A Single Centre, Open Label, One Sequence, Cross-over Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of Single Inhaled Doses of Nemiralisib in Healthy Subjects
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A single centre, open label, one sequence, cross-over study to evaluate 
the effect of itraconazole on the pharmacokinetics of single inhaled doses of nemiralisib 
in healthy subjects.
Protocol Number: 206874
Short Title: A study to evaluate the effect of itraconazole on the PK of nemiralisib
Compound Number:
GSK2269557
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND Number 125676
Approval Date: 12-DEC-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................7
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................12
3.3.1.
Risk Assessment .........................................................................13
3.3.2.
Benefit Assessment.....................................................................15
3.3.3.
Overall Benefit:Risk Conclusion...................................................15
4.
OBJECTIVES AND ENDPOINTS...........................................................................15
5.
STUDY DESIGN ....................................................................................................15
5.1.
Overall Design ............................................................................................15
5.2.
Number of Participants ...............................................................................17
5.3.
Participant and Study Completion...............................................................17
5.4.
Scientific Rationale for Study Design ..........................................................17
5.5.
Dose Justification........................................................................................18
6.
STUDY POPULATION...........................................................................................19
6.1.
Inclusion Criteria.........................................................................................19
6.2.
Exclusion Criteria........................................................................................20
6.3.
Lifestyle Restrictions...................................................................................21
6.3.1.
Meals and Dietary Restrictions ....................................................21
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................22
6.3.3.
Activity .........................................................................................22
6.4.
Screen Failures...........................................................................................22
7.
TREATMENTS.......................................................................................................23
7.1.
Treatments Administered............................................................................23
7.2.
Dose Modification .......................................................................................23
7.3.
Method of Treatment Assignment ...............................................................24
7.4.
Blinding.......................................................................................................24
7.5.
Preparation/Handling/Storage/Accountability..............................................24
7.6.
Treatment Compliance................................................................................24
7.7.
Concomitant Therapy..................................................................................24
7.8.
Treatment after the End of the Study ..........................................................25
8.
DISCONTINUATION CRITERIA.............................................................................26
8.1.
Discontinuation of Study Treatment ............................................................26
8.1.1.
Liver Chemistry Stopping Criteria ................................................26
8.1.2.
QTc Stopping Criteria ..................................................................26
8.1.3.
FEV1 stopping criteria ..................................................................27
8.1.4.
Other study stopping criteria ........................................................27
8.1.5.
Temporary Discontinuation ..........................................................27
8.1.6.
Rechallenge.................................................................................27
8.1.6.1.
Study Treatment Restart or Re-challenge...................27
 
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8.2.
Withdrawal from the Study..........................................................................27
8.3.
Lost to Follow Up........................................................................................28
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................28
9.1.
Efficacy Assessments.................................................................................29
9.2.
Adverse Events...........................................................................................29
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................29
9.2.2.
Method of Detecting AEs and SAEs.............................................30
9.2.3.
Follow-up of AEs and SAEs.........................................................30
9.2.4.
Regulatory Reporting Requirements for SAEs .............................30
9.2.5.
Pregnancy ...................................................................................30
9.3.
Treatment of Overdose...............................................................................31
9.4.
Safety Assessments ...................................................................................31
9.4.1.
Physical Examinations.................................................................31
9.4.2.
Vital Signs....................................................................................32
9.4.3.
Electrocardiograms......................................................................32
9.4.4.
Spirometry ...................................................................................32
9.4.5.
Clinical Safety Laboratory Assessments ......................................32
9.5.
Pharmacokinetics .......................................................................................33
9.6.
Pharmacodynamics ....................................................................................33
9.7.
Genetics .....................................................................................................33
9.8.
Biomarkers .................................................................................................33
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................33
10. STATISTICAL CONSIDERATIONS........................................................................34
10.1.
Sample Size Determination ........................................................................34
10.1.1.
Sample Size Sensitivity................................................................35
10.2.
Populations for Analyses ............................................................................35
10.3.
Statistical Analyses.....................................................................................35
10.3.1.
Pharmacokinetic Analyses...........................................................36
10.3.2.
Safety Analyses...........................................................................36
10.3.3.
Interim Analyses ..........................................................................37
11. REFERENCES.......................................................................................................38
12. APPENDICES........................................................................................................39
12.1.
Appendix 1: Abbreviations and Trademarks................................................39
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................41
12.3.
Appendix 3: Study Governance Considerations..........................................43
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................47
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................52
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................55
 
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1.
SYNOPSIS
Protocol Title: A single centre, open label, one sequence, cross-over study to evaluate 
the effect of itraconazole on the pharmacokinetics of single inhaled doses of nemiralisib 
in healthy subjects.
Short Title: A study to evaluate the effect of itraconazole on the PK of nemiralisib
Rationale:
The in vitro Cytochromes P450 (CYP) phenotyping study and in vitro inhibition data 
indicate CYP3A4 may be the major route of clearance for nemiralisib. Therefore, the co-
administration of drug therapies which modulate CYP3A4 (specifically CYP3A4 
inhibitors) may alter the exposure of nemiralisib (i.e. increase in exposure). Current 
recommendations by regulatory agencies Food and Drug Administration (FDA) and 
European Medicines Agency (EMA) specify that “when metabolism is a significant 
pathway (i.e. constitutes 25% or more of the drug’s overall elimination) in vivo studies 
using appropriate inhibitor(s)/inducer(s) are warranted”. In line with recommendations, 
this clinical drug interaction study with itraconazole (a potent CYP3A4 inhibitor) is 
required. Ongoing and future clinical studies using nemiralisib will use the data generated 
from this current study to justify inclusion / exclusion criteria based on concomitant 
medications which affect CYP3A4 and potentially inform dose modification in case of 
co-administration with medication affecting CYP3A4 activity.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To characterize the effect of repeat oral 
dosing of itraconazole on the 
pharmacokinetics of a single inhaled 
dose of nemiralisib in healthy subjects

AUC(0-∞), AUC(0-t), Cmax, tmax , t1/2
Secondary
To investigate the safety and tolerability 
of single inhaled dose of nemiralisib, when 
dosed alone and concomitantly with 
itraconazole, in healthy subjects
To investigate the pharmacokinetics of 
itraconazole and hydroxy-itraconazole 
when co-administered with nemiralisib
Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG) and spirometry
AUC(0-∞), AUC(0-t), Cmax, tmax, t1/2
AUC(0-∞) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time, AUC(0-t):
Area under the plasma concentration versus time curve from time zero to t, Cmax; maximum observed plasma 
concentration, tmax : time to Cmax, t1/2:  Terminal phase half-life
 
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Overall Design:
This is a Phase I, single centre, open label, one sequence cross-over study to be 
conducted in healthy males and females of non-child bearing potential. The study will 
evaluate the Pharmacokinetic (PK), safety and tolerability of nemiralisib when 
administered alone and when administered concomitantly with repeat doses of 
itraconazole, a known strong inhibitor of CYP3A4, to simulate a steady-state exposure of 
itraconazole. 
The pharmacokinetics of itraconazole and hydroxy-itraconazole (its hydroxy-metabolite) 
will be assessed to provide precise estimates of its pharmacokinetics to validate and 
support any interaction observed with nemiralisib as well as future usage via in silico
modelling for nemiralisib and other drugs.  
Number of Participants:
Approximately 20 participants will be enrolled such that approximately 16 evaluable 
participants complete the study. 
Treatment Groups and Duration:
Each participant will participate in the study for approximately 7 weeks. They will 
complete a screening visit, 2 treatment periods (nemiralisib alone followed by nemiralisib 
co-administered with itraconazole), and a follow up visit. 
Screening: 
Participants must be screened within 21 days before the first dose (Day 1), and must meet 
all eligibility criteria.  
Period 1:
-
Participants will be admitted to the clinical research unit on Day -1 and will 
remain in-house until collection of the final PK sample on Day 6. 
-
On Day 1, participants will receive a single dose of 100 mcg nemiralisib. 
Period 2:
-
There will be a washout of at least 14 days between the administration of 
nemiralisib in Period 1 and the administration of nemiralisib in Period 2. 
-
Participants will be admitted to the clinical research unit on Day -1 and will 
remain in-house until collection of the final PK sample on Day 11. 
-
From Day 1 to 10 inclusive, participants will receive a single dose of 200 mg 
itraconazole in the morning. 
-
On Day 5, participants will receive a single dose of 100 mcg nemiralisib one hour 
after the dose of 200 mg itraconazole.
Follow-up:
Participants will be instructed to return for a follow-up visit 5-10 days after the last
dose of itraconazole.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Screening and Follow-up
Procedure
Screening (up to 21 days 
before Day 1)
Follow-up (within 5−10 days of 
last dose itraconazole)
Notes
Informed consent
X
Demography 
X
Inclusion and exclusion criteria
X
Past and current medical conditions  
X
Medical history (includes substance usage)
X
Substances: Drugs, Alcohol, tobacco and caffeine
Physical examination
X
X
Full examination (including height and weight) at 
screening, brief examination at follow-up
Vital signs
X
Triplicate 
12-lead ECG 
X
X
Triplicate 
FEV1 and FVC 
X
Triplicate
Laboratory assessments (hematology and clinical 
chemistry)
X
X
Urinalysis
X
HIV, Hepatitis B and C screening
X
If test otherwise performed within 3 months prior to 
first dose of study treatment, testing at screening is 
not required
Alcohol breath test & drug screen
X
Includes urine cotinine test
SAE review
X
X
AE review 
X
ECG: Electrocardigram, FEV1: Forced expiratory volume in 1 second, FVC: Forced vital capacity, HIV: Human immunodeficiency virus, AE: Adverse event, SAE: Serious adverse event.
 
 
 
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Table 2
Period 1
Procedure
Treatment Period Days
Notes
–1
1
2
3
4
5
6
Admission
X
Discharge
X
Alcohol breath test & drug screen
X
Includes urine cotinine test
Laboratory assessments (hematology, clinical 
chemistry and urinalysis)
X
X
Day −1 results to be reviewed before dosing on Day 1
Brief physical examination
X
X
Inhaler (ElliptaTM) training
X
Training conducted by reviewing the Patient Information Leaflet with 
the participant. Additional training may be conducted at the discretion 
of the investigator.
FEV1
X
Triplicate.
12-lead ECG
X
X
Single measurement. Pre-dose on Day 1.
Vital signs
X
X
Single measurement. Pre-dose on Day 1.
Study treatment (nemiralisib)
X
Pharmacokinetic (PK) (nemiralisib)
X
X
X
X
X
X
pre-dose, and 5 min, 30 min, 2 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h 
and 120 h post-dose 
AE review
==============================
SAE review
X
==============================
Concomitant medication review
X
==============================
 
 
 
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Table 3
Period 2
Procedure
Treatment Period Days
Notes
–1
1
2
3
4
5
6
7
8
9
10
11
Admission
X
Discharge
X
Alcohol breath test & drug screen
X
Includes urine cotinine test
Brief physical examination
X
X
Laboratory assessments 
(hematology, clinical chemistry and 
urinalysis)
X
X
Pre-dose at all timepoints. Day −1 results to be 
reviewed before dosing on Day 1. 
Clinical chemistry only 
X
X
X
X
Pre-dose at all timepoints. Day 4 results to be reviewed 
before itraconazole dosing on Day 5.
12-lead ECG
X
X
X
X
X
X
Single measurement. Pre-dose and 3h post-dose 
(itraconazole) on Day 1. Pre-dose at all other 
timepoints, Day 4 results to be reviewed before 
itraconazole dosing on Day 5.
Vital signs
X
X
X
X
X
X
Single measurement. Pre-dose at all timepoints
Study treatment (itraconazole)
X
X
X
X
X
X
X
X
X
X
Approx. 1 h post standard meal. 
FEV1
X
Triplicate
Inhaler (Ellipta) training
X
Training conducted by reviewing the Patient Information 
Leaflet with the participant. Additional training may be 
conducted at the discretion of the investigator. 
Study treatment (nemiralisib)
X
1 h post itraconazole administration.
PK (nemiralisib)
X
X
X
X
X
X
X
pre-dose, and 5 min, 30 min, 2 h, 6 h, 12 h, 24 h, 48 h, 
72 h, 96 h, 120 h and 144 h post-dose (nemiralisib)
 
 
 
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Procedure
Treatment Period Days
Notes
–1
1
2
3
4
5
6
7
8
9
10
11
PK (itraconazole + hydroxy-
itraconazole)
X
X
X
Pre-dose, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h 
post-dose (itraconazole) on Day 1
Pre-dose, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h 
and 24 h hours post-dose (itraconazole) on Day 5
AE review
==================================================
SAE review
X
==================================================
Concomitant medication review
X
==================================================

The timing and number of planned study assessments, including safety and pharmacokinetic assessments may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by 
the relevant study team member and then archived in the sponsor and site study files, but will not constitute a protocol 
amendment. The 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 (ICF).
 
 
 
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3.
INTRODUCTION
3.1.
Study Rationale
The in vitro CYP phenotyping study and in vitro inhibition data indicate CYP3A4 may be 
the major route of clearance for nemiralisib (Investigator’s Brochure [GlaxoSmithKline 
Document Number 2012N141231_08]). Therefore, the co-administration of drug 
therapies which modulate CYP3A4 (specifically CYP3A4 inhibitors) may alter the 
exposure of nemiralisib (i.e. increase in exposure). Current recommendations by 
regulatory agencies Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) ([EMA, 2012], [FDA, 2017]) specify that “when metabolism is a 
significant pathway (i.e. constitutes 25% or more of the drug’s overall elimination) in 
vivo studies using appropriate inhibitor(s)/inducer(s) are warranted”. In line with 
recommendations, this clinical drug interaction study with itraconazole (a potent
CYP3A4 inhibitor) is required. Ongoing and future clinical studies using nemiralisib will 
use the data generated from this current study to justify inclusion / exclusion criteria
based on concomitant medications which affect CYP3A4 and potentially inform dose 
modification in case of co-administration with medication affecting CYP3A4 activity.
3.2.
Background
Nemiralisib (also known as GSK2269557) is a potent and highly selective inhaled 
phosphoinositide 3-kinase (PI3K)-delta () inhibitor, being developed as an anti-
inflammatory agent for the treatment of Chronic obstructive pulmonary disease (COPD)
and other inflammatory lung disease such as asthma and bronchiectasis.  PI3Kis a 
member of the Class IA family of PI3Ks, that converts the membrane phospholipid 
phosphatidylinositol 4,5-biphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate 
(PIP3).  PIP3 is a second messenger in many cellular processes including cell growth, 
differentiation and migration. 
PI3Khas specific roles in mediating antigen receptor and cytokine signalling in T-cells, 
mast cells and B-cells. PI3Kis thought to play an important part in various epithelial 
responses relevant for the development of COPD, asthma and bronchiectasis. Chronic 
treatment with antibiotics such as macrolides is increasingly used in these conditions to 
prevent exacerbations. Since macrolides, and other drugs used to treat co-morbidities 
associated with these conditions, are CYP3A4 inhibitors it is important to ensure that co-
administration of these drugs does not substantially alter systemic nemiralisib levels. 
Hence, in this study the systemic pharmacokinetics of nemiralisib will be examined with 
the co-administration of itraconazole, a strong CYP3A4 inhibitor
Nemiralisib has already been administered as a nebulised solution and dry powder 
formulation in single and repeated doses to healthy subjects and patients with asthma and 
COPD, and has been well tolerated across the range of doses used.  A detailed description 
of the chemistry, pharmacology, efficacy, and safety of nemiralisib is provided in the 
Investigator’s Brochure [GlaxoSmithKline Document Number 2012N141231_08].
 
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3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of nemiralisib may be found in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2012N141231_08].
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of itraconazole may be found in the FDA label
(Itraconazole Prescribing Information, 2010).
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP)
Bronchospasm
Can potentially occur with any inhaled treatment.
All doses of study treatment will be administered 
in the clinical pharmacology unit in the presence 
of trained clinical staff. 
Treatment with a short-acting inhaled 
bronchodilator will be available and administered 
as appropriate and determined by the 
Investigator. Participants will receive no more 
nemiralisib treatment and may be withdrawn 
from the study.
Mucosal irritancy
Detected in 13 week toxicology study in the dog.
Participants will be regularly monitored for AEs. 
No evidence of mucosal irritancy has been seen 
so far in clinical studies.
Itraconazole administration
The most common Adverse Drug Reactions 
associated with the administration of itraconazole 
are: 
-
Upper respiratory tract infections
-
Increased hepatic enzymes
-
Hypoacusis
-
Headache
-
Abdominal pain
-
Diarrhea
Only healthy participants will be allowed to 
participate in the proposed study.
Exclusion criteria, close monitoring of clinical 
parameters and adverse events will be 
conducted. Stopping criteria will be utilised to 
mitigate and assess cardiovascular and liver 
effects.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
-
Nausea
-
Fatigue
-
Arrhythmia
-
Cough
-
Sore throat
-
Back pain 
Refer to the FDA label (Itraconazole Prescribing 
Information, 2010) for itraconazole for the full list 
of Adverse Drug Reactions.
 
 
 
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3.3.2.
Benefit Assessment
Healthy participants in this study will receive no direct medical benefit.  They may 
however benefit from the thorough medical assessments they receive during the course of 
the study.
3.3.3.
Overall Benefit:Risk Conclusion
It is considered acceptable to conduct this study in healthy participants, because whilst 
they will receive no direct medical benefit, the risks from the study treatment and 
procedures are minimal.  The study will be conducted in a fully equipped clinical 
pharmacology unit with access to hospital emergency facilities.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the effect of repeat oral 
dosing of itraconazole on the 
pharmacokinetics of a single inhaled
dose of nemiralisib in healthy 
participants 

AUC(0-∞), AUC(0-t), Cmax, tmax , t1/2
Secondary
To investigate the safety and tolerability 
of single inhaled dose of nemiralisib, when 
dosed alone and concomitantly with 
itraconazole, in healthy participants
To investigate the pharmacokinetics of 
itraconazole and hydroxy-itraconazole 
when co-administered with nemiralisib
Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG) and spirometry
AUC(0-∞), AUC(0-t), Cmax, tmax, t1/2
AUC(0-∞) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time, AUC(0-t):
Area under the plasma concentration versus time curve from time zero to t, Cmax; maximum observed plasma 
concentration, tmax : time to Cmax, t1/2:  Terminal phase half-life
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, single centre, open label, one sequence cross-over study to be 
conducted in healthy males and females of non-child bearing potential. The study will 
evaluate the PK, safety and tolerability of nemiralisib when administered alone and when 
 
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administered concomitantly with repeat doses of itraconazole, a known strong inhibitor of 
CYP3A4, to simulate a steady-state exposure of itraconazole. 
The pharmacokinetics of itraconazole and hydroxy-itraconazole (its hydroxy-metabolite)
will be assessed to provide precise estimates of its pharmacokinetics to validate and 
support any interaction observed with nemiralisib as well as future usage via in silico
modelling for nemiralisib and other drugs.  
Each participant will participate in the study for approximately 7 weeks. They will 
complete a screening visit, 2 treatment periods (nemiralisib alone followed by nemiralisib 
co-administered with itraconazole), and a follow up visit (see Figure 1).  
Figure 1
Overall study schematic
Screening: 
Participants must be screened within 21 days before the first dose (Day 1), and must meet 
all eligibility criteria.  
Period 1:
-
Participants will be admitted to the clinical research unit on Day -1 and will 
remain in-house until collection of the final PK sample on Day 6. 
-
On Day 1, participants will receive a single dose of 100 mcg nemiralisib. 
Period 2:
 
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-
There will be a washout of at least 14 days between the administration of 
nemiralisib in Period 1 and the administration of nemiralisib in Period 2. 
-
Participants will be admitted to the clinical research unit on Day -1 and will 
remain in-house until collection of the final PK sample on Day 11. 
-
From Day 1 to 10 inclusive, participants will receive a single dose of 200 mg 
itraconazole in the morning. 
-
On Day 5, participants will receive a single dose of 100 mcg nemiralisib one hour 
after the dose of 200 mg itraconazole.
-
Participants will receive the administration of nemiralisib on Day 5 and 
itraconazole doses on Day 5 to Day 10 only if there are no findings that are 
considered clinically significant by the Investigator (in consultation with the 
medical monitor if needed) during review of Day 4 clinical chemistry and ECG.
-
Itraconazole will be administered at approximately the same time every day and 
approximately 1 h after a standard breakfast.
-
Nemiralisib will be administered at approximately the same time in Period 1 and 
in Period 2. 
Follow-up:
Participants will be instructed to return for a follow-up visit 5-10 days after the last
dose of itraconazole.
5.2.
Number of Participants
Approximately 20 participants will be enrolled such that approximately 16 evaluable 
participants complete the study. Evaluable participants are those who have at least one 
nemiralisib PK sample taken in both periods 1 and 2, and have completed dosing up to 
the point of any withdrawal.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the Sponsor.
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 for the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This is a drug-drug interaction study in healthy males and females of non-child bearing 
potential. Participants will be dosed with nemiralisib before and during co-administration 
of itraconazole and will act as their own control. A sufficient wash-out period is included 
(at least 14-days between nemiralisib dose administrations in Period 1 and in Period 2) to 
remove any effect or residual systemic exposure from the first dose of nemiralisib before 
starting itraconazole dose administration in Period 2. 
 
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An open label design was considered appropriate because the primary objective 
(pharmacokinetic parameters) does not require blinding and no pharmacodynamic 
markers were included in the study. 
Woman of child bearing potential are excluded from participation in this study because 
itraconazole has shown reproduction toxicity in animal studies. In addition, there is 
limited information on the use of itraconazole during pregnancy and during post-
marketing experience, cases of congenital abnormalities have been reported.
5.5.
Dose Justification
The chosen dose level of nemiralisib in this study is 100 mcg delivered via the Ellipta 
device. This dose level has been chosen as it is within the current dose range chosen for 
investigation in the ongoing phase 2b study 200879 (50 to 750 mcg) and has previously 
demonstrated an adequately characterizable PK profile. The optimal efficacious dose is 
currently unknown but in a previous clinical study in patients (study PII116678 in 
exacerbating COPD patients) dosed at 1000 mcg/day (equivalent to 500 mcg using the 
Ellipta device and the formulation proposed in this Drug drug interaction [DDI] study) a 
positive primary endpoint was achieved (airway volume as measured by functional CT 
imaging). The 100 mcg dose level will provide an adequate exposure margin over pre-
clinical exposure stopping criteria (based on toxicology No observed adverse event level 
[NOAEL] and toxicokinetics) should the exposure to nemiralisib increase significantly
when co-administered with a CYP3A4 inhibitor. Using the predicted exposure of 
nemiralisib at 100 mcg in humans (extrapolated exposures of 0.41 ng/mL and 1.2 
ng.h/mL for Cmax and AUC24 respectively) and using the 13 week dog NOAEL 
exposures (680 ug/kg/day NOAEL on week 13 for male and female combined of 21 
ng/mL and 79 ng.h/mL respectively) gave margins of approximately 51-fold and 66-fold 
for Cmax and AUC24 respectively. These margins are considered to provide sufficient 
cover for any potential increase in nemiralisib exposures that co-administration of 
itraconazole would be anticipated to cause. The analytical assay for nemiralisib and the 
known exposure range over the proposed sampling regimen is deemed appropriate to 
fully characterise the profile out to 120 hours post dose in Period 1 and 144 hours post 
dose in Period 2, following a 100 mcg single dose. Preliminary data from an ongoing trial 
(207674 PK bridge study single doses phase 2b material) defined terminal elimination 
half-life to be approximately 40 hours with a Tmax observed in the sample taken 
immediately post dose (5 mins) which fell off rapidly in a biexponential manner. The 
long elimination half-life of nemiralisib is the driver behind the length of the sampling 
regimen. Nemiralisib is also an in vitro inhibitor of CYP3A4 (Ki of 4.2 µM [GSK report 
reference 2017N345216_00]) however as systemic concentrations are likely to be < 3 nM 
(1 ng/mL) following a single inhaled dose of only 100 µg the inhibition is predicted to be 
negligible.  
The typical adult dose of itraconazole is 200 mg for up to 12 weeks although intermittent 
usage can be up to 400 mg/day. Itraconazole dosing of 200 mg once daily for 5 days prior 
to the concomitant victim (nemiralisib) dose will enable the victim interaction to be 
observed on a background of steady state exposure and similar to that seen in clinical 
practise [Ke, 2014]. A more recent publication describing the best practices around the 
use of itraconazole as a potent CYP3A4 inhibitor in DDI studies recommends at least a 3 
 
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day lead-in with co-administration of the victim compound on Day 4 [Liu, 2016]. 
Maximum inhibition was also seen if the victim drug was given one hour after 
itraconazole administration [Ke, 2014]. Itraconazole administration will continue after 
the dose of nemiralisib to ensure that inhibition is maintained throughout the elimination
phase of nemiralisib.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 75 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 evaluation.
3.
Normal spirometry at Screening (FEV1 and FVC ≥80% of predicted. Predicted 
values will be based upon [Quanjer, 2012]. Measurements to be taken in triplicate. 
The highest value of each individual component must be ≥80% of predicted).
4.
A participant with a clinical abnormality or laboratory parameter(s) (except for liver 
function tests) outside the reference range for the population being studied may be 
included only if the investigator, in consultation with the medical monitor if needed, 
agree and document that the finding is unlikely to introduce additional risk factors 
and will not interfere with the study procedures.
Weight
5.
Body weight >50 kg and body mass index (BMI) within the range 18.0 – 35.0 kg/m2 
(inclusive).
Sex
6.
Male and/or female
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 10 days after the last dose of 
study treatment and refrain from donating sperm during this period.
b. Female participants: 
 
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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
7.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History or presence of cardiovascular, respiratory (except childhood asthma, which 
has now remitted), hepatic, renal, gastrointestinal, endocrine, hematological, 
psychiatric or neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; constituting a risk when taking the study 
treatment; or interfering with the interpretation of data 
2.
Abnormal blood pressure [as determined by the investigator]
3.
Liver function test results above the upper limit of normal (ULN)
4.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
5.
QTcF >450 msec 
Prior/Concomitant Therapy
6.
Past or intended use of over-the-counter or prescription medication including herbal 
medications within 14 days prior to dosing (Specific medications listed in Section 
7.7 may be allowed)
Prior/Concurrent Clinical Study Experience
7.
Participation in the study would result in loss of blood or blood products in excess of 
500 mL within any 90 day period
8.
Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day
9.
Current enrolment or past participation within the last 30 days before signing of 
consent in this or any other clinical study involving an investigational study 
treatment or any other type of medical research 
Diagnostic assessments
10. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C 
antibody test result at screening.
 
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NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) test is 
obtained
11. 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
12. Positive human immunodeficiency virus (HIV) antibody test (according to local 
policies).
13. Positive drug/alcohol test at screening or on admission (Day -1)
14. Regular use of known drugs of abuse
Other Exclusions
15. Regular alcohol consumption within 6 months prior to the study defined as: 

an average weekly intake of >14 drinks for males or >7 drinks for females. One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. 
16. Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or 
nicotine-containing products within 6 months of screening, or a total pack year
history of >5 pack years.
[number of pack years = (number of cigarettes per day/20) x number of years 
smoked]
17. Sensitivity to any of the study treatments, or components thereof (including lactose 
and Magnesium Stearate), or drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates participation in the study
18. Unwillingness to follow the lifestyle restrictions described in Section 6.3.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
Participants must be willing to comply with dietary and meal constraints outlined in this 
section.

While in the clinic, meals will not contain any of the items listed below:
-
Artificial sweeteners such as mannitol, sorbitol, xylitol, Splenda or other non-
absorbable dietary sugars
-
Grapefruit or grapefruit juice and pomelos
-
Apple or orange juice. Apples and oranges are permitted but not the juice of 
either.
 
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-
Anything from the mustard green family (i.e., no mustard greens, kale, kohlrabi, 
broccoli, collard greens, brussel sprouts, or watercress).
-
Charbroiled meats.

Participants must also abstain from eating any of the items listed above for at least 7 
days before checking into the clinic, except there is no restriction on artificial 
sweeteners while the participants are outside the clinic.

Participants will fast for at least 6 hours before a fasting glucose sample is taken
(fasted at screening only).

On Period 1, Day 1, participants will receive a standard breakfast 2 hours before 
drug administration (nemiralisib). Participants will remain fasted until 2 hours post-
dose (nemiralisib). 

In Period 2, on all dosing days, participants will receive a standard breakfast 1 hour 
before drug administration (itraconazole). On Day 5, participants will remain fasted 
until 2 hours post-dose (nemiralisib). 

At all other times, snacks and meals will be provided by the clinical unit.  

Water will be allowed as desired except for one hour before and one hour after all 
drug administration occasions.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each study period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 
24 hours before the start of dosing until after collection of the final pharmacokinetic 
sample.

During each study period, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final pharmacokinetic sample. 

Use of tobacco products is not allowed from 6 months prior to screening and until 
after the final follow-up visit. 
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities only during studies.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
 
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demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Rescreened participants should be assigned a new participant 
number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment 
Name:
Nemiralisib ELLIPTA
Itraconazole
Dosage formulation:
Nemiralisib succinate blended 
with lactose and magnesium 
stearate1
US sourced, commercially 
available itraconazole 
capsules
Unit dose 
strength(s)/Dosage 
level(s):
100 mcg Dry Powder Inhaler 
(single-strip presentation) with 
30 doses per inhaler / 100 
mcg total dose 
100 mg per capsule / 200 mg 
(2 capsules) per day 
Route of 
Administration 
Oral Inhalation
Oral
Dosing instructions:
Inhale ONCE from this 
Inhaler, as directed
To be administered with 
240 mL of water and approx. 
1 h after a standard meal.
Packaging and 
Labeling
Study Treatment will be 
provided in a foil overwrap. 
Each foil overwrap will be 
labelled as required per 
country requirement.
Itraconazole will be sourced by 
the clinical site
Manufacturer
GSK
Itraconazole will be sourced by 
the clinical site
1.
Magnesium stearate 0.4% w/w of total drug product
7.2.
Dose Modification
Not applicable
 
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7.3.
Method of Treatment Assignment
All participants will receive the same treatments in the periods/days specified in Section 
5.1.
7.4.
Blinding
This is an open-label study. 
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.
6.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance
Participants will 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.  Study site personnel will 
examine each participant’s mouth to ensure that the study treatment was ingested
(itraconazole only).
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:
 
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
reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 14 days before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the Medical Monitor.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants are eligible for study participation.
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found 
in Appendix 6.
8.1.2.
QTc Stopping Criteria
A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTcF >500 msec,

Change from baseline: QTcF >60 msec
The decision to withdraw a participant will be based on an average QTcF value of 
triplicate ECGs.  If an ECG demonstrates a prolonged QTcF, obtain 2 more ECGs over a 
brief period (5−10 minutes), and then use the averaged QTcF values of the 3 ECGs to 
determine whether the participant should be discontinued from the study.
 
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8.1.3.
FEV1 stopping criteria
A participant who experiences a fall in FEV1 of 25% from baseline (screening) will be 
withdrawn from the study.  Triplicate FEV1 measurements will be taken.  The decision to 
withdraw a participant will be based on the highest of the 3 measurements.
Participants who are withdrawn and are found to have respiratory symptoms should 
undergo appropriate diagnostic tests, to be agreed by the investigator and sponsor 
medical monitor.
8.1.4.
Other study stopping criteria
A participant will be discontinued from the study if they experience a serious adverse 
event and/or unacceptable adverse events, as determined by the investigator and/or 
medical monitor.  Every effort should be made to complete safety follow-up procedures 
after a participant is discontinued from study drug.
The study will be halted for an internal safety review if there is a SAE or 2 severe AEs, 
considered to be at least possibly related to the study treatment (nemiralisib or 
itraconazole).
8.1.5.
Temporary Discontinuation
A participant withdrawn from the study treatment will no longer continue in the trial.
8.1.6.
Rechallenge
8.1.6.1.
Study Treatment Restart or Re-challenge
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.

Participants who are withdrawn should complete any safety assessments that the 
investigator considers necessary for the well being of the participant, and the 
assessments planned for the follow-up visit.
 
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8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

If assessments are scheduled for the same nominal time, then the assessments should 
occur in the following order:
 
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1. 12-lead ECG
2. vital signs
3. blood draws.  
Note:  The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
9.1.
Efficacy Assessments
There will be no efficacy assessments for this study. 
9.2.
Adverse Events
Planned time points for all safety assessments are listed in the SoA (Section 2).  
Additional time points for safety tests (such as vital signs, physical exams and laboratory 
safety tests) may be added during the course of the study based on newly available data to 
ensure appropriate safety monitoring.
The definitions of an AE or SAE can be found in Appendix 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 treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).  

All AEs will be collected from the 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 under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.
 
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
The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs (as defined in Section 9.2), 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

Immediate notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until follow-up.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
 
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9.3.
Treatment of Overdose
For this study, any dose of nemiralisib greater than 100 mcg within a 24-hour time period
will be considered an overdose.
GSK does not recommend specific treatment for an overdose of nemiralisib. The 
Investigator (or physician in charge of the participant at the time) will use clinical 
judgment to treat any overdose.
For this study, any dose of itraconazole greater than 200 mg within a 22-hour time period 
will be considered an overdose.
GSK does not recommend specific treatment for an overdose of itraconazole. The 
Investigator (or physician in charge of the participant at the time) will use clinical 
judgment and the information available in the FDA label to treat any overdose.
In the event of an overdose, the Investigator (or treating physician) should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 14 days).
3.
Obtain a plasma sample for PK analysis within 7 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.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded at screening.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
 
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9.4.2.
Vital Signs

Vital signs will be measured in a supine or semi-supine position after 5 minutes 
rest and will include temperature, systolic and diastolic blood pressure, and 
pulse and respiratory rate.

For time points where vital signs are collected in triplicate, only systolic and 
diastolic blood pressure, and pulse rate should be repeated.  There should be at 
least a 2 minute interval between readings.

Baseline will be defined as the mean of the 3 pre-dose measurements taken on 
Day 1 for each Period.
9.4.3.
Electrocardiograms

12-lead ECGs will be measured in a supine or semi-supine position after 5 
minutes rest.

12-lead ECGs will be obtained at each time point during the study, as outlined in 
the SoA (see Section 2).  This will be performed using an ECG machine that 
automatically calculates the heart rate and measures PR interval, QRS duration, 
QT and QTcF intervals.  Refer to Section 8.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.

At time points at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession (no more than 2 minutes 
apart).  The full set of triplicates should be completed in less than 4 minutes.
9.4.4.
Spirometry

Spirometry assessments will be performed whilst the participant is in a seated 
position (if the assessment is done on a bed, the participant’s legs should be over 
the edge).

Spirometry assessments will be repeated until 3 technically acceptable 
measurements have been made. The highest of the 3 values will be recorded in the 
CRF. 

Refer to Section 8.1.3. for the FEV1 withdrawal criterion.
9.4.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source
documents.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or at the follow-up visit should be repeated until 
 
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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.
9.5.
Pharmacokinetics
A 2 mL blood sample for PK analysis of nemiralisib will be collected at each time-point
listed in the SoA. A 2 mL blood sample for PK analysis of itraconazole and hydroxy-
itraconazole will be collected at each time-point listed in the SoA.  
At timepoints where nemiralisib, itraconazole and hydroxy-itraconazole are measured, a 
single 3 mL blood sample will be collected. 
The actual date and time of each blood sample collection will be recorded.  Sample 
storage and shipping instructions will be included in the Study reference manual (SRM)
or equivalent.
Analysis of plasma samples for nemiralisib will be performed within PTS-IVIVT-BIB, 
GlaxoSmithKline. Concentrations of nemiralisib will be determined in plasma samples 
using the currently approved bioanalytical methodology. Raw data will be archived at 
GSK.
Analysis of plasma samples for itraconazole and hydroxy-itraconazole will be performed 
under the control of PTS-IVIVT-BIB/TPR GlaxoSmithKline. Concentrations of 
itraconazole and hydroxy-itraconazole will be determined in plasma samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site for a specified portion of the retention period.
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.
 
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10.
STATISTICAL CONSIDERATIONS
The primary objective of the study is to characterize the effect of repeat oral dosing of 
itraconazole on the pharmacokinetics of a single inhaled dose of nemiralisib in healthy 
participants.  No formal hypotheses will be tested.
10.1.
Sample Size Determination
The sample size has primarily been based on feasibility; however it has also been chosen 
such that the estimated level of precision achieved for AUC(0-∞) and Cmax is considered 
to be acceptable.
Variability estimates have been taken from preliminary PK data (with nominal sampling 
times) for the 207674 study, since it used the same formulation as in this study.  The 
500mcg dose is the closest to 100mcg, so this has been chosen; indeed variability has 
been observed to increase with dose, so this is considered a conservative estimate.
Study 207674 observed total between subject standard deviations (SD) on the loge scale 
of  0.382 for AUC(0-∞) and 0.411 for Cmax. Based on correlation observed in the 
201544 study (rho=0.253 and 0.302 for AUC(0-∞) and Cmax respectively) the within 
subject SD on the loge scale has been assumed to be 0.330 for AUC(0-∞) and 0.343 for 
Cmax for this study.
It is consequently estimated that with 16 subjects providing the relevant PK parameter 
data, the upper bound of the 90% confidence interval (CI) will be within approximately 
22% of the point estimate and the lower bound within 18% for AUC(0-∞). For Cmax 
the upper bound of the 90% CI is estimated to be within approximately 23% of the point 
estimate and the lower bound within 19%.  The following gives the expected CIs under 
the assumption of various ratios between the two groups:
Ratio   
(nemiralisib co-administered with itraconazole 
/ nemiralisib administered alone)
CI
AUC(0-∞)
Cmax
1
(0.82, 1.22)
(0.81, 1.23)
2
(1.64, 2.44)
(1.63, 2.46)
5
(4.10, 6.09)
(4.07, 6.14)
 
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10.1.1.
Sample Size Sensitivity
If the within subject standard deviation observed in AUC(0-∞) and Cmax is 10% or
20% higher than estimated, the upper and lower bounds of the 90% CI would be as 
follows: 
% increase 
in SD
SD
Percentage Within which the 90% CI lies
Upper bound
Lower bound
AUC(0-∞)
10%
0.3634
24%
20%
20%
0.3965
25%
20%
Cmax
10%
0.3773
27%
21%
20%
0.4116
28%
22%
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants screened and for whom a record exists on the study 
database.
Enrolled
All participants who passed screening and entered the study. 
Included are: run-in failures and participants who took treatment.
Safety
All participants enrolled in the study, who took at least 1 dose of 
study treatment. Participants will be analysed according to the 
treatment they actually received.
Pharmacokinetic
All participants enrolled in the study who took at least 1 dose of 
study treatment and for whom a pharmacokinetic sample was 
obtained
and analysed. Participants will be analysed according to the
treatment they received.
10.3.
Statistical Analyses
Statistical analysis will be performed by, or under the direct auspices of Clinical
Statistics, GlaxoSmithKline. Complete details of the planned statistical analyses will be
provided in the Reporting and Analysis Plan (RAP).
 
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10.3.1.
Pharmacokinetic Analyses
All PK analyses will be performed on the Pharmacokinetic Population.
Endpoint
Statistical Analysis Methods
Primary
Plasma nemiralisib concentration-time data will be analysed by non-
compartmental methods using WinNonlin. Calculations will be based on the 
actual sampling times recorded during the study.
From the plasma concentration-time data, the following pharmacokinetic
parameters will be determined for both Day 1 in period1 and Day 5 in period 
2, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (Tmax), area under the plasma concentration-time curve [AUC(0-t) 
and AUC(0-∞)], terminal half life (t1/2) and the percentage of extrapolation for 
AUC(0-∞).
Pharmacokinetic concentration data will be presented in graphical and/or 
tabular form.
Derived pharmacokinetic parameters will be listed [subjects with greater than 
20% extrapolated AUC (0-∞) will be highlighted] and descriptive statistics (n, 
arithmetic mean, SD, 95% CI, minimum, median and maximum) will be 
calculated for all pharmacokinetic parameters by treatment.
In addition, for loge-transformed variables the geometric mean with 
associated 95% CI, SD on loge-scale and between subject coefficient [%CVb 
(100 * √ (exp(SD2) -1)] will be provided, where the SD is the standard 
deviation of loge transformed data.
To estimate the ratio of exposure of nemiralisib administered alone and co-
administered following repeat doses of itraconazole, mixed effects analyses 
will be performed for both loge transformed Cmax and loge transformed 
AUC(0-∞). The geometric mean ratios will be provided along with 90% 
confidence intervals and the mean squared error (MSE).
Secondary
Plasma itraconazole concentration-time data and PK parameters [Cmax, 
Tmax, AUC(0-t), AUC(0-∞) and t1/2] for both Day 1 (first dose of 
itraconazole) and Day 5 (5th Day of dosing Itraconazole or steady state) in 
period 2, will be analysed, listed and summarised as described for 
nemiralisib.  
No formal statistical analysis will occur.
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
 
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Endpoint
Statistical Analysis Methods
Secondary
Adverse events (AE), clinical laboratory values, vital signs, electrocardiogram
(ECG) and spirometry, will be listed and summarized by treatment.
10.3.3.
Interim Analyses
A preliminary analysis of PK may be performed following the availability of the PK data, 
for internal decision making.
 
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11.
REFERENCES
European Medicines Agency (EMA), Guideline on the investigation of drug interactions, 
Committee for Human Medicinal Products (CHMP), 2012, CPMP/EWP/560/95/Rev. 1 
Corr. 2
GlaxoSmithKline Document Number 2012N141231_08. GSK2269557 Investigator’s 
Brochure, Version 09. 13-Dec-2017.
GlaxoSmithKline Document Number 2017N345216_00. A Mechanistic Static Model-
Based Evaluation of the Potential Magnitude of Increase in Theophylline Exposure 
(AUC) when co-administered with GSK2269557. 13-Dec-2017.
Itraconazole Prescribing Information: Available at
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022484S000lbl.pdf. 
Accessed 04-Dec-2017
Ke AB, Zamek-Gliszczynski MJ, Higgins JW, Hall SD. Itraconazole and 
Clarithromycinas Ketoconazole Alternatives for Clinical CYP3A Inhibition Studies. 
Clinical Pharmacology & Therapeutics. 2014; 95:473-6.
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E et al. Best practices for the 
use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies. J 
Clin Pharmacol. 2016; 56(2):143-51
Quanjer PH, Stanojevic S; Cole T et al. Multi-ethnic reference values for spirometry for 
the 3–95-yr age range: the global lung function 2012 equations. European Respiratory 
Journal. 2012; 40: 1324–1343
U.S. Department of Health and Human Services Food and Drug Administration (FDA), 
Clinical Drug Interaction  Studies - Study Design, Data Analysis, and Clinical 
Implications, Guidance for Industry, Draft Guidance, Center for Drug Evaluation and 
Research (CDER), 2017. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse event
ALT
Alanine transaminase
AST
Aspartate Aminotransferase
AUC
Area under the curve
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum observed plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CT
computerised tomography
CYP
Cytochromes P450
DDI
Drug drug interaction
ECG
Electrocardigram
EMA
European Medicines Agency
FDA
Food and drug administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
IEC
Independent ethics committee
INR
International normalized ratio
IRB
Institutional review board
kg
Killogram
mcg/ ug
Microgram
mg
Milligram
mL
Milliliter
MSDS
Material Safety Data Sheet
MSE
Mean squared error
ng
Nanogram
NOAEL
No observed adverse event level
PI3K
Phosphoinositide 3-kinase
PIP2
phospholipid phosphatidylinositol 4,5-biphosphate
PIP3
phosphatidylinositol 3,4,5-trisphosphate
PK
Pharmacokinetic
QTc 
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia’s 
 
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formula
RAP
Reporting and analysis plan
RNA
Ribonucleic Ac
SAE
Serious adverse event
SD
Standard deviation
SOA
Schedule of activities
SRM
Study reference manual
SUSAR
Suspected unexpected serious adverse reactions
t1/2
Half life
tmax
Time to Cmax
ULN
Upper limit of normal 
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
WinNonlin
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume Mean 
Corpuscular Hemoglobin
%Reticulocytes
White Blood Cell count 
with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total and 
direct bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose (fasted at 
screening only)
Calcium
Alkaline phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase 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)

Alcohol breath test and urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)

Urine cotinine

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
 
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Laboratory 
Assessments
Parameters
hepatitis C virus antibody)
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 6. 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).
 
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
 
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the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed 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 
 
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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 from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF 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 Data Entry 
Tracking Guidelines or equivalent document.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
 
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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
 
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one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

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.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
 
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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 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.
 
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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrolment.
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 
 
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
Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 5 when having 
penile-vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame.

In addition, male participants must refrain from donating sperm for duration of 
study and for at least 10 days after the last dose.
Table 5
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 / ligation
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
 
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Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
 
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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
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 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin <2xULN  and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 7 days 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 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
 
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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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