutamol is administered 15 to 30 min prior to spirometry at screening for diagnostic 
purposes.  Short-acting bronchodilators should not be used from 6 h prior to each 
morning dose administration until 4 h after that dose.  If they become medically 
necessary during that time, short-acting bronchodilators may be administered as needed 
by the clinical staff only and their use must be documented.  
For participants with COPD, use of long-acting bronchodilators is allowed, but their use
must be modified twice during the study as follows:  at screening and on Day 1, they 
must not be taken for at least 2 h prior to spirometry.
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the Medical Monitor.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Participants are not allowed to take oral corticosteroids from 4 weeks prior to screening 
and for the duration of the study.
For participants with COPD, self administration of short-acting inhaled bronchodilators is 
not allowed at screening, from 4 h prior to spirometry until spirometry is completed.  Self 
administration of short-acting inhaled bronchodilators is not allowed during treatment 
period from 6 h prior to each morning dose administration until 4 h after that dose.  
Didanosine and azathioprine are not allowed.
Except as permitted in Section 7.7.1, participants must abstain from taking prescription or 
non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 
days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication until completion of the follow-up visit, 
unless in the opinion of the Investigator and sponsor the medication will not interfere 
with the study.


2016N290366_00
CONFIDENTIAL
205822
53
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because most of the participants are healthy and 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 
specific post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
If participant is withdrawn from study treatment, this constitutes withdrawal from study.  
Participants will have to be followed up for safety reasons as deemed necessary by the 
Investigator and should be encouraged to return for a follow-up visit as specified in the 
SoA (Section 2).  If this is not possible, procedures specified for the follow-up visit can 
be performed at the last visit that the participant attends.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined above
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


2016N290366_00
CONFIDENTIAL
205822
54

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation  is in the 
best interest of the participant.
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 6.
8.1.2.
QTc Stopping Criteria
A participant who meets either bulleted criterion below will be withdrawn from the 
study:  

QTc, QTcF >500 msec,

Change from baseline: QTc >60 msec
For participants with COPD with underlying bundle branch block, follow the 
discontinuation criteria listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
>500 msec
450 – 480 msec
≥530 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
See the SoA (Section 2) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed.
8.1.3.
Other Stopping Criteria
Data will be reviewed by the investigator and sponsor for consideration of potential study 
pausing or stopping if:


2016N290366_00
CONFIDENTIAL
205822
55
Two (2) or more subjects, within a dose-level, receiving study treatment experience grade 
3 respiratory adverse event that are deemed possibly or probably related to study drug by 
the investigator.
Two (2) or more subjects, within a dose-level, receiving study treatment experience a 
grade 3 hematologic adverse event that are deemed possibly or probably related to study 
drug by the investigator.
Two (2) or more subjects, within a dose-level, receiving study treatment experience 
severe hypersensitivity related adverse event that are deemed possibly or probably related 
to study drug by the investigator.
Two (2) or more subjects, within a dose-level, receiving study treatment experience a 
grade 3 vital signs (heart rate and/ or blood pressure) adverse event that are deemed 
possibly or probably related to study drug by the investigator.
One (1) or more subjects receiving study treatment experience anaphylaxis that is deemed 
possibly or probably related to study drug by the investigator.
In case of dose limiting toxicities at a given dose level, dose escalation will be stopped 
and a lower or intermediate dose may be introduced.
8.1.4.
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 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 (Section 2) for data to be collected at follow-up and for any further 
evaluations that need to be completed.

Participants will have to be followed up for safety reasons as deemed necessary by 
the Investigator and should be encouraged to return for a follow-up visit as specified 
in the SoA (Section 2).  If this is not possible, procedures specified for the follow-up 
visit can be performed at the last visit that the participant attends.


2016N290366_00
CONFIDENTIAL
205822
56
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 (Section 2).

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA
(Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA (Section 2).

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

The following time window tolerances apply to all protocol assessments:


2016N290366_00
CONFIDENTIAL
205822
57
Predose 
- 60 to 0 min (- 60 to -15 min for spirometry)
0h - 4h post
- 5 / + 10 min
5h – 24h post
- 10 / + 10 min
9.1.
Efficacy Assessments
There are no efficacy assessments in this study.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).  However, any SAEs assessed as related 
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study.

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 case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately and 
no later than in 24 h, as indicated in Appendix 4. The investigator will submit any 
updated SAE data to the sponsor within 24 h of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.


2016N290366_00
CONFIDENTIAL
205822
58
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information eg, summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular  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 Cardiovascular CRFs are presented as queries in response to reporting of certain 
Cardiovascular MedDRA terms. The Cardiovascular information should be recorded in 
the specific cardiovascular section of the CRF within one week of receipt of a 
Cardiovascular 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.


2016N290366_00
CONFIDENTIAL
205822
59
9.2.6.
Pregnancy

Female participants of child bearing potential are excluded from this study

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until 7 months after the last dose of study 
treatment.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.7.
Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for inhalation. In order to fulfill 
regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 7.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2.1, Section 9.2.2, Section 9.2.3, Section 9.2.4 and Appendix 4 of 
the protocol. 
9.2.7.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented, and reported during all periods of the study in which the 
medical device is used. 

If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the 
sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 7.
9.2.7.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 9.2.1, Section 9.2.2, Section 9.2.3, and 
Section 9.2.4). This applies to all participants, including those who discontinue study 
treatment or the study.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.


2016N290366_00
CONFIDENTIAL
205822
60
9.2.7.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Medical device incidents will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

The Medical Device Incident Report Form will be sent to the sponsor by facsimile 
transmission. If facsimile transmission is unavailable, then notification by telephone 
is acceptable for incidents, with a copy of the "Medical Device Incident Report 
Form" sent by overnight mail.

The same individual will be the contact for the receipt of medical device reports and 
SAE.
9.2.7.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.3.
Treatment of Overdose
For this study, any dose of CCI15106-IP greater than the dose specified for the treatment 
period within a 24 h time period [4 h] will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
CCI15106 can no longer be detected systemically (at least 302 days).
3.
Obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).


2016N290366_00
CONFIDENTIAL
205822
61
9.4.1.
Screening Assessments
Cardiovascular medical history/risk factors 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.  
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
9.4.2.
Physical Examinations

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems, and skin. 
Height and weight will also be measured and recorded. Oral exam will be 
performed.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).  Oral exam will also 
be performed.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.3.
Vital Signs

Vital signs will be measured in semi-supine position and will include oral or 
tympanic temperature, pulse rate, respiratory rate, and systolic and diastolic blood 
pressure. The same method of temperature assessment should be used throughout 
the study.

For BAL, vital signs will also include oxygen saturation and will be evaluated and 
recorded before, every 5 minutes during the procedure, at the end of, and between 30 
and 60 minutes after the bronchoscopy. 

Blood pressure and pulse measurements will be assessed 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).

Three readings of blood pressure and pulse rate will be taken where indicated as 
triplicate in SoA (Section 2) and all three readings will be recorded.


2016N290366_00
CONFIDENTIAL
205822
62
9.4.4.
Electrocardiograms

Triplicate OR single 12-lead ECG will be obtained in semi-supine position after 5 
minutes rest as outlined in the SoA (Section 2) 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.  

At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes.

Continuous cardiac telemetry will be performed where indicated in SoA (Section 2). 
Full disclosures will be reviewed in detail and the review maintained as part of the 
participant’s source documents.
9.4.5.
Spirometry

Spirometry (FEV1 and FVC) will be performed at time points specified in the SoA
(Section 2).  Further tests should be performed, at the discretion of the investigator, if 
the participant has symptoms that could suggest bronchospasm.

Spirometry manoeuvres will be conducted according to ATS/ERS 2005 spirometry 
standards [Miller, 2005]. The greatest FEV1 and the greatest FVC from 3 technically 
acceptable and reproducible manoeuvres will be recorded. 

For participants with COPD, at screening, 400 g salbutamol will be administered 
15-30 minutes prior to performing spirometry.  FEV1 and FVC percent predicted 
values will be derived using the Global Lung Function Initiative reference values 
[Quanjer, 2012].
9.4.6.
Capillary pCO2
The pCO2 levels will be measured at the times indicated in SoA (Section 2).  The 
participant’s hand will be heated in warm water (42 degrees) for about 10 minutes and a 
capillary blood sample will be collected by skin puncture using a lancet or automated 
incision device.
9.4.7.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency. 

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.


2016N290366_00
CONFIDENTIAL
205822
63

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 302 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).
9.4.8.
Environmental and Bystander Exposure Evaluation
Exposure monitoring will be conducted in accordance with the principles outlined in 
prEN 689:2016, the draft European standard for workplace exposure assessment to 
airborne contaminants [prEN 689:2016].
9.4.8.1.
Air Monitoring
During and after the first daily dose on Days 1, 7 and 14 in Cohort B Part 1, static air 
samples will be collected on filters within air pumps positioned in two locations in the 
room.  The air disturbance caused by the pumps is negligible and would not be expected 
to alter the normal air flow patterns in the room.  Marks may be placed on the floor to 
indicate position of the participant and positions of pumps to ensure consistency 
throughout the study.  Samples will be run over 20 and 60 min following dosing in each 
location.  An additional set of samples over 60 min will be taken before the start of 
dosing on Day 1 to provide a background benchmark for reference.
On days when static air sampling is performed, the dosing sessions will have to be 
separated by the time necessary to collect the 60 min air sample.
Sampling devices (Institute of Occupational Medicine [IOM] sampling heads connected 
to sampling pumps) shall be used to measure CCI15106 concentration.  The IOM filter 
cassette assembly will be prepared using an immersion-extraction procedure to avoid any 
errors through wall deposition.  Whenever possible, the Hygienist will observe the room 
through a glass in the door for the duration of sampling to make observations and note 
relevant contextual information to assist in the interpretation of the exposure 
measurements.
Air sample analysis will be performed by the Bureau Veritas laboratory (Bureau Veritas 
North America Inc, 95 Oakwood Road, Lake Zurich, IL, 60047).  For air sampling, field 
blanks (filters which have been handled during the survey but not had air pulled through 
them) will be submitted with samples to check for accidental contamination during 
sample handling and storage.  An average of one blank for every ten field samples will be 
sent for analysis.


2016N290366_00
CONFIDENTIAL
205822
64
9.4.8.2.
Bystander Monitoring
Please refer to Figure 1 for the illustration of the design.  Each dosing participant will be 
assigned a designated bystander for the duration of dosing.  Two participants will dose at 
the same time in sitting position.  The designated bystander will be seated facing their 
dosing participant within approximately 1 m of him/her. The first dosing participant will 
inhale the dose (both capsules), and then the second dosing participant will inhale the 
dose (both capsules).  Please refer to Section 7.5 for detailed instructions on dosing.  
Each participant and their bystander will stay seated for the next 15 min, after which they 
will leave the dosing room.  The staff will exit the room prior to bystander loading the 
capsule into the device (see Section 7.5) and remain outside the room for at least 15 min 
after dosing observing through a glass door.
Figure 1
Bystander and participant design illustration
The next two bystanders will be positioned near the next 2 dosing participants, and so on 
until all dosing is completed.  This procedure will be followed for all doses in Cohort B
Part 1, with the same bystanders positioned next to the same inhaling participant.  After 
the first daily dose on days 1, 7 and 14, blood will be collected from bystanders 15 min 
after dosing (at ~tmax for CCI15106).  Additionally, personal exposure air samples will 
be collected on filters placed on each bystander after the first daily dose on days 1, 7 and 
14. The filters will be worn during dosing and for 15-minute period after dosing.  Static 
air monitoring will be performed at the same time during and after the first daily dose on 
days 1, 7 and 14.  During these dosing sessions, each set of two dosing participants will 
be separated by the time necessary to collect the 60 min air sample.
The filters used for personal exposure (IOM sampling heads connected to sampling 
pumps) shall be used to measure CCI15106 concentration in the person’s breathing zone.  
The IOM filter cassette assembly will be prepared using an immersion-extraction 
procedure to avoid any errors through wall deposition.  Whenever possible, the Hygienist 
will observe the room through a glass in the door for the duration of sampling to make 


2016N290366_00
CONFIDENTIAL
205822
65
observations and note relevant contextual information to assist in the interpretation of the 
exposure measurements.
See Section 9.5 for PK assessments of bystanders.
9.5.
Pharmacokinetics
9.5.1.
Blood Sample Collection
Blood samples for PK analysis of CCI15106 in plasma will be collected at the time points 
indicated in SoA (Section 2).  One 3 mL blood sample will be collected at each time 
point and the actual date and time of each sample collection will be recorded.  The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the SRM OR equivalent. 
9.5.2.
BAL Sample Collection
BAL samples for ELF concentration analysis of CCI15106, urea, and cell counts will be 
collected at the time points indicated in SoA (Section 2).  The actual date and time of 
each BAL sample collection will be recorded.  
Details of BAL sample collection, processing, storage, and shipping procedures are 
provided in the SRM OR equivalent.
Due to the analysis methodology, any cells present in the ELF will be disrupted and their 
content released and analyzed together with the supernatant. 
9.5.3.
Urea Blood Sample
A 2 mL blood sample will be collected into Lithium Heparin tubes as soon as practically 
possible before the BAL samples.  
Processing for plasma, storage and shipping procedures will be provided in the SRM or 
equivalent.
9.5.4.
Sample Analysis
BAL and plasma analysis will be performed under the control of PTS-DMPK, GSK, the 
details of which will be included in the SRM OR equivalent. Concentrations of 
CCI15106 will be determined in plasma and BAL samples using the currently approved 
bioanalytical methodology. Plasma and BAL urea concentrations will be determined by 
Clinical Pathology, Safety Assessment, GSK.  Raw data will be stored in the Good 
Laboratory Practices archives, GSK.
For bystander exposure, a plasma concentration of less than 0.5 ng/mL (the Limit Of 
Quantification of the method) represents an acceptable exposure since this is 29-fold 
lower than the highest plasma concentration measured at the no effect dose level for 
teratogenicity in the most sensitive species (rat [Rebetol SPC, 2009]).


2016N290366_00
CONFIDENTIAL
205822
66
Once the plasma and BAL samples have been analyzed for CCI15106, any remaining 
plasma or BAL may be used for other compound-related metabolites analyses, 
microbiome analysis, or other exploratory analyses that inform the effect of the drug on 
the body or the disease, the results of which will be reported under a separate protocol.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
Sample size is based on feasibility and though no formal power calculations are 
performed, the sample size is deemed adequate to provide a preliminary assessment of 
safety prior to progression to the next study. 
Part 1
In Part 1, the study plans to enrol healthy participants in 3 cohorts.  In Cohort A, there 
will be 6 participants on active and 2 on placebo, in cohort B, there will be 12 on active 
and 2 on placebo.  In cohort C, there will be 14 subjects who will participate as 
bystanders and they will be associated with the dosing subjects in Cohort B on a one to 
one basis for the entire duration of dosing.  All subjects in Cohort B will also undergo 
BAL.   
Part 2:
In Part 2, 22 participants with COPD are planned to be enrolled.  Cohort A will have 
6 participants on active dose and 2 on placebo and Cohort B will have 12 participants on 
active and 2 on placebo.  Fourteen participants (12 active and 2 placebo) enrolled in 
Cohort B Part 2 will also undergo BAL.
Although the sample size is not based on statistical criteria, general probabilities can be 
determined on the likelihood of seeing adverse events. For example, in Parts 1 and 2, in 


2016N290366_00
CONFIDENTIAL
205822
67
treatment groups where 6 patients will receive the active drug, if the true adverse 
outcome rate is 5%, the chance of seeing at least one adverse outcome at a given dose is 
26%. Similarly, if the true adverse outcome rate is 20%, the chance of seeing at least one 
adverse outcome at a given dose is 73%. For the treatment groups with 12 subjects 
receiving the active treatment, if the true adverse outcome rate is 5%, the chance of 
seeing at least one adverse outcome at a given dose is 46%. Similarly, if the true adverse 
outcome rate is 20%, the chance of seeing at least one adverse outcome at a given dose is 
93%.  This level of predictability is deemed adequate within this Phase 1 setting prior to 
commencement of the next study.
10.1.1.
Sample Size Sensitivity
As sample size is based on feasibility, no sample size sensitivity was performed.
10.1.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Screened

Comprise of all participants who consent to 
participate in the clinical study.

Defined separately for Part 1 and Part 2.
Safety

Comprise of all participants who receive at least 
one dose of study treatment.

This population will be based on the treatment 
the participant actually received.

Defined separately for Part 1 (excluding 
Cohort C) and Part 2.

Safety

Study Population
Systemic 
Pharmacokinetic
Concentration

Participants who receive at least one dose of 
study treatment and who undergo plasma PK 
sampling and have at least one postdose
concentration result.

PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be 
excluded.

Defined separately for Part 1 (excluding 
Cohort C) and Part 2.

PK
Lung ELF
Concentration 
Population

Participants who receive at least one dose of 
study treatment and who undergo BAL sampling
and have postdose lung ELF CCI15106 and 
urea concentration result.

BAL


2016N290366_00
CONFIDENTIAL
205822
68
Population
Definition / Criteria
Analyses Evaluated

Lung ELF samples that may be affected by 
protocol deviations, will be reviewed by the 
study team to determine whether or not the 
sample will be excluded.

Defined separately for Part 1 and Part 2
Bystander Safety 
Population (Part 
1, Cohort C)

Participants who are present at least once in the 
room with the participant receiving the dose.

Safety

Study Population
Bystander PK 
Population (Part 
1, Cohort C)

Participants who are present at least once in the 
room with the participant receiving the dose, 
undergo plasma PK sampling and have post-
dose concentration result.

PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be 
excluded.

PK
10.3.
Statistical Analyses
The analysis and reporting of Part 1 may be conducted prior to the completion of Part 2.
For all parts, the analysis and reporting will be performed after the datasets are authorized 
and released for reporting.
Data will be listed and summarized according to GSK reporting standards, where 
applicable.  Listings will be sorted by cohort, participant and time; summaries will be 
presented by cohort, treatment, and time.    
Descriptive summaries will include n, mean, standard deviation (SD), median, minimum, 
and maximum, geometric mean with associated 95% confidence interval (CI), and the 
between-participant coefficient of variation (%CVb) for continuous variables, n and 
percent will be used as summary statistics for categorical variables.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise.  If there are multiple assessments collected at the 
same scheduled time, the average of these assessments will be used.  For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.1 or higher of the SAS system will be used to analyze the data as well as to 
generate tables, figures, and listings.
Complete details will be documented in the RAP.


2016N290366_00
CONFIDENTIAL
205822
69
10.3.1.
Safety Analyses
All safety analyses will be based on the Safety Population.
Endpoint
Statistical Analysis Methods
Adverse events (AEs)
The proportion of participants reporting AEs will be tabulated by 
treatment and by cohort.  AEs will also be tabulated by severity and 
relationship.
Clinical laboratory
Laboratory results will be included in the reporting of this study for 
hematology, clinical chemistry, and urinalysis. Based upon laboratory 
normal ranges, the laboratory test results will be categorized according 
to the normal range as low (below the lower limit), normal (within the 
normal range) and high (above the upper limit). Summary statistics for 
change from baseline will also be tabulated.
Electrocardiogram
(ECG)
The ECG parameters of PR, QRS, QT, QTc, QTcF and HR (bpm) will be 
reported. Overall assessment of ECG (Investigator’s judgment) will be 
recorded as Normal, Abnormal - Not Clinically Significant and Abnormal -
Clinically Significant. Summary statistics for change from baseline will 
also be tabulated.
Telemetry
Overall assessment of Telemetry (Investigator’s judgment) will be 
recorded as Normal, Abnormal - Not Clinically Significant and Abnormal -
Clinically Significant.
Spirometry
% Predicted forced expiratory volume in 1 second (FEV1) and forced 
vital capacity (FVC) values will be tabulated for each timepoint.
Vital signs 
assessments
The following Vital Signs measurements will be tabulated: supine systolic 
and diastolic blood pressure, pulse rate, respiratory rate and 
temperature. Summary statistics for change from baseline will also be 
tabulated.
Monodose RS01
Device safety
Safety incidents reported from use of medical device will be tabulated.
10.3.2.
Pharmacokinetic Analyses
PK analysis will be the responsibility of the Clinical Pharmacokinetics Modeling & 
Simulation Department (CPMS) within GSK.  Plasma CCI15106 concentration-time data 
will be analyzed by non-compartmental methods with WinNonlin 5.3 and above.  
Calculations will be based on the actual sampling times recorded during the study.  From 
the plasma concentration-time data, the following PK parameters may be determined, as 
data permit:  maximum observed plasma concentration (Cmax), time to Cmax (tmax), 
area under the plasma concentration-time curve [AUC(0-last) and AUC(0-∞) where data 


2016N290366_00
CONFIDENTIAL
205822
70
permit for single dose, and AUC(0-τ) for repeat dose], elimination half-life (t1/2), and 
clearance (CL/F) as data permit.
AUC(0-24), or AUC(0-48), or AUC(0-τ) and Cmax following single and repeat doses 
may be used for assessment of dose proportionality.
Trough concentration (Cτ) samples collected on the specified days may be used to assess 
attainment of steady state.  To estimate the extent of accumulation after repeat dosing, the 
observed accumulation ratio (Ro) may be determined.  
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from Cohorts B of Part 1 and Part 2.
PK data will be presented in graphical and/or tabular form and will be summarized 
descriptively.  A population PK model (POP PK) may be developed with all available 
data as appropriate and may be reported separately.  Further details of the analysis plan 
and methods will be detailed within the RAP and data analysis plan OR equivalent. 
Individual lung ELF concentration data will be summarised, listed and displayed 
graphically on both linear and semi-logarithmic scales for the Cohorts with available ELF
data.  Where data permit, the individual lung ELF concentration data may be plotted 
against the plasma concentration measured prior to BAL sampling.
All pharmacokinetic data will be stored in the Archives, GSK Pharmaceuticals, R&D.
PK exploratory analyses will be described in the reporting and analysis plan. The 
population PK analysis if conducted, will be presented separately from the main clinical 
study report.
10.3.3.
Bystander and Environmental exposure Analyses
The plasma concentration data from bystanders will be summarised descriptively and 
listed. The amount of CCI15106 obtained from filters will be tabulated and reported.  
Additional analyses, where deemed necessary, will be described in the RAP.
If data permit, the plasma concentration measured from bystanders may be plotted 
against the data collected from the air filters.
10.3.4.
Interim Analyses
No formal interim analyses are planned for this study.   Safety and tolerability will be 
evaluated as described in Section 5.1.  Systemic and, where available, lung PK may also 
be evaluated.


2016N290366_00
CONFIDENTIAL
205822
71
11.
REFERENCES
Copegus (ribavirin) Tablets. United States Prescribing Information. Genentech. August, 
2015. Available at: http://www.gene.com/download/pdf/copegus_prescribing.pdf. 
Accessed October 15, 2015.
Copegus 200 mg Film-coated Tablets. Summary of Product Characteristics. January, 
2015. Available at: http://www.medicines.org.uk/emc/medicine/11755/spc. Accessed 
October 15, 2015.
De Franceschi L, Fattovich G, Turini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic 
anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection:
role of membrane oxidative damage.  Hepatology. 2000;31:997-1004.
Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British 
Thoracic Society guideline for diagnostic flexible bronchoscopy in adults. Thorax. 2013;
68:i1–i44.
GlaxoSmithKline Document Number 2015N242219_00.  Assessment of the 
pharmacokinetics of CCI15106 (Ribavirin) following single inhaled administration of a 
range of Liquidia PRINT formulations in Wistar Han Rats (GSK Study Number N20691-
39).  October 2015.
GlaxoSmithKline Document Number 2015N249287_00.  Ribavirin Inhibits Replication 
of Human Rhinovirus, Respiratory Syncytial Virus and Influenza Virus in Air-Liquid 
Interface Cell Cultures. October 2015.
GlaxoSmithKline Document Number 2015N250735_00.  Investigator's Brochure for 
inhaled CCI15106 and inhalation device.  October 2015.
GlaxoSmithKline Document Number 2017N312240_00. CCI15106 (cylinder particle): 
Toxicity study by inhalation administration to Wistar Han rats for 4 weeks. 2017.
GlaxoSmithKline Document Number 2017N312247_00. CCI15106 (cylinder particle): 
Toxicity study by inhalation administration to beagle dogs for 4 weeks. 2017.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2
Kaufmann W, Baderb R, Ernst H, Harada T, Hardisty J, Kittel B, et al. 1st International 
ESTP Expert Workshop: ‘‘Larynx squamous metaplasia’’. A re-consideration of 
morphology and diagnostic approaches in rodent studies and its relevance for human risk 
assessment.  Experimental and Toxicologic Pathology. 2009;61:591-603.
Kurai D, Saraya T, Ishii H, Takizawa H. Virus-induced exacerbations in asthma and
COPD. Frontiers in Microbiology. 2013;4:1-12.
Lewis DJ. Morphological assessment of pathological changes within the rat larynx. 
Toxicologic Pathology. 1991;19:352-357. 


2016N290366_00
CONFIDENTIAL
205822
72
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.
Standardisation of spirometry.  Eur Respir J. 2005; 26:319-338.
Morgenstern B, Michaelis M, Baer P, Doerr H, Cinatl J. Ribavirin and interferon-b
synergistically inhibit SARS-associated coronavirus replication in animal and human
cell lines. Biochem Biophys Res Comm. 2005; 326:905-908.
prEN 689:2016 (E), Workplace exposure; measurement of exposure by inhalation to 
chemical agents – strategy for testing compliance with occupational exposure limit 
values, Comité Européen de Normalisation, Brussels, Belgium, draft, 18 March 2016.
Preston SL, Drusano GL, Glue P, Nash J, Gupta SK, and McNamara P.  
Pharmacokinetics and Absolute Bioavailability of Ribavirin in Healthy Volunteers as 
Determined by Stable-Isotope Methodology.  Antimicrobial agents and chemotherapy. 
1999, 43:2451–2456.
Quanjer PH, Stanojevic S, Cole T, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations.  Eur Respir J. 2012; 40:1324–1343.
Rebetol (ribavirin USP) capsules for oral use; (ribavirin USP) oral solution.  United 
States Prescribing Information.  Merck & Co., INC.  May 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020903s053,021546s009lbl.p
df
Rebetol 200 mg Hard Capsules.  Summary of Product Characteristics. Merck Sharp & 
Dohme Limited, 07 May 2009.  Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000246/WC500048210.pdf
Stryjek-Kaminska D, Ochsendorf F, Roder C, Wolter M, Zeuzem S Photoallergic Skin 
Reaction to Ribavirin. Am J Gastroenterol 1999; 94:1686-1688. 
Thomas E, Ghany MG, Liang TJ, The application and mechanism of action of 
ribbavirin in therapy of hepatitis C. Antiviral Chemistry and Chemotherapy, 2012; 
23:1-12.
Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global
Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive
Pulmonary Disease. Am J of Resp and Critical Care Medicine. 2013;187:347-365.
Virazole (Ribavirin for Inhalation Solution). United States Prescribing Information. 
Valeant Pharmaceuticals North America LLC, April 2013.
Virazole.  Summary of Product Characteristics, December 2014.  Available at: 
https://www.medicines.org.uk/emc/medicine/866#CLINICAL_PRECAUTIONS


2016N290366_00
CONFIDENTIAL
205822
73
Weber A, Computational Modeling Summary to Support Candidate Selection of Inhaled 
PRINT Cyrstallin Ribavirn (CCI15106)-PVOH (99-1 w-w) 0.9x1-um Cylindrical 
Particles.  PIER accession 6301434, 2017.


2016N290366_00
CONFIDENTIAL
205822
74
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
%CV
Coefficient of variation
%CVb
Between-subject coefficient of variation
g
Microgram
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-)
AUC from time zero to end of dosing interval
AUC(0-)
AUC from time zero to infinity
AUC(0-24)
AUC from time zero to 24 hours
AUC(0-t)
AUC from time zero to the time of last quantifiable concentration
BAL
Bronchoalveolar lavage
BMI
Body mass index
CCI15106-CFI
CCI15106 capsules for inhalation
CI
Confidence interval
CL/F
clearance
Cmax
Concentration at maximum
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPMS
Clinical Pharmacology Modeling and Simulation
CRF
Case report form
ECG
Electrocardiogram
ELF
Epithelial lining fluid
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FTIH
First time in human
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B surface antigen
Hep B
Hepatitis B
Hep C
Hepatitis C
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Heart rate
HRT
Hormone replacement therapy
HRV
Human rhinovirus


2016N290366_00
CONFIDENTIAL
205822
75
IB
Investigator brochure
ICH
International conference on harmonization
IEC
Independent Ethics Committee
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
Kg
Kilogram
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
mg
milligram
min
Minute
mL
Milliliter
mm Hg
Millimeter of mercury
NOAEL
No observed adverse effect level
PK
Pharmacokinetics
POP PK
Population PK
PRINT
Particle Replication In Non-wetting Templates
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RSV
respiratory syncytial virus
RTP
Ribavirin triphosphate
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SRM
Study Reference Manual
t1/2
Elimination half-life
Tmax
Time of maximum concentration
ULN
Upper limit of normal
USP
United States Pharmacopeia
USPI
United States Prescribing Information
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
WinNonlin


2016N290366_00
CONFIDENTIAL
205822
76
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 2 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 2
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red blood cells (RBC)
Indices:
Mean corpuscular 
hemoglobin (MCV)
Mean corpuscular 
volume (MCH)
%Reticulocytes
White blood cell (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
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 


2016N290366_00
CONFIDENTIAL
205822
77
Laboratory 
Assessments
Parameters
C virus antibody)

Serum pregnancy test in women

Coagulation parameters in the BAL cohorts
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).


2016N290366_00
CONFIDENTIAL
205822
78
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 International conference on harmonization (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. 


2016N290366_00
CONFIDENTIAL
205822
79

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


2016N290366_00
CONFIDENTIAL
205822
80
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 subjects, 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.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 


2016N290366_00
CONFIDENTIAL
205822
81
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 Agreement to 
definition of source data.
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


2016N290366_00
CONFIDENTIAL
205822
82
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


2016N290366_00
CONFIDENTIAL
205822
83
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.
Guidance for Grading Adverse Events
Taken from the Food and Drug Administration (FDA) Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.
The purpose of this appendix is to provide guidance and it is to be used in conjunction 
with the investigator’s judgment.
Guidance for Grading Vital Signs Adverse Events
Vital Signs *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever (°C) **
(°F) *
38.0 – 38.4
100.4 – 101.1
38.5 – 38.9
101.2 – 102.0
39.0 – 40
102.1 – 104
> 40
> 104
Tachycardia - beats 
per minute
101 – 115
116 – 130
> 130
ER visit or 
hospitalization for 
arrhythmia
Bradycardia - beats 
per minute***
50 – 54
45 – 49
< 45
ER visit or 
hospitalization for 
arrhythmia
Hypertension 
(systolic) - mm Hg
141 – 150
151 – 155
> 155
ER visit or 
hospitalization for 
malignant 
hypertension
Hypertension 
(diastolic) - mm Hg
91 – 95
96 – 100
> 100
ER visit or 
hospitalization for 
malignant 
hypertension
Hypotension 
(systolic) – mm Hg
85 – 89
80 – 84
< 80
ER visit or 
hospitalization for 
hypotensive shock
Respiratory Rate –
breaths per minute
17 – 20
21 – 25
> 25
Intubation
* Participant should be at rest for all vital sign measurements
** Oral temperature; no recent hot or cold beverages or smoking
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when 
characterizing
Allergic Reactions
Grade 1 allergic reaction (Pruritis without rash):
Participants with Grade 1 allergic reaction should be evaluated by the investigator
immediately. The study drug should be permanently discontinued if the following signs
or symptoms are noted at any time:
• Temperature >38.5°C


2016N290366_00
CONFIDENTIAL
205822
84
• Eosinophilia
• Respiratory involvement including brochospasm, laryngospasm, or angioedema
• Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 allergic 
reaction may continue the study drug at the discretion of the investigator. The participant
should be advised to contact the investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken. If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed. The 
participant should remain on the study to be followed for safety and PK.
Grade 2 allergic reaction (Localized urticaria):
Participants with Grade 2 allergic reaction should be evaluated by the investigator
immediately. The study drug should be permanently discontinued if the following signs
or symptoms are noted at any time:
• Temperature >38.5°C
• Eosinophilia
• Respiratory involvement including brochospasm, laryngospasm, or angioedema
• Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 allergic 
reaction may continue the study drug at the discretion of the investigator. The participant
should be advised to contact the investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken. If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed. The 
participant should remain on the study to be followed for safety and PK.
Grade 3 allergic reaction (Generalized urticaria or angioedema):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial. Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.


2016N290366_00
CONFIDENTIAL
205822
85
Revised ACTG Toxicity
Grade
Definition
Investigator action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue therapy
Grade 4
Anaphylaxis
Discontinue therapy
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect


2016N290366_00
CONFIDENTIAL
205822
86
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.
Definition of Cardiovascular Events (CV) 
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 


2016N290366_00
CONFIDENTIAL
205822
87
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
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 


2016N290366_00
CONFIDENTIAL
205822
88
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 

New or updated information will be recorded in the originally completed 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 Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor and 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 SRM.


2016N290366_00
CONFIDENTIAL
205822
89
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 3 when having penile-vaginal 
intercourse with a woman of childbearing potential 


2016N290366_00
CONFIDENTIAL
205822
90

Men with a pregnant or breastfeeding partner are not eligible to participate.

In addition male participants must refrain from donating sperm for duration of 
study and for 7 months after study completion or from last dose.
Table 3
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
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. 
Female participants
Female participants of childbearing potential are not eligible to participate. 
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. 


2016N290366_00
CONFIDENTIAL
205822
91

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who can become pregnant are not eligible to participate


2016N290366_00
CONFIDENTIAL
205822
92
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology. 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 h

Record the liver event data, and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline (see 
MONITORING below)

Do not restart or rechallenge participant with 
study treatment
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Blood sample for pharmacokinetic 
(PK) analysis, obtained within 48 h of 
last dose4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant 
medications on the concomitant 
medications report formincluding 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 


2016N290366_00
CONFIDENTIAL
205822
93
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin)  and perform liver 
event follow up assessments within  24-72 hrs 

Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James,2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease.  Collect Liver 
Imaging and/or Liver Biopsy data.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally,if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick,indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excludingstudies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value 
stated will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
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.


2016N290366_00
CONFIDENTIAL
205822
94
12.7.
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK
medical devices provided for use in the study (see Section 7.1 for the list of GSK medical 
devices).
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects


2016N290366_00
CONFIDENTIAL
205822
95
Examples of incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident. 
This includes any amendment to the device design to prevent recurrence.


2016N290366_01
CONFIDENTIAL
GlaxoSmithKline group of companies
205822
1
TITLE PAGE
Protocol Title: A double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study to investigate the safety, tolerability, and 
pharmacokinetics of CCI15106 inhalation powder in healthy participants and participants 
with moderate chronic obstructive pulmonary disease (COPD) including evaluation of 
environmental and healthy by-stander exposure levels during dosing.
Protocol Number: 205822 /01
Short Title: Study of safety and drug levels of CCI15106 inhalation powder in healthy 
adults and adults with moderate chronic obstructive pulmonary disease.  Study of 
CCI15106 levels in people standing near the person inhaling the drug.
Compound Number:
CCI15106
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT  2017-001070-42
Approval Date: 31-MAY-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD
PPD
PPD


2016N290366_01
CONFIDENTIAL
205822
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
31-May-2017
Original Protocol
20-Apr-2017
Amendment 01 31-May-2017
Overall Rationale for the Amendment: Changes requested after regulatory reviews
Section # 
and Name
Description of Change
Brief Rationale
8.1.3 Other 
Stopping 
Criteria
Added additional stopping criteria
Enhancing safety parameters in the study
5.1 Overall 
Design
Added PK review to all reviews 
required to proceed between study 
cohorts
Enhancing review requirements between 
study cohorts
1. Synopsis
2. Schedule 
of Activities
5.1  Overall 
Design
Added requirement to call male 
participants approximately 7 
months after study completion to 
ensure their partner is not 
pregnant
Enhancing safety monitoring


2016N290366_01
CONFIDENTIAL
205822
4
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................19
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Benefit Assessment.....................................................................29
3.3.3.
Overall Benefit:Risk Conclusion...................................................29
4.
OBJECTIVES AND ENDPOINTS...........................................................................30
5.
STUDY DESIGN ....................................................................................................31
5.1.
Overall Design ............................................................................................31
5.2.
Number of Participants ...............................................................................35
5.3.
Participant and Study Completion...............................................................36
5.4.
Scientific Rationale for Study Design ..........................................................36
5.5.
Dose Justification........................................................................................37
6.
STUDY POPULATION...........................................................................................38
6.1.
Inclusion Criteria.........................................................................................38
6.1.1.
Inclusion Criteria for Healthy Participants and Bystanders...........38
6.1.2.
Inclusion Criteria for Participants with COPD...............................39
6.2.
Exclusion Criteria........................................................................................40
6.2.1.
Exclusion Criteria for Healthy Participants and Bystanders..........40
6.2.2.
Exclusion Criteria for Participants with COPD..............................43
6.3.
Lifestyle Restrictions...................................................................................45
6.3.1.
Meals and Dietary Restrictions ....................................................45
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................46
6.3.3.
Activity .........................................................................................46
6.4.
Screen Failures...........................................................................................46
7.
TREATMENTS.......................................................................................................47
7.1.
Treatments Administered............................................................................48
7.1.1.
Medical Devices...........................................................................49
7.2.
Dose Modification .......................................................................................49
7.3.
Method of Treatment Assignment ...............................................................50
7.4.
Blinding.......................................................................................................50
7.5.
Preparation/Handling/Storage/Accountability..............................................51
7.6.
Treatment Compliance................................................................................53
7.7.
Concomitant Therapy..................................................................................54
7.7.1.
Permitted Medications and Non-Drug Therapies..........................54
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................54
7.8.
Treatment after the End of the Study ..........................................................55


2016N290366_01
CONFIDENTIAL
205822
5
8.
DISCONTINUATION CRITERIA.............................................................................55
8.1.
Discontinuation of Study Treatment ............................................................55
8.1.1.
Liver Chemistry Stopping Criteria ................................................55
8.1.2.
QTc Stopping Criteria ..................................................................56
8.1.3.
Other Stopping Criteria ................................................................56
8.1.4.
Rechallenge.................................................................................57
8.2.
Withdrawal from the Study..........................................................................57
8.3.
Lost to Follow Up........................................................................................58
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................58
9.1.
Efficacy Assessments.................................................................................59
9.2.
Adverse Events...........................................................................................59
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................59
9.2.2.
Method of Detecting AEs and SAEs.............................................60
9.2.3.
Follow-up of AEs and SAEs.........................................................60
9.2.4.
Regulatory Reporting Requirements for SAEs .............................60
9.2.5.
Cardiovascular and Death Events................................................60
9.2.6.
Pregnancy ...................................................................................61
9.2.7.
Medical Device Incidents (Including Malfunctions).......................61
9.2.7.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................61
9.2.7.2.
Follow-up of Medical Device Incidents........................61
9.2.7.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................62
9.2.7.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................62
9.3.
Treatment of Overdose...............................................................................62
9.4.
Safety Assessments ...................................................................................62
9.4.1.
Screening Assessments ..............................................................63
9.4.2.
Physical Examinations.................................................................63
9.4.3.
Vital Signs....................................................................................63
9.4.4.
Electrocardiograms......................................................................64
9.4.5.
Spirometry ...................................................................................64
9.4.6.
Capillary pCO2 ............................................................................64
9.4.7.
Clinical Safety Laboratory Assessments ......................................64
9.4.8.
Environmental and Bystander Exposure Evaluation.....................65
9.4.8.1.
Air Monitoring .............................................................65
9.4.8.2.
Bystander Monitoring..................................................66
9.5.
Pharmacokinetics .......................................................................................67
9.5.1.
Blood Sample Collection..............................................................67
9.5.2.
BAL Sample Collection ................................................................67
9.5.3.
Urea Blood Sample......................................................................67
9.5.4.
Sample Analysis ..........................................................................67
9.6.
Pharmacodynamics ....................................................................................68
9.7.
Genetics .....................................................................................................68
9.8.
Biomarkers .................................................................................................68
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................68
10. STATISTICAL CONSIDERATIONS........................................................................68
10.1.
Sample Size Determination ........................................................................68


2016N290366_01
CONFIDENTIAL
205822
6
10.1.1.
Sample Size Sensitivity................................................................69
10.1.2.
Sample Size Re-estimation or Adjustment...................................69
10.2.
Populations for Analyses ............................................................................69
10.3.
Statistical Analyses.....................................................................................70
10.3.1.
Safety Analyses...........................................................................71
10.3.2.
Pharmacokinetic Analyses...........................................................71
10.3.3.
Bystander and Environmental exposure Analyses .......................72
10.3.4.
Interim Analyses ..........................................................................72
11. REFERENCES.......................................................................................................73
12. APPENDICES........................................................................................................76
12.1.
Appendix 1: Abbreviations and Trademarks................................................76
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................78
12.3.
Appendix 3: Study Governance Considerations..........................................80
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................84
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................91
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................94
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................96


2016N290366_01
CONFIDENTIAL
205822
7
1.
SYNOPSIS
Protocol Title: A double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study to investigate the safety, tolerability, and 
pharmacokinetics of CCI15106 inhalation powder in healthy participants and participants 
with moderate chronic obstructive pulmonary disease (COPD).  A concomitant study to 
evaluate environmental and healthy bystander exposure levels during dosing.
Short Title: Study of safety and drug levels of CCI15106 inhalation powder in healthy 
adults and adults with moderate chronic obstructive pulmonary disease.  Study of 
CCI15106 levels in people standing near the person inhaling the drug.
Rationale:
This study is the first administration of CCI15106 inhalation powder hard capsules 
(CCI15106:polyvinyl alcohol 99:1 w/w 0.9x1 m cylinder shape crystalline particles
presented in capsules, from here on referred to as CCI15106-IP) to humans. This study 
will evaluate the safety, tolerability, and lung and systemic pharmacokinetics (PK) of
CCI15106-IP delivered using Monodose RS01 device in healthy participants and in 
participants with moderate COPD.  
The intention of this study is to provide sufficient confidence in the safety of the 
molecule delivered by inhalation to inform progression to further repeat dose and proof
of concept studies.
A different formulation of CCI15106 (CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 
m pollen shape particles) has been previously administered to humans in the first time 
in human study (FTiH) 202031.  
Marketed CCI15106 is classified as teratogenic and is contra-indicated in women who are 
pregnant and in male partners of pregnant women and it is important to understand 
whether bystanders may be exposed to CCI15106 when it is used by patients in a dry 
powder, inhaled form.  This study will evaluate the levels of CCI15106 in room air and in 
the plasma of bystanders.  The study aims to replicate the real-life scenarios of dosing as 
close as possible.  Real-life scenarios may include dosing of multiple patients in a single 
room in a nursing home or dosing of a single patient at home.  A realistic worst-case 
scenario for bystanders is dosing of multiple patients in a standard size room in a nursing 
home.  


2016N290366_01
CONFIDENTIAL
205822
8
Objectives and Endpoints:
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
CCI15106-IP following single and repeat 
escalating doses in healthy participants and 
participants with moderate COPD.

To determine systemic PK of CCI15106
following single and repeat escalating doses 
of CCI15106-IP in healthy participants and 
participants with moderate COPD.

To evaluate potential inhalation exposure of 
bystanders to airborne CCI15106 during 
self-administered dosing of participants.

To evaluate the distribution and persistence 
of airborne CCI15106 in room air post-
dosing.

Adverse events (AEs), clinical laboratory, 
electrocardiogram (ECG), telemetry, 
spirometry, and vital signs assessments.

Derived systemic PK parameters of 
CCI15106: Single dose: area under the 
curve (AUC) from time zero to the time of 
last quantifiable concentration (AUC[0-last]),
concentration at maximum (Cmax), time of 
maximum concentration (tmax), AUC from 
time zero to infinity (AUC[0-]) elimination 
half-life (t1/2), clearance (CL/F), as data 
permit.
Repeat dose: AUC from time zero to end of 
dosing interval (AUC[0-]) (=12 hours [h] 
for twice daily dose regimen), Cmax, tmax,
elimination half-life (t1/2) as data permit.

Concentration of CCI15106 in plasma of 
bystanders 15-20 minutes (min) after dosing
(at predicted tmax) and amount of 
CCI15106 accumulated on filters fitted on 
bystander over 15 min after dosing.

Amount of CC15106 in room air assessed 
by measuring amount of CCI15106 
accumulated over 20 and 60 min intervals 
during and immediately post-dosing on 
filters fitted on stationary pumps placed in 
the room.
Secondary

To determine the concentration of 
CCI15106 in the lung of healthy participants 
and participants with moderate COPD
following repeat dosing of CCI15106-IP.

To investigate the performance of the 
Monodose RS01 device for the 
administration of CCI15106-IP in healthy 
participants and participants with moderate 
COPD.

Concentrations of CCI15106 in lung 
epithelial lining fluid (ELF) assessed by 
bronchoalveolar lavage.  

Device safety and performance parameters, 
including medical device incidents reporting, 
as well as systemic PK and lung CCI15106 
concentrations.


2016N290366_01
CONFIDENTIAL
205822
9
Overall Design:
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, 
single and repeat escalating dose study.  Investigator and participants will be blinded to 
treatment type (active or placebo), but will know what dose of the medication is being 
administered.  Part 1 will investigate single and repeat ascending doses in healthy 
participants and investigate environmental and bystander exposure.  Part 2 will evaluate 
single and repeat dose in participants with moderate COPD.  Participants may only be 
enrolled in one study part and randomized to one cohort per the randomization schedule.
Study schematic is presented below:


2016N290366_01
CONFIDENTIAL
205822
10
Number of Participants:
Approximately 36 healthy participants and approximately 22 participants with COPD 
will be randomized in this study for dosing.  
Treatment Groups and Duration:
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106-
IP or Placebo with 3:1 ratio.  In Cohort B Part 1 and Cohort B Part 2, participants will be 
randomized with 6:1 ratio.   Cohort C Part 1 will not be randomized or dosed, but each 
bystander participant will be assigned to a dosing participant.  Screening visit will occur 
within 30 days of dosing for cohorts in Part 1 and within 45 days of dosing for cohorts in 
Part 2.  Doses administered and treatment duration for participants in each specific cohort 
will be as defined in the study schematic above. Participants will return for the follow-up 
visit approximately 30 days after discharge.  All male participants will also be called
approximately 7 months after the follow-up visit to ensure no partner pregnancy.
The total study duration will be approximately 82 days for Cohort A Part 1; 
approximately 75 days for Cohort B Part 1 and Cohort C Part 1; approximately 77 days 
for Cohort A Part 2; and approximately 90 days for Cohort B Part 2.
2.
SCHEDULE OF ACTIVITIES (SOA)
If assessments are scheduled for the same nominal time, THEN the assessments should 
occur in the following order pre-dose:
1. Telemetry start
2. spirometry
3. 12-lead electrocardiogram (ECG)
4. vital signs
5. blood draws
  
and in the following order post-dose:
1.
12-lead ECG
2. vital signs
3. blood draws
4. spirometry
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, or others assessments may be altered during the course of the 
study based on newly available data (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring. 


2016N290366_01
CONFIDENTIAL
205822
11

Any change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GlaxoSmithKline (GSK) study team member and then archived in the 
study sponsor and site study files, but this will not constitute a protocol 
amendment. 

The institutional review board (IRB)/independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 


2016N290366_01
CONFIDENTIAL
205822
12
Screening and follow-up procedures for all cohorts
Procedure
Screening, 30 
days before D1 for 
Part 1 or 45 days 
before D1 for Part 
21
Follow up
302 days after the 
last dosing day2
Notes
Informed consent
X
1.
Screening assessments can be performed over multiple screening visits
2.
All male participants will be called approximately 7 months after the follow-up visit to 
ensure no partner pregnancy
3.
If test otherwise performed within 3 months prior to first dose of study treatment, testing 
at screening is not required
4.
To be drawn fasting (for at least 8 h)
5.
To be administered to participants with COPD only, 15-30 minutes prior to spirometry
6.
To be done at screening for participants with COPD only, following salbutamol dosing
7.
To be performed in the bronchoalveolar lavage (BAL) cohorts only to confirm participant 
eligibility
8.
To be performed in the BAL cohorts only to confirm participant eligibility.  Can be done 
pre-dose on Day -1 instead, if required
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including 
height and weight, oral examination 
X
Brief physical examination, oral 
examination
X
Medical history (includes substance 
usage  and Family history of 
premature CV disease)
X
Substance testing (drugs, alcohol)
X
Assessment of child-bearing potential 
for females
X
Serum pregnancy test in women
X
X
Human immunodeficiency virus (HIV), 
Hepatitis B (Hep B) and Hepatitis C
(Hep C) screen3
X
Haematology, clinical chemistry and 
urinalysis (include liver chemistries)4
X
X
Salbutamol administration5
X
Spirometry6
X
12-lead ECG and vital signs
X
X
Coagulation parameters7
X
Capillary pCO28
X
PK blood sample
X
AE review 
X
SAE review
X
X
Concomitant medication review
X
X


2016N290366_01
CONFIDENTIAL
205822
13
Schedule for Cohort A Part 1
Procedure
Treatment Period, Days
-1
11
2
31
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Inclusion and exclusion criteria
X
Brief physical examination, oral 
examination
X
X
Substance testing (drugs, alcohol, tobacco)
X
Inhaler device training2
X
Serum pregnancy test in women
X
Admittance to clinic
X
Randomization
X3
Discharge
X4
Haematology, clinical chem and urinalysis 
(include liver chem)5
X
X
X
X
X
Spirometry
X1
X1
X6
X7
X7
X7
X6
Telemetry (starting 30 min pre-morning 
dose and continuous at least 4h post-
morning dose)
X1
X1
X
X
X
12-lead ECG and vital signs
XX
X
X1
X1
X8
X8
X8
X8
X8
X8
X8
X8
CCI15106-IP or placebo treatment, device 
incident assessment
X1
X1
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
X9
PK blood sample10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE review
========================================================================================
SAE review
=============================================================================================
Concomitant medication review
=============================================================================================
1.
Single dose days.  Follow schedule for Day 1 of Part 2 Cohort A
2.
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion.  
3.
Can be performed on Day 1 prior to dosing
4.
After all procedures and assessments are complete
5.
To be drawn fasting (for at least 8 h)
6.
To be performed at the following timepoints in the mornings only: pre-dose, and 0.25, 0.5, 1, 4 h post-dose 
7.
To be performed at the following timepoints in the mornings only: pre-dose and 4 h post-dose 
8.
ECG and vital signs to be obtained 2 h after the morning dose


2016N290366_01
CONFIDENTIAL
205822
14
9.
BID
10. PK samples on days 1, 3, 6, and 19 will be collected at the following timepoints:  pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 h.  On day 2, one sample in the morning (24h post 
day 1 dose). On days 4 and 5, one sample on each morning (24h and 48h post day 3 dose). On days 6 and 19, the evening dose will be given after 12 h post-dose sample is 
collected.  On all other days, PK sample will be collected once, before the morning dose (if on dosing days).


2016N290366_01
CONFIDENTIAL
205822
15
Schedule for Cohort A Part 2 (and all other single dose administrations)
Procedure
Treatment Period, Days (D) and hours (h)
D-1
D1
D2
Pre-
dose
0h
0.25h
0.5h
0.75h
1h
2h
4h
6h
8h
10h
12h
24h
Inclusion and exclusion criteria
X
Brief physical examination, oral examination
X
X
Substance testing (drugs, alcohol)
X
Serum pregnancy test in women
X
Admittance to clinic
X
Inhaler device training1
X
Randomization
X2
Discharge
X3
Haematology, clinical chem and urinalysis (include liver chem)4
X
X
Spirometry
X5
X6
X
X6
X6
Telemetry
30 min pre-dose and continuous until at least 4 h 
post-dose
12-lead ECG and vital signs
XXX
X
X
X
X
X
X
CCI15106-IP or placebo treatment
X
PK blood sample7
X
X
X
X
X
X
X
X
X
X
X
X
AE review
=================================================================
SAE review
==============================================================================
Concomitant medication review
==============================================================================
1.
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion
2.
Can be performed on Day 1 prior to dosing
3.
After all assessments are completed
4.
To be drawn fasting (for at least 8 h)
5.
To be performed within 15 to 60 minutes pre-dose
6.
To be performed after ECG, VS and PK blood draw are obtained
7.
Additional PK collection time points may be added to better characterize the PK profile


2016N290366_01
CONFIDENTIAL
205822
16
Repeat dose schedule to be followed for repeat dose cohorts in Parts 1 and 2 (other than Cohort A Part 1)
Procedure
Treatment Period, Days 
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Inclusion and exclusion criteria
X
Brief physical examination, oral examination
X
X
Substance testing (drugs, alcohol, tobacco1)
X
Inhaler device training2
X
Serum pregnancy test in women
X
Admittance to clinic
X
Randomization
X3
Discharge
X4
Dosing procedure training with bystanders
X5
Haematology, clinical chem and urinalysis (include liver chem)6
X
X
X
Spirometry
X7
X8
X8
X8
X7
Telemetry (starting 30 min pre-morning dose and continuous at 
least 4h post-morning dose)
X
X
X9
12-lead ECG and vital signs10
XXX
X
X
X
X
X
X
X11
X11
CCI15106-IP or placebo treatment BID, device incident 
assessment BID12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample13
X
X
X
X
X
X
X
X
X
BAL
X14
Urea blood sample
X15
AE review
=================================================================
SAE review
==============================================================================
Concomitant medication review
==============================================================================
1.
Tobacco test to be performed only in healthy participants 
2.
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion.  
3.
Can be performed on Day 1 prior to dosing
4.
After all procedures and assessments are complete
5.
To be done only in Cohort(s) where bystanders are present.  Can be performed on Day -1 instead, if desired. Other time-points may be added per investigators discretion.
6.
To be drawn fasting (for at least 8 h)
7.
To be performed at the following timepoints in the mornings only: pre-dose, and 0.25 (in participants with COPD only), 0.5, 1, 4 h post-dose 
8.
To be performed at the following timepoints in the mornings only: pre-dose and 4 h post-dose


2016N290366_01
CONFIDENTIAL
205822
17
9.
Telemetry may be performed on Days 11 or 12 instead, not to coincide with the BAL procedure.
10. ECG and vital signs to be obtained 2 h after the morning dose
11. When BAL is performed, vital signs and ECG will be performed before and after the procedure and oxygen saturation will be measured continuously. 
12. For cohort with bystanders, BID doses may have 1.5 h window.
13. PK samples on days 1 and 14 will be collected at the following timepoints:  pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 h.  The evening dose will be given after 12 h post-dose 
sample is collected.  On all other days, PK sample will be collected once, before the morning dose.  When BAL is performed, one additional PK sample will be collected after 
dosing immediately prior to bronchoscopy
14. Done once during these four days, as soon as possible (within 1 h) after the first dose of the day
15. To be collected immediately before bronchoscopy


2016N290366_01
CONFIDENTIAL
205822
18
Schedule for Cohort C Part 1 (bystanders and air monitoring), to be executed concomitantly with Cohort B 
Part 1
Procedure
Treatment Period, Days 
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Inclusion and exclusion criteria
X
Brief physical examination, oral examination
X
X
Substance testing (drugs, alcohol, tobacco)
X
Serum pregnancy test in women
X
Admittance to clinic
X
Discharge
X1
Training2
X
Haematology, clinical chem and urinalysis (include liver chem)3
X
X
X
Exposure to dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample
X4
X4
X4
X
Stationary pump air monitoring5
X
X
X
Personal exposure pump monitoring6
X
X
X
12-lead ECG and vital signs
XXX
X7
X7
X7
X7
X7
X7
X7
X7
AE review
=================================================================
SAE review
=================================================================================
Concomitant medication review
=================================================================================
1.
After all procedures and assessments are complete
2.
Day -1 training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion
3.
To be drawn fasting (for at least 8 h)
4.
PK samples will be collected pre-dose and 15 min after the dosing participant takes their first daily dose.  In addition, on days 7 and 14, one sample on each day will be collected 
before the dosing participant takes the first daily dose. On day 15, one sample will be collected before discharge.
5.
Samples of air to be collected for 20 and 60 min during and after the first morning dose
6.
Samples of air to be collected for 15 min during and after the first morning dose
7.
ECG and vital signs to be obtained 2 h after the exposure to morning dose


2016N290366_01
CONFIDENTIAL
205822
19
3.
INTRODUCTION
3.1.
Study Rationale
This study is the first administration of CCI15106-IP (CCI15106:polyvinyl alcohol 99:1
w/w 0.9x1 m cylinder shape crystalline particles produced using Liquidia’s Particle 
Replication In Non-wetting Templates [PRINT] technology) to humans. The study will 
evaluate the safety, tolerability, and lung and systemic pharmacokinetics (PK) of single 
and repeat ascending doses of CCI15106-IP delivered by inhalation in healthy 
participants and in participants with moderate chronic obstructive pulmonary disease 
(COPD).  The study will use a Monodose RS01 device for drug delivery by inhalation.
A different formulation of CCI15106 (CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 
m pollen shape particles) has been previously administered to humans in the first time 
in human study (FTiH) 202031.  That formulation was referred to as CCI15106 capsules 
for inhalation (CCI15106-CFI).
The intention of this study is to provide sufficient information regarding the safety of the 
molecule to inform progression to further repeat dose and proof of concept studies. The 
dose range proposed in this study is based on a starting dose previously investigated with 
the different formulation in the FTiH and escalating to a dose not to exceed the the no 
observed adverse effect level (NOAEL) in the most sensitive species (Section 5.5).
The other intention of this study is to investigate the level of CCI15106 that will be 
released into the air and may be found in the blood of the bystanders around participants
inhaling CCI15106-IP.
3.2.
Background
CCI15106 is ribavirin, which is a generic, broad spectrum nucleoside antiviral, 
discovered in the early 1970s, with both clinical and nonclinical data available, which 
is approved and used for oral administration in the treatment of chronic hepatitis C 
virus.  It is also approved for respiratory syncytial virus (RSV) bronchiolitis by 
pulmonary inhalation in paediatric patients.  CCI15106 is active versus RSV, human 
metapneumovirus, parainfluenza, influenza, adenovirus, and human rhinovirus (HRV), 
although HRV is 4-15-fold less susceptible than the others (GlaxoSmithKline 
Document Number 2015N249287_00). Based upon published data coronaviruses 
could also be susceptible without co-administration of interferon [Kurai, 2013, 
Morgenstern, 2005].  CCI15106 is not considered to be the active form, rather it is 
actively transported into target organs/cells and converted to ribavirin triphosphate 
(RTP) believed to be the active form against the viruses [Thomas, 2012]. The major 
limitation of the use of CCI15106 is hemolytic anemia due to accumulation of RTP in 
red blood cells and teratogenicity.   
Liquidia’s Particle Replication In Non-wetting Templates (PRINT) technology uses 
lithographic etching processes to produce particles with highly defined size and shape. 
CCI15106 plus the excipient, polyvinyl alcohol, are combined in a ratio of 99:1 w:w
using Liquidia’s technology to produce CCI15106-IP, a highly dispersible powder of 
uniform 0.9x1 m cylinder shape particles which has afforded a 24-fold increase in lung 


2016N290366_01
CONFIDENTIAL
205822
20
concentration at maximum (Cmax) relative to micronised CCI15106:Lactose formulation 
in a solid dose inhaled rat PK study (GlaxoSmithKline Document Number 
2015N242219_00 [N20691-39]). The size and uniformity of the Liquidia particles 
provides an opportunity to improve the efficiency of CCI15106 administration to the lung 
while limiting systemic exposure that has the potential to limit hemolytic anemia and 
teratogenicity. 
Acute exacerbations of COPD are a significant cause of morbidity and mortality 
[Vestbo, 2013; Kurai, 2013]. Multiple studies show that viral and/or bacterial 
respiratory infections are the most commonly associated triggers of COPD 
exacerbations.  Respiratory viruses are detected in 20-60% of acute exacerbations of 
COPD [Kurai, 2013].
High efficiency lung delivery of broad spectrum CCI15106-containing engineered 
particles will establish an antiviral state in the lung.  This has the potential to prevent the 
establishment or spread of the virus in the lower respiratory tract from the upper 
respiratory tract and/or increase the viral clearance translating to prevention of an 
exacerbation or a decrease in exacerbation severity and/or duration.
CCI15106 has been previously administered to humans in a different formulation, 
CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 m pollen shape PRINT particles
(CCI15106 capsules for inhalation, referred to as CCI15106-CFI).  Forty eight healthy 
participants have been administered a single dose of that formulation in one FTiH study 
202031 and 12 participants received placebo.  This study was planned as a double-blind 
(sponsor unblind), randomized, placebo-controlled, single and repeat escalating dose 
study to investigate the safety, tolerability, and pharmacokinetics of CCI15106-CFI in 
healthy participants and participants with moderate chronic obstructive pulmonary 
disease (COPD).  In the single dose part of the study, CCI15106-CFI was administered 
by inhalation using Modified Air Inlet Rotahaler device at doses of 7.5 mg, 15 mg, 30 
mg, and 60 mg.  Overall, no clinically meaningful changes in vital signs or 
electrocardiograms (ECGs) were observed.  There were no serious adverse events (SAEs) 
reported.  Of the 60 subjects in the study, 25 reported adverse events (AEs) and 12 
reported possibly drug-related AEs.  The most common AEs were headache and cough 
(11 and 3 subjects, respectively).  The comprehensive review conducted after single dose 
cohorts revealed acceptable safety profile, but lung epithelial lining fluid (ELF) levels of 
CCI15106 measured with 30 or 60 mg dose were below the levels predicted by pre-
clinical evaluations and the increase in dose from 30 to 60 mg did not appear to result in a 
substantial increase in the lung concentration.  Development of the CCI15106-CFI 
formulation was terminated before dosing repeat dose or COPD cohorts as a new 
formulation (CCI15106-IP) was developed that has higher ratio of active pharmaceutical 
ingredient to inactive ingredients per unit of powder and allows achieving the same dose 
in 1 capsule instead of 4. This is expected to lead to a higher lung ELF Cmax. The 
decision to terminate was not based on safety data.   
Marketed formulations of CCI15106 are classified as teratogenic and is contra-indicated 
in women who are pregnant and in male partners of pregnant women.  Currently 
approved aerosolised forms of CCI15106 are recommended to be administered in a 
negative pressure environment [Virazole USPI 2013].  It is important to understand 
whether bystanders may be exposed to CCI15106 when it is used by patients in a dry 


2016N290366_01
CONFIDENTIAL
205822
21
powder, inhaled form.  The most likely route of exposure of bystanders will be through 
inhalation of powder released during dosing. The study aims to replicate the real-life 
scenarios of dosing as close as possible.  Real-life scenarios may include dosing of 
multiple patients in a single room in a nursing home or dosing of a single patient at home.  
A realistic worst-case scenario is dosing of multiple patients in a standard size room in a 
nursing home.  
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of CCI15106 may be found in the Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 2015N250735_02].  Information 
specific to the approved formulations of CCI15106 can be found in the labels for oral 
CCI15106 approved for the treatment of hepatitis C and CCI15106 nebulizer approved 
for the treatment of respiratory syncytial infections in children [Rebetol SPC 2009; 
Virazole USPI 2013].  
Based on pre-clinical safety assessment studies summarized in the IB and the clinical 
experience with CCI15106-CFI, as well as oral and inhaled (nebulised) CCI15106, the 
following clinical parameters will be monitored throughout the study in order to better 
characterize the safety and tolerability of CCI15106-IP (Section 3.3.1).  Refer to SoA,
Section 2, for the timing of all clinical assessments.


2016N290366_01
CONFIDENTIAL
205822
22
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product, CCI15106-IP
Teratogenicity and embryocidal effects
CCI15106 showed embryocidal and teratogenic effects in animals.  The no 
observed adverse effect level (NOAEL) in oral embryofetal development 
studies in rats and rabbits was 0.3 mg/kg/day, considerably lower than the 
maximum proposed inhaled clinical dose of 120 mg/day CCI15106 (0.02-
fold to 0.05-fold based on mg/m2).  In addition, human seminal fluid contains 
2-fold higher concentrations of CCI15106 compared to serum.  There are 
limited data from the use of CCI15106 in pregnant women (5 cases of 
measles-pneumonia and 1 case of influenza-pneumonia)) [Virazole SPC, 
2014]. Four pregnancies were completed and resulted in the birth of healthy 
children. A further 7 cases are known in which nurses administered Virazole 
dry substance during pregnancy (n=6) or just before conception (n=1). In 6 
cases, healthy children were born. In one case, a chromosomal 
translocation was reported with mild developmental delay [Virazole SPC, 
2014].
Women of child-bearing potential and male partners of 
women who are pregnant or breastfeeding will be 
excluded.  Effective contraception for female partners of 
male participants will be required up to 7 months post 
study.  
Any pregnancies that occur during the study or up to 7 
months post study will be reported by the investigator to 
the pregnancy registry.  
The informed consent form will describe these reproductive 
risks, as well as the risk to female partners of male 
participants.
Systemic exposure for the target clinical dose of CCI15106 
is expected to be lower than exposure for currently 
available oral and nebulized CCI15106.  The maximum 
inhaled total daily single dose of CCI15106 in Protocol 
205822 will be 120 mg and the maximum inhaled multiple 
daily doses will be 60 mg twice daily (BID).  These 
proposed maximum clinical doses are significantly lower 
than the currently approved doses of CCI15106 (800-1400
mg for Copegus and Rebetol and 6 g for inhaled Virazole).
Mutagenicity
CCI15106 is clastogenic in vitro and in vivo but is Ames negative.  The 
pattern of genotoxicity is consistent with that reported for other nucleoside 
analogues.  Point of departure modelling (an accepted method of risk 
assessment for nucleoside analogues) indicates a negligible genotoxic 
concern.  CCI15106 was not tumorigenic in lifetime rodent studies at doses 
up to 75 mg/kg/day in the mouse and 40 mg/kg/day in the rat (3-fold the 
The data indicate a negligible genotoxic concern, which is 
mitigated by the lower expected systemic and lung 
exposure compared with currently available oral and 
nebulized CCI15106 and shorter duration of clinical 
treatment (14 days).  The maximum inhaled single total 
daily dose of 120 mg or multiple total daily doses of 60 mg 


2016N290366_01
CONFIDENTIAL
205822
23
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
maximum proposed inhaled clinical dose of CCI15106-IP based on mg/m2), 
or in the transgenic p53() mouse model at doses of up to 300 mg/kg/day.
BID for Protocol 205822 are significantly lower than the 
currently approved doses of CCI15106 (800-1400mg for 
Copegus and Rebetol and 6 g for inhaled Virazole).
Increased exposure in participants with 
severe renal impairment 
As CCI15106/ribavirin is substantially excreted by the kidneys, exposure 
may be increased in those with pre-existing renal impairment
CCI15106 is contraindicated in patients with chronic renal failure, patients 
with creatinine clearance < 50mL/min, and/or on hemodialysis [Rebetol
SPC, 2009] However, the Copegus labels allow dose modifications for 
patients with CrCl <50 mL/min [Copegus USPI, 2015; Copegus SPC, 2015].
The maximum inhaled single total daily dose of 120 mg or 
multiple total daily doses of 60 mg BID proposed for 
Protocol 205822 are significantly lower than the currently 
approved doses of CCI15106 (800-1400mg for Copegus 
and Rebetol and 6 g for inhaled Virazole).
COPD patients with impaired renal function (eGFR <30 
cc/min, using CKD-EPI equation) will be excluded and 
renal function will be monitored.
Pulmonary effects
GSK’s formulations:
In toxicity studies conducted by GSK, no adverse pulmonary toxicity was 
observed following administration of either CCI15106:trehalose:trileucine 
particles or CCI15106-IP in GSK studies of 28 day duration at dose levels of 
32.5 mg/kg in rat or 34.2 mg/kg in dog.  The deposited lung doses at the 
NOAELs on the 28 day studies using CCI15106-IP were estimated 6- to 8-
fold higher than in human at the maximum proposed clinical administration 
of CCI15106-IP of 120 mg/day (conservatively assuming 100% human lung 
deposition). Adverse lung pathology (including neutrophilic inflammatory 
cell infiltrates) and unscheduled deaths were observed in rats in a 14 day 
inhaled tolerability study with CCI15106-IP at an estimated dose of 68.7 
mg/kg.  Rat deaths and lung pathology have been reported during oral and 
inhalation toxicology programs for approved/marketed formulations of 
CCI15106 at systemic exposures and inhalation dose levels similar or less 
than those delivered in this study.
As CCI15106-IP is dry powder, it has a reduced risk of acute lung effects
compared to low osmolarity nebulised solution.  No bronchospasms were 
observed in the FTIH study 202031; however there were occurrences of 
non-serious cough and dyspnoea.  Maximal amounts of powder 
administered were higher in the FTIH study than those planned for the 
Repeat dosing will be evaluated in healthy participants in 
this study prior to dosing in participants with COPD.  
Patients with poorly controlled COPD will be excluded (see 
Section 6.2.2).  Lung function will be monitored with 
frequent spirometry and physical examinations will be 
conducted.  If they become medically necessary, short-
acting bronchodilators may be administered as needed by 
the clinical staff.  Oxygen and resuscitation measures will 
be available in the unit in the event they would be needed.
The trial is to be conducted in a dedicated phase I unit with 
supplementary (Medicines & Healthcare Products 
Regulatory Agency) accreditation and experience in the 
conduct of Phase I studies.


2016N290366_01
CONFIDENTIAL
205822
24
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
current study. 
Labels of approved formulations:
Virazole SPC (13 November 2014) includes the following:

Sudden deterioration in pulmonary function associated with 
aerosolized CCI15106/ ribavirin has been observed in children, 
and significant deterioration in pulmonary function has been 
observed in patients with asthma and chronic obstructive 
pulmonary disease (COPD)  during CCI15106/ribavirin treatment.

Bronchospasm has been reported following CCI15106/ribavirin 
use by patients with COPD and asthma.
Pulmonary adverse reactions reported in clinical studies or in postmarketing 
use of aerosolized CCI15106/ribavirin include bacterial pneumonia, 
pneumothorax, laryngitis, pharyngitis, dyspnoea, cough, hypo- and 
hyperventilation, apnoea, and bronchospasm.
Haemolytic anaemia
The primary toxicity of approved formulations of CCI15106 is haemolytic 
anemia, which was observed in 10% of oral CCI15106 plus interferon 
alpha2b combination-treated participants and occurs within 1 to 2 weeks of 
start of therapy [Rebetol USPI, 2015].  Haemolytic anemia associated with 
CCI15106 may result in worsening of cardiac disease that has led to fatal 
and nonfatal myocardial infarction.  CCI15106 is known to accumulate in the 
red blood cells and may cause hemolysis, which may result in increased uric 
acid [De Franceschi, 2000].  Anemia has been shown to occur frequently 
with experimental oral and intravenous CCI15106 in humans [Virazole USPI, 
2013].  Haemolytic anaemia is monitorable and reversible with reduction / 
cessation of treatment [Rebetol USPI, 2015].
GSK formulations:
In toxicity studies conducted by GSK, mild anaemia was seen in 4 week 
studies following inhalation administration of CCI15106:trehalose:trileucine 
particles (rat and dog) or CCI15106-IP (rat only).  
Participants will be monitored regularly with complete 
blood counts and hematocrit, as per SoA (Section 2).  
Participants with hemoglobinopathies will be excluded. 
Due to the short dose and duration and the red blood cell 
count monitoring in place, laboratory monitoring for 
hemolysis is not warranted in this study.  Participants will 
have an ECG assessment prior to and during the study.  
Cardiac monitoring, including assessment of blood 
pressure and heart rate, along with 12-lead 
electrocardiograms (ECGs) will be performed, per protocol.  
If cardiac status deteriorates on therapy, study medication
should be suspended and/or discontinued.  


2016N290366_01
CONFIDENTIAL
205822
25
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiac effects
GSK formulations:
Heart toxicity was not observed in definitive 4 week toxicity studies in rats 
and dogs following inhalation administration of 
CCI15106:trehalose:trileucine particles or CCI15106-IP.  Minimal 
lymphocytic/mononuclear or mixed inflammatory cell infiltrate in the 
myocardium was observed following inhalation administrations of 68.7 
mg/kg/day as CCI15106-IP at higher dose levels during a 14 day tolerability 
study (AUC0-24h was 5-fold higher than the human AUC0-24h estimated at 120 
mg CCI15106-IP).  These findings were also observed following oral and 
inhalation administrations of approved/marketed formulations of CCI15106-
IP and do not, therefore, present at a greater risk compared to 
marketed/approved CCI15106 formulations which are approved for 
administration at higher inhaled and oral dose levels/ systemic exposures 
and administered for longer treatment durations than those proposed for 
CCI15106-IP. 
There were no cardiac events reported in the FTIH study of CCI15106-CFI.
The following cardiovascular adverse reactions have been reported in 
clinical studies and in the postmarketing setting of CCI15106, which 
included severely ill infants with life-threatening underlying disease:  cardiac 
arrest, hypotension, bradycardia, and digitalis toxicity [Virazole USPI, 2013].  
Bigeminy, bradycardia, and tachycardia, have been described in patients 
with underlying cardiac disease.
Participants will have ECG prior to dosing and will be 
assessed prior to and during therapy by 12-lead ECG and 
telemetry.  If cardiac status deteriorates on therapy, study 
medication should be suspended and/or discontinued.  
Participants with uncontrolled or unstable cardiac diseases 
will be excluded.
Photosensitization
Photosensitivity reaction has been reported commonly in clinical trials and in 
the postmarketing setting for CCI15106 [Rebetol SPC, 2009].  Photoallergic 
reaction with CCI15106 has been described in the literature [Stryjek-
Kaminska, 1999].
Physical examination to include skin exams will be 
performed and documented as per SoA (Section 2).  Any 
findings suggesting photosensitivity reaction will be 
promptly addressed according to appropriate standard of 
care and followed up for resolution.
Oral erosions
Ulcerative stomatitis, stomatitis, mouth ulceration are undesirable effects 
associated with CCI15106 [Rebetol SPC, 2009].  Nasal erosions were 
Physical examination to include oral exam will be 
performed and documented as per SoA (Section 2).  Any 


2016N290366_01
CONFIDENTIAL
205822
26
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
observed in the squamous epithelium of the nasal turbinates of a proportion 
of dogs (but not rats) receiving the high dose (25.1 mg/kg/day) following 
administration of CCI15106-CFI and ≥16.3 mg/kg following administration 
CCI15106-IP for 4 weeks.  These effects were considered non adverse and 
unlikely to be clinically relevant since CCI15106  will be administered to 
humans by oral inhalation, compared with oro-nasal administration (over 60 
minutes) in the dog study, thereby minimising the potential for nasal 
exposure.  Histopathological findings in rats included epithelial changes in 
the larynx (squamous metaplasia) in animals given the control article and 
CCI15106 formulation over 4 weeks. These changes were low in incidence 
and severity and showed full recovery following completion of the off-dose 
period. The findings were consistent with low grade non-specific irritation 
and, being an adaptive change of low severity, are considered non-adverse 
[Kaufmann, 2009] and a poor predictor of irritancy in humans given that the 
rat larynx is known to be particularly sensitive to inhaled irritants [Lewis, 
1991].
findings suggesting oral erosion will be promptly 
addressed according to appropriate standard of care and 
followed up for resolution.
Testicular toxicity
Testicular toxicity:  Testicular toxicity was seen in mice treated orally with 
CCI15106 for 3 to 6 months at doses of 15 mg/kg/day and [Rebetol SPC, 
2009].  Recovery occurred within one or two spermatogenic cycles.  No 
stage specific or cell specific abnormalities of spermatogenesis were 
observed in GSK studies which were conducted on the testes of rats 
(CCI15106:trehalose:trileucine particles and CCI15106-IP) and dogs 
(CCI15106-IP only) during definitive 4 week inhalation toxicity studies.
Given the shorter duration of clinical treatment (14 days) 
and lower expected exposure compared with currently 
available oral and nebulized CCI15106, the risk of 
testicular toxicity is considered to be low.  


2016N290366_01
CONFIDENTIAL
205822
27
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures 
BAL procedure
BAL requires bronchoscopy and sedation.  Bronchoscopy can be performed 
safely on an outpatient basis [Du Rand, 2013], however, serious 
complications occurred in 1.1% of patients, including mortality in 0.02% of 
patients in a retrospective series (n=20,986 patients).  Common adverse 
events reported with bronchoscopy, included tachycardia/bradycardia, major 
and minor bleeding, bronchospasm, laryngospasm, cough, dyspnea, sore
throat, apnea, seizure, desaturation, pneumothorax, and pulmonary edema.
BAL will be performed by an experienced pulmonologist in 
dedicated bronchoscopy suite with close monitoring in 
recovery area post procedure.
Other
Bystander exposure, including healthcare 
workers 
Detectible levels of CCI15196-IP may be present in the immediate inhalation
area during routine care activities.
Labels of approved formulations:
The Virazole patient information leaflet (last revision August 2014) states the 
following:

Virazole is to be administered in a hospital setting only, by a 
doctor or a nurse.

The nebuliser through which Virazole is given should be turned off 
5 to 10 minutes before visitors see the patient to minimise 
unnecessary exposure to Virazole.

Pregnant women, women who are trying to become pregnant, and 
sexually active men should avoid exposure to Virazole, because 
the risk of harm to an unborn baby is unknown.  Breast-feeding 
women are also to avoid exposure to Virazole.
Postmarketing surveillance of CCI15106 has revealed reports of adverse 
events in individuals providing direct care to infants receiving aerosolized 
CCI15106 [Virazole USPI 2013].  The most common signs and symptoms 
were headache, conjunctivitis, rhinitis, nausea, rash, dizziness, pharyngitis, 
Levels in air and in bystanders will be assessed.
Whenever study participants are dosed outside the 
negative pressure room, all hospital personnel will be 
asked to leave the room and will not re-enter until 15 min 
after dosing.    
Pregnant women or women of child-bearing potential will
be warned of the potential risks. 
Training on the potential health hazard will be provided to 
study personnel, including protective equipment, 
monitoring, and waste disposal. 
No women of child-bearing potential will be enrolled as 
participants or as bystanders.


2016N290366_01
CONFIDENTIAL
205822
28
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and lacrimation.  Several cases of bronchospasm and/or chest pain have 
been reported, usually in individuals with reactive airways disease. Seven 
cases are known in which nurses administered Virazole dry substance
during pregnancy (n=6) or just before conception (n=1). In 6 cases, healthy 
children were born. In one case, a chromosomal translocation was reported 
with mild developmental delay.
Exposure risk for additional medications administered in the study (Salbutamol):
See package leaflet (https://www.medicines.org.uk/emc/PIL.22837.latest.pdf).


2016N290366_01
CONFIDENTIAL
205822
29
3.3.2.
Benefit Assessment
As this Phase I study is being conducted to assess the safety and PK in healthy 
participants and participants with COPD, there is no direct clinical benefit to study 
participants. Participation in this study may contribute to the process of developing new 
therapies in an area of unmet need.
3.3.3.
Overall Benefit:Risk Conclusion
CCI15106 is an approved product as an oral agent in combination with interferon or 
(pegylated and non-pegylated) for chronic hepatitis C in patients 3 years of age and older 
with compensated liver disease (Copegus, Rebetol), and is approved in the nebulised 
form for use in infants and young children with severe respiratory syncytial virus 
infections (Virazole). CCI15106-CFI has been administered to healthy participants in 
single doses up to 60 mg with acceptable safety and tolerability profile.  The risk of 
adverse effects is minimized for the population being investigated in the proposed study 
by careful selection of participants for the study, the relatively short duration of exposure, 
and the extent of safety monitoring incorporated into the study.  The highest dose planned 
in this study (single dose of 120 mg or multiple doses of 60 mg BID) is significantly 
lower than the currently approved doses of CCI15106 (800-1400 mg for Copegus and 
Rebetol and 6 g for aerosolized Virazole).  The risk to study staff will be managed by 
occupational precautions.


2016N290366_01
CONFIDENTIAL
205822
30
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
CCI15106-IP following single and repeat 
escalating doses in healthy participants and 
participants with moderate COPD.

To determine systemic PK of CCI15106
following single and repeat escalating doses 
of CCI15106-IP in healthy participants and 
participants with moderate COPD.

To evaluate potential inhalation exposure of 
bystanders to airborne CCI15106 during 
self-administered dosing of participants.

To evaluate the distribution and 
persistence of airborne CCI15106 in room 
air post-dosing.

Adverse events (AEs), clinical laboratory, 
electrocardiogram (ECG), telemetry, 
spirometry, and vital signs assessments.

Derived systemic PK parameters of 
CCI15106: Single dose: area under the 
curve (AUC) from time zero to the time of 
last quantifiable concentration (AUC[0-last]),
concentration at maximum (Cmax), time of 
maximum concentration (tmax), AUC from 
time zero to infinity (AUC[0-]) elimination 
half-life (t1/2), clearance (CL/F), as data 
permit.
Repeat dose: AUC from time zero to end of 
dosing interval (AUC[0-]) (=12 hours [h] 
for twice daily dose regimen), Cmax, tmax,
elimination half-life (t1/2) as data permit.

Concentration of CCI15106 in plasma of 
bystanders 15-20 minutes (min) after dosing 
(at predicted tmax) and amount of 
CCI15106 accumulated on filters fitted on 
bystander over 15 min after dosing.

Amount of CC15106 in room air assessed 
by measuring amount of CCI15106 
accumulated over 20 and 60 min intervals 
during and immediately post-dosing on 
filters fitted on stationary pumps placed in 
the room.
Secondary

To determine the concentration of 
CCI15106 in the lung of healthy participants 
and participants with moderate COPD
following repeat dosing of CCI15106-IP.

To investigate the performance of the
Monodose RS01 device for the 
administration of CCI15106-IP in healthy 
participants and participants with moderate 
COPD.

Concentrations of CCI15106 in lung 
epithelial lining fluid (ELF) assessed by 
bronchoalveolar lavage (BAL).

Device safety and performance parameters, 
including medical device incidents reporting, 
as well as systemic PK and lung CCI15106 
concentrations.


2016N290366_01
CONFIDENTIAL
205822
31
Objectives
Endpoints
Tertiary/Exploratory 

To assess dose proportionality of 
CCI15106-IP versus systemic PK 
parameters.

To explore the relationship of drug exposure 
to safety and tolerability parameters after 
single and repeat escalating doses of 
CCI15106-IP in healthy participants and 
participants with moderate COPD.

To extrapolate study outcomes to a realistic
worst case real-life scenario of dosing 
multiple patients in a single room in a 
nursing home.

Comparisons of doses administered and 
systemic PK parameters of CCI15106: 
AUC(0-24) or AUC(0-) and Cmax.

The dose or plasma exposure parameters
for CCI15106 and the relationship of these 
to safety and tolerability parameters, as 
data permit.

Comparison of the study room with a 
potential nursing home room, including 
room dimensions, patient density, 
ventilation (air change rates per hour)
5.
STUDY DESIGN
5.1.
Overall Design
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, 
single and repeat escalating dose study.  Investigator and participants will be blinded to 
treatment type (active or placebo), but will know what dose of the medication is being 
administered.  Part 1 will investigate single and repeat ascending doses in healthy 
participants and investigate environmental and bystander exposure.  Part 2 will evaluate 
single and repeat dose in participants with moderate COPD.  Participants may only be 
enrolled in one study part and randomized to one cohort per the randomization schedule.


2016N290366_01
CONFIDENTIAL
205822
32
Study schematic is presented below:


2016N290366_01
CONFIDENTIAL
205822
33
The following reviews will be conducted during the study progression:

In Part 1, Cohort B dosing can begin only after review of safety/tolerability and PK 
of all dosing in Part 1 Cohort A (see Section 7.2 for composition of the review 
team).    

In Part2, Cohort A dosing can begin only after review of safety/tolerability and PK 
for a single dose administration of 60 and 120 mg in all participants in Part 1 Cohort
A (see Section 7.2 for composition of the review team).  

In Part 2, Cohort B dosing can begin only after the comprehensive review of all data 
obtained in Part 1, including safety and systemic PK, as well as lung PK where 
available (see Section 7.2 for composition of the review team) and after review of 
safety/tolerability of Part 2 Cohort A.    

Environmental and bystander exposure review may be conducted at any time after 
the data are collected.  Until this review is completed and exposure found 
acceptable, all subsequent cohorts will be dosed in the negative pressure 
environment. 

The planned doses may be modified, repeated or cancelled based upon 
safety/tolerability/ and/or PK from preceding cohorts (See Section 7.2 for more 
information).  Single doses will not exceed 120 mg and repeat doses 60 mg BID.

The planned dose frequency or duration may be modified based on emerging 
safety/tolerability and PK data from previous cohorts.  The total daily dose will not 
exceed 120 mg.

The number of cohorts may be reduced or expanded if needed.


2016N290366_01
CONFIDENTIAL
205822
34

All participants in Part 1 Cohort B and in Part 2 Cohort B (60 mg BID dose for both 
Cohorts) will undergo BAL once during the study on days 10, 11, 12, or 13 after the 
first (morning) dose.  Based on the lung ELF concentrations of CCI15106 observed, 
additional double-blinded, single-blinded or open-label repeat dose cohort(s) may be 
added at a dose not to exceed 120 mg daily.  The total number of participants will 
not exceed that specified in Section 5.2.

BAL may be used in the additional cohorts to obtain a more accurate estimation of 
the dose to lung exposure ratio and provide data for future dose predictions.  
There will be approximately 3 cohorts of healthy participants in this study and 
approximately 2 cohorts of participants with moderate COPD.  Participants in the dosing 
cohorts will be randomized to receive either CCI15106-IP or matching Liquidia particles
without the active ingredient (lactose:polyvinyl alcohol 98:2 w/w 0.9x1 m cylinder 
shape amorphous particles, referred to as placebo).  Participants in Cohort C will be 
assigned to participants in Cohort B on a one to one basis for the entire duration of the 
study.
Screening visit will occur within 30 days of dosing for cohorts in Part 1 and within 45 
days of dosing for cohorts in Part 2.  
For Cohort A Part 1, 60 mg single dose will be administered on Day 1; 120 mg single 
dose will be administered on Day 3; and then 30 mg dose will be administered BID on 
Days 6-19.  Participants will report to the unit on Day -1 for assessments and 
randomization (randomization can also be done on Day 1, prior to dosing). Participants 
will be dosed the following morning on Day 1 followed by post-dose assessments. Blood 
for PK assessments will be collected for the next 48 hours (h).  On Day 3 (after collection 
of 48 h PK time point), participants will receive a single dose of 120 mg followed by 
post-dose assessments and PK assessments for the next 72 h.  Repeat dosing will begin
on the morning of Day 6 (after collection of 72 h PK time point) and will continue for 
14 days BID.  Participants will remain in the unit for additional 2 days until 72 h PK 
timepoint is collected.  Dosing frequency and duration may be adjusted based on 
emerging safety and tolerability data. Participants will return for the follow-up visit 
approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy.
For Cohort B Part 1, Repeat Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization
(randomization can also be done on Day 1, prior to dosing). Dosing will begin on the
morning of Day 1 and continue for 14 days BID.  Dosing frequency and duration may be 
adjusted based on emerging safety and tolerability data. BAL procedure will be 
performed as soon as possible (within 1 h) after the first (morning) dose on one of the 
following days: 10, 11, 12, or 13.  Participants will be discharged on Day 15 following
completion of all post-dose assessments after the last dose, or later if additional PK 
collection or other assessments are required.  Participants will return for the follow-up 
visit approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy.
For Cohort C Part 1, 14 healthy participants will be enrolled to evaluate bystander 
exposure and will follow Cohort C Part 1 SoA.  Bystanders and air exposure will be 
evaluated concomitantly with Cohort B Part 1.  Bystanders will report to the unit on Day 


2016N290366_01
CONFIDENTIAL
205822
35
-1 and will remain for all 14 days of dosing of Cohort B.  They will be positioned in the 
room with the dosing participants for every dose taken, as described in Section 9.4.8.  Air 
sampling and bystander PK evaluation will be conducted on days 1, 7, and 14 as 
described in Section 9.4.8.  Bystanders will be discharged on Day 15 following 
completion of all post-dose assessments after the last dose.  Bystanders will return for the 
follow-up visit approximately 30 days after discharge.  All male participants will also be 
called approximately 7 months after the follow-up visit to ensure no partner pregnancy.
For Cohort A Part 2, Single Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing).  They will be dosed the 
following morning on Day 1 followed by post-dose assessments.  Participants will be 
discharged following completion of the post-dose assessments the next day (Day 2).  
They will return for the follow-up visit approximately 30 days after discharge.  All male 
participants will also be called approximately 7 months after the follow-up visit to ensure 
no partner pregnancy.
For Cohort B Part 2, Repeat Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing).  Dosing will begin on the 
morning of Day 1 and continue for 14 days BID.  Dosing frequency and duration may be 
adjusted based on emerging safety and tolerability data.  BAL procedure will be 
performed as soon as possible (within 1 h) after the first (morning) dose on one of the 
following days: 10, 11, 12, or 13.  Participants will be discharged on Day 15 following 
completion of all post-dose assessments after the last dose, or later if additional PK 
collection or other assessments are required.  Participants will return for the follow-up 
visit approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy.
The total study duration will be approximately 82 days for Cohort A Part 1; 
approximately 75 days for Cohort B Part 1 and Cohort C Part 1; approximately 77 days
for Cohort A Part 2; and approximately 90 days for Cohort B Part 2.  
5.2.
Number of Participants
Approximately 36 healthy participants and approximately 22 participants with COPD 
will be randomized in this study for dosing.  
Evaluable participants will be defined in the Reporting and Analysis Plan (RAP).
Additional participants or cohorts may be enrolled to allow for evaluation of additional 
dose levels or to increase numbers on prior doses or to increase the number of bystanders. 
The total number of participants in this study will not exceed 86 and the total number of 
cohorts will not exceed 7, including the bystander cohort(s).
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the investigator.


2016N290366_01
CONFIDENTIAL
205822
36
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
Participants and all site personnel, with the exception of the study pharmacist or 
designee, will be blinded to participant randomization throughout the study.  The GSK
study team participating in the dose escalation meetings will review blinded data and will 
be un-blinded on a need to know basis only if necessary to facilitate review of the safety, 
tolerability and PK data as appropriate in real time to inform dose escalation decisions.  
The GSK study team or personnel at any contract research organization that may be 
involved in data management or in statistics and programming will not reveal the 
treatment assignments to the site personnel or participants. 
In repeat dosing cohorts, CCI15106-IP will be administered for 14 days to mimic the 
expected duration of treatment in target patient populations. 
Inclusion of Bronchoscopy
BAL will be performed on 14 healthy participants (Cohort B Part 1) and 14 participants 
with COPD (Cohort B Part 2) to evaluate levels of CCI15106 in the ELF.  BAL will be 
performed once, as soon as possible (within 1h) after the first (morning) dose.  This will 
allow assessment of CCI15106 levels at around tmax in the ELF.  The timing of BAL in 
Part 2 Cohort B may be adjusted based on BAL results obtained in Part 1.  Available 
models [Weber, 2017] predict that the level of CCI15106 in the bronchoalveolar fluid
following 14 days of 60 mg BID dosing may be achieved above 200 M around Tmax
which is above the EC50 for all respiratory viruses including HRV and expected to 
prevent or minimise the migration of an upper respiratory tract viral infection to the lower 
respiratory tract. These data will enable a more accurate estimation of the dose to lung 
exposure ratio and provide valuable information for future dose predictions. 
Inclusion of Participants with COPD Cohort
Due to potential exposure differences as a function of COPD-induced lung damage, 
participants with moderate COPD will be included to aid in dose selection for the future 
proof of concept studies in participants with COPD.  This cohort will also help obtain 
some safety and tolerability data in this patient population prior to a wider administration 
in the Proof of Concept study.
Inclusion of Bystander Cohort
Due to known teratogenic potential of CCI15106, we need to evaluate how much of it 
gets into the environment around the dosing participant to ensure that no potentially 
pregnant bystanders are put at-risk due to secondary exposure.  Participants dosed in the 


2016N290366_01
CONFIDENTIAL
205822
37
Cohort used to evaluate environmental and bystander exposure will be dosed outside a 
negative pressure enclosure.  All other participants will be dosed inside the enclosure.  
When participants dose outside the enclosure, all personnel will leave the room and not 
re-enter until 15 min after dosing.  During this time, participants will be observed through 
a window in the door.
5.5.
Dose Justification
The dose proposed for Part 1 Cohort A is based on the data from 202031 where 
CCI15106-CFI up to 60 mg single dose has been evaluated, and no SAEs or severe AEs 
were observed, as well as the investigation of the four week toxicity and toxicokinetics in 
rats and dogs in which the NOAEL was determined [GSK Document Number 
2017N312240_00 and GSK Document Number 2017N312247_00].
Table 1 below shows the safety margins in terms of lung and systemic exposure with 
respect to the NOAEL obtained from the pre-clinical studies, and the folder cover with 
respect to the systemic exposure following oral administration of the marketed dose 
(1200 mg/day) in humans for the doses proposed in this study.  These data indicated 
reasonable safety margins for Cohort A in Parts 1 and 2, where single dose of CCI15106-
IP will be administered.
The selection of appropriate dose for Part 1 Cohort B will be performed upon 
consideration of available safety, tolerability and systemic PK data from Part 1 cohort A. 
The review data set for this selection will, at minimum, consist of: any adverse events, 
liver function test results, vital signs, ECG, spirometry data, and laboratory findings, and 
any available systemic PK results. 
The selection of appropriate dose for Part 2 Cohort A will be performed upon 
consideration of available safety and tolerability data following the single doses (60 and 
120 mg) in all participants in Cohort A of Part 1.
The selection of appropriate dose for Part 2 Cohort B will be performed upon 
consideration of available safety, tolerability, systemic PK and lung concentration data 
from Part 1 Cohort B.
The dose level in any cohort may be titrated up or down based on emerging safety, 
tolerability, and systemic PK and lung data where available.  The maximum dose will not 
exceed 120 mg per day.


2016N290366_01
CONFIDENTIAL
205822
38
Table 1
Prediction of Human Systemic and Lung Exposure and Safety 
Margins of CCI15106
Dose 
Frequency
Proposed 
human 
dose per 
day (mg) 
Human 
Lung 
Dose 
(mg/g)
Lung 
Safety 
Margin 
(Rats)
Lung 
Safety 
Margin 
(Dogs)
Human 
Systemic 
expoure         
AUC(0-24) 
(ng.h/mL) *
Systemic 
Safety 
Margin 
(Rats)
Systemic 
Safety 
Margin 
(Dogs)
Systemic 
Safety 
Margin 
(human 
Oral 
Ribavirin)
Assume 100% lung deposition in humans
SD
60
0.06
12
16
SD
120
0.12
6
8
Assume 59% lung deposition in humans
SD
60
0.04
20
26
552
17
40
92
SD
120
0.07
10
13
1104
8
20
46
BD**
30
0.04
20
26
3080
3
7
16
BD
60
0.07
10
13
6150
2
4
8
Assumptions:
human: body weight 70 kg, lung weight 1000 g; 100% or 59% inhaled dose into lungs are assumed
59% was predicted from the MPPD for lung deposition of the device
rat: mean body weight 0.244kg, mean lung weight 1.145 g, 10% inhaled dose into lungs;
dog: mean body weight 8 kg, mean lung weight 73.1 g, 25% inhaled dose into lungs.
Rat NOAEL dose = 32.5 mg/kg, AUC=9.34 g.h/mL (whole study means)
Dog NOAEL dose = 34.2 mg/kg, AUC=22.2 g.h/mL (whole study means)
Human oral AUC(0-24) =2xAUC0-12=50.722 g.h/mL (Steady state) [Copegus USPI, 2015]
* human systemic AUC(0-24) is predicted from a mechanistic model [Weber, 2017]
** BD - twice daily dosing; AUC(0-24) on Day 14 
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
6.1.1.
Inclusion Criteria for Healthy Participants and Bystanders
Participants are eligible to be included in the study only if all of the following criteria 
apply.  Rescreening is allowed only if approved by the Medical Monitor.
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.


2016N290366_01
CONFIDENTIAL
205822
39
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
3.
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator (in 
consultation with the Medical Monitor if required) decide and document that the
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.  
Weight
4.
Body weight 50 kg for males and 45 kg for females and body mass index (BMI) 
within the range 19 to 31 kg/m2 (inclusive) for males and 17 to 31 kg/m2 (inclusive)
for females.
Sex
5.
Male OR Female
a. Male participants:
A male participant with female partner of child bearing potential must agree to use 
contraception as detailed in Appendix 5 of this protocol during the treatment period 
and for at least 7 months 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 not pregnant (see Appendix 5),
not breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in 
Appendix 5.  
Informed Consent
6.
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.
6.1.2.
Inclusion Criteria for Participants with COPD
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 40 to 75 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics


2016N290366_01
CONFIDENTIAL
205822
40
2.
Diagnosed with moderate COPD (GOLD class II) by a qualified physician as defined 
by the GOLD guidelines (http://www.goldcopd.org/).
3.
The participant has spirometry at screening, conducted 15-30 minutes after 
administration of 400 microgram (g) salbutamol via metered dose inhaler showing:

post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% and 
<80% predicted normal [Quanjer, 2012] and

post-bronchodilator FEV1/ forced vital capacity (FVC)<0.7, where FEV1 is 
forced expiratory volume in 1 second and FVC is forced vital capacity. 
4.
Participant is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).
5.
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor if required agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Weight
6.
Body weight ≥ 45 kg and BMI within the range 17 – 32 kg/m2 (inclusive).
Sex
7.
Male OR Female
a. Male participants:
A male participant with female partner of child bearing potential must agree to use 
contraception as detailed in Appendix 5 of this protocol during the treatment period 
and for at least 7 months 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 not pregnant (see Appendix 5),
not breastfeeding, and not a WOCBP as defined in Appendix 5.  
Informed Consent
8.
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
6.2.1.
Exclusion Criteria for Healthy Participants and Bystanders
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 


2016N290366_01
CONFIDENTIAL
205822
41
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
4.
QTc > 450 msec
NOTES:

The QTc is the QT interval corrected for heart rate (HR) according to 
Fridericia’s formula (QTcF), machine-read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial.

For purposes of data analysis, QTcF will be used as specified in the RAP.
5.
Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<40 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcF interval 
>450 msec
6.
Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, 
metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions 
that, in the opinion of the investigator may place the participant at an unacceptable 
risk as a participant in this trial or may interfere with the absorption, distribution, 
metabolism or excretion of drugs.
Prior/Concomitant Therapy
7.
Past or intended use of over-the-counter or prescription medication (including herbal 
medications) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is longer) prior to dosing until completion of the follow-up 
visit, unless in the opinion of the Investigator and sponsor the medication will not 
interfere with the study.  Specific medications listed in Section 7.7 may be allowed.
Prior/Concurrent Clinical Study Experience
8.
Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 month period.
9.
Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.


2016N290366_01
CONFIDENTIAL
205822
42
10. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
Diagnostic assessments
11. Hemoglobin (Hgb) below the lower level of the normal range with one repeat testing 
allowed, or known hemoglobinopathies.
12. Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, and erythema multiforme.
13. Presence of Hepatitis B surface antigen (HBsAg) at screening, Positive Hepatitis C 
antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
15. Positive pre-study drug/alcohol screen
16. Positive HIV antibody test
17. Regular use of known drugs of abuse
Other Exclusions
18. Male partners of women who are pregnant or lactating
19. Regular alcohol consumption within 3 months prior to the study defined as: 

an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits. 
20. Breath test indicative of smoking at day -1.
21. History of sensitivity to any of the study medications, including CCI15106 or 
components thereof and, for cohorts that will undergo BAL, those that may be used in 
association with the BAL procedure or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.
22. For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage 
including hypercapnia >50 mm Hg, abnormal blood coagulation parameters, known 
or suspected intolerance of medications necessary for bronchoscopy, refractory 
hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial 
infarction.
23. Documented lactose allergy/intolerance for dosing cohorts.


2016N290366_01
CONFIDENTIAL
205822
43
6.2.2.
Exclusion Criteria for Participants with COPD
1.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
4.
QTc > 450 msec or QTc > 480 msec in participants with Bundle Branch Block
NOTES:

The QTc is the QT interval corrected for HR according to Fridericia’s formula 
(QTcF), machine-read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial.

For purposes of data analysis, QTcF will be used as specified in the RAP.
5.
Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<40 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcF interval 
>450 msec
6.
Participant has poorly controlled COPD, defined as the occurrence of either of the 
following:
Acute worsening of COPD requiring use of antibiotics or systemic corticosteroids 
in the 6 weeks prior to screening visit OR
More than 2 exacerbations of COPD requiring treatment with oral steroids in the 
preceding year or hospitalization for the treatment of COPD within 3 months of 
screening or more than twice during the preceding year.
7.
History of an upper or lower respiratory tract infection requiring antibiotics in the 4 
weeks prior to screening
8.
Participant has a diagnosis of active tuberculosis, lung cancer, clinically overt 
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that 
might, in the opinion of the Investigator, compromise the safety of the participant or 
affect the interpretation of the results. 
9.
Unstable or uncontrolled cardiac disease.


2016N290366_01
CONFIDENTIAL
205822
44
10. Participants who have past or current medical conditions or diseases that are not well 
controlled and, which as judged by the Investigator, may affect participant safety or 
influence the outcome of the study.  (Note: Patients with adequately treated and well 
controlled concurrent medical conditions (e.g. hypertension) ARE permitted to be 
entered into the study).
Prior/Concomitant Therapy
11. Participants are not allowed to take oral corticosteroids from 4 weeks prior to 
screening and for the duration of the study.
12. Participants taking medications for any chronic conditions have to be on stable doses 
for 4 weeks prior to screening and until after completion of the treatment period.  
This includes COPD maintenance therapies (e.g. inhaled corticosteroids, long-acting 
beta-agonists, long-acting muscarinic agonists).
13. Didanosine and azathioprine are not allowed.
14. Use of short-acting inhaled bronchodilators is allowed, but participants must be able 
to discontinue their medications several times during the study as described in 
Section 7.7.
15. Use of long-acting bronchodilators is allowed, but participants must be able to 
modify the schedule of their medications twice during the study as defined in 
Section 7.7.
Prior/Concurrent Clinical Study Experience
16. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
17. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
18. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
Diagnostic assessments
19. Impaired renal function (eGFR <30 cc/min, using CKD-EPI equation).
20. Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, and erythema multiforme.
21. Hgb below the lower level of the normal range with one repeat testing allowed or 
known hemoglobinopathies.
22. Presence of Hepatitis B surface antigen (HBsAg) at screening, Positive Hepatitis C 
antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained


2016N290366_01
CONFIDENTIAL
205822
45
23. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
24. Positive pre-study drug/alcohol screen
25. Positive human immunodeficiency virus (HIV) antibody test
26. Regular use of known drugs of abuse
Other Exclusions
27. Male partners of women who are pregnant or lactating
28. Regular alcohol consumption within 3 months prior to the study defined as: 

an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits. 
29. Unable to refrain from smoking for 2 h prior to dosing and until all assessments are 
complete for 4 h after dosing and also for 1 h prior to any vital signs and ECG 
assessments.
30. History of sensitivity to any of the study medications, including CCI15106 or 
components thereof and, for cohorts that will undergo BAL, those that may be used in 
association with the BAL procedure or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.
31. For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage 
including hypercapnia >50 mm Hg, abnormal blood coagulation parameters, known 
or suspected intolerance of medications necessary for bronchoscopy, refractory 
hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial 
infarction.
32. Documented lactose allergy/intolerance.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants will be allowed soft drinks without caffeine starting from 2 h after 
dosing, including both AM and PM doses.  Standardized meals will be provided 
while the participant is confined to the clinical research unit, as outlined below.

Participants will report to the clinic fasting (for at least 8 h) for screening visit, Day -
1 of treatment periods and for follow-up visit.

At all mealtimes, food will be served only after completion of protocol specified 
procedures scheduled at or around the same time.


2016N290366_01
CONFIDENTIAL
205822
46

The morning dose of the CCI15106-IP will be given after fasting (for at least 8 h).  
The evening dose of the CCI15106-IP will be given at least 2 h after food.  The 
doses will be approximately 12 h apart.  For the first dose for any participant in the 
study, water should not be allowed for 2 h prior to dosing.  For all other doses, water 
will be allowed freely.

Participants should not eat for 2 h after dose administration for the single dose 
cohorts and after the first dose of the multiple dose cohorts.

Breakfast will not be provided on the mornings of the BAL, however a snack is 
permitted on this day after the end of the procedure, as long as it does not interfere 
with any study related procedures.

All other meals and snacks may be provided as per the clinics schedule.  Should a 
mealtime interfere with a study procedure such as BAL, the investigator in 
consultation with the sponsor, may modify the meal times to ensure safety of the 
participants.  Also, the fasting requirements may be modified or removed at any time 
during the study at the discretion of the sponsor in consultation with the investigator.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 h 
prior to the start of dosing until the participants leave the clinical unit. 

During each dosing session, participants will abstain from alcohol for 24 h prior to 
the start of dosing until the participants leave the clinical unit. 

For healthy participants, use of tobacco products is not allowed from screening until 
after participants leave the clinical unit.

Participants with COPD who use tobacco products will be instructed that use of 
nicotine-containing products (including nicotine patches) will not be permitted while 
they are in the Clinical Unit.  Participants with COPD will be escorted by staff for 
smoking breaks except during the period for 2 h prior to dosing and until all 
assessments are complete for 4 h after dosing.
6.3.3.
Activity

Participants will abstain from strenuous exercise from screening until follow-up visit.
Participants may participate in light recreational activities during studies (eg, 
watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.


2016N290366_01
CONFIDENTIAL
205822
47
Individuals who do not meet the criteria for participation in this study may be rescreened 
only upon approval of Medical Monitor.  Rescreened participants should be assigned a 
different screening 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.


2016N290366_01
CONFIDENTIAL
205822
48
7.1.
Treatments Administered
Study Treatment 
Name:
CCI15106-IP
Placebo
Dosage formulation:
1 capsule
1 capsule
Unit dose 
strength(s)/Dosage 
level(s):
30 mg of CCI15106
As 30.3 mg of CCI15106: 
polyvinyl alcohol 99:1 w/w 
PRINT 0.9x1 m cylinder
shape crystalline particles
30.3 mg of lactose: polyvinyl 
alcohol 98:2 w/w PRINT 0.9x1 m 
cylinder shape amorphous 
particles
Route of 
Administration 
By inhalation
By inhalation
Dosing instructions:
Each inhalation will follow 
instructions provided with 
the device.  The number of 
inhalations will depend on 
the dose.
The morning dose to be 
taken fasting (at least 8 h).  
For repeat dose cohorts, the 
evening dose to be taken at 
least 2 h after food.
For repeat dose cohort(s) 
with bystander exposure 
monitoring, a 1.5 h window 
is allowed.
Each inhalation will follow 
instructions provided with the 
device.  The number of inhalations 
will depend on the dose.
The morning dose to be taken 
fasting (at least 8 h).  For repeat 
dose cohorts, the evening dose to 
be taken at least 2 h after food.
For repeat dose cohorts with 
bystander exposure monitoring, a 
1.5 h window is allowed.
Packaging and 
Labeling
Study Treatment will be 
provided in a HDPE (high 
density polyethylene) bottle. 
Each bottle contains 2 
capsules and a desiccant 
canister.  Each bottle is 
overwrapped in a foil pouch 
containing a desiccant 
sachet. Each bottle and 
each pouch will be labelled 
as required per country 
requirement.
Study Treatment will be provided 
in a HDPE bottle. Each bottle 
contains 2 capsules and a 
desiccant canister.  Each bottle is 
overwrapped in a foil pouch 
containing a desiccant sachet. 
Each bottle and each pouch will
be labelled as required per 
country requirement.
Device
Monodose RS01
Monodose RS01
Manufacturer
Plastiape S.p.A.
Plastiape S.p.A.


2016N290366_01
CONFIDENTIAL
205822
49
7.1.1.
Medical Devices

The GSK manufactured medical devices (or devices manufactured for GSK by a
third party) provided for use in this study are Monodose RS01.

Instructions for medical device use are provided in the Study Reference Manual 
(SRM).

GSK medical device incidents, including those resulting from malfunctions of the
device, must be detected, documented, and reported by the investigator throughout 
the study (see Section 9.2).
7.2.
Dose Modification

This protocol allows some alteration from the currently outlined dosing schedule.  
The maximum daily dose administered will not exceed 120 mg per day either as a 
single dose or as 60 mg BID.

The decision to proceed to Part 1 Cohort B will be made by the GSK Study Team
comprised at a minimum of the team leader, medical monitor, Global Clinical Safety 
and Pharmacovigilance scientist or physician (Clinical Pharmacokineticist, 
Statistician and Preclinical Safety Assessment as necessary), and the Investigator or 
delegate based on safety and tolerability data obtained in all participants at the prior 
dose levels in Part 1.  The actual doses to be administered may be adjusted based on 
safety, tolerability, and preliminary PK data if appropriate, at previous dose levels; 
these dose adjustments may involve either an increase or a decrease in the planned 
dose.  The highest dose in the study will not exceed 120 mg per day either as a single 
dose or as 60 mg BID.

The decision to proceed to participants with COPD will be made by the GSK Study 
Team comprised at a minimum of the team leader, medical monitor, Global Clinical 
Safety and Pharmacovigilance scientist or physician (Clinical Pharmacokineticist, 
Statistician and Preclinical Safety Assessment as necessary), and the Investigator or 
delegate based on safety and tolerability data obtained after single dosing completes 
in healthy participants in Part 1 Cohort A.  

The actual doses to be administered may be adjusted based on safety, tolerability, 
and preliminary PK data if appropriate, at previous dose levels; these dose 
adjustments may involve either an increase or a decrease in the planned dose.  

The dosing schedule may also be adjusted to expand a dosing cohort to further 
evaluate safety and PK findings at a given dose level, or to add cohorts to evaluate 
additional dose levels.  The study procedures for these additional participant(s) or 
cohort(s) will be the same as that described for other study participants.


2016N290366_01
CONFIDENTIAL
205822
50
7.3.
Method of Treatment Assignment
No treatment assignment will be performed for bystander cohort(s).
For all other cohorts, participants will be centrally randomized using an Interactive Web 
Response System.
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106-
IP or Placebo with 3:1 ratio.  In Cohort B Part 1 and Cohort B Part 2, participants will be 
randomized with 6:1 ratio. 
Study treatment will be dispensed at all times indicated in the SoA (Section 2).
7.4.
Blinding
This will be a double-blind (sponsor unblinded) study.  The GSK study team participating 
in the dose escalation meetings will be blinded to the participant’s treatment assignment 
and will be un-blinded only if necessary to facilitate review of the safety, tolerability and 
PK data as appropriate in real time to inform dose escalation decisions.
However, the study team performing the analyses to support dose escalation decisions 
will be unblinded to allow accurate assessment of the data, including the study 
pharmacokineticists, statisticians, programmers and data managers, who will have access 
to the randomization codes for analysis purposes. If additional contract research 
organizations are involved in data analysis or in statistical analysis and programming, the 
same will apply to their staff as well.
Participants will be randomized to receive study treatment.  Investigators will remain 
blinded to each participant’s assigned study treatment throughout the course of the study.  
In order to maintain this blind, an otherwise uninvolved 3rd party will be responsible for 
the reconstitution and dispensation of all study treatment and will ensure that there are no 
differences in time taken to dispense following randomization.
This 3rd party will instruct the participant to avoid discussing the taste, dosing frequency, 
or packaging of the study treatment with the investigator or with other participants.
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to un-blinded study treatment records at the site(s) to verify that 
randomization/dispensing has been done accurately.
Additional double-blinded, single-blinded or open-label repeat dose cohort(s) may be 
added at a dose not to exceed 120 mg daily.  

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. 

Investigators have direct access to the participant’s individual study treatment. 


2016N290366_01
CONFIDENTIAL
205822
51

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. 

The date and reason for the unblinding must be fully documented.
A participant may continue in the study if that participant’s treatment assignment is 
unblinded, upon discussion with the medical monitor.  
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.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.

Capsules should be kept refrigerated (2-8°C) in their sealed packaging, protected 
from moisture. 

Monodose RS01 devices will be supplied in bulk.  After use, the devices will be 
placed in a plastic bag, and the bag will be labelled with the participant number, day 
of dosing, and date.  Devices will be disposed of at site after reconciliation is verified 
by study monitor.

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).  

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM or equivalent. 

Precaution will be taken to avoid direct contact with the study treatment.  No women 
of child-bearing potential will administer study treatment.  Staff administering the 
study treatment will wear protective gown and gloves.  A Material Safety Data Sheet  
describing occupational hazards and recommended handling precautions will be 
provided to the investigator.  In the case of unintentional occupational exposure 
notify the monitor, Medical Monitor and/or GSK study contact.


2016N290366_01
CONFIDENTIAL
205822
52
Dosing Procedure for Cohorts not Used for Environmental Exposure 
Monitoring

Participants will inhale the dose from the Monodose RS01 device inside a negative 
pressure room or enclosure.

The investigator/designee will remove the capsule from the bottle and load it into the 
Monodose RS01 device one at a time in a safety cabinet.  One device will be used per 
capsule.  The investigator/designee will be trained to load the capsule into the device
and pierce the capsule ready for inhalation (empty capsules will be used for training).

The participant will inhale the dose, and staff will observe participant doing it.  Staff 
will be trained to listen for a rattle that the device makes during successful dosing.  
After dosing, the Monodose RS01 device will be placed in a plastic bag, and the bag 
will be labelled with the participant number, day of dosing, and date.

The participant will be trained to use a “fast and deep” inspiration technique per 
inhalation, to achieve rapidly consecutive maximal inhalations (empty capsules will 
be used for training).  This will ensure optimal and consistent treatment delivery.  For 
participants, the training session will be on either Day -1 or on Day 1, prior to 
administration of the first dose.  Subsequent assessment of Monodose RS01 device
technique, and repeat device training where deemed necessary by the 
investigator/designee, will take place immediately before administration of each dose. 
Dosing Procedure for Cohorts Used for Environmental Exposure 
Monitoring

Participants will inhale the dose from the Monodose RS01 device in a room 
designated for dosing. All investigators/designees will leave the room and observe 
dosing participants and bystanders through a glass in the door.  Only participants 
inhaling the dose and designated bystanders are allowed in the room during inhalation 
of the dose.

The bystander will remove the capsule from the bottle and load it into the Monodose 
RS01 device one at a time.  One device will be used per dose (2 capsules in this 
cohort).  The bystander will be trained to load the capsule into the device and pierce 
the capsule ready for inhalation (empty capsules will be used for training).    

The bystander will pass loaded and charged device to the dosing participant. 

The participant will inhale the dose, and staff will observe participant doing it through 
a glass in the door.  The bystander will be trained to listen for a rattle that the device 
makes during successful dosing.  After dosing, the participant will pass the device 
back to the bystander.

The bystander will open the device, remove the capsule and place it on the table 
between the dosing participant and the bystander.  The bystander will then load the 
second capsule into the same device, pierce the capsule and pass the loaded device 
back to the dosing participant.

The participant will inhale the second dose, the bystander will listen for a rattle that 
the device makes during successful dosing and staff will observe participant doing it 


2016N290366_01
CONFIDENTIAL
205822
53
through a glass in the door.  After dosing, the participant will pass the device back to 
the bystander.

The bystander will open the device, remove the second capsule, and place the open 
device with both capsules on the table between the dosing participant and the 
bystander. 

The bystander and participant will remain seated around the table for 15 min.  After 
this time, the bystander will place the Monodose RS01 device and both used capsules
into the plastic bag labelled with the participant number, day of dosing, and date.  
After that is done, bystander and participant can leave the room.  The bystander will 
need to wash their hands prior to leaving the room.

The participant will be trained to use a “fast and deep” inspiration technique per 
inhalation, to achieve rapidly consecutive maximal inhalations (empty capsules will 
be used for training).  This will ensure optimal and consistent treatment delivery.  For 
participants and bystanders, the training session will be on either Day -1 or on Day 1, 
prior to administration of the first dose.  Subsequent assessment of Monodose RS01
device technique, and repeat device training where deemed necessary by the 
investigator/designee, will take place immediately before administration of each dose. 
7.6.
Treatment Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff. 
The participants 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.  
If failure of the capsule actuation is suspected (i.e. due to failure to pierce the capsule 
during device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose.  If dosing failure is suspected 
for any other reason, the participant may have to be excluded after consultation with the 
Medical Monitor.
The Monodose RS01 devices will be under the supervision of the study organisers at all 
times during the clinical trial. 


2016N290366_01
CONFIDENTIAL
205822
54
7.7.
Concomitant Therapy
7.7.1.
Permitted Medications and Non-Drug Therapies
Paracetamol or Acetaminophen, at doses of ≤2 grams/day is permitted.
Medications associated with the BAL procedure are permitted, but these medications are 
to be disclosed to the Sponsor prior to dosing any participants.
Participants with COPD taking medications for any chronic conditions have to be on 
stable doses for 4 weeks prior to screening and until after completion of the treatment 
period.
Salbutamol is administered 15 to 30 min prior to spirometry at screening for diagnostic 
purposes.  Short-acting bronchodilators should not be used from 6 h prior to each 
morning dose administration until 4 h after that dose.  If they become medically 
necessary during that time, short-acting bronchodilators may be administered as needed 
by the clinical staff only and their use must be documented.  
For participants with COPD, use of long-acting bronchodilators is allowed, but their use
must be modified twice during the study as follows:  at screening and on Day 1, they 
must not be taken for at least 2 h prior to spirometry.
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the Medical Monitor.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Participants are not allowed to take oral corticosteroids from 4 weeks prior to screening 
and for the duration of the study.
For participants with COPD, self administration of short-acting inhaled bronchodilators is 
not allowed at screening, from 4 h prior to spirometry until spirometry is completed.  Self 
administration of short-acting inhaled bronchodilators is not allowed during treatment 
period from 6 h prior to each morning dose administration until 4 h after that dose.  
Didanosine and azathioprine are not allowed.
Except as permitted in Section 7.7.1, participants must abstain from taking prescription or 
non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 
days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication until completion of the follow-up visit, 
unless in the opinion of the Investigator and sponsor the medication will not interfere 
with the study.


2016N290366_01
CONFIDENTIAL
205822
55
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because most of the participants are healthy and 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 
specific post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
If participant is withdrawn from study treatment, this constitutes withdrawal from study.  
Participants will have to be followed up for safety reasons as deemed necessary by the 
Investigator and should be encouraged to return for a follow-up visit as specified in the 
SoA (Section 2).  If this is not possible, procedures specified for the follow-up visit can 
be performed at the last visit that the participant attends.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined above


2016N290366_01
CONFIDENTIAL
205822
56

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation  is in the 
best interest of the participant.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6. 
8.1.2.
QTc Stopping Criteria
A participant who meets either bulleted criterion below will be withdrawn from the 
study:  

QTc, QTcF >500 msec,

Change from baseline: QTc >60 msec
For participants with COPD with underlying bundle branch block, follow the 
discontinuation criteria listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
>500 msec
450 – 480 msec
≥530 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
See the SoA (Section 2) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed.
8.1.3.
Other Stopping Criteria
Dosing will be stopped for any individual participant in case of SAEs and in case of any 
AEs which in the opinion of the investigator might jeopardise the health of the trial 
participant. 


2016N290366_01
CONFIDENTIAL
205822
57
Additionally, dosing will be stopped and the study will be put on halt if any of the below 
scenarios occurred.  If following an internal safety review the Sponsor deems it 
appropriate to restart the trial, this can be done following approval of a substantial 
amendment:
Two (2) or more subjects, within a dose-level, receiving study treatment experience grade 
3 respiratory adverse event that are deemed possibly or probably related to study drug by 
the investigator.
Two (2) or more subjects, within a dose-level, receiving study treatment experience a
grade 3 hematologic adverse event that are deemed possibly or probably related to study 
drug by the investigator.
Two (2) or more subjects, within a dose-level, receiving study treatment experience 
severe hypersensitivity related adverse event that are deemed possibly or probably related 
to study drug by the investigator.
Two (2) or more subjects, within a dose-level, receiving study treatment experience a 
grade 3 vital signs (heart rate and/ or blood pressure) adverse event that are deemed 
possibly or probably related to study drug by the investigator.
One (1) or more subjects receiving study treatment experience anaphylaxis that is deemed 
possibly or probably related to study drug by the investigator.
8.1.4.
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 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 (Section 2) for data to be collected at follow-up and for any further 
evaluations that need to be completed.

Participants will have to be followed up for safety reasons as deemed necessary by 
the Investigator and should be encouraged to return for a follow-up visit as specified 
in the SoA (Section 2).  If this is not possible, procedures specified for the follow-up 
visit can be performed at the last visit that the participant attends.


2016N290366_01
CONFIDENTIAL
205822
58
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 (Section 2).

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA
(Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA (Section 2).

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

The following time window tolerances apply to all protocol assessments:


2016N290366_01
CONFIDENTIAL
205822
59
Predose 
- 60 to 0 min (- 60 to -15 min for spirometry)
0h - 4h post
- 5 / + 10 min
5h – 24h post
- 10 / + 10 min
9.1.
Efficacy Assessments
There are no efficacy assessments in this study.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).  However, any SAEs assessed as related 
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study.

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 case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately and 
no later than in 24 h, as indicated in Appendix 4. The investigator will submit any 
updated SAE data to the sponsor within 24 h of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.


2016N290366_01
CONFIDENTIAL
205822
60
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information eg, summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular  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 Cardiovascular CRFs are presented as queries in response to reporting of certain 
Cardiovascular MedDRA terms. The Cardiovascular information should be recorded in 
the specific cardiovascular section of the CRF within one week of receipt of a 
Cardiovascular 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.


2016N290366_01
CONFIDENTIAL
205822
61
9.2.6.
Pregnancy

Female participants of child bearing potential are excluded from this study

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until 7 months after the last dose of study 
treatment.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.7.
Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for inhalation.  In order to fulfill 
regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 7.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2.1, Section 9.2.2, Section 9.2.3, Section 9.2.4 and Appendix 4 of 
the protocol. 
9.2.7.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented, and reported during all periods of the study in which the 
medical device is used. 

If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the 
sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 7.
9.2.7.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 9.2.1, Section 9.2.2, Section 9.2.3, and 
Section 9.2.4). This applies to all participants, including those who discontinue study 
treatment or the study.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.


2016N290366_01
CONFIDENTIAL
205822
62
9.2.7.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Medical device incidents will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

The Medical Device Incident Report Form will be sent to the sponsor by facsimile 
transmission. If facsimile transmission is unavailable, then notification by telephone 
is acceptable for incidents, with a copy of the "Medical Device Incident Report 
Form" sent by overnight mail.

The same individual will be the contact for the receipt of medical device reports and 
SAE.
9.2.7.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.3.
Treatment of Overdose
For this study, any dose of CCI15106-IP greater than the dose specified for the treatment 
period within a 24 h time period [4 h] will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
CCI15106 can no longer be detected systemically (at least 302 days).
3.
Obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).


2016N290366_01
CONFIDENTIAL
205822
63
9.4.1.
Screening Assessments
Cardiovascular medical history/risk factors 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.  
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
9.4.2.
Physical Examinations

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems, and skin. 
Height and weight will also be measured and recorded. Oral exam will be 
performed.

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).  Oral exam will also 
be performed.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.3.
Vital Signs

Vital signs will be measured in semi-supine position and will include oral or 
tympanic temperature, pulse rate, respiratory rate, and systolic and diastolic blood 
pressure. The same method of temperature assessment should be used throughout 
the study.

For BAL, vital signs will also include oxygen saturation and will be evaluated and 
recorded before, every 5 minutes during the procedure, at the end of, and between 30 
and 60 minutes after the bronchoscopy. 

Blood pressure and pulse measurements will be assessed 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).

Three readings of blood pressure and pulse rate will be taken where indicated as 
triplicate in SoA (Section 2) and all three readings will be recorded.


2016N290366_01
CONFIDENTIAL
205822
64
9.4.4.
Electrocardiograms

Triplicate OR single 12-lead ECG will be obtained in semi-supine position after 5 
minutes rest as outlined in the SoA (Section 2) 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.  

At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes.

Continuous cardiac telemetry will be performed where indicated in SoA (Section 2). 
Full disclosures will be reviewed in detail and the review maintained as part of the 
participant’s source documents.
9.4.5.
Spirometry

Spirometry (FEV1 and FVC) will be performed at time points specified in the SoA 
(Section 2).  Further tests should be performed, at the discretion of the investigator, if 
the participant has symptoms that could suggest bronchospasm.

Spirometry manoeuvres will be conducted according to ATS/ERS 2005 spirometry 
standards [Miller, 2005]. The greatest FEV1 and the greatest FVC from 3 technically 
acceptable and reproducible manoeuvres will be recorded. 

For participants with COPD, at screening, 400 g salbutamol will be administered 
15-30 minutes prior to performing spirometry.  FEV1 and FVC percent predicted 
values will be derived using the Global Lung Function Initiative reference values 
[Quanjer, 2012].
9.4.6.
Capillary pCO2
The pCO2 levels will be measured at the times indicated in SoA (Section 2).  The 
participant’s hand will be heated in warm water (42 degrees) for about 10 minutes and a 
capillary blood sample will be collected by skin puncture using a lancet or automated 
incision device.
9.4.7.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency. 

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.


2016N290366_01
CONFIDENTIAL
205822
65

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 302 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).
9.4.8.
Environmental and Bystander Exposure Evaluation
Exposure monitoring will be conducted in accordance with the principles outlined in 
prEN 689:2016, the draft European standard for workplace exposure assessment to 
airborne contaminants [prEN 689:2016].
9.4.8.1.
Air Monitoring
During and after the first daily dose on Days 1, 7 and 14 in Cohort B Part 1, static air 
samples will be collected on filters within air pumps positioned in two locations in the 
room.  The air disturbance caused by the pumps is negligible and would not be expected 
to alter the normal air flow patterns in the room.  Marks may be placed on the floor to 
indicate position of the participant and positions of pumps to ensure consistency 
throughout the study.  Samples will be run over 20 and 60 min following dosing in each 
location.  An additional set of samples over 60 min will be taken before the start of 
dosing on Day 1 to provide a background benchmark for reference.
On days when static air sampling is performed, the dosing sessions will have to be 
separated by the time necessary to collect the 60 min air sample.
Sampling devices (Institute of Occupational Medicine [IOM] sampling heads connected 
to sampling pumps) shall be used to measure CCI15106 concentration.  The IOM filter 
cassette assembly will be prepared using an immersion-extraction procedure to avoid any 
errors through wall deposition.  Whenever possible, the Hygienist will observe the room 
through a glass in the door for the duration of sampling to make observations and note 
relevant contextual information to assist in the interpretation of the exposure 
measurements.
Air sample analysis will be performed by the Bureau Veritas laboratory (Bureau Veritas 
North America Inc, 95 Oakwood Road, Lake Zurich, IL, 60047).  For air sampling, field 
blanks (filters which have been handled during the survey but not had air pulled through 
them) will be submitted with samples to check for accidental contamination during 
sample handling and storage.  An average of one blank for every ten field samples will be 
sent for analysis.


2016N290366_01
CONFIDENTIAL
205822
66
9.4.8.2.
Bystander Monitoring
Please refer to Figure 1 for the illustration of the design.  Each dosing participant will be 
assigned a designated bystander for the duration of dosing.  Two participants will dose at 
the same time in sitting position.  The designated bystander will be seated facing their 
dosing participant within approximately 1 m of him/her. The first dosing participant will 
inhale the dose (both capsules), and then the second dosing participant will inhale the 
dose (both capsules).  Please refer to Section 7.5 for detailed instructions on dosing.  
Each participant and their bystander will stay seated for the next 15 min, after which they 
will leave the dosing room.  The staff will exit the room prior to bystander loading the 
capsule into the device (see Section 7.5) and remain outside the room for at least 15 min 
after dosing observing through a glass door.
Figure 1
Bystander and participant design illustration
The next two bystanders will be positioned near the next 2 dosing participants, and so on 
until all dosing is completed.  This procedure will be followed for all doses in Cohort B
Part 1, with the same bystanders positioned next to the same inhaling participant.  After 
the first daily dose on days 1, 7 and 14, blood will be collected from bystanders 15 min 
after dosing (at ~tmax for CCI15106).  Additionally, personal exposure air samples will 
be collected on filters placed on each bystander after the first daily dose on days 1, 7 and 
14. The filters will be worn during dosing and for 15-minute period after dosing.  Static 
air monitoring will be performed at the same time during and after the first daily dose on 
days 1, 7 and 14.  During these dosing sessions, each set of two dosing participants will 
be separated by the time necessary to collect the 60 min air sample. 
The filters used for personal exposure (IOM sampling heads connected to sampling 
pumps) shall be used to measure CCI15106 concentration in the person’s breathing zone.  
The IOM filter cassette assembly will be prepared using an immersion-extraction 
procedure to avoid any errors through wall deposition.  Whenever possible, the Hygienist 
will observe the room through a glass in the door for the duration of sampling to make 


2016N290366_01
CONFIDENTIAL
205822
67
observations and note relevant contextual information to assist in the interpretation of the 
exposure measurements.
See Section 9.5 for PK assessments of bystanders.
9.5.
Pharmacokinetics
9.5.1.
Blood Sample Collection
Blood samples for PK analysis of CCI15106 in plasma will be collected at the time points 
indicated in SoA (Section 2).  One 3 mL blood sample will be collected at each time 
point and the actual date and time of each sample collection will be recorded.  The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the SRM OR equivalent. 
9.5.2.
BAL Sample Collection
BAL samples for ELF concentration analysis of CCI15106, urea, and cell counts will be 
collected at the time points indicated in SoA (Section 2).  The actual date and time of 
each BAL sample collection will be recorded.  
Details of BAL sample collection, processing, storage, and shipping procedures are 
provided in the SRM OR equivalent.
Due to the analysis methodology, any cells present in the ELF will be disrupted and their 
content released and analyzed together with the supernatant. 
9.5.3.
Urea Blood Sample
A 2 mL blood sample will be collected into Lithium Heparin tubes as soon as practically 
possible before the BAL samples.  
Processing for plasma, storage and shipping procedures will be provided in the SRM or 
equivalent.
9.5.4.
Sample Analysis
BAL and plasma analysis will be performed under the control of PTS-DMPK, GSK, the 
details of which will be included in the SRM OR equivalent. Concentrations of 
CCI15106 will be determined in plasma and BAL samples using the currently approved 
bioanalytical methodology. Plasma and BAL urea concentrations will be determined by 
Clinical Pathology, Safety Assessment, GSK.  Raw data will be stored in the Good 
Laboratory Practices archives, GSK.
For bystander exposure, a plasma concentration of less than 0.5 ng/mL (the Limit Of 
Quantification of the method) represents an acceptable exposure since this is 29-fold 
lower than the highest plasma concentration measured at the no effect dose level for 
teratogenicity in the most sensitive species (rat [Rebetol SPC, 2009]).


2016N290366_01
CONFIDENTIAL
205822
68
Once the plasma and BAL samples have been analyzed for CCI15106, any remaining 
plasma or BAL may be used for other compound-related metabolites analyses, 
microbiome analysis, or other exploratory analyses that inform the effect of the drug on 
the body or the disease, the results of which will be reported under a separate protocol.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
Sample size is based on feasibility and though no formal power calculations are 
performed, the sample size is deemed adequate to provide a preliminary assessment of 
safety prior to progression to the next study. 
Part 1
In Part 1, the study plans to enrol healthy participants in 3 cohorts.  In Cohort A, there 
will be 6 participants on active and 2 on placebo, in cohort B, there will be 12 on active 
and 2 on placebo.  In cohort C, there will be 14 subjects who will participate as 
bystanders and they will be associated with the dosing subjects in Cohort B on a one to 
one basis for the entire duration of dosing.  All subjects in Cohort B will also undergo 
BAL.   
Part 2:
In Part 2, 22 participants with COPD are planned to be enrolled.  Cohort A will have 
6 participants on active dose and 2 on placebo and Cohort B will have 12 participants on 
active and 2 on placebo.  Fourteen participants (12 active and 2 placebo) enrolled in 
Cohort B Part 2 will also undergo BAL.
Although the sample size is not based on statistical criteria, general probabilities can be 
determined on the likelihood of seeing adverse events. For example, in Parts 1 and 2, in 


2016N290366_01
CONFIDENTIAL
205822
69
treatment groups where 6 patients will receive the active drug, if the true adverse 
outcome rate is 5%, the chance of seeing at least one adverse outcome at a given dose is 
26%. Similarly, if the true adverse outcome rate is 20%, the chance of seeing at least one 
adverse outcome at a given dose is 73%. For the treatment groups with 12 subjects 
receiving the active treatment, if the true adverse outcome rate is 5%, the chance of 
seeing at least one adverse outcome at a given dose is 46%. Similarly, if the true adverse 
outcome rate is 20%, the chance of seeing at least one adverse outcome at a given dose is 
93%.  This level of predictability is deemed adequate within this Phase 1 setting prior to 
commencement of the next study.
10.1.1.
Sample Size Sensitivity
As sample size is based on feasibility, no sample size sensitivity was performed.
10.1.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Definition / Criteria
Analyses Evaluated
All Participants 
Screened

Comprise of all participants who consent to 
participate in the clinical study.

Defined separately for Part 1 and Part 2.
Safety

Comprise of all participants who receive at least 
one dose of study treatment.

This population will be based on the treatment 
the participant actually received.

Defined separately for Part 1 (excluding 
Cohort C) and Part 2.

Safety

Study Population
Systemic 
Pharmacokinetic
Concentration

Participants who receive at least one dose of 
study treatment and who undergo plasma PK 
sampling and have at least one postdose
concentration result.

PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be 
excluded.

Defined separately for Part 1 (excluding 
Cohort C) and Part 2.

PK
Lung ELF
Concentration 
Population

Participants who receive at least one dose of 
study treatment and who undergo BAL sampling
and have postdose lung ELF CCI15106 and 
urea concentration result.

BAL


2016N290366_01
CONFIDENTIAL
205822
70
Population
Definition / Criteria
Analyses Evaluated

Lung ELF samples that may be affected by 
protocol deviations, will be reviewed by the 
study team to determine whether or not the 
sample will be excluded.

Defined separately for Part 1 and Part 2
Bystander Safety 
Population (Part 
1, Cohort C)

Participants who are present at least once in the 
room with the participant receiving the dose.

Safety

Study Population
Bystander PK
Population (Part 
1, Cohort C)

Participants who are present at least once in the 
room with the participant receiving the dose, 
undergo plasma PK sampling and have post-
dose concentration result.

PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be 
excluded.

PK
10.3.
Statistical Analyses
The analysis and reporting of Part 1 may be conducted prior to the completion of Part 2.
For all parts, the analysis and reporting will be performed after the datasets are authorized 
and released for reporting.
Data will be listed and summarized according to GSK reporting standards, where 
applicable.  Listings will be sorted by cohort, participant and time; summaries will be 
presented by cohort, treatment, and time.    
Descriptive summaries will include n, mean, standard deviation (SD), median, minimum, 
and maximum, geometric mean with associated 95% confidence interval (CI), and the 
between-participant coefficient of variation (%CVb) for continuous variables, n and 
percent will be used as summary statistics for categorical variables.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise.  If there are multiple assessments collected at the 
same scheduled time, the average of these assessments will be used.  For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.1 or higher of the SAS system will be used to analyze the data as well as to 
generate tables, figures, and listings.
Complete details will be documented in the RAP.


2016N290366_01
CONFIDENTIAL
205822
71
10.3.1.
Safety Analyses
All safety analyses will be based on the Safety Population.
Endpoint
Statistical Analysis Methods
Adverse events (AEs)
The proportion of participants reporting AEs will be tabulated by 
treatment and by cohort.  AEs will also be tabulated by severity and 
relationship.
Clinical laboratory
Laboratory results will be included in the reporting of this study for 
hematology, clinical chemistry, and urinalysis. Based upon laboratory 
normal ranges, the laboratory test results will be categorized according 
to the normal range as low (below the lower limit), normal (within the 
normal range) and high (above the upper limit). Summary statistics for 
change from baseline will also be tabulated.
Electrocardiogram
(ECG)
The ECG parameters of PR, QRS, QT, QTc, QTcF and HR (bpm) will be 
reported. Overall assessment of ECG (Investigator’s judgment) will be 
recorded as Normal, Abnormal - Not Clinically Significant and Abnormal -
Clinically Significant. Summary statistics for change from baseline will 
also be tabulated.
Telemetry
Overall assessment of Telemetry (Investigator’s judgment) will be 
recorded as Normal, Abnormal - Not Clinically Significant and Abnormal -
Clinically Significant.
Spirometry
% Predicted forced expiratory volume in 1 second (FEV1) and forced 
vital capacity (FVC) values will be tabulated for each timepoint.
Vital signs 
assessments
The following Vital Signs measurements will be tabulated: supine systolic 
and diastolic blood pressure, pulse rate, respiratory rate and 
temperature. Summary statistics for change from baseline will also be 
tabulated.
Monodose RS01
Device safety
Safety incidents reported from use of medical device will be tabulated.
10.3.2.
Pharmacokinetic Analyses
PK analysis will be the responsibility of the Clinical Pharmacokinetics Modeling & 
Simulation Department (CPMS) within GSK.  Plasma CCI15106 concentration-time data 
will be analyzed by non-compartmental methods with WinNonlin 5.3 and above.  
Calculations will be based on the actual sampling times recorded during the study.  From 
the plasma concentration-time data, the following PK parameters may be determined, as 
data permit:  maximum observed plasma concentration (Cmax), time to Cmax (tmax), 
area under the plasma concentration-time curve [AUC(0-last) and AUC(0-∞) where data 


2016N290366_01
CONFIDENTIAL
205822
72
permit for single dose, and AUC(0-τ) for repeat dose], elimination half-life (t1/2), and 
clearance (CL/F) as data permit.
AUC(0-24), or AUC(0-48), or AUC(0-τ) and Cmax following single and repeat doses 
may be used for assessment of dose proportionality.
Trough concentration (Cτ) samples collected on the specified days may be used to assess 
attainment of steady state.  To estimate the extent of accumulation after repeat dosing, the 
observed accumulation ratio (Ro) may be determined.  
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from Cohorts B of Part 1 and Part 2.
PK data will be presented in graphical and/or tabular form and will be summarized 
descriptively.  A population PK model (POP PK) may be developed with all available 
data as appropriate and may be reported separately.  Further details of the analysis plan 
and methods will be detailed within the RAP and data analysis plan OR equivalent. 
Individual lung ELF concentration data will be summarised, listed and displayed 
graphically on both linear and semi-logarithmic scales for the Cohorts with available ELF 
data.  Where data permit, the individual lung ELF concentration data may be plotted 
against the plasma concentration measured prior to BAL sampling.
All pharmacokinetic data will be stored in the Archives, GSK Pharmaceuticals, R&D.
PK exploratory analyses will be described in the reporting and analysis plan. The 
population PK analysis if conducted, will be presented separately from the main clinical 
study report.
10.3.3.
Bystander and Environmental exposure Analyses
The plasma concentration data from bystanders will be summarised descriptively and 
listed.  The amount of CCI15106 obtained from filters will be tabulated and reported.  
Additional analyses, where deemed necessary, will be described in the RAP.
If data permit, the plasma concentration measured from bystanders may be plotted 
against the data collected from the air filters.
10.3.4.
Interim Analyses
No formal interim analyses are planned for this study.   Safety and tolerability will be 
evaluated as described in Section 5.1.  Systemic and, where available, lung PK may also 
be evaluated.


2016N290366_01
CONFIDENTIAL
205822
73
11.
REFERENCES
Copegus (ribavirin) Tablets. United States Prescribing Information. Genentech. August, 
2015. Available at: http://www.gene.com/download/pdf/copegus_prescribing.pdf. 
Accessed October 15, 2015.
Copegus 200 mg Film-coated Tablets. Summary of Product Characteristics. January, 
2015. Available at: http://www.medicines.org.uk/emc/medicine/11755/spc. Accessed 
October 15, 2015.
De Franceschi L, Fattovich G, Turini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic 
anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection:
role of membrane oxidative damage.  Hepatology. 2000;31:997-1004.
Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British 
Thoracic Society guideline for diagnostic flexible bronchoscopy in adults. Thorax. 2013;
68:i1–i44.
GlaxoSmithKline Document Number 2015N242219_00.  Assessment of the 
pharmacokinetics of CCI15106 (Ribavirin) following single inhaled administration of a 
range of Liquidia PRINT formulations in Wistar Han Rats (GSK Study Number N20691-
39).  October 2015.
GlaxoSmithKline Document Number 2015N249287_00.  Ribavirin Inhibits Replication 
of Human Rhinovirus, Respiratory Syncytial Virus and Influenza Virus in Air-Liquid 
Interface Cell Cultures. October 2015.
GlaxoSmithKline Document Number 2015N250735_02.  Investigator's Brochure for 
inhaled CCI15106 and inhalation device.  October 2015.
GlaxoSmithKline Document Number 2017N312240_00. CCI15106 (cylinder particle): 
Toxicity study by inhalation administration to Wistar Han rats for 4 weeks. 2017.
GlaxoSmithKline Document Number 2017N312247_00. CCI15106 (cylinder particle): 
Toxicity study by inhalation administration to beagle dogs for 4 weeks. 2017.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2
Kaufmann W, Baderb R, Ernst H, Harada T, Hardisty J, Kittel B, et al. 1st International 
ESTP Expert Workshop: ‘‘Larynx squamous metaplasia’’. A re-consideration of 
morphology and diagnostic approaches in rodent studies and its relevance for human risk 
assessment.  Experimental and Toxicologic Pathology. 2009;61:591-603.
Kurai D, Saraya T, Ishii H, Takizawa H. Virus-induced exacerbations in asthma and
COPD. Frontiers in Microbiology. 2013;4:1-12.
Lewis DJ. Morphological assessment of pathological changes within the rat larynx. 
Toxicologic Pathology. 1991;19:352-357. 


2016N290366_01
CONFIDENTIAL
205822
74
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry.  Eur Respir J. 2005; 26:319-338.
Morgenstern B, Michaelis M, Baer P, Doerr H, Cinatl J. Ribavirin and interferon-b
synergistically inhibit SARS-associated coronavirus replication in animal and human
cell lines. Biochem Biophys Res Comm. 2005; 326:905-908.
prEN 689:2016 (E), Workplace exposure; measurement of exposure by inhalation to 
chemical agents – strategy for testing compliance with occupational exposure limit 
values, Comité Européen de Normalisation, Brussels, Belgium, draft, 18 March 2016.
Preston SL, Drusano GL, Glue P, Nash J, Gupta SK, and McNamara P.  
Pharmacokinetics and Absolute Bioavailability of Ribavirin in Healthy Volunteers as 
Determined by Stable-Isotope Methodology.  Antimicrobial agents and chemotherapy. 
1999, 43:2451–2456.
Quanjer PH, Stanojevic S, Cole T, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations.  Eur Respir J. 2012; 40:1324–1343.
Rebetol (ribavirin USP) capsules for oral use; (ribavirin USP) oral solution.  United 
States Prescribing Information.  Merck & Co., INC.  May 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020903s053,021546s009lbl.p
df
Rebetol 200 mg Hard Capsules.  Summary of Product Characteristics. Merck Sharp & 
Dohme Limited, 07 May 2009.  Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000246/WC500048210.pdf
Stryjek-Kaminska D, Ochsendorf F, Roder C, Wolter M, Zeuzem S Photoallergic Skin 
Reaction to Ribavirin. Am J Gastroenterol 1999; 94:1686-1688. 
Thomas E, Ghany MG, Liang TJ, The application and mechanism of action of 
ribbavirin in therapy of hepatitis C. Antiviral Chemistry and Chemotherapy, 2012; 
23:1-12.
Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global
Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive
Pulmonary Disease. Am J of Resp and Critical Care Medicine. 2013;187:347-365.
Virazole (Ribavirin for Inhalation Solution). United States Prescribing Information. 
Valeant Pharmaceuticals North America LLC, April 2013.
Virazole.  Summary of Product Characteristics, December 2014.  Available at: 
https://www.medicines.org.uk/emc/medicine/866#CLINICAL_PRECAUTIONS


2016N290366_01
CONFIDENTIAL
205822
75
Weber A, Computational Modeling Summary to Support Candidate Selection of Inhaled 
PRINT Cyrstallin Ribavirn (CCI15106)-PVOH (99-1 w-w) 0.9x1-um Cylindrical 
Particles.  PIER accession 6301434, 2017.


2016N290366_01
CONFIDENTIAL
205822
76
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
%CV
Coefficient of variation
%CVb
Between-subject coefficient of variation
g
Microgram
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-)
AUC from time zero to end of dosing interval
AUC(0-)
AUC from time zero to infinity
AUC(0-24)
AUC from time zero to 24 hours
AUC(0-t)
AUC from time zero to the time of last quantifiable concentration
BAL
Bronchoalveolar lavage
BMI
Body mass index
CCI15106-CFI
CCI15106 capsules for inhalation
CI
Confidence interval
CL/F
clearance
Cmax
Concentration at maximum
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPMS
Clinical Pharmacology Modeling and Simulation
CRF
Case report form
ECG
Electrocardiogram
ELF
Epithelial lining fluid
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FTIH
First time in human
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B surface antigen
Hep B
Hepatitis B
Hep C
Hepatitis C
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Heart rate
HRT
Hormone replacement therapy
HRV
Human rhinovirus


2016N290366_01
CONFIDENTIAL
205822
77
IB
Investigator brochure
ICH
International conference on harmonization
IEC
Independent Ethics Committee
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
Kg
Kilogram
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
mg
milligram
min
Minute
mL
Milliliter
mm Hg
Millimeter of mercury
NOAEL
No observed adverse effect level
PK
Pharmacokinetics
POP PK
Population PK
PRINT
Particle Replication In Non-wetting Templates
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RSV
respiratory syncytial virus
RTP
Ribavirin triphosphate
SAE
Serious adverse event
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SRM
Study Reference Manual
t1/2
Elimination half-life
Tmax
Time of maximum concentration
ULN
Upper limit of normal
USP
United States Pharmacopeia
USPI
United States Prescribing Information
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
WinNonlin


2016N290366_01
CONFIDENTIAL
205822
78
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 2 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 2
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red blood cells (RBC) 
Indices:
Mean corpuscular 
hemoglobin (MCV)
Mean corpuscular 
volume (MCH)
%Reticulocytes
White blood cell (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
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 


2016N290366_01
CONFIDENTIAL
205822
79
Laboratory 
Assessments
Parameters
C virus antibody) 

Serum pregnancy test in women

Coagulation parameters in the BAL cohorts
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).


2016N290366_01
CONFIDENTIAL
205822
80
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 International conference on harmonization (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. 


2016N290366_01
CONFIDENTIAL
205822
81

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


2016N290366_01
CONFIDENTIAL
205822
82
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 subjects, 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.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 


2016N290366_01
CONFIDENTIAL
205822
83
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 Agreement to 
definition of source data.
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


2016N290366_01
CONFIDENTIAL
205822
84
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


2016N290366_01
CONFIDENTIAL
205822
85
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.
Guidance for Grading Adverse Events
Taken from the Food and Drug Administration (FDA) Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.
The purpose of this appendix is to provide guidance and it is to be used in conjunction 
with the investigator’s judgment.
Guidance for Grading Vital Signs Adverse Events
Vital Signs *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever (°C) **
(°F) *
38.0 – 38.4
100.4 – 101.1
38.5 – 38.9
101.2 – 102.0
39.0 – 40
102.1 – 104
> 40
> 104
Tachycardia - beats 
per minute
101 – 115
116 – 130
> 130
ER visit or 
hospitalization for 
arrhythmia
Bradycardia - beats 
per minute***
50 – 54
45 – 49
< 45
ER visit or 
hospitalization for 
arrhythmia
Hypertension 
(systolic) - mm Hg
141 – 150
151 – 155
> 155
ER visit or 
hospitalization for 
malignant 
hypertension
Hypertension 
(diastolic) - mm Hg
91 – 95
96 – 100
> 100
ER visit or 
hospitalization for 
malignant 
hypertension
Hypotension 
(systolic) – mm Hg
85 – 89
80 – 84
< 80
ER visit or 
hospitalization for 
hypotensive shock
Respiratory Rate –
breaths per minute
17 – 20
21 – 25
> 25
Intubation
* Participant should be at rest for all vital sign measurements
** Oral temperature; no recent hot or cold beverages or smoking
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when 
characterizing
Allergic Reactions
Grade 1 allergic reaction (Pruritis without rash):
Participants with Grade 1 allergic reaction should be evaluated by the investigator
immediately. The study drug should be permanently discontinued if the following signs
or symptoms are noted at any time:
• Temperature >38.5°C


2016N290366_01
CONFIDENTIAL
205822
86
• Eosinophilia
• Respiratory involvement including brochospasm, laryngospasm, or angioedema
• Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 allergic 
reaction may continue the study drug at the discretion of the investigator. The participant
should be advised to contact the investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken. If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed. The 
participant should remain on the study to be followed for safety and PK.
Grade 2 allergic reaction (Localized urticaria):
Participants with Grade 2 allergic reaction should be evaluated by the investigator
immediately. The study drug should be permanently discontinued if the following signs
or symptoms are noted at any time:
• Temperature >38.5°C
• Eosinophilia
• Respiratory involvement including brochospasm, laryngospasm, or angioedema
• Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 allergic 
reaction may continue the study drug at the discretion of the investigator. The participant
should be advised to contact the investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken. If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK.
Grade 3 allergic reaction (Generalized urticaria or angioedema):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial. Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.


2016N290366_01
CONFIDENTIAL
205822
87
Revised ACTG Toxicity
Grade
Definition
Investigator action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue therapy
Grade 4
Anaphylaxis
Discontinue therapy
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:
c.
Results in death
d.
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.
e.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
f.
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.
g.
Is a congenital anomaly/birth defect


2016N290366_01
CONFIDENTIAL
205822
88
h.
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.
Definition of Cardiovascular Events (CV) 
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 


2016N290366_01
CONFIDENTIAL
205822
89
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
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 


2016N290366_01
CONFIDENTIAL
205822
90
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 

New or updated information will be recorded in the originally completed 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 Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor and 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 SRM.


2016N290366_01
CONFIDENTIAL
205822
91
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 3 when having penile-vaginal 
intercourse with a woman of childbearing potential 


2016N290366_01
CONFIDENTIAL
205822
92

Men with a pregnant or breastfeeding partner are not eligible to participate.

In addition male participants must refrain from donating sperm for duration of 
study and for 7 months after study completion or from last dose.
Table 3
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
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. 
Female participants
Female participants of childbearing potential are not eligible to participate. 
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. 


2016N290366_01
CONFIDENTIAL
205822
93

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who can become pregnant are not eligible to participate


2016N290366_01
CONFIDENTIAL
205822
94
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology. 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 h

Record the liver event data, and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline (see 
MONITORING below)

Do not restart or rechallenge participant with 
study treatment
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Blood sample for pharmacokinetic 
(PK) analysis, obtained within 48 h of 
last dose4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant 
medications on the concomitant 
medications report formincluding 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 


2016N290366_01
CONFIDENTIAL
205822
95
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin)  and perform liver 
event follow up assessments within  24-72 hrs 

Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James,2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease.  Collect Liver 
Imaging and/or Liver Biopsy data.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally,if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick,indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excludingstudies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value 
stated will not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
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.


2016N290366_01
CONFIDENTIAL
205822
96
12.7.
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK
medical devices provided for use in the study (see Section 7.1 for the list of GSK medical 
devices).
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects


2016N290366_01
CONFIDENTIAL
205822
97
Examples of incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident. 
This includes any amendment to the device design to prevent recurrence.


2016N290366_02 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
205822 
 
1 
 
TITLE PAGE 
Protocol Title: A double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study to investigate the safety, tolerability, and 
pharmacokinetics of CCI15106 inhalation powder in healthy participants and participants 
with moderate chronic obstructive pulmonary disease (COPD) including evaluation of 
environmental and healthy by-stander exposure levels during dosing. 
Protocol Number: 205822 /02 
Short Title: Study of safety and drug levels of CCI15106 inhalation powder in healthy 
adults and adults with moderate chronic obstructive pulmonary disease.  Study of 
CCI15106 levels in people standing near the person inhaling the drug. 
Compound Number: 
CCI15106  
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Number(s):  EudraCT  2017-001070-42 
Approval Date: 11-OCT-2017 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


PPD
PPD
PPD


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
3 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
11-Oct-2017 
Amendment 1 
31-May-2017 
Original Protocol 
20-Apr-2017 
 
Amendment 02 11-Oct-2017 
Overall Rationale for the Amendment: ensuring that the COPD population in this 
study is more reflective of the real-world COPD population.  
Section # and Name 
Description of Change 
Brief Rationale 
6.1.2 Inclusion Criteria 
for Participants with 
COPD 
Changed BMI 
requirements 
Ensuring that the COPD population in this 
study is more reflective of the real-world 
COPD population 
6.2.2 Exclusion Criteria 
for Participants with 
COPD 
Removed some of the 
exclusion criteria for 
screening ECG 
Ensuring that the COPD population in this 
study is more reflective of the real-world 
COPD population 
6.2.2 Exclusion Criteria 
for Participants with 
COPD 
Reworded exclusion 
criterion around pulmonary 
diseases that participants 
can have, in addition to 
COPD 
Ensuring that the COPD population in this 
study is more reflective of the real-world 
COPD population 
7.3 Treatment 
assignment 
9 Study Assessments 
and Procedures 
Several changes made 
previously via Note to file 
Changes and clarifications made 
previously via Notes to file are now 
incorporated into the protocol 
 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
4 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ............................................................................................................... 7 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 10 
3. 
INTRODUCTION .................................................................................................... 19 
3.1. 
Study Rationale .......................................................................................... 19 
3.2. 
Background ................................................................................................ 19 
3.3. 
Benefit/Risk Assessment ............................................................................ 21 
3.3.1. 
Risk Assessment ......................................................................... 22 
3.3.2. 
Benefit Assessment ..................................................................... 29 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 29 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 30 
5. 
STUDY DESIGN .................................................................................................... 31 
5.1. 
Overall Design ............................................................................................ 31 
5.2. 
Number of Participants ............................................................................... 35 
5.3. 
Participant and Study Completion ............................................................... 36 
5.4. 
Scientific Rationale for Study Design .......................................................... 36 
5.5. 
Dose Justification ........................................................................................ 37 
6. 
STUDY POPULATION ........................................................................................... 38 
6.1. 
Inclusion Criteria ......................................................................................... 38 
6.1.1. 
Inclusion Criteria for Healthy Participants and Bystanders ........... 38 
6.1.2. 
Inclusion Criteria for Participants with COPD ............................... 39 
6.2. 
Exclusion Criteria ........................................................................................ 40 
6.2.1. 
Exclusion Criteria for Healthy Participants and Bystanders .......... 40 
6.2.2. 
Exclusion Criteria for Participants with COPD .............................. 43 
6.3. 
Lifestyle Restrictions ................................................................................... 45 
6.3.1. 
Meals and Dietary Restrictions .................................................... 45 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 46 
6.3.3. 
Activity ......................................................................................... 46 
6.4. 
Screen Failures........................................................................................... 46 
7. 
TREATMENTS ....................................................................................................... 46 
7.1. 
Treatments Administered ............................................................................ 47 
7.1.1. 
Medical Devices ........................................................................... 48 
7.2. 
Dose Modification ....................................................................................... 48 
7.3. 
Method of Treatment Assignment ............................................................... 49 
7.4. 
Blinding ....................................................................................................... 49 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 50 
7.6. 
Treatment Compliance ................................................................................ 52 
7.7. 
Concomitant Therapy.................................................................................. 53 
7.7.1. 
Permitted Medications and Non-Drug Therapies .......................... 53 
7.7.2. 
Prohibited Medications and Non-Drug Therapies ......................... 53 
7.8. 
Treatment after the End of the Study .......................................................... 54 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
5 
8. 
DISCONTINUATION CRITERIA ............................................................................. 54 
8.1. 
Discontinuation of Study Treatment ............................................................ 54 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 54 
8.1.2. 
QTc Stopping Criteria .................................................................. 55 
8.1.3. 
Other Stopping Criteria ................................................................ 55 
8.1.4. 
Rechallenge ................................................................................. 56 
8.2. 
Withdrawal from the Study .......................................................................... 56 
8.3. 
Lost to Follow Up ........................................................................................ 57 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 57 
9.1. 
Efficacy Assessments ................................................................................. 58 
9.2. 
Adverse Events........................................................................................... 58 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 58 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 59 
9.2.3. 
Follow-up of AEs and SAEs ......................................................... 59 
9.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 59 
9.2.5. 
Cardiovascular and Death Events ................................................ 59 
9.2.6. 
Pregnancy ................................................................................... 60 
9.2.7. 
Medical Device Incidents (Including Malfunctions) ....................... 60 
9.2.7.1. 
Time Period for Detecting Medical Device 
Incidents ..................................................................... 60 
9.2.7.2. 
Follow-up of Medical Device Incidents ........................ 60 
9.2.7.3. 
Prompt Reporting of Medical Device Incidents 
to Sponsor .................................................................. 61 
9.2.7.4. 
Regulatory Reporting Requirements for 
Medical Device Incidents ............................................ 61 
9.3. 
Treatment of Overdose ............................................................................... 61 
9.4. 
Safety Assessments ................................................................................... 61 
9.4.1. 
Screening Assessments .............................................................. 62 
9.4.2. 
Physical Examinations ................................................................. 62 
9.4.3. 
Vital Signs .................................................................................... 62 
9.4.4. 
Electrocardiograms ...................................................................... 63 
9.4.5. 
Spirometry ................................................................................... 63 
9.4.6. 
Capillary pCO2 ............................................................................ 63 
9.4.7. 
Clinical Safety Laboratory Assessments ...................................... 63 
9.4.8. 
Environmental and Bystander Exposure Evaluation ..................... 64 
9.4.8.1. 
Air Monitoring ............................................................. 64 
9.4.8.2. 
Bystander Monitoring .................................................. 65 
9.5. 
Pharmacokinetics ....................................................................................... 66 
9.5.1. 
Blood Sample Collection .............................................................. 66 
9.5.2. 
BAL Sample Collection ................................................................ 66 
9.5.3. 
Urea Blood Sample ...................................................................... 66 
9.5.4. 
Sample Analysis .......................................................................... 66 
9.6. 
Pharmacodynamics .................................................................................... 67 
9.7. 
Genetics ..................................................................................................... 67 
9.8. 
Biomarkers ................................................................................................. 67 
9.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .................................................................................................. 67 
10. STATISTICAL CONSIDERATIONS ........................................................................ 67 
10.1. 
Sample Size Determination ........................................................................ 67 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
6 
10.1.1. 
Sample Size Sensitivity ................................................................ 68 
10.1.2. 
Sample Size Re-estimation or Adjustment ................................... 68 
10.2. 
Populations for Analyses ............................................................................ 68 
10.3. 
Statistical Analyses ..................................................................................... 69 
10.3.1. 
Safety Analyses ........................................................................... 70 
10.3.2. 
Pharmacokinetic Analyses ........................................................... 70 
10.3.3. 
Bystander and Environmental exposure Analyses ....................... 71 
10.3.4. 
Interim Analyses .......................................................................... 71 
11. REFERENCES ....................................................................................................... 72 
12. APPENDICES ........................................................................................................ 75 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 75 
12.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 77 
12.3. 
Appendix 3: Study Governance Considerations .......................................... 79 
12.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 83 
12.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 90 
12.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 93 
12.7. 
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 95 
12.8. 
Appendix 8: Protocol Amendment History ................................................... 97 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
7 
1. 
SYNOPSIS 
Protocol Title: A double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study to investigate the safety, tolerability, and 
pharmacokinetics of CCI15106 inhalation powder in healthy participants and participants 
with moderate chronic obstructive pulmonary disease (COPD).  A concomitant study to 
evaluate environmental and healthy bystander exposure levels during dosing. 
Short Title: Study of safety and drug levels of CCI15106 inhalation powder in healthy 
adults and adults with moderate chronic obstructive pulmonary disease.  Study of 
CCI15106 levels in people standing near the person inhaling the drug. 
Rationale: 
This study is the first administration of CCI15106 inhalation powder hard capsules 
(CCI15106:polyvinyl alcohol 99:1 w/w 0.9x1 µm cylinder shape crystalline particles 
presented in capsules, from here on referred to as CCI15106-IP) to humans.  This study 
will evaluate the safety, tolerability, and lung and systemic pharmacokinetics (PK) of 
CCI15106-IP delivered using Monodose RS01 device in healthy participants and in 
participants with moderate COPD.   
The intention of this study is to provide sufficient confidence in the safety of the 
molecule delivered by inhalation to inform progression to further repeat dose and proof 
of concept studies.  
A different formulation of CCI15106 (CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 
µm pollen shape particles) has been previously administered to humans in the first time 
in human study (FTiH) 202031.   
Marketed CCI15106 is classified as teratogenic and is contra-indicated in women who are 
pregnant and in male partners of pregnant women and it is important to understand 
whether bystanders may be exposed to CCI15106 when it is used by patients in a dry 
powder, inhaled form.  This study will evaluate the levels of CCI15106 in room air and in 
the plasma of bystanders.  The study aims to replicate the real-life scenarios of dosing as 
close as possible.  Real-life scenarios may include dosing of multiple patients in a single 
room in a nursing home or dosing of a single patient at home.  A realistic worst-case 
scenario for bystanders is dosing of multiple patients in a standard size room in a nursing 
home.   
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
8 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To investigate the safety and tolerability of 
CCI15106-IP following single and repeat 
escalating doses in healthy participants and 
participants with moderate COPD. 
 
• To determine systemic PK of CCI15106 
following single and repeat escalating doses 
of CCI15106-IP in healthy participants and 
participants with moderate COPD. 
 
 
 
 
 
 
• To evaluate potential inhalation exposure of 
bystanders to airborne CCI15106 during 
self-administered dosing of participants. 
 
 
 
 
• To evaluate the distribution and persistence 
of airborne CCI15106 in room air post-
dosing. 
• Adverse events (AEs), clinical laboratory, 
electrocardiogram (ECG), telemetry, 
spirometry, and vital signs assessments. 
 
 
• Derived systemic PK parameters of 
CCI15106: Single dose: area under the 
curve (AUC) from time zero to the time of 
last quantifiable concentration (AUC[0-last]), 
concentration at maximum (Cmax), time of 
maximum concentration (tmax), AUC from 
time zero to infinity (AUC[0-∞]) elimination 
half-life (t1/2), clearance (CL/F), as data 
permit.  
Repeat dose: AUC from time zero to end of 
dosing interval (AUC[0-τ]) (τ=12 hours [h] 
for twice daily dose regimen), Cmax, tmax, 
elimination half-life (t1/2) as data permit. 
• Concentration of CCI15106 in plasma of 
bystanders 15-20 minutes (min) after dosing 
(at predicted tmax) and amount of 
CCI15106 accumulated on filters fitted on 
bystander over 15 min after dosing. 
 
 
• Amount of CC15106 in room air assessed 
by measuring amount of CCI15106 
accumulated over 20 and 60 min intervals 
during and immediately post-dosing on 
filters fitted on stationary pumps placed in 
the room. 
Secondary 
• To determine the concentration of 
CCI15106 in the lung of healthy participants 
and participants with moderate COPD 
following repeat dosing of CCI15106-IP. 
 
• 
To investigate the performance of the 
Monodose RS01 device for the 
administration of CCI15106-IP in healthy 
participants and participants with moderate 
COPD. 
• Concentrations of CCI15106 in lung 
epithelial lining fluid (ELF) assessed by 
bronchoalveolar lavage.   
 
 
 
• Device safety and performance parameters, 
including medical device incidents reporting, 
as well as systemic PK and lung CCI15106 
concentrations. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
9 
Overall Design: 
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, 
single and repeat escalating dose study.  Investigator and participants will be blinded to 
treatment type (active or placebo), but will know what dose of the medication is being 
administered.  Part 1 will investigate single and repeat ascending doses in healthy 
participants and investigate environmental and bystander exposure.  Part 2 will evaluate 
single and repeat dose in participants with moderate COPD.  Participants may only be 
enrolled in one study part and randomized to one cohort per the randomization schedule. 
Study schematic is presented below: 
 
 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
10 
Number of Participants: 
Approximately 36 healthy participants and approximately 22 participants with COPD 
will be randomized in this study for dosing.     
Treatment Groups and Duration: 
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106-
IP or Placebo with 3:1 ratio.  In Cohort B Part 1 and Cohort B Part 2, participants will be 
randomized with 6:1 ratio.   Cohort C Part 1 will not be randomized or dosed, but each 
bystander participant will be assigned to a dosing participant.  Screening visit will occur 
within 30 days of dosing for cohorts in Part 1 and within 45 days of dosing for cohorts in 
Part 2.  Doses administered and treatment duration for participants in each specific cohort 
will be as defined in the study schematic above.  Participants will return for the follow-up 
visit approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy. 
The total study duration will be approximately 82 days for Cohort A Part 1; 
approximately 75 days for Cohort B Part 1 and Cohort C Part 1; approximately 77 days 
for Cohort A Part 2; and approximately 90 days for Cohort B Part 2. 
2. 
SCHEDULE OF ACTIVITIES (SOA) 
If assessments are scheduled for the same nominal time, THEN the assessments should 
occur in the following order pre-dose: 
1. Telemetry start 
2. spirometry 
3. 12-lead electrocardiogram (ECG) 
4. vital signs 
5. blood draws 
   
and in the following order post-dose: 
1. 
12-lead ECG 
2. vital signs 
3. blood draws  
4. spirometry 
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time. 
• 
The timing and number of planned study assessments, including safety, 
pharmacokinetic, or others assessments may be altered during the course of the 
study based on newly available data (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
11 
• 
Any change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GlaxoSmithKline (GSK) study team member and then archived in the 
study sponsor and site study files, but this will not constitute a protocol 
amendment.  
• 
The institutional review board (IRB)/independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
12 
Screening and follow-up procedures for all cohorts 
Procedure 
Screening, ≤ 30 
days before D1 for 
Part 1 or ≤ 45 days 
before D1 for Part 
21  
Follow up 
30±2 days after the 
last dosing day2 
Notes 
Informed consent 
X 
 
1. Screening assessments can be performed over multiple screening visits 
2. All male participants will be called approximately 7 months after the follow-up visit to 
ensure no partner pregnancy 
3. If test otherwise performed within 3 months prior to first dose of study treatment, testing 
at screening is not required 
4. To be drawn fasting (for at least 8 h) 
5. To be administered to participants with COPD only, 15-30 minutes prior to spirometry 
6. To be done at screening for participants with COPD only, following salbutamol dosing 
7. To be performed in the bronchoalveolar lavage (BAL) cohorts only to confirm participant 
eligibility 
8. To be performed in the BAL cohorts only to confirm participant eligibility.  Can be done 
pre-dose on Day -1 instead, if required 
 
 
Inclusion and exclusion criteria 
X 
 
Demography 
X 
 
Full physical examination including 
height and weight, oral examination  
X 
 
Brief physical examination, oral 
examination 
 
X 
Medical history (includes substance 
usage  and Family history of 
premature CV disease) 
X 
 
Substance testing (drugs, alcohol) 
X 
 
Assessment of child-bearing potential 
for females 
X 
 
Serum pregnancy test in women 
X 
X 
Human immunodeficiency virus (HIV), 
Hepatitis B (Hep B) and Hepatitis C 
(Hep C) screen3 
X 
 
Haematology, clinical chemistry and 
urinalysis (include liver chemistries)4 
X 
X 
Salbutamol administration5 
X 
 
Spirometry6 
X 
 
12-lead ECG and vital signs 
X 
X 
Coagulation parameters7 
X 
 
Capillary pCO28 
X 
 
PK blood sample 
 
X 
AE review  
 
X 
SAE review 
X 
X 
Concomitant medication review 
X 
X 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
13 
Schedule for Cohort A Part 1 
Procedure 
Treatment Period, Days 
 
-1 
11 
2 
31 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination, oral 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Substance testing (drugs, alcohol, tobacco) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaler device training2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test in women 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admittance to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
Haematology, clinical chem and urinalysis 
(include liver chem)5 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Spirometry 
 
X1 
 
X1 
 
 
X6 
 
X7 
 
 
X7 
 
 
 
 
X7 
 
 
X6 
 
 
 
Telemetry (starting 30 min pre-morning 
dose and continuous at least 4h post-
morning dose) 
 
X1 
 
X1 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
12-lead ECG and vital signs 
XX
X 
X1 
 
X1 
 
 
X8 
 
X8 
X8 
 
X8 
X8 
X8 
 
X8 
 
X8 
 
 
 
 
 
CCI15106-IP or placebo treatment, device 
incident assessment 
 
X1 
 
X1 
 
 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
 
 
 
PK blood sample10 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
AE review 
 
======================================================================================== 
SAE review 
============================================================================================= 
Concomitant medication review 
============================================================================================= 
1. 
Single dose days.  Follow schedule for Day 1 of Part 2 Cohort A 
2. 
Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion.   
3. 
Can be performed on Day 1 prior to dosing 
4. 
After all procedures and assessments are complete 
5. 
To be drawn fasting (for at least 8 h) 
6. 
To be performed at the following timepoints in the mornings only: pre-dose, and 0.25, 0.5, 1, 4 h post-dose  
7. 
To be performed at the following timepoints in the mornings only: pre-dose and 4 h post-dose  
8. 
ECG and vital signs to be obtained 2 h after the morning dose  
9. 
BID 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
14 
10. PK samples on days 1, 3, 6, and 19 will be collected at the following timepoints:  pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 h.  On day 2, one sample in the morning (24h post day 1 dose). On days 
4 and 5, one sample on each morning (24h and 48h post day 3 dose). On days 6 and 19, the evening dose will be given after 12 h post-dose sample is collected.  On all other days, PK sample will be 
collected once, before the morning dose (if on dosing days). 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
15 
Schedule for Cohort A Part 2 (and all other single dose administrations) 
Procedure 
Treatment Period, Days (D) and hours (h) 
D-1 
 D1 
D2 
 
Pre-
dose 
0h 
0.25h 
0.5h 
0.75h 
1h 
2h 
4h 
6h 
8h 
10h 
12h 
24h 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination, oral examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Substance testing (drugs, alcohol) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test in women 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admittance to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaler device training1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
Haematology, clinical chem and urinalysis (include liver chem)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Spirometry 
 
X5 
 
X6 
X 
 
X6 
 
X6 
 
 
 
 
 
Telemetry 
 
 
30 min pre-dose and continuous until at least 4 h 
post-dose 
 
 
 
 
 
12-lead ECG and vital signs 
 
XXX 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
CCI15106-IP or placebo treatment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample7 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE review 
 
================================================================= 
SAE review 
============================================================================== 
Concomitant medication review 
============================================================================== 
1. Day -1 inhaler training may be done on Day 1 instead, before the first dose administration.  Other time-points may be added per investigators discretion 
2. Can be performed on Day 1 prior to dosing 
3. After all assessments are completed 
4. To be drawn fasting (for at least 8 h) 
5. To be performed within 15 to 60 minutes pre-dose 
6. To be performed after ECG, VS and PK blood draw are obtained 
7. Additional PK collection time points may be added to better characterize the PK profile 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
16 
Repeat dose schedule to be followed for repeat dose cohorts in Parts 1 and 2 (other than Cohort A Part 1) 
Procedure 
Treatment Period, Days  
 
-1 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination, oral examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Substance testing (drugs, alcohol, tobacco1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaler device training2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test in women 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admittance to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
Dosing procedure training with bystanders 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, clinical chem and urinalysis (include liver chem)6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Spirometry 
 
X7 
 
X8 
 
 
X8 
 
 
 
 
X8 
 
 
X7 
 
Telemetry (starting 30 min pre-morning dose and continuous at 
least 4h post-morning dose) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X9 
 
 
12-lead ECG and vital signs10 
XXX 
X 
 
X 
X 
 
X 
X 
X 
 
X11 
 
X11 
 
 
 
CCI15106-IP or placebo treatment BID, device incident 
assessment BID12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood sample13 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
BAL 
 
 
 
 
 
 
 
 
 
 
X14 
 
 
Urea blood sample 
 
 
 
 
 
 
 
 
 
 
X15 
 
 
AE review 
 
================================================================= 
SAE review 
============================================================================== 
Concomitant medication review 
============================================================================== 
1. Tobacco test to be performed only in healthy participants  
2. Day -1 inhaler training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion.   
3. Can be performed on Day 1 prior to dosing 
4. After all procedures and assessments are complete 
5. To be done only in Cohort(s) where bystanders are present.  Can be performed on Day -1 instead, if desired. Other time-points may be added per investigators discretion. 
6. To be drawn fasting (for at least 8 h) 
7. To be performed at the following timepoints in the mornings only: pre-dose, and 0.25 (in participants with COPD only), 0.5, 1, 4 h post-dose  
8. To be performed at the following timepoints in the mornings only: pre-dose and 4 h post-dose 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
17 
9. Telemetry may be performed on Days 11 or 12 instead, not to coincide with the BAL procedure. 
10. ECG and vital signs to be obtained 2 h after the morning dose 
11. When BAL is performed, vital signs and ECG will be performed before and after the procedure and oxygen saturation will be measured continuously.  
12. For cohort with bystanders, BID doses may have ±1.5 h window. 
13. PK samples on days 1 and 14 will be collected at the following timepoints:  pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 h.  The evening dose will be given after 12 h post-dose 
sample is collected.  On all other days, PK sample will be collected once, before the morning dose.  When BAL is performed, one additional PK sample will be collected after 
dosing immediately prior to bronchoscopy 
14. Done once during these four days, as soon as possible (within 1 h) after the first dose of the day 
15. To be collected immediately before bronchoscopy 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
18 
Schedule for Cohort C Part 1 (bystanders and air monitoring), to be executed concomitantly with Cohort B 
Part 1 
Procedure 
Treatment Period, Days  
 
-1 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination, oral examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Substance testing (drugs, alcohol, tobacco) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test in women 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admittance to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
Training2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, clinical chem and urinalysis (include liver chem)3 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Exposure to dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood sample 
 
X4 
 
 
 
 
 
X4 
 
 
 
 
 
 
X4 
X 
Stationary pump air monitoring5 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Personal exposure pump monitoring6 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
12-lead ECG and vital signs 
XXX 
X7 
 
X7 
X7 
 
X7 
X7 
X7 
 
X7 
 
X7 
 
 
 
AE review 
 
================================================================= 
SAE review 
================================================================================= 
Concomitant medication review 
================================================================================= 
1. After all procedures and assessments are complete 
2. Day -1 training may be done on Day 1 instead, before the first dose administration. Other time-points may be added per investigators discretion 
3. To be drawn fasting (for at least 8 h) 
4. PK samples will be collected pre-dose and 15 min after the dosing participant takes their first daily dose.  In addition, on days 7 and 14, one sample on each day will be collected 
before the dosing participant takes the first daily dose. On day 15, one sample will be collected before discharge. 
5. Samples of air to be collected for 20 and 60 min during and after the first morning dose 
6. Samples of air to be collected for 15 min during and after the first morning dose 
7. ECG and vital signs to be obtained 2 h after the exposure to morning dose 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
19 
3. 
INTRODUCTION 
3.1. 
Study Rationale 
This study is the first administration of CCI15106-IP (CCI15106:polyvinyl alcohol 99:1 
w/w 0.9x1 µm cylinder shape crystalline particles produced using Liquidia’s Particle 
Replication In Non-wetting Templates [PRINT] technology) to humans.  The study will 
evaluate the safety, tolerability, and lung and systemic pharmacokinetics (PK) of single 
and repeat ascending doses of CCI15106-IP delivered by inhalation in healthy 
participants and in participants with moderate chronic obstructive pulmonary disease 
(COPD).  The study will use a Monodose RS01 device for drug delivery by inhalation. 
A different formulation of CCI15106 (CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 
µm pollen shape particles) has been previously administered to humans in the first time 
in human study (FTiH) 202031.  That formulation was referred to as CCI15106 capsules 
for inhalation (CCI15106-CFI). 
The intention of this study is to provide sufficient information regarding the safety of the 
molecule to inform progression to further repeat dose and proof of concept studies.  The 
dose range proposed in this study is based on a starting dose previously investigated with 
the different formulation in the FTiH and escalating to a dose not to exceed the the no 
observed adverse effect level (NOAEL) in the most sensitive species (Section 5.5).  
The other intention of this study is to investigate the level of CCI15106 that will be 
released into the air and may be found in the blood of the bystanders around participants 
inhaling CCI15106-IP. 
3.2. 
Background 
CCI15106 is ribavirin, which is a generic, broad spectrum nucleoside antiviral, 
discovered in the early 1970s, with both clinical and nonclinical data available, which 
is approved and used for oral administration in the treatment of chronic hepatitis C 
virus.  It is also approved for respiratory syncytial virus (RSV) bronchiolitis by 
pulmonary inhalation in paediatric patients.  CCI15106 is active versus RSV, human 
metapneumovirus, parainfluenza, influenza, adenovirus, and human rhinovirus (HRV), 
although HRV is 4-15-fold less susceptible than the others (GlaxoSmithKline 
Document Number 2015N249287_00).  Based upon published data coronaviruses 
could also be susceptible without co-administration of interferon [Kurai, 2013, 
Morgenstern, 2005].  CCI15106 is not considered to be the active form, rather it is 
actively transported into target organs/cells and converted to ribavirin triphosphate 
(RTP) believed to be the active form against the viruses [Thomas, 2012].  The major 
limitation of the use of CCI15106 is hemolytic anemia due to accumulation of RTP in 
red blood cells and teratogenicity.     
Liquidia’s Particle Replication In Non-wetting Templates (PRINT) technology uses 
lithographic etching processes to produce particles with highly defined size and shape.  
CCI15106 plus the excipient, polyvinyl alcohol, are combined in a ratio of 99:1 w:w 
using Liquidia’s technology to produce CCI15106-IP, a highly dispersible powder of 
uniform 0.9x1 µm cylinder shape particles which has afforded a 24-fold increase in lung 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
20 
concentration at maximum (Cmax) relative to micronised CCI15106:Lactose formulation 
in a solid dose inhaled rat PK study (GlaxoSmithKline Document Number 
2015N242219_00 [N20691-39]).  The size and uniformity of the Liquidia particles 
provides an opportunity to improve the efficiency of CCI15106 administration to the lung 
while limiting systemic exposure that has the potential to limit hemolytic anemia and 
teratogenicity.  
Acute exacerbations of COPD are a significant cause of morbidity and mortality 
[Vestbo, 2013; Kurai, 2013].  Multiple studies show that viral and/or bacterial 
respiratory infections are the most commonly associated triggers of COPD 
exacerbations.  Respiratory viruses are detected in 20-60% of acute exacerbations of 
COPD [Kurai, 2013]. 
High efficiency lung delivery of broad spectrum CCI15106-containing engineered 
particles will establish an antiviral state in the lung.  This has the potential to prevent the 
establishment or spread of the virus in the lower respiratory tract from the upper 
respiratory tract and/or increase the viral clearance translating to prevention of an 
exacerbation or a decrease in exacerbation severity and/or duration. 
 
CCI15106 has been previously administered to humans in a different formulation, 
CCI15106:Trehalose:Trileucine 35/55/10 w/w 1 µm pollen shape PRINT particles 
(CCI15106 capsules for inhalation, referred to as CCI15106-CFI).  Forty eight healthy 
participants have been administered a single dose of that formulation in one FTiH study 
202031 and 12 participants received placebo.  This study was planned as a double-blind 
(sponsor unblind), randomized, placebo-controlled, single and repeat escalating dose 
study to investigate the safety, tolerability, and pharmacokinetics of CCI15106-CFI in 
healthy participants and participants with moderate chronic obstructive pulmonary 
disease (COPD).  In the single dose part of the study, CCI15106-CFI was administered 
by inhalation using Modified Air Inlet Rotahaler device at doses of 7.5 mg, 15 mg, 30 
mg, and 60 mg.  Overall, no clinically meaningful changes in vital signs or 
electrocardiograms (ECGs) were observed.  There were no serious adverse events (SAEs) 
reported.  Of the 60 subjects in the study, 25 reported adverse events (AEs) and 12 
reported possibly drug-related AEs.  The most common AEs were headache and cough 
(11 and 3 subjects, respectively).  The comprehensive review conducted after single dose 
cohorts revealed acceptable safety profile, but lung epithelial lining fluid (ELF) levels of 
CCI15106 measured with 30 or 60 mg dose were below the levels predicted by pre-
clinical evaluations and the increase in dose from 30 to 60 mg did not appear to result in a 
substantial increase in the lung concentration.  Development of the CCI15106-CFI 
formulation was terminated before dosing repeat dose or COPD cohorts as a new 
formulation (CCI15106-IP) was developed that has higher ratio of active pharmaceutical 
ingredient to inactive ingredients per unit of powder and allows achieving the same dose 
in 1 capsule instead of 4.  This is expected to lead to a higher lung ELF Cmax.  The 
decision to terminate was not based on safety data.    
Marketed formulations of CCI15106 are classified as teratogenic and is contra-indicated 
in women who are pregnant and in male partners of pregnant women.  Currently 
approved aerosolised forms of CCI15106 are recommended to be administered in a 
negative pressure environment [Virazole USPI 2013].  It is important to understand 
whether bystanders may be exposed to CCI15106 when it is used by patients in a dry 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
21 
powder, inhaled form.  The most likely route of exposure of bystanders will be through 
inhalation of powder released during dosing.  The study aims to replicate the real-life 
scenarios of dosing as close as possible.  Real-life scenarios may include dosing of 
multiple patients in a single room in a nursing home or dosing of a single patient at home.  
A realistic worst-case scenario is dosing of multiple patients in a standard size room in a 
nursing home.   
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of CCI15106 may be found in the Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 2015N250735_02].  Information 
specific to the approved formulations of CCI15106 can be found in the labels for oral 
CCI15106 approved for the treatment of hepatitis C and CCI15106 nebulizer approved 
for the treatment of respiratory syncytial infections in children [Rebetol SPC 2009; 
Virazole USPI 2013].   
 
Based on pre-clinical safety assessment studies summarized in the IB and the clinical 
experience with CCI15106-CFI, as well as oral and inhaled (nebulised) CCI15106, the 
following clinical parameters will be monitored throughout the study in order to better 
characterize the safety and tolerability of CCI15106-IP (Section 3.3.1).  Refer to SoA, 
Section 2, for the timing of all clinical assessments. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
22 
3.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Investigational Product, CCI15106-IP 
Teratogenicity and embryocidal effects 
CCI15106 showed embryocidal and teratogenic effects in animals.  The no 
observed adverse effect level (NOAEL) in oral embryofetal development 
studies in rats and rabbits was 0.3 mg/kg/day, considerably lower than the 
maximum proposed inhaled clinical dose of 120 mg/day CCI15106 (0.02-
fold to 0.05-fold based on mg/m2).  In addition, human seminal fluid contains 
∼2-fold higher concentrations of CCI15106 compared to serum.  There are 
limited data from the use of CCI15106 in pregnant women (5 cases of 
measles-pneumonia and 1 case of influenza-pneumonia)) [Virazole SPC, 
2014].  Four pregnancies were completed and resulted in the birth of healthy 
children.  A further 7 cases are known in which nurses administered Virazole 
dry substance during pregnancy (n=6) or just before conception (n=1).  In 6 
cases, healthy children were born. In one case, a chromosomal 
translocation was reported with mild developmental delay [Virazole SPC, 
2014]. 
Women of child-bearing potential and male partners of 
women who are pregnant or breastfeeding will be 
excluded.  Effective contraception for female partners of 
male participants will be required up to 7 months post 
study.   
Any pregnancies that occur during the study or up to 7 
months post study will be reported by the investigator to 
the pregnancy registry.   
The informed consent form will describe these reproductive 
risks, as well as the risk to female partners of male 
participants.   
Systemic exposure for the target clinical dose of CCI15106 
is expected to be lower than exposure for currently 
available oral and nebulized CCI15106.  The maximum 
inhaled total daily single dose of CCI15106 in Protocol 
205822 will be 120 mg and the maximum inhaled multiple 
daily doses will be 60 mg twice daily (BID).  These 
proposed maximum clinical doses are significantly lower 
than the currently approved doses of CCI15106 (800-1400 
mg for Copegus and Rebetol and 6 g for inhaled Virazole). 
Mutagenicity 
CCI15106 is clastogenic in vitro and in vivo but is Ames negative.  The 
pattern of genotoxicity is consistent with that reported for other nucleoside 
analogues.  Point of departure modelling (an accepted method of risk 
assessment for nucleoside analogues) indicates a negligible genotoxic 
concern.  CCI15106 was not tumorigenic in lifetime rodent studies at doses 
up to 75 mg/kg/day in the mouse and 40 mg/kg/day in the rat (∼3-fold the 
maximum proposed inhaled clinical dose of CCI15106-IP based on mg/m2), 
The data indicate a negligible genotoxic concern, which is 
mitigated by the lower expected systemic and lung 
exposure compared with currently available oral and 
nebulized CCI15106 and shorter duration of clinical 
treatment (≤ 14 days).  The maximum inhaled single total 
daily dose of 120 mg or multiple total daily doses of 60 mg 
BID for Protocol 205822 are significantly lower than the 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
23 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
or in the transgenic p53(±) mouse model at doses of up to 300 mg/kg/day. 
currently approved doses of CCI15106 (800-1400mg for 
Copegus and Rebetol and 6 g for inhaled Virazole). 
Increased exposure in participants with 
severe renal impairment  
 
As CCI15106/ribavirin is substantially excreted by the kidneys, exposure 
may be increased in those with pre-existing renal impairment 
CCI15106 is contraindicated in patients with chronic renal failure, patients 
with creatinine clearance < 50mL/min, and/or on hemodialysis [Rebetol 
SPC, 2009] However, the Copegus labels allow dose modifications for 
patients with CrCl <50 mL/min [Copegus USPI, 2015; Copegus SPC, 2015]. 
The maximum inhaled single total daily dose of 120 mg or 
multiple total daily doses of 60 mg BID proposed for 
Protocol 205822 are significantly lower than the currently 
approved doses of CCI15106 (800-1400mg for Copegus 
and Rebetol and 6 g for inhaled Virazole).  
COPD patients with impaired renal function (eGFR <30 
cc/min, using CKD-EPI equation) will be excluded and 
renal function will be monitored. 
Pulmonary effects 
GSK’s formulations: 
In toxicity studies conducted by GSK, no adverse pulmonary toxicity was 
observed following administration of either CCI15106:trehalose:trileucine 
particles or CCI15106-IP in GSK studies of 28 day duration at dose levels of 
≤32.5 mg/kg in rat or ≤34.2 mg/kg in dog.  The deposited lung doses at the 
NOAELs on the 28 day studies using CCI15106-IP were estimated 6- to 8- 
fold higher than in human at the maximum proposed clinical administration 
of CCI15106-IP of 120 mg/day (conservatively assuming 100% human lung 
deposition).  Adverse lung pathology (including neutrophilic inflammatory 
cell infiltrates) and unscheduled deaths were observed in rats in a 14 day 
inhaled tolerability study with CCI15106-IP at an estimated dose of 68.7 
mg/kg.  Rat deaths and lung pathology have been reported during oral and 
inhalation toxicology programs for approved/marketed formulations of 
CCI15106 at systemic exposures and inhalation dose levels similar or less 
than those delivered in this study. 
As CCI15106-IP is dry powder, it has a reduced risk of acute lung effects 
compared to low osmolarity nebulised solution.  No bronchospasms were 
observed in the FTIH study 202031; however there were occurrences of 
non-serious cough and dyspnoea.  Maximal amounts of powder 
administered were higher in the FTIH study than those planned for the 
Repeat dosing will be evaluated in healthy participants in 
this study prior to dosing in participants with COPD.  
Patients with poorly controlled COPD will be excluded (see 
Section 6.2.2).  Lung function will be monitored with 
frequent spirometry and physical examinations will be 
conducted.  If they become medically necessary, short-
acting bronchodilators may be administered as needed by 
the clinical staff.  Oxygen and resuscitation measures will 
be available in the unit in the event they would be needed. 
The trial is to be conducted in a dedicated phase I unit with 
supplementary (Medicines & Healthcare Products 
Regulatory Agency) accreditation and experience in the 
conduct of Phase I studies. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
24 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
current study.   
Labels of approved formulations: 
Virazole SPC (13 November 2014) includes the following: 
• 
Sudden deterioration in pulmonary function associated with 
aerosolized CCI15106/ ribavirin has been observed in children, 
and significant deterioration in pulmonary function has been 
observed in patients with asthma and chronic obstructive 
pulmonary disease (COPD)  during CCI15106/ribavirin treatment. 
• 
Bronchospasm has been reported following CCI15106/ribavirin 
use by patients with COPD and asthma. 
Pulmonary adverse reactions reported in clinical studies or in postmarketing 
use of aerosolized CCI15106/ribavirin include bacterial pneumonia, 
pneumothorax, laryngitis, pharyngitis, dyspnoea, cough, hypo- and 
hyperventilation, apnoea, and bronchospasm. 
Haemolytic anaemia 
The primary toxicity of approved formulations of CCI15106 is haemolytic 
anemia, which was observed in 10% of oral CCI15106 plus interferon 
alpha2b combination-treated participants and occurs within 1 to 2 weeks of 
start of therapy [Rebetol USPI, 2015].  Haemolytic anemia associated with 
CCI15106 may result in worsening of cardiac disease that has led to fatal 
and nonfatal myocardial infarction.  CCI15106 is known to accumulate in the 
red blood cells and may cause hemolysis, which may result in increased uric 
acid [De Franceschi, 2000].  Anemia has been shown to occur frequently 
with experimental oral and intravenous CCI15106 in humans [Virazole USPI, 
2013].  Haemolytic anaemia is monitorable and reversible with reduction / 
cessation of treatment [Rebetol USPI, 2015]. 
GSK formulations: 
In toxicity studies conducted by GSK, mild anaemia was seen in 4 week 
studies following inhalation administration of CCI15106:trehalose:trileucine 
particles (rat and dog) or CCI15106-IP (rat only).   
Participants will be monitored regularly with complete 
blood counts and hematocrit, as per SoA (Section 2).  
Participants with hemoglobinopathies will be excluded. 
Due to the short dose and duration and the red blood cell 
count monitoring in place, laboratory monitoring for 
hemolysis is not warranted in this study.  Participants will 
have an ECG assessment prior to and during the study.  
Cardiac monitoring, including assessment of blood 
pressure and heart rate, along with 12-lead 
electrocardiograms (ECGs) will be performed, per protocol.  
If cardiac status deteriorates on therapy, study medication 
should be suspended and/or discontinued.   


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
25 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Cardiac effects 
GSK formulations: 
Heart toxicity was not observed in definitive 4 week toxicity studies in rats 
and dogs following inhalation administration of 
CCI15106:trehalose:trileucine particles or CCI15106-IP.  Minimal 
lymphocytic/mononuclear or mixed inflammatory cell infiltrate in the 
myocardium was observed following inhalation administrations of 68.7 
mg/kg/day as CCI15106-IP at higher dose levels during a 14 day tolerability 
study (AUC0-24h was 5-fold higher than the human AUC0-24h estimated at 120 
mg CCI15106-IP).  These findings were also observed following oral and 
inhalation administrations of approved/marketed formulations of CCI15106-
IP and do not, therefore, present at a greater risk compared to 
marketed/approved CCI15106 formulations which are approved for 
administration at higher inhaled and oral dose levels/ systemic exposures 
and administered for longer treatment durations than those proposed for 
CCI15106-IP.  
There were no cardiac events reported in the FTIH study of CCI15106-CFI. 
The following cardiovascular adverse reactions have been reported in 
clinical studies and in the postmarketing setting of CCI15106, which 
included severely ill infants with life-threatening underlying disease:  cardiac 
arrest, hypotension, bradycardia, and digitalis toxicity [Virazole USPI, 2013].  
Bigeminy, bradycardia, and tachycardia, have been described in patients 
with underlying cardiac disease. 
Participants will have ECG prior to dosing and will be 
assessed prior to and during therapy by 12-lead ECG and 
telemetry.  If cardiac status deteriorates on therapy, study 
medication should be suspended and/or discontinued.  
Participants with uncontrolled or unstable cardiac diseases 
will be excluded. 
Photosensitization 
Photosensitivity reaction has been reported commonly in clinical trials and in 
the postmarketing setting for CCI15106 [Rebetol SPC, 2009].  Photoallergic 
reaction with CCI15106 has been described in the literature [Stryjek-
Kaminska, 1999]. 
 
Physical examination to include skin exams will be 
performed and documented as per SoA (Section 2).  Any 
findings suggesting photosensitivity reaction will be 
promptly addressed according to appropriate standard of 
care and followed up for resolution. 
Oral erosions 
Ulcerative stomatitis, stomatitis, mouth ulceration are undesirable effects 
associated with CCI15106 [Rebetol SPC, 2009].  Nasal erosions were 
Physical examination to include oral exam will be 
performed and documented as per SoA (Section 2).  Any 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
26 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
observed in the squamous epithelium of the nasal turbinates of a proportion 
of dogs (but not rats) receiving the high dose (25.1 mg/kg/day) following 
administration of  CCI15106-CFI and ≥16.3 mg/kg following administration 
CCI15106-IP for 4 weeks.  These effects were considered non adverse and 
unlikely to be clinically relevant since CCI15106  will be administered to 
humans by oral inhalation, compared with oro-nasal administration (over 60 
minutes) in the dog study, thereby minimising the potential for nasal 
exposure.  Histopathological findings in rats included epithelial changes in 
the larynx (squamous metaplasia) in animals given the control article and 
CCI15106 formulation over 4 weeks.  These changes were low in incidence 
and severity and showed full recovery following completion of the off-dose 
period. The findings were consistent with low grade non-specific irritation 
and, being an adaptive change of low severity, are considered non-adverse 
[Kaufmann, 2009] and a poor predictor of irritancy in humans given that the 
rat larynx is known to be particularly sensitive to inhaled irritants [Lewis, 
1991]. 
findings suggesting oral erosion will be promptly 
addressed according to appropriate standard of care and 
followed up for resolution. 
Testicular toxicity 
Testicular toxicity:  Testicular toxicity was seen in mice treated orally with 
CCI15106 for 3 to 6 months at doses of 15 mg/kg/day and [Rebetol SPC, 
2009].  Recovery occurred within one or two spermatogenic cycles.  No 
stage specific or cell specific abnormalities of spermatogenesis were 
observed in GSK studies which were conducted on the testes of rats 
(CCI15106:trehalose:trileucine particles and CCI15106-IP) and dogs 
(CCI15106-IP only) during definitive 4 week inhalation toxicity studies. 
Given the shorter duration of clinical treatment (≤ 14 days) 
and lower expected exposure compared with currently 
available oral and nebulized CCI15106, the risk of 
testicular toxicity is considered to be low.   


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
27 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Study Procedures  
BAL procedure 
BAL requires bronchoscopy and sedation.  Bronchoscopy can be performed 
safely on an outpatient basis [Du Rand, 2013], however, serious 
complications occurred in 1.1% of patients, including mortality in 0.02% of 
patients in a retrospective series (n=20,986 patients).  Common adverse 
events reported with bronchoscopy, included tachycardia/bradycardia, major 
and minor bleeding, bronchospasm, laryngospasm, cough, dyspnea, sore 
throat, apnea, seizure, desaturation, pneumothorax, and pulmonary edema. 
BAL will be performed by an experienced pulmonologist in 
dedicated bronchoscopy suite with close monitoring in 
recovery area post procedure. 
Other 
Bystander exposure, including healthcare 
workers  
Detectible levels of CCI15196-IP may be present in the immediate inhalation 
area during routine care activities. 
Labels of approved formulations: 
The Virazole patient information leaflet (last revision August 2014) states the 
following: 
• 
Virazole is to be administered in a hospital setting only, by a 
doctor or a nurse. 
• 
The nebuliser through which Virazole is given should be turned off 
5 to 10 minutes before visitors see the patient to minimise 
unnecessary exposure to Virazole. 
• 
Pregnant women, women who are trying to become pregnant, and 
sexually active men should avoid exposure to Virazole, because 
the risk of harm to an unborn baby is unknown.  Breast-feeding 
women are also to avoid exposure to Virazole. 
Postmarketing surveillance of CCI15106 has revealed reports of adverse 
events in individuals providing direct care to infants receiving aerosolized 
CCI15106 [Virazole USPI 2013].  The most common signs and symptoms 
were headache, conjunctivitis, rhinitis, nausea, rash, dizziness, pharyngitis, 
Levels in air and in bystanders will be assessed. 
Whenever study participants are dosed outside the 
negative pressure room, all hospital personnel will be 
asked to leave the room and will not re-enter until 15 min 
after dosing.     
Pregnant women or women of child-bearing potential will 
be warned of the potential risks.  
Training on the potential health hazard will be provided to 
study personnel, including protective equipment, 
monitoring, and waste disposal.  
No women of child-bearing potential will be enrolled as 
participants or as bystanders. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
28 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
and lacrimation.  Several cases of bronchospasm and/or chest pain have 
been reported, usually in individuals with reactive airways disease.  Seven 
cases are known in which nurses administered Virazole dry substance 
during pregnancy (n=6) or just before conception (n=1).  In 6 cases, healthy 
children were born.  In one case, a chromosomal translocation was reported 
with mild developmental delay. 
Exposure risk for additional medications administered in the study (Salbutamol): 
See package leaflet (https://www.medicines.org.uk/emc/PIL.22837.latest.pdf).


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
29 
3.3.2. 
Benefit Assessment 
As this Phase I study is being conducted to assess the safety and PK in healthy 
participants and participants with COPD, there is no direct clinical benefit to study 
participants.  Participation in this study may contribute to the process of developing new 
therapies in an area of unmet need. 
3.3.3. 
Overall Benefit:Risk Conclusion 
CCI15106 is an approved product as an oral agent in combination with interferon α or β 
(pegylated and non-pegylated) for chronic hepatitis C in patients 3 years of age and older 
with compensated liver disease (Copegus, Rebetol), and is approved in the nebulised 
form for use in infants and young children with severe respiratory syncytial virus 
infections (Virazole).  CCI15106-CFI has been administered to healthy participants in 
single doses up to 60 mg with acceptable safety and tolerability profile.  The risk of 
adverse effects is minimized for the population being investigated in the proposed study 
by careful selection of participants for the study, the relatively short duration of exposure, 
and the extent of safety monitoring incorporated into the study.  The highest dose planned 
in this study (single dose of 120 mg or multiple doses of 60 mg BID) is significantly 
lower than the currently approved doses of CCI15106 (800-1400 mg for Copegus and 
Rebetol and 6 g for aerosolized Virazole).  The risk to study staff will be managed by 
occupational precautions. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
30 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To investigate the safety and tolerability of 
CCI15106-IP following single and repeat 
escalating doses in healthy participants and 
participants with moderate COPD. 
 
• To determine systemic PK of CCI15106 
following single and repeat escalating doses 
of CCI15106-IP in healthy participants and 
participants with moderate COPD. 
 
 
 
 
 
 
• To evaluate potential inhalation exposure of 
bystanders to airborne CCI15106 during 
self-administered dosing of participants. 
 
 
 
• 
To evaluate the distribution and 
persistence of airborne CCI15106 in room 
air post-dosing. 
• Adverse events (AEs), clinical laboratory, 
electrocardiogram (ECG), telemetry, 
spirometry, and vital signs assessments. 
 
 
• Derived systemic PK parameters of 
CCI15106: Single dose: area under the 
curve (AUC) from time zero to the time of 
last quantifiable concentration (AUC[0-last]), 
concentration at maximum (Cmax), time of 
maximum concentration (tmax), AUC from 
time zero to infinity (AUC[0-∞]) elimination 
half-life (t1/2), clearance (CL/F), as data 
permit.  
Repeat dose: AUC from time zero to end of 
dosing interval (AUC[0-τ]) (τ=12 hours [h] 
for twice daily dose regimen), Cmax, tmax, 
elimination half-life (t1/2) as data permit. 
• Concentration of CCI15106 in plasma of 
bystanders 15-20 minutes (min) after dosing 
(at predicted tmax) and amount of 
CCI15106 accumulated on filters fitted on 
bystander over 15 min after dosing. 
 
• Amount of CC15106 in room air assessed 
by measuring amount of CCI15106 
accumulated over 20 and 60 min intervals 
during and immediately post-dosing on 
filters fitted on stationary pumps placed in 
the room. 
Secondary 
• To determine the concentration of 
CCI15106 in the lung of healthy participants 
and participants with moderate COPD 
following repeat dosing of CCI15106-IP. 
 
• 
To investigate the performance of the 
Monodose RS01 device for the 
administration of CCI15106-IP in healthy 
participants and participants with moderate 
COPD. 
• Concentrations of CCI15106 in lung 
epithelial lining fluid (ELF) assessed by 
bronchoalveolar lavage (BAL). 
 
 
• Device safety and performance parameters, 
including medical device incidents reporting, 
as well as systemic PK and lung CCI15106 
concentrations. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
31 
Objectives 
Endpoints 
Tertiary/Exploratory  
• To assess dose proportionality of 
CCI15106-IP versus systemic PK 
parameters. 
 
• To explore the relationship of drug exposure 
to safety and tolerability parameters after 
single and repeat escalating doses of 
CCI15106-IP in healthy participants and 
participants with moderate COPD. 
 
• To extrapolate study outcomes to a realistic 
worst case real-life scenario of dosing 
multiple patients in a single room in a 
nursing home.  
• 
Comparisons of doses administered and 
systemic PK parameters of CCI15106: 
AUC(0-24) or AUC(0-τ) and Cmax. 
• 
The dose or plasma exposure parameters 
for CCI15106 and the relationship of these 
to safety and tolerability parameters, as 
data permit. 
 
• 
Comparison of the study room with a 
potential nursing home room, including 
room dimensions, patient density, 
ventilation (air change rates per hour) 
 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, 
single and repeat escalating dose study.  Investigator and participants will be blinded to 
treatment type (active or placebo), but will know what dose of the medication is being 
administered.  Part 1 will investigate single and repeat ascending doses in healthy 
participants and investigate environmental and bystander exposure.  Part 2 will evaluate 
single and repeat dose in participants with moderate COPD.  Participants may only be 
enrolled in one study part and randomized to one cohort per the randomization schedule. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
32 
Study schematic is presented below: 
 
 
 
 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
33 
The following reviews will be conducted during the study progression: 
 
• 
In Part 1, Cohort B dosing can begin only after review of safety/tolerability and PK 
of all dosing in Part 1 Cohort A (see Section 7.2 for composition of the review 
team).     
• 
In Part2, Cohort A dosing can begin only after review of safety/tolerability and PK 
for a single dose administration of 60 and 120 mg in all participants in Part 1 Cohort 
A (see Section 7.2 for composition of the review team).   
• 
In Part 2, Cohort B dosing can begin only after the comprehensive review of all data 
obtained in Part 1, including safety and systemic PK, as well as lung PK where 
available (see Section 7.2 for composition of the review team) and after review of 
safety/tolerability of Part 2 Cohort A.     
• 
Environmental and bystander exposure review may be conducted at any time after 
the data are collected.  Until this review is completed and exposure found 
acceptable, all subsequent cohorts will be dosed in the negative pressure 
environment.  
• 
The planned doses may be modified, repeated or cancelled based upon 
safety/tolerability/ and/or PK from preceding cohorts (See Section 7.2 for more 
information).  Single doses will not exceed 120 mg and repeat doses 60 mg BID. 
• 
The planned dose frequency or duration may be modified based on emerging 
safety/tolerability and PK data from previous cohorts.  The total daily dose will not 
exceed 120 mg. 
• 
The number of cohorts may be reduced or expanded if needed. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
34 
• 
All participants in Part 1 Cohort B and in Part 2 Cohort B (60 mg BID dose for both 
Cohorts) will undergo BAL once during the study on days 10, 11, 12, or 13 after the 
first (morning) dose.  Based on the lung ELF concentrations of CCI15106 observed, 
additional double-blinded, single-blinded or open-label repeat dose cohort(s) may be 
added at a dose not to exceed 120 mg daily.  The total number of participants will 
not exceed that specified in Section 5.2. 
• 
BAL may be used in the additional cohorts to obtain a more accurate estimation of 
the dose to lung exposure ratio and provide data for future dose predictions.     
There will be approximately 3 cohorts of healthy participants in this study and 
approximately 2 cohorts of participants with moderate COPD.  Participants in the dosing 
cohorts will be randomized to receive either CCI15106-IP or matching Liquidia particles 
without the active ingredient (lactose:polyvinyl alcohol 98:2 w/w 0.9x1 µm cylinder 
shape amorphous particles, referred to as placebo).  Participants in Cohort C will be 
assigned to participants in Cohort B on a one to one basis for the entire duration of the 
study. 
Screening visit will occur within 30 days of dosing for cohorts in Part 1 and within 45 
days of dosing for cohorts in Part 2.   
For Cohort A Part 1, 60 mg single dose will be administered on Day 1; 120 mg single 
dose will be administered on Day 3; and then 30 mg dose will be administered BID on 
Days 6-19.  Participants will report to the unit on Day -1 for assessments and 
randomization (randomization can also be done on Day 1, prior to dosing).  Participants 
will be dosed the following morning on Day 1 followed by post-dose assessments.  Blood 
for PK assessments will be collected for the next 48 hours (h).  On Day 3 (after collection 
of 48 h PK time point), participants will receive a single dose of 120 mg followed by 
post-dose assessments and PK assessments for the next 72 h.  Repeat dosing will begin 
on the morning of Day 6 (after collection of 72 h PK time point) and will continue for 
14 days BID.  Participants will remain in the unit for additional 2 days until 72 h PK 
timepoint is collected.  Dosing frequency and duration may be adjusted based on 
emerging safety and tolerability data.  Participants will return for the follow-up visit 
approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy.  
For Cohort B Part 1, Repeat Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing).  Dosing will begin on the 
morning of Day 1 and continue for 14 days BID.  Dosing frequency and duration may be 
adjusted based on emerging safety and tolerability data.  BAL procedure will be 
performed as soon as possible (within 1 h) after the first (morning) dose on one of the 
following days: 10, 11, 12, or 13.  Participants will be discharged on Day 15 following 
completion of all post-dose assessments after the last dose, or later if additional PK 
collection or other assessments are required.  Participants will return for the follow-up 
visit approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy. 
For Cohort C Part 1, 14 healthy participants will be enrolled to evaluate bystander 
exposure and will follow Cohort C Part 1 SoA.  Bystanders and air exposure will be 
evaluated concomitantly with Cohort B Part 1.  Bystanders will report to the unit on Day 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
35 
-1 and will remain for all 14 days of dosing of Cohort B.  They will be positioned in the 
room with the dosing participants for every dose taken, as described in Section 9.4.8.  Air 
sampling and bystander PK evaluation will be conducted on days 1, 7, and 14 as 
described in Section 9.4.8.  Bystanders will be discharged on Day 15 following 
completion of all post-dose assessments after the last dose.  Bystanders will return for the 
follow-up visit approximately 30 days after discharge.  All male participants will also be 
called approximately 7 months after the follow-up visit to ensure no partner pregnancy. 
For Cohort A Part 2, Single Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing).  They will be dosed the 
following morning on Day 1 followed by post-dose assessments.  Participants will be 
discharged following completion of the post-dose assessments the next day (Day 2).  
They will return for the follow-up visit approximately 30 days after discharge.  All male 
participants will also be called approximately 7 months after the follow-up visit to ensure 
no partner pregnancy. 
For Cohort B Part 2, Repeat Dose SoA will be followed for the duration of the study.  
Participants will report to the unit on Day -1 for assessments and randomization 
(randomization can also be done on Day 1, prior to dosing).  Dosing will begin on the 
morning of Day 1 and continue for 14 days BID.  Dosing frequency and duration may be 
adjusted based on emerging safety and tolerability data.  BAL procedure will be 
performed as soon as possible (within 1 h) after the first (morning) dose on one of the 
following days: 10, 11, 12, or 13.  Participants will be discharged on Day 15 following 
completion of all post-dose assessments after the last dose, or later if additional PK 
collection or other assessments are required.  Participants will return for the follow-up 
visit approximately 30 days after discharge.  All male participants will also be called 
approximately 7 months after the follow-up visit to ensure no partner pregnancy. 
The total study duration will be approximately 82 days for Cohort A Part 1; 
approximately 75 days for Cohort B Part 1 and Cohort C Part 1; approximately 77 days 
for Cohort A Part 2; and approximately 90 days for Cohort B Part 2.   
5.2. 
Number of Participants 
Approximately 36 healthy participants and approximately 22 participants with COPD 
will be randomized in this study for dosing.     
Evaluable participants will be defined in the Reporting and Analysis Plan (RAP). 
Additional participants or cohorts may be enrolled to allow for evaluation of additional 
dose levels or to increase numbers on prior doses or to increase the number of bystanders.  
The total number of participants in this study will not exceed 86 and the total number of 
cohorts will not exceed 7, including the bystander cohort(s). 
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the investigator. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
36 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4. 
Scientific Rationale for Study Design 
Participants and all site personnel, with the exception of the study pharmacist or 
designee, will be blinded to participant randomization throughout the study.  The GSK 
study team participating in the dose escalation meetings will review blinded data and will 
be un-blinded on a need to know basis only if necessary to facilitate review of the safety, 
tolerability and PK data as appropriate in real time to inform dose escalation decisions.  
The GSK study team or personnel at any contract research organization that may be 
involved in data management or in statistics and programming will not reveal the 
treatment assignments to the site personnel or participants.  
 
In repeat dosing cohorts, CCI15106-IP will be administered for 14 days to mimic the 
expected duration of treatment in target patient populations.  
Inclusion of Bronchoscopy 
BAL will be performed on 14 healthy participants (Cohort B Part 1) and 14 participants 
with COPD (Cohort B Part 2) to evaluate levels of CCI15106 in the ELF.  BAL will be 
performed once, as soon as possible (within 1h) after the first (morning) dose.  This will 
allow assessment of CCI15106 levels at around tmax in the ELF.  The timing of BAL in 
Part 2 Cohort B may be adjusted based on BAL results obtained in Part 1.  Available 
models [Weber, 2017] predict that the level of CCI15106 in the bronchoalveolar fluid 
following 14 days of 60 mg BID dosing may be achieved above 200 µM around Tmax 
which is above the EC50 for all respiratory viruses including HRV and expected to 
prevent or minimise the migration of an upper respiratory tract viral infection to the lower 
respiratory tract.  These data will enable a more accurate estimation of the dose to lung 
exposure ratio and provide valuable information for future dose predictions.  
Inclusion of Participants with COPD Cohort  
Due to potential exposure differences as a function of COPD-induced lung damage, 
participants with moderate COPD will be included to aid in dose selection for the future 
proof of concept studies in participants with COPD.  This cohort will also help obtain 
some safety and tolerability data in this patient population prior to a wider administration 
in the Proof of Concept study.  
Inclusion of Bystander Cohort  
Due to known teratogenic potential of CCI15106, we need to evaluate how much of it 
gets into the environment around the dosing participant to ensure that no potentially 
pregnant bystanders are put at-risk due to secondary exposure.  Participants dosed in the 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
37 
Cohort used to evaluate environmental and bystander exposure will be dosed outside a 
negative pressure enclosure.  All other participants will be dosed inside the enclosure.  
When participants dose outside the enclosure, all personnel will leave the room and not 
re-enter until 15 min after dosing.  During this time, participants will be observed through 
a window in the door. 
5.5. 
Dose Justification 
The dose proposed for Part 1 Cohort A is based on the data from 202031 where 
CCI15106-CFI up to 60 mg single dose has been evaluated, and no SAEs or severe AEs 
were observed, as well as the investigation of the four week toxicity and toxicokinetics in 
rats and dogs in which the NOAEL was determined [GSK Document Number 
2017N312240_00 and GSK Document Number 2017N312247_00]. 
Table 1 below shows the safety margins in terms of lung and systemic exposure with 
respect to the NOAEL obtained from the pre-clinical studies, and the folder cover with 
respect to the systemic exposure following oral administration of the marketed dose 
(1200 mg/day) in humans for the doses proposed in this study.  These data indicated 
reasonable safety margins for Cohort A in Parts 1 and 2, where single dose of CCI15106-
IP will be administered. 
The selection of appropriate dose for Part 1 Cohort B will be performed upon 
consideration of available safety, tolerability and systemic PK data from Part 1 cohort A. 
The review data set for this selection will, at minimum, consist of: any adverse events, 
liver function test results, vital signs, ECG, spirometry data, and laboratory findings, and 
any available systemic PK results.  
The selection of appropriate dose for Part 2 Cohort A will be performed upon 
consideration of available safety and tolerability data following the single doses (60 and 
120 mg) in all participants in Cohort A of Part 1. 
The selection of appropriate dose for Part 2 Cohort B will be performed upon 
consideration of available safety, tolerability, systemic PK and lung concentration data 
from Part 1 Cohort B. 
The dose level in any cohort may be titrated up or down based on emerging safety, 
tolerability, and systemic PK and lung data where available.  The maximum dose will not 
exceed 120 mg per day. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
38 
Table 1 
Prediction of Human Systemic and Lung Exposure and Safety 
Margins of CCI15106 
Dose 
Frequency 
Proposed 
human 
dose per 
day (mg)  
Human 
Lung 
Dose 
(mg/g) 
Lung 
Safety 
Margin 
(Rats) 
Lung 
Safety 
Margin 
(Dogs) 
Human 
Systemic 
expoure         
AUC(0-24) 
(ng.h/mL) * 
Systemic 
Safety 
Margin 
(Rats) 
Systemic 
Safety 
Margin 
(Dogs) 
Systemic 
Safety 
Margin 
(human 
Oral 
Ribavirin) 
Assume 100% lung deposition in humans 
SD 
60 
0.06 
12 
16 
  
  
  
  
SD 
120 
0.12 
6 
8 
  
  
  
  
Assume 59% lung deposition in humans 
SD 
60 
0.04 
20 
26 
552 
17 
40 
92 
SD 
120 
0.07 
10 
13 
1104 
8 
20 
46 
BD** 
30 
0.04 
20 
26 
3080 
3 
7 
16 
BD 
60 
0.07 
10 
13 
6150 
2 
4 
8 
Assumptions: 
human: body weight 70 kg, lung weight 1000 g; 100% or 59% inhaled dose into lungs are assumed 
59% was predicted from the MPPD for lung deposition of the device 
 
 rat: mean body weight 0.244kg, mean lung weight 1.145 g, 10% inhaled dose into lungs; 
dog: mean body weight 8 kg, mean lung weight 73.1 g, 25% inhaled dose into lungs. 
 
Rat NOAEL dose = 32.5 mg/kg, AUC=9.34 µg.h/mL (whole study means) 
 
 
Dog NOAEL dose = 34.2 mg/kg, AUC=22.2 µg.h/mL (whole study means) 
 
 
Human oral AUC(0-24) =2xAUC0-12=50.722 µg.h/mL (Steady state) [Copegus USPI, 2015] 
* human systemic AUC(0-24) is predicted from a mechanistic model [Weber, 2017] 
 
** BD - twice daily dosing; AUC(0-24) on Day 14  
 
 
 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
6.1.1. 
Inclusion Criteria for Healthy Participants and Bystanders 
Participants are eligible to be included in the study only if all of the following criteria 
apply.  Rescreening is allowed only if approved by the Medical Monitor. 
Age 
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent. 
 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
39 
Type of Participant and Disease Characteristics 
2. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.  
3. A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator (in 
consultation with the Medical Monitor if required) decide and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.   
Weight 
4. Body weight ≥50 kg for males and 45 kg for females and body mass index (BMI) 
within the range 19 to 31 kg/m2 (inclusive) for males and 17 to 31 kg/m2 (inclusive) 
for females. 
Sex 
5. Male OR Female 
a. Male participants: 
A male participant with female partner of child bearing potential must agree to use 
contraception as detailed in Appendix 5 of this protocol during the treatment period 
and for at least 7 months 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 not pregnant (see Appendix 5), 
not breastfeeding, and not a woman of childbearing potential (WOCBP) as defined in 
Appendix 5.   
Informed Consent 
6. 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. 
6.1.2. 
Inclusion Criteria for Participants with COPD 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Participant must be 40 to 75 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
40 
2. Diagnosed with moderate COPD (GOLD class II) by a qualified physician as defined 
by the GOLD guidelines (http://www.goldcopd.org/). 
3. The participant has spirometry at screening, conducted 15-30 minutes after 
administration of 400 microgram (µg) salbutamol via metered dose inhaler showing: 
• post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% and 
<80% predicted normal [Quanjer, 2012] and 
• post-bronchodilator FEV1/ forced vital capacity (FVC)<0.7, where FEV1 is 
forced expiratory volume in 1 second and FVC is forced vital capacity.   
4. Participant is a smoker or an ex-smoker with a smoking history of at least 10 pack 
years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). 
5. A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor if required agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures. 
Weight 
6. Body weight ≥ 45 kg and BMI within the range 17 – 34 kg/m2 (inclusive), unless 
morbidly obese. 
Sex 
7. Male OR Female 
c. Male participants: 
A male participant with female partner of child bearing potential must agree to use 
contraception as detailed in Appendix 5 of this protocol during the treatment period 
and for at least 7 months after the last dose of study treatment and refrain from 
donating sperm during this period. 
d. Female participants:  
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and not a WOCBP as defined in Appendix 5.   
Informed Consent 
8. 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 
6.2.1. 
Exclusion Criteria for Healthy Participants and Bystanders 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
41 
2. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).  
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)  
4. QTc > 450 msec 
NOTES: 
• 
The QTc is the QT interval corrected for heart rate (HR) according to 
Fridericia’s formula (QTcF), machine-read or manually over-read. 
• 
The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial. 
• 
For purposes of data analysis, QTcF will be used as specified in the RAP. 
5. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination): 
 
Males 
Females 
Heart rate 
<40 and >100 bpm 
<50 and >100 bpm 
PR Interval 
<120 and >220 msec 
QRS duration 
<70 and >120 msec 
QTcF interval  
>450 msec 
 
6. Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, 
metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions 
that, in the opinion of the investigator may place the participant at an unacceptable 
risk as a participant in this trial or may interfere with the absorption, distribution, 
metabolism or excretion of drugs. 
Prior/Concomitant Therapy 
7. Past or intended use of over-the-counter or prescription medication (including herbal 
medications) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is longer) prior to dosing until completion of the follow-up 
visit, unless in the opinion of the Investigator and sponsor the medication will not 
interfere with the study.  Specific medications listed in Section 7.7 may be allowed. 
Prior/Concurrent Clinical Study Experience 
8. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 month period. 
9. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
42 
10. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
Diagnostic assessments 
11. Hemoglobin (Hgb) below the lower level of the normal range with one repeat testing 
allowed, or known hemoglobinopathies. 
12. Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, and erythema multiforme. 
13. Presence of Hepatitis B surface antigen (HBsAg) at screening, Positive Hepatitis C 
antibody test result at screening. 
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained 
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment 
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing 
15. Positive pre-study drug/alcohol screen 
16. Positive HIV antibody test 
17. Regular use of known drugs of abuse 
Other Exclusions 
18. Male partners of women who are pregnant or lactating 
19. Regular alcohol consumption within 3 months prior to the study defined as:  
• 
an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits.  
20. Breath test indicative of smoking at day -1. 
21. History of sensitivity to any of the study medications, including CCI15106 or 
components thereof and, for cohorts that will undergo BAL, those that may be used in 
association with the BAL procedure or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.  
22. For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage 
including hypercapnia >50 mm Hg, abnormal blood coagulation parameters, known 
or suspected intolerance of medications necessary for bronchoscopy, refractory 
hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial 
infarction. 
23. Documented lactose allergy/intolerance for dosing cohorts. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
43 
6.2.2. 
Exclusion Criteria for Participants with COPD 
1. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)  
2. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
4. QTc > 450 msec or QTc > 480 msec in participants with Bundle Branch Block 
NOTES: 
• 
The QTc is the QT interval corrected for HR according to Fridericia’s formula 
(QTcF), machine-read or manually over-read. 
• 
The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be used 
to calculate the QTc for an individual participant and then the lowest QTc value 
used to include or discontinue the participant from the trial. 
• 
For purposes of data analysis, QTcF will be used as specified in the RAP. 
5. Participant has poorly controlled COPD, defined as the occurrence of either of the 
following: 
• Acute worsening of COPD requiring use of antibiotics or systemic corticosteroids 
in the 6 weeks prior to screening visit OR 
• More than 2 exacerbations of COPD requiring treatment with oral steroids in the 
preceding year or hospitalization for the treatment of COPD within 3 months of 
screening or more than twice during the preceding year. 
6. History of an upper or lower respiratory tract infection requiring antibiotics in the 4 
weeks prior to screening 
7. Participant has a diagnosis of active tuberculosis, lung cancer, or any other 
respiratory condition that might, in the opinion of the Investigator, compromise the 
safety of the participant or affect the interpretation of the results.  Participants with 
other respiratory disorders (e.g. clinically significant: asthma, pulmonary fibrosis, 
bronchiectasis) are excluded if these conditions are the primary cause of their 
respiratory symptoms. 
8. Unstable or uncontrolled cardiac disease. 
9. Participants who have past or current medical conditions or diseases that are not well 
controlled and, which as judged by the Investigator, may affect participant safety or 
influence the outcome of the study.  (Note: Patients with adequately treated and well 
controlled concurrent medical conditions (e.g. hypertension) ARE permitted to be 
entered into the study). 
Prior/Concomitant Therapy 
10. Participants are not allowed to take oral corticosteroids from 4 weeks prior to 
screening and for the duration of the study. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
44 
11. Participants taking medications for any chronic conditions have to be on stable doses 
for 4 weeks prior to screening and until after completion of the treatment period.  
This includes COPD maintenance therapies (e.g. inhaled corticosteroids, long-acting 
beta-agonists, long-acting muscarinic agonists). 
12. Didanosine and azathioprine are not allowed. 
13. Use of short-acting inhaled bronchodilators is allowed, but participants must be able 
to discontinue their medications several times during the study as described in 
Section 7.7. 
14. Use of long-acting bronchodilators is allowed, but participants must be able to 
modify the schedule of their medications twice during the study as defined in 
Section 7.7. 
Prior/Concurrent Clinical Study Experience 
15. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months. 
16. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
17. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day. 
Diagnostic assessments 
18. Impaired renal function (eGFR <30 cc/min, using CKD-EPI equation). 
19. Known severe hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic 
epidermal necrolysis, and erythema multiforme. 
20. Hgb below the lower level of the normal range with one repeat testing allowed or 
known hemoglobinopathies. 
21. Presence of Hepatitis B surface antigen (HBsAg) at screening, Positive Hepatitis C 
antibody test result at screening. 
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained 
22. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment 
NOTE: Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing 
23. Positive pre-study drug/alcohol screen 
24. Positive human immunodeficiency virus (HIV) antibody test 
25. Regular use of known drugs of abuse 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
45 
Other Exclusions 
26. Male partners of women who are pregnant or lactating 
27. Regular alcohol consumption within 3 months prior to the study defined as:  
• 
an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits.  
28. Unable to refrain from smoking for 2 h prior to dosing and until all assessments are 
complete for 4 h after dosing and also for 1 h prior to any vital signs and ECG 
assessments. 
29. History of sensitivity to any of the study medications, including CCI15106 or 
components thereof and, for cohorts that will undergo BAL, those that may be used in 
association with the BAL procedure or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.  
30. For cohorts that will undergo BAL, contraindications to bronchoalveolar lavage 
including hypercapnia >50 mm Hg, abnormal blood coagulation parameters, known 
or suspected intolerance of medications necessary for bronchoscopy, refractory 
hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial 
infarction. 
31. Documented lactose allergy/intolerance. 
6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
• 
Participants will be allowed soft drinks without caffeine starting from 2 h after 
dosing, including both AM and PM doses.  Standardized meals will be provided 
while the participant is confined to the clinical research unit, as outlined below. 
• 
Participants will report to the clinic fasting (for at least 8 h) for screening visit, Day -
1 of treatment periods and for follow-up visit. 
• 
At all mealtimes, food will be served only after completion of protocol specified 
procedures scheduled at or around the same time. 
• 
The morning dose of the CCI15106-IP will be given after fasting (for at least 8 h).  
The evening dose of the CCI15106-IP will be given at least 2 h after food.  The 
doses will be approximately 12 h apart.  For the first dose for any participant in the 
study, water should not be allowed for 2 h prior to dosing.  For all other doses, water 
will be allowed freely. 
• 
Participants should not eat for 2 h after dose administration for the single dose 
cohorts and after the first dose of the multiple dose cohorts. 
• 
Breakfast will not be provided on the mornings of the BAL, however a snack is 
permitted on this day after the end of the procedure, as long as it does not interfere 
with any study related procedures. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
46 
• 
All other meals and snacks may be provided as per the clinics schedule.  Should a 
mealtime interfere with a study procedure such as BAL, the investigator in 
consultation with the sponsor, may modify the meal times to ensure safety of the 
participants.  Also, the fasting requirements may be modified or removed at any time 
during the study at the discretion of the sponsor in consultation with the investigator. 
 
6.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 h 
prior to the start of dosing until the participants leave the clinical unit.  
• 
During each dosing session, participants will abstain from alcohol for 24 h prior to 
the start of dosing until the participants leave the clinical unit.  
• 
For healthy participants, use of tobacco products is not allowed from screening until 
after participants leave the clinical unit. 
• 
Participants with COPD who use tobacco products will be instructed that use of 
nicotine-containing products (including nicotine patches) will not be permitted while 
they are in the Clinical Unit.  Participants with COPD will be escorted by staff for 
smoking breaks except during the period for 2 h prior to dosing and until all 
assessments are complete for 4 h after dosing. 
6.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise from screening until follow-up visit. 
Participants may participate in light recreational activities during studies (eg, 
watching television, reading). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this study may be rescreened 
only upon approval of Medical Monitor.  Rescreened participants should be assigned a 
different screening 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. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
47 
7.1. 
Treatments Administered 
Study Treatment 
Name: 
CCI15106-IP 
Placebo 
Dosage formulation: 
1 capsule 
1 capsule 
Unit dose 
strength(s)/Dosage 
level(s): 
30 mg of CCI15106 
 
As 30.3 mg of CCI15106: 
polyvinyl alcohol 99:1 w/w 
PRINT 0.9x1 µm cylinder 
shape crystalline particles  
 
 
30.3 mg of lactose: polyvinyl 
alcohol 98:2 w/w PRINT 0.9x1 µm 
cylinder shape amorphous 
particles 
Route of 
Administration  
By inhalation 
By inhalation 
Dosing instructions: 
 
Each inhalation will follow 
instructions provided with 
the device.  The number of 
inhalations will depend on 
the dose. 
The morning dose to be 
taken fasting (at least 8 h).  
For repeat dose cohorts, the 
evening dose to be taken at 
least 2 h after food. 
For repeat dose cohort(s) 
with bystander exposure 
monitoring, a ±1.5 h window 
is allowed. 
Each inhalation will follow 
instructions provided with the 
device.  The number of inhalations 
will depend on the dose. 
The morning dose to be taken 
fasting (at least 8 h).  For repeat 
dose cohorts, the evening dose to 
be taken at least 2 h after food. 
For repeat dose cohorts with 
bystander exposure monitoring, a 
±1.5 h window is allowed. 
Packaging and 
Labeling 
 
Study Treatment will be 
provided in a HDPE (high 
density polyethylene) bottle. 
Each bottle contains 2 
capsules and a desiccant 
canister.  Each bottle is 
overwrapped in a foil pouch 
containing a desiccant 
sachet. Each bottle and 
each pouch will be labelled 
as required per country 
requirement. 
Study Treatment will be provided 
in a HDPE bottle. Each bottle 
contains 2 capsules and a 
desiccant canister.  Each bottle is 
overwrapped in a foil pouch 
containing a desiccant sachet. 
Each bottle and each pouch will 
be labelled as required per 
country requirement. 
Device 
Monodose RS01 
Monodose RS01 
Manufacturer 
Plastiape S.p.A. 
Plastiape S.p.A. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
48 
7.1.1. 
Medical Devices 
• 
The GSK manufactured medical devices (or devices manufactured for GSK by a 
third party) provided for use in this study are Monodose RS01. 
• 
Instructions for medical device use are provided in the Study Reference Manual 
(SRM). 
• 
GSK medical device incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout 
the study (see Section 9.2). 
 
7.2. 
Dose Modification 
• 
This protocol allows some alteration from the currently outlined dosing schedule.  
The maximum daily dose administered will not exceed 120 mg per day either as a 
single dose or as 60 mg BID. 
• 
The decision to proceed to Part 1 Cohort B will be made by the GSK Study Team 
comprised at a minimum of the team leader, medical monitor, Global Clinical Safety 
and Pharmacovigilance scientist or physician (Clinical Pharmacokineticist, 
Statistician and Preclinical Safety Assessment as necessary), and the Investigator or 
delegate based on safety and tolerability data obtained in all participants at the prior 
dose levels in Part 1.  The actual doses to be administered may be adjusted based on 
safety, tolerability, and preliminary PK data if appropriate, at previous dose levels; 
these dose adjustments may involve either an increase or a decrease in the planned 
dose.  The highest dose in the study will not exceed 120 mg per day either as a single 
dose or as 60 mg BID. 
• 
The decision to proceed to participants with COPD will be made by the GSK Study 
Team comprised at a minimum of the team leader, medical monitor, Global Clinical 
Safety and Pharmacovigilance scientist or physician (Clinical Pharmacokineticist, 
Statistician and Preclinical Safety Assessment as necessary), and the Investigator or 
delegate based on safety and tolerability data obtained after single dosing completes 
in healthy participants in Part 1 Cohort A.   
• 
The actual doses to be administered may be adjusted based on safety, tolerability, 
and preliminary PK data if appropriate, at previous dose levels; these dose 
adjustments may involve either an increase or a decrease in the planned dose.   
• 
The dosing schedule may also be adjusted to expand a dosing cohort to further 
evaluate safety and PK findings at a given dose level, or to add cohorts to evaluate 
additional dose levels.  The study procedures for these additional participant(s) or 
cohort(s) will be the same as that described for other study participants. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
49 
7.3. 
Method of Treatment Assignment 
No treatment assignment will be performed for bystander cohort(s). 
For all other cohorts, participants will be randomized at the clinic using RandAll-
generated randomization schedule prepared by GSK. 
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106-
IP or Placebo with 3:1 ratio.  In Cohort B Part 1 and Cohort B Part 2, participants will be 
randomized with 6:1 ratio.  
Study treatment will be dispensed at all times indicated in the SoA (Section 2). 
7.4. 
Blinding 
This will be a double-blind (sponsor unblinded) study.  The GSK study team participating 
in the dose escalation meetings will be blinded to the participant’s treatment assignment 
and will be un-blinded only if necessary to facilitate review of the safety, tolerability and 
PK data as appropriate in real time to inform dose escalation decisions. 
However, the study team performing the analyses to support dose escalation decisions 
will be unblinded to allow accurate assessment of the data, including the study 
pharmacokineticists, statisticians, programmers and data managers, who will have access 
to the randomization codes for analysis purposes.  If additional contract research 
organizations are involved in data analysis or in statistical analysis and programming, the 
same will apply to their staff as well. 
Participants will be randomized to receive study treatment.  Investigators will remain 
blinded to each participant’s assigned study treatment throughout the course of the study.  
In order to maintain this blind, an otherwise uninvolved 3rd party will be responsible for 
the reconstitution and dispensation of all study treatment and will ensure that there are no 
differences in time taken to dispense following randomization. 
This 3rd party will instruct the participant to avoid discussing the taste, dosing frequency, 
or packaging of the study treatment with the investigator or with other participants. 
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to un-blinded study treatment records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
Additional double-blinded, single-blinded or open-label repeat dose cohort(s) may be 
added at a dose not to exceed 120 mg daily.   
  
• 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.  
• Investigators have direct access to the participant’s individual study treatment.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
50 
• 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.  
• The date and reason for the unblinding must be fully documented.  
A participant may continue in the study if that participant’s treatment assignment is 
unblinded, upon discussion with the medical monitor.   
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. 
7.5. 
Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
• Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
• Capsules should be kept refrigerated (2-8°C) in their sealed packaging, protected 
from moisture.  
• Monodose RS01 devices will be supplied in bulk.  After use, the devices will be 
placed in a plastic bag, and the bag will be labelled with the participant number, day 
of dosing, and date.  Devices will be disposed of at site after reconciliation is verified 
by study monitor. 
• 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).   
• Further guidance and information for final disposition of unused study treatment are 
provided in the SRM or equivalent.  
• Precaution will be taken to avoid direct contact with the study treatment.  No women 
of child-bearing potential will administer study treatment.  Staff administering the 
study treatment will wear protective gown and gloves.  A Material Safety Data Sheet  
describing occupational hazards and recommended handling precautions will be 
provided to the investigator.  In the case of unintentional occupational exposure 
notify the monitor, Medical Monitor and/or GSK study contact. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
51 
Dosing Procedure for Cohorts not Used for Environmental Exposure 
Monitoring 
• Participants will inhale the dose from the Monodose RS01 device inside a negative 
pressure room or enclosure. 
• The investigator/designee will remove the capsule from the bottle and load it into the 
Monodose RS01 device one at a time in a safety cabinet.  One device will be used per 
capsule.  The investigator/designee will be trained to load the capsule into the device 
and pierce the capsule ready for inhalation (empty capsules will be used for training).   
• The participant will inhale the dose, and staff will observe participant doing it.  Staff 
will be trained to listen for a rattle that the device makes during successful dosing.  
After dosing, the Monodose RS01 device will be placed in a plastic bag, and the bag 
will be labelled with the participant number, day of dosing, and date. 
• The participant will be trained to use a “fast and deep” inspiration technique per 
inhalation, to achieve rapidly consecutive maximal inhalations (empty capsules will 
be used for training).  This will ensure optimal and consistent treatment delivery.  For 
participants, the training session will be on either Day -1 or on Day 1, prior to 
administration of the first dose.  Subsequent assessment of Monodose RS01 device 
technique, and repeat device training where deemed necessary by the 
investigator/designee, will take place immediately before administration of each dose.    
Dosing Procedure for Cohorts Used for Environmental Exposure 
Monitoring 
• Participants will inhale the dose from the Monodose RS01 device in a room 
designated for dosing.  All investigators/designees will leave the room and observe 
dosing participants and bystanders through a glass in the door.  Only participants 
inhaling the dose and designated bystanders are allowed in the room during inhalation 
of the dose. 
• The bystander will remove the capsule from the bottle and load it into the Monodose 
RS01 device one at a time.  One device will be used per dose (2 capsules in this 
cohort).  The bystander will be trained to load the capsule into the device and pierce 
the capsule ready for inhalation (empty capsules will be used for training).     
• The bystander will pass loaded and charged device to the dosing participant.  
• The participant will inhale the dose, and staff will observe participant doing it through 
a glass in the door.  The bystander will be trained to listen for a rattle that the device 
makes during successful dosing.  After dosing, the participant will pass the device 
back to the bystander. 
• The bystander will open the device, remove the capsule and place it on the table 
between the dosing participant and the bystander.  The bystander will then load the 
second capsule into the same device, pierce the capsule and pass the loaded device 
back to the dosing participant. 
• The participant will inhale the second dose, the bystander will listen for a rattle that 
the device makes during successful dosing and staff will observe participant doing it 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
52 
through a glass in the door.  After dosing, the participant will pass the device back to 
the bystander. 
• The bystander will open the device, remove the second capsule, and place the open 
device with both capsules on the table between the dosing participant and the 
bystander.  
• The bystander and participant will remain seated around the table for 15 min.  After 
this time, the bystander will place the Monodose RS01 device and both used capsules 
into the plastic bag labelled with the participant number, day of dosing, and date.  
After that is done, bystander and participant can leave the room.  The bystander will 
need to wash their hands prior to leaving the room. 
• The participant will be trained to use a “fast and deep” inspiration technique per 
inhalation, to achieve rapidly consecutive maximal inhalations (empty capsules will 
be used for training).  This will ensure optimal and consistent treatment delivery.  For 
participants and bystanders, the training session will be on either Day -1 or on Day 1, 
prior to administration of the first dose.  Subsequent assessment of Monodose RS01 
device technique, and repeat device training where deemed necessary by the 
investigator/designee, will take place immediately before administration of each dose.  
 
7.6. 
Treatment Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff.  
The participants 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.   
If failure of the capsule actuation is suspected (i.e. due to failure to pierce the capsule 
during device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose.  If dosing failure is suspected 
for any other reason, the participant may have to be excluded after consultation with the 
Medical Monitor. 
 
The Monodose RS01 devices will be under the supervision of the study organisers at all 
times during the clinical trial.   
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
53 
7.7. 
Concomitant Therapy 
7.7.1. 
Permitted Medications and Non-Drug Therapies 
Paracetamol or Acetaminophen, at doses of ≤2 grams/day is permitted. 
Medications associated with the BAL procedure are permitted, but these medications are 
to be disclosed to the Sponsor prior to dosing any participants. 
Participants with COPD taking medications for any chronic conditions have to be on 
stable doses for 4 weeks prior to screening and until after completion of the treatment 
period. 
Salbutamol is administered 15 to 30 min prior to spirometry at screening for diagnostic 
purposes.  Short-acting bronchodilators should not be used from 6 h prior to each 
morning dose administration until 4 h after that dose.  If they become medically 
necessary during that time, short-acting bronchodilators may be administered as needed 
by the clinical staff only and their use must be documented.   
For participants with COPD, use of long-acting bronchodilators is allowed, but their use 
must be modified twice during the study as follows:  at screening and on Day 1, they 
must not be taken for at least 2 h prior to spirometry. 
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the Medical Monitor. 
7.7.2. 
Prohibited Medications and Non-Drug Therapies 
Participants are not allowed to take oral corticosteroids from 4 weeks prior to screening 
and for the duration of the study. 
For participants with COPD, self administration of short-acting inhaled bronchodilators is 
not allowed at screening, from 4 h prior to spirometry until spirometry is completed.  Self 
administration of short-acting inhaled bronchodilators is not allowed during treatment 
period from 6 h prior to each morning dose administration until 4 h after that dose.   
Didanosine and azathioprine are not allowed. 
Except as permitted in Section 7.7.1, participants must abstain from taking prescription or 
non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 
days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication until completion of the follow-up visit, 
unless in the opinion of the Investigator and sponsor the medication will not interfere 
with the study. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
54 
7.8. 
Treatment after the End of the Study 
Participants will not receive any additional treatment from GSK after completion of the 
study because most of the participants are healthy and 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 
specific post-study treatment. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
If participant is withdrawn from study treatment, this constitutes withdrawal from study.  
Participants will have to be followed up for safety reasons as deemed necessary by the 
Investigator and should be encouraged to return for a follow-up visit as specified in the 
SoA (Section 2).  If this is not possible, procedures specified for the follow-up visit can 
be performed at the last visit that the participant attends. 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.   
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
Discontinuation of study treatment for abnormal liver tests is required when: 
• 
a participant meets one of the conditions outlined above 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
55 
• 
when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant. 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.  
8.1.2. 
QTc Stopping Criteria 
A participant who meets either bulleted criterion below will be withdrawn from the 
study:   
• 
QTc, QTcF >500 msec, 
• 
Change from baseline:  QTc >60 msec 
For participants with COPD with underlying bundle branch block, follow the 
discontinuation criteria listed below: 
Baseline QTc with Bundle Branch Block Discontinuation QTc with Bundle 
Branch Block 
< 450 msec 
>500 msec 
450 – 480 msec 
≥530 msec 
 
• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled. 
• 
For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well. 
• 
Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.   
• 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.   
See the SoA (Section 2) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed.  
8.1.3. 
Other Stopping Criteria 
Dosing will be stopped for any individual participant in case of SAEs and in case of any 
AEs which in the opinion of the investigator might jeopardise the health of the trial 
participant.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
56 
Additionally, dosing will be stopped and the study will be put on halt if any of the below 
scenarios occurred.  If following an internal safety review the Sponsor deems it 
appropriate to restart the trial, this can be done following approval of a substantial 
amendment: 
Two (2) or more subjects, within a dose-level, receiving study treatment experience grade 
3 respiratory  adverse event that are deemed possibly or probably related to study drug by 
the investigator. 
Two (2) or more subjects, within a dose-level, receiving study treatment experience a 
grade 3  hematologic adverse event that are deemed possibly or probably related to study 
drug by the investigator. 
Two (2) or more subjects, within a dose-level, receiving study treatment experience 
severe hypersensitivity related adverse event that are deemed possibly or probably related 
to study drug by the investigator. 
Two (2) or more subjects, within a dose-level, receiving study treatment experience a 
grade 3 vital signs (heart rate and/ or blood pressure) adverse event that are deemed 
possibly or probably related to study drug by the investigator. 
One (1) or more subjects receiving study treatment experience anaphylaxis that is deemed 
possibly or probably related to study drug by the investigator. 
8.1.4. 
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 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 (Section 2) for data to be collected at follow-up and for any further 
evaluations that need to be completed. 
• 
Participants will have to be followed up for safety reasons as deemed necessary by 
the Investigator and should be encouraged to return for a follow-up visit as specified 
in the SoA (Section 2).  If this is not possible, procedures specified for the follow-up 
visit can be performed at the last visit that the participant attends. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
57 
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 (Section 2).  
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• 
Adherence to the study design requirements, including those specified in the SoA 
(Section 2), is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA (Section 2). 
• 
The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
• 
The following time window tolerances apply to all protocol assessments: 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
58 
Predose  
 - 60 to 0 min (- 60 to -15 min for spirometry) 
0h - 4h post 
- 5 / + 10 min 
5h – 24h post 
- 20 / + 20 min 
 
9.1. 
Efficacy Assessments 
There are no efficacy assessments in this study. 
9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8).  
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).  However, any SAEs assessed as related 
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study.  
• 
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 case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately and 
no later than in 24 h, as indicated in Appendix 4. The investigator will submit any 
updated SAE data to the sponsor within 24 h of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
59 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4. 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information eg, summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
9.2.5. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular  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 Cardiovascular CRFs are presented as queries in response to reporting of certain 
Cardiovascular MedDRA terms.  The Cardiovascular information should be recorded in 
the specific cardiovascular section of the CRF within one week of receipt of a 
Cardiovascular 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. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
60 
9.2.6. 
Pregnancy 
• 
Female participants of child bearing potential are excluded from this study  
• 
Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until 7 months after the last dose of study 
treatment. 
• 
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5. 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
9.2.7. 
Medical Device Incidents (Including Malfunctions) 
Medical devices are being provided for use in this study for inhalation.  In order to fulfill 
regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices.  
The definition of a Medical Device Incident can be found in Appendix 7. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2.1, Section 9.2.2, Section 9.2.3, Section 9.2.4 and Appendix 4 of 
the protocol.  
9.2.7.1. 
Time Period for Detecting Medical Device Incidents 
• 
Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented, and reported during all periods of the study in which the 
medical device is used.  
• 
If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the 
sponsor. 
• 
The method of documenting Medical Device Incidents is provided in Appendix 7. 
9.2.7.2. 
Follow-up of Medical Device Incidents 
• 
All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 9.2.1, Section 9.2.2, Section 9.2.3, and 
Section 9.2.4). This applies to all participants, including those who discontinue study 
treatment or the study. 
• 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
• 
New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
61 
9.2.7.3. 
Prompt Reporting of Medical Device Incidents to Sponsor 
• 
Medical device incidents will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device incident. 
• 
The Medical Device Incident Report Form will be sent to the sponsor by facsimile 
transmission. If facsimile transmission is unavailable, then notification by telephone 
is acceptable for incidents, with a copy of the "Medical Device Incident Report 
Form" sent by overnight mail. 
• 
The same individual will be the contact for the receipt of medical device reports and 
SAE. 
9.2.7.4. 
Regulatory Reporting Requirements for Medical Device Incidents 
• 
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 
• 
The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC. 
9.3. 
Treatment of Overdose 
For this study, any dose of CCI15106-IP greater than the dose specified for the treatment 
period within a 24 h time period [±4 h] will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. 
Contact the Medical Monitor immediately. 
2. 
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
CCI15106 can no longer be detected systemically (at least 30±2 days). 
3. 
Obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis). 
4. 
Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
9.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 2). 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
62 
9.4.1. 
Screening Assessments 
Cardiovascular medical history/risk factors 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.   
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study. 
9.4.2. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems, and skin.  
Height and weight will also be measured and recorded.  Oral exam will be 
performed. 
• 
A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).  Oral exam will also 
be performed. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
9.4.3. 
Vital Signs 
• 
Vital signs will be measured in semi-supine position and will include oral or 
tympanic temperature, pulse rate, respiratory rate, and systolic and diastolic blood 
pressure.  The same method of temperature assessment should be used throughout 
the study. 
• 
For BAL, vital signs will also include oxygen saturation.  Oxygen saturation will be 
evaluated and recorded before, every 5 minutes during the procedure, at the end of, 
and between 30 and 60 minutes after the bronchoscopy.  
• 
Blood pressure and pulse measurements will be assessed 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). 
• 
Three readings of blood pressure and pulse rate will be taken where indicated as 
triplicate in SoA (Section 2) and all three readings will be recorded. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
63 
9.4.4. 
Electrocardiograms 
• 
Triplicate OR single 12-lead ECG will be obtained in semi-supine position after 5 
minutes rest as outlined in the SoA (Section 2) 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.   
• 
At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes. 
• 
Continuous cardiac telemetry will be performed where indicated in SoA (Section 2).  
Full disclosures will be reviewed in detail and the review maintained as part of the 
participant’s source documents. 
9.4.5. 
Spirometry 
• 
Spirometry (FEV1 and FVC) will be performed at time points specified in the SoA 
(Section 2).  Further tests should be performed, at the discretion of the investigator, if 
the participant has symptoms that could suggest bronchospasm. 
• 
Spirometry manoeuvres will be conducted according to ATS/ERS 2005 spirometry 
standards [Miller, 2005]. The greatest FEV1 and the greatest FVC from 3 technically 
acceptable and reproducible manoeuvres will be recorded.  
• 
For participants with COPD, at screening, 400 µg salbutamol will be administered 
15-30 minutes prior to performing spirometry.  FEV1 and FVC percent predicted 
values will be derived using the Global Lung Function Initiative reference values 
[Quanjer, 2012]. 
 
9.4.6. 
Capillary pCO2 
The pCO2 levels will be measured at the times indicated in SoA (Section 2).  The 
participant’s hand will be heated in warm water (42 degrees) for about 10 minutes and a 
capillary blood sample will be collected by skin puncture using a lancet or automated 
incision device. 
 
9.4.7. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency.  
• 
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. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
64 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30±2 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).  
  
9.4.8. 
Environmental and Bystander Exposure Evaluation 
Exposure monitoring will be conducted in accordance with the principles outlined in 
prEN 689:2016, the draft European standard for workplace exposure assessment to 
airborne contaminants [prEN 689:2016]. 
9.4.8.1. 
Air Monitoring 
During and after the first daily dose on Days 1, 7 and 14 in Cohort B Part 1, static air 
samples will be collected on filters within air pumps positioned in two locations in the 
room.  The air disturbance caused by the pumps is negligible and would not be expected 
to alter the normal air flow patterns in the room.  Marks may be placed on the floor to 
indicate position of the participant and positions of pumps to ensure consistency 
throughout the study.  Samples will be run over 20 and 60 min following dosing in each 
location.  An additional set of samples over 60 min will be taken before the start of 
dosing on Day 1 to provide a background benchmark for reference. 
On days when static air sampling is performed, the dosing sessions will have to be 
separated by the time necessary to collect the 60 min air sample. 
Sampling devices (Institute of Occupational Medicine [IOM] sampling heads connected 
to sampling pumps) shall be used to measure CCI15106 concentration.  The IOM filter 
cassette assembly will be prepared using an immersion-extraction procedure to avoid any 
errors through wall deposition.  Whenever possible, the Hygienist will observe the room 
through a glass in the door for the duration of sampling to make observations and note 
relevant contextual information to assist in the interpretation of the exposure 
measurements. 
Air sample analysis will be performed by the Bureau Veritas laboratory (Bureau Veritas 
North America Inc, 95 Oakwood Road, Lake Zurich, IL, 60047).  For air sampling, field 
blanks (filters which have been handled during the survey but not had air pulled through 
them) will be submitted with samples to check for accidental contamination during 
sample handling and storage.  An average of one blank for every ten field samples will be 
sent for analysis. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
65 
9.4.8.2. 
Bystander Monitoring 
Please refer to Figure 1 for the illustration of the design.  Each dosing participant will be 
assigned a designated bystander for the duration of dosing.  Two participants will dose at 
the same time in sitting position.  The designated bystander will be seated facing their 
dosing participant within approximately 1 m of him/her.  The first dosing participant will 
inhale the dose (both capsules), and then the second dosing participant will inhale the 
dose (both capsules).  Please refer to Section 7.5 for detailed instructions on dosing.  
Each participant and their bystander will stay seated for the next 15 min, after which they 
will leave the dosing room.  The staff will exit the room prior to bystander loading the 
capsule into the device (see Section 7.5) and remain outside the room for at least 15 min 
after dosing observing through a glass door. 
Figure 1 
Bystander and participant design illustration 
 
 
The next two bystanders will be positioned near the next 2 dosing participants, and so on 
until all dosing is completed.  This procedure will be followed for all doses in Cohort B 
Part 1, with the same bystanders positioned next to the same inhaling participant.  After 
the first daily dose on days 1, 7 and 14, blood will be collected from bystanders 15 min 
after dosing (at ~tmax for CCI15106).  Additionally, personal exposure air samples will 
be collected on filters placed on each bystander after the first daily dose on days 1, 7 and 
14.  The filters will be worn during dosing and for 15-minute period after dosing.  Static 
air monitoring will be performed at the same time during and after the first daily dose on 
days 1, 7 and 14.  During these dosing sessions, each set of two dosing participants will 
be separated by the time necessary to collect the 60 min air sample.  
The filters used for personal exposure (IOM sampling heads connected to sampling 
pumps) shall be used to measure CCI15106 concentration in the person’s breathing zone.  
The IOM filter cassette assembly will be prepared using an immersion-extraction 
procedure to avoid any errors through wall deposition.  Whenever possible, the Hygienist 
will observe the room through a glass in the door for the duration of sampling to make 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
66 
observations and note relevant contextual information to assist in the interpretation of the 
exposure measurements. 
See Section 9.5 for PK assessments of bystanders. 
9.5. 
Pharmacokinetics 
9.5.1. 
Blood Sample Collection 
Blood samples for PK analysis of CCI15106 in plasma will be collected at the time points 
indicated in SoA (Section 2).  One 3 mL blood sample will be collected at each time 
point and the actual date and time of each sample collection will be recorded.  The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.   
Processing, storage and shipping procedures are provided in the SRM OR equivalent.  
9.5.2. 
BAL Sample Collection 
BAL samples for ELF concentration analysis of CCI15106, urea, and cell counts will be 
collected at the time points indicated in SoA (Section 2).  The actual date and time of 
each BAL sample collection will be recorded.   
Details of BAL sample collection, processing, storage, and shipping procedures are 
provided in the SRM OR equivalent.  
Due to the analysis methodology, any cells present in the ELF will be disrupted and their 
content released and analyzed together with the supernatant.  
9.5.3. 
Urea Blood Sample 
A 2 mL blood sample will be collected into Lithium Heparin tubes as soon as practically 
possible before the BAL samples.   
Processing for plasma, storage and shipping procedures will be provided in the SRM or 
equivalent. 
9.5.4. 
Sample Analysis 
BAL and plasma analysis will be performed under the control of Platform Technology 
and Sciences – in Vitro/in Vivo Translation and Third Party Resourcing, GSK, the details 
of which will be included in the SRM OR equivalent.  Concentrations of CCI15106 will 
be determined in plasma and BAL samples using the currently approved bioanalytical 
methodology.  Plasma and BAL urea concentrations will be determined by Clinical 
Pathology, Safety Assessment, GSK.  Raw data will be stored in the Good Laboratory 
Practices archives, GSK. 
For bystander exposure, a plasma concentration of less than 0.5 ng/mL (the Limit Of 
Quantification of the method) represents an acceptable exposure since this is 29-fold 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
67 
lower than the highest plasma concentration measured at the no effect dose level for 
teratogenicity in the most sensitive species (rat [Rebetol SPC, 2009]). 
Once the plasma and BAL samples have been analyzed for CCI15106, any remaining 
plasma or BAL may be used for other compound-related metabolites analyses, 
microbiome analysis, or other exploratory analyses that inform the effect of the drug on 
the body or the disease, the results of which will be reported under a separate protocol. 
9.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
9.7. 
Genetics 
Genetics are not evaluated in this study. 
9.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
9.9. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample Size Determination 
Sample size is based on feasibility and though no formal power calculations are 
performed, the sample size is deemed adequate to provide a preliminary assessment of 
safety prior to progression to the next study.  
Part 1 
In Part 1, the study plans to enrol healthy participants in 3 cohorts.  In Cohort A, there 
will be 6 participants on active and 2 on placebo, in cohort B, there will be 12 on active 
and 2 on placebo.  In cohort C, there will be 14 subjects who will participate as 
bystanders and they will be associated with the dosing subjects in Cohort B on a one to 
one basis for the entire duration of dosing.  All subjects in Cohort B will also undergo 
BAL.    
Part 2: 
In Part 2, 22 participants with COPD are planned to be enrolled.  Cohort A will have 
6 participants on active dose and 2 on placebo and Cohort B will have 12 participants on 
active and 2 on placebo.  Fourteen participants (12 active and 2 placebo) enrolled in 
Cohort B Part 2 will also undergo BAL. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
68 
Although the sample size is not based on statistical criteria, general probabilities can be 
determined on the likelihood of seeing adverse events.  For example, in Parts 1 and 2, in 
treatment groups where 6 patients will receive the active drug, if the true adverse 
outcome rate is 5%, the chance of seeing at least one adverse outcome at a given dose is 
26%.  Similarly, if the true adverse outcome rate is 20%, the chance of seeing at least one 
adverse outcome at a given dose is 73%. For the treatment groups with 12 subjects 
receiving the active treatment, if the true adverse outcome rate is 5%, the chance of 
seeing at least one adverse outcome at a given dose is 46%.  Similarly, if the true adverse 
outcome rate is 20%, the chance of seeing at least one adverse outcome at a given dose is 
93%.  This level of predictability is deemed adequate within this Phase 1 setting prior to 
commencement of the next study. 
10.1.1. 
Sample Size Sensitivity 
As sample size is based on feasibility, no sample size sensitivity was performed. 
10.1.2. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation is planned. 
10.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Definition / Criteria 
Analyses Evaluated 
All Participants 
Screened 
• Comprise of all participants who consent to 
participate in the clinical study. 
• Defined separately for Part 1 and Part 2. 
 
Safety 
• Comprise of all participants who receive at least 
one dose of study treatment. 
• This population will be based on the treatment 
the participant actually received. 
• Defined separately for Part 1 (excluding 
Cohort C) and Part 2. 
• Safety 
• Study Population 
Systemic 
Pharmacokinetic 
Concentration 
• Participants who receive at least one dose of 
study treatment and who undergo plasma PK 
sampling and have at least one postdose 
concentration result. 
• PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be 
excluded.  
• Defined separately for Part 1 (excluding 
Cohort C) and Part 2. 
• PK 
Lung ELF 
Concentration 
• Participants who receive at least one dose of 
study treatment and who undergo BAL sampling 
and have postdose lung ELF CCI15106 and 
• BAL 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
69 
Population 
Definition / Criteria 
Analyses Evaluated 
Population 
 
urea concentration result. 
• Lung ELF samples that may be affected by 
protocol deviations, will be reviewed by the 
study team to determine whether or not the 
sample will be excluded.  
• Defined separately for Part 1 and Part 2 
Bystander Safety 
Population (Part 
1, Cohort C) 
• Participants who are present at least once in the 
room with the participant receiving the dose. 
 
• Safety 
• Study Population 
 
Bystander PK 
Population (Part 
1, Cohort C) 
• Participants who are present at least once in the 
room with the participant receiving the dose, 
undergo plasma PK sampling and have post-
dose concentration result. 
•  PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be 
excluded. 
• PK 
 
 
10.3. 
Statistical Analyses 
The analysis and reporting of Part 1 may be conducted prior to the completion of Part 2.   
For all parts, the analysis and reporting will be performed after the datasets are authorized 
and released for reporting. 
Data will be listed and summarized according to GSK reporting standards, where 
applicable.  Listings will be sorted by cohort, participant and time; summaries will be 
presented by cohort, treatment, and time.     
Descriptive summaries will include n, mean, standard deviation (SD), median, minimum, 
and maximum, geometric mean with associated 95% confidence interval (CI), and the 
between-participant coefficient of variation (%CVb) for continuous variables, n and 
percent will be used as summary statistics for categorical variables. 
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise.  If there are multiple assessments collected at the 
same scheduled time, the average of these assessments will be used.  For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables. 
Version 9.1 or higher of the SAS system will be used to analyze the data as well as to 
generate tables, figures, and listings. 
Complete details will be documented in the RAP. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
70 
10.3.1. 
Safety Analyses 
All safety analyses will be based on the Safety Population. 
Endpoint 
Statistical Analysis Methods 
Adverse events (AEs) 
The proportion of participants reporting AEs will be tabulated by 
treatment and by cohort.  AEs will also be tabulated by severity and 
relationship. 
Clinical laboratory 
Laboratory results will be included in the reporting of this study for 
hematology, clinical chemistry, and urinalysis.  Based upon laboratory 
normal ranges, the laboratory test results will be categorized according 
to the normal range as low (below the lower limit), normal (within the 
normal range) and high (above the upper limit).  Summary statistics for 
change from baseline will also be tabulated. 
Electrocardiogram 
(ECG) 
The ECG parameters of PR, QRS, QT, QTc, QTcF and HR (bpm) will be 
reported. Overall assessment of ECG (Investigator’s judgment) will be 
recorded as Normal, Abnormal - Not Clinically Significant and Abnormal - 
Clinically Significant. Summary statistics for change from baseline will 
also be tabulated. 
Telemetry 
Overall assessment of Telemetry (Investigator’s judgment) will be 
recorded as Normal, Abnormal - Not Clinically Significant and Abnormal - 
Clinically Significant. 
Spirometry 
% Predicted forced expiratory volume in 1 second (FEV1) and forced 
vital capacity (FVC) values will be tabulated for each timepoint.  
 
Vital signs 
assessments 
The following Vital Signs measurements will be tabulated: supine systolic 
and diastolic blood pressure, pulse rate, respiratory rate and 
temperature. Summary statistics for change from baseline will also be 
tabulated. 
Monodose RS01 
Device safety 
Safety incidents reported from use of medical device will be tabulated. 
10.3.2. 
Pharmacokinetic Analyses 
PK analysis will be the responsibility of the Clinical Pharmacokinetics Modeling & 
Simulation Department (CPMS) within GSK.  Plasma CCI15106 concentration-time data 
will be analyzed by non-compartmental methods with WinNonlin 5.3 and above.  
Calculations will be based on the actual sampling times recorded during the study.  From 
the plasma concentration-time data, the following PK parameters may be determined, as 
data permit:  maximum observed plasma concentration (Cmax), time to Cmax (tmax), 
area under the plasma concentration-time curve [AUC(0-last) and AUC(0-∞) where data 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
71 
permit for single dose, and AUC(0-τ) for repeat dose], elimination half-life (t1/2), and 
clearance (CL/F) as data permit. 
AUC(0-24), or AUC(0-48), or AUC(0-τ) and Cmax following single and repeat doses 
may be used for assessment of dose proportionality. 
Trough concentration (Cτ) samples collected on the specified days may be used to assess 
attainment of steady state.  To estimate the extent of accumulation after repeat dosing, the 
observed accumulation ratio (Ro) may be determined.   
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from Cohorts B of Part 1 and Part 2. 
PK data will be presented in graphical and/or tabular form and will be summarized 
descriptively.  A population PK model (POP PK) may be developed with all available 
data as appropriate and may be reported separately.  Further details of the analysis plan 
and methods will be detailed within the RAP and data analysis plan OR equivalent.  
Individual lung ELF concentration data will be summarised, listed and displayed 
graphically on both linear and semi-logarithmic scales for the Cohorts with available ELF 
data.  Where data permit, the individual lung ELF concentration data may be plotted 
against the plasma concentration measured prior to BAL sampling. 
All pharmacokinetic data will be stored in the Archives, GSK Pharmaceuticals, R&D. 
PK exploratory analyses will be described in the reporting and analysis plan.  The 
population PK analysis if conducted, will be presented separately from the main clinical 
study report.  
10.3.3. 
Bystander and Environmental exposure Analyses 
The plasma concentration data from bystanders will be summarised descriptively and 
listed.  The amount of CCI15106 obtained from filters will be tabulated and reported.  
Additional analyses, where deemed necessary, will be described in the RAP. 
If data permit, the plasma concentration measured from bystanders may be plotted 
against the data collected from the air filters. 
10.3.4. 
Interim Analyses 
No formal interim analyses are planned for this study.   Safety and tolerability will be 
evaluated as described in Section 5.1.  Systemic and, where available, lung PK may also 
be evaluated. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
72 
11. 
REFERENCES 
Copegus (ribavirin) Tablets. United States Prescribing Information. Genentech. August, 
2015. Available at: http://www.gene.com/download/pdf/copegus_prescribing.pdf. 
Accessed October 15, 2015. 
Copegus 200 mg Film-coated Tablets. Summary of Product Characteristics. January, 
2015. Available at: http://www.medicines.org.uk/emc/medicine/11755/spc. Accessed 
October 15, 2015. 
De Franceschi L, Fattovich G, Turini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic 
anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: 
role of membrane oxidative damage.  Hepatology. 2000;31:997-1004. 
Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British 
Thoracic Society guideline for diagnostic flexible bronchoscopy in adults.  Thorax. 2013; 
68:i1–i44. 
GlaxoSmithKline Document Number 2015N242219_00.  Assessment of the 
pharmacokinetics of CCI15106 (Ribavirin) following single inhaled administration of a 
range of Liquidia PRINT formulations in Wistar Han Rats (GSK Study Number N20691-
39).  October 2015. 
GlaxoSmithKline Document Number 2015N249287_00.  Ribavirin Inhibits Replication 
of Human Rhinovirus, Respiratory Syncytial Virus and Influenza Virus in Air-Liquid 
Interface Cell Cultures.  October 2015. 
GlaxoSmithKline Document Number 2015N250735_02.  Investigator's Brochure for 
inhaled CCI15106 and inhalation device.  October 2015. 
GlaxoSmithKline Document Number 2017N312240_00.  CCI15106 (cylinder particle): 
Toxicity study by inhalation administration to Wistar Han rats for 4 weeks.  2017. 
GlaxoSmithKline Document Number 2017N312247_00.  CCI15106 (cylinder particle): 
Toxicity study by inhalation administration to beagle dogs for 4 weeks.  2017. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2 
Kaufmann W, Baderb R, Ernst H, Harada T, Hardisty J, Kittel B, et al. 1st International 
ESTP Expert Workshop: ‘‘Larynx squamous metaplasia’’. A re-consideration of 
morphology and diagnostic approaches in rodent studies and its relevance for human risk 
assessment.  Experimental and Toxicologic Pathology. 2009;61:591-603.  
Kurai D, Saraya T, Ishii H, Takizawa H. Virus-induced exacerbations in asthma and 
COPD.  Frontiers in Microbiology. 2013;4:1-12. 
Lewis DJ. Morphological assessment of pathological changes within the rat larynx. 
Toxicologic Pathology. 1991;19:352-357.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
73 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry.  Eur Respir J. 2005; 26:319-338. 
Morgenstern B, Michaelis M, Baer P, Doerr H, Cinatl J. Ribavirin and interferon-b 
synergistically inhibit SARS-associated coronavirus replication in animal and human 
cell lines. Biochem Biophys Res Comm. 2005; 326:905-908. 
prEN 689:2016 (E), Workplace exposure; measurement of exposure by inhalation to 
chemical agents – strategy for testing compliance with occupational exposure limit 
values, Comité Européen de Normalisation, Brussels, Belgium, draft, 18 March 2016. 
Preston SL, Drusano GL, Glue P, Nash J, Gupta SK, and McNamara P.  
Pharmacokinetics and Absolute Bioavailability of Ribavirin in Healthy Volunteers as 
Determined by Stable-Isotope Methodology.  Antimicrobial agents and chemotherapy. 
1999, 43:2451–2456. 
Quanjer PH, Stanojevic S, Cole T, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3–95-yr age range: the global lung function 2012 
equations.  Eur Respir J. 2012; 40:1324–1343. 
Rebetol (ribavirin USP) capsules for oral use; (ribavirin USP) oral solution.  United 
States Prescribing Information.  Merck & Co., INC.  May 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020903s053,021546s009lbl.p
df 
Rebetol 200 mg Hard Capsules.  Summary of Product Characteristics. Merck Sharp & 
Dohme Limited, 07 May 2009.  Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000246/WC500048210.pdf 
Stryjek-Kaminska D, Ochsendorf F, Roder C, Wolter M, Zeuzem S Photoallergic Skin 
Reaction to Ribavirin. Am J Gastroenterol 1999; 94:1686-1688.  
Thomas E, Ghany MG, Liang TJ, The application and mechanism of action of 
ribbavirin in therapy of hepatitis C. Antiviral Chemistry and Chemotherapy, 2012; 
23:1-12. 
Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global 
Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive 
Pulmonary Disease.  Am J of Resp and Critical Care Medicine. 2013;187:347-365. 
Virazole (Ribavirin for Inhalation Solution). United States Prescribing Information. 
Valeant Pharmaceuticals North America LLC, April 2013. 
Virazole.  Summary of Product Characteristics, December 2014.  Available at: 
https://www.medicines.org.uk/emc/medicine/866#CLINICAL_PRECAUTIONS 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
74 
Weber A, Computational Modeling Summary to Support Candidate Selection of Inhaled 
PRINT Cyrstallin Ribavirn (CCI15106)-PVOH  (99-1 w-w)  0.9x1-um Cylindrical 
Particles.  PIER accession 6301434, 2017. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
75 
12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
%CV 
Coefficient of variation 
%CVb 
Between-subject coefficient of variation 
µg 
Microgram 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC(0-τ) 
AUC from time zero to end of dosing interval 
AUC(0-∞) 
AUC from time zero to infinity 
AUC(0-24) 
AUC from time zero to 24 hours 
AUC(0-t) 
AUC from time zero to the time of last quantifiable concentration 
BAL 
Bronchoalveolar lavage 
BMI 
Body mass index 
CCI15106-CFI 
CCI15106 capsules for inhalation 
CI 
Confidence interval 
CL/F 
clearance 
Cmax 
Concentration at maximum 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CRF 
Case report form 
ECG 
Electrocardiogram 
ELF 
Epithelial lining fluid 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle stimulating hormone 
FTIH 
First time in human 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GSK 
GlaxoSmithKline 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 
Hep B 
Hepatitis B 
Hep C 
Hepatitis C 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
HRV 
Human rhinovirus 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
76 
IB 
Investigator brochure 
ICH 
International conference on harmonization 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
Kg 
Kilogram 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
mg 
milligram 
min 
Minute 
mL 
Milliliter 
mm Hg 
Millimeter of mercury 
NOAEL 
No observed adverse effect level 
PK 
Pharmacokinetics 
POP PK 
Population PK 
PRINT 
Particle Replication In Non-wetting Templates 
QTcF 
QT interval corrected for heart rate according to Fridericia’s 
formula 
RAP 
Reporting and Analysis Plan 
RBC 
Red blood cells 
RSV 
respiratory syncytial virus 
RTP 
Ribavirin triphosphate 
SAE 
Serious adverse event 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SRM 
Study Reference Manual 
t1/2 
Elimination half-life 
Tmax 
Time of maximum concentration 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
USPI 
United States Prescribing Information 
WBC 
White blood cells 
WOCBP 
Woman of childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
77 
12.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 2 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 2 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
Red blood cells (RBC) 
Indices: 
Mean corpuscular 
hemoglobin (MCV) 
Mean corpuscular 
volume (MCH) 
%Reticulocytes 
White blood cell (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 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, and ketones by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
78 
Laboratory 
Assessments 
Parameters 
C virus antibody)  
• Serum pregnancy test in women 
• Coagulation parameters in the BAL cohorts 
The results of each test must be entered into the CRF. 
 
NOTES : 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT ≥3 × upper limit of normal (ULN) and 
bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
79 
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 International conference on harmonization (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.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
80 
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law.  The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
81 
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 subjects, 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. 
• 
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
82 
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 Agreement to 
definition of source data. 
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 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
83 
12.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
84 
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. 
 
Guidance for Grading Adverse Events 
Taken from the Food and Drug Administration (FDA) Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 
The purpose of this appendix is to provide guidance and it is to be used in conjunction 
with the investigator’s judgment. 
 
Guidance for Grading Vital Signs Adverse Events 
Vital Signs * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
(°F) * 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats 
per minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats 
per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension 
(systolic) - mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension 
(diastolic) - mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
(systolic) – mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
* Participant should be at rest for all vital sign measurements 
** Oral temperature; no recent hot or cold beverages or smoking 
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when 
characterizing 
Allergic Reactions 
Grade 1 allergic reaction (Pruritis without rash): 
Participants with Grade 1 allergic reaction should be evaluated by the investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time: 
•  Temperature >38.5°C 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
85 
•  Eosinophilia 
•  Respiratory involvement including brochospasm, laryngospasm, or angioedema 
•  Any indication of internal organ involvement (hepatitis, nephritis) 
In the absence of the above signs or symptoms, participants with Grade 1 allergic 
reaction may continue the study drug at the discretion of the investigator.  The participant 
should be advised to contact the investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen.  If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK. 
Grade 2 allergic reaction (Localized urticaria): 
Participants with Grade 2 allergic reaction should be evaluated by the investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time: 
•  Temperature >38.5°C 
•  Eosinophilia 
•  Respiratory involvement including brochospasm, laryngospasm, or angioedema 
•  Any indication of internal organ involvement (hepatitis, nephritis) 
In the absence of the above signs or symptoms, participants with Grade 2 allergic 
reaction may continue the study drug at the discretion of the investigator.  The participant 
should be advised to contact the investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen.  If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves.  
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK. 
Grade 3 allergic reaction (Generalized urticaria or angioedema): 
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken. 
Grade 4 allergic reaction (Anaphylaxis): 
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
86 
Revised ACTG Toxicity 
Grade 
Definition 
Investigator action 
Grade 1 
Pruritus without rash 
May continue therapy 
Grade 2 
Localized urticaria 
May continue therapy 
Grade 3 
Generalized urticaria 
Angioedema 
Discontinue therapy 
Grade 4 
Anaphylaxis 
Discontinue therapy 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
87 
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. 
 
Definition of Cardiovascular Events (CV)  
 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
88 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
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 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
89 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.  
• 
New or updated information will be recorded in the originally completed 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 Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor and 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 SRM. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
90 
12.5. 
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
1. 
Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male participants 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent  
• 
Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 3 when having penile-vaginal 
intercourse with a woman of childbearing potential  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
91 
• 
Men with a pregnant or breastfeeding partner are not eligible to participate.  
• 
In addition male participants must refrain from donating sperm for duration of 
study and for 7 months after study completion or from last dose. 
Table 3 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
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.  
 
Female participants 
Female participants of childbearing potential are not eligible to participate.  
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.  


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
92 
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
Female Participants who can become pregnant are not eligible to participate 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
93 
12.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology.  
Phase I liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria – Liver Stopping Event 
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2 ≥ 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments following Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue  study treatment 
• Report the event to GSK within 24 h 
• Record the liver event data, and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline (see 
MONITORING below) 
• Do not restart or rechallenge participant with 
study treatment 
MONITORING: 
If ALT≥3xULN AND bilirubin ≥ 2xULN  or INR 
>1.5:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline 
• A specialist or hepatology consultation is 
recommended 
• Viral hepatitis serology3 
• Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend  
• Blood sample for pharmacokinetic 
(PK) analysis, obtained within 48 h of 
last dose4 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin≥2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
94 
 
If ALT≥3xULN AND bilirubin < 2xULN  and INR 
≤1.5:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin)  and perform liver 
event follow up assessments within  24-72 hrs  
• Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline 
alcohol intake case report form 
If ALT≥3xULN AND bilirubin ≥ 2xULN  
or INR >1.5: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James,2009]).  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease.  Collect Liver 
Imaging and/or Liver Biopsy data. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT ≥ 3xULN and bilirubin ≥ 2xULN. 
Additionally,if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick,indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excludingstudies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value 
stated will not apply to participants receiving anticoagulants 
3. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 
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. 
 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
95 
12.7. 
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
Definition and Documentation of Medical Device Incidents 
Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 7.1 for the list of GSK medical 
devices).  
Medical Device Incident Definition 
• 
A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health. 
• 
Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel. 
 
It is sufficient that: 
• 
An incident associated with a device happened and 
• 
The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health. 
A serious deterioration in state of health can include any of the following: 
• 
Life-threatening illness 
• 
Permanent impairment of body function or permanent damage to body structure 
• 
Condition necessitating medical or surgical intervention to prevent one of the 
above  
• 
Fetal distress, fetal death, or any congenital abnormality or birth defects 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
96 
Examples of incidents 
• 
A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse. 
• 
A participant’s study treatment is interrupted or compromised by a medical device 
failure. 
• 
A misdiagnosis due to medical device failure leads to inappropriate treatment. 
• 
A participant’s health deteriorates due to medical device failure. 
 
Documenting Medical Device Incidents 
Medical Device Incident Documenting 
• 
Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form. 
• 
For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4. 
• 
The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK. 
• 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident. 
• 
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident. 
This includes any amendment to the device design to prevent recurrence. 


2016N290366_02 
CONFIDENTIAL 
 
 
 
205822 
 
97 
12.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 1 (31-May-2017) 
Overall Rationale for the Amendment: Changes requested after regulatory reviews 
Section # 
and Name 
Description of Change 
Brief Rationale 
8.1.3 Other 
Stopping 
Criteria 
Added additional stopping criteria 
Enhancing safety parameters in the study 
5.1 Overall 
Design 
Added PK review to all reviews 
required to proceed between study 
cohorts 
Enhancing review requirements between 
study cohorts 
1. Synopsis 
2. Schedule 
of Activities 
5.1  Overall 
Design 
Added requirement to call male 
participants approximately 7 
months after study completion to 
ensure their partner is not 
pregnant 
Enhancing safety monitoring 
 
 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205822
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
A double-blind (sponsor unblind), randomized, placebo 
controlled, single and repeat escalating dose study to 
investigate the safety, tolerability, and pharmacokinetics of 
CCI15106 inhalation powder in healthy participants and 
participants with moderate chronic obstructive pulmonary 
disease (COPD) including evaluation of environmental and 
healthy by-stander exposure levels during dosing.
Compound Number 
:
CCI15106
Effective Date 
:
30-Oct-2018
Description:

The purpose of this RAP is to describe the planned safety, tolerability and 
pharmacokinetic analyses and outputs to be presented in the Clinical Study Report 
for the study 205822. This RAP will be provided to the study team members to 
convey the content of the Statistical Analysis Complete (SAC) deliverable.

Bystander and Environmental Exposure Analyses is tabulated and reported in a 
separate report.
RAP Author(s):
Approver
Date
Approval Method
 Clinical Statistics, ID
30-Oct-2018
PharmaTMF
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205822
2
RAP Team Approvals:
Approver
Date
Approval Method
Executive Medical Director, R&D Infectious 
Diseases
29-Oct-2018
Email Approval
Director, Clinical Pharmacology
30-Oct-2018
Email Approval
Regional Study Manager, NLD CRT PCPS
29-Oct-2018
PharmaTMF
Principal Clinical Data Manager, RD, PCPS
29-Oct-2018
PharmaTMF
 
Associate Manager (ID, Clinical Programming)
30-Oct-2018
PharmaTMF
Principal Programmer/Analyst, RD PCPS
29-Oct-2018
PharmaTMF
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
 
30-Oct-2018
PharmaTMF
Statistics Director, RD PCPS
29-Oct-2018
PharmaTMF
Associate Manager (ID, Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205822
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses...................................................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment & Sub-group Display Descriptors.....................................11
5.2.
Baseline Definitions ....................................................................................12
5.2.1.
Baseline Definitions .....................................................................12
5.2.2.
Derivations and Handling of Missing Baseline Data.....................12
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
6.1.1.
Disposition and Withdrawals........................................................14
6.1.2.
Demographic and other Baseline Characteristics.........................15
6.1.3.
Medications .................................................................................15
7.
SAFETY ANALYSES .............................................................................................16
7.1.
Study Medication Exposure ........................................................................17
7.2.
Adverse Events Analyses ...........................................................................17
7.3.
Clinical Laboratory Analyses.......................................................................18
7.4.
ECG Evaluations ........................................................................................18
7.5.
Telemetry Evaluations ................................................................................18
7.6.
Spirometry Evaluations...............................................................................19
7.7.
Vital Signs...................................................................................................19
7.8.
Bystander and Environmental Exposure Analyses......................................19
8.
PHARMACOKINETIC ANALYSES.........................................................................20
8.1.
Overview of Planned Pharmacokinetic Analyses ........................................20
8.1.1.
Drug Concentration Measures .....................................................20
8.1.1.1.
Derivation of Lung ELF Drug (CCI15106) 
Concentration Data.....................................................21
8.1.2.
Pharmacokinetic Parameters.......................................................21
8.1.2.1.
Deriving Pharmacokinetic Parameters........................21


CONFIDENTIAL
205822
4
8.1.2.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................23
9.
POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................24
10. REFERENCES.......................................................................................................25
11. APPENDICES........................................................................................................26
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................26
11.1.1.
Exclusions from Per Protocol Population .....................................26
11.2.
Appendix 2: Schedule of Activities ..............................................................27
11.2.1.
Protocol Defined Schedule of Events...........................................27
11.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................32
11.3.1.
Study Phases ..............................................................................32
11.3.1.1.
Study Phases for Concomitant Medication .................32
11.3.2.
Treatment States for Adverse Events Data..................................33
11.4.
Appendix 4: Data Display Standards & Handling Conventions....................34
11.4.1.
Reporting Process .......................................................................34
11.4.2.
Reporting Standards....................................................................34
11.4.3.
Reporting Standards for Pharmacokinetic....................................35
11.5.
Appendix 5: Derived and Transformed Data ...............................................36
11.5.1.
General........................................................................................36
11.5.2.
Study Population..........................................................................36
11.5.3.
Safety ..........................................................................................37
11.6.
Appendix 6: Reporting Standards for Missing Data.....................................38
11.6.1.
Premature Withdrawals................................................................38
11.6.2.
Handling of Missing Data.............................................................38
11.6.2.1.
Handling of Missing and Partial Dates ........................38
11.7.
Appendix 7: Values of Potential Clinical Importance ...................................39
11.7.1.
Laboratory Values........................................................................39
11.7.2.
ECG.............................................................................................40
11.7.3.
Vital Signs....................................................................................40
11.8.
Appendix 8: Pop PK Dataset Specification..................................................41
11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................43
11.9.1.
Abbreviations...............................................................................43
11.9.2.
Trademarks .................................................................................44
11.10. Appendix 10: List of Data Displays..............................................................45
11.10.1. Data Display Numbering..............................................................45
11.10.2. Mock Example Shell Referencing ................................................45
11.10.3. Deliverables.................................................................................45
11.10.4. Study Population Tables..............................................................46
11.10.5. Safety Tables...............................................................................50
11.10.6. Pharmacokinetic Tables...............................................................57
11.10.7. Pharmacokinetic Figures .............................................................58
11.10.8. ICH Listings .................................................................................60
11.10.9. Non-ICH Listings..........................................................................66
11.11. Appendix 11: Example Mock Shells for Data Displays ................................67


CONFIDENTIAL
205822
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2016N290366_02
11-OCT-2017
Amendment 2
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Bystander and Environmental Exposure Analyses will be reported in a separate report.
The Lung ELF Concentration population for analysis is renamed to BAL PK in order to 
keep it consistent with the other Phase I study (202031).
The All Participants Screened, Safety, Systemic Pharmacokinetic Concentration (PK), the 
BAL PK analysis populations are not defined separately for Part 1 and Part 2 as 
mentioned in the protocol.
For the data disclosure outputs regarding “Summary of Age Ranges”, the Enrolled 
population is defined in this RAP.
The term "Subjects" is used to refer to the “Participants” in certain sections of this 
document including the TFLs.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To investigate the safety and 
tolerability of CCI15106-IP following 
single and repeat escalating doses in 
healthy participants and participants 
with moderate COPD.

Adverse events (AEs), clinical laboratory,
electrocardiogram (ECG), telemetry, spirometry, and vital 
signs assessments.

To determine systemic PK of 
CCI15106 following single and repeat 
escalating doses of CCI15106-IP in 
healthy participants and participants 
with moderate COPD.

Derived systemic PK parameters of CCI15106: Single 
dose: area under the curve (AUC) from time zero to the 
time of last quantifiable concentration (AUC[0-last]),
concentration at maximum (Cmax), time of maximum 
concentration (tmax), AUC from time zero to infinity 
(AUC[0-∞]) elimination half-life (t1/2), clearance (CL/F), 
as data permit.
Repeat dose: AUC from time zero to end of dosing 
interval (AUC[0-]) (=12 hours [h] for twice daily dose 
regimen), Cmax, tmax, elimination half-life (t1/2) as data 
permit.

To evaluate potential inhalation 
exposure of bystanders to airborne 

Concentration of CCI15106 in plasma of bystanders 15-
20 minutes (min) after dosing (at predicted tmax) and 


CONFIDENTIAL
205822
6
Objectives
Endpoints
CCI15106 during self-administered 
dosing of participants.
amount of CCI15106 accumulated on filters fitted on
bystander over 15 min after dosing.

To evaluate the distribution and
persistence of airborne CCI15106 in 
room air post-dosing.

Amount of CC15106 in room air assessed by measuring 
amount of CCI15106 accumulated over 20 and 60 min 
intervals during and immediately post-dosing on filters 
fitted on stationary pumps placed in the room.
Secondary Objectives
Secondary Endpoints

To determine the concentration of
CCI15106 in the lung of healthy 
participants and participants with 
moderate COPD following repeat 
dosing of CCI15106-IP.

Concentrations of CCI15106 in lung epithelial lining fluid 
(ELF) assessed by bronchoalveolar lavage (BAL).

To investigate the performance of the
Monodose RS01 device for the 
administration of CCI15106-IP in 
healthy participants and participants 
with moderate COPD.

Device safety and performance parameters, including 
medical device incidents reporting, as well as systemic 
PK and lung CCI15106 concentrations.
Exploratory Objectives
Exploratory Endpoints

To assess dose proportionality of
CCI15106-IP versus systemic PK 
parameters.

Comparisons of doses administered and systemic PK 
parameters of CCI15106: AUC(0-24) or AUC(0-) and 
Cmax.

To explore the relationship of drug 
exposure to safety and tolerability 
parameters after single and repeat 
escalating doses of CCI15106-IP in 
healthy participants and participants 
with moderate COPD.

The dose or plasma exposure parameters for CCI15106 
and the relationship of these to safety and tolerability 
parameters, as data permit.

To extrapolate study outcomes to a 
realistic worst case real-life scenario 
of dosing multiple patients in a single 
room in a nursing home.

Comparison of the study room with a potential nursing 
home room, including room dimensions, patient density,
ventilation (air change rates per hour).


CONFIDENTIAL
205822
7
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
This is a two-part, double-blind (sponsor unblind), randomized, placebo-controlled, single 
and repeat escalating dose study. Investigator and participants will be blinded to treatment 
type (active or placebo), but will know what dose of the medication is being administered. 
Part 1 will investigate single and repeat ascending doses in healthy participants and 
investigate environmental and bystander exposure. Part 2 will evaluate single and repeat 
dose in participants with moderate COPD. Participants may only be enrolled in one study 
part and randomized to one cohort per the randomization schedule.


CONFIDENTIAL
205822
8
Overview of Study Design and Key Features
The following reviews will be conducted during the study progression:
Dosing

For Cohort A Part 1, 60 mg single dose will be administered on Day 1; 120 mg single 
dose will be administered on Day 3; and then 30 mg dose will be administered BID on
Days 6-19.

For Cohort B Part 1, Repeat Dose Schedule of Activities (SoA) will be followed for the 
duration of the study. Dosing will begin on the morning of Day 1 and continue for 14 
days BID. Dosing frequency and duration may be adjusted based on emerging safety 
and tolerability data.

For Cohort C Part 1, 14 healthy participants will be enrolled to evaluate bystander 
exposure and will follow Cohort C Part 1 SoA. Bystanders and air exposure will be
evaluated concomitantly with Cohort B Part 1.

For Cohort A Part 2, Single Dose SoA will be followed for the duration of the study.

For Cohort B Part 2, Repeat Dose SoA will be followed for the duration of the study.
Dosing will begin on the morning of Day 1 and continue for 14 days BID. Dosing 
frequency and duration may be adjusted based on emerging safety and tolerability 
data.
Time & 
Events
Details of the Schedule of Activities can be found in Appendix 2, Section 11.2
Treatment 
Assignment
In Cohort A Part 1 and in Cohort A Part 2, participants will be randomized to CCI15106- IP 
or Placebo with 3:1 ratio. In Cohort B Part 1 and Cohort B Part 2, participants will be
randomized with 6:1 ratio. Cohort C Part 1 will not be randomized or dosed, but each
bystander participant will be assigned to a dosing participant. Screening visit will occur
within 30 days of dosing for cohorts in Part 1 and within 45 days of dosing for cohorts in
Part 2.
Interim 
Analysis
No formal interim analyses are planned for this study. Safety and tolerability will be 
evaluated as described in the design features above. Systemic and, where available, lung 
PK may also be evaluated.
2.4.
Statistical Hypotheses
The primary objective of the study is to investigate the safety and tolerability of 
CCI15106-IP following single and repeat escalating doses in healthy participants and 
participants with moderate COPD. No statistical hypotheses will be tested.


CONFIDENTIAL
205822
9
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analyses are planned for this study. Safety and tolerability will be 
evaluated as described in Section 2.3. Systemic and, where available, lung PK may also 
be evaluated.
3.2.
Final Analyses
Safety and PK analyses are the primary statistical analyses for this study.
Data will be listed and summarized according to GSK reporting standards, where
applicable. All the displays will be split by part. Study population tables would be 
presented by cohort and a combined placebo (of all cohorts with the exception of Part 1, 
Cohort C (bystanders)). For Safety displays, listings will be sorted by dose, participant 
and time; summaries will be presented by dose and time for different parts of the study. 
Participants receiving placebo may be combined into one treatment group in the 
summaries within each part.
Descriptive summaries will include n, mean, standard deviation (SD), median, minimum,
and maximum, geometric mean with associated 95% confidence interval (CI), and the
between-participant coefficient of variation (%CVb) for continuous variables related to 
PK parameters, n and percent will be used as summary statistics for categorical variables.
Version 9.4 or higher of the SAS system will be used to analyse the data as well as to
generate tables, figures, and listings.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Participants
Screened

Comprises of all participants who consent to participate 
in the clinical study.

Screen Failures
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
Safety

Comprises of all participants who receive at least one 
dose of study treatment during the study.

This population will be based on the treatment the 
participant actually received.

Safety

Study Population
Systemic 
Pharmacokinetic 
Concentration
(PK)

Participants who receive at least one dose of study 
treatment and who undergo plasma PK sampling and 
have at least one post-dose concentration result.

PK samples that may be affected by protocol deviations 
will be reviewed by the study team to determine whether 

PK


CONFIDENTIAL
205822
10
Population
Definition / Criteria
Analyses Evaluated
or not the sample will be excluded.
BAL PK

Healthy participants who receive at least one dose of 
study treatment and who undergo BAL sampling and 
have post-dose lung ELF CCI15106 and urea 
concentration result.

Lung ELF samples that may be affected by protocol 
deviations, will be reviewed by the study team to 
determine whether or not the sample will be excluded.

BAL
Bystander Safety
Population (Part
1, Cohort C)

Participants who are present at least once in the room 
with the participant receiving the dose.

Safety

Study Population
Bystander PK 
Population (Part
1, Cohort C)

Participants who are present at least once in the room 
with the participant receiving the dose, undergo plasma 
PK sampling and have post-dose concentration result.

PK samples that may be affected by protocol deviations 
will be reviewed by the study team to determine whether 
or not the sample will be excluded.

PK
Refer to Appendix 11: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.


CONFIDENTIAL
205822
11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS

There are no planned examinations of covariates and subgroups.

There are no planned adjustments made for multiple centres in this study as this is a 
single centre study.

There are no planned adjustments for multiple comparisons or multiplicity.
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Display Header
Footnote Treatment 
Description
Order 
[1]
S1
CCI15106-IP  60 
mg  – Single Dose
CCI15106 SD 60mg(HV)
CCI15106-IP  60 mg 
Single Dose for Part 1, 
Cohort A 
1
S2
CCI15106-IP 120 
mg  – Single Dose
CCI15106 SD 120mg(HV)
CCI15106-IP 120 mg 
Single Dose for Part 1, 
Cohort A 
2
R1
CCI15106-IP  30 
mg  – BID
CCI15106 BID 30mg(HV)
CCI15106-IP  30 mg BID
for Part 1, Cohort A 
3
R2
CCI15106-IP  60 
mg  – BID
CCI15106 BID 60mg(HV)
CCI15106-IP  60 mg BID
For Part 1, Cohort B 
4
P
Placebo
Placebo(HV)
Placebo for Part 1 Cohorts 
A and B
5
S1
CCI15106-IP  60 
mg  – Single Dose
CCI15106 SD 
60mg(COPD)
CCI15106-IP  60 mg 
Single Dose for Part 2, 
Cohort A COPD 
6
R2
CCI15106-IP  60 
mg  – BID
CCI15106 BID 
60mg(COPD)
CCI15106-IP  60 mg BID
for Part 2, Cohort B COPD
7
P
Placebo
Placebo(COPD)
Placebo for Single Dose 
and BID for COPD
8
BYS
Bystander Cohort
Bystander
Bystander
9
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.


CONFIDENTIAL
205822
12
5.2.
Baseline Definitions
5.2.1.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment.
For tabulated safety summaries, only the scheduled assessments will be included in the 
summary tables.
Parameter
Study Assessments Considered as Baseline
Baseline Used 
in Data Display
Screening
Day -1
Day 1 (Pre-
Dose)
Safety
12 Lead ECG & Vital Signs
X
-
X
Day 1 (Pre-Dose)
Spirometry
X
-
X
Day 1 (Pre-Dose)
Haematology/Chemistry/Urinalysis
X
X
-
Day - 1 
Telemetry
-
-
X
Day 1 (Pre-Dose)
NOTES:

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the 
value for that time point.
5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 5.2.1 will be used for derivations for 
endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data are missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on change from baseline displays wherever applicable.
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.
Table 1
Overview of Appendices
Section
Component
11.2
Appendix 2: Assessment Windows
11.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Derived and Transformed Data


CONFIDENTIAL
205822
13
Section
Component
11.6
Appendix 6: Reporting Standards for Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance


CONFIDENTIAL
205822
14
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified.
All the displays will be split by part. Study population tables would be presented by 
cohort and a combined placebo (of all cohorts).
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 Displays Generated
Table
Figure
Listing
Randomization
Randomization
Y
Subject Disposition
Subject Disposition
Y
Y
Reason for Screening Failures
Y
Y
Reason for Withdrawals
Y
Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Study Populations
Y
Demography
Demographics Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Medical Condition & Concomitant Medications
Medical Conditions (Current/Past)
Y
Y
Concomitant Medications
Y
Y
NOTES:

Y = Yes display generated.
6.1.1.
Disposition and Withdrawals
All participants who provide informed consent will be accounted for in this study. In each 
study part, subject disposition will be tabulated for each study treatment and for all 
participants combined with the number of participants who are randomly assigned to 
treatment, complete the study and prematurely discontinue as well as the reason for early 
discontinuation.  A listing will present dates of completion or early withdrawal and the 
reason for early discontinuation, if applicable, for each participant.  
Listings of study eligibility, treatment randomization and study treatment administration 
will be provided for each study part based on the layout mentioned above.


CONFIDENTIAL
205822
15
6.1.2.
Demographic and other Baseline Characteristics
Individual subject demographics and baseline characteristics (medical history and results 
from drug and alcohol screens, smoking/nicotine history) will be presented in listings for 
each study part.  
Demographic characteristics such as age, sex, race, ethnicity, height, weight, and body 
mass index (BMI) will be summarized and tabulated by treatment and for all participants 
overall for each study part.  Descriptive statistics will be presented for age, height, 
weight, and BMI.  Frequency counts and percent will be presented for sex, race and
ethnicity.
6.1.3.
Medications
All prior and concomitant medications will be listed for each study part based on the 
layout mentioned earlier. Summaries of all medications taken during the course of the 
study will be presented in tabular form for each study part using GSK Drug Dictionary 
1.3. The number and percentage of participants taking concomitant medications will be 
summarized by cohort and overall for each study part separately. For each participant, the 
medication will be counted only once within a given preferred drug name level. A 
participant may appear more than once if he/she has more than one concomitant 
medication coded under different categories, however, the participant will be counted 
only once in the overall category. 
Please refer to Appendix 3: Study Phases and Treatment Emergent Adverse Events for 
definition of prior, concomitant and post-treatment medications. Handling of partial dates 
for medications is outlined in Appendix 6: Reporting Standards for Missing Data.


CONFIDENTIAL
205822
16
7.
SAFETY ANALYSES
The primary safety analyses for this study will be based on the Safety population for each 
dose taken, analysed separately for study parts, unless otherwise specified.
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by dose, participant and time; summaries will be 
presented by dose and time for different parts of the study. Participants receiving placebo 
may be combined into one treatment group in the summaries within each part. 
For categorical variables, the population size (N for sample size and n for available data) 
and the percentage (of available data) for each class of variable will be presented. 
Continuous variables will be summarized using descriptive statistics, including N, mean, 
standard deviation (SD), median, minimum and maximum values.
Table 3 provides an overview of the planned safety analyses for each study part, unless 
otherwise specified, with full details of data displays being presented in Appendix 11:
List of Data Displays.
Table 3
Overview of Planned Safety Analyses
Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure
Extent of Exposure  
Y 
Y
Adverse Events1
All AE’s
Y
Y
Serious AE’s
Y
Y
Treatment related AE’s
Y
Y
AE’s leading to 
Withdrawal
Y
Y
Laboratory Values 
Clinical Chemistry2
Y
Y
Y
Hematology
Y
Y
Y
Coagulation
Y
Y
Urinalysis
Y
Y
ECG’s3
ECG Findings
Y
Y
ECG Values
Y
Y
Y
Vital Signs3
Vitals Values
Y
Y
Y
Spirometry
Spiromtery
Y
Y
Telemetry
Telemetry Findings
Y
Y


CONFIDENTIAL
205822
17
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual participant observed raw data.
1.
Listings will include participant’s numbers for individual AE’s & AE system organ classes, preferred 
terms and verbatim text.
2.
Chemistry summaries will include both changes from baseline & emergent results by PCI criteria. 
3.
Listings and summaries for ECGs and vital signs include treatment emergent PCI results
7.1.
Study Medication Exposure
Exposure to study medication as the number of doses administered will be presented for 
each treatment for each Part.
7.2.
Adverse Events Analyses
Adverse Events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary, Version 21.0.
See Appendix 3: Study Phases and Treatment Emergent Adverse Events to determine 
treatment states for AE data. Handling of partial dates for AEs is outlined in Appendix 6: 
Reporting Standards for Missing Data. In the rare case when it is not possible to assess 
treatment emergence, the AE will be classified as treatment emergent (i.e. the worst 
case). 
AE Severity is classified as mild (grade = 1), moderate (grade = 2), or severe (grade = 3). 
AEs with a missing severity will be classified as severe. If a participant reports an AE 
more than once within that SOC (System Organ Class)/ PT (Preferred Term), the AE 
with the worst case severity will be used in the corresponding severity summaries.
Relationship to study treatment, as indicated by the Investigator, is classified as “not 
related” or “related”. AEs with a missing relationship to study medication will be 
regarded as “related” to study medication. 
All AE tabulations will be performed separately for Part 1 and Part 2, by dose, and will 
include the number and percentage of participants. For each study part and cohort, 
incidence of AEs will be tabulated by the following:

All AEs by SOC and PT

All related AEs by SOC and PT

All AEs by SOC, PT and Severity

All related AEs by SOC, PT and Severity


CONFIDENTIAL
205822
18
All AEs leading to permanent discontinuation of study treatment will be identified by 
using the variable pertaining to outcome on the Adverse Events page of the CRF, and 
listed separately for each study part and cohort.
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse 
Events page of the CRF, and will be listed separately for each study part.
The details of the planned displays are provided in Appendix 11: List of Data Displays.
7.3.
Clinical Laboratory Analyses
Laboratory results will be included in the reporting of this study for hematology, 
coagulation, clinical chemistry, and urinalysis.  
Protocol-specified clinical laboratory tests will be summarized using descriptive 
statistics.  The statistics will be presented for each scheduled assessment during the study 
and change from baseline to each scheduled assessment. Presentations will use SI Units, 
as provided by the labs or converted from values in other units. Clinical laboratory data 
collected during unscheduled visits of study conduct that were not required per protocol, 
such as for special testing to evaluate an AE, will be listed and not summarized. 
Based upon laboratory normal ranges, the laboratory test results will be categorized 
according to the normal range as low (below the lower limit), normal (within the normal 
range) and high (above the upper limit). Summary statistics for change from baseline
based on PCI will also be tabulated. The details of the planned displays are in Appendix
11: List of Data Displays.
7.4.
ECG Evaluations
The following ECG parameters will be reported for each study part: PR, QRS, QT, QTc, 
QTcF and HR (bpm). Replicate quantitative values taken per time point will be averaged 
for all analysis and reporting. Summary statistics for change from baseline will also be 
tabulated.
Overall assessment of ECG (Investigator’s judgment) will be recorded as follows:

Normal

Abnormal, Not Clinically Significant

Abnormal, Clinically Significant
7.5.
Telemetry Evaluations
Overall assessment of Telemetry (Investigator’s judgment) will be recorded as follows:

Normal


CONFIDENTIAL
205822
19

Abnormal, Not Clinically Significant

Abnormal, Clinically Significant
All measurements will be listed.
7.6.
Spirometry Evaluations
The following parameters will be reported for each timepoint: FEV1 and FVC. The 
maximum of the measurements will be calculated.  All measurements will be listed.
% Predicted Normal FEV1   = (Max FEV1/Predicted Normal FEV1)x100
% Predicted FVC   = (Max FVC/Predicted Normal FVC)x100
7.7.
Vital Signs
The following Vital Signs measurements will be reported for each study part: supine 
systolic and diastolic blood pressure, pulse rate, respiratory rate and temperature. 
For participants undergoing BAL, vital signs will also include oxygen saturation.
Triplicate quantitative values taken per time point will be averaged for all analysis and 
reporting.
Summary statistics for collected vital signs, change from baseline, and summary of PCI
will also be tabulated.
7.8.
Bystander and Environmental Exposure Analyses
The bystander and environmental analysis will be analyzed and presented in a separate 
report.


CONFIDENTIAL
205822
20
8.
PHARMACOKINETIC ANALYSES
8.1.
Overview of Planned Pharmacokinetic Analyses
The PK analyses will be based on the “Systemic Pharmacokinetic Concentration”
population for the plasma drug concentration data, and “BAL PK Population” for the 
lung ELF concentration data, unless otherwise specified.
Table 4 provides an overview of the planned analyses, with full details being presented in 
Appendix 11: List of Data Displays. 
Table 4
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Plasma Drug 
Concentrations
Y
Y 
[1] 
[2]
[3]
[4]
Y
[1]
Y
Y
[1]
[2]
Y
[1]
Derived PK 
Parameters
Y
Y
Y
Y
Y
[7]
Y
[8]
Lung ELF CCI15106 
Concentration
Y
Y
[5]
Y
[6]
Y
Y
[1]
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual participant observed raw data.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Separate Mean (± SD) and Median plots will be generated, for the BD cohorts, overlay the day 1 and 
day 14 on same plot where possible.
3.
Mean (± SD) and Median plots by cohorts a) to compare over the first 12hours for 60mg in HV (part 1) 
and COPD (part 2); b) to compare the 60mg SD (over 24h) HV vs COPD; c) to compare the 60mg BD 
HV vs COPD one for each of the intense sampling day (day 1, day 14).
4.
Boxplot of plasma drug concentration at the follow up visit by cohort.
5.
Boxplot of Lung CCI15106 concentration by cohort (HV vs COPD).
6.
Lung CCI15106 concentration by Subject ID.
7.
Dose proportionality of single and repeat dose and accumulation ratios from Cohorts A and B will be 
evaluated in Part 1 and Part 2.
8.
Supportive SAS Output from Statistical Analysis of Loge-transformed Plasma PK Parameters.
8.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions.


CONFIDENTIAL
205822
21
8.1.1.1.
Derivation of Lung ELF Drug (CCI15106) Concentration Data
Urea concentration data will be used to calculate the dilution effect of the BAL A 
correction for dilution will be applied to all BAL drug concentrations as follows:
Factor
Dilution
mL
ng
ion
Concentrat
Drug
BAL
mL
ng
ion
Concentrat
Drug
Lung


)
/
(
)
/
(
where 
8.1.2.
Pharmacokinetic Parameters
8.1.2.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 4: Data Display Standards & Handling Conventions for the 
treatment of concentrations below the assay’s lower limit of quantification (LLQ).

The PK parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using Phoenix WinNonlin™6.4 or higher 
(Pharsight Corporation, a Certara Company, Princeton, NJ), and/or SAS™Version 9.4
or higher.  Graphics may be prepared using the same versions of SAS™, or Phoenix
WinNonlin™, or with SigmaPlot™12.5, or higher (Systat Software, Inc., San Jose, 
California).

All calculations of non-compartmental parameters will be based on actual sampling 
times, except for the purpose of interim reviews where nominal sampling times will 
be used.

Pharmacokinetic parameters described in Table 5 (Cohorts A, Part 1 and Part 2) and 
Table 6 (Cohort A, Part 1, Cohorts B, Part 1 and Part 2) will be determined from the 
plasma concentration-time data, as data permits, for CCI15106 (ribavirin). 
Table 5
Derived Pharmacokinetic Parameters (Cohorts A, Part 1 and Part 2 –
Single dose)
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (ng·h/mL) after each single dose will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity (ng·h/mL) will be calculated 
by linear up/log down trapezoidal summation as: 
AUC = AUC(0-t) + C(t) / z
AUC(0-12)
Area under the concentration-time curve from time zero to 12 hours post dose, e.g. for 


CONFIDENTIAL
205822
22
Parameter
Parameter Description
cohort A part 1, AUC(0-12) will be calculated after the 60mg SD (day 1), 120mg SD (day 3), 
and first dose of 30mg BD (day 6)
AUC(0-24)
Area under the concentration-time curve from time zero to 24 hours post dose, e.g. for 
cohort A part 1, AUC(0-24) will be calculated after the 60mg SD (day 1), 120mg SD (day 3)
AUC(0-48)
Area under the concentration-time curve from time zero to 48 hours post dose, e.g. for 
cohort A part 1, AUC(0-24) will be calculated after the 60mg SD (day 1), 120mg SD (day 3)
Cmax
Maximum observed concentration in plasma (ng/mL), determined directly from the 
concentration-time data.
tmax
Time to reach Cmax (h), determined directly from the concentration-time data.
t½
Apparent terminal half-life (h) will be calculated as: 
t½ = ln2 / z
z
Apparent terminal rate constant (1/h), determined by linear regression of the terminal points 
of the log-linear concentration-time curve.  Visual assessment will be used to identify the 
terminal linear phase of the concentration-time profile.  A minimum of 3 data points will be 
used for determination.
CL/F
Apparent inhaled plasma clearance after dosing (L/h), calculated as administered dose 
divided by AUC(0-∞).
NOTES:

Additional parameters may be included as required.
Table 6
Derived Pharmacokinetic Parameters (Cohort A, Part 1, Cohorts B, 
Part 1 and Part 2 – Repeat Dose)
Parameter
Parameter Description
AUC(0-)
Area under the concentration-time curve in the plasma during a dosing interval (ng·h/mL) on 
day 1 and day 14, calculated by linear up/log down trapezoidal summation.  Actual elapsed 
time at the end of the dosing interval will be used for the calculation. =12 for BID dosing 
regimen
Cmax
Maximum observed concentration in plasma (ng/mL), determined directly from the 
concentration-time data.
tmax
Time to reach Cmax (h), determined directly from the concentration-time data.
t½
Apparent terminal half-life (h) will be calculated as: 
t½ = ln2 / z
z
Apparent terminal rate constant (1/h), determined by linear regression of the terminal points 
of the log-linear concentration-time curve.  Visual assessment will be used to identify the 
terminal linear phase of the concentration-time profile.  A minimum of 3 data points will be 
used for determination.
NOTES:

Additional parameters may be included as required.
Individual lung ELF concentration data will be summarised, listed and displayed 
graphically on both linear and semi-logarithmic scales for the Cohorts with available ELF 
data. Where data permit, the individual lung ELF concentration data may be plotted 
against the plasma concentration measured prior to BAL sampling.


CONFIDENTIAL
205822
23
8.1.2.2.
Statistical Analysis of Pharmacokinetic Parameters
Geometric mean will be included for PK parameters, wherever applicable.
The following PK statistical analyses will only be performed, if sufficient data is 
available (i.e. if participants have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses
Endpoint(s)

All endpoints, except tmax and %AUCex, will be natural-log transformed prior to the analysis

Dose Proportionality: AUC(0-24) or AUC(0-48), or AUC(0-) and Cmax, for single dose and repeat dose of 
Part 1

Steady State Assessment in BID dosing: Ctrough (using pre-dose concentration from day 6 in Cohort A 
Part 1, and day 2 onwards in Cohorts B, Part 1 and Part 2)  

Accumulation in BID dosing: accumulation ratio will be calculated for AUC(0-) as [AUC(0-), on Day 
19/AUC(0--), on Day 6 for Cohort A in Part 1, or AUC(0-) on Day 14/AUC(0--) on Day 1 for Cohorts B of 
both Part 1 and Part 2, from the ANOVA model
Model Specification

Dose Proportionality will be assessed separately by means of power model: y = α*doseβ where y 
denotes the PK parameter being analyzed. PK parameters will be normalized to 60mg dose and then 
log transformed prior to analysis
If the power model does not show dose proportionality then pairwise analysis of variance (ANOVA) may be 
used as an exploratory analysis to understand the dose where dose proportionality fails

Analysis of variance (ANOVA), considering study Day as fixed effect and subject as a random effect in 
the model, will be performed using SAS Mixed Linear Models procedure to evaluate in the assessment 
of steady state in models included at least 3 days of pre-dose concentrations (like Days 4,6,8; Days 
6,8,10, Days 10,12,14 relative to first dose of repeat dosing). This will be done for each of the repeat 
dose treatments.

Analysis of variance (ANOVA), considering study Day as fixed effect and subject as a random effect in 
the model, will be performed using SAS Mixed Linear Models procedure to evaluate in the assessment 
accumulation, where geometric least squares mean ratio of AUC(0-) on Day 19/AUC(0-) on Day 6 for 
Cohort A in Part 1, AUC(0-) on Day 14/AUC(0--) on Day 1 for Cohorts B and 90% CI will be calculated.
Note: Subjects will be fit as a fixed effect for the assessment of accumulation if the model fails to converge.

Estimates of within-subject variability for Cmax, t1/2, AUC(0-) and CL/F will be provided, where CVw(%) 
= SQRT(exp(MSE) – 1)×100 and MSE is the residual mean squared error from the model. CVw 
represents a pooled measure of within-subject variability in repeat dose group.
Model Results Presentation

Dose Proportionality: The intercept α and the slope β with corresponding 90% CIs will be estimated and 
presented for each PK parameter

Steady State Assessment: Estimated slope parameter with 90% CI will be presented.

Accumulation and Time Invariance: Geometric means with 90% CIs by parameter and day will be 
presented. Ratio of geometric means with corresponding 90% CIs for Day 14/ Day 1 for Cohort B or 
Day 19/Day 6 for Cohort A of Part 1 will also be presented. 

Comparative Plot of Individual Plasma PK Parameter Versus Treatment will be generated.

Individual and box plots of Pre-dose concentrations will be generated. 

The SAS output from the statistical models will be included in a listing of supportive SAS output. 


CONFIDENTIAL
205822
24
9.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
Population pharmacokinetics modelling may be conducted and reported separately.
The detailed PopPK methodology will be described in a separate RAP where appropriate. 
The required data for the analyses are provided in Appendix 8: Population 
Pharmacokinetic (PopPK) Analyses and are subject to delivery soon after DBF.


CONFIDENTIAL
205822
25
10.
REFERENCES
GlaxoSmithKline Document Numbers 2015N238595_00 (Original – 24-SEP-2015): A 
Double-Blind, Placebo-Controlled, Dose Escalation, First Time in Human Study to 
Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending 
Doses of GSK3389404 in Healthy Subjects.
Whitehead J. Easy-to-implement Bayesian methods for dose-escalation studies in healthy 
subjects. Biostatistics. 2001; 2:47-61.


CONFIDENTIAL
205822
26
11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Exclusions from Per Protocol Population
N/A


CONFIDENTIAL
205822
27
11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Screening and follow-up procedures for all cohorts


CONFIDENTIAL
205822
28
Schedule for Cohort A Part 1


CONFIDENTIAL
205822
29
Schedule for Cohort A Part 2 (and all other single dose administrations)


CONFIDENTIAL
205822
30
Repeat dose schedule to be followed for repeat dose cohorts in Parts 1 and 2 (other than Cohort A Part 1)


CONFIDENTIAL
205822
31
Schedule for Cohort C Part 1 (bystanders and air monitoring), to be executed concomitantly with Cohort B Part 1


CONFIDENTIAL
205822
32
11.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
11.3.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
dosing.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date
11.3.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


CONFIDENTIAL
205822
33
11.3.2.
Treatment States for Adverse Events Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date if AE start time not available; else 
AE Start Date time < Study Treatment Start Date time
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on CRF OR value is missing.
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


CONFIDENTIAL
205822
34
11.4.
Appendix 4: Data Display Standards & Handling 
Conventions
11.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used to perform all data analyses, generate 
tables, figures and listings.
Reporting Area
HARP Server
: us1salx00259
HARP Compound
: \arprod\cci15106\mid205822\final_03
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (AdaM IG Version 1.0).

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files may be generated for SAC tables..
11.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected.

Numeric data will be reported at the precision collected on the CRF.

The reported precision from non CRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses.


CONFIDENTIAL
205822
35
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13. and Standards for the Transfer and Reporting of PK 
Data using HARP
11.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
[Insert document name]. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Data
Descriptive Summary 
Statistics (Log 
Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) of log-
transformed data and between geometric coefficient of variation (CVb (%)) will be 
reported.
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
N, n, geometric mean, 95% CI (Lower, Upper), standard deviation (SD), median, 
minimum and maximum
Listings
Interval, number of observations included in calculation of lambda_z, regression 
coefficient and percent AUC extrapolated (%AUCex)


CONFIDENTIAL
205822
36
11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from randomisation date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Date ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1    
11.5.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
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

Subjects who were randomized but did not report a treatment start date will be categorised as having 
zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.


CONFIDENTIAL
205822
37
11.5.3.
Safety
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 

Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01

Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


CONFIDENTIAL
205822
38
11.6.
Appendix 6: Reporting Standards for Missing Data
11.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as completion of 
all visits of the study including the follow-up visit.

Withdrawn subjects may be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
11.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data are 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 are 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 subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The 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 and 
hence the event is considered On-treatment as per Appendix 3: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the 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.


CONFIDENTIAL
205822
39
11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
[Insert as Required]
[Units]
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
mmol/L
30
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN


CONFIDENTIAL
205822
40
11.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 
<480 
≥ 480 
< 500  
≥ 500 
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 [
> 110 
Change from Baseline
Increase from Baseline QTc
msec
> 30  
< 60 
msec
≥ 60  
11.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Systolic Blood Pressure
mmHg
≥ 40
≥ 40
Diastolic Blood Pressure
mmHg
≥ 20
≥ 20
Heart Rate
bpm
≥ 30
≥ 30


CONFIDENTIAL
205822
41
11.8.
Appendix 8: Pop PK Dataset Specification
For the purpose of population PK analysis, the raw plasma concentration data in the 
systemic PK population (including all the available plasma concentration data) will be 
merged for each individual with the following demographic and baseline/screening 
variables where available. In addition, the 12-ECG data as listed below will be merged 
with plasma concentration data by the planned time.
The dataset will be a comma delimited ASCII text file, named as: NM.205822.PK.v1.csv.
Variable
Description
Format
Unit
Missing
Note
AGE
Subject Age
Num
Specify
-99
From source data.
SEX
Subject gender 
Integer
None
Never
0=Male, 1=Female
SEXTEXT
Subject gender 
text
Char
None
Never
Text corresponding to code for SEX
BMI
Baseline Body 
Mass Index
Num
Specify
-99
From source data.
Formula: Weight(kg)/(height(m)**2)
WT
Baseline Subject 
weight
Num
Specify
-99
From source data.
HT
Baseline Subject 
height
Num
Specify
-99
From source data.
RACE
Subject race code1
Integer
None
-99
From source data e.g.
1=African American / African Heritage
2=American Indian or Alaska Native
3=Asian – Central / South Asian Heritage
4=Asian – East Asian Heritage
5=Asian – Japanese Heritage
6=Asian – South East Asian Heritage
7=Asian – Mixed Race
8=Native Hawaiian or other Pacific Islander
9=White – Arabic / North African Heritage
10=White – White / Caucasian / European 
Heritage
11=White – Mixed Race
12=Mixed Race
RACETXT
Subject race text
Char
None
Never
Text corresponding to code for RACE
ETHN
Subject ethnicity
Num
None
-99
From source data definition. 
E.g 1=Hispanic or Latino, 2=Non-Hispanic
ETHNTEXT
Subject ethnicity 
text
Char
None
Never
Text corresponding to code for ETHN.
SCR
Serum Creatinine
Num
micromol/L
-99
Baseline/screening defined in the source 
dataset
CRCL
Baseline 
Creatinine 
Clearance 
Num
mL/min
-99
From source data.
formula e.g.
Creatinine Clearance will be calculated 
based on the Cockcroft-Gault equation.

CrCL (ml/min) = [140 – AGE (in 
years)]*Weight(kg)*0.85 (for 
female patients) / [72* Serum 
Creatinine (micromol/L) * 0.0113
ALT
Alanine 
aminotransferase 
Num
-99
Baseline/screening defined in the source 
dataset
AST
Aspartate 
aminotransferase
Num
-99
Baseline/screening defined in the source 
dataset
ALB
Albumin
Num
-99
Baseline/screening defined in the source 


CONFIDENTIAL
205822
42
Variable
Description
Format
Unit
Missing
Note
dataset
TBIL
Total bilirubin
Num
-99
Baseline/screening defined in the source 
dataset
ECGTM
Clock time of ECG 
recording in hours
Num
ECGTM should be calculated as: hr + 
min/60
e.g. if clock time of ECG recording is 09:30, 
then ECGTM= 9 + 30/60= 9.5
HR
Heart rate in bpm
Num
bpm
As in source dataset
HRBL
Baseline heart rate 
in bpm
Num
bpm
As in source dataset
PR
PR interval in ms
Num
ms
As in source dataset
PRBL
Baseline 
corresponding PR 
interval in ms
Num
ms
As in source dataset
QRS
QRS complex 
duration in ms
Num
ms
As in source dataset
QRSBL
Baseline 
corresponding 
QRS interval in ms
Num
ms
As in source dataset
QT
Uncorrected QT 
interval in ms
Num
ms
As in source dataset
QTBL
Baseline 
uncorrected QT 
interval in ms
Num
ms
As in source dataset
QTcF
QT with Fridericia’s 
correction in ms
Num
ms
As in source dataset
QTcFBL
Baseline QT with 
Fridericia’s 
correction in ms
Num
ms
As in source dataset
RR
RR interval in ms
Num
ms
As in source dataset
RRBL
Baseline 
corresponding RR 
interval in ms
Num
ms
As in source dataset


CONFIDENTIAL
205822
43
11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan


CONFIDENTIAL
205822
44
Abbreviation
Description
SDTM
Study Data Tabulation Model
SoA
Schedule of Activities
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ADVAIR
NONMEM
SAS
SigmaPlot
WinNonlin


CONFIDENTIAL
205822
45
11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.30
N/A
Efficacy
N/A
N/A
Safety
3.1 to 3.60
N/A
Pharmacokinetic
4.1 to 4.7
4.1 to 4.12
Population Pharmacokinetic (PopPK)
N/A
N/A
Pharmacodynamic and / or Biomarker
N/A
N/A
Pharmacokinetic / Pharmacodynamic
N/A
N/A
Section
Listings
ICH Listings
1 to 66
Other Listings
66 to 82
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
11.10.3.
Deliverables
Delivery [Priority] [1]
Description
DS [X]
During Study
DE [X]
Dose Escalation
IA SAC [X]
Interim Analysis Statistical Analysis Complete
SAC [X]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


CONFIDENTIAL
205822
46
11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1
Summary of Participant Disposition – Part 1
The general layout of all the study 
population tables would follow mock 
shell SAFE_T1 for the column headers 
and order for both Part 1 and Part 2 
tables.
This will not include Cohort C, Part 1.
SAC
1.2.
Safety
ES1
Summary of Participant Disposition – Part 2
SAC
1.3.
Bystander 
Safety (Part 
1, Cohort C)
ES1
Summary of Participant Disposition – Bystander
Only for Cohort C, Part 1.
SAC
1.4.
All 
Participants 
Screened)
ES6
Summary of Screening Status and Reasons for Screen Failure –
Part 1
This will not include Cohort C, Part 1.
SAC
1.5.
All 
Participants 
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure –
Part 2
SAC
1.6.
All 
Participants 
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure –
Bystander
Only for Cohort C, Part 1.
SAC
Protocol Deviation
1.7.
Safety
DV1
Summary of Important Protocol Deviations – Part 1
This will not include Cohort C, Part 1.
SAC
1.8.
Safety
DV1
Summary of Important Protocol Deviations – Part 2
SAC


CONFIDENTIAL
205822
47
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.9.
Bystander 
Safety (Part 
1, Cohort C)
DV1
Summary of Important Protocol Deviations - Bystander
Only for Cohort C, Part 1.
SAC
Population Analysed
1.10.
All Screened
SP1A
Summary of Study Populations – Part 1
SAC
1.11.
All Screened
SP1A
Summary of Study Populations – Part 2
SAC
1.12.
Bystander 
Safety (Part 
1, Cohort C)
SP1A
Summary of Study Populations – Bystander
Only for Cohort C, Part 1.
SAC
Demographic and Baseline Characteristics
1.13.
Safety
DM1
Summary of Demographic Characteristics – Part 1
This will not include Cohort C, Part 1.
SAC
1.14.
Safety
DM1
Summary of Demographic Characteristics – Part 2
SAC
1.15.
Bystander 
Safety (Part 
1, Cohort C)
DM1
Summary of Demographic Characteristics – Bystander
Only for Cohort C, Part 1.
SAC
1.16.
Safety
DM5
Summary of Race and Racial Combinations – Part 1
This will not include Cohort C, Part 1.
SAC
1.17.
Safety (Part 
2)
DM5
Summary of Race and Racial Combinations – Part 2
SAC
1.18.
Bystander 
Safety (Part 
1, Cohort C)
DM5
Summary of Race and Racial Combinations – Bystander
Only for Cohort C, Part 1.
SAC
1.19.
Safety
DM6
Summary of Race and Racial Combination Details – Part 1
This will not include Cohort C, Part 1.
SAC
1.20.
Safety (Part 
2)
DM6
Summary of Race and Racial Combination Details – Part 2
SAC


CONFIDENTIAL
205822
48
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.21.
Bystander 
Safety (Part 
1, Cohort C)
DM6
Summary of Race and Racial Combination Details – Bystander
Only for Cohort C, Part 1.
SAC
1.22.
Enrolled
DM11
Summary of Age Ranges – Part 1
This will not include Cohort C, Part 1.
Please include the footnote: “[1] Age is 
calculated based on screening date, 
using date of birth, truncated to integer 
value.
Note that only the year of birth has 
been collected where the day and 
month would be 30th June for all 
subjects.”
SAC
1.23.
Enrolled
DM11
Summary of Age Ranges – Part 2
Please include the footnote: “[1] Age is 
calculated based on screening date, 
using date of birth, truncated to integer 
value.
Note that only the year of birth has 
been collected where the day and 
month would be 30th June for all 
subjects.”
SAC
1.24.
Enrolled
DM11
Summary of Age Ranges – Bystander
Only for Cohort C, Part 1.
Please include the footnote: “[1] Age is 
calculated based on screening date, 
using date of birth, truncated to integer 
value.
Note that only the year of birth has 
been collected where the day and 
month would be 30th June for all 
subjects.”
SAC


CONFIDENTIAL
205822
49
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.25.
Safety
MH1
Summary of [Current/Past] Medical Conditions – Part 1
This will not include Cohort C, Part 1.
SAC
1.26.
Safety
MH1
Summary of [Current/Past] Medical Conditions – Part 2
SAC
1.27.
Bystander 
Safety (Part 
1, Cohort C)
MH1
Summary of [Current/Past] Medical Conditions - Bystander
Only for Cohort C, Part 1.
SAC
1.28.
Safety
CM1
Summary of Concomitant Medications – Part 1
This will not include Cohort C, Part 1.
SAC
1.29.
Safety
CM1
Summary of Concomitant Medications – Part 2
SAC
1.30.
Bystander 
Safety (Part 
1, Cohort C)
CM1
Summary of Concomitant Medications – Bystander
Only for Cohort C, Part 1.
SAC
1.31.
Safety
NS1
Summary of Number of Subjects by Country and Site ID - Part 1
This will not include Cohort C, Part 1.
SAC
1.32.
Safety
NS1
Summary of Number of Subjects by Country and Site ID - Part 2
SAC
1.33.
Bystander 
Safety (Part 
1, Cohort C)
NS1
Summary of Number of Subjects by Country and Site ID -
Bystander
Only for Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
50
11.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term – Part 1
The general layout of all the safety
tables would follow mock shell 
SAFE_T4 for the column headers and 
order for both Part 1 and Part 2 tables.
This will not include Cohort C, Part 1.
SAC
3.2.
Safety
AE1
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term – Part 2
SAC
3.3.
Bystander 
Safety (Part 
1, Cohort C)
AE1
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term – Bystander
SAC
3.4.
Safety
AE1
Summary of Treatment Related Adverse Events by System 
Organ Class and Preferred Term – Part 1
This will not include Cohort C, Part 1.
SAC
3.5.
Safety
AE1
Summary of Treatment Related Adverse Events by System 
Organ Class and Preferred Term – Part 2
SAC
3.6.
Bystander 
Safety (Part 
1, Cohort C)
AE1
Summary of Treatment Related Adverse Events by System 
Organ Class and Preferred Term – Bystander
SAC
3.7.
Safety
AE5A
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Maximum Severity – Part 1
This will not include Cohort C, Part 1.
SAC
3.8.
Safety
AE5A
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Maximum Severity – Part 2
SAC


CONFIDENTIAL
205822
51
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.9.
Bystander 
Safety (Part 
1, Cohort C)
AE5A
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Maximum Severity – Bystander
SAC
3.10.
Safety
AE5A
Summary of Treatment Related Adverse Events by System 
Organ Class and Maximum Severity – Part 1
This will not include Cohort C, Part 1.
SAC
3.11.
Safety
AE5A
Summary of Treatment Related Adverse Events by System 
Organ Class and Maximum Severity – Part 2
SAC
3.12.
Bystander 
Safety (Part 
1, Cohort C)
AE5A
Summary of Treatment Related Adverse Events by System 
Organ Class and Maximum Severity – Bystander
SAC
3.13.
Safety
AE1
Summary of All Serious Adverse Events – Part 1
This will not include Cohort C, Part 1.
SAC
3.14.
Safety
AE1
Summary of All Serious Adverse Events – Part 2
SAC
3.15.
Bystander 
Safety (Part 
1, Cohort C)
AE1
Summary of All Serious Adverse Events – Bystander
Only for Cohort C, Part 1.
SAC
3.16.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study –
Part 1 
This will not include Cohort C, Part 1.
SAC
3.17.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study –
Part 2
SAC
3.18.
Bystander 
Safety (Part 
1, Cohort C)
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study –
Bystander
SAC
Laboratory: Chemistry 
3.19.
Safety
LB1
Summary of Chemistry Changes from Baseline by Visit – Part 1
This will not include Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
52
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.20.
Safety
LB1
Summary of Chemistry Changes from Baseline by Visit – Part 2
SAC
3.21.
Bystander 
Safety (Part 
1, Cohort C)
LB1
Summary of Chemistry Changes from Baseline by Visit –
Bystander
Only for Cohort C, Part 1.
SAC
3.22.
Safety
LB17
Summary of Clinical Chemistry Values by Potential Clinical 
Importance – Part 1
This will not include Cohort C, Part 1.
SAC
3.23.
Safety
LB17
Summary of Clinical Chemistry Values by Potential Clinical 
Importance – Part 2
SAC
3.24.
Bystander 
Safety (Part 
1, Cohort C)
LB17
Summary of Clinical Chemistry Values by Potential Clinical 
Importance – Bystander
Only for Cohort C, Part 1.
SAC
Laboratory: Hematology
3.25.
Safety
LB1
Summary of Haematology Changes from Baseline by Visit –
Part 1
This will not include Cohort C, Part 1.
SAC 
3.26.
Safety
LB1
Summary of Haematology Changes from Baseline by Visit –
Part 2
SAC 
3.27.
Bystander 
Safety (Part 
1, Cohort C)
LB1
Summary of Haematology Changes from Baseline by Visit –
Bystander
Only for Cohort C, Part 1.
SAC 
3.28.
Safety
LB17
Summary of Hematology Values by Potential Clinical Importance
– Part 1
This will not include Cohort C, Part 1.
SAC
3.29.
Safety
LB17
Summary of Hematology Values by Potential Clinical Importance
– Part 2
SAC
3.30.
Bystander 
Safety (Part 
1, Cohort C)
LB17
Summary of Hematology Values by Potential Clinical Importance
– Bystander
Only for Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
53
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Coagulation
3.31.
Safety
LB1
Summary of Coagulation Changes from Baseline by Visit – Part 
1
Only for Cohorts B, Part 1.
SAC
3.32.
Safety
LB1
Summary of Coagulation Changes from Baseline by Visit – Part 
2
Only for Cohorts B, Part 2.
SAC
Telemetry
3.33.
Safety
Non-standard 
SAFE_T2
Summary of Telemetry Findings – Part 1 
This will not include Cohort C, Part 1.
SAC 
3.34.
Safety
Non-standard 
SAFE_T2
Summary of Telemetry Findings – Part 2
SAC 
Spirometry
3.35.
Safety
Non-standard 
SAFE_T3
Summary of Spirometry Data – Part 1
This will not include Cohort C, Part 1.
SAC 
3.36.
Safety
Non-standard 
SAFE_T3
Summary of Spirometry Data – Part 2
SAC 
ECG
3.37.
Safety
EG1
Summary of ECG Findings by Visit – Part 1
This will not include Cohort C, Part 1.
SAC 
3.38.
Safety
EG1
Summary of ECG Findings by Visit – Part 2
SAC 
3.39.
Bystander 
Safety (Part 
1, Cohort C)
EG1
Summary of ECG Findings by Visit – Bystander
Only for Cohort C, Part 1.
SAC 
3.40.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit –
Part 1
This will not include Cohort C, Part 1.
SAC 


CONFIDENTIAL
205822
54
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.41.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit –
Part 2
SAC 
3.42.
Bystander 
Safety (Part 
1, Cohort C)
EG2
Summary of Change from Baseline in ECG Values by Visit –
Bystander
Only for Cohort C, Part 1.
SAC 
3.43.
Safety
Non-standard 
SAFE_T7
Frequency of Maximum ECG Values by PCI Category – Part 1
Compute and display Maximum by day.
SAC
3.44.
Safety
Non-standard 
SAFE_T7
Frequency of Maximum ECG Values by PCI Category – Part 2
SAC
3.45.
Bystander 
Safety (Part 
1, Cohort C)
Non-standard 
SAFE_T7
Frequency of Maximum ECG Values by PCI Category –
Bystander
Compute and display Maximum by day.
Only for Cohort C, Part 1.
SAC
3.46.
Safety
Non-standard 
SAFE_T8
Frequency of Worst Change from Baseline Values of QTcB and 
QTcF by PCI Category – Part 1
Compute and display Maximum by day.
SAC
3.47.
Safety
Non-standard 
SAFE_T8
Frequency of Worst Change from Baseline Values of QTcB and 
QTcF by PCI Category – Part 2
SAC
3.48.
Bystander 
Safety (Part 
1, Cohort C)
Non-standard 
SAFE_T8
Frequency of Worst Change from Baseline Values of QTcB and 
QTcF by PCI Category – Bystander
Compute and display Maximum by day.
Only for Cohort C, Part 1.
SAC
Vital Signs
3.49.
Safety
VS1
Summary of Vital Signs by Visit – Part 1
This will not include Cohort C, Part 1.
SAC
3.50.
Safety
VS1
Summary of Vital Signs by Visit – Part 2
SAC
3.51.
Bystander 
Safety (Part 
1, Cohort C)
VS1
Summary of Vital Signs by Visit – Bystander
Only for Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
55
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.52.
Safety
VS1
Summary of Change from Baseline in Vital Signs by Visit – Part 
1
This will not include Cohort C, Part 1.
SAC 
3.53.
Safety
VS1
Summary of Change from Baseline in Vital Signs by Visit – Part 
2
SAC 
3.54.
Bystander 
Safety (Part 
1, Cohort C)
VS1
Summary of Change from Baseline in Vital Signs by Visit –
Bystander
Only for Cohort C, Part 1.
SAC 
3.55.
Safety
VS2
Summary of Vital Signs by PCI – Part 1
This will not include Cohort C, Part 1.
SAC
3.56.
Safety
VS2
Summary of Vital Signs by PCI – Part 2
SAC
3.57.
Bystander 
Safety (Part 
1, Cohort C)
VS2
Summary of Vital Signs by PCI - Bystander 
Only for Cohort C, Part 1.
SAC
Exposure and Treatment Compliance
3.58
Safety
Non-standard 
SAFE_T5
Summary of Extent of Exposure to Study Treatment – Part 1
This will not include Cohort C, Part 1.
SAC
3.59
Safety
Non-standard 
SAFE_T5
Summary of Extent of Exposure to Study Treatment – Part 2
SAC


CONFIDENTIAL
205822
56
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.60
Bystander 
Safety (Part 
1, Cohort C)
Non-standard 
SAFE_T5
Summary of Extent of Exposure to Study Treatment – Bystander
SAC


CONFIDENTIAL
205822
57
11.10.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
4.1.
Systemic PK
PK01
Summary of CCI15106 Plasma Pharmacokinetic Concentration-
Time Data [ng/mL] by Cohort and Visit 
SAC 
4.2.
Systemic PK
PK01
Summary of plasma CCI15106 Concentration Data at Follow Up 
visit [ng/mL] by Cohort
This will not include Cohort C, Part 1.
SAC
4.3.
BAL PK
PK01
Summary of Lung ELF CCI15106 Concentration Data [ng/mL] by
Cohort
SAC
PK Derived Parameters
4.4.
Systemic PK
PK03
Summary of Derived CCI15106 Plasma Pharmacokinetic 
Parameters by Cohort and Visit 
This will not include Cohort C, Part 1.
SAC 
4.5.
Systemic PK
Non-Standard
PK_T1
Summary of Assessment of Dose Proportionality (Part 1 and 
Part 2)
Only for Cohorts A, Part 1 and Part 2.
SAC
4.6.
Systemic PK
Non-Standard
PK_T2
Summary of Assessment of Steady State (Part 1 and Part 2)
This will not include Cohort C, Part 1.
SAC
4.7.
Systemic PK
Non-Standard
PK_T3
Summary of Assessment of Accumulation (Part 1 and Part 2)
For Cohort A, Cohort B, Part 1, and 
Cohort B, Part 2.
SAC


CONFIDENTIAL
205822
58
11.10.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Mean/Median Concentration Plots
4.1.
Systemic PK
PK17
Mean (+SD) CCI15106 Plasma Concentration-Time Plot (Linear 
and Semi-log) (Part 1)
For Part 1, Overlay all cohorts and 
doses on same page, plot time upto 1) 
72 hours post dose 2) 12 hours post 
dose [excluding the data after the 2nd
dose following the BD doses for both 1] 
& 2] to see better the earlier timepoitns.
3) plot to overlay day 1 and day 14 after 
the 30mg BD
SAC 
4.2.
Systemic PK
PK17
Mean (+SD) CCI15106 Plasma Concentration-Time Plot (Linear 
and Semi-log) (Part 2)
For Part 2, 1) overlay day 1 and day 14 
for each cohort (doses); 2) overlay all 
cohorts (doses) on same page for each 
full PK sampling day, Day 1 and Day 14
SAC 
4.3.
Systemic PK
PK17
Mean (+SD) CCI15106 Trough Plasma Concentration by study 
day (Linear and Semi-log) (Part 1 and Part 2)
Overlay the all cohorts on same page
SAC
4.4.
Systemic PK
PK17
Mean (+SD) CCI15106 Plasma Concentration-Time Plot by 
Cohort (to compare between HV and COPD) (Linear and Semi-
log)
1) plot to overlay only data after 60mg 
SD (part 1 cohort A and part 2 cohort A)
2) plot to overlay data after 60mg BD 
(part 1 cohort B and part 2 cohort B), 
overlay all full PK sampling day (day 1 
and day 14) as well as population on 
same page
SAC 
4.5.
Systemic PK
Boxplot of pre-BAL plasma concentration by cohort (Linear and 
Semi-log)
Create a legend mentioning:
Cohort B, Part 1 – Healthy
Cohort B Part 2 - COPD
SAC 


CONFIDENTIAL
205822
59
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.6.
BAL PK
Boxplot of Lung ELF CCI15106 concentration by cohort (Linear 
and Semi-log)
SAC
Individual Concentration Plots
4.7.
Systemic PK
PK16a
Individual CCI15106 Plasma Concentration-Time Plot 
(Linear and Semi-log) (Part 1)
For Cohort A, overlay profiles after the 
60mg, 120mg, and overlay profiles on 
day 1 and day 14 (after 30mg BD) on 
the same plot
For Cohort B, overlay profiles on day 1 
and day 14 on the same plot
SAC 
4.8.
Systemic PK
PK16a
Individual CCI15106 Plasma Concentration-Time Plot 
(Linear and Semi-log) (Part 2)
For Cohort B, also overlay profiles on 
day 1 and day 14 on the same plot 
(ignore pre-dose PK from day 2 to day 
12, and day 15)
SAC 
4.9.
Systemic PK
Non-Standard
PK_F1
CCI15106 trough Plasma Concentration versus Study Day 
(Part 1 and Part 2)
Use line plot, All pre-dose from Day 2 
following the BD regimens onwards 
Linear scale only
SAC
4.10.
Systemic PK
Non-Standard
PK_F1
CCI15106 Plasma Concentration at follow up visit versus 
Subject ID (Part 1 and Part 2) 
Scatter Plot
SAC
4.11.
BAL PK
Non-Standard 
PK_F2
Scatter Plot of Lung Drug Concentration versus Subject ID 
(Part 1 and Part 2)
X Axis: Subject ID
Y-Axis: ELF Values
SAC
4.12.
BAL PK
Non-Standard 
PK_F2
Scatter Plot of Lung Drug Concentration versus Plasma 
Drug Concentration (BAL cohorts in Part 1 and Part 2) 
data for all patients on same page
separate colours for healthy and COPD 
patients
Cohorts B for both parts
The template is similar to PK_F2, only 
change the X-axis to plasma drug 
concentration.
SAC


CONFIDENTIAL
205822
60
11.10.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Randomization
1.
Safety
TA1
Listing of Randomized and Actual Treatments – Part 1
This will not include Cohort C, Part 1.
SAC
2.
Safety
TA1
Listing of Randomized and Actual Treatments – Part 2
SAC
Subject Disposition
3.
Safety
ES2
Listing of Reasons for Study Withdrawal – Part 1
This will not include Cohort C, Part 1.
SAC
4.
Safety
ES2
Listing of Reasons for Study Withdrawal – Part 2
SAC
5.
Bystander 
Safety (Part 
1, Cohort C)
ES2
Listing of Reasons for Study Withdrawal – Bystander
Only for Cohort C, Part 1.
SAC
6.
All 
Participants 
Screened
ES7
Listing of Reasons for Screen Failure – Part 1
This will not include Cohort C, Part 1.
SAC
7.
All 
Participants 
Screened
ES7
Listing of Reasons for Screen Failure – Part 2
SAC
8.
Bystander 
Safety (Part 
1, Cohort C)
ES7
Listing of Reasons for Screen Failure – Bystander
Only for Cohort C, Part 1.
SAC
9.
Safety
SD2
Listing of Subjects with Study Drug Stopping Record – Part 1
This will not include Cohort C, Part 1.
SAC
10.
Safety
SD2
Listing of Subjects with Study Drug Stopping Record – Part 2
SAC
Protocol Deviations
11.
Safety
DV2
Listing of Important Protocol Deviations – Part 1
This will not include Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
61
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.
Safety
DV2
Listing of Important Protocol Deviations – Part 2
SAC
13.
Bystander 
Safety (Part 
1, Cohort C)
DV2
Listing of Important Protocol Deviations – Bystander
Only for Cohort C, Part 1.
SAC
14.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations –
Part 1
This will not include Cohort C, Part 1.
SAC
15.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations –
Part 2
SAC
16.
Bystander 
Safety (Part 
1, Cohort C)
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations –
Bystander
Only for Cohort C, Part 1.
SAC
Demographic and Baseline Characteristics
17.
Safety
DM2
Listing of Demographic Characteristics – Part 1
This will not include Cohort C, Part 1.
SAC
18.
Safety
DM2
Listing of Demographic Characteristics – Part 2
SAC
19.
Bystander 
Safety (Part 
1, Cohort C)
DM2
Listing of Demographic Characteristics – Bystander
Only for Cohort C, Part 1.
SAC
20.
Safety
DM9
Listing of Race – Part 1
This will not include Cohort C, Part 1.
SAC
21.
Safety
DM9
Listing of Race – Part 2
SAC
22.
Bystander 
Safety (Part 
1, Cohort C)
DM9
Listing of Race - Bystander
Only for Cohort C, Part 1.
SAC
Prior and Concomitant Medications
23.
Safety
CP_CM3
Listing of Concomitant Medications – Part 1
This will not include Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
62
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
24.
Safety
CP_CM3
Listing of Concomitant Medications – Part 2
SAC
25.
Bystander 
Safety (Part 
1, Cohort C)
CP_CM3
Listing of Concomitant Medications – Bystander
Only for Cohort C, Part 1.
SAC
Exposure and Treatment Compliance
26.
Safety
EX4
Listing of Exposure Data – Part 1
This will not include Cohort C, Part 1.
SAC
27.
Safety
EX4
Listing of Exposure Data – Part 2
SAC
28.
Bystander 
Safety (Part 
1, Cohort C)
EX4
Listing of Exposure Data – Part 2
SAC
Adverse Events
29.
Safety
AE9CP
Listing of All Adverse Events – Part 1
This will not include Cohort C, Part 1.
SAC
30.
Safety
AE9CP
Listing of All Adverse Events – Part 2
SAC
31.
Bystander 
Safety (Part 
1, Cohort C)
AE9CP
Listing of All Adverse Events – Bystander
Only for Cohort C, Part 1.
SAC
32.
Safety
AE9CP
Listing of Serious Adverse Events – Part 1
This will not include Cohort C, Part 1.
SAC
33.
Safety
AE9CP
Listing of Serious Adverse Events – Part 2
This will not include Cohort C, Part 1.
SAC
34.
Bystander 
Safety (Part 
1, Cohort C)
AE9CP
Listing of Serious Adverse Events – Bystander
Only for Cohort C, Part 1.
SAC
35.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment – Part 1
This will not include Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
63
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
36.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment – Part 2
SAC
37.
Bystander 
Safety (Part 
1, Cohort C)
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment – Bystander
Only for Cohort C, Part 1.
SAC
All Laboratory
38.
Safety
LB5
Listing of Haematology Laboratory Data – Part 1
This will not include Cohort C, Part 1.
SAC
39.
Safety
LB5
Listing of Haematology Laboratory Data – Part 2
SAC
40.
Bystander 
Safety (Part 
1, Cohort C)
LB5
Listing of Haematology Laboratory Data – Bystander
Only for Cohort C, Part 1.
SAC
41.
Safety
LB5
Listing of Clinical Chemistry Laboratory Data – Part 1
This will not include Cohort C, Part 1.
SAC
42.
Safety
LB5
Listing of Clinical Chemistry Laboratory Data – Part 2
SAC
43.
Bystander 
Safety (Part 
1, Cohort C)
LB5
Listing of Clinical Chemistry Laboratory Data – Bystander
Only for Cohort C, Part 1.
SAC
44.
Safety
LB5
Listing of Coagulation Laboratory Data – Part 1
This will not include Cohort A and 
Cohort C, Part 1.
SAC
45.
Safety
LB5
Listing of Coagulation Laboratory Data – Part 2
Only for Cohort B, Part 2.
SAC
46.
Safety
UR2a
Listing of Urinalysis Data – Part 1
This will not include Cohort C, Part 1.
SAC
47.
Safety
UR2a
Listing of Urinalysis Data – Part 2
SAC
48.
Bystander 
Safety (Part 
1, Cohort C)
UR2a
Listing of Urinalysis Data – Bystander
Only for Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
64
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
49.
Safety
EG3
Listing of ECG Values – Part 1
This will not include Cohort C, Part 1.
SAC
50.
Safety
EG3
Listing of ECG Values – Part 2
SAC
51.
Bystander 
Safety (Part 
1, Cohort C)
EG3
Listing of ECG Values - Bystander
Only for Cohort C, Part 1.
SAC
52.
Safety
EG5
Listing of ECG Findings – Part 1
This will not include Cohort C, Part 1.
SAC
53.
Safety
EG5
Listing of ECG Findings – Part 2
SAC
54.
Bystander 
Safety (Part 
1, Cohort C)
EG5
Listing of ECG Findings – Bystander
Only for Cohort C, Part 1.
SAC
55.
Safety
EG3
Listing of All ECG Values for Subjects with Any Values of 
Potential Clinical Importance – Part 1
This will not include Cohort C, Part 1.
SAC
56.
Safety
EG3
Listing of All ECG Values for Subjects with Any Values of 
Potential Clinical Importance – Part 2
SAC
57.
Bystander 
Safety (Part 
1, Cohort C)
EG3
Listing of All ECG Values for Subjects with Any Values of 
Potential Clinical Importance – Bystander
Only for Cohort C, Part 1.
SAC
Spirometry
58.
Safety
Non-Standard 
SAFE_L1
Listing of Spirometry Values – Part 1
This will not include Cohort C, Part 1.
SAC
59.
Safety
Non-Standard 
SAFE_L1
Listing of Spirometry Values – Part 2
SAC


CONFIDENTIAL
205822
65
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Telemetry
60.
Safety
Non-Standard 
SAFE_L2
Listing of Telemetry Values – Part 1
This will not include Cohort C, Part 1.
SAC
61.
Safety
Non-Standard 
SAFE_L2
Listing of Telemetry Values – Part 1
SAC
Vital Signs
62.
Safety
VS4
Listing of Vital Signs – Part 1
This will not include Cohort C, Part 1.
SAC
63.
Safety
VS4
Listing of Vital Signs – Part 2
SAC
64.
Bystander 
Safety (Part 
1, Cohort C)
VS4
Listing of Vital Signs - Bystander
Only for Cohort C, Part 1.
SAC
65.
Safety
VS4
Listing of All Vital Signs for Subjects with Any values of Potential 
Clinical Importance – Part 1
This will not include Cohort C, Part 1.
SAC
66.
Safety
VS4
Listing of All Vital Signs for Subjects with Any values of Potential 
Clinical Importance – Part 2
SAC
67.
Bystander 
Safety (Part 
1, Cohort C)
VS4
Listing of All Vital Signs for Subjects with Any values of Potential 
Clinical Importance – Bystander
Only for Cohort C, Part 1.
SAC


CONFIDENTIAL
205822
66
11.10.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetics
68.
Systemic PK
PK08
Listing of CCI15106 Plasma Pharmacokinetic Concentration-
Time Data by Cohort and Study Day
SAC
69.
Systemic PK
PK14
Listing of Derived CCI15106 Plasma Pharmacokinetic 
Parameters Cohort and Study Day
SAC
Safety
70.
Safety
MH2
Listing of Medical Conditions – Part 1
This will not include Cohort C, Part 1.
SAC
71.
Safety
MH2
Listing of Medical Conditions – Part 2
SAC
72.
Bystander 
Safety (Part 
1, Cohort C)
MH2
Listing of Medical Conditions – Bystander
Only for Cohort C, Part 1.
SAC
73.
Safety
SU2
Listing of Substance Use – Part 1
This will not include Cohort C, Part 1.
SAC
74.
Safety
SU2
Listing of Substance Use – Part 2
SAC
75.
Bystander 
Safety (Part 
1, Cohort C)
SU2
Listing of Substance Use – Bystander
Only for Cohort C, Part 1.
SAC
76.
All Screened 
Population
IE4
Listing of Study Eligibility – Part 1
SAC
77.
All Screened 
Population
IE4
Listing of Study Eligibility – Part 2
SAC


CONFIDENTIAL
205822
67
11.11.
Appendix 11: Example Mock Shells for Data Displays
Example SAFE_T1
Protocol: 205822                                                                                 Page 1 of 2
Population: Safety
                                                 Table 1.61
                               Summary of Demographic Characteristics – Part 1
                                                      Cohort A       Cohort B       Placebo
                                                      (N=6)          (N=12)         (N=4)
           --------------------------------------------------------------------------------------
           Sex
             n                                          6             12              4
             Male                                       6 (100%)      12 (100%)       4 (100%)
             Female                                     0              0              0
           Age (y)
             n                                          6             12              4
             Mean                                      39.8           35.4           43.3
             SD                                         9.75          11.18           9.54
             Median                                    40.0           31.0           44.0
             Min.                                      25             25             32
             Max.                                      52             57             53
           Ethnicity
             n                                          6             12              4
             HISPANIC OR LATINO                         0              1   (8%)       0
             NOT HISPANIC OR LATINO                     6 (100%)      11  (92%)       4 (100%)
           Race
             n                                          6             12              4
             WHITE - WHITE/CAUCASIAN/EUROPEAN           5  (83%)       9  (75%)       4 (100%)
             HERITAGE
             AFRICAN AMERICAN/AFRICAN HERITAGE          1  (17%)       2  (17%)       0
             Multiple                                   0              1   (8%)       0
.
.


CONFIDENTIAL
205822
68
Example SAFE_T2
Protocol: 205822
Population: Safety
Table X
Summary of Telemetry Findings – Part 1
Cohort A
Cohort B
Placebo
(N=157)
(N=160)
(N=160)
Time Period 1
  n
156 
160 
160 
  Normal 
81  (52%)
90  (56%)
90  (56%)
  Abnormal, not clinically significant
75  (48%)
69  (43%)
69  (43%)
  Abnormal, clinically significant
  0 
  1  (<1%)
  1  (<1%)
  
Time Period 2
  n 
117 
123 
123 
  Normal
50  (43%)
67  (54%)
67  (54%)
  Abnormal, not clinically significant
64  (55%)
55  (45%)
55  (45%)
  Abnormal, clinically significant 
  2   (2%)
  1  (<1%)
  1  (<1%)
.
.
.
.
.


CONFIDENTIAL
205822
69
Example SAFE_T3
Protocol: 205822
Population: Safety
Table X
Summary of Spirometry Results – Part 1
CCI15106 
60mg SD
CCI15106 
120mg SD
CCI15106 
30mg BID
Placebo
(N=157)
(N=160)
(N=160)
(N=160)
Time Period 1
  n
156
160
160
%Predicted FEV1
%Predicted FVC
52%
55%
56%
45%
56%
45%
Time Period 2
  n 
117
123
123
%Predicted FEV1
%Predicted FVC
52%
55%
56%
45%
56%
45%
.
.
.
.
.
% Predicted FEV1   = (Max FEV1/Predicted Normal FEV1)x100
% Predicted FVC   = (Max FVC/Predicted Normal FVC)x100


CONFIDENTIAL
205822
70
Example SAFE_T4
Protocol: 205822                                                                                 Page 1 of 2
Population: Safety
                                                 Table 3.51
                               Summary of All Serious Adverse Events - Part1
    System Organ Class                        CCI15106    CCI15106    CCI15106    CCI15106
      Preferred Term                          60 mg SD    120 mg SD   30 mg BID   60 mg BID   Placebo
    ----------------------------------------------------------------------------------------------------
      ANY EVENT                                 1 (17%)     0          4 (67%)     9 (75%)     1 (25%)
    Blood and lymphatic system disorders
      Any event                                 0           0           0           1  (8%)     0
      Lymphadenopathy                           0           0           0           1  (8%)     0
    Gastrointestinal disorders
      Any event                                 0           0           1 (17%)     2 (17%)     0
      Diarrhoea                                 0           0           0           1  (8%)     0
      Mouth ulceration                          0           0           1 (17%)     0           0
      Vomiting                                  0           0           0           2 (17%)     0
    General disorders and administration
    site conditions
      Any event                                 0           0           0           5 (42%)     0
      Asthenia                                  0           0           0           1  (8%)     0
      Chest pain                                0           0           0           1  (8%)     0
      Feeling hot                               0           0           0           2 (17%)     0
      Influenza like illness                    0           0           0           1  (8%)     0
      Malaise                                   0           0           0           3 (25%)     0
    Infections and infestations
      Any event                                 0           0           1 (17%)     1  (8%)     0
      Nasopharyngitis                           0           0           1 (17%)     0           0
      Upper respiratory tract infection         0           0           0           1  (8%)     0
    Injury, poisoning and procedural
    complications
…………


CONFIDENTIAL
205822
71
Example SAFE_T5
Protocol: 205822                                                                                 Page 1 of 1
Population: Safety
                                                 Table X
                         Summary of Extent of Exposure to Study Treatment  - Part 1
                                                                      CCI15106     CCI15106
                                            CCI15106 SD  CCI15106 SD  BID          BID
                                            60mg(HV)     120mg(HV)    30mg(HV)     60mg(HV)     Placebo(HV)
                     Period                (N=6)        (N=6)        (N=6)        (N=12)       (N=4)
-----------------------------------------------------------------------------------------------------------
Time on Study         PERIOD 1    n         x            x            x            xx            x
Treatment (days) [1]
                                  Mean      x.x          x            x            xx.x         xx.x
                                  SD        x.xx         x            x           x.xx         xx.xx
                                  Median    x.x          x            x            xx.x         xx.x
                                  Min.      x            x            x            xx           x
                                  Max.      x            x            x            xx           xx
                      PERIOD 2    n         x            x            x            x            x
                                  Mean      x            x.x          x            x            x.x
                                  SD        x            x.xx         x            x            x.xx
                                  Median    x            x.x          x            x            x.x
                                  Min.      x            x            x            x            x
                                  Max.      x            x            x            x            x
                      PERIOD 3    n         x            x            x            x            x
                                  Mean      x            x            xx.x         x            xx.x
                                  SD        x            x            x.xx         x            x.xx
                                  Median    x            x            xx.x         x            xx.x
                                  Min.      x            x            xx           x            xx
                                  Max.      x            x            xx           x            xx
Subject Daily Dose    PERIOD 1    n         x            x            x            xx           x
(mg) [2]
                                  Mean      xx.x         x            x            xx.x         x.x
                                  SD        x.xx         x            x            x.xx         x.xx


CONFIDENTIAL
205822
72
                                  Median    xx.x         x            x            xx.x         x.x
                                  Min.      xx           x            x            xx           x
                                  Max.      xx           x            x            xx           x
                      PERIOD 2    n         x            x            x            x            x
                                  Mean      x            xx.x         x            x            x.x
                                  SD        x            x.xx         x            x            x.xx
                                  Median    x            xx.x         x            x            x.x
                                  Min.      x            x            x            x            x
                                  Max.      x            xx           x            x            x
                      PERIOD 3    n         x            x            x            x            x
                                  Mean      x            x            xx.x         x            x.x
                                  SD        x            x            x.xx         x            x.xx
                                  Median    x            x            x.x          x            x.x
                                  Min.      x            x            xx           x            x
                                  
   Max.      x            x            xx           x            x
Cumulative Actual     PERIOD 1    n         x            x            x            xx           x
Dose (mg)
                                  Mean      xx.x         x            x            x.x          x.x
                                  SD        x.xx         x            x            x.xx         x.xx
                                  Median    xx.x         x            x            x.x          x.x
                                  Min.      x            x            x            xx           x
                                  Max.      xx           x            x            xx           x
                      PERIOD 2    n         x            x            x            x            x
                                  Mean      x            x.x          x            x            x.x
                                  SD        x            x.xx         x            x            x.xx
                                  Median    x            x.x          x            x            x.x
                                  Min.      x            xx           x            x            x
                                  Max.      x            xx           x            x            x
                      PERIOD 3    n         x            x            x            x           x
                                  Mean      x            x            xx.x         x            x.x
                                  SD        x            x            x.x          x            x.xx
                                  Median    x            x            xx.x         x            x.x
                                  Min.      x            x            xx           x            x
                                  Max.      x            x            xx           x            x


CONFIDENTIAL
205822
73
Note: [1]The time on study drug does not exclude dose interruptions.
[2]The subject daily dose (the cumulative actual dose divide by the duration of exposure)
is calculated for each subject first and the summary statistics are calculated based on the
subject average daily dose.


CONFIDENTIAL
205822
74
Example SAFE_T6
Protocol: 205822                                                                            Page 1 of 1
Population: Safety
                                                 Table X
                Frequency of Worst Change from Baseline Values of QTcB and QTcF by PCI Category
                                                                       CCI15106-CFI -  CCI15106-CFI -
                                                                       1 capsule -     2 capsules -
                                                       Placebo         Single Dose     Single Dose
     ECG Test             Visit        Category        (N=12)          (N=6)           (N=6)
     -------------------------------------------------------------------------------------------------
     QTcB Interval,       BASELINE     n               12              6               6
     Aggregate (msec)
                          Worst Post   n               12              6               6
                          Baseline     Increase<=30    12(100%)        6(100%)         6(100%)
                                       30<Increase<=60 0               0               0
                                       Increase>60     0               0               0
     
     QTcF Interval,       Baseline     n               12              6               6
     Aggregate (msec)
                          
                          Worst Post   n               12              6               6
                          Baseline     Increase<=30    12(100%)        6(100%)         6(100%)
                                       30<Increase<=60 0               0               0
                                       Increase>60     0               0              0


CONFIDENTIAL
205822
75
Example SAFE_T7
Protocol: 205822                                                                            Page 1 of 1
Population: Safety
                                                 Table X
                              Frequency of Maximum ECG Values by PCI Category
                                                                        CCI15106-CFI -  CCI15106-CFI -
                                                                        1 capsule -     2 capsules -
                                                        Placebo         Single Dose     Single Dose
     ECG Test             Visit        Category         (N=12)          (N=6)           (N=6)
     --------------------------------------------------------------------------------------------------
     PR Interval,         BASELINE     n                12              6               6
     Aggregate (msec)
                                       Value<110        0               0               0
                                       110<=Value<=220  12(100%)        6(100%)         6(100%)
                                       Value>220        0               0               0
                          WORST POST   n                12              6               6
                          BASELINE     Value<110        0               0               0
                                       110<=Value<=220  12(100%)        6(100%)         6(100%)
                                       Value>220        0               0               0
     QRS Duration,        SCREENING    n                12              6               6
     Aggregate (msec)
                                       Value<75         0               0               0
                                       75<=Value<=110   11(92%)         6(100%)         6(100%)
                                       Value>110        1(8%)           0               0
                          WORST POST   n                12              6               6
                          BASELINE     Value<75         0               0               0
                                       75<=Value<=110   11(92%)         6(100%)         6(100%)
                                       Value>110        1(8%)           0               0
     QTcB Interval,       SCREENING    n                12              6               6
     Aggregate (msec)


CONFIDENTIAL
205822
76
                                       Value<=450       11(92%)         6(100%)         6(100%)
                                       450<Value<480    1(8%)           0               0
                                       480<=Value<500   0               0               0
                                       Value>=500       0               0               0
                          WORST POST   n                12              6               6
                          BASELINE     Value<=450       11(92%)         5(83%)          6(100%)
                                       450<Value<480    1(8%)           1(17%)          0
                                       480<=Value<500   0               0               0
                                       Value>=500       0               0               0
Repeat for QTcF
Note: Percentages may not add up to 100 for QRS Duration and PR Interval as there is a possibility of a 
patient being counted under both low and high categories.


CONFIDENTIAL
205822
77
Example 
: PK_T1
Page 1 of n
Protocol
: 205822
Population
: Systemic PK
Table 3.1.13
Summary of Assessment of Dose Proportionality (Part 1 and Part 2)
Slope
Intercept
Parameter 
Study 
Day
n
Estimate
SE
90% CI
Estimate
SE
90% CI
Coefficient of 
Determination
Note(s):
CI = confidence interval; SE = standard error.
Source:  SAS Output XX


CONFIDENTIAL
205822
78
Example 
: PK_T2
Page 1 of n
Protocol
: 205822
Population
: Systemic PK
Table 3.1.16
Summary of Assessment of Steady State (Part 1 and Part 2)
Slope
Parameter 
n
Estimate
SE
90% CI
Note(s):
CI = confidence interval; SE = standard error.
Source:  SAS Output XX


CONFIDENTIAL
205822
79
Example 
: PK_T3
Page 1 of n
Protocol
: 205822
Population
: Systemic PK
Table 3.1.17
Summary of Assessment of Accumulation (Part 1 and Part 2)
Dose 
Level
Parameter 
(unit)
Study 
Day
n
Geometric 
LS Mean
Geometric 
LS Mean
95% CI
Ratio of 
Geometric 
Means
90% CI
p-value
Note(s):
LS = least squares; CI = confidence interval. 
Accumulation was assessed using a linear mixed effects model with day as a fixed effect and subject as a 
random effect.


CONFIDENTIAL
205822
80
Source:  SAS Output XX
Example 
: SAFE_L1
Page 1 of n
Protocol
: 205822
Population
: Safety (Part 1)
Listing 59
Listing of Spirometry Values – Part 1
Spirometry
Cohort
/ 
Subj.
Visit
/ 
Study 
Day
Visit 
date
Test
Time 
of 
first 
exhal
ation
Reading 1
Reading 2
Reading 3
Highest 
reading
%predicted


CONFIDENTIAL
205822
81
Source:  SAS Output XX
Example 
: SAFE_L2
Page 1 of n
Protocol
: 205822
Population
: Safety (Part 1)
Listing 62
Listing of Telemetry Values – Part 1
Telemetry
Cohort
/ 
Subj.
Visit
/ 
Study 
Day
Visit 
date
Date 
started
Time 
started
Date 
stopped
Time 
stopped
Telemetry Result


CONFIDENTIAL
205822
82
Example 
: PK_F1
Protocol
: 205822
Population
: Systemic PK
Figure xxx: CCI15106 trough Plasma Concentration versus Study Day (Part 2)
PPD


CONFIDENTIAL
205822
83
Example 
: PK_F2
Protocol
: 205822
Population
: BAL PK
Figure XXX Scatter Plot of Lung Drug Concentration versus Subject ID (Part 1 and Part 2)
PPD