Clinical trial NCT02593539
Conditions: Activated PI3K-delta Syndrome
Keywords: APDS Safety Pharmacokinetics GSK2269557 PASLI
Sponsor: GlaxoSmithKline
Start date: 2016-07-22; Completion date: 2020-06-04
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label study conducted to investigate safety, pharmacokinetics and pharmacodynamics of repeat doses of inhaled nemiralisib (NEMI) in participants with activated phosphoinositide 3-kinase (PI3K) delta syndrome /p110 delta-activating mutation causing senescent T Cells, lymphadenopathy and immunodeficiency (APDS/PASLI)

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Nemiralisib
Intervention descriptions: intervention 1: Participants will be administered nemiralisib

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An open-label, single arm study to investigate the safety, 
pharmacokinetics and pharmacodynamics of repeat doses of 
inhaled nemiralisib in patients with APDS/PASLI
Compound Number:
GSK2269557
Development Phase:
IIA
Effective Date:
15-JUN-2018
Protocol Amendment Number:  03
Author s: 
, (Respiratory R&D); 
 (Respiratory R&D); 
 (GCSD),
(GCSD); 
 (Clinical 
Statistics); 
 (Respiratory R&D); 
 (CPMS); 
(CPMS)
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N238311_00
2015-OCT-23
Original
2015N238311_01
2016-FEB-25
Amendment No. 1
Summary of Protocol Amendment 01 (a detailed description of the amendment is 
provided in Appendix 6):
1. Minor change to the wording of the exploratory efficacy endpoint has been made. 
2. Reference to randomisation of subjects removed for clarity and accuracy.
3. Mitigation strategy of the APDS exacerbation risk has been updated to ensure 
consistency with the weeks the clinic visits occur on, as described in the protocol
4. Removal of instruction on the need for precautionary measures to protect against 
potential photosensitive effects of GSK2269557 (following new non-clinical data 
supporting the discharge of this risk to humans)
5. Maximum weekly alcohol consumption for males reduced from 21 to 14 units.
Updated to reflect current UK guideline following the recent change in advice.
6. Additional exclusion criteria added to exclude subjects who provide a positive 
sample in a pre-study drug screen.
7. Immunoglobulins added to the list of PD lymphocyte assessments to provide 
further characteristics pertaining to lung infection in APDS patients. 
8. Time and Events Table for Screening and Run-in Period updated as follows:
–
Immunoglobulins added to the list of PD lymphocyte assessments 
–
Timing of PD sample collection for bacterial DNA fragment analysis added 
and to ensure consistency with body text.
–
Laboratory tests for clotting status added to clinical visit #1 for subjects 
consenting to the BAL sub-study.
9. Time and Events Table for Treatment Period and Follow-up updated as follows:
–
Timing of reviews of APDS exacerbation and respiratory tract infection 
history added to make consistent with body text.
–
Day 2 PK blood sample (which refers to Day 1 24 hr timepoint) removed from 
table for clarity 
–
Immunoglobulins added to the list of PD lymphocyte assessments
–
Timing of PD sample collection for bacterial DNA fragment analysis added to 
ensure consistency with body text.
–
Laboratory tests for clotting status added to Day 83 (-4/+2) for subjects 
consenting to the BAL sub-study.
10.
Removal of ‘severity of infection’ as a measurement taken during the 
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screening and critical baseline assessments
11.
Clarification of the period during which details of pregnancies in female 
subjects will be collected after the start of dosing
12.
Addition of two haematology laboratory tests for clotting status to be 
performed at clinical visit #1 and Day 83 (-4/+2) for subjects consenting to 
the BAL sub-study.
13.
Clinical Chemistry section amended to clarify that blood glucose test is a 
non-fasting measurement.
14.
Additional text added to clarify which lung lobe will be targeted during the 
BAL procedure.
15.
Proposed analyses of BAL updated to indicate that proteomic analysis will be 
performed on the lavage supernatant not the cell pellet.
16.
Additional text added to analysis section to clarify the timing of reporting of 
exploratory biomarker data to ensure publication of data pertaining to core 
primary and secondary measures is not delayed.
2015N238311_02
2016-NOV-02
Amendment No. 2
Summary of Protocol Amendment 02 (a detailed description of the amendment is 
provided in Appendix 6):
1. Replace the administration of GSK2269557 via the DISKUS device (1000 g) by a 
comparable dose administered via the ELLIPTA device (700 g)
2. Include patients with APDS1 with new disease-associated mutations and APDS2 with 
mutations in the PIK3R1 regulatory subunit of class IA phosphoinositide 3 kinases. 
3. Administrative changes and clarifications.
2015N238311_03
2018-JUN-15
Amendment No. 3
Summary of Protocol Amendment 03 (a detailed description of the amendment is 
provided in Appendix 6):
1.
Replace the administration of nemiralisib in a blend containing 0.6% MgSt, via a 
dry powder ELLIPTA inhaler (700 µg) by a comparable dose nemiralisib in a blend 
containing 0.4% magnesium stearate (MgSt) administered via the ELLIPTA device (500 
µg). 
2.
Exploratory Phamacodynamics endpoint Volatile Organic Chemicals (VOCs) 
analysis in breath removed as capabilities not available at study site.
3.
Risk assessment table updated with post inhalation cough.
4.
Change to inclusion criteria 3 the lower limit BMI cut off to 17 kg/m2 and the 
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lower limit for weight to 40kg. These patients have a longstanding chronic condition and 
so are more likely to fall outside the normal range for BMI. Therefore adoption of a 
slightly lower BMI for this patient group is considered appropriate and safe.
5.
Change to inclusion criteria 4. Based on the predicted margins for semen 
exposure on findings across the reproductive toxicology studies range between 29811 and 
192452 fold, which are well above the threshold for concern, and the absence of 
genotoxic effects in cellular assays, the requirement for additional contraception for 
males with partners of child bearing potential has been removed. 
6.
Change to exclusion criteria 5 concomitant medication. Adjusted in line with 
latest drug interaction data. Information about interaction with inhibitors of CYP3A4 
substrates has been added for consistency since this has also been implemented for the 
most recent studies.
7.
Dose reduction removed as dose strength is 500µg / blister, therefore dose 
reduction will no longer be an option. 
8.
Time and Event schedule visit window added to Follow Up Visit.
9.
Administrative changes, including change from the compound number
GSK2269557 to the INN nemiralisib, corrections, relevant updates, including reporting 
time frame of pregnancy information and clarifications also made.
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
Primary 
Medical 
Monitor 
 
GSK, Gunnels Wood 
Road, Stevenage, 
Hertfordshire, SG1 
2NY, UK
Secondary 
Medical 
Monitor
GSK, Stockley
Park West 1-3
Ironbridge Road,
Middlesex, UB11
1BT, UK
SAE contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):  2015-004876-31.
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204745
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204745......................................................11
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................17
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................20
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................23
4.6.1.
Risk Assessment .........................................................................23
4.6.2.
Benefit Assessment.....................................................................30
4.6.3.
Overall Benefit: Risk Conclusion..................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................34
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Liver Chemistry Stopping Criteria ................................................35
5.4.1.1.
Study Treatment Restart or Re-challenge...................36
5.4.2.
QTc Stopping Criteria ..................................................................36
5.4.3.
Other Safety Stopping Criteria .....................................................37
5.5.
Subject and Study Completion....................................................................38
6.
STUDY TREATMENT ............................................................................................38
6.1.
Investigational Product and Other Study Treatment....................................38
6.2.
Treatment Assignment................................................................................38
6.3.
Planned Dose Adjustments.........................................................................38
6.4.
Subject Specific Dose Adjustment Criteria..................................................39
6.5.
Blinding.......................................................................................................39
6.6.
Packaging and Labeling..............................................................................39
6.7.
Preparation/Handling/Storage/Accountability..............................................39
6.8.
Compliance with Study Treatment Administration.......................................40
6.9.
Treatment of Study Treatment Overdose....................................................40
6.10.
Treatment after the End of the Study ..........................................................40
6.11.
Lifestyle and/or Dietary Restrictions............................................................41
6.11.1.
Caffeine, Alcohol, and Tobacco ...................................................41
6.11.2.
Activity .........................................................................................41
6.12.
Concomitant Medications and Non-Drug Therapies....................................41
6.12.1.
Permitted Medications and Non-Drug Therapies..........................41
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................42
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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................43
7.1.
Time and Events Table...............................................................................45
7.2.
Screening and Critical Baseline Assessments ............................................50
7.3.
Safety .........................................................................................................50
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................50
7.3.1.2.
Method of Detecting AEs and SAEs ...........................51
7.3.1.3.
Follow-up of AEs and SAEs........................................51
7.3.1.4.
Cardiovascular and Death Events ..............................51
7.3.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................52
7.3.1.6.
Regulatory Reporting Requirements for SAEs............52
7.3.2.
Pregnancy ...................................................................................52
7.3.3.
Physical Exams ...........................................................................53
7.3.4.
Vital Signs....................................................................................53
7.3.5.
Electrocardiogram (ECG).............................................................53
7.3.6.
Spirometry ...................................................................................53
7.3.6.1.
FEV1 (1 hr Post-dose).................................................53
7.3.6.2.
(Screening Only) Bronchodilator 
Responsiveness Testing (reversibility)........................53
7.3.7.
Clinical Safety Laboratory Assessments ......................................54
7.4.
Pharmacokinetics .......................................................................................55
7.4.1.
Blood Sample Collection..............................................................55
7.4.2.
Urea Blood Sample......................................................................56
7.4.3.
Sample Analysis ..........................................................................56
7.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................56
7.5.1.
Pharmacodynamic Biomarkers in Blood ......................................56
7.5.2.
Pharmacodynamic Biomarkers in Induced Sputum......................57
7.6.
Bronchoscopy/BAL (BAL sub-study only)....................................................57
7.7.
Efficacy.......................................................................................................58
7.7.1.
Number and rate of lower/upper respiratory tract infection...........58
7.7.2.
FEV1 (Pre-dose)..........................................................................58
7.7.3.
Patient Exit Interview ...................................................................58
7.8.
Patient Diary...............................................................................................59
7.9.
Genetics .....................................................................................................59
8.
DATA MANAGEMENT ...........................................................................................59
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................60
9.1.
Sample Size Considerations.......................................................................60
9.2.
Data Analysis Considerations .....................................................................60
9.2.1.
Analysis Populations....................................................................60
9.3.
Key Elements of Analysis Plan ...................................................................60
9.3.1.
Interim Analyses ..........................................................................60
9.3.2.
Primary Analyses.........................................................................60
9.3.2.1.
Exploratory Biomarker Analyses.................................60
9.3.3.
Patient Exit Interview ...................................................................61
10. STUDY GOVERNANCE CONSIDERATIONS........................................................61
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............61
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10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................61
10.3.
Quality Control (Study Monitoring) ..............................................................62
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................63
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................64
11. REFERENCES.......................................................................................................65
12. APPENDICES........................................................................................................67
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................67
12.2.
Appendix 2 - Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................70
12.3.
Appendix 3 - Genetic Research ..................................................................73
12.4.
Appendix 4 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................76
12.4.1.
Definition of Adverse Events........................................................76
12.4.2.
Definition of Serious Adverse Events...........................................77
12.4.3.
Definition of Cardiovascular Events .............................................78
12.4.4.
Recording of AEs and SAEs ........................................................79
12.4.5.
Evaluating AEs and SAEs............................................................79
12.4.6.
Reporting of SAEs to GSK...........................................................81
12.5.
Appendix 5 - Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................82
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............82
12.5.2.
Collection of Pregnancy Information ............................................83
12.6.
Appendix 6 - Protocol Amendment Changes ..............................................84
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1.
PROTOCOL SYNOPSIS FOR STUDY 204745
Rationale
The purpose of this study is to investigate the safety, pharmacokinetics (PK) and 
pharmacodynamics (PD) during 84 days treatment with 500 g of inhaled nemiralisib in 
addition to standard of care, in patients with activated phosphoinositide 3-kinase delta 
syndrome 1/p110delta-activating mutation causing senescent T Cells, lymphadenopathy 
and immunodeficiency (APDS1/PASLI-CD) and activated phosphoinositide 3-kinase 
delta syndrome 2/p110delta-activating mutation causing senescent T Cells, 
lymphadenopathy and immunodeficiency (APDS2/PASLI-R1).
To date nemiralisib has been administered to healthy subjects (smokers and 
non-smokers), patients with: stable Chronic Obstructive Pulmonary Disease (COPD); 
patients experiencing a COPD exacerbation; and patients with persistent, uncontrolled 
asthma.  As this study is the first administration of nemiralisib to patients with APDS, 
this study will provide safety, tolerability, efficacy and pharmacokinetic data in this 
patient population.  
The study will also explore the pharmacodynamic effects of once daily (OD) repeat 
inhaled doses of nemiralisib administered to APDS patients on biomarkers in blood and 
sputum. In a sub-study, subjects will undergo bronchoalveolar lavage (BAL) to 
investigate lymphocyte biology in the lungs after dosing with nemiralisib.
Objectives/Endpoints
Objectives
Endpoints
Primary
Safety
To assess the safety and tolerability of 84 
days repeat dosing of inhaled nemiralisib
in patients with APDS

Adverse Events (AE)

Vital signs

12-lead electrocardiogram (ECG)

Clinical laboratory parameters,

Spirometry (forced expiratory volume in 
1 second (FEV1) 1 hr post-dose) 
Secondary
Pharmacokinetics
To define the plasma pharmacokinetics 
(PK) of inhaled nemiralisib following 
repeat dosing in patients with APDS.
Nemiralisib trough plasma concentration 
following single and repeated treatment.
Exploratory
Pharmacodynamics: 
To understand lung disease biology in 
patients with APDS and to explore the 
pharmacodynamic effects of inhaled 
nemiralisib.
Endpoints may include, but are not limited to:
In blood and sputum, analysis of:
Cellular PIP3 peak area as a proportion 
of (PIP3 peak area + PIP2 peak area)
Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)
Immune cell subsets
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Objectives
Endpoints
Exploratory phospho-protein biomarkers 
(e.g. pAKT)
Exploratory messenger ribonucleic acid
(mRNA) biomarkers
In  BAL cell pellet/ lavage supernatant
when available, analysis of:
Lymphocyte cell subsets
Exploratory phospho-protein biomarkers 
(e.g. pAKT)
Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)
Exploratory mRNA biomarkers
Proteomic markers (lavage supernatant 
only)
Antibody levels
In blood, analysis of:
Bacterial DNA fragments
Pharmacokinetics
To define the lung trough concentration 
of nemiralisib after repeat dosing
Trough nemiralisib concentration in lung 
epithelial lining fluid (ELF) and 
bronchoalveolar lavage (BAL) cell pellet at 
Day 84 visit.
Efficacy
To assess the efficacy of inhaled 
nemiralisib administered once daily for 
84 days in patients with APDS.

The number and rate of pulmonary 
and/or ear and sinus infections requiring 
anti-microbial treatment compared to 
subject’s historical baseline

Change from baseline (Day 1) in trough 
FEV1at Day 14 and Day 83 (pre-
bronchodilator)
Overall Design
This is a single-centre, open-label, uncontrolled, single group, study in patients with 
APDS 1 and 2. 

Eligible subjects will be enrolled in the study and receive nemiralisib 500 g once 
daily for 83 days (-4/+2 days).

Nemiralisib will be administered via the ELLIPTA™ Dry Powder Inhaler (DPI).

In an optional sub-study, subjects will undergo bronchoalveolar lavage (BAL) to 
investigate lymphocyte biology in the lungs after dosing with nemiralisib for 84 
days (-4/+2 days).
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Treatment Arms and Duration
Subjects will be required to participate in the following visits:
Pre-screening: subjects will visit the study clinic to sign the Informed Consent Form and 
undergo review of demography, APDS exacerbation history and concomitant 
medications. Any medication changes made by the investigator will be recorded.    
Screening: Subjects will visit the study clinic for an assessment of eligibility criteria up 
to 42 days before the treatment period (Day -1). Subjects meeting the eligibility criteria, 
which can be assessed at the screening visit, will visit the study clinic up to 7 days before 
first dose to complete the baseline assessments. 
Note: Pre-screening and screening visits may occur on the same day, as appropriate.
PD Baseline assessment (Visit #1): Subjects will undergo a range of baseline 
assessments described in the Time & Event table, including providing a sample of blood 
and induced sputum. 
Optional BAL sub-study: subjects willing to participate in the BAL sub-study will 
undergo a bronchoscopy/BAL baseline assessment (BAL visit #1). This may occur either
on day 2 of the PD baseline assessment or during a separate visit, as appropriate.
Treatment Period: Once daily treatment of nemiralisib will start on Day 1. 

Subjects will visit the study clinic the day before dosing (Day -1) and undergo a range 
of baseline assessments described in the Time & Event table.

Once daily study treatment administration will start on Day 1. Subjects will remain in 
the study clinic until all the safety assessments have been completed on Day 2, and 
there are no safety concerns.

Subjects will then dose at home for the remainder of the treatment period (with the 
exception of clinic visit days, when they will dose in the study clinic). On Day 14 ± 2, 
Day 28 (-4/+2 days), Day 56 (-4/+2 days), Day 83 (-4/+2 days) and Day 84 (-4/+2 
days) (optional sub-study patients only), subjects will return to the study clinic on an 
outpatient basis, in order to complete the assessments described in the Time & Event 
table.

Between Day 2 and Day 84, subjects will be contacted weekly by telephone or a 
research nurse will visit them at home, to ensure there are no safety concerns. During 
this period subjects will be encouraged to contact the study clinic immediately upon 
the worsening of any symptoms. 
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Follow up period: 

Subjects will receive telephone calls at 1-2 weeks and 4-6 weeks after their last dose. 
These will be used to ensure there are no safety concerns and to monitor the number 
and rate of lower/upper respiratory tract infections requiring antimicrobial therapy.

Three months after the end of treatment, subjects will return to the study clinic to 
perform a range of follow-up assessments, described in the Time & Event table.
The total duration of the study is approximately 30 weeks, including pre-
screening/screening and follow-up.
Type and Number of Subjects
Patients with Documented Type 1 or 2 APDS/PASLI-associated genetic PI3Kmutation 
(e.g. E1021K, N334K, E525K and C416R) 

Up to 20 subjects will be enrolled into the study with the aim to ensure 
approximately 4 subjects complete dosing and critical assessments.
Analysis
Safety data will be graphically presented, summarised and listed as appropriate. Data 
permitting, the pharmacodynamic endpoints will also be summarised, and may be 
analysed if deemed appropriate. 
2.
INTRODUCTION
Nemiralisib is a potent and highly selective inhaled PI3Kinhibitor being developed as 
an agent for the treatment of inflammatory airways diseases.
2.1.
Study Rationale
The purpose of this study is to investigate the safety, pharmacokinetics (PK) and 
pharmacodynamics (PD) during 84 days treatment with 500 g of inhaled nemiralisib in 
addition to standard of care, in patients with activated phosphoinositide 3-kinase delta 
syndrome 1/p110delta-activating mutation causing senescent T Cells, lymphadenopathy 
and immunodeficiency (APDS1/PASLI-CD) and activated phosphoinositide 3-kinase 
delta syndrome 2/p110delta-activating mutation causing senescent T Cells, 
lymphadenopathy and immunodeficiency (APDS2/PASLI-R1).
To date nemiralisib has been administered to healthy subjects (smokers and 
non-smokers), patients with stable Chronic Obstructive Pulmonary Disease (COPD),
patients experiencing a COPD exacerbation and patients with persistent, uncontrolled 
asthma.  As this study is the first administration of nemiralisib to patients with APDS, 
this study will provide safety, tolerability, efficacy and pharmacokinetic data in this 
patient population.  
The study will also explore the pharmacodynamic effects of once daily repeat inhaled 
doses of nemiralisib administered to APDS patients on biomarkers in blood and sputum. 
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In a sub-study, subjects will undergo bronchoalveolar lavage (BAL) to investigate 
lymphocyte biology in the lungs after dosing with nemiralisib.
2.2.
Brief Background
PI3Kis a member of the Class IA family of phosphoinositides 3-kinases (PI3Ks) that 
convert 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 [Okkenhaug, 2007] and roles in neutrophil chemotaxis and activation 
[Sadhu, 2003]. 
APDS1 (PASLI-CD) is a rare (prevalence estimated to be <1/1,000,000), combined
primary immune deficiency syndrome caused by a dominant gain-of-function 
heterozygous mutation in p110, the catalytic subunit of phosphoinositide 3-kinase 
(PI3K). A number of mutations e.g. E1021K, N334K, E525K and C416R, with E1021K 
the most common [Angulo, 2013; Lucas, 2014] have been described. Clinically, APDS is 
characterized by recurrent respiratory infections with Streptococcus pneumoniae and 
Haemophilus influenzae, causing structural lung damage (small airways disease and 
bronchiectasis). In addition, some patients experience severe infections with Herpes-
group viruses, and there is an increased risk of B cell malignancy [Lear, 2014]. Typically, 
disease in APDS patients is difficult to manage, with the use of prophylactic antibiotic 
and antiviral agents, i.v. antibiotics, and immunoglobulin replacement being the mainstay 
of treatment. The limited treatment options available to these patients’ means early death 
from infection-related causes remains a prominent feature of the disease [Lear, 2014].
Recently, APDS 2 (PASLI-R1), a primary immunodeficiency resulting from autosomal 
dominant gain-of-function mutations in PI3KR1, the gene coding for the regulatory 
subunit of class PI3Ks, has been described. The clinical, immunological and 
histopathological features of APDS2 are similar to those described in APDS1 patients 
[Elkaim, 2016, Olbrich, 2016].       
Immunologically, these patients have increased transitional but decreased memory B 
cells, circulating senescent T cells, increased IgM but reduced IgG2 levels, and impaired 
vaccine responses [Angulo, 2013; Lucas, 2014] . In vitro the E1021K mutation enhanced 
the membrane association and kinase activity of p110. Biochemically, patient-derived 
lymphocytes displayed increased basal and stimulated phospho-AKT and PIP3 (the 
second messenger product of PI3K), a propensity for activation induced cell death 
(AICD) and impaired cytokine production. Importantly, selective PI3Kinhibitors 
IC87114 and GS-1101 (CAL-101, idelalisib) reduced activity of the mutant kinase in 
vitro and in patient T cells ex vivo, and prevented AICD, suggesting a novel, target-
specific therapy for APDS [Angulo, 2013]. 
Nemiralisib is a potent and highly selective inhaled PI3Kinhibitor and therefore has the 
potential to be a novel therapy in patients with APDS. 
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Nemiralisib has been administered to healthy volunteers and healthy smokers in previous 
studies, as follows: 

Study PII115117 (healthy volunteers): single and repeat doses of a nebulised solution 
of nemiralisib – daily doses up to 6400 g for 7 days.

Study PII116617 (healthy smokers): single and repeat doses of a dry powder 
formulation (DISKUS™dry powder inhaler; DPI) of nemiralisib – single doses up to 
3000 g, and daily doses up to 2000 g for 14 days

Study 201544 (healthy volunteers): single centre, three part, randomised, study to 
evaluate the safety, tolerability and pharmacokinetics of nemiralisib administered via 
the ELLIPTA™dry powder inhaler (0.6% MgSt formulation) – single doses up to 
200 µg, and daily doses of 200 µg for 10 days.

Study 205759 (healthy Japanese volunteers): single and repeat doses of nemiralisib 
administered via the ELLIPTA™ DPI (0.6% MgSt formulation) – single doses up to 
700 µg, and daily doses up to 700 µg for 10 days.

Study 207674 (healthy volunteers): single dose of nemiralisib 750 µg or a single dose 
of 500 µg administered via the ELLIPTA™ DPI (0.4% MgSt formulation) (study 
completed but not yet reported).

Study 206764 (healthy volunteers):  An open-label study in healthy male subjects, to 
determine the excretion balance and pharmacokinetics of [14C]-GSK2269557, 
administered as a single intravenous micro-tracer (concomitant with an inhaled non-
radiolabelled dose) and a single oral dose (study completed but not yet reported).

Study 206874 (healthy volunteers): one sequence cross over study (nemiralisib 100 
µg (via the ELLIPTA™ DPI (0.4% MgSt formulation) alone followed by nemiralisib 
100 µg co-administered with itraconazole). A study to evaluate the effect of 
itraconazole on the PK of nemiralisib (study completed but not yet reported)
Nemiralisib was well tolerated across the range of doses tested.
Nemiralisib has been administered to COPD patients in the following studies:

Study PII115119 (stable COPD patients): daily doses of up to 2000 g nemiralisib
administered via the DISKUS™DPI for 14 days. 

Study PII116678 (patients experiencing a COPD exacerbation): daily doses of 1000 
µg nemiralisib administered via the DISKUS™DPI for 12 weeks.
Nemiralisib has been administered to patients with persistent, uncontrolled asthma:
•
Study 201543 (patients with persistent, uncontrolled asthma): daily doses of 1000 
µg nemiralisib are being administered via the DISKUS™DPI for 28 days
There are also two ongoing studies (not reported) in COPD patients: 

Study 201928 (patients experiencing a COPD exacerbation): daily doses of 700 g 
nemiralisib being administered via the ELLIPTA™DPI (0.6% MgSt formulation) for 
12 weeks.
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
Study 200879 (patients experiencing an acute COPD exacerbation): daily doses up to 
750µg nemiralisib administered via the ELLIPTA™DPI (0.4% MgSt formulation) 
for 84 days in a dose ranging study.
More information about the non-clinical and clinical studies is available in the 
investigator’s brochure (IB) [GlaxoSmithKline Document Number 2012N141231_08].
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
Safety
To assess the safety and tolerability of 84 
days repeat dosing of inhaled nemiralisib
in patients with APDS

Adverse Events (AE)

Vital signs

12-lead electrocardiogram (ECG)

Clinical laboratory parameters,

Spirometry (forced expiratory volume in 
1 second (FEV1)1 hr post-dose) 
Secondary
Pharmacokinetics
To define the plasma pharmacokinetics 
(PK) of inhaled nemiralisib following 
repeat dosing in patients with APDS.
Nemiralisib trough plasma concentration 
following single and repeated treatment.
Exploratory
Pharmacodynamics: 
To understand lung disease biology in 
patients with APDS and to explore the 
pharmacodynamic effects of inhaled 
nemiralisib.
Endpoints may include, but are not limited to:
In blood and sputum, analysis of:
Cellular PIP3 peak area as a proportion 
of (PIP3 peak area + PIP2 peak area)
Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)
Immune cell subsets
Exploratory phospho-protein biomarkers 
(e.g. pAKT)
Exploratory messenger ribonucleic acid
(mRNA) biomarkers
In  BAL cell pellet/lavage supernatant when 
available, analysis of:
Lymphocyte cell subsets
Exploratory phospho-protein biomarkers 
(e.g. pAKT)
Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)
Exploratory mRNA biomarkers
Proteomic markers (lavage supernatant 
only)
Antibody levels
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Objectives
Endpoints
In blood, analysis of:
Bacterial DNA fragments
Pharmacokinetics
To define the lung trough concentration 
of nemiralisib after repeat dosing
Trough nemiralisib concentration in lung 
epithelial lining fluid (ELF) and 
Bronchoalveolar lavage (BAL) cell pellet at 
Day 84 visit.
Efficacy
To assess the efficacy of inhaled 
nemiralisib administered once daily for 
84 days in patients with APDS.

The number and rate of pulmonary 
and/or ear and sinus infections requiring 
anti-microbial treatment compared to 
subject’s historical baseline

Change from baseline (Day 1) in trough 
FEV1 at Day 14 and Day 83 (pre-
bronchodilator)
4.
STUDY DESIGN
4.1.
Overall Design
This is a single-centre, open-label, uncontrolled single group study in patients with APDS
1 and 2. 

Eligible subjects will enter the study and receive nemiralisib 500 g once daily for 
up to 83 days (-4/+2 days).

Nemiralisib will be administered via the ELLIPTA Dry Powder Inhaler (DPI).

In an optional sub-study, subjects will undergo bronchoalveolar lavage (BAL) to 
investigate lymphocyte biology in the lungs after dosing with nemiralisib for 84 
days (-4/+2 days).
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Figure 1
Study Design Schematic
4.2.
Treatment Arms and Duration
Subjects will be required to participate in the following visits:
Pre-screening: Subjects will visit the study clinic for signing the Informed Consent Form 
and undergo review of demography, APDS exacerbation history and concomitant 
medications. Any medication changes made by the investigator will be recorded.    
Screening: Subjects will visit the study clinic for an assessment of eligibility criteria up 
to 42 days before the treatment period (Day -1). Subjects meeting the eligibility criteria, 
which can be assessed at the screening visit, will visit the study clinic up to 7 days before 
first dose to complete the baseline assessments. 
Note: Pre-screening and screening visits may occur on the same day, as appropriate.
PD Baseline assessment (Visit #1): Subjects will undergo a range of baseline 
assessments described in the Time & Event table (Section 7.1), including providing a 
sample of blood and induced sputum. 
Optional BAL sub-study: Subjects willing to participate in the BAL sub-study will 
undergo a bronchoscopy/BAL baseline assessment (BAL visit #1). This may occur either
on day 2 of the PD baseline assessment or during a separate visit, as appropriate.
Treatment Period: Once daily treatment of nemiralisib will start on Day 1. 

Subjects will visit the study clinic the day before dosing (Day -1) and undergo a range 
of baseline assessments described in the Time & Event table (Section 7.1).

Once daily study treatment administration will start on Day 1. Subjects will remain in 
the study clinic until all the safety assessments have been completed on Day 2, and 
there are no safety concerns.
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
Subjects will then dose at home for the remainder of the treatment period (with the 
exception of clinic visit days, when they will dose in the study clinic). On Day 14 ± 2, 
Day 28 (-4/+2 days), Day 56 (-4/+2 days), Day 83 (-4/+2 days)  and Day 84 (-4/+2 
days) (optional sub-study patients only), subjects will return to the study clinic on an 
outpatient basis, in order to complete the assessments described in the Time & Event 
table (Section 7.1). 

Between Day 2 and Day 84, subjects will be contacted weekly by telephone or a 
research nurse will visit them at home, to ensure there are no safety concerns. During 
this period subjects will be encouraged to contact the study clinic immediately upon 
the worsening of any symptoms. 
Follow up period: 

Subjects will receive telephone calls at 1-2 weeks and 4-6 weeks after their last dose. 
These will be used to ensure there are no safety concerns and to monitor the number 
and rate of lower/upper respiratory tract infections requiring antimicrobial therapy.

Three months after the end of treatment, subjects will return to the study clinic to 
perform a range of follow-up assessments, described in the Time & Event table 
(Section 7.1).
The total duration of the study is approximately 30 weeks, including pre-
screening/screening and follow-up.
4.3.
Type and Number of Subjects
Patients with Documented type 1 APDS/PASLI-associated genetic PI3Kmutation (i.e. 
E1021K, N334K, E525K and C416R) 
Up to 20 subjects will be enrolled into the study with the aim to ensure approximately 4 
subjects complete dosing and critical assessments.
4.4.
Design Justification
This single arm exploratory study is designed to provide initial information on the 
mechanism of disease including airway biology in this rare APDS patient population, and 
to identify any initial safety and tolerability issues following 12-weeks dosing with 
500 g nemiralisib. The data collected in this study will be used to inform the design of 
more expansive studies with nemiralisib in this disease in the future.
Single arm (no 
placebo)
Given the rareness of this disease and the limited number of eligible 
subjects, a placebo control was not included. This maximises the 
number of subjects on-drug and thereby offers an opportunity to 
better understand the pharmacodynamic effect of the drug in this 
disease.
Treatment period

Safety: The safety aim of this study is to assess any frequent, 
safety events which deviate from prior safety data. The 12-week 
treatment period builds on significant prior data collected in 
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healthy volunteers, COPD and asthma patients where 
nemiralisib has been well tolerated up to 12 weeks treatment.  
No drug-related serious adverse event(s) (SAEs) have been 
observed to date. The most common AEs to date are post-
inhalation cough and headache. 

PK: Nemiralisib reaches steady state after 5-7 days repeat 
dosing. Assessing plasma PK at day 14 & 83 will enable the 
assessment of a sustained level of nemiralisib exposure in this 
patient cohort. 

PD: Changes in a range of PD markers have been measured 
during studies in patients with COPD, following 2 weeks dosing 
with nemiralisib.
Endpoint 
measurements
The study has been designed to be rich in pharmacodynamic 
biomarkers to support the evaluation of airway biology in 
patients with APDS, and the effect of nemiralisib (administered 
directly to the lung) on the disease. These are assessed from 
blood, sputum and BAL (where available) samples.
While there is a strong genetic association between the 
mechanism of disease in APDS and drug action, and there is in-
vitro peripheral lymphocyte data to support the use of PI3K 
delta inhibitors in APDS (discussed in Section 2.2), there is no 
airway-specific in-vitro or in-vivo data from patients with APDS
Frequency of 
clinic visits
Subjects in this study will be monitored more closely than they 
would be in clinical practice with clinic visits after 14, 28, 56 
and 83 days of dosing, and weekly telephone contact or visit by 
a research nurse. The frequency of the visits will allow for the 
early identification of deteriorating disease and appropriate 
diagnostic evaluation and management of subjects. 
Subject safety will also be assured by the application of strict 
withdrawal criteria in the event of deterioration of the subjects’ 
condition.
Pre-screening 
visit
Inclusion of a pre-screening visit will enable the assessment of 
subjects’ concomitant medications ahead of screening. This allows 
time ahead of dosing, if changes are required, to ensure patients are 
stable on alternative medications 
Pre-treatment 
baseline visits
To mitigate against the inclusion of a placebo control, we are taking 
two sets of pharmacodynamic samples prior to dosing to obtain a 
more robust baseline measurements.
Follow-up period 
and clinic visit
The inclusion of a 3-month follow-up period will enable the 
tracking of sinus, ear and pulmonary infection rate post-drug. 
This will control for the seasonality of infection frequency, 
which is important for the efficacy endpoint.
The measurement of PD markers at the 3 month follow-up 
period will enable us to obtain more robust baseline 
measurements
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4.5.
Dose Justification
The formulation of Nemiralisib has been changed to the current formulation of 
nemiralisib with lactose monohydrate/0.4% Magnesium Stearate (MgSt) which is the 
proposed final formulation and currently being investigated in the dose ranging study.
The previous formulation currently used in the study is blended with lactose and 0.6% 
MgSt). The reduction in concentration of MgSt in the new formulation has resulted in a 
change in the respirable mass of the drug product and hence a reduction in dose is 
possible. The blend containing 0.4% MgSt is considered the final formulation and 
intended for progression into Phase III and favours a lower total doses of drug for further 
development.
The dose chosen for this study is 500 g of nemiralisib per day administered via a dry 
powder ELLIPTA inhaler containing 0.4% MgSt for a duration of up to 84 days (-4/+2 
days) and is expected to be equivalent to a dose of either 700 µg nemiralisib blended with 
0.6% MgSt administered via the ELLIPTA DPI or the 1000 g administered via DISKUS 
in terms of the dose deposited and retained within the lungs based on PK parameters 
(AUC and Cmax). The delivered dose and deposition profile to the lungs is a function of 
the device and formulation which is reflected in the observed data (plasma 
pharmacokinetics) for all the formulations. Data and plasma exposures have been 
generated (completed or ongoing studies) in human for these different devices and 
formulations (up to 2000 µg in DISKUS once daily for 14 days in PII116617; 700 µg in 
ELLIPTA DPI (0.6% MgSt formulation) once daily for 10 days in 205759 and 750 µg in 
ELLIPTA DPI (0.4% MgSt formulation) once daily for 3 months in the ongoing 2b study 
200879 in exacerbating COPD patients). A recent healthy volunteer trial using the  
ELLIPTA DPI 0.4% MgSt formulation has been compared (using plasma exposure 
following 500 µg) with the data generated for each device and formulation in terms of the 
observed trough (24 hours post dose) concentrations and these are shown in the following 
table.
Table 1
Observed plasma concentrations on Day 1 at trough (24 hours post 
dose) in healthy volunteers following inhaled Nemiralisib 
administration by device/material  
Study
Device/Material
Population
Dose 
(µg)
Plasma Ctrough (24 hrs post Day 
1 dose) pg/mL
Geometric mean
95% CI
PII116617
DISKUS
HVT
1000*
196
167-230
205759
ELLIPTA DPI 
0.6%MgSt
HVT - Japanese
700
239
180-316
207674^
ELLIPTA DPI 
0.4%MgSt
HVT
500
166
120-228
* Extrapolated from 2000 µg (Ctrough at 24h of 392 pg/mL and 90% confidence interval of 
334-460) dose level since 1000 µg was not a dose level in study PII116617
^ Preliminary data from a completed but unreported trial 207674
The selected 500 ug dose is expected to achieve a similar level of inhibition of PI3Kδ 
within the lungs during the treatment phase of this study on a once a day regimen as the 
700 µg administered via ELLIPTA DPI (0.6% MgSt formulation) or 1000 µg 
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administered via DISKUS. This dose has been selected based on previous safety and 
tolerability data in humans including healthy subjects, healthy smokers and COPD 
patients including exacerbating patients following nemiralisib administration via a 
DISKUS DPI, and healthy subjects via ELLIPTA DPI, as well as pharmacokinetics and 
demonstration of target (PI3K) inhibition by observed changes in biomarkers. This will 
be the first time nemiralisib is dosed to patients who have been identified as having 
APDS, and it is assumed that these patients will have a similar lung deposition, 
distribution and plasma exposure to healthy volunteers and COPD patients.  No 
differences between populations of healthy volunteers and patient groups has been 
observed in inhaled systemic plasma exposure parameters in studies to date.
The nature of the mutation in APDS 1 and 2 patients causes a modification in the 
catalytic and regulatory subunits of PI3Krespectively leading to a lower activation 
threshold of the enzyme and hence a faster rate of PIP2 conversion, higher levels of PIP3, 
and by implication, localised immune-suppression and a predisposition to infection and 
subsequent tissue damage [Angulo, 2013, Elkaim, 2016]. Nemiralisib is a competitive 
antagonist preventing ATP driven PIP2 conversion and is therefore expected to achieve 
similar levels of PI3Kenzyme inhibition in APDS patients to those seen in healthy 
subjects, but lead to an overall greater reduction in PIP3.
The target site of action for inhaled PI3Kδ inhibition is the intracellular compartment of 
immune cells resident in lung tissue and lumen. Nemiralisib has a high potency and 
selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL). The pathophysiology of APDS is 
not fully understood, but is believed to involve a significant neutrophil component as well 
as T/B-cell and leukocyte driven effects. The predicted steady-state intracellular 
concentration of nemiralisib at trough (24h) in the lungs of APDS patients is 
approximately 156 ng/mL (3.3 ng/mL free drug) following 500 g ELLIPTA DPI 0.4% 
MgSt formulation, implying PI3Kinhibition in excess of 80% throughout the dosing 
interval in all cell types of interest. Systemic exposure and tissue concentrations are 
predicted to be extremely low (Cmax of 4.5 ng/mL, 0.09 ng/mL free drug), implying very 
little PI3Kinhibition outside of the lung.
Pharmacodynamic assessments conducted during the trial will monitor target engagement 
and downstream effects to be measured with a view to confirming the PKPD 
relationships in these APDS patients.
Any patient participating in this study prior to approval of the protocol supporting the 
switch to the ELLIPTA DPI (0.4% MgSt) will complete the study with the ELLIPTA 
DPI (0.6% MgSt). Patients enrolled after approval of the ELLIPTA device (0.4% MgSt) 
will start and complete the study with the ELLIPTA DPI (0.4% MgSt).
4.6.
Benefit:Risk Assessment
4.6.1.
Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
nemiralisib can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
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Number 2012N141231_08]. The following section outlines the risk assessment and 
mitigation strategy for this protocol.
GlaxoSmithKline (GSK) has assessed this study for any potential risks that a subject may 
experience. The investigational medicinal product nemiralisib has an acceptable safety
profile for clinical use and there are no significant associated risks. This conclusion is 
supported by the results of previously conducted and currently ongoing clinical studies 
with nemiralisib in healthy subjects, patients with COPD and patients with asthma.
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Table 2
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., nemiralisib]
Paradoxical bronchospasm that may 
be life-threatening
Known effect associated with inhaled 
treatment
Treat immediately with a short-acting inhaled 
bronchodilator. Nemiralisib should be discontinued 
immediately, the subject assessed and, if necessary, 
an alternative therapy instituted as deemed 
appropriate by the investigator or the attending 
physician. Subjects will be withdrawn from the 
study.
Mucosal irritancy
Preclinical toxicology findings
Not observed in clinical studies to date. Carefully 
monitor subjects (AEs, lung function – spirometry).
Post-inhalation cough immediately 
following inhalation of study 
treatment (nemiralisib)
In the Proof-of-Concept (PoC) study 
PII116678, which was conducted in 126 
randomized participants from a 
population similar to this protocol and a 
previous formulation of nemiralisib 
(DISKUS formulation blended with only 
one excipient, lactose), there was a higher 
incidence of treatment-related, mild and 
moderate adverse events of cough 
(Preferred Term) reported immediately 
after dosing in exacerbating subjects in 
the nemiralisib DISKUS 1000 mcg QD 
group (n=22 [35%] compared 
exacerbating subjects in the placebo 
DISKUS group (n=2 [3%]). For the 22 
The ICF will inform participants that in previous 
clinical trials, post-inhalation cough has been 
reported following nemiralisib administration and 
that the post-inhalation cough is considered related 
to nemiralisib. 
In addition, participants will be able to record any 
AE’s (including events of post-inhalation cough) in 
the diary card provided (See Section 7.8).
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
subjects in the nemiralisib 1000 mcg 
group, the events for 20 of the subjects 
were considered by the Investigator to be 
related to study treatment. From the 
review of reported terms, cough often 
occurred immediately after dosing and in 
some subjects it seemed to repeat on most 
of the dosing days.
Cough was reported to be generally mild 
or moderate and resolved after stopping 
dosing. Three subjects (all in the 
nemiralisib DISKUS 1000 mcg QD 
group) discontinued the study due to 
cough. Additional details are provided in 
the Nemiralisib (GSK2269557) 
Investigator’s Brochure.
APDS exacerbation 
An exacerbation of APDS is defined 
as a culture-documented or suspected 
bacterial, viral or fungal infection, 
either organ-specific (local) or 
systemic, which requires antimicrobial 
treatment or leads to a change in 
APDS management. This could 
include emergency room treatment or 
Common risk for this patient population 
is the occurrence of recurrent episodes of 
infections (these may vary in severity and
be bacterial or viral in nature) affecting a 
number of different organs (e.g. ear, 
lung). Some of these infections may be 
systemic. 
Subjects will visit the study clinic frequently 
(week 2, 4, 8 and 12) and will be monitored 
remotely by phone in-between these clinic visits. 
Furthermore subjects will be taking nemiralisib in 
addition to their standard of care and will be 
monitored by qualified investigators for any 
AE/SAE/exacerbation. 
In the event of a suspected exacerbation, the 
subject will undergo an appropriate diagnostic 
and clinical work-up, with treatment including, 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
hospitalization.  
but not limited to, antimicrobial treatment 
instituted as needed by the investigator or 
attending physician. Treatment should take local 
guidelines, especially on local antimicrobial 
resistance, into consideration.   
Hypersensitivity to lactose
Lactose is an excipient in the 
investigational product formulation
Subjects with milk protein allergy or known 
hypersensitivity to lactose or any other ingredient of 
the preparation will be excluded from participating 
in the study.
Unknown risks to an embryo, fetus or 
nursing infant
There are no studies with nemiralisib in 
pregnant or lactating women.
As specified in the protocol: 
Women who are pregnant, lactating or are 
planning on becoming pregnant during the study 
are not eligible to participate. Female subjects 
must be postmenopausal or using a highly 
effective contraception method to avoid 
pregnancy while in this study.
If a female subject becomes pregnant during the 
study, she must let the study doctor know 
immediately. The study medication will be 
stopped.
For women of reproductive potential, a 
pregnancy test will be performed at Screening, on 
Day 1 and Day 28 and at the Follow-up Visit.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Spirometry procedures
Shortness of breath, coughing, light 
headedness or fainting, and/or chest 
tightness
If any of these symptoms occur, spirometry will be 
stopped and the subject will receive medical 
treatment. 
Sputum induction
Bronchoconstriction may occur following 
inhalation of saline
Subjects will receive a bronchodilator prior to 
sputum induction
Sputum induction will be performed and 
monitored by suitably trained medical staff.
The procedure must be stopped immediately and 
the subject treated with a short-acting inhaled 
bronchodilator or other appropriate treatment will 
be administered deemed by the Investigator or the 
attending physician.
Bronchoscopy and BAL
Sore throat, haemoptysis and 
pneumothorax may occur 24-48 hours 
after the procedure
There is also a small risk of transient 
pyrexia that typically occurs within 24-
48-hours of the BAL procedure.    
Bronchoscopy/BAL will be performed by an 
experienced bronchoscopist in accordance with the 
guidelines published by the British Thoracic 
Society, 2013 [Du Rand, 2013] in a dedicated 
endoscopy area.
The use of sedation and local anaesthetics for the 
bronchoscopy will be closely controlled and 
subjects will be pre-medicated with bronchodilator 
and will be continuously monitored throughout the 
procedure. The procedure is therefore considered 
low risk 
In case of an adverse event following the BAL 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
procedure (subjects will be informed of the 
symptoms that may signify infection or 
pneumothorax), subjects will be admitted to the 
unit/hospital for observation at the discretion of the 
investigator (if this occurs before discharge from 
the endoscopy unit) or asked to return in case 
symptoms occur after discharge, and will be 
managed accordingly.     
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4.6.2.
Benefit Assessment
The following are key benefits:

All subjects will undergo a thorough medical assessment during the study. 
Subjects will have frequent study clinic visit and telephone calls for the evaluation 
of their disease symptoms. During these visits, subjects will have spirometry tests, 
ECG, vital signs monitoring, and physical examinations. Monitoring for 
worsening of their disease will also take place.  

Subjects may benefit from the knowledge that they are contributing to the process 
of developing a new treatment in an area of unmet need, even if not directly 
beneficial for them

All subjects will continue (with changes, where needed, to antimicrobial treatment 
that are not strong cytochrome (CYP)3A4 inhibitors) to receive established 
standard of care  
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures to minimise risk to subjects, the potential risks 
associated with nemiralisib and the study procedures, are considered to be minimal and 
justified by the anticipated benefits that may be afforded to patients with APDS who have 
no other treatment options.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
Male and female subjects aged 18 or older at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Patients with a clinical phenotype consistent with APDS, including a history of 
recurrent (frequency greater than would be expected in an immunocompetent 
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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
individual) ear, sinus or pulmonary infections, and who have a known type 1 APDS-
associated genetic PI3Kmutation (e.g. E1021K, N334K, E525K and C416R) or type 
2 APDS-associated mutation 
WEIGHT
3. Body weight 40 kg and body mass index (BMI) 17 kg/m2 (inclusive)
SEX
4. Female subject. A female subject is eligible to participate if she is not pregnant (as 
confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not 
lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as:
o
Pre-menopausal females with one of the following:
–
Documented tubal ligation
–
Documented hysteroscopic tubal occlusion procedure with follow-
up confirmation of bilateral tubal occlusion 
–
Hysterectomy
–
Documented Bilateral Oophorectomy
o
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on 
hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-menopausal 
status prior to study enrolment.

Reproductive potential and agrees to follow one of the options listed in the-
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of-Reproductive Potential (FRP) (see Appendix 5) from 30 days prior to the first-
dose of study medication and until completion of the follow-up telephone call at-
1-2 weeks from last dose.

The investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception.
INFORMED CONSENT
5. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Alanine aminotransferase (ALT) >2xULN and bilirubin >1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%). 
2.
Current or chronic history of liver disease except where hepatomegaly is 
identified by their clinician to be secondary to APDS, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
3.
QTc > 450 millisecond (msec) or QTc > 480 msec in subjects with Bundle Branch 
Block
NOTES: 

The QTc is the QT interval corrected for heart rate (HR) according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and discontinuation 
for an individual subject should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
4.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator, in 
consultation with the Medical Monitor if required, agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with 
the study procedures.
CONCOMITANT MEDICATIONS
5.
CYTOCHROME P450 3A4:
Strong CYP3A4 substrates:
Strong inhibitors of cytochrome P450 3A4: Currently, only limited in vivo 
information is available on the in vivo metabolism of nemiralisib; and, the role of 
cytochrome P450s (CYPs) in the elimination of nemiralisib is based upon in vitro 
data. In vitro studies indicate that nemiralisib is predominantly metabolised by 
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CYP3A4 enzymes with minor contributions from CYP1A1, CYP1A2, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 and CYP2J2. Co-administration of nemiralisib with 
CYP3A4 inhibitors may result in increased systemic exposure to nemiralisib. 
Regular or chronic treatment with medications that are considered strong inhibitors 
of CYP3A4 are not permitted:
•
Antiretrovirals including protease inhibitors (e.g., indinavir, nelfinavir,ritonavir, 
saquinavir, atazanavir)
•
Oral antifungal treatments such as ketoconazole and itraconazole. Short courses 
of up to 14 days are allowed for fluconazole and voriconazole,but chronic 
administrations are not permitted. It is recommended that amphotericin or
posaconazole are used as oral antifungal treatment of choice.
•
Antibiotics such as telithromycin and troleandomycin (macrolide). Short courses 
up to 14 days are allowed for mibefradil (calcium channel blocker), erythromycin 
and clarithromycin (including intravenous clarithromycin) but chronic 
administrations are not permitted. Azithromycin may be used chronically and is 
recommended as the macrolide antibiotic of choice.
•
Anti-epileptic treatments; and anti-tuberculous therapy.
These medications must all have been stopped at least 14 days prior to first dose of 
study treatment.
Sensitive narrow therapeutic index CYP3A4 substrates:                        
Nemiralisib is a time-dependent inhibitor of CYP3A4 and co-administration of 
CYP3A4 substrates with nemiralisib may result in increased systemic exposure to 
the CYP3A4 substrate. Regular or chronic treatment with medications that are 
considered sensitive narrow therapeutic index substrates of CYP3A4 are, therefore, 
not permitted:
•
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine and tacrolimus.
These medications must all have been stopped at least 14 days prior to first dose of 
study treatment.

Intravenous and oral theophylline will be allowed according to the approved 
label/Prescribing Information, since a specific mechanistic model constructed for 
nemiralisib co-administered with theophylline, suggests a negligible effect of 
nemiralisib on theophylline exposure. Monitoring of patients receiving IV 
theophylline will be required in line with normal practice.
•
Use of unstable dosing regimen with i.v. Ig / s.c. Ig in the last 6 months before 
screening. Stable maintenance immunoglobulin regimen, as per local practice, 
such as regular injections with a consistent dosing interval (e.g. monthly) is 
acceptable.
•
Previous use of an mTOR antagonist (e.g. rapamycin, everolimus) or PI3K delta 
inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first 
dosing.
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RELEVANT HABITS
6.
History of regular alcohol consumption within 6 months of the study defined as 
an average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a 
half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of 
spirits.
7.
A positive pre-study drug screen. The detection of drugs (e.g. benzodiazepines, 
opioid analgesia) taken for a legitimate medical purpose would not necessarily be 
an exclusion to study participation and would be at the discretion of the principle 
investigator in discussion with the medical monitor.
CONTRAINDICATIONS 
8.
History of sensitivity to any of the study medications, or components thereof 
(including lactose) or a history of drug or other allergy (including a milk protein 
allergy) that, in the opinion of the investigator or Medical Monitor, 
contraindicates their participation.
9.
History of previous intolerance of the induced sputum procedure.
10. BAL sub study only: History of bronchospasm in response to the 
bronchoscopy/BAL procedure.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody 
test result at screening or within 3 months prior to first dose of study treatment.
12. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 56 days.
13. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dose of study 
medication in the current study: 30 days, 5 half-lives or twice the duration of the 
biological effect of the investigational product (whichever is longer).
14. A positive test for human immunodeficiency virus (HIV) antibody.
15. Exposure to more than 4 investigational medicinal products within 12 months 
prior to the first dose of study medication.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, Protocol Deviations and Serious Adverse Events 
(Section 7.3.1.6).
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Subjects who have failed screening may be re-screened once, at the discretion of the 
Principal Investigator in consultation with the GSK medical monitor.
In the event of a suspected exacerbation (as defined in Table 2), the subject will undergo 
an appropriate diagnostic and clinical work-up, with treatment including, but not limited 
to, antimicrobial treatment instituted as needed by the investigator or attending physician. 
Treatment should take local guidelines, especially on local antimicrobial resistance, into 
consideration. Any such subject will be allowed to be rescreened once following an 
exacerbation, after undergoing appropriate clinical review and when the Principal 
Investigator in consultation with the medical monitor consider the infection to have 
resolved.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the study 
clinic for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”.
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Subjects withdrawn from study treatment will also be withdrawn from the study. Subjects 
who are withdrawn should complete the assessments planned for the early withdrawal
visit within 2 weeks of withdrawal (see Table 6). The subject will also receive a follow-
up telephone call within 1−2 weeks after the last dose of study medication, if the early 
withdrawal visit was conducted during the first week following withdrawal. The reason 
for withdrawal will be recorded in the case report form (CRF)
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
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For subjects with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for 
data analysis.  Safety ECGs and other non-protocol specified ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  

Single QTc values will be used unless an ECG demonstrates a prolonged QTc 
interval. If this occurs, two more ECGs will be taken over a brief period (e.g. 5-
10mins), and then the averaged QTc values of the three ECGs will be used to 
determine whether the subject should be discontinued from the study.
5.4.3.
Other Safety Stopping Criteria
A subject will be withdrawn from the study if they meet any of the following stopping
criteria:

Unacceptable adverse events related to study drug or study procedures.

Clinically significant and relevant changes in laboratory parameters, spirometry or 
ECG recordings as judged by the Investigator, in consultation with the medical 
monitor if necessary

Paradoxical bronchospasm.

Pregnancy (female subjects).

If during the study, a strong inhibitor of CYP3A4 is prescribed, the study drug 
should be stopped for the duration of the treatment with the strong inhibitor and not 
restarted for at least two-weeks after the strong inhibitor has been stopped. In the 
event that the co-prescribed drug cannot be stopped, the study drug should be 
permanently stopped and the patient withdrawn from the study.
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5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit/contact.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Table 3
Study Treatments
Product name:
Nemiralisib ELLIPTA DPI
(500 g)
Formulation description:
Nemiralisib blended with lactose and magnesium stearate in 
ELLIPTA DPI
Dosage form:
Dry powder for inhalation
Unit dose strength:
500 g / blister
Route of Administration
Inhalation
Dosing instructions:
Inhale ONCE in the MORNING as directed
A patient instruction leaflet for the ELLIPTA DPI will be provided to all enrolled subjects.
6.2.
Treatment Assignment
The study is an open-label design. 
All subjects will be assigned nemiralisib 500 g once daily.
A new randomisation will be produced to accommodate the inclusion of a third treatment 
arm into the study. This is to allow for the reporting of the data to be performed on a 
treatment level where appropriate.
6.3.
Planned Dose Adjustments
Due to the small size of the study, no planned study level dose adjustments are allowed. 
Dose adjustment may be permitted at a subject level, however, as outlined in Section 6.4.
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6.4.
Subject Specific Dose Adjustment Criteria
In the event of adverse events, or if unacceptable pharmacological effects, reasonably 
attributable in the opinion of the investigator and/or medical monitor to dosing with 
nemiralisib, treatment will be halted and safety review of the subject will be undertaken. 
6.5.
Blinding
This will be an open-label study and investigators will have direct access to the subject’s 
individual study treatment. 
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).

Damaged or faulty inhalers will be recorded and returned to GSK for further 
investigation. Full details of the process are contained in the study reference 
manual (SRM).

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

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.
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6.8.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered at the study clinic will be recorded in the source documents.  
The subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and the counter reading after completing dose administration will 
be recorded. Compliance will be checked by the site staff at each planned visit.
A record of the number of ELLIPTA DPIs dispensed to each subject and the number of 
actuations administered, read from the dose counter for each ELLIPTA DPI, must be 
maintained and reconciled with study treatment and compliance records.
Treatment start and stop dates, including dates for treatment delays will also be recorded 
in the CRF.
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of nemiralisib > 1000 g within a 24 hour time period ± 2 hours 
will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose the investigator, must:
1.
Contact the Medical Monitor immediately
2.
Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until nemiralisib can no longer be detected systemically 
(at least 14 days for nemiralisib – though this will not be confirmed by direct 
measurement of plasma concentration)
3.
Obtain a plasma sample for pharmacokinetic (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 subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the safety and efficacy of nemiralisib has not yet been defined in APDS 
patients. Treatment after the end of the study will continue as per the standard of care for 
APDS at the site.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition, whether or not GSK is providing specific 
post-study treatment.
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6.11.
Lifestyle and/or Dietary Restrictions
Refrain from consumption of Seville oranges, grapefruit or grapefruit juice and/or 
pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the 
first dose of study medication until after the final dose.
6.11.1.
Caffeine, Alcohol, and Tobacco
Subjects must refrain from alcohol for 24 hours prior to each blood collection for clinical 
laboratory tests.
Subjects must refrain from smoking for at least 2 hours prior to the respiratory tests, 
sputum induction and BAL (optional sub study) conducted at the study clinic.
6.11.2.
Activity
Subjects must abstain from strenuous exercise for 24 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies

Decongestants:  Subjects may take decongestants, but must refrain for 24 hours 
prior to ECG measurements.

Intranasal corticosteroids:  Subjects may take intranasal corticosteroids to 
control symptoms of allergic disorders. 

Topical corticosteroids:  Subjects may use topical corticosteroids for 
dermatological diseases.  

Inhaled corticosteroids: Subjects may take inhaled corticosteroids, if deemed 
appropriate, to manage underlying airway inflammation.

Immunotherapy for allergies:  Immunotherapy for the treatment of allergies is 
allowed, provided it was initiated 4 weeks prior to Screening and subjects remain 
in the maintenance phase for the duration of the study.

Antihistamines:  Short-acting and long-acting antihistamines, as well as 
antihistamine eye drops are allowed to control symptoms of allergic disorders  

Influenza vaccination

Pneumococcal vaccination
All medications for other disorders may be continued throughout the study, provided that, 
in the opinion of the investigator (in consultation with the GSK Medical Monitor), their 
use will not affect the subject’s lung function or safety assessments. 
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6.12.2.
Prohibited Medications and Non-Drug Therapies
Concomitant use of inhibitors of CYP3A4 substrates is not permitted. Acute 
administration (up to 14-day dosing) of some of the 3A4 inhibitors is, however, 
permitted. See Section 6.2 Exclusion Criteria 5 for detail. Where clinically appropriate, 
an alternative drug in the same class (or unrelated class) that is not a strong CYP3A4 
inhibitor can, after signing informed consent, be substituted for the original strong 
inhibitor of these enzymes (Table 4). If during the study, a strong inhibitor of CYP3A4 is 
prescribed, the study drug should be stopped for the duration of the treatment with the 
strong inhibitor and not restarted for at least two-weeks after the strong inhibitor has been 
stopped. In the event that the co-prescribed drug cannot be stopped, the study drug should 
be permanently stopped and the patient withdrawn from the study (see Section 5.4.3).
Use of unstable dosing regimen with i.v. Ig / s.c. Ig in the last 6 months before screening. 
Stable maintenance immunoglobulin regimen, as per local practice, such as regular 
injections with a consistent dosing interval (e.g., monthly) is acceptable.
Previous use of a PI3K delta inhibitor (selective or non-selective PI3K inhibitors) or 
mTOR antagonists within 6 weeks prior to first dosing
Table 4
Inhibitors of CYP3A4 substrates and alternatives
Class of Drug
CYP3A4 Inhibitors
Possible Alternative(s)
Macrolide antibiotics
clarithromycin
azithromycin
troleandomycin
telithromycin
erythromycin
Antifungal
itraconazole
amphotericin
posaconazole
ketoconazole
voriconazole
fluconazole
Anti-retroviral (PI)
indinavir
Tipranavir. 
Other classes e.g. NNRT
lopinavir/ritonavir
nelfinavir
ritonavir
saquinavir
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Class of Drug
CYP3A4 Inhibitors
Possible Alternative(s)
atazanavir
Anti-HCV (PI)
boceprevir
Other classes e.g. Ribavirin, Peginterferon alfa
telaprevir
Non-selective CaChB
mibrefradil
amlodipine
Non-peptide ADH inhibitor conivaptan
Anti-HT2 Antidepressant 
nefazodone
Other classes 
SSRI Anti-depressants
fluoxetine
fluvoxamine
paroxetine 
Other classes 
Class IA Anti-arrythmic 
quinidine
Smoking cessation
buproprion 
NRT 
Immunosuppressant
cyclosporine
rapamycin
tacrolimus
everolimus
Ergot alkaloid
ergotamine
dihydroergotamine
Opioid
fentanyl
alfentanil
Antipsychotic
pimozide
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Tables Section 7.1
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The following points must be noted: 
If assessments are scheduled for the same nominal time, THEN the assessments should
occur in the following order:
1. physical examinations
2. vital signs
3. 12-lead ECG
4. lung function tests (spirometry)
5. blood draws
6. pregnancy test
7. sputum induction

Note: The timing of the assessments must allow the blood draw to occur at the exact 
nominal time.
The timing and number of planned study assessments, including safety, pharmacokinetic, 
pharmacodynamic/biomarker assessments may be altered during the course of the study 
based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 
The change in timing or addition of time points for any planned study assessments must 
be documented in a Note to File which is approved by the relevant GSK study team 
member and then archived in the study sponsor and site study files, but this will not 
constitute a protocol amendment. 
The institutional review board (IRB)/ Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the Informed Consent Form. 
No more than 500 mL of blood will be collected over the duration of the study, including 
any extra assessments that may be required.
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7.1.
Time and Events Table
Table 5
Time and Events Table for Screening and Run-in Period
Procedure
Pre-
Screening
Screening
Clinic visit #1
Notes
(up to 42 days prior to dosing)
At least 7 days prior to dosing 
Informed consent
X
Pre-screening and screening may occur on the same visit, 
if appropriate
Concomitant medication 
review
X
Review of exacerbation 
history
X
Demography
X
X
SAE review 
X
X
X
Inclusion and exclusion 
criteria
X
Full physical exam, including 
height and weight
X
Brief physical examination
X
Medical history (includes 
substance usage and Family 
history of premature CV 
disease)
X
Substances: Drugs, Alcohol, tobacco
Past and current medical 
conditions  (including ear, 
sinus and pulmonary 
infection history, 
cardiovascular medical 
history and therapy history)
X
Vital signs (Blood pressure 
(BP), heart rate (HR), 
temperature and respiratory 
rate)
X
X
Triplicate measurements of BP and HR
12-lead ECG
X
X
Triplicate
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Procedure
Pre-
Screening
Screening
Clinic visit #1
Notes
(up to 42 days prior to dosing)
At least 7 days prior to dosing 
Spirometry (incl. reversibility)
X
Laboratory assessments 
(include hematology, 
biochemistry, Urinalysis) 
X
X
HIV, Hep B and Hep C 
screen
X
Blood pregnancy test (only 
WCBP)
X
PD blood sample: 
Lymphocyte assessments 
(subset counts, soluble 
proinflammatory mediators, 
phosphoprotein biomarkers, 
immunoglobulins.)
X
PD blood sample: PIP2/PIP3
assessments
X
PD blood sample: mRNA 
biomarkers
X
PD blood sample: bacterial 
DNA fragment analysis
X
Sputum induction
X
Should sputum induction fail or be insufficient, the subject 
will be allowed to return within 48 hours for a further 
attempt to obtain an adequate sample
BAL sub-study only: 
Bronchoscopy/BAL
X
Performed on a different day to the sputum induction.
For measurement of PD
BAL sub-study only: 
Additional haematology 
assessments
X
For clotting status (Activated partial thromboplastin time 
(aPTT), Prothrombin time (PT))
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Table 6
Time and Events Table for Treatment Period and Follow-up
Procedure
Treatment Period 
Follow-up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal
(within 
2 wks)
1-2 
wks
and
4-6 
wks
7
Day
-1
1
2
14
2 to 
84
28
56
83
84‡
3 mths
Notes
Visit window
N/A
N/A
N/A
2 
days
3 
days
-4 / +2
days
-4 / +2
days
-4 / +2 
days
-4 / +2
days
±2 
weeks
In-Patient
X
X
X
Out-Patient 
X
X
X
X
X
X
X
Telephone Contact/
Research nurse visit
X 
weekly
X
Except weeks where subjects have a clinic visit
SAFETY ASSESSMENTS
Brief physical exam
X
X
X
X
X
X
X
Pre-dose
AE/SAE review
===================================================
X
X
Concomitant medication review
===================================================
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Pre-dose. Single assessment
12-lead ECG
X
X
X
X
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test 
X
X
X
X
X
only WCBP
Laboratory assessments (include 
haematology, biochemistry, 
Urinalysis) 
X
X
X
X
X
X
X
Pre-dose
STUDY TREATMENT
ELLIPTA inhaler training
X










Review of the Patient Information Leaflet with the 
subject (no device will be used). Additional training 
may be conducted at the discretion of the 
investigator
Study drug administration

========================================


Daily in the morning before breakfast, (with the 
exception of days when the subjects have a 
planned visit to the clinic. On those days, they will 
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Procedure
Treatment Period 
Follow-up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal
(within 
2 wks)
1-2 
wks
and
4-6 
wks
7
Day
-1
1
2
14
2 to 
84
28
56
83
84‡
3 mths
Notes
Visit window
N/A
N/A
N/A
2 
days
3 
days
-4 / +2
days
-4 / +2
days
-4 / +2 
days
-4 / +2
days
±2 
weeks
In-Patient
X
X
X
Out-Patient 
X
X
X
X
X
X
X
Telephone Contact/
Research nurse visit
X 
weekly
X
Except weeks where subjects have a clinic visit
be dosed at the clinic). 
Assessment of study treatment 
compliance
X
X
X
X
X
EFFICACY ASSESSMENTS
Exit interview
X
X
Exit interview may be held at the study clinic or the 
subject’s home, within 7 days of last dose. 
OTHER ASSESSMENTS
Review of APDS exacerbation and 
respiratory tract infection history 
X
X
X
X
X
X
X
Including ear, sinus and pulmonary infections. 
FEV1 Pre-Dose
X
X
X
X
X
For efficacy
FEV1 1hr Post-Dose
X
X
X
For safety 
Blood sample for PK
X
X
X
X
Day 1: Pre-dose, 5 min, 3 h and 24 h post-dose. 
Pre-dose at all other visits. 
PD blood sample: Lymphocyte 
assessments
X
X
X
X
X
Pre-dose. Subset counts, soluble proinflammatory 
mediators, phosphoprotein biomarkers, 
immunoglobulins.
PD blood sample: PIP2/PIP3
assessments
X
X
X
X
X
Pre-dose. 
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Procedure
Treatment Period 
Follow-up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal
(within 
2 wks)
1-2 
wks
and
4-6 
wks
7
Day
-1
1
2
14
2 to 
84
28
56
83
84‡
3 mths
Notes
Visit window
N/A
N/A
N/A
2 
days
3 
days
-4 / +2
days
-4 / +2
days
-4 / +2 
days
-4 / +2
days
±2 
weeks
In-Patient
X
X
X
Out-Patient 
X
X
X
X
X
X
X
Telephone Contact/
Research nurse visit
X 
weekly
X
Except weeks where subjects have a clinic visit
PD blood sample: mRNA biomarkers
X
X
X
X
X
Pre-dose.
PD blood sample: bacterial DNA 
fragment analysis
X
X
X
X
X
Pre-dose.
Sputum induction
X
X
X
X
Pre-dose. Should sputum induction fail or be 
insufficient, the subject will be allowed to return 
within 48 hours for a further attempt to obtain an 
adequate sample
BAL sub-study only: Additional 
haematology assessments
X
For clotting status (Activated partial thromboplastin 
time (aPTT), Prothrombin time (PT))
BAL sub-study only: 
Bronchoscopy/BAL
X
For measurement of PK and PD
BAL sub-study only: 
Blood sample for urea PK 
X
BAL sub-study only: 
Blood sample for plasma PK
X
Genetic Sample
X
Optional assessment – the subject must provide 
additional consent for the genetic sample. Genetic 
sample can be taken at any time after 
randomisation.
‡ Day 84 visit will only occur if a subject has agreed to take part in the BAL sub-study, dosing will continue until the D84 visit.
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
Ear, sinus and pulmonary infection history will be captured over the preceding 2 year 
period, including number, timing, pathogen (if known), and treatment.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the patient’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as AEs/SAEs, vital signs, 
ECG, physical exams, spirometry and laboratory safety tests) may be added during the 
course of the study based on newly available data to ensure appropriate safety 
monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g. protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the three month 
follow-up visit (see Section 7.3.1.3), at the timepoints specified in the Time and 
Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.
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
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4 and Appendix 5
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 4.
7.3.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
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7.3.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An exacerbation of APDS is defined as a culture-documented or suspected bacterial, viral 
or fungal infection, either organ-specific (local) or systemic, which requires antimicrobial 
treatment or leads to a change in APDS management. This could include emergency 
room treatment or hospitalization.  
APDS exacerbations, as defined above (Table 2), will be reported in the corresponding 
eCRF pages. APDS exacerbations are associated with the disease to be studied, so will 
not be recorded as AEs unless they meet the definition of SAE, as defined in Appendix 4.
APDS exacerbations that meet the definition of SAE will be recorded on the appropriate 
SAE form, and will be reported to GSK, as stated in Appendix 4
7.3.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until the 3 month follow-up visit.
Details of pregnancies for female partners of male participants will not be routinely 
collected; however, voluntary reports of such incidents will be captured through the GSK 
standard reporting mechanism.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
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7.3.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Investigators must pay special attention to clinical signs related to previous serious 
illnesses
7.3.4.
Vital Signs
Vital signs will be measured (triplicate at screening) in semi-supine position after 5 
minutes rest and will include temperature, systolic and diastolic blood pressure and pulse 
rate and respiratory rate.
7.3.5.
Electrocardiogram (ECG)
Single 12-lead ECGs (triplicate at screening) will be obtained at each timepoint during 
the study using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. 
Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc readings that may 
be necessary.
7.3.6.
Spirometry
7.3.6.1.
FEV1 (1 hr Post-dose)
FEV1 will be measured using a spirometer at the time indicated in the time and events 
table [Section 7.1]. All sites will use their existing spirometry equipment. 
Subjects should not use their rescue medication for at least 4 hours before each FEV1 
assessment, unless essential for clinical need.
For each observation, at least 3 valid (with no more than 8) efforts will be obtained in 
accordance with the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) standards [Miller, 2005]. Record 3 FEV1 measurements in the CRF
A full description of the timing and conduct of spirometry procedures will be provided in 
the SRM.     
7.3.6.2.
(Screening Only) Bronchodilator Responsiveness Testing (reversibility)
At screening, reversibility in FEV1 will be assessed. Reversibility evaluations must follow 
the recommendations of the ATS/ERS task force [Miller,2005]. 
FEV1 will be measured pre-salbutamol and within 10 to 40 minutes following 400 mcg 
salbutamol MDI – 4 inhalations of 100 mcg (a spacer device may be used if required). 
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Percent reversibility will be calculated as follows:
7.3.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 7, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 7. 
Table 7
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
Red blood 
cells (RBC) 
Indices:
White blood cells (WBC) count 
with Differential:
RBC Count
Mean 
corpuscular 
volume
(MCV)
Neutrophils
Hemoglobin
Mean 
corpuscular 
hemoglobin
(MCH)
Lymphocytes
Hematocrit
Monocytes
Activated partial 
thromboplastin time 
(aPTT)3
Eosinophils
Prothrombin time (PT)3
Basophils
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Laboratory 
Assessments
Parameters
Clinical 
Chemistry 1
Blood urea 
nitrogen
(BUN)/Urea
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non 
fasted)
Calcium
Alkaline phosphatise
Albumin
CRP
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum or urine hCG Pregnancy test (as needed for women of child 
bearing potential) 2
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 
5.4.1 and Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or ethics committee.
3.
BAL sub-study only: Day 1 Clinic Visit #1, and Day 83 -4/+2 days.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology must be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
A 2 mL blood sample for PK analysis of nemiralisib will be collected at the time points 
indicated in Section 7.1 Time and Events. The actual date and time of each blood sample 
collection will be recorded. In addition, the date and time of dosing on the days prior to 
Day 14 and 28 will be recorded. 
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The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring.  
Processing, storage and shipping procedures are provided in the SRM.
7.4.2.
Urea Blood Sample
Collect a 2ml blood sample into Lithium Heparin tubes either at the same time as the Day 
84 trough PK sample if BAL occurs on or before 12 noon or as soon as practically 
possible after the BAL samples if BAL occurs after 12 noon.
Processing, storage and shipping procedures are provided in the SRM.Bronchoalveolar 
Lavage (BAL) Sample Collection
BAL samples for pharmacokinetic analysis of nemiralisib will be collected during the 
bronchoscopy at the time point listed in Section 7.1. Details of BAL sample collection 
can be found in Section 7.6. Processing, storage and shipping procedures are provided in 
the SRM.
7.4.3.
Sample Analysis
Plasma analysis for nemiralisib will be performed under the control of PTS- Drug 
Metabolism and Pharmacokinetics (DMPK)/Scinovo, GlaxoSmithKline. Lung epithelial 
lining fluid (ELF) and BAL cell pellet analysis for nemiralisib will be performed under 
the management of PTS-DMPK, GlaxoSmithKline. Concentrations of nemiralisib will be 
determined using the currently approved bioanalytical methodology. Raw data will be 
archived at the bioanalytical site (detailed in the SRM).
Plasma and lavage analysis for urea quantification will be performed under the 
management of Clinical Pathology, Safety Assessment, GlaxoSmithKline. 
Concentrations of urea will be determined in plasma and lavage samples using the 
currently approved analytical methodology. Raw data will be stored in the good 
laboratory practice (GLP) Archives, GlaxoSmithKline. 
7.5.
Biomarker(s)/Pharmacodynamic Markers
7.5.1.
Pharmacodynamic Biomarkers in Blood
The following blood samples will be collected for PD analysis of nemiralisib at the time 
points indicated in Section 7.1 Time and Events:

5 mL for analysis of cellular PIP3 peak area 

20 mL for lymphocyte assessments (subset counts, soluble proinflammatory 
mediators, phosphoprotein biomarkers, immunoglobulins)

2.5 mL for analysis of messenger ribonucleic acid (mRNA) biomarkers

5 mL for bacterial DNA fragment analysis
The actual date and time of each blood sample collection will be recorded. The timing of 
PD samples may be altered and/or PD samples may be obtained at additional time points 
to ensure thorough PD monitoring.
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Details of PD sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.2.
Pharmacodynamic Biomarkers in Induced Sputum
Hypertonic saline (starting at a concentration of 0.9%) induced sputum samples will be 
collected. The sputum induction process is detailed in the SRM.
Should sputum induction fail or be insufficient, the subject may return within 48 hours 
for a further attempt to obtain an adequate sample.
To maximise the ability to measure multiple PD markers, the sputum samples will be 
assessed for either PIP/PIP3 ratio or cytokines and mRNA transcriptome (detailed in 
Table 8) at different time points before and after administration of nemiralisib. Upon the 
review of data from the first two subjects this approach could be altered to focus on only 
PIP/PIP3 ratio or the range of cytokines and mRNA transcriptome at all time points. 
Additional parameters may be analysed if sufficient induced sputum sample is available 
once samples for the other assessments have been collected.
Further information on collection, processing, storage and shipping procedures are 
provided in the Study Reference Manual. 
Table 8
Proposed Biomarkers for Analysis in Sputum Samples
PIP2/
PIP3
Lymphocyte 
subsets
Phospho-
proteins
Inflammatory 
mediators
mRNA
Clinic visit #1
X
Day -1
X
X
X
X
Day 14
X
Day 83
X
X
X
X
6m Follow-up 
(3m post-dose)*
X
X
X
X
* Assessment of PIP2/PIP3 ratio may replace other measurements at the 6m follow-up 
time-point, based on the assessment of the data at prior time-points. 
7.6.
Bronchoscopy/BAL (BAL sub-study only)

Bronchial alveolar lavage (BAL) will be collected at bronchoscopy at the time 
indicated in the time and events table [Section 7.1].

The bronchoscopy must be conducted by an experienced bronchoscopist in 
accordance with the guidelines published by the British Thoracic Society [Du Rand, 
2013].

The right middle lobe (RML) will be preferentially selected for lavage unless 
historical thoracic CT/chest X-ray (when available) indicate significant underlying 
structural lung disease/abnormality. In cases where the RML is not considered 
appropriate, an alternative lobe will be selected after review and discussion between 
the bronchoscopist, PI and medical monitor. In instances where historical thoracic 
CT/chest X-rays are not available, the RML will be selected.
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
Providing sufficient sample volume is available, samples will be processed and 
analysed for the biomarkers as detailed in Table 9. In the event of insufficient sample 
being available, priority will be given to the measurement of inflammatory mediators 
and lymphocyte subsets.

Further information on collection, processing, storage and shipping procedures are 
provided in the Study Reference Manual (SRM).
Table 9
Proposed Analysis of BAL
Sample fraction
Pharmacokinetics
Pharmacodynamic Markers
PK
Urea
Inflammatory 
mediators
Antibody 
levels
Lymphocyte 
subsets
Proteomics
Epithelial Lining 
Fluid
X
X
X
X
X
Cell pellet
X
X
7.7.
Efficacy
7.7.1.
Number and rate of lower/upper respiratory tract infection
The number and rate of ear, sinus and/or pulmonary infections requiring antimicrobial 
therapy will be monitored and recorded.
7.7.2.
FEV1 (Pre-dose)
FEV1 will be measured using a spirometer at the times indicated in the time and events 
table [Section 7.1]. All sites will use their existing spirometry equipment. 
For each observation, at least 3 valid (with no more than 8) efforts will be obtained, in 
accordance with the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) standards [Miller, 2005]. 
Pre-dose FEV1 measured on Day 14, Day 83 or upon early withdrawal should be within 
1 hour of the time FEV1 was measured on Day 1.
Subjects should not use their rescue medication for at least 4 hours before each FEV1 
assessment, unless essential for clinical need. If a subject uses their rescue medication
within 4 hours of the FEV1 assessment, the subject may be asked to return within 48 h 
for another attempt.
Further details are provided in the SRM
7.7.3.
Patient Exit Interview
An exit interview will be administered to all study participants (within 7 days of final 
visit or early withdrawal). The questions included in the interview will be designed to 
more fully understand the patient’s experience with APDS, the respiratory aspects of the 
disease that are most important to them, the perceived efficacy of the study medication 
and the study itself. Subjects will be asked to consent to the exit interview within the 
context of study consent. 
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A specialist contract research organisation will be commissioned to conduct this part of 
the study. The organisation will develop a protocol for conducting the exit interviews, a 
semi-structured interview guide and data collection sheet and the qualitative analysis 
plan. The contract research organisation (CRO) will conduct the interviews using an 
experienced qualitative interviewer, analyse the data from the interviews and provide a 
final report and supporting documentation. Interviews will be audio recorded for the 
purposes of accurate analysis.
This assessment will be completed by all study participants and may be held at the study 
clinic or the subject’s home. The exit interview will be conducted, transcribed and 
analysed in English as outlined in the Interview Discussion Guide. 
7.8.
Patient Diary
The subjects will be provided with a diary to record the following data when at home: 

Time and date of each dose administration.

Adverse Events and concomitant medications taken.
7.9.
Genetics
Information regarding genetic research is included in Appendix 3.
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated medication 
dictionary, GSKDrug.  
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Sample Size Considerations
The sample size for this study is based on the feasibility of recruitment of this population.
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
Population
Definition / Criteria
Screened
All subjects who were screened
All subject
All subjects who receive at least one dose of the study treatment.
9.3.
Key Elements of Analysis Plan
9.3.1.
Interim Analyses
Formal interim analyses will not be performed. However, safety and pharmacodynamic 
data will be reviewed on an ongoing basis for internal decision making purposes, to 
ensure subject safety and in order to maximise the ability to measure multiple PD 
markers, based on sample availability (as discussed in Section 7.5.2). Further details are 
provided in the RAP.
9.3.2.
Primary Analyses
Safety data will be graphically presented, summarised and listed by, or under the direct 
auspices of, Clinical Statistics, GlaxoSmithKline.
Statistical analyses, when applicable, of safety data will be performed by, or under the 
direct auspices of, Clinical Statistics, GlaxoSmithKline.  
The three formulations of nemiralisib may be presented by treatment arm or pooled 
where appropriate. Full details of all statistical analyses will be pre- specified in the RAP 
prior to unfreezing of the database.
9.3.2.1.
Exploratory Biomarker Analyses
The results of exploratory biomarker investigations (e.g. bacterial DNA fragment 
analysis) may be reported separately from the main clinical study report.  All endpoints 
of interest from all comparisons will be descriptively and/or graphically summarized as 
appropriate to the data.
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.
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9.3.3.
Patient Exit Interview
The qualitative data collected in the patient exit interviews will be analyzed separately by 
outsourcing to a specialist consultant.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
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assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures (SOP).

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
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applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication

Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects,
as appropriate.

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.
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11.
REFERENCES
Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al 
Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and 
airway damage. Science 2013; 342:866–71.
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British 
Thoracic Society guideline for diagnostic flexible bronchoscopy in adults. Thorax 
2013;68:i1–i44
Elkaim E, Neven, B, Bruneau J, et al. Clinical and immunologic phenotype associated 
with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study. J Allergy Clin 
Immunol 2016; 138 (1); 210-228  
GlaxoSmithKline Document Number 2012N141231_08: GSK2269557 Investigator’s 
Brochure. 31-AUG-2015
Gorin MB.Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, et al. 
Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011: 50.  
Table 3-2
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals.  ICH M3 (R2). 2009.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Lear S, Condliffe A. Respiratory infection and primary immune deficiency - what does 
the general physician need to know? J R Coll Physicians Edinb. 2014;44(2):149-55
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-
activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ 
result in T cell senescence and human immunodeficiency. Nat Immunol 2014; 15:88–97.
Miller Perform assessments according to the site’s local operating procedures and 
American Thoracic Society (ATS)/European Respiratory Society/(ERS) standards 2005. 
Okkenhaug K, Ali K and Vanhaesebroeck B. Antigen receptor signalling: A distinctive 
role for the p110δisoform of PI3K. Trends in Immunology, 2007; 28: 80–7
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Olbrich P, Lorenz M, Daball P, et al. Activated PI3K delta syndrome type 2: two 
patients,a novel mutation, and review of the literature, Pediatr Allergy Immunol; 2016, 
27: 640-644   
Sadhu C, Dick K, Tino WT, Staunton DE. Selective role of PI3K delta in neutrophil 
inflammatory responses Biochem Biophys Res Commun. 2003 Sep 5;308(4):764-9.
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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
µg
Microgram
µL
Microliter
AE
Adverse Event
AICD
activation induced cell death
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of Variance
APDS
Activated PI3K Delta Syndrome
AST
Aspartate aminotransferase (SGOT)
ATS
American Thoracic Society
BAL
Bronchial alveolar lavage
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary diseases
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacokinetics Modelling & Simulation
CRF
Case Report Form
CV
Cardiovascular 
CYP
Cytochrome P
DBP
Diastolic blood pressure
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
ELF
Epithelial Lining Fluid
ERS
European Respiratory Society
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
HR
Heart rate
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
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IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IL
Interleukin
IP
Investigational Product
IRB
Institutional Review Board
IU
International Unit
I-V
Intravenous
Kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MgSt
Magnesium Stearate
mL
Milliliter
MMP9
Matrix metallopeptidase 9
mRNA
Messenger ribonucleic acid
MSDS
Material Safety Data Sheet
msec
Milliseconds
OD
Once daily 
PASLI
p110delta-activating mutation causing senescent T Cells, 
lymphadenopathy and immunodeficiency
PD
Pharmacodynamic
PI3K
Phosphoinositide 3-Kinase
PIP2
Phosphatidylinositol 4,5-bisphosphate
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate
PK
Pharmacokinetic
PoC
Proof-of-Concept
PSRI
Periodic Safety Reports for Investigators
QC
Quality control
QD
Once daily
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
SRM
Study Reference Manual
TNF
Tumor necrosis factor
UK
United Kingdom
ULN
Upper limit of normal
US
United States
UV
ultraviolet
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VOC
Volatile Organic Chemical
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
None
ELLIPTA
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12.2.
Appendix 2 - Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(See MONITORING below)

Do not restart/ subject with study treatment 
unless allowed per protocol and GSK Medical 
Governance approval is granted (Appendix 4 )  

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 7 days  after last 
dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
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for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24-72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG 
or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
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12.3.
Appendix 3 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including any treatment regimens under investigation in 
this study or any concomitant medicines;

APDS susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample
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If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
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12.4.
Appendix 4 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
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Events NOT meeting definition of an AE include:
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a. Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  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 disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere 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 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy
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Cardiovascular Events (CV) Definition:

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
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Assessment of Intensity
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
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12.5.
Appendix 5 - Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 
o
Injectable progestogen [Hatcher, 2011]
o
Contraceptive vaginal ring [Hatcher, 2011]
o
Percutaneous contraceptive patches [Hatcher, 2011]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH M3 (R2),
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
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12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue 
study medication.
Male participants with partners who become pregnant
•
Investigator will not routinely attempt to collect pregnancy information on any 
male participant’s female partner(s) who becomes pregnant while the male participant is 
participating in this study; however, voluntary reports of such incidents will be captured 
through the GSK standard reporting mechanism. 
•
If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, 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 - Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study.
Summary of Amendment Changes with Rationale
The protocol has been amended as follows:
1. Minor change to the wording of the exploratory efficacy endpoint has been made. 
2. Reference to randomisation of subjects removed for clarity and accuracy.
3. Mitigation strategy of the APDS exacerbation risk has been updated to ensure 
consistency with the weeks the clinic visits occur on, as described in the protocol
4. Removal of instruction on the need for precautionary measures to protect against 
potential photosensitive effects of GSK2269557 (following new non-clinical data 
supporting the discharge of this risk to humans)
5. Maximum weekly alcohol consumption for males reduced from 21 to 14 units. 
Updated to reflect current UK guideline following the recent change in advice.
6. Additional exclusion criteria added to exclude subjects who provide a positive sample 
in a pre-study drug screen.
7. Immunoglobulins added to the list of PD lymphocyte assessments to provide further 
characteristics pertaining to lung infection in APDS patients. 
8. Time and Events Table for Screening and Run-in Period updated as follows:
–
Immunoglobulins added to the list of PD lymphocyte assessments 
–
Timing of PD sample collection for bacterial DNA fragment analysis added 
and to ensure consistency with body text.
–
Laboratory tests for clotting status added to clinical visit #1 for subjects 
consenting to the BAL sub-study.
9. Time and Events Table for Treatment Period and Follow-up updated as follows:
–
Timing of reviews of APDS exacerbation and respiratory tract infection 
history added to make consistent with body text.
–
Day 2 PK blood sample (which refers to Day 1 24 hr timepoint) removed from 
table for clarity 
–
Immunoglobulins added to the list of PD lymphocyte assessments
–
Timing of PD sample collection for bacterial DNA fragment analysis added to 
ensure consistency with body text.
–
Laboratory tests for clotting status added to Day 83 (-4/+2) for subjects 
consenting to the BAL sub-study.
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10. Removal of ‘severity of infection’ as a measurement taken during the screening and 
critical baseline assessments
11. Clarification of the period during which details of pregnancies in female subjects will 
be collected after the start of dosing 
12. Addition of two haematology laboratory tests for clotting status to be performed at 
clinical visit #1 and Day 83 (-4/+2) for subjects consenting  to the BAL sub-study.
13. Clinical Chemistry section amended to clarify that blood glucose test is a non-fasting 
measurement.
14. Additional text added to clarify which lung lobe will be targeted during the BAL 
procedure.
15. Proposed analyses of BAL updated to indicate that proteomic analysis will be 
performed on the Epithelial Lining Fluid not the cell pellet. 
16. Additional text added to analysis section to clarify the timing of reporting of 
exploratory biomarker data to ensure publication of data pertaining to core primary 
and secondary measures is not delayed.
List of Specific Changes (Bold text depicts new text while strike 
through text depicts deleted text)
Change 1:
The wording of the exploratory efficacy endpoint has been modified:
Page 11. Section 1. PROTOCOL SYNOPSIS FOR STUDY 
The frequency and number and rate of pulmonary and/or ear and sinus infections 
requiring anti-microbial treatment compared to subject’s historical baseline
Page 13. Overall design. Follow up period. 
Subjects will receive telephone calls at 1-2 weeks and 4-6 weeks after their last dose. 
These will be used to ensure there are no safety concerns and to monitor the frequency 
and number and rate of lower/upper respiratory tract infections requiring antimicrobial 
therapy.
Page 16. Section 3. OBJECTIVE(S) AND ENDPOINT(S). Exploratory Efficacy 
Endpoint:
The frequency and number and rate of pulmonary and/or ear and sinus infections 
requiring anti-microbial treatment compared to subject’s historical baseline
Page 18. Section 4.2.Treatment Arms and Duration. Follow up period: 
Subjects will receive telephone calls at 1-2 weeks and 4-6 weeks after their last dose. 
These will be used to ensure there are no safety concerns and to monitor the frequency 
frequency and number and rate of lower/upper respiratory tract infections requiring 
antimicrobial therapy
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Page 54. Section 7.7.1. Frequency of lower/upper respiratory tract infection
7.7.1.  Frequency Number and rate of lower/upper respiratory tract infection
The rate and number and rate of ear, sinus and/or pulmonary infections requiring 
antimicrobial therapy will be monitored and recorded.
Rationale 1
Updated for clarity as frequency and number allude to the same measurement. Rate of 
infection more accurately describes the intended parameter.
CHANGE 2:
Reference to randomisation removed for clarity and accuracy.
Page 11. Section 1. Overall Design
This is a multi-centre, non-randomised, open-label, uncontrolled, single group, study in 
patients with APDS. 
Page 17. Section 4.2. Overall Design
This is be a multi-centre, non-randomised, open-label, uncontrolled single group study in 
patients with APDS. 
Page 34. Section 6.2. Treatment Assignment
The study is a non-randomised, open-label design. 
Page 56. Section 9.2.1. Analysis Populations
Population
Definition / Criteria
Screened
All subjects who were screened
All subject
All randomised subjects who receive at least one dose of the study 
treatment.
Rationale 2
Subjects are randomized to study treatment for statistical purposes so the use of ‘non-
randomised’ is inaccurate. Reference to subjects being ‘randomised’ has also been 
removed in order to remove any potential for confusion with the open-label design.
CHANGE 3:
Text for the mitigation strategy of the APDS exacerbation risk modified:
Page 20. Section 4.6.1. Risk Assessment. Table 1:
Subjects will visit the study clinic frequently (week 2, 6, 4, 8 and 12)
Rationale 3
Updated to be consistent with the weeks the clinic visits occur on, as described in the 
protocol.
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CHANGE 4: 
Removal of text in Risk Assessment that described precautionary measures to be taken by 
participating patients in order to protect against potential photosensitive effects.
Page 22. Section 4.6.1. Risk Assessment. Table 1, Row 3.
Potential 
photosensitivity
In the absorption spectrum for 
GSK2269557 there are peaks at the 
boundary of the ultraviolet (UV) light 
[UVA/UVB] region with a lambda max at 
320 nm (molar extinction coefficient 
43800 L/Mol/cm), with smaller peaks at 
305 nm and 332 nm
Subjects will be advised 
to take UV protection 
measures (see Section 
6.11).
Page 37. Section 6.11. Lifestyle and/or Dietary Restrictions. Paragraph 1
Removal of text that described precautionary measures to be taken by participating 
patients in order to protect against potential photosensitive effects:
Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose of study 
medication. Subjects are to be advised that they should wear protective clothing (e.g. sun 
hat, long sleeves) and use a broad spectrum UVA/UVB sunscreen (SPF ≥ 30) when 
outdoors.
Rationale 4
The availability of data from a completed in-vivo study supporting the removal of 
phototoxicity precautions. 
CHANGE 5: 
Maximum weekly alcohol consumption for males reduced from 21 to 14 units.
Page 27. Section 5.3. Exclusion Criteria. Relevant Habits - Number 8.
History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >21 units for males or >14 units for females >14 units. One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of 
wine or 1 (25 mL) measure of spirits.
Rationale 5
Updated to reflect current UK guideline following the recent change in advice.
CHANGE 6: 
Additional exclusion criteria added to exclude subjects who provide a positive sample in 
a pre-study drug screen.
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Page 29. Section 5.3. Exclusion Criteria. Relevant Habits - Number 9
ADDED TEXT
A positive pre-study drug screen. The detection of drugs (e.g. benzodiazepines, 
opioid analgesia) taken for a legitimate medical purpose would not necessarily be an 
exclusion to study participation and would be at the discretion of the principle 
investigator in discussion with the medical monitor.
Page 50. Section 7.3.7. Clinical Safety Laboratory Assessments. 
Table 6. Other screening tests
ADDED BULLET

Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)
Rationale 6
To remove subjects who are taking substances which may have an adverse interaction 
with the study drug or adversely impair study participation and compliance with study 
procedures. 
CHANGE 7:
Immunoglobulins added to the list of PD lymphocyte assessments.
Page 52. Section 7.5.1. Pharmacodynamic Biomarkers in Blood
15. 20 mL for lymphocyte assessments (subset counts, soluble proinflammatory 
mediators, phosphoprotein biomarkers, immunoglobulins)
Rationale 7
To provide further characteristics pertaining to lung infection in APDS patients. 
CHANGE 8:
Page 41. Section 7.1. Time and events table for Screening and Run-in Period 
updated as follows:
Table 4.  Row 17
Immunoglobulins added to the list of PD lymphocyte assessments. 
PD blood sample: Lymphocyte assessments (subset counts, soluble proinflammatory 
mediators, phosphoprotein biomarkers, immunoglobulins)
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Table 4.  Row 20.
New row added to T&E tables to clarify the timing of PD sample collection for bacterial 
DNA fragment analysis and to make consistent with body text.
Procedure
Pre-
Screening
Screening
Clinic visit #1
Notes
PD blood 
sample: 
bacterial DNA 
fragment 
analysis
X
Table 4. Row 23.
Row added to reflect the additional haematology tests which will be performed at clinic 
visit #1:
Procedure
Pre-
Screening
Screening
Clinic visit #1
Notes
BAL sub-study 
only: Additional 
haematology 
assessments
X
For clotting status (Activated 
partial thromboplastin time (aPTT), 
Prothrombin time (PT))
Rationale 8
To provide clearer and consistent instruction on when procedures should be performed 
during screening and clinic visit #1.
CHANGE 9:
Page 43, Section 7.1. Time and Events for Treatment Period and Follow-up
updated as follows:
Table 5. Row 15.
New row added to T&E tables to clarify the timing of reviews of APDS exacerbation and 
respiratory tract infection history and to make consistent with body text.
Procedure
Treatment Period 
Follow-
up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal 
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83 84‡
3 
mths
Notes
Visit window N/A N/A N/A 2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / +2
days
Review of APDS 
exacerbation and 
respiratory tract 
infection history 
X
X
X
X
X
X
X
Including ear, sinus and 
pulmonary infections. 
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Table 5. Row 17.
Day 2 PK blood sample (which refers to Day 1 24 hr timepoint) removed from table for 
clarity and to avoid a duplicate blood sample being taken in addition to the Day 1, 24 hr 
sample. 
Procedure
Treatment Period 
Follow-
up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal 
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83 84‡
3 
mths
Notes
Visit window N/A N/A N/A 2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / +2
days
Blood sample for PK
X
X
X
X
X
Day 1: Pre-dose, 5 min, 3 h 
and 24 h post-dose. 
Pre-dose at all other visits.
Table 5. Row 19.
Pre-dose. Subset counts, soluble proinflammatory mediators, phosphoprotein biomarkers, 
immunoglobulins.
Table 5.  Row 21.
New row added to T&E tables to clarify the timing of PD sample collection for bacterial 
DNA fragment analysis and to make consistent with body text.
Procedure
Treatment Period 
Follow-
up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal 
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83 84‡
3 
mths
Notes
Visit window N/A N/A N/A 2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / +2
days
PD blood sample: 
bacterial DNA fragment 
analysis
X
X
X
X
X
Pre-dose.
Table 5. Row 24.
Row added to reflect the additional haematology tests which will be performed at Day 83 (-4 
/+2):
Procedure
Treatment Period 
Follow-
up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal 
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83 84‡
3 
mths
Notes
Visit window N/A N/A N/A 2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / +2
days
BAL sub-study only: 
Additional haematology 
assessments
X
For clotting status 
(Activated partial 
thromboplastin time 
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Procedure
Treatment Period 
Follow-
up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal 
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83 84‡
3 
mths
Notes
Visit window N/A N/A N/A 2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / +2
days
(aPTT), Prothrombin time 
(PT))
Rationale 9
To provide clearer and consistent instruction on when procedures should be performed 
during the treatment and follow-up periods
CHANGE 10:
Removal of ‘severity’ of historical infections as a parameter captured during screening.
Page 46. Section 7.2. Screening and Critical Baseline Assessments
Ear, sinus and pulmonary infection history will be captured over the preceding 2 year 
period, including number, timing, pathogen (if known), severity (if known) and 
treatment.
Rationale 10
Information unlikely to be available or will be unreliable due to degree of subjectivity in 
the assessment.
CHANGE 11: 
Clarification of the period during which details of pregnancies in female subjects will be 
collected after the start of dosing
Page 48. Section 7.3.2. Pregnancy
Details of all pregnancies in female subjects and if indicated female partners of male 
subjects will be collected after the start of dosing and until the 3 month follow-up visit 
call.
Rationale 11
To ensure that instances of pregnancies are collected for sufficiently long enough to 
ensure that the chance of a fetus being exposed to the study drug is minimized. 
CHANGE 12: 
Haematology section of Table 6, updated to allow two additional tests (aPTT and PT) to 
assess clotting status in subjects consenting to participate in the BAL sub-study:
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Page 50. Section 7.3.7. Clinical Safety Laboratory Assessments.
Haematology. Table 6.
Haematology
Platelet Count
Red blood 
cells (RBC) 
Indices:
White blood cells (WBC) count 
with Differential:
RBC Count
Mean 
corpuscular 
volume
(MCV)
Neutrophils
Hemoglobin
Mean 
corpuscular 
hemoglobin
(MCH)
Lymphocytes
Hematocrit
Monocytes
Activated partial 
thromboplastin time 
(aPTT)3
Eosinophils
Prothrombin time (PT)3
Basophils
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 
5.4.1 and Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or ethics committee.
3.
BAL sub-study only: Day 1 Clinic Visit #1, and Day 83 -4/+2 days.  
Rationale 12
To ensure patients consenting to participate in the BAL study and undergoing 
bronchoscopy do not have evidence of an underlying coagulopathy that would preclude 
bronchoscopy. This is consistent with clinical best practice. Addition of tests for activated 
partial thromboplastin time (aPTT) and prothrombin time (PT) for patients who consent 
to BAL procedure required to ensure clotting factors are normal ahead of BAL procedure.
CHANGE 13: 
Clinical Chemistry section of Table 6, amended to indicate that blood glucose test is a 
non-fasting measurement
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Page 50. Section 7.3.7. Clinical Safety Laboratory Assessments. 
Clinical Chemistry. Table 6.
Clinical 
Chemistry 1
Blood urea nitrogen
(BUN)/Urea
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose (non-
fasted)
Calcium
Alkaline 
phosphatise
Albumin
CRP
Rationale 13
To clarify that subjects do not need to fast prior to glucose test.
CHANGE 14: 
Additional text added to clarify which lung lobe will be targeted during the BAL 
procedure.
Page 53. Section 7.6. Bronchoscopy/BAL (BAL sub-study only).
ADDED BULLET #3 

The right middle lobe (RML) will be preferentially selected for lavage unless 
historical thoracic CT/chest X-ray (when available) indicate significant 
underlying structural lung disease/abnormality. In cases where the RML is not 
considered appropriate, an alternative lobe will be selected after review and 
discussion between the bronchoscopist, PI and medical monitor. In instances 
where historical thoracic CT/chest X-rays are not available, the RML will be 
selected.
Rationale 14
To provide clearer instruction with regard which lung lobe to target for the BAL to 
ensure the sample is obtained from the most relevant area of the lung.
CHANGE 15: 
Page 54. Section 7.6. Bronchoscopy/BAL (BAL sub-study only).
Table 8. Proposed Analysis of BAL
Proposed analyses of BAL updated to indicate that proteomic analysis will be performed 
on the Epithelial Lining Fluid not the cell pellet, as currently stated. 
Rationale 15
Correction of a previous error.
CHANGE 16: 
Additional text added to analysis section to clarify the timing of reporting of exploratory 
biomarker data.
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Page 56. Section 9.3.2.1. Exploratory Biomarker Analyses
The results of exploratory biomarker investigations (e.g. VOC in breath and 
bacterial DNA fragment analysis) may be reported separately from the main clinical 
study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data.
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.
Rationale 16
To ensure publication of data pertaining to core primary and secondary measures is not 
delayed for exploratory endpoint data.
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AMENDMENT 2
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study.
List of Specific Changes and Rationale (Bold text depicts new text 
while strike through text depicts deleted text)
Change 1:
Replace the administration of GSK2269557 via the DISKUS device (1000 g) by a
comparable dose administered via the ELLIPTA device (700 g)
Throughout the protocol: change “1000 g” to “700 g” and “DISKUS” to 
“ELLIPTA”
Page 21/22, Section 4.5. Dose justification:
The dose chosen for this study is 700 g of GSK2269557 per day administered via a dry 
powder ELLIPTA inhaler for a duration of up to 84 days (-4/+2 days) and is expected 
to be equivalent to a dose of 1000 g administered via DISKUS in terms of the dose 
deposited and retained within the lungs based on PK parameters (AUC and 
Ctrough). This dose has been selected based on previous safety and tolerability data in 
humans (healthy subjects, healthy smokers and COPD patients including exacerbating 
patients following GSK2269557 administration via a DISKUS DPI, and healthy 
subjects via ELLIPTA DPI),  as well as pharmacokinetics and demonstration of target 
(PI3K) inhibition by observed changes in biomarkers. This will be the first time 
GSK2269557 is dosed to patients who have been identified as having APDS, and it is 
assumed that these patients will have a similar lung deposition, distribution and plasma 
exposure to healthy volunteers and COPD patients (who had similar exposure).  Twice 
the proposed dose (2000 g in DISKUS) using the same formulation has previously been 
given once daily to healthy male smokers for 14 days (study PII116617) and to . A total 
daily dose up to 2000 g of GSK2269557 is currently being studied in stable COPD 
patients via a dry powder inhaler for 14 days (study PII115119). A total daily dose of
1000 g is currently being studied in exacerbating COPD patients for 3 months (study 
PII116678 and study 201928) and patients with persistent, uncontrolled asthma for 28 
days (study 201543).  
The target site of action for inhaled PI3Kδ inhibition is the intracellular compartment of 
immune cells resident in lung tissue and lumen. GSK2269557 has a high potency and 
selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL). The pathophysiology of APDS is 
not fully understood, but is believed to involve a significant neutrophil component as well 
as T/B-cell and leukocyte driven effects. The predicted steady-state intracellular 
concentration of GSK2269557 at trough (24h) in the lungs of APDS patients is about 183 
ng/mL (3.8 ng/mL free drug), implying PI3Kinhibition in excess of 80% throughout the 
inter-dosing interval in all cell types of interest. Systemic and tissue concentrations are 
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predicted to be extremely low (Cmax of 1.8 ng/mL, 0.04 ng/mL free drug), implying very 
little PI3Kinhibition (<30%) outside of the lung.
During the development of GSK2269557 as a dry powder for inhalation a switch has 
been made both in terms of device (to ELLIPTA) as well as formulation (addition of 
magnesium stearate as a formulation stabiliser). PK data has been used to calculate 
an equivalent 1000 g dose from DISKUS in the ELLIPTA delivered drug product.  
Plasma PK data obtained from study 201544 with ELLIPTA DPI (part B, 200 g 
OD for 14 days) (study completed but report not yet available) showed about 35% 
increase in systemic exposure compared to the steady state exposure of GSK2269557 
following DISKUS DPI in study PII116617, Under the assumption that the ratio of 
intracellular concentration of GSK2269557 at trough in the lungs of APDS patients 
and plasma concentration stays the same, it is expected that 700 g ELLIPTA  DPI 
will produce similar PI3Kinhibitions in the lungs as that with 1000 g DISKUS
DPI.
Figure 2 shows the single dose day 1 median concentration time data derived from 
study 201544 when healthy volunteers were dosed with 200 g via the 
ELLIPTAdevice together with the data for DISKUS derived from study PII116617 
(extrapolated down from the 500 g data). The 35% difference can clearly be seen 
in particular in the latter time points. The 35% increase in exposure (AUC and 
Ctrough) is reflective of an observed increase in respirable mass as measured by in 
vitro drug product performance (Aerodynamic Particle Size Distribution). In 
addition to the overall increase in respirable mass there is a change in the 
distribution within the respirable mass fraction, with the magnesium stearate 
formulation of the ELLIPTA DPI producing a higher level of very fine particles. 
The approximate 350% increase seen in the Cmax is believed to be reflective of this 
difference in distribution. The very fine particles are predicted to be deposited more 
to the alveolar region and hence absorbed more rapidly therefore contributing to 
the initial Cmax. It is assumed that the increase in Ctrough is reflective of the additional 
drug being deposited in the peripheral compartment (in this case the effect 
compartment of the resident cells of the lung) and it’s therefore this measure which 
has defined the appropriate comparator to compare the two devices to match effect 
compartment exposure response.
The increased Cmax in the ELLIPTA device would result in a median Day 1 
concentration of approx 1.4 ng/mL achieving approximately 3.1 ng/mL at steady-
state (> Day 6) which would still result in a low level of systemic pharmacology at 
peak of approximately 23 or 39% inhibition respectively whilst maintaining 
pharmacology (≥ 80%) in the lungs. However these peak levels are likely to drop off 
rapidly in plasma as can be seen in Figure 2.
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Figure 2 Median Plasma Concentrations Post Single Inhaled Dose in Healthy 
Volunteers Following Dosing via Either DISKUS or ELLIPTA
Page 37, Section 6.1. Investigational Product and Other Study Treatment:
Product name:
GSK2269557 DISKUS ELLIPTA DPI
(500 g)
GSK2269557 ELLIPTA DPI
(100 g)
Formulation 
description:
GSK2269557 blended with lactose 
and magnesium stearate in 
ELLIPTA DPILactose blend 
containing
GSK2269557 in DISKUS DPI
GSK2269557 blended with lactose 
and magnesium stearate in 
ELLIPTA DPI
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength:
500 g / blister
100 g / blister
Route of 
Administration 
Inhalation
Inhalation
Dosing 
instructions:
Inhale as directed
Inhale as directed
Dosing 
instructions:
2 inhalations to be taken every day before breakfast (with the exception of 
days when the subjects have a planned visit to the study clinic. On those days, 
they will be dosed at the clinic). The subject should hold their breath for 10 
seconds before exhaling. Inhalations should be taken approximately 30 
seconds apart
A patient instruction leaflet for the ELLIPTA DPI will be provided to all enrolled 
subjects. Demonstration inhalers will be provided to each site in order for the 
investigator to demonstrate correct use of the DISKUS DPI to subjects. The 
demonstration inhalers will be marked clearly with bright yellow labels.
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Page 37, Section 6.2. Treatment Assignment
A new randomisation will be produced to accommodate the inclusion of a second 
treatment arm into the study. This is to allow for the reporting of the data to be 
performed on a treatment level where appropriate.
Page 37, Section 6.9., Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557 > 2000 1400 g within a 24 hour time period ± 
2 hours will be considered an overdose.
Page 60, Section 9.3.2. Primary Analyses
The two formulations of GSK2269557 may be presented by treatment arm or pooled 
where appropriate. Full details of all statistical analyses will be pre specified in the 
RAP prior to unfreezing of the database.
Rationale 1
To date GSK2269557 has been developed as a lactose-blended powder delivered by oral 
inhalational via the DISKUS device. However, it is planned to commercialize 
GSK2269557 using the ELLIPTA device and to include magnesium stearate as a 
stabiliser. Therefore, the production of GSK2269557 in the DISKUS device will be 
discontinued and all future studies, including the current study, will be 
conducted/completed using the ELLIPTA device. Any patient currently participating in 
or enrolled in the study prior to approval of a protocol supporting the switch to the 
ELLIPTA device will complete the study with the DISKUS device. Patients enrolled 
after approval of the latter, will start and complete the study with the ELLIPTA device. 
The dose selected and approved in the current DISKUS device is 1000 g, with the 
equivalent dose in the ELLIPTA being 700g. 
Change 2:
Include patients with APDS1 with new disease-associated mutations and APDS2 with 
mutations in the PIK3R1 regulatory subunit of class IA phosphoinositide 3 kinases.
Throughout the protocol: Change “Type 1 APDS/PASLI” to “Type 1 or 2 
APDS/PASLI”
Page 10, Section 1. Protocol Synopsis for study 204745 (Rationale) and Page 14, 
Section 2.1. Study Rationale:
GSK2269557 in addition to standard of care, in patients with activated phosphoinositide 
3-kinase delta syndrome 1/p110delta-activating mutation causing senescent T Cells, 
lymphadenopathy and immunodeficiency (APDS1/PASLI-CD) and activated 
phosphoinositide 3-kinase delta syndrome 2/p110delta-activating mutation causing
senescent T Cells, lymphadenopathy and immunodeficiency (APDS2/PASLI-R1).
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Page 14, Section 2.2. Brief Background:
APDS1 (PASLI-CD) is a rare (prevalence estimated to be <1/1,000,000), combined 
primary immune deficiency syndrome caused by a dominant gain-of-function 
heterozygous mutation in p110, the catalytic subunit of phosphoinositide 3-kinase 
(PI3K). A number of Currently there are four described mutations e.g. E1021K, 
N334K, E525K and C416R, with E1021K the most common [Angulo, 2013; Lucas, 
2014] have been described. Clinically, APDS is characterized by recurrent respiratory 
infections with Streptococcus pneumoniae and Haemophilus influenzae, causing 
structural lung damage (small airways disease and bronchiectasis). In addition, some 
patients experience severe infections with Herpes-group viruses, and there is an increased 
risk of B cell malignancy [Lear, 2014]. Typically, disease in APDS patients is difficult to 
manage, with the use of prophylactic antibiotic and antiviral agents, i.v. antibiotics, and 
immunoglobulin replacement being the mainstay of treatment. The limited treatment 
options available to these patients’ means early death from infection-related causes 
remains a prominent feature of the disease [Lear, 2014]. Recently, APDS 2 (PASLI-R1),
a primary immunodeficiency resulting from autosomal dominant gain-of-function
mutations in PI3KR1, the gene coding for the regulatory subunit of class PI3Ks, has 
been described. The clinical, immunological and histopathological features of 
APDS2 are similar to those described in APDS1 patients [Elkaim, 2016, Olbrich, 
2016]. 
Page 29/30, Section 5.1. Inclusion Criteria
2. Patients with a clinical phenotype consistent with APDS, including a history of 
recurrent (frequency greater than would be expected in an immunocompetent 
individual) ear, sinus or pulmonary infections, and who have a known type 1 
APDS-associated genetic PI3Kmutation (e.g. E1021K, N334K, E525K and 
C416R) or type 2 APDS-associated mutation
Rationale 2
Following review of the clinical characteristics, biology and histopathological features of 
APDS type 2 or PASLI-R1, it is clear that this is similar to that in patients with APDS 
type 1 or PASLI-CD and therefore it is anticipated that any effect of GSK2269557 would 
be similar in both disease types. Therefore, it is considered appropriate to include patients 
with APDS type 2 into this study. 
Change 3:
Administrative changes:
Page 2, Summary of Protocol Amendment 01 (item 15)
15. Proposed analyses of BAL updated to indicate that proteomic analysis will be 
performed on the lavage supernatant Epithelial Lining Fluid not the cell pellet
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Page 10, Objectives and Endpoints and page 17, Section 3.0., Objectives and 
Endpoints:
In  BAL cell pellet/ ELF lavage supernatant when available, analysis of:
Lymphocyte cell subsets
Exploratory phospho-protein biomarkers (e.g. pAKT)
Soluble proinflammatory mediators (including IL-8, IL-6, TNFα & MMP9)
Exploratory mRNA biomarkers
Proteomic markers (lavage supernatant only)
Antibody levels
Page 15, Section 2.2., Brief Background

Study 201544 (healthy volunteers): single centre, three part, randomised, study to 
evaluate the safety, tolerability and pharmacokinetics of GSK2269557 
administered via the ELLIPTAdry powder inhaler to healthy subjects (study 
completed but not yet reported).
GSK2269557 was well tolerated across the range of doses tested.
GSK2269557 has been administered to stable COPD patients in study PII115119:

Study PII115119 (stable COPD patients): daily doses of up to 2000 g 
GSK2269557 are being administered via the DISKUS DPI for 14 days. 
There are also four three ongoing studies (not reported), three two in COPD patients and 
one in asthma patients: 

Study PII115119 (stable COPD patients): daily doses of up to 2000 g GSK2269557 
are being administered via the DISKUS DPI for 14 days. 
Page 35, Section 5.4., Withdrawal/Stopping Criteria
Subjects withdrawn from study treatment will also be withdrawn from the study. 
Subjects who are withdrawn should complete the assessments planned for the early 
withdrawal visit within 2 weeks of withdrawal (see Table 5). The subject will also 
receive a follow-up telephone call within 1−2 weeks after the last dose of study 
medication, if the early withdrawal visit was conducted during the first week 
following withdrawal (see Table 5). The reason for withdrawal will be recorded in the 
case report form (CRF)
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Page 45, Section 7.1., Time and Events Table (Table 5)
Procedure
Treatment Period 
Follow-up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal 
(within 
2 wks)
1-2 
wks
and
4-6 
wks
7
Day
-1
1
2
14
2 to 84
28
56
83
84‡
3 mths
Notes
Visit window
N/A
N/A
N/A
2 
days
3 
days
-4 / +2
days
-4 / +2
days
-4 / +2
days
In-Patient
X
X
X
Out-Patient 
X
X
X
X
X
X
X
Telephone Contact/
Research nurse visit
X 
weekly
X
Except weeks where subjects have a clinic visit
SAFETY ASSESSMENTS
Brief physical exam
X
X
X
X
X
X
X
Pre-dose
AE/SAE review
===================================================
X
X
Concomitant medication review
===================================================
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Pre-dose. Single assessment
12-lead ECG
X
X
X
X
X
X
X
X
Pre-dose. Single assessment
Urine pregnancy test 
X
X
X
X
X
only WCBP
Laboratory assessments (include 
haematology, biochemistry, 
Urinalysis) 
X
X
X
X
X
X
X
Pre-dose
STUDY TREATMENT
DISKUS ELLIPTA inhaler 
demonstration and practice training
X










Review of the Patient Information Leaflet with 
the subject (no device will be used). Additional 
training may be conducted at the discretion of 
the investigator
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Rationale 3
Clarifications, corrections of typographical errors and inconsistencies.
AMENDMENT 3
List of Specific Changes and Rationale (Bold text depicts new text while strike 
through text depicts deleted text)
Change 1: 
Replace the administration of nemiralisib in a blend containing 0.6% MgSt, via a dry 
powder ELLIPTA inhaler (700 µg) by a comparable dose nemiralisib in a blend 
containing 0.4% magnesium stearate (MgSt) administered via the ELLIPTA device (500 
µg).
Throughout the protocol: change “700 µg” to “500 µg” of nemiralisib.
Section 4.5.
Dose Justification:
The formulation of Nemiralisib has been changed to the current formulation of 
nemiralisib with lactose monohydrate/0.4% Magnesium Stearate (MgSt) which is 
the proposed final formulation and currently being investigated in the dose ranging 
study. The previous formulation currently used in the study is blended with lactose 
and 0.6% MgSt). The reduction in concentration of MgSt in the new formulation 
has resulted in a change in the respirable mass of the drug product and hence a 
reduction in dose is possible. The blend containing 0.4% MgSt is considered the 
final formulation and intended for progression into Phase III and favours a lower 
total doses of drug for further development.
The dose chosen for this study is 7500 g of GSK2269557nemiralisib per day 
administered via a dry powder ELLIPTA inhaler containing 0.4% MgSt for a duration 
of up to 84 days (-4/+2 days) and is expected to be equivalent to a dose of either 700 µg 
nemiralisib blended with 0.6% MgSt administered via the ELLIPTA DPI or the 
1000 g administered via DISKUS in terms of the dose deposited and retained within the 
lungs based on PK parameters (AUC and Ctroughmax). The delivered dose and deposition 
profile to the lungs is a function of the device and formulation which is reflected in 
the observed data (plasma pharmacokinetics) for all the formulations. Data and 
plasma exposures have been generated (completed or ongoing studies) in human for 
these different devices and formulations (up to 2000 µg in DISKUS once daily for 14 
days in PII116617; 700 µg in ELLIPTA DPI (0.6% MgSt formulation) once daily for 
10 days in 205759 and 750 µg in ELLIPTA DPI (0.4% MgSt formulation) once daily 
for 3 months in the ongoing 2b study 200879 in exacerbating COPD patients). A 
recent healthy volunteer trial using the ELLIPTA DPI 0.4% MgSt formulation has 
been compared (using plasma exposure following 500 µg) with the data generated 
for each device and formulation in terms of the observed trough (24 hours post 
dose) concentrations and these are shown in the following table.
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Table 01: Observed plasma concentrations on Day 1 at trough (24 hours post dose) 
in healthy volunteers following inhaled Nemiralisib administration by 
device/material  
Study
Device/Material
Population
Dose 
(µg)
Plasma Ctrough (24 hrs post Day 
1 dose) pg/mL
Geometric mean
95% CI
PII116617
DISKUS
HVT
1000*
196
167-230
205759
ELLIPTA DPI 
0.6%MgSt
HVT - Japanese
700
239
180-316
207674^
ELLIPTA DPI 
0.4%MgSt
HVT
500
166
120-228
* Extrapolated from 2000 µg (Ctrough at 24h of 392 pg/mL and 90% confidence interval of 
334-460) dose level since 1000 µg was not a dose level in study PII116617
^ Preliminary data from a completed but unreported trial 207674
The selected 500 ug dose is expected to achieve a similar level of inhibition of PI3Kδ 
within the lungs during the treatment phase of this study on a once a day regimen as 
the 700 µg administered via ELLIPTA DPI (0.6% MgSt formulation) or 1000 µg 
administered via DISKUS. This dose has been selected based on previous safety and 
tolerability data in humans including (healthy subjects, healthy smokers and COPD 
patients including exacerbating patients following GSK2269557nemiralisib 
administration via a DISKUS DPI, and healthy subjects via ELLIPTA DPI), as well as 
pharmacokinetics and demonstration of target (PI3K) inhibition by observed changes in 
biomarkers. This will be the first time GSK2269557nemiralisib is dosed to patients who 
have been identified as having APDS, and it is assumed that these patients will have a 
similar lung deposition, distribution and plasma exposure to healthy volunteers and 
COPD patients. (who had similar exposure).  Twice the proposed dose (2000 g in 
DISKUS) using the same formulation has previously been given once daily to No 
differences between populations of healthy male smokers for 14 days (study 
PII116617)volunteers and to stable COPD patients (study PII115119). A total daily dose 
of 1000 g is currently being studied in exacerbating COPD patients for 3 months (study 
PII116678 and study 201928) and patients with persistent, uncontrolled asthma for 28 
days (study 201543).  patient groups has been observed in inhaled systemic plasma 
exposure parameters in studies to date.
The nature of the mutation in APDS 1 and 2 patients causes a modification in the 
catalytic and regulatory subunits of PI3Krespectively leading to a lower activation 
threshold of the enzyme and hence a faster rate of PIP2 conversion, higher levels of PIP3, 
and by implication, localised immune-suppression and a predisposition to infection and 
subsequent tissue damage [Angulo, 2013, Elkaim, 2016]. GSK2269557Nemiralisib is a 
competitive antagonist preventing ATP driven PIP2 conversion and is therefore expected 
to achieve similar levels of PI3Kenzyme inhibition in APDS patients to those seen in 
healthy subjects, but lead to an overall greater reduction in PIP3.
The target site of action for inhaled PI3Kδ inhibition is the intracellular compartment of 
immune cells resident in lung tissue and lumen. GSK2269557Nemiralisib has a high 
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potency and selectivity at the PI3Kenzyme (Ki value 0.1 ng/mL). The pathophysiology 
of APDS is not fully understood, but is believed to involve a significant neutrophil 
component as well as T/B-cell and leukocyte driven effects. The predicted steady-state 
intracellular concentration of GSK2269557nemiralisib at trough (24h) in the lungs of 
APDS patients is aboutapproximately 18356 ng/mL (3.83 ng/mL free drug) following 
10500 g DISKUSELLIPTA DPI 0.4% MgSt formulation, implying PI3Kinhibition 
in excess of 80% throughout the inter-dosing interval in all cell types of interest. 
Systemic exposure and tissue concentrations are predicted to be extremely low (Cmax of 
1.84.5 ng/mL, 0.049 ng/mL free drug), implying very little PI3Kinhibition (<30%)
outside of the lung.
During the development of GSK2269557 as a dry powder for inhalation a switch has 
been made both in terms of device (to ELLIPTA) as well as formulation (addition of 
magnesium stearate as a formulation stabiliser). PK data has been used to calculate an 
equivalent 1000 g dose from DISKUS in the ELLIPTA delivered drug product.  Plasma 
PK data obtained from study 201544 with ELLIPTA DPI (part B, 200 g OD for 14 
days) (study completed but report not yet available) showed about 35% increase in 
systemic exposure compared to the steady state exposure of GSK2269557 following 
DISKUS DPI in study PII116617, Under the assumption that the ratio of intracellular 
concentration of GSK2269557 at trough in the lungs of APDS patients and plasma 
concentration stays the same, it is expected that 700 g ELLIPTA  DPI will produce 
similar PI3Kinhibitions in the lungs as that with 1000 g DISKUS DPI.
Figure 2 shows the single dose day 1 median concentration time data derived from study 
201544 when healthy volunteers were dosed with 200 g via the ELLIPTA device 
together with the data for DISKUS derived from study PII116617 (extrapolated down 
from the 500 g data). The 35% difference can clearly be seen in particular in the latter 
time points. The 35% increase in exposure (AUC and Ctrough) is reflective of an observed 
increase in respirable mass as measured by in vitro drug product performance 
(Aerodynamic Particle Size Distribution). In addition to the overall increase in respirable 
mass there is a change in the distribution within the respirable mass fraction, with the 
magnesium stearate formulation of the ELLIPTA DPI producing a higher level of very 
fine particles. The approximate 350% increase seen in the Cmax is believed to be reflective 
of this difference in distribution. The very fine particles are predicted to be deposited 
more to the alveolar region and hence absorbed more rapidly therefore contributing to the 
initial Cmax. It is assumed that the increase in Ctrough is reflective of the additional drug 
being deposited in the peripheral compartment (in this case the effect compartment of the 
resident cells of the lung) and it’s therefore this measure which has defined the 
appropriate comparator to compare the two devices to match effect compartment 
exposure response.
The increased Cmax in the ELLIPTA device would result in a median Day 1 concentration 
of approx 1.4 ng/mL achieving approximately 3.1 ng/mL at steady-state (> Day 6) which 
would still result in a low level of systemic pharmacology at peak of approximately 23 or 
39% inhibition respectively whilst maintaining pharmacology (≥ 80%) in the lungs. 
However these peak levels are likely to drop off rapidly in plasma as can be seen in 
figure2.
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Figure 2 Median Plasma Concentrations Post Single Inhaled Dose in Healthy 
Volunteers Following Dosing via Either DISKUS or ELLIPTA
Pharmacodynamic assessments conducted during the trial will monitor target engagement 
and downstream effects to be measured with a view to confirming the PKPD 
relationships in these APDS patients.
Any patient participating in this study prior to approval of the protocol supporting 
the switch to the ELLIPTA DPI (0.4% MgSt) will complete the study with the 
ELLIPTA DPI (0.6% MgSt). Patients enrolled after approval of the ELLIPTA 
device (0.4% MgSt) will start and complete the study with the ELLIPTA DPI (0.4% 
MgSt).
Section 6.1.
Investigational Product and Other Study Treatment:
Product name:
GSK2269557Nemiralisib ELLIPTA 
DPI
(500 g)
GSK2269557 ELLIPTA DPI
(100 g)
Formulation 
description:
GSK2269557Nemiralisib blended 
with lactose and magnesium stearate 
in ELLIPTA DPI
GSK2269557 blended with lactose 
and magnesium stearate in ELLIPTA 
DPI
Dosage form:
Dry powder for inhalation
Dry powder for inhalation
Unit dose 
strength:
500 g / blister
100 g / blister
Route of 
Administration
Inhalation
Inhalation
Dosing 
instructions:
Inhale ONCE in the MORNING as 
directed
Inhale as directed
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Section 6.2.
Treatment Assignment
The study is an open-label design. 
All subjects will be assigned GSK2269557nemiralisib 7500 g once daily.
A new randomisation will be produced to accommodate the inclusion of a secondthird
treatment arm into the study. This is to allow for the reporting of the data to be performed 
on a treatment level where appropriate.
Section 6.9.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2269557nemiralisib > 14000 g within a 24 hour time 
period ± 2 hours will be considered an overdose.
Section 7.8.
Patient Diary
The subjects will be provided with a diary to record the following data when at home: 
•
Time and date of each dose administration and number of inhalations.
Section 9.3.2.
Primary Analyses
The twohree formulations of GSK2269557nemiralisib may be presented by treatment 
arm or pooled where appropriate. Full details of all statistical analyses will be pre-
specified in the RAP prior to unfreezing of the database.
Rationale 1:
The formulation of Nemiralisib has been changed to the current formulation of 
nemiralisib with lactose monohydrate/0.4% Magnesium Stearate (MgSt) which is the 
proposed final formulation. Any patient participating in this study prior to approval of the 
protocol supporting the switch to the ELLIPTA DPI (0.4% MgSt) will complete the study 
with the ELLIPTA DPI (0.6% MgSt). Patients enrolled after approval of the ELLIPTA 
device (0.4% MgSt) will start and complete the study with the ELLIPTA DPI (0.4% 
MgSt).
Change 2:
Exploratory Phamacodynamics endpoint Volatile Organic Chemicals (VOCs) analysis in 
breath removed.
Section 1
PROTOCOL SYNOPSIS FOR STUDY 204745 and Section 3
OBJECTIVE(S) AND ENDPOINT(S)
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Exploratory
Pharmacodynamics: 
To understand lung disease biology in 
patients with APDS and to explore the 
pharmacodynamic effects of inhaled 
GSK2269557nemiralisib.
Endpoints may include, but are not limited to:
In blood and sputum, analysis of:
Cellular PIP3 peak area as a proportion 
of (PIP3 peak area + PIP2 peak area)
Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)
Immune cell subsets
Exploratory phospho-protein biomarkers 
(e.g. pAKT)
Exploratory messenger ribonucleic acid
(mRNA) biomarkers
In  BAL cell pellet/ lavage supernatant
when available, analysis of:
Lymphocyte cell subsets
Exploratory phospho-protein biomarkers 
(e.g. pAKT)
Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)
Exploratory mRNA biomarkers
Proteomic markers (lavage supernatant 
only)
Antibody levels
In blood, analysis of:
Bacterial DNA fragments
In breath, analysis of: 
Volatile organic chemicals (VOCs)
Section 7
STUDY ASSESSMENTS AND PROCEDURES
If assessments are scheduled for the same nominal time, THEN the assessments should
occur in the following order:
1. physical examinations
2. vital signs
3. 12-lead ECG
4. lung function tests (spirometry)
5. blood draws
6. pregnancy test
7. volatile organic compounds (VOCs)
8. sputum induction
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
Note: The timing of the assessments must allow the blood draw to occur at the exact 
nominal time.
Section 7.1.
Time and Events Table
Procedure
Pre-
Screeni
ng
Screening
Clinic visit #1
Notes
(up to 42 days prior 
to dosing)
At least 7 days 
prior to dosing 
Breath sample for 
VOC analysis
X
X
Only performed if capabilities exist at 
the study site to take samples of 
breath condensate.
Procedure
Treatment Period 
Follow-up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal
(within 
2 wks)
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83
84‡
3 
mths
Notes
Visit window N/A N/A
N/A
2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / 
+2 
days
-4 / 
+2
days
±2 
weeks
Breath sample for 
VOC analysis
X
X
X
X
X
X
X
Pre-dose. Only 
performed if 
capabilities exist 
at the study site 
to take samples 
of breath 
condensate.
Section 7.6.1.
Volatile organic chemicals (VOCs) in breath
Section 7.6.1. Volatile organic chemicals (VOCs) in breath
If capabilities exist at the study site, samples of breath condensate will be taken for 
assessment of VOCs following treatment with GSK2269557, at the time points indicated
in the Time Events Table [Section 7.1].
Subjects will be asked to refrain from drinking alcohol or applying cosmetics on the day 
of the test. 
Subjects will wear a tight-fitting mask supplied with air and with a sample tube attached, 
and breathe normally until 5 L of exhaled breath are collected through the sample tube. 
For further information on collection, processing, storage and shipping procedures are 
provided in the Study Reference Manual (SRM).
Section 9.3.2.1. 
Exploratory Biomarker Analyses
The results of exploratory biomarker investigations (e.g. VOC in breath and bacterial 
DNA fragment analysis) may be reported separately from the main clinical study report.  
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All endpoints of interest from all comparisons will be descriptively and/or graphically 
summarized as appropriate to the data.
Rational 2:
Exploratory Phamacodynamics endpoint Volatile Organic Chemicals (VOCs) analysis in 
breath removed as capabilities not available at study site.
Change 3:
Risk assessment table updated with post inhalation cough.
Section 4.6.1.
Risk Assessment
Post-inhalation cough 
immediately following 
inhalation of study 
treatment 
(nemiralisib)
In the Proof-of-Concept 
(PoC) study PII116678, 
which was conducted in 
126 randomized 
participants from a 
population similar to 
this protocol and a 
previous formulation of 
nemiralisib (DISKUS 
formulation blended 
with only one excipient, 
lactose), there was a 
higher incidence of 
treatment-related, mild 
and moderate adverse 
events of cough 
(Preferred Term) 
reported immediately 
after dosing in 
exacerbating subjects in 
the nemiralisib DISKUS 
1000 mcg QD group 
(n=22 [35%] compared 
exacerbating subjects in 
the placebo DISKUS 
group (n=2 [3%]). For 
the 22 subjects in the 
nemiralisib 1000 mcg 
group, the events for 20 
of the subjects were 
considered by the 
Investigator to be 
related to study 
treatment. From the 
The ICF will inform 
participants that in previous 
clinical trials, post-inhalation 
cough has been reported 
following nemiralisib 
administration and that the 
post-inhalation cough is 
considered related to 
nemiralisib. 
In addition, participants will be 
able to record any AE’s 
(including events of post-
inhalation cough) in the diary 
card provided (See Section 7.8).
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review of reported 
terms, cough often 
occurred immediately 
after dosing and in some 
subjects it seemed to 
repeat on most of the 
dosing days.
Cough was reported to 
be generally mild or 
moderate and resolved 
after stopping dosing. 
Three subjects (all in the 
nemiralisib DISKUS 
1000 mcg QD group) 
discontinued the study 
due to cough. Additional 
details are provided in 
the Nemiralisib 
(GSK2269557) 
Investigator’s Brochure.
Rational 3:
In previous clinical trials, post-inhalation cough has been reported following nemiralisib 
administration. Post-inhalation cough is considered related to nemiralisib and therefore 
added as a potential risk. 
Change 4:
Change to inclusion criteria 3 the lower limit BMI cut off to 17 kg/m2 and the lower limit 
for weight to 40kg. 
Section 5.1.
Inclusion Criteria
WEIGHT
3. Body weight 450 kg and body mass index (BMI) 187 kg/m2 (inclusive)
Rational 4:
APDS patients have a longstanding chronic condition and so are more likely to fall 
outside the normal range for BMI. Therefore adoption of a slightly lower BMI for this 
patient group is considered appropriate and safe.
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Change 5:
Change to inclusion criteria 4. The requirement for additional contraception for males 
with partners of child bearing potential has been removed. 
Section 4.6.1.
Risk Assessment
Unknown risks to an 
embryo, fetus or 
nursing infant
There are no studies with 
GSK2269557nemiralisib
in pregnant or lactating 
women.
As specified in the protocol: 
Women who are pregnant, 
lactating or are planning on 
becoming pregnant during the 
study are not eligible to 
participate. Female subjects 
must be postmenopausal or 
using a highly effective 
contraception method to avoid 
pregnancy while in this study.
If a female subject becomes 
pregnant during the study, she 
must let the study doctor 
know immediately. The study 
medication will be stopped.
For women of reproductive 
potential, a pregnancy test will 
be performed at Screening, on 
Day 1 and Day 28 and at the 
Follow-up Visit.
Male subjects with female 
partners of reproductive 
potential must use highly 
effective contraception 
methods to avoid pregnancy 
while in this study.
Section 5.1.
Inclusion Criteria
SEX
4. Male subject. Male subjects with female partners of child bearing potential must 
comply with the following contraception requirements from the time of first dose 
of study medication until completion of the follow-up telephone call at 1-2 weeks 
from last dose.
Vasectomy with documentation of azoospermia.  
Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 
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SEX

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g. male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by ICH [ICH M3 (R2),
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Section 7.3.2.
Pregnancy
Details of all pregnancies in female subjects and if indicated female partners of male 
subjects will be collected after the start of dosing and until the 3 months follow-up visit.
Details of pregnancies for female partners of male participants will not be routinely 
collected; however, voluntary reports of such incidents will be captured through the 
GSK standard reporting mechanism.
Section 12.5.2.
Collection of Pregnancy Information
Male participants with partners who become pregnant
•
Investigator will not routinely attempt to collect pregnancy information on 
any male participant’s female partner(s) who becomes pregnant while the male 
participant is participating in this study; however, voluntary reports of such 
incidents will be captured through the GSK standard reporting mechanism. •If 
pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, 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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•
Investigator will attempt to collect pregnancy information on any female partner 
of a male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 
•
After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 2 weeks 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.
Rational 5:
Based on the predicted margins for semen exposure on findings across the reproductive 
toxicology studies range between 29811 and 192452 fold, which are well above the 
threshold for concern, and the absence of genotoxic effects in cellular assays, the 
requirement for additional contraception for males with partners of child bearing 
potential has been removed. Details of pregnancies for female partners of male 
participants will not be routinely collected; however, voluntary reports of such incidents 
will be captured through the GSK standard reporting mechanism.
Change 6:
Change to exclusion criteria 5 concomitant medication. 
Section 4.6.2.
Benefit Assessment

All subjects will continue (with changes, where needed, to antimicrobial treatment 
that are not strong cytochrome (CYP)3A4/CYP2D6 inhibitors) to receive 
established standard of care  
Section 5.2. 
Exclusion Criteria
CONCOMITANT MEDICATIONS
5. Regular or chronic treatment with strong inhibitors of CYP3A4 and/or CYP2D6 
(this includes some anti-epileptic treatments, macrolide antibiotics, oral antifungal 
treatments and anti-tuberculosis therapy (see Section 6.12.2) are prohibited from the 
screening visit until the end of treatment visit. Where clinically appropriate, an 
alternative drug in the same class (or unrelated class) that is not a strong CYP3A4 
and/or CYP2D6 inhibitor can, after signing informed consent, be substituted for the 
original strong inhibitor of these enzymes.CYTOCHROME P450 3A4:          
Strong CYP3A4 substrates:                        
Strong inhibitors of cytochrome P450 3A4: Currently, only limited in vivo 
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information is available on the in vivo metabolism of nemiralisib; and, the role 
of cytochrome P450s (CYPs) in the elimination of nemiralisib is based upon in 
vitro data. In vitro studies indicate that nemiralisib is predominantly 
metabolised by CYP3A4 enzymes with minor contributions from CYP1A1, 
CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2J2. Co-
administration of nemiralisib with CYP3A4 inhibitors may result in increased 
systemic exposure to nemiralisib. Regular or chronic treatment with 
medications that are considered strong inhibitors of CYP3A4 are not permitted:
•
Antiretrovirals including protease inhibitors (e.g., indinavir, 
nelfinavir,ritonavir, saquinavir, atazanavir)
•
Oral antifungal treatments such as ketoconazole and itraconazole. Short 
courses of up to 14 days are allowed for fluconazole and voriconazole, but 
chronic administrations are not permitted. It is recommended that 
amphotericin or posaconazole are used as oral antifungal treatment of choice.
•
Antibiotics such as telithromycin and troleandomycin (macrolide). Short 
courses up to 14 days are allowed for mibefradil (calcium channel blocker), 
erythromycin and clarithromycin (including intravenous clarithromycin) but 
chronic administrations are not permitted. Azithromycin may be used 
chronically and is recommended as the macrolide antibiotic of choice.
•
Anti-epileptic treatments; and anti-tuberculous therapy.
These medications must all have been stopped at least 14 days prior to first dose 
of study treatment.
Sensitive narrow therapeutic index CYP3A4 substrates:                        
Nemiralisib is a time-dependent inhibitor of CYP3A4 and co-administration of 
CYP3A4 substrates with nemiralisib may result in increased systemic exposure 
to the CYP3A4 substrate. Regular or chronic treatment with medications that 
are considered sensitive narrow therapeutic index substrates of CYP3A4 are, 
therefore, not permitted:
•
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine and tacrolimus.
These medications must all have been stopped at least 14 days prior to first dose
of study treatment.
•
Intravenous and oral theophylline will be allowed according to the approved 
label/Prescribing Information, since a specific mechanistic model constructed 
for nemiralisib co-administered with theophylline, suggests a negligible effect of 
nemiralisib on theophylline exposure. Monitoring of patients receiving IV 
theophylline will be required in line with normal practice.
6.       Use of unstable dosing regimen with i.v. Ig / s.c. Ig in the last 6 months before 
screening. Stable maintenance immunoglobulin regimen, as per local practice, such 
as regular injections with a consistent dosing interval (e.g. monthly) is acceptable.
7.       Previous use of an mTOR antagonist (e.g. rapamycin, everolimus) or PI3K delta 
inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first 
dosing.
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Section 5.4.3.
Other Safety Stopping Criteria

If during the study, a strong inhibitor of CYP3A4 and/or CYP2D6 is prescribed, the 
study drug should be stopped for the duration of the treatment with the strong 
inhibitor and not restarted for at least two-weeks after the strong inhibitor has been 
stopped. In the event that the co-prescribed drug cannot be stopped, the study drug 
should be permanently stopped and the patient withdrawn from the study.
Section 6.12.2. 
Prohibited Medications and Non-Drug Therapies
Concomitant use of inhibitors of CYP3A4 substrates is not permitted. Acute 
administration (up to 14-day dosing) of some of the 3A4 inhibitors is, however, 
permitted. See Section 6.2 Exclusion Criteria 5 for detail. Regular or chronic 
treatment with strong inhibitors of CYP3A4 and/or CYP2D6 (this includes some anti-
epileptic treatments, macrolide antibiotics, oral antifungal treatments, and anti-
tuberculosis therapy (Table) are prohibited from the screening visit until the end of 
treatment visit. Where clinically appropriate, an alternative drug in the same class (or 
unrelated class) that is not a strong CYP3A4 and/or CYP2D6 inhibitor can, after signing 
informed consent, be substituted for the original strong inhibitor of these enzymes (Table 
4). If during the study, a strong inhibitor of CYP3A4 and/or CYP2D6 is prescribed, the 
study drug should be stopped for the duration of the treatment with the strong inhibitor 
and not restarted for at least two-weeks after the strong inhibitor has been stopped. In the 
event that the co-prescribed drug cannot be stopped, the study drug should be 
permanently stopped and the patient withdrawn from the study (see Section 5.4.3).
Table 34 Inhibitors of CYP3A4/CYP2D6 substrates and alternatives
Class of Drug
CYP3A4 Inhibitors
Possible Alternative(s)
Macrolide antibiotics
clarithromycin
azithromycin
erythromycin 
troleandomycin
telithromycin
erythromycin
Antifungal
itraconazole
Fluconazole
amphotericin
posaconazole
ketoconazole
posaconazole
voriconazole
fluconazole
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Anti-retroviral (PI)
indinavir
Tipranavir. 
Other classes e.g. NNRT
lopinavir/ritonavir
nelfinavir
ritonavir
saquinavir
atazanavir
Anti-HCV (PI)
boceprevir
Other classes e.g. Ribavirin, Peginterferon alfa
telaprevir
Non-selective CaChB
mibrefradil*
amlodipine
Non-peptide ADH inhibitor conivaptan
Anti-HT2 Antidepressant 
nefazodone*
Other classes 
*withdrawn 
Class of Drug
CYP2D6
Alternatives
SSRI Anti-depressants
fluoxetine
fluvoxamine
paroxetine 
Other classes 
Class IA Anti-arrythmic 
quinidine
Smoking cessation
buproprion 
NRT 
Immunosuppressant
cyclosporine
rapamycin
tacrolimus
everolimus
Ergot alkaloid
ergotamine
dihydroergotamine
Opioid
fentanyl
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alfentanil
Antipsychotic
pimozide
Rational 6:
Adjusted in line with latest drug interaction data. Information about interaction with 
inhibitors of CYP3A4 substrates has been added for consistency since this has also been 
implemented for the most recent studies.
Change 7:
Dose reduction removed.
Section 6.4.
Subject Specific Dose Adjustment Criteria
In the event of adverse events, or if unacceptable pharmacological effects, reasonably 
attributable in the opinion of the investigator and/or medical monitor to dosing with 
GSK2269557nemiralisib, treatment will be halted and safety review of the subject will 
be undertaken. Following relevant reporting and discussion with the GSK Medical 
Monitor and relevant GSK personnel, consideration may be given to reducing the dose of 
GSK2269557 to 500 g O.D.
Section 6.8. 
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered at the study clinic will be recorded in the source documents.  
The subjects will be asked to complete a diary when dose administration takes place at 
home. The date, time and number of inhalations (the counter reading after completing 
dose administration) will be recorded. Compliance will be checked by the site staff at 
each planned visit.
A record of the number of ELLIPTA DPIs dispensed to each subject and the number of 
actuations administered, read from the dose counter for each ELLIPTA DPI, must be 
maintained and reconciled with study treatment and compliance records.
Treatment start and stop dates, including dates for treatment delays and / or dose 
reductions will also be recorded in the CRF.
Rational 7:
Dose reduction removed as dose strength is 500µg / blister, therefore dose reduction will 
no longer be an option.
Change 8:
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Time and Event schedule visit window added to Follow Up Visit.
Section 7.1.
Time and Events Table
Procedure
Treatment Period 
Follow-up 
Period
Clinic Visit
2
3
4
5
6
Early 
with-
drawal
(within 
2 wks)
1-2 
wks
and
4-6 
wks
7
Day -1
1
2
14
2 to 
84
28
56
83
84‡
3 
mths
Notes
Visit window N/A
N/A
N/A
2 
days
3 
days
-4 / 
+2
days
-4 / 
+2
days
-4 / 
+2 
days
-4 / 
+2
days
±2 
weeks
Rational 8:
To provide clearer instruction with regard to time windows
Change 9:
Administrative changes, including change from the compound number GSK2269557 to 
the INN nemiralisib, corrections, relevant updates, including reporting time frame of 
pregnancy information and clarifications also made.
Throughout the protocol: change “GSK2269557 µg” to “nemiralisib”.
Medical Monitor/Sponsor Information Page updated
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
 
 
GSK, Stockley
Park West 1-3
Ironbridge 
Road,
Middlesex, 
UB11
1BT, UKGSK, 
Gunnels Wood 
Road, 
Stevenage, 
Hertfordshire, 
SG1 2NY, UK
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Secondary 
Medical 
Monitor
 
 
GSK, Stockley
Park West 1-3
Ironbridge 
Road,
Middlesex, 
UB11
1BT, UK
Section 2.2. 
Brief Background

Study 201544 (healthy volunteers): single centre, three part, randomised, study to 
evaluate the safety, tolerability and pharmacokinetics of GSK2269557nemiralisib 
administered via the ELLIPTA™dry powder inhaler to healthy subjects (study 
completed but not yet reported)(0.6% MgSt formulation) – single doses up to 200 
µg, and daily doses of 200 µg for 10 days.

Study 205759 (healthy Japanese volunteers): single and repeat doses of 
nemiralisib administered via the ELLIPTA™ DPI (0.6% MgSt formulation) –
single doses up to 700 µg, and daily doses up to 700 µg for 10 days.

Study 207674 (healthy volunteers): single dose of nemiralisib 750 µg or a single 
dose of 500 µg administered via the ELLIPTA™ DPI (0.4% MgSt formulation) 
(study completed but not yet reported).

Study 206764 (healthy volunteers):  An open-label study in healthy male subjects, 
to determine the excretion balance and pharmacokinetics of [14C]-GSK2269557, 
administered as a single intravenous micro-tracer (concomitant with an inhaled 
non-radiolabelled dose) and a single oral dose (study completed but not yet 
reported).

Study 206874 (healthy volunteers): one sequence cross over study (nemiralisib 
100 µg (via the ELLIPTA™ DPI (0.4% MgSt formulation) alone followed by 
nemiralisib 100 µg co-administered with itraconazole). A study to evaluate the 
effect of itraconazole on the PK of nemiralisib (study completed but not yet 
reported)
GSK2269557Nemiralisib was well tolerated across the range of doses tested.
GSK2269557Nemiralisib has been administered to stableCOPD patients in the 
following studyiesPII115119:

Study PII115119 (stable COPD patients): daily doses of up to 2000 g 
GSK2269557nemiralisib are being administered via the DISKUS™DPI for 14 days. 

Study PII116678 (patients experiencing a COPD exacerbation): daily doses of 
1000 µg nemiralisib administered via the DISKUS™ DPI for 12 weeks.
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Nemiralisib has been administered to patients with persistent, uncontrolled asthma:
•
Study 201543 (patients with persistent, uncontrolled asthma): daily doses of 
1000 µg nemiralisib are being administered via the DISKUS™ DPI for 28 days
There are also threewo ongoing studies (not reported), two in COPD patientsand one in 
asthma patients: 

Study PII116678 (patients experiencing a COPD exacerbation): daily doses of 1000 
g GSK2269557 are being administered via the DISKUS DPI for 12 weeks.

Study 201928 (patients experiencing a COPD exacerbation): daily doses of 1000700 
g GSK2269557nemiralisib are being administered via the DISKUSELLIPTA™
DPI (0.6% MgSt formulation) for 12 weeks.

Study 201543 (patients with persistent, uncontrolled asthma): daily doses of 1000 g 
GSK2269557 are being administered via the DISKUS DPI for 28 days

Study 200879 (patients experiencing an acute COPD exacerbation): daily doses up 
to 750µg nemiralisib administered via the ELLIPTA™ DPI (0.4% MgSt 
formulation) for 84 days in a dose ranging study
Section 1
PROTOCOL SYNOPSIS FOR STUDY 204745 and Section 4.1.
Overall Design
This is a multisingle-centre, open-label, uncontrolled, single group, study in patients with 
APDS 1 and 2. 
Eligible subjects will be enrolled in the study and receive GSK2269557nemiralisib
7500 g once daily for 843 days (-4/+2 days).
Section 1
PROTOCOL SYNOPSIS FOR STUDY 204745 and Section 4.2.
Treatment Arms and Duration
•
Subjects will then dose at home for the remainder of the treatment period 
(with the exception of clinic visit days, when they will dose in the study clinic). 
On Day 14 ± 2, Day 28 (-4/+2 days), Day 56 (-4/+2 days), Day 83 (-4/+2 days)  
and Day 84 (-4/+2 days) (optional sub-study patients only), subjects will return 
to the study clinic on an outpatient basis, in order to complete the assessments 
described in the Time & Event table (Section 7.1).
Section 4.4. 
Design Justification
Treatment period

12 weeks is the maximum dosing period possible with the 
pre-clinical safety data available. 

Safety: The safety aim of this study is to assess any 
frequent, safety events which deviate from prior safety data. 
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The 12-week treatment period builds on significant prior 
data collected in healthy volunteers, and COPD and asthma
patients where GSK2269557nemiralisib has been well 
tolerated up to 12 weeks treatment.  No drug-related serious 
adverse event(s) (SAEs) have been observed to date. The 
most common AEs to date are post-inhalation cough and 
headache. 

PK: GSK2269557Nemiralisib reaches steady state after 5-7 
days repeat dosing. Assessing plasma PK at day 14 & 83 
will enable the assessment of a sustained level of 
GSK2269557nemiralisib exposure in this patient cohort. 

PD: Changes in a range of PD markers have been measured 
during studies in patients with COPD, following 2 weeks 
dosing with GSK2269557nemiralisib.
Section 7.1.
Time and Events Table
    ‡ Day 84 visit will only occur if a subject has agreed to take part in the BAL sub-study, 
dosing will continue until the D84 visit.
Section 7.7.3. 
Patient Exit Interview
This assessment will be completed by all study participants and may be held at allthe 
study clinics or the subject’s home. The exit interview will be conducted, transcribed 
and analysed in English as outlined in the Interview Discussion Guide. 
Section 12.5.2.
Collection of Pregnancy Information
•
Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks24 hours of learning of a subject's pregnancy.
Rational 9:
Administrative changes, relevant updates and clarifications.
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SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204745 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for 204745: An open-label, 
single arm study to investigate the safety, pharmacokinetics 
and pharmacodynamics of repeat doses of inhaled 
GSK2269557 in patients with APDS/PASLI 
Compound Number  : GSK2269557 
Effective Date  
: Refer to Document Date 
 
Description: 
• The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204745. 
• This RAP is intended to describe the final analyses required for the study.  
• This version of the RAP includes amendments to the originally approved Critical 
Components of the RAP. 
• This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s): 
Author 
 
Principal Statistician (Clinical Statistics) 
 
Associate Statistician (Clinical Statistics) 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204745 
 
2 
 
RAP Team Reviews: 
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer 
Date 
 
15-DEC-2020 
Global Clinical Development Manager (Respiratory Global 
Clinical Sciences and Discovery) 
 
19-NOV-2020 
Early Discovery Lead  
(Respiratory Early Discovery Leaders) 
 
28-NOV-2020 
Sr Director Clinical Pharmacology (Respiratory Clinical 
Pharmacology Modelling and Simulation) 
 
17-DEC-2020 
Discovery Medicine Physician Director (Discovery Medicine) 
 
26-NOV-2020 
Programming Leader 
(Respiratory, Clinical Programming) 
Clinical Statistics and Clinical Programming Line Approvals: 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Veeva Clinical Vault eSignature) 
Approver 
 
Statistics Director  
(Respiratory, Clinical Statistics) 
 
Programming Director 
(Respiratory, Clinical Programming) 
 
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CONFIDENTIAL 
 
 
 
 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 7 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Hypotheses / Statistical Analyses ................................................. 9 
3. 
PLANNED ANALYSES .......................................................................................... 10 
3.1. 
Interim Analyses ......................................................................................... 10 
3.2. 
Final Analyses ............................................................................................ 10 
4. 
ANALYSIS POPULATIONS ................................................................................... 10 
4.1. 
Protocol Deviations ..................................................................................... 10 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 12 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 12 
5.2. 
Baseline Definitions .................................................................................... 13 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 14 
6. 
STUDY POPULATION ANALYSES ....................................................................... 15 
6.1. 
Overview of Planned Study Population Analyses ........................................ 15 
7. 
SAFETY ANALYSES ............................................................................................. 16 
7.1. 
Adverse Events Analyses ........................................................................... 16 
7.2. 
Clinical Laboratory Analyses ....................................................................... 16 
7.3. 
Other Safety Analyses ................................................................................ 16 
8. 
PHARMACOKINETIC ANALYSES ......................................................................... 17 
8.1. 
Secondary Pharmacokinetic Analyses ........................................................ 17 
8.1.1. 
Endpoint / Variables ..................................................................... 17 
8.1.1.1. 
Drug Concentration Measures .................................... 17 
8.1.1.2. 
Derived Pharmacokinetic Parameters......................... 17 
8.1.2. 
Summary Measure ...................................................................... 17 
8.1.3. 
Population of Interest ................................................................... 17 
8.1.4. 
Strategy for Intercurrent Events ................................................... 17 
8.1.5. 
Statistical Analyses / Methods ..................................................... 17 
8.2. 
Exploratory Pharmacokinetic Analyses ....................................................... 18 
8.2.1. 
Endpoint / Variables ..................................................................... 18 
8.2.1.1. 
Drug Concentration Measures .................................... 18 
8.2.1.2. 
Derived Pharmacokinetic Parameters......................... 18 
8.2.2. 
Summary Measure ...................................................................... 18 
8.2.3. 
Population of Interest ................................................................... 18 
8.2.4. 
Strategy for Intercurrent Events ................................................... 18 
8.2.5. 
Statistical Analyses / Methods ..................................................... 19 
9. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 20 
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9.1. 
Exploratory Pharmacodynamic and Biomarker Analyses ............................ 20 
9.1.1. 
Endpoint / Variables ..................................................................... 20 
9.1.2. 
Summary Measure ...................................................................... 20 
9.1.3. 
Population of Interest ................................................................... 20 
9.1.4. 
Strategy for Intercurrent Events ................................................... 20 
9.1.5. 
Statistical Analyses / Methods ..................................................... 20 
9.1.5.1. 
Statistical Methodology Specification .......................... 21 
10. EFFICACY ANALYSES .......................................................................................... 22 
10.1. 
Exploratory Efficacy Analyses ..................................................................... 22 
10.1.1. 
Endpoint / Variables ..................................................................... 22 
10.1.2. 
Summary Measure ...................................................................... 22 
10.1.3. 
Strategy for Intercurrent Events ................................................... 22 
10.1.4. 
Statistical Analyses / Methods ..................................................... 22 
11. REFERENCES ....................................................................................................... 23 
12. APPENDICES ........................................................................................................ 24 
12.1. 
Appendix 1: Protocol Deviation Management ............................................. 24 
12.2. 
Appendix 2: Schedule of Activities .............................................................. 25 
12.3. 
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 30 
12.3.1. 
Study Phases .............................................................................. 30 
12.3.1.1. Study Phases for Concomitant Medication ................. 30 
12.3.2. 
Treatment States for Adverse Events .......................................... 30 
12.3.3. 
Treatment Emergent Flag for Adverse Events ............................. 31 
12.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 32 
12.4.1. 
Reporting Process ....................................................................... 32 
12.4.2. 
Reporting Standards .................................................................... 32 
12.4.3. 
Reporting Standards for Pharmacokinetic .................................... 33 
12.5. 
Appendix 5: Derived and Transformed Data ............................................... 34 
12.5.1. 
General ........................................................................................ 34 
12.5.2. 
Study Population .......................................................................... 34 
12.5.3. 
Safety .......................................................................................... 35 
12.5.4. 
Pharmacokinetic .......................................................................... 35 
12.5.5. 
Pharmacodynamic and Biomarker ............................................... 37 
12.5.6. 
Efficacy ........................................................................................ 38 
12.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 39 
12.6.1. 
Premature Withdrawals ................................................................ 39 
12.6.2. 
Handling of Missing Data ............................................................. 39 
12.6.2.1. Handling of Missing and Partial Dates ........................ 40 
12.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 42 
12.7.1. 
Laboratory Values ........................................................................ 42 
12.7.2. 
ECG ............................................................................................. 43 
12.7.3. 
Vital Signs .................................................................................... 43 
12.8. 
Appendix 8: Data Output Framework .......................................................... 44 
12.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 45 
12.9.1. 
Abbreviations ............................................................................... 45 
12.9.2. 
Trademarks ................................................................................. 46 
12.10. Appendix 10: List of Data Displays.............................................................. 47 
12.10.1. Data Display Numbering .............................................................. 47 
12.10.2. Mock Example Shell Referencing ................................................ 47 
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12.10.3. Deliverables ................................................................................. 47 
12.10.4. Study Population Tables .............................................................. 48 
12.10.5. Efficacy Tables ............................................................................ 49 
12.10.6. Safety Tables ............................................................................... 50 
12.10.7. Pharmacokinetics Table ............................................................... 51 
12.10.8. Pharmacodynamic and Biomarker Tables .................................... 52 
12.10.9. Pharmacodynamic and Biomarker Figures .................................. 53 
12.10.10. ICH Listings ................................................................................. 54 
12.10.11. Non-ICH Listings .......................................................................... 57 
12.11. Appendix 11: Example Mock shells for Data Displays ................................. 58 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Revision Chronology: 
2015N238311_00 23-OCT-
2015 
Original 
2015N238311_01 25-FEB-2016 Amendment No. 1 [Update to include modification requested by 
MHRA to extend the duration of contraception after end of study} 
2015N238311_02 02-
NOV_2016 
Amendment No. 2 [To change IMP device from Diskus to Ellipta] 
2015N238311_03 15-JUN-2017 Amendment No. 3 [New formulation GSK2269557 will be 
administered via the ELLIPTA™ dry powder inhaler (DPI) 
formulated in a blend containing 0.4% MgSt (magnesium stearate). 
The previous formulation contained 0.6% MgSt.] 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were Changes from the originally planned statistical analysis specified in the 
protocol are outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for 
Changes 
The exploratory endpoints specified in 
Protocol amendment 3 were: 
 
Endpoints may include, but are not 
limited to: 
In blood and sputum, analysis of: 
• Cellular PIP3 peak area as a 
proportion of (PIP3 peak area + 
PIP2 peak area) 
• Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & 
MMP9) 
• Immune cell subsets 
• Exploratory phospho-protein 
biomarkers (e.g. pAKT) 
• Exploratory messenger ribonucleic 
acid (mRNA) biomarkers 
 
In BAL cell pellet/lavage supernatant 
when available, analysis of: 
• Lymphocyte cell subsets 
The exploratory endpoints specified in 
this RAP are: 
 
Endpoints may include, but are not 
limited to: 
In blood and sputum, analysis of: 
• Cellular PIP3 peak area as a 
proportion of (PIP3 peak area + PIP2 
peak area) 
• Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & MMP9)  
• Immune cell subsets (In Sputum 
only) 
• Lymphocyte cell subsets 
• Exploratory phospho-protein 
biomarkers (e.g. pAKT) 
• Antibody levels 
 
In BAL cell pellet/lavage supernatant 
when available, analysis of:  
• Lymphocyte cell subsets 
Exploratory mRNA 
biomarkers (in 
blood, sputum, BAL 
cell pellet/lavage 
supernatant); 
proteomic markers 
(in lavage 
supernatant) and 
bacterial DNA 
fragments (in 
blood) analysis 
were not 
conducted. As a 
result, they have 
been removed from 
the RAP. 
 
 
 
 
 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for 
Changes 
• Exploratory phospho-protein 
biomarkers (e.g. pAKT) 
•  Soluble proinflammatory mediators 
(including IL-8, IL-6, TNFα & 
MMP9) 
• Exploratory mRNA biomarkers 
• Proteomic markers (lavage 
supernatant only) 
• Antibody levels 
 
In blood, analysis of: 
• Bacterial DNA fragments  
• Exploratory phospho-protein 
biomarkers (e.g. pAKT) 
• Immune cell subsets 
• Soluble proinflammatory mediators 
(IL-8, IL-6, TNFα & MMP9) 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
Safety 
• To assess the safety and tolerability of 84 
days repeat dosing of inhaled nemiralisib in 
patients with APDS 
• Adverse Events (AE) 
• Vital signs 
• 12-lead electrocardiogram (ECG) 
• Clinical laboratory parameters 
• Spirometry (forced expiratory volume in 1 second 
(FEV1)1 hr post-dose) 
Secondary Objectives 
Secondary Endpoints 
Pharmacokinetics 
• To define the plasma pharmacokinetics (PK) 
of inhaled nemiralisib following repeat dosing 
in patients with APDS. 
• Nemiralisib trough plasma concentration following 
single and repeated treatment. 
Exploratory Objectives 
Exploratory Endpoints 
Pharmacodynamics: 
• To understand lung disease biology in 
patients with APDS and to explore the 
pharmacodynamic effects of inhaled 
nemiralisib. 
Endpoints may include, but are not limited to: 
In blood and sputum, analysis of: 
• Cellular PIP3 peak area as a proportion of (PIP3 
peak area + PIP2 peak area)  
• Soluble proinflammatory mediators (IL-8, IL-6, 
TNFα & MMP9)  
• Immune cell subsets (In Sputum Only) 
• Lymphocyte cell subsets 
• Exploratory phospho-protein biomarkers (e.g. 
pAKT) 
• Antibody Levels 
 
In BAL cell pellet/lavage supernatant when 
available, analysis of: 
• Lymphocyte cell subsets 
• Exploratory phospho-protein biomarkers (e.g. 
pAKT) 
• Immune cell subsets 
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Objectives 
Endpoints 
• Soluble proinflammatory mediators (including IL-8, 
IL-6, TNFα & MMP9) 
Pharmacokinetics: 
• To define the lung trough concentration 
of nemiralisib after repeat dosing 
• Trough nemiralisib concentration in lung epithelial 
lining fluid (ELF) and Bronchoalveolar lavage 
(BAL) cell pellet at Day 84 visit. 
Efficacy: 
• To assess the efficacy of inhaled 
• nemiralisib administered once daily for 84 
days in patients with APDS. 
• The number and rate of pulmonary and/or ear and 
sinus infections requiring anti-microbial treatment 
compared to subject’s historical baseline. 
• Change from baseline (Day 1) in trough FEV1 at 
Day 14 and Day 83 (prebronchodilator) 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• This is a single-center, open-label, uncontrolled, single group, study designed 
to provide initial information on the mechanism of disease including airway 
biology in rare APDS patient population, and to identify any initial safety and 
tolerability issues following 12-weeks dosing with 500 µg nemiralisib. 
• Eligible subjects will be enrolled in the study and receive nemiralisib 500 µg 
once daily for 83 days (-4/+2 days). 
• Nemiralisib will be administered via the ELLIPTA™ Dry Powder Inhaler (DPI). 
In an optional sub-study, subjects will undergo bronchoalveolar lavage (BAL) 
to investigate lymphocyte biology in the lungs after dosing with nemiralisib for 
84 days (-4/+2 days). 
Time & 
Events 
• Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• This is an open-label single group study; all subjects will receive Nemiralisib 
once daily for up to 83 days (-4/+2 days). 
• Note: due to the protocol amendments subjects may have been assigned to 
Nemiralisib 1000 µg via the Diskus device, Nemiralisib 700 µg via the Ellipta 
device or Nemiralisib 500 µg via the Ellipta device depending on the protocol 
amendment they were enrolled on. These treatments are intended to be 
comparable. 
Interim 
Analysis 
• No interim analysis will be performed in this study. However, safety and 
pharmacodynamic data will be reviewed on an ongoing basis for internal 
decision-making purposes, to ensure subject safety and in order to maximize 
the ability to measure multiple PD markers, based on sample availability 
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
No formal statistical hypotheses will be tested. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
Formal interim analyses will not be performed. However, safety, pharmacokinetic and 
pharmacodynamic data will be reviewed on an ongoing basis for internal decision-
making purposes, to ensure subject safety and to maximise the ability to measure multiple 
PD markers based on sample availability. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• All participants who were screened for eligibility  
• This population will be based on the treatment the 
subject received. 
o If participants receive no treatment, then they will 
be summarised according to “No Treatment” 
• Study Population 
All Subjects 
• All subjects who receive at least one dose of the study 
treatment.  
• This population will be based on the treatment the 
subject received.  
• Study Population 
• Safety 
• Efficacy 
• PD/Biomarker 
Pharmacokinetic 
(PK) 
• All participants in the ‘All Subjects’ population who had 
at least 1 non-missing PK assessment (Non-quantifiable 
[NQ] values will be considered as non-missing values).  
• This population will be based on the treatment the 
subject received. 
Note: PK samples that may be affected by protocol 
deviations will be reviewed by the study team to determine 
whether or not the sample will be excluded. 
• PK 
Refer to Appendix 10: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
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Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan Version2.0 [19/Feb/2019]. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A listing of all inclusion/exclusion criteria deviations will be provided. This will be based 
on data as recorded on the inclusion/exclusion page of the eCRF. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
A 
GSK2269557 1000 mcg 
NEMI 1000mcg Diskus 
1 
B 
GSK2269557 700 mcg 
NEMI 700mcg Ellipta 
2 
C 
Nemiralisib 500 mcg 
NEMI 500mcg Ellipta 
3 
This will be derived as subjects in RandALL 
codes A/B/C 
All NEMI 
4 
This will be derived as subjects who did not 
receive any treatment 
No Treatment 
5 
 
Note: 
• Due to the protocol amendments subjects may have been assigned to Nemiralisib 
1000 µg via the Diskus device, Nemiralisib 700 µg via the Ellipta device or 
Nemiralisib 500 µg via the Ellipta device depending on the protocol amendment 
they were enrolled on. These treatments were intended to be comparable hence 
the “All NEMI” Treatment group will be created. 
• Pharmacodynamic and Biomarker, Efficacy and study population (except 
exposure summary) domain summaries will be presented for “All NEMI” 
Treatment group only.   
•  “NEMI 1000mcg Diskus” / “NEMI 700mcg Ellipta”/ “NEMI 500mcg Ellipta” 
treatment groups will be presented in PK domain and all listings. 
• “NEMI 1000mcg Diskus” / “NEMI 700mcg Ellipta”/ “NEMI 500mcg Ellipta” 
and “All NEMI” treatment groups will be presented in Safety Domain summaries 
and Exposure Summary Tables. 
 
 
 
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5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. 
Parameter 
Study Assessments Considered as 
Baseline 
Baseline Used in 
Data Display 
Screening 
Clinic 
Visit 1 
Day -1 
Day 1  
(Pre-
Dose) 
Efficacy 
FEV11 
X 
 
 
X 
Day 1 (Pre dose) 
Ear, sinus and pulmonary infection 
history 
X 
 
 
 
Screening 
Safety 
Vital signs 
X 
X 
X 
X 
Day 1 (Pre dose) 
12-lead ECG 
X 
X 
X 
X 
Day 1 (Pre dose) 
Spirometry 
X 
 
 
X 
Day 1(Pre dose) 
Laboratory assessments 
X 
X 
X 
 
Day -1 
Pharmacodynamic and Biomarkers 
PD blood sample2 
 
X 
X 
 
Day -1 
BAL sub-study only: 
Bronchoscopy/BAL 
 
X 
 
 
Clinic Visit 1 
(At least 7 days 
prior to dosing) 
BAL sub-study only:  
Additional haematology 
Assessments3 
 
X 
 
 
Clinic Visit 1 
(At least 7 days 
prior to dosing) 
1 – prebronchodilator 
2 - PD blood sample to include, but not limited to Lymphocyte assessments, PIP2/PIP3 assessments, 
soluble proinflammatory mediators 
3 - For clotting status (Activated partial thromboplastin time (aPTT), Prothrombin time (PT)) 
 
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5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
12.3 
Appendix 3: Study Phases and Treatment Emergent Adverse Events 
12.4 
Appendix 4: Data Display Standards & Handling Conventions 
12.5 
Appendix 5: Derived and Transformed Data 
12.6 
Appendix 6: Reporting Standards for Missing Data 
12.7 
Appendix 7: Values of Potential Clinical Importance 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
Study population analyses, including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance, will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 10: List of Data Displays. 
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7. 
SAFETY ANALYSES 
The safety analyses will be based on the “All Subjects” population, unless otherwise 
specified. 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays. 
7.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 10: List of Data Displays. 
7.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays. 
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8. 
PHARMACOKINETIC ANALYSES 
8.1. 
Secondary Pharmacokinetic Analyses 
8.1.1. 
Endpoint / Variables 
• Nemiralisib plasma concentration  
8.1.1.1. 
Drug Concentration Measures  
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 12.4.3 
Reporting Standards for Pharmacokinetic) 
8.1.1.2. 
Derived Pharmacokinetic Parameters 
No pharmacokinetic parameters will be calculated. concentration measured 24 hours 
post-dose/pre-dose are assumed to be trough concentrations. 
8.1.2. 
Summary Measure 
The geometric mean of Nemiralisib plasma concentration following single (Day 1: Pre-
dose, 5 min, 3 h and 24 h post-dose) and repeated treatment (Day 14 Pre-dose, Day 83 
Pre-dose and Early withdrawal) will be summarised for the treatment groups: “NEMI 
1000mcg Diskus”, “NEMI 700mcg Ellipta” and “NEMI 500mcg Ellipta”. Flag will be  
derived to see whether values range fall within the 2-fold range to check data decision 
framework as detailed in Section 12.8  
8.1.3. 
Population of Interest  
The plasma pharmacokinetic summaries will be based on the “Pharmacokinetic” 
population. 
8.1.4. 
Strategy for Intercurrent Events 
Intercurrent events have been considered e.g. discontinuation of treatment and treatment 
switching. Due to the exploratory nature of this study and small sample size we accept 
these intercurrent events may have an impact on the endpoints which we are unable to 
quantify. Therefore, a treatment policy approach will be adopted hence the actual values 
of the endpoint, regardless of whether the intercurrent event has occurred, will be 
analysed. 
8.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics and listed. 
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8.2. 
Exploratory Pharmacokinetic Analyses 
8.2.1. 
Endpoint / Variables 
Nemiralisib concentration in lung epithelial lining fluid (ELF) and Bronchoalveolar 
lavage (BAL) cell pellet at Day 84 visit. 
 
8.2.1.1. 
Drug Concentration Measures  
Lung epithelial lining fluid (ELF) and BAL cell pellet analysis for nemiralisib will be 
performed under the management of PTS-DMPK, GlaxoSmithKline. Concentrations of 
nemiralisib will be determined using the currently approved bioanalytical methodology. 
8.2.1.2. 
Derived Pharmacokinetic Parameters 
No lung pharmacokinetic parameters will be calculated; concentration measured 24 hours 
post-dose/pre-dose are assumed to be trough concentrations. 
8.2.2. 
Summary Measure 
The geometric mean of Nemiralisib concentration in the lung epithelial lining fluid (ELF) 
and Bronchoalveolar lavage (BAL) cell pellet at Day 84 visit will be summarised for the 
treatment groups: “NEMI 1000mcg Diskus”, “NEMI 700mcg Ellipta” and “NEMI 
500mcg Ellipta”.  
 
• BAL fluid and plasma urea data, along with the derived Dilution Factor (see Section 
12.5.4 for derivation ) for each wash, will be listed. See Section 12.6.2 for the 
handling of BLQ values when calculating the Dilution Factor 
• BAL fluid concentrations of GSK2269557 and derived ELF concentrations of 
GSK2269557 (corrected for by Dilution Factor) for each wash will be listed. In 
addition, volumes of ELF and the amount of GSK2269557 in the BAL fluid sample 
will be included in the listing, in order to derive the pooled ELF concentration of 
GSK2269557 (across all the washes). All applicable derivations are detailed in 
Section 12.5.4 
 
8.2.3. 
Population of Interest  
The lung pharmacokinetic summaries will be based on the “Pharmacokinetic” population. 
8.2.4. 
Strategy for Intercurrent Events 
Intercurrent events have been considered e.g. discontinuation of treatment, treatment 
switching and death. Due to the exploratory nature of this study and small sample size we 
accept these intercurrent events may have an impact on the endpoints which we are 
unable to quantify. Therefore, a treatment policy approach will be adopted hence the 
actual values of the endpoint regardless of whether the intercurrent event has occurred 
will be analysed. 
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8.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics and listed. 
 
 
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9. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES 
9.1. 
Exploratory Pharmacodynamic and Biomarker Analyses 
9.1.1. 
Endpoint / Variables 
Endpoints may include, but are not limited to: 
In blood and sputum, analysis of: 
• Cellular PIP3 peak area as a proportion of (PIP3 peak area + PIP2 peak area)  
• Soluble proinflammatory mediators (IL-8, IL-6, TNFα & MMP9)  
• Immune cell subsets (In Sputum Only) 
• Lymphocyte cell subsets 
• Exploratory phospho-protein biomarkers (e.g. pAKT) 
• Antibody Levels 
 
In BAL cell pellet/lavage supernatant when available, analysis of: 
• Lymphocyte cell subsets 
• Exploratory phospho-protein biomarkers (e.g. pAKT) 
• Immune cell subsets 
• Soluble proinflammatory mediators (including IL-8, IL-6, TNFα & MMP9) 
9.1.2. 
Summary Measure 
Absolute and Change from Baseline/Ratio to Baseline will summarised using descriptive 
statistics for each timepoint as defined in Section 9.1.1 
9.1.3. 
Population of Interest  
The pharmacodynamics analyses will be based on the “All Subjects” population, unless 
otherwise specified. 
9.1.4. 
Strategy for Intercurrent Events 
Several intercurrent events have been considered e.g. infections, use of rescue 
medication, discontinuation of treatment, treatment switching and death. Due to the 
exploratory nature of this study and small sample size we accept these intercurrent events 
may have an impact on the endpoints which we are unable to quantify. Therefore, a 
treatment policy approach will be adopted hence the actual values of the endpoint 
regardless of whether the intercurrent event has occurred will be analysed. 
9.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
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9.1.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
Loge-transformed PIP3 Area Proportion 
Model Specification 
• will be analyzed using mixed models repeated measures (MMRM) models for Blood Sample 
Type. 
• Terms fitted in the model will include: 
o Fixed Effect: Processing Type, Visit 
o Random Effect: Subject 
o Repeated: Visit 
Note: Per the analysis population all subjects will be within the “All NEMI” treatment group 
and as such treatment arm need not be included as a fixed effect in the model  
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.  
• In the event that this model fails to converge, the estimates will not be reported. 
• Point estimates for the adjusted means on the loge scale, the mean ratio between processing 
Type and associated 95% confidence interval will be constructed using the residual variance 
for the following combination of interest: 
o Unstimulated+DMSO / Stimulated+DMSO 
o Unstimulated+DMSO / Unstimulated+NEMI  
o Stimulated+DMSO / Stimulated+NEMI 
Model Checking & Diagnostics 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable. 
Model Results Presentation 
• The point estimate and confidence interval obtained from MMRM analysis will be 
exponentially back-transformed to obtain Adjusted (least square) geometric means for each 
processing type  
• The adjusted mean ratio and associated 95% confidence interval for the following processing 
type combinations: 
o Unstimulated+DMSO / Stimulated+DMSO 
o Unstimulated+DMSO / Unstimulated+NEMI  
o Stimulated+DMSO / Stimulated+NEMI 
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10. 
EFFICACY ANALYSES 
10.1. 
Exploratory Efficacy Analyses 
10.1.1. 
Endpoint / Variables 
• Pulmonary and/or ear and sinus infections requiring anti-microbial treatment, refer to 
Section 12.5.6. for how these will be programmatically identified. 
• FEV1 
 
10.1.2. 
Summary Measure 
The number and rate (per 84 days) of pulmonary and/or ear and sinus infections requiring 
anti- microbial treatment will be calculated for each subject. 
Mean change from baseline FEV1 at Day 14:pre-dose, Day 83:pre-dose, early withdrawal 
and 3 month follow up will be summarised for the “All NEMI” treatment group. 
10.1.3. 
Strategy for Intercurrent Events 
Several intercurrent events have been considered e.g. infections, use of rescue 
medication, discontinuation of treatment, treatment switching and death. Due to the 
exploratory nature of this study and small sample size we accept these intercurrent events 
may have an impact on the endpoints which we are unable to quantify. Therefore, a 
treatment policy approach will be adopted hence the actual values of the endpoint 
regardless of whether the intercurrent event has occurred will be analysed. 
10.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be listed. 
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11. 
REFERENCES 
GlaxoSmithKline Document Number 2012N141231_10. Nemiralisib (GSK2269557) 
Investigator's Brochure: 03-AUG-2018 
GlaxoSmithKline Document Number 2015N238311_03. An open-label, single arm study 
to investigate the safety, pharmacokinetics and pharmacodynamics of repeat doses of 
inhaled nemiralisib in patients with APDS/PASLI 30-MAY-2017 
 
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12. 
APPENDICES 
12.1. 
Appendix 1: Protocol Deviation Management  
Instream and final analysis population reviews as per SOP 130050 will be conducted. 
Please Refer to Section 4.1 for handling and Reporting of Protocol Deviations. 
 
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12.2. 
Appendix 2: Schedule of Activities 
Time and Events Table for Screening and Run-in Period 
 
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Time and Events Table for Treatment Period and Follow-up 
 
 
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‡ Day 84 visit will only occur if a subject has agreed to take part in the BAL sub-study, dosing will continue until the D84 visit.
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12.3. 
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events 
12.3.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date. 
Study Phase 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Study Treatment Stop Date  
Post-Treatment 
Date > Study Treatment Stop Date  
NOTES:  
• Time of study treatment dosing and start/stop time of assessments and events should be considered, if 
collected. 
 
12.3.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
12.3.2. 
Treatment States for Adverse Events 
Flag 
Definition 
Pre-Treatment 
• If AE onset date is before the treatment start date. 
• 
AE Start Date < Study Treatment Start Date 
Treatment 
Emergent  
(On-Treatment) 
• If AE onset date is on or after treatment start date & on or before treatment stop 
date. 
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date. 
Post-Treatment 
• If AE onset date is after the treatment stop date. 
• 
AE Start Date > Study Treatment Stop Date 
NOTES:  
• If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
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12.3.3. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• If AE onset date is on or after treatment start date & on or before treatment stop 
date.  
• Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date 
NOTES:  
• If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
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12.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
12.4.1. 
Reporting Process 
Software 
• The currently supported versions of SAS software (version 9.4) will be used. 
Reporting Area 
HARP Server 
: UK1SALX00175.corpnet2.com 
HARP Compound 
: ARPROD/GSK2269557/mid204745 
Analysis Datasets  
• Analysis datasets will be created according to Legacy GSK A&R dataset standards and Integrated 
Data Standards Library 
Generation of RTF Files 
• RTF files will be generated for all tables 
12.4.2. 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
• Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
• A project wide decision was made to present GSK2269557 as Nemiralisib (abbreviated to NEMI) 
refer to Section 5.1 for further details.  
Formats 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting 
of data based on the raw data collected, unless otherwise stated. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
• Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the subject’s listings.  
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses. 
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Unscheduled Visits 
• Unscheduled visits will not be included in summary tables and/or figures 
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
12.4.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
Note: Use the separate NEMI DISKUS and NEMI ELLIPTA treatment groups 
 
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12.5. 
Appendix 5: Derived and Transformed Data 
12.5.1. 
General 
Multiple Measurements at One Analysis Time Point 
Where multiple measurements are recorded for a particular time point, all available data will be listed. 
The mean of the measurements will be calculated and used in the derivation of summary statistics; 
except in the following cases: 
• FEV1 data: in the calculation of summary statistics, the maximum of triplicate readings will be 
used. 
• Biomarker data: in the calculation of summary statistics/for statistical analyses, assuming the data 
appears log normally distributed, the geometric mean of the two replicates will be used. 
 
If there are two values within a protocol scheduled visit the value closest to the target day for that window 
will be used. If values are the same distance from the target, then the mean will be taken. 
 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of related 
summary tables. This will also be applicable to relevant Potential Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from First Dose Date: 
• Ref Date = Missing              → Study Day = Missing  
• Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
12.5.2. 
Study Population 
Demographics 
Age 
• GSK standard IDSL algorithms will be used for calculating age at Screening where birth date will be 
imputed as follows: 
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Birth date will be presented in listings as ‘YYYY’. 
• Refer to IDSL standards for age range categories. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)^2] 
Extent of Exposure 
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• Participants who were assigned a treatment but did not report a treatment start date will be 
categorised as having zero days of exposure.  
• The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Counter Readings x Container Dose) 
• If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
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12.5.3. 
Safety 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to add 
or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Decimal Places =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Decimal Place   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Decimal Places = ‘< x’ becomes x – 1     
 
ECG Parameters 
RR Interval 
• IF RR interval (msec) is not provided directly, then RR can be derived as: 
[1] If QTcB is machine read & QTcF is not provided, then: 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
• If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected value then 
do not derive. 
Corrected QT Intervals 
• When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fridericia’s (QTcF) 
formulas will be calculated, in msec, depending on the availability of other measurements. 
• IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:  
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
 
12.5.4. 
Pharmacokinetic 
ELF Drug Concentrations 
Urea concentration data in plasma and BAL will be used to calculate the dilution effect of the lavage 
which is used to extract the epithelial lining fluid (ELF) from the lung compartment. A correction for 
dilution will be applied to all BAL analytes to derive corrected concentrations i.e. each BAL analyte will be 
adjusted to account for the magnitude of dilution during the BAL procedure using urea plasma 
concentration as a reference point. A correction for dilution will be applied to all BAL fluid drug 
concentrations for each wash as follows: 
 
𝐸𝐿𝐹 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝑝𝑔/𝑚𝑙) 
= 𝐵𝐴𝐿 𝐷𝑟𝑢𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝑝𝑔/𝑚𝑙) ∗𝐷𝑖𝑙𝑢𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟  
 
 
Where 
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𝐷𝑖𝑙𝑢𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟= 𝑈𝑟𝑒𝑎 𝑃𝑙𝑎𝑠𝑚𝑎 𝑝𝑟𝑒−𝑏𝑟𝑜𝑛𝑐ℎ
𝑈𝑟𝑒𝑎 𝐵𝐴𝐿  
 
Additionally, for each wash, the Volume of ELF in BAL fluid and the Total Drug in BAL fluid will be 
calculated as follows: 
𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐸𝐿𝐹 𝑖𝑛 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 (𝑚𝐿) = 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
𝐷𝑖𝑙𝑢𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟
 
 
𝐷𝑟𝑢𝑔 𝑖𝑛 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 (𝑝𝑔) = 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 𝐷𝑟𝑢𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝑝𝑔
𝑚𝐿) ∗ 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿) 
 
 
Data will then be pooled across all three washes as follows: 
𝑇𝑜𝑡𝑎𝑙 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐸𝐿𝐹 𝑖𝑛 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 (𝑚𝐿)
= 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐸𝐿𝐹 𝑖𝑛 𝐵𝐴𝐿𝑤𝑎𝑠ℎ1 + 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐸𝐿𝐹 𝑖𝑛 𝐵𝐴𝐿𝑤𝑎𝑠ℎ2
+ 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐸𝐿𝐹 𝑖𝑛 𝐵𝐴𝐿𝑤𝑎𝑠ℎ3 
 
𝑇𝑜𝑡𝑎𝑙 𝐷𝑟𝑢𝑔 𝑖𝑛 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 (𝑝𝑔) = 𝐷𝑟𝑢𝑔 𝑖𝑛 𝐵𝐴𝐿𝑤𝑎𝑠ℎ1 + 𝐷𝑟𝑢𝑔 𝑖𝑛 𝐵𝐴𝐿𝑤𝑎𝑠ℎ2 + 𝐷𝑟𝑢𝑔 𝑖𝑛 𝐵𝐴𝐿𝑤𝑎𝑠ℎ3 
 
𝑃𝑜𝑜𝑙𝑒𝑑 𝐸𝐿𝐹 𝐷𝑟𝑢𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝑝𝑔
𝑚𝐿) =
𝑇𝑜𝑡𝑎𝑙 𝐷𝑟𝑢𝑔 𝑖𝑛 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑 (𝑝𝑔)
𝑇𝑜𝑡𝑎𝑙𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐸𝐿𝐹 𝑖𝑛 𝐵𝐴𝐿 𝐹𝑙𝑢𝑖𝑑(𝑚𝐿) 
 
BAL Cell Pellet Drug Concentration 
Cell pellet samples are diluted in a 1:5 ratio. Concentrations will be corrected for the dilution 
before the ratio is calculated on an individual subject level between the raw  lavage result for 
wash 2 and the cell pellet concentration: 
 
𝐷𝑒𝑟𝑖𝑣𝑒𝑑 𝑐𝑒𝑙𝑙 𝑝𝑒𝑙𝑙𝑒𝑡 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
= 𝑐𝑒𝑙𝑙 𝑝𝑒𝑙𝑙𝑒𝑡 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛∗5
𝑤𝑎𝑠ℎ 2 𝑙𝑎𝑣𝑎𝑔𝑒 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛∗𝑑𝑒𝑟𝑖𝑣𝑒𝑑 𝑝𝑜𝑜𝑙𝑒𝑑 𝑙𝑎𝑣𝑎𝑔𝑒 𝐸𝐿𝐹 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 
 
Only the derived concentrations will be included in the listing. 
 
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12.5.5. 
Pharmacodynamic and Biomarker 
Pharmacodynamic 
PIP3 Peak Area Proportion for Sputum Sample 
• PIP3 is the analyte of primary interest for the phospholipid data in sputum/Whole Blood, and Peak Area 
data from the mass spectrometer is the endpoint of interest. However, it is acknowledged that there will be 
some degree of variability between sputum/Whole blood samples due to differences in cell counts, and 
therefore it is favoured to first normalise PIP3 Peak Area values for each sample (by PIP2 Peak Area and 
PIP3 Peak Area); prior to analysis. 
 
• More specifically the parameter of interest is: PIP3 Peak Area proportion.  
PIP3 Peak Area proportion is calculated from PIP2 Peak Area and PIP3 Peak Area, as follows: 
Area
 
Peak
 
PIP3
 
  
Area
 
Peak
 
PIP2
Area
 
Peak
 
PIP3
proportion
Area
Peak
IP
P
+
=
3
 
 
• Evaluability was also assessed by the vendor based on sample outputs being above QC instrumentation 
criteria. Any non-evaluable data (as indicated in the database BIDEVCD=F) will be flagged and excluded 
from any summaries and analyses. 
• PIP3 Peak Area, PIP2 Peak Area and, PIP3 Peak Area proportion, will be summarised by treatment group 
and study day 
PIP3 For Peak Area Proportion for Whole Blood Sample  
PBMCs isolated from whole blood and split 4 ways: - 
o Unstimulated+DMSO (this is an unstimulated sample with the vehicle DMSO added) 
o Unstimulated+NEMI (this is an unstimulated sample incubated with NEMI) 
o Stimulated+DMSO (this is a sample stimulated with CD3+CD28 with the vehicle DMSO added) 
o Stimulated+NEMI (this is a sample stimulated with CD3+CD28 and incubated with NEMI) 
 
 
Individual Subject level Ratio for each of the below list group will be calculated for PIP3 Area proportion 
parameter for each of the timepoint separately  
o Unstimulated+DMSO / Stimulated+DMSO 
o Unstimulated+DMSO / Unstimulated+NEMI 
o Stimulated+DMSO / Stimulated+NEMI 
Note: PIP 3 Peak Area Proportion will be calculated separately for each of the above processing types.  
Exploratory phospho-protein biomarkers(pAKT, AKT) 
Individual Subject level Ratio for each of the below list group will be calculated for each parameter for each of 
the timepoint separately  
o Unstimulated+DMSO / Stimulated+DMSO 
o Unstimulated+DMSO / Unstimulated+NEMI 
o Stimulated+DMSO / Stimulated+NEMI 
 
 
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12.5.6. 
Efficacy 
Efficacy 
Episodes of pulmonary and/or ear and sinus infections requiring anti- microbial treatment 
Episodes of pulmonary and/or ear and sinus infections requiring anti- microbial treatment will be 
programmatically identified as follows: 
1. Adverse Event dataset will be reviewed to identify any pulmonary and/or ear and sinus infections 
• If no AEs of pulmonary and/or ear and sinus infections were recorded, then no pulmonary 
and/or ear and sinus infections requiring anti- microbial treatment will be reported.  
• If AEs of pulmonary and/or ear and sinus infections were recorded, then proceed to step 2 
2. A list of all concomitant medication (i.e. CONMEDS dataset with duplicated removed) will be sent 
to the Medical Monitor to identify and flag any anti-microbial treatments 
• If no anti-microbial treatments were identified, then no pulmonary and/or ear and sinus 
infections requiring anti- microbial treatment will be reported.  
• If anti-microbial treatments were identified, then proceed to step 3 
3. Compare each pulmonary and/or ear and sinus infections AE with anti-microbial treatments 
concomitant medication  
• if antimicrobial treatment was taken within 7 days of the pulmonary and/or ear and sinus 
infections AE, then record as a pulmonary and/or ear and sinus infections requiring anti- 
microbial treatment 
else no pulmonary and/or ear and sinus infections requiring anti- microbial treatment will be reported 
 
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12.6. 
Appendix 6: Reporting Standards for Missing Data 
12.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion (i.e. as specified in the protocol) was defined as subject who 
has completed all phases of the study including the follow-up visit.  
• Withdrawn subjects were not replaced in the study. 
• All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
12.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
 Soluble 
proinflammatory 
mediators 
• Any values below the Lower Limit of Quantification (LLQ) will be assigned a value 
of ½ LLQ for display purposes in Figures and for computation of summary 
statistics.  
• Any values above the Upper Limit of Quantification (ULQ) will be assigned to the 
ULQ for display purposes in Figures and for computation of summary statistics. 
• Where biomarker concentrations are from an assay of an increased dilution factor 
the LLQ and ULQ will be multiplied by this factor.  
• Note: Values sent to biostatistics team are already adjusted for this dilution factor 
Imputed values will be used in tables and figures, unless the proportion of imputed 
values at a given time point is large, in which case the summary statistics may not 
be presented for that time point and/or alternative actions will be taken and 
documented in the study report. 
• Where values are imputed, the number of such imputations will be included as a 
summary statistic in the relevant summary tables. 
Plasma and 
BAL Urea Data 
BLQ values will be imputed with the relevant (plasma or BAL fluid) LLQ divided by 2 
• for the purpose of deriving the Dilution Factor. 
Phospholipid 
Data(PIP2,PIP3) 
There is no quantifiable value for the LLQ for the phospholipid data. However, data 
with a particularly high noise/signal ratio will be deemed non evaluable by the external 
vendor. A flag for evaluability will be included in the listings and non-evaluable 
subjects will be excluded from summaries and analyses. 
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12.6.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in participant listing displays.  
Adverse 
Events 
• Imputations in the adverse events dataset are used for slotting events to the appropriate 
study time periods and for sorting in data listings. 
• Partial dates for AE recorded in the CRF will be imputed using the following conventions: 
Missing start day 
• If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month. 
• Else if study treatment start date is not missing: 
o If month and year of start date = month and year of study 
treatment start date then 
▪ If stop date contains a full date and stop date is earlier 
than study treatment start date then set start date= 1st of 
month. 
▪ Else set start date = study treatment start date. 
o Else set start date = 1st of month. 
Missing start day 
and month 
• If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1. 
• Else if study treatment start date is not missing: 
o If year of start date = year of study treatment start date then 
▪ If stop date contains a full date and stop date is earlier 
than study treatment start date then set start date = 
January 1. 
▪ Else set start date = study treatment start date.       
o Else set start date = January 1. 
Missing stop day  
Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 
• Completely missing start or end dates will remain missing, with no imputation applied.  
Concomitant 
Medications 
• Partial dates for any concomitant medications recorded in the CRF will be imputed using 
the following convention: 
 
Missing start day 
• If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month. 
• Else if study treatment start date is not missing: 
o If month and year of start date = month and year of study 
treatment start date then 
▪ If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 1st of month. 
▪ Else set start date = study treatment start date. 
o Else set start date = 1st of month. 
Missing start day 
and month 
• If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1. 
• Else if study treatment start date is not missing: 
o If year of start date = year of study treatment start date then 
▪ If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = January 1. 
▪ Else set start date = study treatment start date.       
• Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month 
and year)  
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Element 
Reporting Detail 
Missing end day and 
month 
A '31' will be used for the day and 'Dec' will be used for the month. 
Completely missing 
start/end date 
No imputation 
 
• The recorded partial date will be displayed in listings. 
 
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12.7. 
Appendix 7: Values of Potential Clinical Importance 
12.7.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 
1 
Male 
0.33 
0.65 
Female 
0.33 
0.65 
Haemoglobin  
g/L 
 
 
115 
175 
Platelet Count  
x109/ L 
 
100 
600 
While Blood Cell Count (WBC) 
x109/ L 
 
3 
20 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
30  
55 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
umol/L 
 
40 
120 
Glucose (Non-fasting) 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
155 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
 X UL 
AST/SGOT  
U/L 
High 
 X UL 
AlkPhos  
U/L 
High 
 X UL 
T Bilirubin  
µmol/L 
High 
 X UL 
T. Bilirubin + ALT 
µmol/L 
High 
 X UL  Bilirubin 
+ 
 
 
 
U/L 
 X UL L 
 
 
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12.7.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTcF Interval 
msec 
 
≥ 500  
Absolute PR Interval 
msec 
< 100 
>240 
Absolute QRS Interval 
msec 
< 80 
> 120  
HR (Ventricular rate) 
bpm 
< 35 
>100 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
≥ 60  
12.7.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<80 
>160 
Diastolic Blood Pressure 
mmHg 
≤ 40 
≥ 100 
Heart Rate 
bpm 
≤ 40 
≥ 100 
Temperature 
ºC 
≤35.5 
≥ 37.5 
Respiration rate 
breaths/min 
≤ 8 
≥ 20 
 
 
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12.8. 
Appendix 8: Data Output Framework 
To ensure transparent reporting of this study we have considered a decision framework in 
line with the study objectives outlined in Section 2.2. 
• Original aim (primary endpoint) was to understand safety of PI3Kd inhibition in these 
patients. It was unknown at the time what would happen when turning the kinase off 
in an activated mutation state. Safety has been reviewed in stream, with no limiting 
effects observed. 
• Secondary endpoint was PK. It is key to show similar (<2-fold) difference in PK vs 
COPD to be convinced of lung exposure. 
• Exploratory endpoints are target engagement (PIP3), and downstream pharmacology 
(inflammatory cytokines) 
• Team would want to see >30% reduction in PIP3 and >30% reduction in cytokines to 
be convinced of drug action in these patients. 
• Team have significant experience in measuring PIP3 to show target engagement and 
have confidence in this readout. 
• Team also have significant experience in lung cytokine measurement and feel this is 
higher risk due to variability. However, the inflammation should be entirely PI3Kd-
dependent. 
Thus the APDS Study Minimum Thresholds are as follows: 
Endpoint 
APDS Study Minimum Thresholds 
Safety  
(Primary) 
Safety reviewed in stream, with no limiting AEs reported (n=4). No 
cough to date, but post-inhalation wheeze reported in one subject 
PK  
(Secondary) 
Comparable Existing NEMI exposure(Ctau) data is listed in below 
table 
 
Existing NEMI 
exposure 
Ctao (pg/mL) value 
<2 Fold difference 
Interval for Geo. 
Mean 
Day 1: 24h Post-
dose 
166 
 
  (83, 332) 
Day 14: Pre-dose 
687  
 
(344,1374) 
Day 83: Pre-dose 
528 
(264,1056) 
• Flag will be derived to indicate whether Geometric Mean of 
Plasma Ctrough concentration is at particular timepoint mentioned 
above is within comparable <2 fold difference range. 
 
Sputum PIP3  
(Exploratory: Target Engagement) 
>30% reduction PIP3 proportion from baseline 
Sputum Cytokines  
(Exploratory: Downstream 
Pharmacology) 
>30% reduction from baseline IL-8, IL-6, TNFα, MMP9 
PIP3 in PBMCs  
(Exploratory: Confirmation of patient 
sensitivity to PI3Kδ Inhibition) 
PIP3 in PBMCs  
• >30% inhibition (of unstimulated)  
• >50% inhibition (stimulated) 
 
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12.9. 
Appendix 9: Abbreviations & Trade Marks 
12.9.1. 
Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
ELF 
Epithelial lining fluid 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
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12.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
DISKUS 
 
[SAS] 
ELLIPTA 
 
 
HARP 
 
 
RANDALL NG 
 
 
 
 
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12.10. 
Appendix 10: List of Data Displays 
12.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.10 
 
Efficacy 
2.1 to 2.2 
 
Safety 
3.1 to 3.12 
 
Pharmacokinetic 
4.1 to 4.4 
 
Pharmacodynamic and Biomarker 
6.1 to 6.11 
6.1 to 6.6 
Section 
Listings 
ICH Listings 
1 to 29 
Other Listings 
30 to 41 
 
12.10.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock shells for Data Displays 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Pharmacodynamic and Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
NOTES:  
• Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
12.10.3. 
Deliverables 
Delivery  
Description 
SAC 
Final Statistical Analysis Complete 
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12.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Subject Disposition 
1.1. 
All Subjects 
ES1 
 
Summary of Participant Disposition for the Participant 
Conclusion Record 
ICH E3, FDAAA, EudraCT 
SAC 
1.2. 
All Subjects 
SD1  
 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
 
SAC 
1.3. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
 
SAC 
Protocol Deviation 
1.4. 
All Subjects 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
Demographic and Baseline Characteristics 
1.5. 
All Subjects 
DM1  
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC 
1.6. 
All Subjects 
DM11 
Summary of Age Ranges 
EudraCT 
SAC 
1.7. 
All Subjects 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC 
Population Analysed 
1.8. 
Screened 
SP1  
Summary of Study Populations  
Summarize by each treatment group 
(i.e. NEMI 1000mcg Diskus, NEMI 
700mcg Ellipta, NEMI 500mcg Ellipta) 
and ALL NEMI, No Treatment group  
Refer to Table 1.6 in 
gsk2269557/mid201928/final_01 
SAC 
Prior and Concomitant Medications 
1.9. 
All Subjects 
CM1 
Summary of Concomitant Medications 
ICH E3  
 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Exposure and Treatment Compliance 
1.10. 
All Subjects 
EX1  
 
Summary of Exposure to Study Treatment 
 
SAC 
 
12.10.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable  
FEV1 
2.1. 
All Subjects  
PFT1 
Summary of Absolute FEV1 (L) Data  
Refer PII115119/ Part_A /Table 3.18 
Add footnote “Note: Maximum value of 
the three readings has been used.” 
 
SAC 
2.2. 
All Subjects  
PFT3 
Summary of Change from Baseline FEV1 (L) Data  
Refer PII115119/ Part_A /Table 3.19 
 
SAC 
 
 
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12.10.6. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Adverse Events (AEs) 
3.1. 
All Subjects 
AE1  
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
 
ICH E3 
 
SAC 
3.2. 
All Subjects 
AE1            
 
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
ICH E3 
 
SAC 
3.3. 
All Subjects 
AE15  
 
Summary of Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) 
 
Required by Register Disclosure for 
FDAAA and EudraCT. 
SAC 
Serious and Other Significant Adverse Events 
3.4. 
All Subjects 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
 
SAC 
3.5. 
All Subjects 
AE1  
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
by System Organ Class and Preferred Term  
IDSL 
 
SAC 
Laboratory: Chemistry  
3.6. 
All Subjects 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3 
 
SAC 
Laboratory: Hematology 
3.7. 
All Subjects 
LB1 
Summary of Hematology Changes from Baseline 
ICH E3 
 
SAC 
Laboratory: Hepatobiliary (Liver) 
3.8. 
All Subjects 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
IDSL 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
3.9. 
All Subjects 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
IDSL 
 
SAC 
ECG 
3.10. 
All Subjects 
EG1 
Summary of ECG Findings  
IDSL 
 
SAC 
3.11. 
All Subjects 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
 
SAC 
Vital Signs 
3.12. 
All Subjects 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
 
SAC 
12.10.7. 
Pharmacokinetics Table  
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Plasma PK 
4.1. 
PK 
PK01 
Summary of Plasma Nemiralisib Pharmacokinetic 
Concentration-Time Data  
 
SAC 
4.2. 
PK 
PK_T1 
Summary of Log-Transformed Plasma Nemiralisib 
Pharmacokinetic Concentration - Time Data (pg/mL) 
 
Include flag derived for minimum 
threshold criteria as mentioned in 
Section 12.8. 
SAC 
Lung epithelial lining fluid (ELF) and Bronchoalveolar lavage (BAL) 
4.3. 
PK 
PK_T2 
Summary of Urea Dilution Factor Data 
 
SAC 
4.4. 
PK 
PK_T3 
Summary of Derived Lung ELF and Cell Pellet Nemiralisib 
Pharmacokinetic Concentrations and Volume Data 
 
SAC 
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12.10.8. 
Pharmacodynamic and Biomarker Tables 
Pharmacodynamic and Biomarker: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable  
PIP2/PIP3 
6.1. 
All Subjects  
PD_T1 
Summary of Phospholipid Data (Absolute) in Sputum 
 
SAC 
6.2. 
All Subjects 
PD_T3 
Summary of Phospholipid Data (Change from Baseline) in 
Sputum 
Includes only PIP3 Proportion parameter 
SAC 
6.3. 
All Subjects 
PD_T2 
Summary of Phospholipid Data (Absolute) in Blood 
 
SAC 
6.4. 
All Subjects  
PD_T4 
Summary of Phospholipid Data (Change from Baseline) in 
Blood 
Includes only PIP3 Proportion parameter 
SAC 
6.5. 
All Subjects 
PD_T5 
Summary of statistical analysis of Loge transformed PIP3 
Area Proportion  
Refer Table 2.62 in 201928/final_02 RE 
SAC 
Soluble Proinflammatory Mediators 
6.6. 
All Subjects 
 
PD_T6 
Summary Statistics (Absolute): Soluble proinflammatory 
mediators  
Includes IL-8, IL-6, TNFa & MMP9  
 
SAC 
6.7. 
All Subjects 
PD_T6 
Summary Statistics (Change from Baseline): 
Soluble proinflammatory mediators  
Includes IL-8, IL-6, TNFa & MMP9  
 
SAC 
6.8. 
All Subjects 
PD_T7 
Summary Statistics (Log-Transformed Absolute): 
Soluble proinflammatory mediators  
Includes IL-8, IL-6, TNFa & MMP9  
 
SAC 
6.9. 
All Subjects 
PD_T7 
Summary Statistics (Log-Transformed Change from 
Baseline): Soluble proinflammatory mediators  
Includes IL-8, IL-6, TNFa & MMP9  
 
SAC 
Immune cell and Lymphocyte cell subsets 
6.10. All Subjects 
LB1 
Summary of Blood Lymphocyte Cell Subsets (Change from 
Baseline) 
Include Blood Sample type data only 
 
SAC 
Phospho-protein biomarkers(pAKT,AKT) 
6.11. All Subjects  
PD_T2 
Summary of Phospho-protein Biomarkers (Absolute)  
Include Sample type (i.e. Sputum, BAL etc) 
as Page by Variable  
Include pAKT ,AKT parameter  
 
SAC 
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12.10.9. 
Pharmacodynamic and Biomarker Figures 
Pharmacodynamic and Biomarker: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
PIP2, PIP3 
6.1. 
All Subjects 
PD_F1 
Individual subjects profile plot of Phospholipid Data 
in Sputum 
Different colour legend for each subject . 
Ignore processing type panel in mock shell for Sputum 
data.  
Page by Parameter (PIP2,PIP3,PIP3 proportion) 
SAC 
6.2. 
All Subjects 
PD_F2 
Geometric Mean and 95% Confidence Interval for 
Phospholipid Data in Sputum  
Different colour legend for each parameter 
SAC 
6.3. 
All Subjects 
PD_F1 
Individual subjects profile plot of Phospholipid Data 
in Blood 
Page by Parameter (PIP2, PIP3, PIP3 proportion) 
Different colour legend for each subject  
Different plot of processing type and (1st page include 4 
different processing type and 2nd page is for 3different 
processing type comparison values) 
SAC 
6.4. 
All Subjects 
PD_F2 
Geometric Mean and 95% Confidence Interval for 
Phospholipid Data in Blood by Processing Type 
Different colour legend for each processing type  
1st page include figure having 4 different line for each 
processing type estimates and 2nd plot is for 3different 
processing type comparison values) 
SAC 
Phospho-protein biomarkers(pAKT,AKT) 
6.5. 
All Subjects 
PD_F1 
Individual subjects profile plot for phospho-protein 
biomarkers Data in Blood 
Different plot of processing type and (1st page include 4 
different processing type and 2nd page is for 3 different 
processing type comparison values) 
SAC 
6.6. 
All Subjects 
PD_F2 
Geometric Mean and 95% Confidence Interval for 
phospho-protein Biomarkers in Blood by Processing 
Type  
Different colour legend for each processing type  
1st page include figure having 4 different line for each 
processing type estimates  and 2nd plot is for 3different 
processing type comparison values) 
SAC 
 
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12.10.10. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.  
Screened 
ES6 
Listing of Reasons for Screen Failure 
 
SAC 
2.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
SAC 
3.  
All Subjects 
ES2  
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC 
4.  
All Subjects 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
 
SAC 
5.  
All Subjects 
TA1  
Listing of Planned and Actual Treatments 
IDSL 
 
SAC 
Protocol Deviations 
6.  
Screened 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
 
SAC 
7.  
All Subjects 
IE3  
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC 
Populations Analysed 
8.  
Screened 
SP3 
Listing of Participants Excluded from Any Population 
 
SAC 
Demographic and Baseline Characteristics 
9.  
All Subjects 
DM2  
Listing of Demographic Characteristics 
ICH E3 
SAC 
10. 
All Subjects 
DM9  
Listing of Race 
ICH E3 
SAC 
Prior and Concomitant Medications 
11. 
All Subjects 
CM3 
Listing of Concomitant Medications 
IDSL 
 
SAC 
12. 
All Subjects 
POP_L1 
Listing of Ear, Sinus and Pulmonary Infection History over 
Previous Two Years 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Exposure and Treatment Compliance 
13. 
All Subjects 
EX3  
Listing of Exposure Data 
ICH E3 
SAC 
Adverse Events 
14. 
All Subjects 
AE8  
Listing of All Adverse Events 
ICH E3 
SAC 
15. 
All Subjects 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC 
16. 
All Subjects 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC 
Serious and Other Significant Adverse Events 
17. 
All Subjects 
AE8  
 
Listing of Serious Adverse Events  
 
ICH E3 
Include a column to flag fatal and non-
fatal SAEs 
SAC 
18. 
All Subjects 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC 
19. 
All Subjects 
AE8  
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC 
Hepatobiliary (Liver) 
20. 
All Subjects 
MH2 
Listing of Medical Conditions for Participants with Liver 
Stopping Events 
IDSL 
SAC 
21. 
All Subjects 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events 
IDSL 
SAC 
22. 
All Subjects 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
SAC 
All Laboratory 
23. 
All Subjects  
LB5 
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
 
SAC 
24. 
All Subjects  
LB5 
Listing of Laboratory Values of Potential Clinical Importance 
 
SAC 
25. 
All Subjects 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
26. 
All Subjects 
UR2 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
 
SAC 
ECG 
27. 
All Subjects 
EG3  
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
 
SAC 
28. 
All Subjects 
EG5 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding 
IDSL 
 
SAC 
Vital Signs 
29. 
All Subjects 
VS4  
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
 
SAC 
 
 
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12.10.11. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Pharmacokinetic 
30. 
PK 
PK07 
Listing of Plasma Nemiralisib Concentration-time Data 
 
SAC 
31. 
PK 
PK_L1 
Listing of Plasma Urea and BAL Fluid Urea Data 
 
SAC 
32. 
PK 
PK_L2 
Listing of BAL Fluid and Derived Lung ELF Nemiralisib 
Pharmacokinetic Concentration Data  
 
SAC 
Pharmacodynamic (PIP2/PIP3) 
33. 
All Subjects  
PD_L1 
Listing of Phospholipid Data in Sputum 
 
SAC 
34. 
All Subjects 
PD_L2 
Listing of Phospholipid Data in Blood  
 
SAC 
Pharmacodynamic (Soluble proinflammatory mediators) 
35. 
All Subjects 
PD_L3 
Listing of Individual Subject Soluble proinflammatory mediators 
Data 
Refer PII115119/Part A/Listing 34 
SAC 
Pharmacodynamic (Immune cell and Lymphocyte cell subsets) 
36. 
All Subjects  
PD_L4 
Listing of Immune Cell Count Data 
 
SAC 
37. 
All Subjects  
PD_L4 
Listing of Lymphocyte cell subsets 
 
SAC 
Pharmacodynamic (pAKT/AKT) 
38. 
All Subjects  
PD_L6 
Listing of Phospho-protein biomarkers 
 
SAC 
Pharmacodynamic (Antibody Level) 
39. 
All Subjects  
PD_L5 
Listing of Antibody Level 
 
SAC 
Efficacy  
40. 
All Subjects 
PFT8 
Listing of FEV1 (L) Data 
 
 
SAC 
41. 
All Subjects  
EFF_L1 
Listing of Episodes of Pulmonary and/or Ear and Sinus 
Infections Requiring Anti-Microbial Treatment 
 
 
SAC 
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12.11. 
Appendix 11: Example Mock shells for Data Displays 
Data Display Specification will be made available on request 
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