Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 56
Healthy volunteers: yes

Brief summary:
Randomized, Open-label, Single-dose, Single-center, Crossover Study in Healthy Subjects to Assess the Relative Bioavailability of PT010

Detailed description:
A Randomized, Open-label, Single-dose, Single-center, Crossover Study in Healthy Subjects to Assess the Relative Bioavailability of PT010 Administered With and Without a Spacer, and With and Without Oral Charcoal

Arms:
arm 1: Test Formulation (Regimen B or D) or Reference Formulation (Regimen A or C) arm 2: Test Formulation (Regimen (B or D) or Reference Formulation (Regimen A or C) arm 3: Test Formulation (Regimen (B or D) or Reference Formulation (Regimen A or C) arm 4: Test Formulation (Regimen (B or D) or Reference Formulation (Regimen A or C)

Interventions: intervention 1: Regimen A intervention 2: Regimen B intervention 3: Regimen C intervention 4: Regimen D
Intervention descriptions: intervention 1: 2 inhalations BGF MDI; no spacer device; no oral charcoal - reference formulation/total systemic exposure intervention 2: 2 inhalations BGF MDI; AeroChamber Plus Flow-Vu spacer device; no oral charcoal - test formulation/total systemic exposure intervention 3: 2 inhalations BGF MDI; no spacer device; with oral charcoal - reference formulation/lung exposure intervention 4: 2 inhalations BGF MDI; AeroChamber Plus Flow-Vu spacer device; with oral charcoal - test formulation/lung exposure

Protocol document:
Prot_001.pdf: 
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Clinical Trial Protocol: PT010011-00 
Study Title:
A Randomized, Open-label, Single-dose, Single-center, Crossover 
Study in Healthy Subjects to Assess the Relative Bioavailability of 
PT010 Administered With and Without a Spacer, and With and 
Without Oral Charcoal
Study Number:
PT010011 
Study Phase:
I 
Product Name:
PT010: Budesonide, Glycopyrronium, and Formoterol Fumarate 
Inhalation Aerosol, Metered Dose Inhaler (BGF MDI) 
Indication:
Chronic Obstructive Pulmonary Disease 
Investigators: 
Single Center
Sponsor:
Pearl Therapeutics, Inc.
Sponsor Contact: 
Version Number 
Date
Original Protocol: 
1.0
11 September 2017 
Confidentiality Statement
Property of Pearl Therapeutics, Inc.
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of Pearl Therapeutics, Inc. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011 
Version 1.0
Confidential and Proprietary
Page 2 of 62
SYNOPSIS 
Sponsor: 
Pearl Therapeutics, Inc.
Name of Study Drug: 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol (PT010, BGF 
metered dose inhaler [MDI])
Name of Active Ingredient:
Budesonide, Glycopyrronium, and Formoterol Fumarate 
Study Title: 
A Randomized, Open-label, Single-dose, Single center, Crossover Study in Healthy Subjects 
to Assess the Relative Bioavailability of PT010 Administered With and Without a Spacer, 
and With and Without Oral Charcoal 
Study Protocol Number:
PT010011-00 
Study Phase: I 
Primary Objectives:
•
To assess the total systemic exposure of budesonide, glycopyrronium, and formoterol 
administered as BGF MDI with and without a spacer device
•
To assess the lung exposure of budesonide, glycopyrronium, and formoterol administered 
as BGF MDI with and without oral activated charcoal
Secondary Objectives: 
•
To characterize the pharmacokinetic (PK) profiles of budesonide, glycopyrronium, and 
formoterol administered as BGF MDI, with and without a spacer device, and with and 
without oral charcoal 
•
To assess the safety of single doses of BGF MDI in healthy subjects
Study Design: 
This is a Phase I, randomized, open-label, single-dose, single-center, crossover study to 
assess the PK and safety of BGF MDI in healthy subjects (male or female). PK profiles of 
each active ingredient (budesonide, glycopyrronium, and formoterol), will be determined 
after administration of BGF MDI with a spacer device (test) and without a spacer device 
(reference), and with and without the concomitant administration of activated oral charcoal to 
estimate total systemic exposure and lung exposure, respectively.
The study will comprise the following:
•
A screening period with a maximum duration of 28 days.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
Confidential and Proprietary
Page 3 of 62
•
Four Treatment Periods during which subjects will be resident from the afternoon before 
dosing with BGF MDI until at least 24 hours after dosing and discharged on the morning 
of Day 2 of each Treatment Period. There will be a washout period of 5to 14 days 
between Treatment Periods 1, 2, and 3.
•
A follow-up phone call will take place within 5 to 7 days following the last 
administration of BGF MDI.
After providing informed consent, subjects will undergo screening procedures. Subjects 
meeting eligibility criteria will be enrolled into the study and admitted to the study site as an 
inpatient on Day -1 of Treatment Period 1, at which time, continuing eligibility will be 
assessed. Device training will be conducted during screening, on admission to each 
Treatment Period, and prior to dosing on Day 1 of each Treatment Period. In addition to 
training with a placebo MDI device, additional inhalation training tools may be used to help 
ensure the subjects are able to use the MDI device correctly.
Study drug will be administered, under fasted conditions, on the morning of Day 1 of each 
Treatment Period, at approximately the same time of day throughout the study (±30 minutes).
Eligible subjects will receive a single dose of BGF MDI 320/28.8/9.6 μg administered as 
follows:
•
Without a spacer device and without charcoal (regimen A)
•
With a spacer device and without charcoal (regimen B)
•
Without a spacer device and with charcoal (regimen C)
•
With a spacer device and with charcoal (regimen D)
Subjects will receive all 4 regimens (1 regimen per Treatment Period) in 1 of 8 possible 
regimen sequences: AB CD, AB DC, BA CD, BA DC, CD AB, CD BA, DC AB, or DC BA.
These regimen sequences allow for subjects who might drop out after 2 Treatment Periods
only to be included in the PK statistical analysis.
Randomization will be performed on the morning of first dosing (Day 1, Treatment Period
1). Randomization codes will be assigned strictly sequentially in ascending order as subjects 
become eligible. 
During their inpatient stay, subjects will undergo safety assessments and have an indwelling 
intravenous cannula for serial PK blood draws. Subjects will be discharged on the morning of 
Day 2 of each Treatment Period after all protocol-specified assessments are completed. There 
will be a washout period of 5 to 14 days between each Treatment Period.
A follow-up phone call will be conducted 5 to 7 days after Treatment Period 4 dosing or after 
the last dose of study drug, whichever comes first.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
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Confidential and Proprietary
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Study Population:
This study will be conducted in healthy male and female subjects, 18 to 40 years of age 
(inclusive). Approximately 56 subjects will be randomized in order to have approximately 48 
evaluable subjects.
Test Product, Dose, and Mode of Administration: 
Product Name & 
Dose
Product 
Strength
Dosage Form/
Fill Count
Administration
BGF MDI 
320/28.8/9.6 μg
ex-actuator
160/14.4/4.8 μg
per actuation
MDI/
120 inhalations
Regimen A: 2 inhalations BGF MDI; no spacer 
device; no oral charcoal – reference 
formulation/total systemic exposure
Regimen B: 2 inhalations BGF MDI; 
AeroChamber Plus Flow-Vu spacer device; no 
oral charcoal – test formulation/total systemic 
exposure
Regimen C: 2 inhalations BGF MDI; no spacer 
device; with oral charcoal – reference 
formulation/lung exposure
Regimen D: 2 inhalations BGF MDI; 
AeroChamber Plus Flow-Vu spacer device; with 
oral charcoal – test formulation/lung exposure
Non-Investigational Medicinal Product, Dose, and Mode of Administration:
Manufacturer:
Perrigo
Formulation:
Actidose-Aqua® (activated charcoal) 50 g for oral suspension
Strength/Concentration:
50 g/240 mL
Dose regimen:
•
Immediately prior to study drug dose: 10g (approximately 48 mL of 
suspension) which will be mouth-rinsed and swallowed
•
Immediately after study drug dosing: 10 g (approximately 48 mL of 
suspension) which will be mouth-rinsed and swallowed; repeat at 1 
hour and 2 hours post-dose
Route of administration:
Oral
Regimen:
Regimen C: 2 inhalations BGF MDI; no spacer device; with oral charcoal 
– reference formulation/lung exposure
Regimen D: 2 inhalations BGF MDI; AeroChamber Plus Flow-Vu spacer 
device; with oral charcoal – test formulation/lung exposure
Duration of Treatment: 
Each subject will be involved in the study for approximately 13 weeks.
PK Endpoints:
Pharmacokinetics following administration of BGF MDI will be assessed using plasma 
concentrations of budesonide, glycopyrronium, and formoterol pre-dose and at various times 
post-dose on Day 1 of each Treatment Period.
Primary PK parameters


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011 
Version 1.0
Confidential and Proprietary
Page 5 of 62
•
Maximum plasma concentration (Cmax) 
•
Area under the plasma concentration-time curve from 0 the time of the last measurable 
plasma concentration (AUC0-tlast) 
Secondary PK parameters
•
Time to maximum plasma concentration (tmax) 
•
Area under the plasma concentration-time curve from 0 extrapolated to infinity (AUC0-);
Safety Assessments: 
The safety and tolerability profile of BGF MDI will be assessed using adverse event 
reporting, vital sign values, clinical laboratory values, and findings from 12-lead 
electrocardiograms
Statistical Methods: 
PK: 
The PK analyses will be performed for the PK population. Pharmacokinetic parameters will 
be calculated using non-compartmental analysis.
The treatment ratio of BGF MDI with spacer versus BGF MDI without spacer, both in the 
presence and absence of charcoal, will be calculated for budesonide, glycopyrronium, and 
formoterol.
Treatment comparisons of primary PK parameters will be assessed on the difference of log 
transformed Cmax, AUC0-tlast, and AUC0- of budesonide, glycopyrronium, and formoterol 
using a 2-sided 90% confidence interval (CI) approach based on an analysis of variance
model including period and sequence, regimen, and subject as fixed effects. Estimated 
geometric mean ratios with 90% CIs will be provided. 
Safety:
All safety analyses will be performed on the Safety Population. Descriptive statistics will be 
provided for all safety assessments. 
Determination of sample size:
Even though this study is being conducted for estimation purposes,
 a sample size of 48 subjects completing the 
study will provide 90% probability to observe a 1-sided 95% lower confidence bound for the 
geometric mean ratio (D/C) that is greater than 80%.
Date of Original Protocol: 11 September 2017 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
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Version 1.0
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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2 
LIST OF IN-TEXT TABLES ....................................................................................................9 
LIST OF IN-TEXT FIGURES...................................................................................................9 
LIST OF APPENDICES............................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................10 
1 
INTRODUCTION ...........................................................................................................12 
2 
STUDY OBJECTIVES....................................................................................................13 
2.1 
Primary Objectives.................................................................................................13 
2.2 
Secondary Objectives.............................................................................................13 
3 
STUDY ENDPOINTS.....................................................................................................14 
3.1 
Efficacy Endpoints.................................................................................................14 
3.2 
PK Endpoints .........................................................................................................14 
3.2.1 
Primary PK Parameters................................................................................14 
3.2.2 
Secondary PK Parameters............................................................................14 
3.2.3 
Other PK parameters....................................................................................14 
3.3 
Safety Endpoints....................................................................................................14 
4 
INVESTIGATIONAL PLAN..........................................................................................15 
4.1 
Overall Study Design and Plan..............................................................................15 
4.2 
Rationale for Study Design and Control Group.....................................................16 
4.3 
Study Duration.......................................................................................................17 
5 
STUDY POPULATION SELECTION ...........................................................................18 
5.1 
Study Population....................................................................................................18 
5.2 
Inclusion Criteria ...................................................................................................18 
5.3 
Exclusion Criteria ..................................................................................................19 
5.4 
Subject Identification.............................................................................................20 
5.5 
Prior, Concomitant, and Prohibited Medications...................................................20 
5.6 
Restrictions During the Study................................................................................20 
5.7 
Study Withdrawal ..................................................................................................21 
6 
CLINICAL SUPPLY LABELING, PACKAGING, STORAGE, DISPENSING, 
AND RETURN................................................................................................................23 
6.1 
Description of Study Drugs ...................................................................................23 
6.2 
Other Sponsor-Provided Medications Used in the Study......................................23 
6.3 
Packaging and Labeling.........................................................................................24 
6.4 
Storage Requirements ............................................................................................24 
6.5 
Instructions for Preparation of Study Drug for Administration and Dosing .........24 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
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Confidential and Proprietary
Page 7 of 62
6.6 
Instructions for Administration of Activated Oral Charcoal .................................25 
6.7 
Aerochamber Plus Flow-Vu Instructions for Administration and Dispensing of 
Treatments..............................................................................................................25 
6.8 
Dispensing Study Drug..........................................................................................26 
6.9 
Study Drug Accountability/Return of Clinical Supplies .......................................26 
7 
STUDY PROCEDURES .................................................................................................28 
7.1 
Informed Consent...................................................................................................28 
7.2 
Subject Eligibility ..................................................................................................28 
7.3 
PK Assessments.....................................................................................................28 
7.3.1 
Blood Sample Collection Schedule .............................................................28 
7.3.2 
Procedure for Shipping Samples..................................................................29 
7.3.3 
Storage and Destruction of PK Samples......................................................29 
7.4 
Safety Assessments................................................................................................29 
7.4.1 
Medical History ...........................................................................................29 
7.4.2 
Physical Examination...................................................................................29 
7.4.3 
Vital Signs....................................................................................................30 
7.4.4 
12-Lead Electrocardiogram .........................................................................30 
7.4.5 
Clinical Laboratory Tests.............................................................................30 
7.4.5.1 
Laboratory Parameters.......................................................................30 
7.4.5.2 
Sample Collection, Storage, and Shipping ........................................31 
7.5 
Adverse Event Assessments ..................................................................................32 
7.5.1 
Performing Adverse Event (AE) Assessments ............................................32 
7.5.2 
AE Definitions .............................................................................................32 
7.5.3 
Pre-Randomization AEs...............................................................................33 
7.5.4 
Severity ........................................................................................................33 
7.5.5 
Relationship to Study Drug..........................................................................33 
7.5.6 
Clinical Laboratory Adverse Events............................................................33 
7.5.7 
SAEs ............................................................................................................34 
7.5.7.1 
REPORTING SAEs...........................................................................35 
7.5.8 
Supplemental Investigation of SAEs ...........................................................35 
7.5.9 
Post-Study Follow-Up of AEs .....................................................................35 
7.5.10 
Notification of Post-Treatment SAEs..........................................................35 
7.5.11 
IRB/IEC Notification of SAEs.....................................................................36 
7.5.12 
Health Authority Safety Reports..................................................................36 
7.5.13 
Overdose ......................................................................................................36 
7.5.14 
Pregnancy.....................................................................................................36 
7.5.15 
Paternal Exposure ........................................................................................36 
7.6 
Termination of the Study .......................................................................................37 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
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Version 1.0
Confidential and Proprietary
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8 
STUDY ACTIVITIES .....................................................................................................38 
8.1 
Screening (Days –28 to -1) ....................................................................................42 
8.2 
Treatment Periods 1, 2, 3, and 4 ............................................................................42 
8.2.1 
Clinic Admission (Day -1)...........................................................................42 
8.2.2 
Treatment Days (Day 1 to Day 2)................................................................43 
8.3 
Follow-up Phone Call ............................................................................................44 
9 
PLANNED STATISTICAL METHODS ........................................................................45 
9.1 
General Considerations..........................................................................................45 
9.2 
Determination of Sample Size ...............................................................................45 
9.3 
Analysis Populations..............................................................................................45 
9.3.1 
Safety Population.........................................................................................45 
9.3.2 
PK Population..............................................................................................45 
9.4 
Demographics and Baseline Characteristics..........................................................45 
9.5 
Statistical Analysis of PK Variables......................................................................46 
9.5.1 
PK Parameters..............................................................................................46 
9.5.2 
Handling of Values that are Below the Limit of Quantification..................47 
9.5.3 
Statistical Analysis of PK Data....................................................................47 
9.6 
Safety Analysis ......................................................................................................48 
9.6.1 
AEs...............................................................................................................48 
9.6.2 
Vital Signs....................................................................................................48 
9.6.3 
Clinical Laboratory Measurements..............................................................48 
9.6.4 
12-Lead ECGs..............................................................................................48 
9.7 
Randomization.......................................................................................................48 
9.8 
Statistical Software ................................................................................................48 
10 ADMINISTRATIVE CONSIDERATIONS....................................................................49 
10.1 
Regulatory Authority Approval .............................................................................49 
10.2 
Ethical Conduct of the Study and IRB or IEC Approval.......................................49 
10.3 
Subject Information and Consent...........................................................................49 
10.4 
Laboratory Accreditation.......................................................................................50 
10.5 
Confidentiality .......................................................................................................50 
10.5.1 
Confidentiality of Data ................................................................................50 
10.5.2 
Confidentiality of Subject/Patient Records..................................................50 
10.6 
Quality Control and Assurance..............................................................................50 
10.7 
Data Management ..................................................................................................51 
10.8 
Study Monitoring...................................................................................................51 
10.9 
Retention of Data...................................................................................................52 
10.10 Financial Disclosure...............................................................................................52 
10.11 Investigator’s Final Report ....................................................................................52 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
Confidential and Proprietary
Page 9 of 62
10.12 Publication Policy..................................................................................................52 
11 REFERENCE LIST .........................................................................................................54 
LIST OF IN-TEXT TABLES
Table 6-1 
Description of Study Drugs....................................................................23 
Table 6-2 
Other Medications Provided by Sponsor ...............................................23 
Table 7-1 
Time Window for Post-dose PK Assessments.......................................28 
Table 7-2 
List of Laboratory Tests.........................................................................31 
Table 8-1 
Schedule of Events for Screening, Treatment, and Follow-Up .............38 
Table 8-2 
Timing of Assessments on Day 1 During Inpatient Treatment 
Periods 1, 2, and 3........................................................................................................40 
Table 8-3 
Timing of Assessments on Day 1 During Inpatient Treatment Period 
4
................................................................................................................41 
LIST OF IN-TEXT FIGURES
Figure 4-1 
Study Design..........................................................................................16 
LIST OF APPENDICES
Appendix 1 
Instructions for Use of BGF MDI..........................................................55 
Appendix 2 
Aerochamber Plus Flow-Vu Instructions for Use..................................60 
Appendix 3 
Sponsor Signature ..................................................................................61 
Appendix 4 
Investigator’s Signature .........................................................................62 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
AUC0-tlast
Area under the plasma concentration-time curve from 0 to the time of the 
last measurable plasma concentration
AUC0-
Area under the plasma concentration-time curve from 0 extrapolated to 
infinity
BFF MDI
Budesonide and Formoterol Fumarate Metered Dose Inhaler
BGF MDI
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose 
Inhaler
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation 
(according to National Kidney Disease Education Program)
CL/F
Apparent total body clearance
Cmax
Maximum plasma concentration
COPD
Chronic obstructive pulmonary disease
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
FSH
Follicle stimulating hormone
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HbsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICMJE
International Committee of Medical Journal Editors
ICS
Inhaled corticosteroid


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
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IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISMPP
International Society for Medical Publications Professionals
IV
Intravenous
LABA
Long-acting ȕ2-agonist
LAMA
Long-acting muscarinic antagonist
LLQ
Lower limit of quantification
Ȝz
Terminal elimination rate constant
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
NCA
Non-compartmental analysis
OTC
Over-the-counter
PK
Pharmacokinetics
PT009
Budesonide and Formoterol Fumarate Inhalation Aerosol
PT010
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol
QTcF
Fridericia’s corrected QT interval
SAE
Serious adverse event
SAP
Statistical analysis plan
t1/2
Apparent terminal elimination half-life
TEAE
Treatment-emergent adverse event
tlast
Time to last measurable plasma concentration
tmax
Time to maximum plasma concentration
US
United States
Vd/F
Apparent volume of distribution


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
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Clinical Trial Protocol: PT010011
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1
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable 
disease characterized by persistent respiratory symptoms and airflow limitation that is due to 
airway and/or alveolar abnormalities usually caused by significant exposure to noxious 
particles or gases, the most common of which is cigarette smoke. Exacerbations and co-
morbidities contribute to the overall severity in individual patients. Chronic obstructive 
pulmonary disease is a leading cause of morbidity and mortality worldwide and results in a 
significant economic and social burden that is both substantial and increasing. Pharmacologic 
therapy in COPD is used to reduce symptoms, reduce the frequency and severity of 
exacerbations, and improve health status and exercise tolerance as described in the Global 
Initiative for Chronic Obstructive Lung Disease (GOLD 2017) guidelines.
Bronchodilator medications are central to the symptomatic management of COPD. The 
SULQFLSDOEURQFKRGLODWRUWUHDWPHQWVDUHȕ-agonists, anticholinergics, and methylxanthines 
used as monotherapy or in combination. Treatment with long-acting bronchodilators is more 
convenient and more effective at producing maintained symptom relief than treatment with 
short-acting bronchodilators.
Regular treatment with inhaled corticosteroids (ICS) improves symptoms, lung function, and 
quality of life and reduces the frequency of exacerbations in subjects with COPD with a 
forced expiratory volume in 1 second (FEV1) value of <60% of predicted. Withdrawal from 
treatment with ICS may lead to exacerbations in some patients. When combined with a long-
DFWLQJȕ2-agonist (LABA), an ICS is more effective than the individual components in 
improving lung function and quality of life and reducing exacerbations in subjects with 
moderate to very severe COPD (GOLD 2017).
Pearl Therapeutics, Inc. (hereinafter referred to as the Sponsor) is developing the fixed-dose 
ICS/long-acting muscarinic antagonist (LAMA)/LABA triple combination product, 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol (PT010), 
hereafter referred to as Budesonide, Glycopyrronium, and Formoterol Fumarate Metered 
Dose Inhaler (BGF MDI), for the treatment of patients with COPD. Budesonide and 
Formoterol Fumarate Inhalation Aerosol (PT009), hereinafter referred to as Budesonide and 
Formoterol Fumarate (BFF) MDI, is also being developed as a twice daily (BID) fixed dose 
ICS/LABA treatment for patients with COPD.
Budesonide is a well-established corticosteroid approved worldwide in monotherapy and 
combination therapies for the treatment of asthma and allergic rhinitis. It is available in both 
intranasal and orally inhaled formulations. Inhaled budesonide in combination with 
formoterol fumarate dehydrate (ie, Symbicort®) is approved for use in patients with asthma 
and COPD. 
Glycopyrronium is a LAMA that exerts its bronchodilatory effect via muscarinic receptors 
located on smooth muscle cells within the trachea and bronchi. Glycopyrronium is approved 
in many countries in multiple formulations for different indications, including for the 
treatment of COPD. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
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Formoterol fumarate is a selective LABA approved worldwide for use in asthma and COPD. 
In addition, formoterol fumarate is also approved worldwide in combination with budesonide
(eg, Symbicort MDI, Symbicort Turbuhaler®) for use in patients with asthma and COPD. 
When inhaled, formoterol fumarate acts locally in the lung as a bronchodilator. Formoterol 
IXPDUDWHVWLPXODWHVȕDGUHQRUHFHSWRUVLQWKHDLUZD\VLQGXFLQJDLUZD\VPRRWKPXVFOH
relaxation and reducing or preventing bronchoconstriction.
In order to improve coordination of inhaler actuation and inspiration, a valved holding 
chamber (or spacer) may be used with an MDI. A spacer may also reduce the amount of drug 
that is deposited in the oropharynx. The purpose of this study is to establish the relative 
bioavailability of budesonide, glycopyrronium, and formoterol after administration of BGF 
MDI with and without a spacer device in order to include the use of a spacer in the label as 
required in the European Union Specifically, budesonide, glycopyrronium, and formoterol 
delivered via BGF MDI with a spacer device (test) and without a spacer device (reference) 
will be administered with and without the concomitant administration of activated oral 
charcoal to estimate total systemic exposure and lung exposure, respectively.
2
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of this study are the following:
•
To assess the total systemic exposure of budesonide, glycopyrronium, and formoterol 
administered as BGF MDI with and without a spacer device
•
To assess the lung exposure of budesonide, glycopyrronium, and formoterol administered 
as BGF MDI with and without activated oral charcoal
2.2
Secondary Objectives
The secondary objectives of this study are the following:
•
To characterize the pharmacokinetic (PK) profiles of budesonide, glycopyrronium, and 
formoterol administered as BGF MDI, with and without a spacer device, and with and 
without oral charcoal
•
To assess the safety of single doses of BGF MDI in healthy subjects


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3
STUDY ENDPOINTS
3.1
Efficacy Endpoints
Not applicable
3.2
PK Endpoints
The PK after single-dose administration of BGF MDI will be assessed using plasma 
concentrations of budesonide, glycopyrronium, and formoterol for each regimen. 
3.2.1
Primary PK Parameters
•
Maximum plasma concentration (Cmax)
•
Area under the plasma concentration-time curve from 0 the time of the last measurable 
plasma concentration (AUC0-tlast)
3.2.2
Secondary PK Parameters
•
Time to maximum plasma concentration (tmax)
•
Area under the plasma concentration-time curve from 0 extrapolated to infinity (AUC0-);
3.2.3
Other PK parameters
•
Apparent terminal elimination half-life (t½)
•
Apparent total body clearance (CL/F) 
•
Apparent volume of distribution (Vd/F)P
•
7HUPLQDWLRQHOLPLQDWLRQUDWHFRQVWDQWȜ]
•
Time to last measurable plasma concentration (tlast)
3.3
Safety Endpoints
•
Adverse events (AEs)
•
12-lead electrocardiograms (ECGs)
•
Clinical laboratory testing
•
Vital sign measurements


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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a Phase I, randomized, open-label, single-dose, single-center, crossover study to 
assess the PK and safety of BGF MDI in healthy subjects (male or female). The PK profiles 
of each active ingredient (budesonide, glycopyrronium, and formoterol), will be determined 
after administration of BGF MDI with a spacer device (test) and without a spacer device 
(reference), and with and without the concomitant administration of activated oral charcoal to 
estimate total systemic exposure and lung exposure, respectively.
Figure 4-1 summarizes the overall study design, which will comprise the following:
•
A screening period with a maximum duration of 28 days.
•
Four Treatment Periods during which subjects will be resident from the afternoon before 
dosing with BGF MDI until at least 24 hours after dosing and discharged on the morning 
of Day 2 of each Treatment Period. There will be a washout period of 5to 14 days 
between Treatment Periods 1, 2, and 3. 
•
A follow-up phone call will take place within 5 to 7 days following the last 
administration of BGF MDI.
After providing informed consent, subjects will undergo screening procedures. Subjects 
meeting eligibility criteria will be enrolled into the study and admitted to the study site as an 
inpatient on Day -1 of Treatment Period 1, at which time, continuing eligibility will be 
assessed. Device training will be conducted during screening, on admission to each 
Treatment Period, and prior to dosing on Day 1 of each Treatment Period. In addition to 
training with a placebo MDI device, additional inhalation training tools may be used to help 
ensure the subjects are able to use the MDI device correctly.
Study drug will be administered, under fasted conditions, on the morning of Day 1 of each 
Treatment Period, at approximately the same time of day throughout the study (±30 minutes). 
Eligible subjects will receive a single dose of BGF MDI 320/28.8/9.6 μg administered as 
follows:
•
Without a spacer device and without charcoal (regimen A)
•
With a spacer device and without charcoal (regimen B)
•
Without a spacer device and with charcoal (regimen C)
•
With a spacer device and with charcoal (regimen D)
Subjects will receive all 4 regimens (1 regimen per Treatment Period) in 1 of 8 possible 
regimen sequences: AB CD, AB DC, BA CD, BA DC, CD AB, CD BA, DC AB, or DC BA. 


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These regimen sequences allow for subjects who might drop out after 2 Treatment Periods
only to be included in the PK statistical analysis.
Randomization will be performed on the morning of first dosing (Day 1, Treatment Period
1). Randomization codes will be assigned strictly sequentially in ascending order as subjects 
become eligible. 
During their inpatient stay, subjects will undergo safety assessments and have an indwelling 
intravenous cannula for serial PK blood draws. Subjects will be discharged on the morning of 
Day 2 of each Treatment Period after all protocol-specified assessments are completed. There 
will be a washout period of 5 to 14 days between each Treatment Period.
A follow-up phone call will be conducted 5 to 7 days after Treatment Period 4 dosing or after 
the last dose of study drug, whichever comes first.
Figure 4-1
Study Design
4.2
Rationale for Study Design and Control Group
The purpose of this study is to evaluate budesonide, glycopyrronium, and formoterol lung 
and total systemic exposure following administration of BGF MDI. This will be 
accomplished by establishing the relative bioavailability of budesonide, glycopyrronium, and 
formoterol after single-dose administration of BGF MDI with and without a spacer and with 
and without concurrent oral charcoal administration.
A single dose of BGF MDI 320/28.8/9.6 μg (administered as 2 inhalations of BGF MDI 
160/14.4/4.8 μg) will generate sufficient plasma exposure to budesonide, glycopyrronium, 
and formoterol for the assessment of relative bioavailability.


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Considering the elimination half –life of the components of BGF MDI and the time period 
during which plasma concentrations are above the lower limit of quantification, the sampling 
period of 24 hours will be sufficient to adequately estimate the PK parameters.
4.3
Study Duration 
This study will include a Screening Period of up to 28 days and 4 single-dose Treatment 
Periods separated by a Washout Period (minimum of 5 days to a maximum of 14 days) for 
added scheduling flexibility. A follow-up phone call will be conducted 5 to 7 days after 
completion of the last Treatment Period. The maximum participation in the study for each 
subject is approximately 13 weeks. The study is anticipated to run for approximately 3 
months and should not exceed 6 months.


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5
STUDY POPULATION SELECTION
5.1
Study Population
Approximately 56 healthy male or female subjects will be randomized in this study in order 
to ensure approximately 48 subjects complete all 4 Treatment Periods. Subjects who 
withdraw from the study after receiving at least 1 dose of study drug will not be replaced. 
Subjects who are re-screened will maintain 1 screening number throughout the study. The 
study will be conducted at a single center in the United States (US).
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Signed and dated Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB)-approved Informed Consent Form (ICF) before any protocol-specific screening 
procedures are performed
2. Male and female subjects 18 to 40 years of age, inclusive
3. Be in good general health as determined by a thorough medical history and physical 
examination, ECG, vital signs, and clinical laboratory evaluation.
4. Willing and able to complete all study assessments and procedures
5. Agree to one of the following to prevent pregnancy:
-
Non-childbearing potential (ie, physiologically incapable of becoming pregnant, 
including any female who is 2 years post-menopausal, or surgically sterile [defined as 
having a bilateral oophorectomy, hysterectomy or tubal ligation])
-
Practicing abstinence
-
If a sexually active woman of childbearing potential agrees to prevent pregnancy by 
using one of the following methods of birth control from the date the ICF is signed 
until 2 weeks after the final dose of investigational product is taken:
ƕ
Hormonal contraception (eg, oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive)
ƕ
Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide or condom plus spermicide)
ƕ
Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy
-
If a woman of childbearing potential, have a negative serum pregnancy test at 
screening
-
Male subjects who are sexually active must agree to use a double-barrier method of 
contraception (condom with spermicide) from the first dose of randomized study drug 
until 2 weeks after their last dose, and must not donate sperm during their study 
participation period.


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6. Screening laboratory tests must be within normal range or determined to not be clinically 
significant by the Investigator. Subjects must also have normal glomerular filtration rate 
(normal estimated normal glomerular filtration rate [eGFR]  mL/min) using the 
Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI)
7. Screening ECG must be acceptable to the Investigator
8. Demonstrate correct MDI administration technique
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study unless 
otherwise stated:
1. Pregnant or nursing female subjects or subjects who are trying to conceive
2. For female subjects, a positive serum human chorionic gonadotropin (hCG) test at 
screening or a positive urine hCG at admission for any of the 4 Treatment Periods
3. Subjects with clinically significant neurologic, cardiovascular, hepatic, renal, 
endocrinologic, pulmonary, hematological, psychiatric, or other medical illness that 
would interfere with participation in this study
4. Subjects who have cancer that has not been in complete remission for at least 5 years
5. Supine blood pressure (BP) >140/90 mmHg or resting heart rate  bpm at screening
or baseline (pre-dose on Day 1 of the first Treatment Period)
6. Male subjects with symptomatic prostatic hypertrophy that is clinically significant in the
opinion of the Investigator
7. Male subjects with a trans-urethral resection of the prostate or full resection of the 
prostate within 6 months prior to screening
8. Subjects with bladder neck obstruction or urinary retention that is clinically significant in 
the opinion of the Investigator
9. History of substance-related disorders (with the exception of caffeine-related and 
nicotine-related disorders) within 1 year of screening
10. History of smoking or the use of nicotine-containing products within 3 months of 
screening by self-reporting
11. A positive alcohol breathalyzer or urine drug screen for drugs of abuse at screening or at 
the beginning of each Treatment Period
12. Treatment with any prescription or non-prescription drugs including vitamins, herbal, and 
dietary supplements for 28 days or 5 half-lives, whichever is longer, before study drug 
use including restrictions per Sections 5.5and 5.6
13. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is 
longer) prior to the beginning of the screening Period
14. Subjects with a history of an allergic reaction or hypersensitivity to any drug used in this 
study or to any component of the formulations used in this study
15. Subjects with anemia that is considered clinically significant by the Investigator.
16. Seropositivity for human immunodeficiency virus (HIV) at screening


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17. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C antibody at 
screening
18. Subjects with a history of major surgery within 4 weeks or minor surgery within 2 weeks 
of screening
19. Subjects with any flu-like syndrome or other respiratory infections within 2 weeks of 
drug administration or who have been vaccinated with an attenuated live virus within 
4 weeks of drug administration
20. Any other condition and/or situation that causes the Investigator to deem a subject 
unsuitable for the study (eg, inability to medically tolerate the study procedures, or a 
subject’s unwillingness to comply with study-related procedures)
21. Subjects who, in the opinion of the Investigator, have a clinically significant abnormal 
12-lead ECG at screening. A clinically significant abnormal ECG includes, but is not 
limited to, the following:
-
Fridericia corrected QT interval (QTcF) >450 ms for males or >470 ms for females at 
screening
22. Study Investigators, sub-Investigators and coordinators, and their employees or 
immediate family members.
5.4
Subject Identification
All subjects who undergo screening procedures will be assigned a unique screening 
identification number at screening. Only subjects continuing to meet entry 
inclusion/exclusion criteria at Treatment Period 1 will be assigned a unique subject 
randomization number.
5.5
Prior, Concomitant, and Prohibited Medications
Apart from paracetamol/acetaminophen, hormone replacement therapy and systemic 
contraceptives, no concomitant medication or therapy will be allowed. The subjects should 
be instructed that no other medication is allowed, including herbal remedies, vitamin 
supplements and over the counter (OTC) products, without the consent of the Investigator.
When any medication is required, it should be prescribed by the Investigator. Following 
consultation with the Medical Monitor, the Investigator must determine whether or not the 
subject should continue in the study.
The Investigator or designated qualified personnel will assess and record concomitant 
medication usage on the electronic case report form (eCRF). Concomitant medication usage 
will be assessed at screening and throughout the study.
5.6
Restrictions During the Study
The following restrictions apply for the specified times during the study period:


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1. On Day 1 of each Treatment Period, subjects will be fasted for at least 6 hours prior to 
dosing and until after the 4 hours post dose blood draw. No fluids will be allowed apart 
from water, which can be given until 1 hour prior to dosing and resumed 2 hours after 
dosing.
Subjects should not lie fully supine (unless specified for certain assessments) for 4 hours 
after dosing with BGF MDI.
2. Subjects should not engage in any strenuous activity (eg, marathon, marathon training, or
other similar activities) from 72 hours prior to dosing on Day 1 of the first Treatment 
Period until after Treatment Period 4.
3. Prior to each Treatment Period, subjects should abstain from alcohol for 72 hours prior to 
admission to the study unit until after their last PK sample is collected. Between 
Treatment Periods, subjects should consume no more than 2 units of alcohol per day.
4. Prior to each Treatment Period, subjects should abstain from xanthine and/or xanthine 
analogue (caffeine)-containing foods, beverages, and medications from 24 hours prior to 
admission to the study unit until discharge. Examples of such products include coffee, 
tea, chocolate, and cola. When not at the study site, subjects should limit their caffeine 
intake to the equivalent of 3 cups of coffee per day (1 cup = 360 mL soda, 180 mL 
coffee, or 240 mL tea) for the duration of the study.
5. Subjects should abstain from grapefruit or grapefruit juice, Seville oranges (including 
marmalade) and quinine (eg, tonic water) from 7 days prior to admission to the study unit 
on Day -1 of the first Treatment Period until after Day 2 of Treatment Period 4.
6. During the in-patient stay, subjects will receive a standard diet. No food or beverages 
should be consumed while in the clinic other than those provided by the study site.
7. During the outpatient periods, subjects should abstain from consuming high energy 
drinks (eg, Red Bull), food containing poppy seeds (eg, specialty breads and muffins), 
and any over-the-counter (OTC) medication or herbal preparations until after Day 2 of 
the fourth Treatment Period has been completed.
8. Subjects will be instructed to abstain from blood or plasma donation until 3 months after 
study completion.
5.7
Study Withdrawal
The Investigator or medically qualified designee may withdraw a subject at the occurrence of 
any one or more of the following:
•
Protocol deviation
•
AE
•
Subject becomes pregnant
•
Clinically significant change in laboratory parameter(s)
•
Termination of the study by the Sponsor or Investigator
•
Request by the subject to be withdrawn from the study


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•
Investigator’s discretion
Subjects withdrawn from the study after receiving at least 1 dose of study drug will not be 
replaced.


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6
CLINICAL SUPPLY LABELING, PACKAGING, STORAGE, 
DISPENSING, AND RETURN
6.1
Description of Study Drugs
In this protocol, “study drug” refers to an active ingredient or placebo being tested or used as 
a reference in the study (International Conference on Harmonisation E6 (R1). The study drug 
used in this study is described in Table 6-1. Instructions for use/priming are provided in 
Section 6.5, Section 6.6, Section 6.7, Appendix 1 and Appendix 2.
Table 6-1
Description of Study Drugs
Product Name & Dose
Product Strength
Dosage Form/
Fill Count
Administration
BGF MDI 320/28.8/9.6 μg 
ex-actuator
160/14.4/4.8 μg/actuation
MDI
120 inhalations
Taken as 2 inhalations
Note: Study drug will be administered by oral inhalation. A single-dose of study drug will be administered on Day 1 of 
Treatment Periods 1 to 4. Administration of study drug should occur at approximately the same time of day.
6.2
Other Sponsor-Provided Medications Used in the Study
Other Sponsor-provided medications used during the study are described in Table 6-2.
Table 6-2
Other Medications Provided by Sponsor
Product Name & 
Dose
Product Strength
Dosage Form/
Fill Count
Administration
Placebo MDIa
Formulation does 
not contain active 
ingredient
MDI/
120 inhalations
Subjects will use the placebo MDI for 
training purposes only to demonstrate 
proper use of the MDI at screening and on 
Day -1 and Day 1 of each Treatment Period
Actidose-Aqua®
(activated oral 
charcoal
suspension)
50 g/240 mL 
(0.208 g/mL)
Oral suspension
•
Immediately prior to study drug dose: 
10 g (approximately 48 mL of 
suspension) which is to be mouth-
rinsed and swallowed
•
Immediately after study drug dose: 10 g 
(approximately 48 mL of suspension) 
which is to be mouth-rinsed and 
swallowed; repeat at 1 hour and 2 hours 
post dose
•
Administered during regimens C and D
a
Placebo MDI for training purposes. All placebos are created by the Sponsor in the image of the active test product, with 
no active moieties.


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6.3
Packaging and Labeling
Clinical supplies will be packaged to support enrollment of the study. All treatments will be 
open-label. 
Study drug will be packaged in a box and labeled with a single label. Inside the box will be a 
labeled foil pouch containing a labeled MDI canister and actuator.
Each box will be labeled with a 2-part label printed with black ink and may include the 
following items:
Lot # (Packaging Lot Trace ID)
Space for entry of screening #
Component ID#
Randomization #
Fill Count and Dosage Form
Treatment Period #
Storage conditions
Protocol #
Country regulatory requirements
Sponsor address
Translation Key
Abbreviations: #=number; ID=identification
6.4
Storage Requirements
Prior to dispensing, BGF MDI should be stored below 25°C (77°F) in a dry place. Excursions 
permitted up to 30°C (86°F). 
Actidose-Aqua® should be stored between 20°C to 25°C (68°F to77°F) on its side.
All study supplies should be kept in a locked cabinet or room with limited access. The 
temperature of the site’s storage area for study supplies must be monitored by site staff for 
temperature ranges consistent with those specified in this protocol. Documentation of 
temperature monitoring should be maintained at the site and available for review. All study 
supplies contain contents under pressure. Do not use or store near heat or open flame. 
Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into 
a fire or incinerator. Avoid spraying in eyes.
6.5
Instructions for Preparation of Study Drug for Administration and 
Dosing
Individual BGF MDIs will be packaged in a foil pouch and contained in an individual box. 
Both the box and the foil overwrap will have a label with a component ID number. The box 
will be labeled with a 2-part label.
For each subject, study drug will be administered as a single-dose on Day 1 of each of the 4
Treatment Periods. Study drug should be administered in the morning, at approximately the 
same time of day throughout the study (±30 minutes). A total of 56 subject identifiers will be 
randomly assigned to 1 of the following 8 possible regimen sequences: AB CD, AB DC, 


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BA CD, BA DC, CD AB, CD BA, DC AB or DC BA. These regimen sequences allow for 
subjects who might drop out after 2 Treatment Periods only to be included in the statistical 
analysis of the PK.
All MDIs must be primed before the first use. Shaking and priming the inhaler fills a 
chamber inside the canister with the correct dose and mix of medication so that the inhaler is 
ready to use. Priming involves releasing 4 sprays into the air before the first use of the 
inhaler. The MDI must be primed in a separate room, away from the subject treatment area. 
Refer to Appendix 1 for full instructions on priming and administration of BGF MDI.
At screening, on admission to each Treatment Period, and on Day 1 of each Treatment 
Period, subjects will be instructed by site staff on how to use the MDI device correctly using 
placebo MDIs. In addition, MDI training will be supplemented using the Vitalograph AIM 
Aerosol Inhalation Monitor or an equivalent device.
Each dose will consist of 2 puffs from the MDI. BGF MDI will be administered in a separate 
room from the room where blood samples will be drawn. The in-clinic dosing time for study 
drug (BGF MDI) will be recorded as the time of administration of the second puff. During 
administration, subjects and clinic personnel will wear protective clothing and vinyl gloves, 
which will be discarded immediately after administration in the room used for inhalation, to 
avoid subsequent contamination of blood samples, according to the routines at the clinic.
6.6
Instructions for Administration of Activated Oral Charcoal
Actidose—Aqua®, a ready-to-use activated oral charcoal suspension, will be provided by the 
Sponsor. Actidose-Aqua® provides 0.208 g of oral charcoal /mL of suspension.
Actidose-Aqua® will be administered during regimens C and D. Before dosing with study 
drug, subjects will receive 10 g of activated oral charcoal (approximately 48 mL) which they 
are to mouth-rinse and swallow. Immediately after study drug administration, subjects will 
receive another 10 g of activated oral charcoal to mouth-rinse and swallow. This will be 
repeated at 1 and 2 hours post-dose. Post-administration of each dose of oral charcoal,
subjects will rinse their mouths twice with 30 to 60 mL of water which is to be mouth-rinsed
and swallowed.
In total, subjects will receive 40 g activated oral charcoal (or 192 mL) in both regimens C
and D.
6.7
Aerochamber Plus Flow-Vu Instructions for Administration and 
Dispensing of Treatments
The Aerochamber Plus Flow-Vu VHC can be used directly out of the package. Before use 
the VHC cap is to be removed and the chamber is to be examined for any obvious defects.
At the time of first use, ensure that the BGF MDI is primed outside of the VHC according to 
the instructions in Section 6.5 and Appendix 1. Once the MDI is primed, shake the inhaler 
immediately before use per the instructions in Appendix 1. Insert the inhaler into the back 


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part of the chamber, which is the opposite end from the mouthpiece (refer to Appendix 2 for 
a diagram of the VHC).
The inhalation instructions should be followed for taking each dose and subjects should be 
instructed as follows: put the mouthpiece into your mouth and close your lips around the 
mouthpiece to ensure an effective seal. The Flow-Vu indicator only moves if there is a good 
seal. Breathe out gently and press the inhaler at the beginning of a slow inhalation. Use the 
Flow-Vu indicator to assist in the coordination of this step. Breathe in slowly and deeply 
through the mouth until a full breath has been taken. Hold your breath for 5-10 seconds. Slow 
down inhalation if you hear the Flow Signal whistle sound. This means you are inhaling too 
quickly. Administer 1 puff at a time. Shake the MDI prior to each dose inhalation during 
dosing and repeat VHC instructions for use.A new VHC is to be dispensed for each 
Treatment Period in which it is used. Each subject will also be provided with a separate VHC 
for use in practice sessions.
The VHC should not be cleaned. 
Store the VHC at room temperature and keep dry.
Refer to Appendix 2 for instructions for use of the Aerochamber Plus Flow-Vu VHC.
6.8
Dispensing Study Drug
All subjects will receive BGF MDI without spacer and without oral charcoal (regimen A),
BGF MDI with spacer and without oral charcoal (regimen B), BGF MDI without spacer and 
with oral charcoal (regimen C), and BGF MDI with spacer and with oral charcoal 
(regimen D) in a random assignment to 1 of 8 predetermined regimen sequences on the 
morning of the first dosing (Day 1, Treatment Period 1). Randomization codes will be 
assigned in ascending order as subjects become eligible. At screening, Day -1, and before 
study drug dosing on Day 1 of each Treatment Period, subjects will be trained on and must 
demonstrate proper use of an MDI using a bulk-supplied MDI (placebo). Subjects must 
demonstrate the ability to use the MDI correctly, including the ability to coordinate actuation 
with inspiration.
A new BGF MDI will be dispensed for each Treatment Period. On Day 1 of the Treatment 
Period, prior to dosing, the MDI device will be primed in the study site pharmacy by the 
pharmacist and delivered to the delegated staff (See Appendix 1 for MDI device priming 
instructions). On Day 1 of each Treatment Period, subjects will again be trained on and must 
demonstrate proper use of the MDI device. At the time of all study drug dosing, trained site 
staff will be present to ensure that the subject properly administers the required number of 
actuations from the MDI device. Any occurrence of cough, interruption of the inhalation 
process or leakage around the lips/mouth during inhalation will be recorded.
6.9
Study Drug Accountability/Return of Clinical Supplies
Under no circumstance will the Investigator(s) allow the study drugs to be used other 
than as directed by this protocol.


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Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
appropriate designated personnel have access. Storage conditions for the clinical supplies 
should be observed, monitored, and documented. Clinical supplies are to be dispensed only 
in accordance with the protocol. The Investigator is responsible for keeping accurate records 
of the clinical supplies received from the Sponsor, the amount dispensed to and returned by 
the subjects, and the amount remaining at the conclusion of the study. Study drug should be 
handled in accordance with Good Pharmacy Practices. The Medical Monitor should be 
contacted with any questions concerning investigational products where special or protective 
handling is indicated. At the end of the study, all clinical supplies, including partial and 
empty containers, must be returned as directed by the Sponsor.
The study site should check with the Sponsor’s representative for appropriate documentation 
that needs to be completed for drug accountability.
For each subject, all used study drug will be collected. Used subject supplies will be kept at 
room temperature in a secure and locked cabinet until returned to the Sponsor.
Note: Used study drug will be stored separately from unused study drug.
All product complaints (including device malfunctions) must be reported to the Sponsor or 
the Sponsor’s representative using the Product Complaints Form provided in each site’s 
regulatory binder. The Sponsor or the Sponsor’s representative will contact the site to 
evaluate the nature of the complaint, related testing and determine if further action is needed.


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7
STUDY PROCEDURES
7.1
Informed Consent
The ICF must be executed prior to performing any study-related activities. The ICF must be 
approved by the reviewing IEC/IRB. Informed consent will be obtained for all subjects 
participating in the study. Subjects may withdraw consent at any time. Participation in the 
study may be terminated at any time without the subject’s consent as determined by the 
Principal Investigator.
7.2
Subject Eligibility
Eligibility screening of healthy subjects will be completed within 28 days prior to 
administration of the first dose of study drug and will be documented on the eCRF. 
Eligibility will be confirmed at each clinic admission (Day -1).
Screen failures and the reason for failure to meet the study eligibility requirements will be 
documented in the study site source documents and documented in the eCRF.
7.3
PK Assessments
Pharmacokinetic sampling will occur during each Treatment Period. Sample collections will 
be scheduled for the nominal time point and actual collection times will be recorded in the 
source documents (Refer to Table 8-2).
7.3.1
Blood Sample Collection Schedule
Approximately 10 mL of whole blood will be collected within 60 minutes prior to study drug 
dosing and then at 2, 6, 20, and 40 minutes post-dose and 1, 2, 4, 8, 12 and 24 hours post 
dose (see also Table 8-2 and Table 8-3).
Subjects must fast for at least 6 hours prior to study drug administration during each 
Treatment Period. Meals during each Treatment Period will be standard and will begin after
the 4 hour post-dose blood draw.
The recommended time windows for post-dose PK assessments are as follows:
Table 7-1
Time Window for Post-dose PK Assessments
Time Point
Time Window
2 and 6 minutes
±1 minute
20 and 40 minutes and 1 hour
±2 minutes
2 and 4 hours
±5 minutes
8, 12, and 24 hours
±10 minutes
Collection and storage of PK samples will be provided in the laboratory manual


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7.3.2
Procedure for Shipping Samples
Samples are to be shipped frozen by overnight courier to the bioanalytical laboratory for 
analysis. Instructions for sample handling, storage, and shipping will be provided in the 
laboratory manual.
7.3.3
Storage and Destruction of PK Samples
Samples for determination of drug concentration in plasma will be analyzed by the 
bioanalytical laboratory on behalf of the Sponsor using an appropriate bioanalytical method. 
Full details of the analytical method used will be described in a separate bioanalytical report.
Pharmacokinetic samples will be disposed of after the bioanalytical report finalization or 6 
months after issuance of the draft bioanalytical report (whichever is earlier), unless requested 
for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be reported 
separately from the clinical study report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the clinical study 
report but separately in a bioanalytical report.
7.4
Safety Assessments
7.4.1
Medical History
Relevant medical history will be obtained from the subject at screening and at each clinic 
admission (Day -1) and recorded on the source document. Medical history will capture the 
subject’s family health history, history of hospitalization, and history of surgeries.
7.4.2
Physical Examination
A complete physical examination including height and weight will be performed at screening
(height and weight at screening only) and on Day 2 at the end of Treatment Period 4. An 
abbreviated physical examination will be conducted at Day -1 of each Treatment Period. The 
findings of each examination will be recorded on the source documents and clinically 
significant abnormalities will be recorded on the Medical History eCRF (prior to any study 
drug administration) and on the AE eCRF during the randomized Treatment Period. The 
physical examination will include the following:
COMPLETE PHYSICAL EXAMINATION
The complete physical examinations will include an assessment of the general appearance, 
skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, respiratory, 


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cardiovascular, musculoskeletal, abdominal, extremities, neurological and dermatological.
Height and weight will be measured at screening only.
BRIEF (ABBREVIATED) PHYSICAL EXAMINATION
The brief physical examination will include an assessment of the general appearance, skin, 
abdomen, cardiovascular system, and respiratory.
7.4.3
Vital Signs
Vital signs (BP and heart rate) will be determined after a subject has rested for 5 minutes in a
supine position at screening, on the day of each clinic admission (Day -1), on Day 1 prior to 
study drug administration, and on Day 2 of Treatment Period 4 (see Table 8-1).
7.4.4
12-Lead Electrocardiogram
Twelve-lead ECGs will be recorded at screening and on Day 2 of Treatment Period 4
(Table 8-1). Subjects should rest in a supine position for at least 5 minutes before and during 
the ECG recording procedure. Subjects with any ECG abnormality should be evaluated by 
the Investigator to determine if the abnormality is clinically significant. All clinically 
significant abnormalities after administration of randomized study drug will be reported as 
AEs and followed closely by the Investigator in order to assure the safety of the study 
subject.
7.4.5
Clinical Laboratory Tests
7.4.5.1
Laboratory Parameters
Laboratory testing (hematology with differential, chemistry, and urinalysis) will be 
performed using standard methods. Blood and urine samples for the clinical laboratory tests 
listed in Table 7-2 will be collected at screening and on Day 2 of Treatment Period 4
(Table 8-1). Subjects must fast for at least 6 hours prior to any scheduled clinical laboratory 
assessment blood draw.


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Table 7-2 
List of Laboratory Tests
Hematology
Chemistry
Hematocrita
Hemoglobin
Platelet count
Red blood cell count
White blood cell count
WWhite blood cell differential
Mean corpuscular volume 
MCH concentration 
Creatinineb
Potassium 
Sodium 
Chloride 
Magnesium 
Calcium 
Inorganic phosphate
Glucose
Urea
Bilirubin (total)
Bilirubin (direct)
Alanine aminotransferase
Aspartate aminotransferase
Gamma-glutamyltransferase
Alkaline phosphatase
Total protein
Albumin
Urinalysis: Macroscopic examination routinely including specific gravity, pH, protein, glucose, ketones, blood, 
and urobilinogen. A microscopic examination will be performed if warranted based on macroscopic results.
Urine drug screen: A urine sample will be collected at screening and Day-1 of each Treatment Period and 
analyzed (positive or negative) for drugs of abuse including amphetamine, opiate, cocaine, barbiturates, 
benzodiazepines, cotinine and marijuana (tetrahydrocannabinol)
Alcohol breathalyzer test: A breathalyzer test will be performed at screening and Day -1 of each Treatment 
Period for the presence of alcohol (positive or negative)
Serology: Testing for HbsAg, Hepatitis C antibody, and HIV will be performed at screening only. Results of 
each serology test will be reported as either positive or negative.
For females who are not post-menopausal: A serum hCG test at screening and urine hCG test at admission 
will be performed during each of the 4 Treatment Periods.
For females of non-childbearing potential: A serum hCG test at screening will be performed. In addition, a 
serum FSH test for confirmation of non-childbearing status will be performed at screening. 
Abbreviations: FSH=follicle-stimulating hormone; MCH=mean cell hemoglobin
a
Packed cell volume
b
Serum creatinine value will be used to calculate eGFR using CKD-EPI.
7.4.5.2
Sample Collection, Storage, and Shipping
Detailed instructions for laboratory sample collection, processing, and shipping instructions 
will be provided in the 
. laboratory manual. Approximately 480 mL of 
blood will be collected per subject during the study (approximately 440 mL for PK 
assessments and 40 mL for laboratory assessments).
Biological material will be stored and secured in a way that assures that unauthorized access 
is prohibited and the samples are not lost, deteriorated, or accidentally or illegally destroyed. 
Details for storage and shipping will be provided in the 
 laboratory 
manual.


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7.5
Adverse Event Assessments
7.5.1
Performing Adverse Event (AE) Assessments
The Investigator is responsible for promptly documenting and reporting all AEs observed 
during the study in the subject’s eCRF and on the AE Reporting Form. If the AE is 
unexpected, the Investigator should report the AE immediately to the Sponsor. In addition, 
certain AEs (as described in Section 7.5.7) are classified as ‘serious' and must be reported no
later than 24 hours after the Investigator recognizes/classifies the event as a serious adverse 
event (SAE) to the Sponsor or its designee.
In the case of SAEs, after discussing the details of the AE, the Investigator and the Medical 
Monitor may withdraw the subject from the study.
7.5.2
AE Definitions
The following definitions of terms are guided by the International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use, the US Code of Federal Regulations (21 CFR 312.32), and European Union Directive 
2001/83/EC and are included herein.
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug, without any judgment about 
causality. An AE can arise from any use of the drug (eg, off label use, use in combination 
with another drug) and from any route of administration, formulation, or dose, including an 
overdose.
Adverse events include, but are not limited to the following:
•
any symptom or condition not previously reported by the subject (medical history).
•
an exacerbation of a pre-existing symptom or condition.
•
a significant increase in frequency or intensity of a pre-existing episodic event or 
condition.
•
a drug interaction.
•
a condition first detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study.
An AE does not include the following:
•
medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that led to the procedure is an AE (eg, bleeding esophageal 
varices, dental caries).


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•
overdose of either study drug or concurrent medication without any clinical signs or 
symptoms.
•
abnormal laboratory values that are not clinically significant;. if accompanied by 
signs/symptoms, the signs or symptoms are considered an AE.
7.5.3
Pre-Randomization AEs
Any AE occurring from the time the subject signs informed consent until the subject 
administers the first dose of study drug will be summarized as medical history and not as a 
AE unless the event meets the definition of an SAE as defined in Section 7.5.7.
7.5.4
Severity
The Investigator must categorize the severity of each AE according to the following 
guidelines:
Mild: associated with no limitation of usual activities or only slight discomfort; generally not 
requiring alteration or cessation of study drug administration; and/or not needing therapeutic 
intervention.
Moderate: associated with limitation of usual activities or significant discomfort; generally 
requiring alteration or cessation of study drug administration; and/or requiring therapeutic 
intervention.
Severe: associated with inability of subject to carry out usual activities or very marked 
discomfort; considered to be life-threatening; resulting in significant disability or incapacity; 
and requiring therapeutic intervention.
7.5.5
Relationship to Study Drug
The Investigator will assess causal relationship between investigational product and each AE 
and answer yes/no to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes’.
7.5.6
Clinical Laboratory Adverse Events
Many laboratory abnormalities observed during the course of a study will be included under 
a reported AE describing a clinical syndrome (eg., elevated blood urea nitrogen and 
creatinine in the setting of an AE of renal failure, or decreased hemoglobin in a case of
bleeding esophageal varices). Isolated laboratory abnormalities should be reported as AEs if 
they are considered to be clinically significant by the Investigator.


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Criteria for a "clinically significant" laboratory abnormality are the following:
•
a laboratory abnormality that leads to a dose-limiting toxicity (eg, an abnormality that 
results in study drug dose reduction, suspension, or discontinuation).
•
a laboratory abnormality that results in any therapeutic intervention (ie, concomitant 
medication or therapy).
•
any other laboratory abnormality judged by the Investigator to be of any particular 
clinical concern (eg, significant fall in hemoglobin not requiring transfusion).
For laboratory abnormalities that do not meet the above criteria, but are outside of normal 
range (eg, < or > normal reference range), the Investigator should indicate whether the value 
is clinically significant or not clinically significant for the subject.
7.5.7
SAEs
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes:
•
Death
•
A life-threatening AE
•
Inpatient hospitalization or prolongation of existing hospitalization 
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they jeopardize the subject or require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse.
Hospitalization for a pre-existing condition, including elective procedures, which has not 
worsened, does not constitute an SAE.
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does 
not include an adverse reaction or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death.


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An AE or suspected adverse reaction is considered unexpected if it is not listed in the current 
BGF MDI Investigator Brochure or is not listed at the specificity or severity that has been 
observed.
7.5.7.1
REPORTING SAEs
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities 
for AE identification, documentation, grading, assignment of causality, and prompt 
notification of SAEs to the Sponsor. All SAEs must be reported to the Sponsor no later than 
24 hours after the Investigator recognizes/classifies the event as an SAE. All SAEs should be 
documented and reported using the eCRF. At a minimum, a description of the event and the 
Investigator’s judgment of causality must be provided at the time of the initial report using 
the appropriate form (eg, SAE Report Form). After the initial report, as necessary, the 
Investigator must provide any additional information on an SAE to the Sponsor within 2 
working days after he/she receives that information. This follow up information will include 
a detailed summary of hospital records, case reports, autopsy reports, and other pertinent 
documents which will be summarized in the eCRF.
Post-study SAEs must be reported to the Sponsor as described in Section 7.5.9.
The Investigator is responsible for continuing to report any new or relevant follow-up
information that s/he learns about the SAE.
7.5.8
Supplemental Investigation of SAEs
The Investigator and supporting personnel responsible for subject care should discuss with 
the Sponsor any need for supplemental investigations of SAEs. The results of these 
additional assessments conducted must be reported to the Sponsor. If a subject dies during 
participation and if a post-mortem examination is performed, a copy of the autopsy report 
must be submitted to the Sponsor.
7.5.9
Post-Study Follow-Up of AEs
Any AEs that are unresolved at the subject’s last AE assessment in the study are to be
followed up by the Investigator for as long as medically indicated, but without further 
recording in the eCRF. The Sponsor retains the right to request additional information for 
any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
7.5.10
Notification of Post-Treatment SAEs
Investigators are not obligated to actively follow subjects after the completion of the study. 
However, if the Investigator becomes aware of a post-treatment SAE occurring within the 5 
to 7 days following the last dose of study drug, it must be reported to the Sponsor, whether or 
not the event is attributable to study drug. All SAEs must be reported to the Sponsor no later 
than 24 hours after the Investigator recognizes/classifies the event as an SAE.


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7.5.11
IRB/IEC Notification of SAEs
The Investigator is responsible for promptly notifying her/his IRB/IEC of all SAEs, including 
any follow-up information, occurring at her/his site and any SAE regulatory report, including 
any follow-up reports received from the Sponsor. Documentation of IRB/IEC submission 
must be retained for each safety report. The Investigator is also responsible for notifying the 
Sponsor if their IRB/IEC requires revisions to the ICF or other measures based on its review 
of an SAE report.
7.5.12
Health Authority Safety Reports
The Sponsor will submit a safety report to the appropriate Regulatory Agencies for any 
suspected adverse reaction that is both serious and unexpected within the appropriate time 
frame specified by each regulatory agency.
The Sponsor will send copies of each safety report to Investigators who are actively 
participating in a Pearl sponsored clinical study. Safety reports must also be submitted to the 
appropriate IRB/IECs as soon as possible. Documentation of the submission to the IRB/IEC 
must be retained for each safety report.
7.5.13
Overdose
An overdose is defined as any dose greater than the highest dose investigated in this study,
that results in clinical signs and symptoms. In the event of a study drug overdose, the 
Investigator should use their best clinical judgment in treating the overdose, and the Sponsor 
should be contacted. Investigators should refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, AEs, and other significant 
data pertaining to the study drug(s) being administered. Such document(s) may include, but 
are not limited to: the Investigator Brochure for BGF MDI and approved product labeling for 
open-label products.
7.5.14
Pregnancy
To ensure subject safety, each pregnancy from screening until study completion must be 
reported to the Sponsor within 24 hours of learning of its occurrence. The pregnancy should 
be followed in its entirety to ascertain outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a 
Paper Pregnancy Report Form and reported by the Investigator to the Sponsor. Pregnancy 
follow-up should be recorded on the same pregnancy paper form and should include possible 
relationship to the study drug in response to the pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form.
7.5.15
Paternal Exposure
Male subjects who are sexually active must agree to use a double-barrier method of 
contraception (condom with spermicide) from the first dose of study drug until 2 weeks after 


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their last dose, and must not donate sperm during their study participation period. If a male 
subject’s partner becomes pregnant during the course of the study, it must be reported to the 
Sponsor within 24 hours of the Investigator learning of its occurrence.
7.6
Termination of the Study
An Investigator may choose to discontinue study participation at any time with sufficient 
notice by the Investigator, for any reason, as per the terms of the contract.
The Sponsor reserves the right to terminate the study at any time for clinical or 
administrative reasons. Such a termination must be implemented by the Investigator, if 
instructed to do so by the Sponsor, in a time frame that is compatible with the subjects’ 
wellbeing.


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8
STUDY ACTIVITIES
A schedule of events is provided in Table 8-1. Detailed schedules of inpatient 
assessments for Treatment Periods 1, 2, and 3 are provided in Table 8-2 and in Table 8-3
for Treatment Period 4. Refer to Section 7 for study procedure details.
Table 8-1
Schedule of Events for Screening, Treatment, and Follow-Up
Screening
Treatment Periods 1, 2, 3, and 4
Follow-up phone 
call 5 to 7 days 
post-final dose
Day -1
Days 1 and 2
Informed consent
X
Medical history
X
X
Demographics
X
Physical exama
X
X
X
Vital signs (BP, 
heart rate)b
X
X
X
Device training 
(pMDI and, where 
applicable, spacer)c
X
X
X
12-lead ECGd
X
X
Clinical laboratory 
testinge
X
X
Viral serologyf
X
Urinary drug screen 
including cotinine
X
X
Alcohol 
breathalyzer test
X
X
Pregnancy testing 
(females only)g
X
X
FSH (women not of 
child-bearing 
potential only)
X
Eligibility review
X
X
X
Inpatient admission
X
Randomizationh
X
Study drug 
administrationi,j
X
AEsk
X
X
X
X
Concomitant 
medication 
X
X
X
X


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Table 8-1
Schedule of Events for Screening, Treatment, and Follow-Up
Screening
Treatment Periods 1, 2, 3, and 4
Follow-up phone 
call 5 to 7 days 
post-final dose
Day -1
Days 1 and 2
PK assessmentsl
X
Inpatient 
dischargem
X
Abbreviations: AE=adverse event; BP=blood pressure; ECG=electrocardiogram; FSH=follicle-stimulating hormone; 
HbsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; PK=pharmacokinetic; pMDI=pressurized 
metered-dose inhaler; SAE=serious adverse event
a
Refer to Section 7.4.2 for assessments to be included in the physical examination. A full physical 
examination is to be conducted at screening and on Day 2 of Treatment Period 4 (height and weight at 
screening only). A brief physical examination will be done on Day -1 of each Treatment Period.
b
Refer to Section 7.4.3 for details on the timing of vital sign assessments to be obtained during screening, on 
Day -1 and Day 1 of each Treatment Period, and on Day 2 of Treatment Period 4.
c
In addition to training with placebo MDIs, and spacer as applicable inhalation training tools may be used to 
help ensure the subjects are able to use the MDI device correctly. Device training will be conducted during 
screening, on admission to each Treatment Period, and prior to dosing on Day 1 of each Treatment Period.
d
Refer to Section 7.4.4 for details on the timing of ECG assessments to be obtained during screening and on 
Day 2 of Treatment Period 4.
e
Refer to Section 7.4.5 for details on the clinical laboratory assessments to be obtained during screening and 
on Day 2 of Treatment Period 4.
f
Refer to Table 7-2 for details on the serology assessments (HbsAg, hepatitis C antibody, and HIV)
g
Serum pregnancy test will be performed at screening. For women for child-bearing potential, urine 
pregnancy tests will be performed at Day -1 of each Treatment Period.
h
Randomization done on Day 1 of Treatment Period 1.
i
Activated oral charcoal dosing will be administered according to randomization. regimens A & B do not 
receive activated oral charcoal whereas regimens C & D do receive activated oral charcoal. Dosing is as
follows: Immediately prior to study drug dosing, subjects will receive 10 g. immediately after study drug 
dosing, subjects will receive another 10 g; repeat at 1 hour and 2 hours post-dose. Each dose of activated 
oral charcoal will be followed by a mouth-rinse and swallow with 30-60 mL water.
j
Study drug is to be administered on Day 1 (0 h) of each Treatment Period at approximately the same time 
of day throughout the study (±30 minutes).
k
Any AEs collected before the first dose of study drug of Treatment Period 1 should be recorded as medical 
history and not as an AE unless it meets the criteria for an SAE.
l
Refer to Section 7.3, Table 8-2 and Table 8-3 for timing of PK assessments.
m
Discharge to take place after all PK samples have been collected on Day 2 of each Treatment Period. A
washout period of at least 5 days to a maximum of 14 days, must occur after Treatment Periods 1, 2, and 3.


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Table 8-2
Timing of Assessments on Day 1 During Inpatient Treatment Periods 1, 2, and 3
Procedure
Time Relative to Drug Administration
-60 min
0 hr
2 mins
6 mins
20 mins
40 mins
1 hr
2 hrs
4 hrs
8 hrs
12 hrs
24 hrs
PK sample collection
Xa
X
X
X
X
X
X
X
X
X
X
Device training (pMDI 
and, where applicable, 
spacer)b
X
Administer oral 
charcoalc
X
X
X
X
Administration of 
study drugd
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event; PK=pharmacokinetic; pMDI=pressurized metered dose inhaler.
a
Within 60 minutes prior to dosing
b
In addition to training with placebo MDIs, and spacer as applicable inhalation training tools may be used to help ensure the subjects are 
able to use the MDI device correctly.
c
Administer activated oral charcoal immediately pre-dose and immediately post-dose, then 1 hour and 2 hours post dose for regimens C
and D only (refer to Section 6.6 for details regarding activated oral charcoal administration).
d
Study drug will be administered by oral inhalation. A single-dose of study drug will be administered on Day 1 of each Treatment 
Period.


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Table 8-3
Timing of Assessments on Day 1 During Inpatient Treatment Period 4
Procedure
Time Relative to Drug Administration
-60 min
0 hr
2 mins
6 mins
20 mins
40 mins
1 hr
2 hrs
4 hrs
8 hrs
12 hrs
24 hrs
PK sample collection
Xa
X
X
X
X
X
X
X
X
X
X
Device training (pMDI and, where 
applicable, spacer)b
X
Administer oral charcoalc
X
X
X
X
Administration of study drugd
X
12-lead ECG
X
Clinical laboratory testse
X
Vital Signs
X
Physical Examination
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event; PK=pharmacokinetic; pMDI=pressurized metered dose inhaler.
a
Within 60 minutes prior to dosing
b
In addition to training with placebo MDIs, and spacer as applicable inhalation training tools may be used to help insure the subjects are able to 
use the MDI device correctly.
c
Administer activated oral charcoal immediately pre-dose and immediately post-dose then 1 hour and 2 hours post dose for regimens C & D 
(refer to Section 6.6 for details regarding oral charcoal administration).
d
Study drug will be administered by oral inhalation.
e
Refer to Section 7.4.5; for laboratory testing (hematology with differential, chemistry, and urinalysis) to be performed using standard methods. 
Subjects must be fast for at least 6 hours prior to blood draw.


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8.1
Screening (Days –28 to -1)
The following procedures and assessments will be performed during screening and results 
documented in the eCRF and/or source documents:
•
Obtain informed consent
•
Review inclusion/exclusion criteria
•
Obtain demographic data, including age, race, smoking history/status, and relevant 
medical history
•
Conduct a serum pregnancy test for all female subjects (childbearing and non-
childbearing potential)
•
Obtain FSH test for women of non-childbearing potential
•
Conduct complete physical examination including height and weight
•
Obtain vital signs (heart rate and BP) after being supine for 5 minutes
•
Obtain a 12-lead ECG
•
Obtain a urine drug screen including cotinine
•
Conduct an alcohol breathalyzer test
•
Confirm subject’s ability to use MDI and spacer correctly (provide training as needed)
•
Document any prior and concomitant medications
•
Obtain laboratory samples (hematology, serology, chemistry, and urinalysis)
•
Document AEs (Note: AEs that occur prior to dosing will be recorded as medical history 
unless the event meets the definition of an SAE as defined in Section 7.5.7)
8.2
Treatment Periods 1, 2, 3, and 4
8.2.1
Clinic Admission (Day -1)
Subjects will be admitted to the clinic on Day -1, the day prior to administration of study 
drug for each Treatment Period. The results of the following procedures and assessments will 
be documented in the eCRF and/or source documents:
•
Review inclusion/exclusion criteria and confirm subject eligibility to continue
•
Review relevant medical history
•
Review any prior and concomitant medications and document any changes
•
Obtain a urine pregnancy test for all female subjects of childbearing potential
•
Obtain a urine drug screen including cotinine


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•
Conduct alcohol breathalyzer test
•
Conduct a brief physical examination 
•
Obtain vital signs (heart rate and BP) after being supine for 5 minutes
•
Confirm subject’s ability to use MDI and spacer correctly (provide training as needed)
•
Document AEs (Note: AEs that occur prior to first dose of randomized study drug in 
Treatment Period 1will be recorded as medical history unless the event meets the 
definitions of an SAE as defined in Section 7.5.7)
8.2.2
Treatment Days (Day 1 to Day 2)
The following study activities and assessments will be performed on Days 1 and 2 of each 
Treatment Period (unless otherwise indicated) and will be documented in the eCRF and/or 
source documents:
•
Obtain vital signs (heart rate and BP) after being supine for 5 minutes (Day 1 of each 
Treatment Period and Day 2 of Treatment Period 4)
•
Conduct brief physical examination 
•
Review inclusion/exclusion criteria and confirm subject eligibility
•
Confirm subject's ability to use MDI and spacer correctly (provide training as needed)
•
Collect pre-dose PK samples per Table 8-2 for Treatment Periods 1, 2 and 3 and per 
Table 8-3 for Treatment Period 4.
•
Obtain subject randomization number and regimen assignment (with/without 
Aerochamber Plus VHC and with and without charcoal) information in Treatment Period 
1
-
Allow proper time prior to dosing to remove the seal around the study day treatment 
box, and read any instructions for administration of study drug that are to be 
followed. 
-
Refer to Section 6. for detailed instructions for preparation of treatments for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits. 
-
The subject is to be considered randomized after receiving a randomization number. 
-
Ensure appropriate training for the MDI providing instructions for use to the subject. 
The subject should demonstrate proper MDI administration technique prior to dosing
(with and without Aerochamber, with and without oral charcoal), using an AIM or 
equivalent device as appropriate
-
Administer activated oral charcoal pre-dose for regimens C and D only (refer to 
Section 6.6, Table 8-2 and Table 8-3 for details regarding oral charcoal 
administration).


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-
After priming of study drug by site staff, subject should self-administer dose of 
randomized study drug under supervision by site staff (refer to Section 6 and 
Appendix 1 for details regarding study drug priming, dispensing and administration)
-
Administer activated oral charcoal post-dose for regimens C and D only (refer to 
Section 6.6, Table 8-2 and Table 8-3 for details regarding oral charcoal 
administration).
•
Collect post-dose PK samples per Table 8-2 for Treatment Periods 1, 2 and 3 and per 
Table 8-3 for Treatment Period 4. The 24-hour post-dose sample will be collected on the 
morning of Day 2 of all Treatment Periods.
•
Document any AEs (Note: AEs that occur prior to first dose of randomized study drug in 
Treatment Period 1will be recorded as medical history unless the event meets the 
definition of an SAE as defined in Section 7.5.7)
•
Document any use of concomitant medications
•
For Treatment Periods 1, 2, and 3: 
-
Discharge subject from the clinic following completion of all protocol-specified 
procedures and after all available safety data have been reviewed by the Investigator.
-
Schedule the next Treatment Period at least 5 days and no more than 14 days later.
•
For Treatment Period 4:
-
Obtain 12-lead ECG (Treatment Period 4 Day 2 only)
-
Obtain laboratory samples: hematology, chemistry, and urinalysis (Treatment Period
4 Day 2 only)
-
Discharge subject from the clinic following completion of all protocol-specified 
procedures and after all available safety data have been reviewed by the Investigator
-
Schedule follow-up phone call to occur between 5 to 7 days after dosing in Treatment 
Period 4.
8.3
Follow-up Phone Call
Upon completion of the study, a follow-up phone call will be conducted 5 to 7 days after 
Treatment Period 4 dosing or, if the subject withdraws from the study, 5 to 7 days after the 
last dose of study drug.
•
Review and document any AEs and/or concomitant medications


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9
PLANNED STATISTICAL METHODS
9.1 
General Considerations 
The general approach for statistical analyses are provided below. A detailed Statistical 
Analysis Plan (SAP) will be finalized prior to database lock. 
9.2 
Determination of Sample Size 
Even though this study is being conducted for estimation purposes,
 a sample size of 48 subjects 
completing the study will provide 
 probability to observe a 
 lower 
confidence bound for the geometric mean ratio (D/C) that is greater than 
. 
9.3 
Analysis Populations 
9.3.1
Safety Population
Safety and tolerability analyses will be performed on data from all subjects in the Safety 
Population which includes all randomized subjects who received at least 1 dose of BGF 
MDI.
9.3.2
PK Population
The PK Population will consist of all subjects in the Safety Population set for whom at least 
1 of the primary PK parameters for a given analyte can be calculated and who have no 
important protocol deviations thought to impact on the analysis of the PK data (details to be 
provided and documented prior to database lock). Subjects will be analyzed according to 
treatment received rather than randomized.
Pharmacokinetic analysis will be performed using the PK Population. 
9.4 
Demographics and Baseline Characteristics 
Demographic information will include age, gender, ethnicity, and race. Demographics and 
baseline characteristics will be summarized descriptively for both the Safety and PK 
Populations. Height and weight, which are considered baseline characteristics and 
documented as part of the physical examination performed at screening, will be reported with 
the demographic information listed above. 


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9.5
Statistical Analysis of PK Variables 
9.5.1
PK Parameters
Pharmacokinetic parameters will be estimated by non-compartmental analysis (NCA) using 
From the plasma budesonide, 
glycopyrronium and formoterol concentration-time data, the following PK parameters will be 
estimated for each subject where possible: 
AUC0-tlast
The area under the plasma concentration-time curve from 0 to the time of the 
last measurable plasma concentration
AUC0-
The area under the plasma concentration-time curve from 0 extrapolated to 
infinity
Cmax
The maximum plasma concentration, expressed in concentration units 
tmax
The time to reach maximum plasma concentration, expressed in hours
t1/2
The apparent terminal elimination half-life, expressed in hours, calculated as 
OQȜz
CL/F
The apparent total body clearance
Vd/F
The apparent volume of distribution 
Ȝz
The terminal elimination rate constant, calculated from the slope of the terminal 
portion of the ln (drug concentration) versus time curve
tlast
The time to last measurable plasma concentration
The AUC0-tlast and AUC0- will be calculated using the linear-log trapezoidal method.
The PK parameters Cmax and tmax will be obtained from the observed values. 
The Ȝz will be estimated for each subject where feasible by linear regression analysis, 
calculated from the slope of the terminal portion versus time curve. Selection of data points 
WRLQFOXGHLQWKHHVWLPDWLRQRIȜz for each subject for each Treatment Period will be based on 
the following criteria:
•
All samples used should preferably fall in the log-linear elimination phase.
•
At least 3 samples above the lower limit of quantification (LLQ) should be used in the 
estimation.
•
Cmax must not be used in the estimation.  
•
The elimination rate constant will not be estimated where below LLQ values occur in the 
terminal phase between quantifiable (non-zero) values.
In order for the selection to take place the adjusted r2 value reported in 
must be  0.7. 


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9.5.2
Handling of Values that are Below the Limit of Quantification
Plasma concentration values that are reported as below the LLQ will be set to missing in the 
NCA. Actual sampling timepoints relative to dosing will be used for the NCA where 
available. If the actual sampling time is unknown, the scheduled protocol time may be used 
for the calculation of derived PK parameters. No formal “outlier” analysis is planned. 
All values below LLQ, except pre-dose, will be assigned a value of ½ LLQ for all descriptive 
statistics categories.
9.5.3
Statistical Analysis of PK Data
Descriptive statistics for plasma concentrations of budesonide, glycopyrronium, and 
formoterol by regimen and nominal timepoint will be summarized on the linear and log-
linear scale using the PK Population. Individual plasma concentrations at each nominal and 
actual time point for each regimen will be listed by subject using the Safety Population.
The treatment ratio of each of the test formulations (regimen B or regimen D) will be 
compared to the reference formulations (regimen A or regimen C) for budesonide, 
glycopyrronium, and formoterol.
The statistical analysis will be conducted separately for the following:
•
Total systemic exposure: regimen B versus regimen A
•
Lung exposure: regimen D versus regimen C
Treatment comparisons of primary PK parameters will be assessed on the difference of log-
transformed Cmax, AUC0-tlast and AUC0- of budesonide, glycopyrronium, and formoterol 
using a 2-sided 90% CI approach based on an analysis of variance model including period,
sequence, regimen and subject as fixed effects. Estimated geometric mean ratios with 90% 
CIs will be provided. 
Only the data for the comparison under investigation will be included in the statistical 
analysis, e.g., when comparing regimen B and regimen A, the data for the other regimens
will be removed from the dataset. Subjects must have a primary PK parameter available for 
both regimens for the given analyte under consideration in order to be included in a specific 
analysis. A subject may therefore be included in the analysis for one parameter and not for 
another.
Descriptive statistics for PK parameters by regimen will be summarized. The number of 
observations (n), mean, coefficient of variation (CV) %), standard deviation, standard error, 
median, minimum, maximum, geometric mean, and geometric coefficient of variation by 
regimen will be provided.
No hypothesis test will be performed for this study.


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9.6
Safety Analysis
No formal statistical analysis of safety data is planned. Safety data will be summarized by 
regimen and listed based on the Safety Population. 
9.6.1
AEs
Adverse events occurring during each Treatment Period will be summarized by the number 
of subjects experiencing an event and tabulated at the level of the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, and system organ class. The version of 
MedDRA current at the time of database lock will be used for the final analysis of data. 
Tabulations will be broken down by severity, seriousness, AEs leading to discontinuation, 
and by relationship to study drug. No hypothesis tests will be performed. Tables will 
summarize the overall incidence of AEs and the incidence for each regimen, based on the 
four different conditions (with/without oral charcoal, with/without spacer).
9.6.2
Vital Signs
Subjects with out-of-range values will be listed.
9.6.3
Clinical Laboratory Measurements
Subjects with out-of-range values will be listed.
9.6.4
12-Lead ECGs
Subjects with out-of-range values will be listed.
9.7 
Randomization 
This study will be conducted as a 4-period, 8-sequence, 4-regimen, crossover design. The 
experimental design was chosen to be balanced with respect to period, sequence and first-
order carryover effects. Thus, eligible subjects will be equally randomized to 1 of the 
following 8 regimen sequences: AB CD, AB DC, BA CD, BA DC, CD AB, CD BA, DC AB 
or DC BA.
9.8 
Statistical Software 
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed 


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10 ADMINISTRATIVE CONSIDERATIONS
10.1
Regulatory Authority Approval
The Sponsor will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements prior to a 
site initiating the study in that country.
10.2
Ethical Conduct of the Study and IRB or IEC Approval
The study will be conducted in accordance with Good Clinical Practice (GCP). These 
standards respect the following guidelines:
•
Guideline for GCP E6(R1): Consolidated Guideline (International Conference on 
Harmonization of Technical Requirements for the Registration of Pharmaceuticals for 
Human Use, May 1996).
•
US CFR dealing with clinical studies (21 CFR parts 50, 54, 56, and 312).
•
Declaration of Helsinki, concerning medical research in humans (Ethical Principles for 
Medical Research Involving Human Subjects) 
http://www.wma.net/en/10home/index.html.
•
Any additional regulatory requirements.
The Investigator (or Sponsor, where applicable) is responsible for ensuring that this protocol, 
the site’s ICF, and any other information that will be presented to potential subjects (eg,
advertisements or information that supports or supplements the ICF) are reviewed and 
approved by the appropriate IRB/IEC. The Investigator agrees to allow the IRB/IEC direct 
access to all relevant documents. The IRB/IEC must be constituted in accordance with all 
applicable regulatory requirements.
The Sponsor will provide the Investigator with relevant document(s)/data that are needed for 
IRB/IEC review and approval of the study. If the protocol, the ICF, or any other information 
that the IRB/IEC has approved for presentation to potential subjects is amended during the 
study, the Investigator is responsible for ensuring the IRB/IEC reviews and approves, where 
applicable, these amended documents. The Investigator must follow all applicable regulatory 
requirements pertaining to the use of an amended ICF including obtaining IRB/IEC approval 
of the amended form before new subjects consent to take part in the study using this version 
of the form. The IRB/IEC approval of the amended ICF/other information and the approved 
amended ICF/other information must be forwarded to the Sponsor promptly.
10.3
Subject Information and Consent
The study will be conducted in accordance with applicable subject privacy requirements. The 
proposed ICF, which must be in compliance with applicable regulations, must be reviewed 
and approved by the IRB/IEC and the Sponsor prior to initiation of the study.


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The Investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and entry into the study. A copy of the signed 
ICF will be provided to the subject. The original will be retained by the Investigator.
10.4
Laboratory Accreditation
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations in that state and/or country. Reference values and/or 
normal ranges for the test results must be provided to the Sponsor. The Sponsor must be 
notified promptly in writing of any changes occurring in reference values during the course 
of the study.
10.5
Confidentiality
10.5.1
Confidentiality of Data
By signing this protocol, the Investigator affirms to the Sponsor that information furnished to 
the Investigator by the Sponsor will be maintained in confidence and such information will 
be divulged to the IRB/IEC, or similar or expert committee; affiliated institution; and 
employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the Investigator, except to the extent that it is included in a 
publication.
10.5.2
Confidentiality of Subject/Patient Records
By signing this protocol, the Investigator agrees that the Sponsor (or representative), 
IRB/IEC, or Regulatory Agency representatives may consult and/or copy study documents in 
order to verify worksheet/case report form data. By signing the consent form, the 
subject/patient agrees to this process. If study documents will be photocopied during the 
process of verifying worksheet/case report form information, the subject/patient will be 
identified by unique code only; full names/initials will be masked prior to transmission to the 
Sponsor. In addition, the Investigator agrees to treat all subject/patient data used and 
disclosed in connection with this study in accordance with all applicable privacy laws (ie,
Health Insurance Portability and Accountability Act), rules, and regulations.
10.6
Quality Control and Assurance
The Sponsor is responsible for implementing and maintaining quality control and quality 
assurance systems with written standard operating procedures to ensure that studies are 
conducted and data are generated, documented, and reported in compliance with the protocol, 
accepted standards of GCP, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of a clinical study.


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10.7
Data Management
Data management procedures and information for this protocol will be provided by the 
Sponsor.
10.8
Study Monitoring
In accordance with applicable regulations, GCP, and the Sponsor’s procedures, clinical 
monitors will contact the site prior to subject enrollment to review the protocol and data 
collection procedures with site staff. In addition, the monitor will periodically contact the 
site, including conducting on-site visits. The extent, nature, and frequency of on-site visits 
will be based on such considerations as the study objective and/or endpoints, the purpose of 
the study, study design complexity, and enrollment rate.
During these contacts, the monitor will:
•
Check the progress of the study
•
Review study data collected
•
Conduct source document verification
•
Identify any issues and address their resolution
This will be done in order 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 
amendments), GCP, and all applicable regulatory requirements
The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant concerns. Upon completion of the study, the monitor will conduct the following 
activities in conjunction with the Investigator or site staff, as appropriate:
•
Return of all study data to the Sponsor 
•
Data queries
•
Accountability, reconciliation, and arrangements for unused investigational product(s)
•
Review of site study records for completeness
After the final review of the study files, the files should be secured for the appropriate time 
period as specified in Section 10.9. The Investigator will also permit inspection of the study 


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files by the Sponsor’s Quality Assurance auditors, and authorized representatives of the Food 
and Drug Administration (FDA) or other applicable regulatory agencies.
10.9
Retention of Data
Documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced must be maintained for review by the Sponsor’s Quality
Assurance auditors and by all applicable regulatory authorities. The period of time these 
documents must be maintained is governed by applicable regulations. The Sponsor or its 
designee will inform the Investigator when these documents may be destroyed. The Sponsor 
or its designee must be notified in writing at least 6 months prior to the intended date of 
disposal of any study record related to this protocol to allow the Sponsor to make alternate 
storage arrangements.
10.10 Financial Disclosure
The Principal Investigator or sub-Investigators named on FDA Form 1572 will need to 
complete a financial disclosure form prior to study initiation, at any time during the study 
execution if new information needs to be disclosed, and for 1 year after study completion. 
Investigators should make the IRB/IEC aware of any financial interests that the Investigator 
has in the investigational product.
10.11 Investigator’s Final Report
Shortly after completion of the Investigator's participation in the study, the Investigator will 
submit a written report to the Sponsor.
10.12 Publication Policy
The Sponsor intends to publish the results of all of the clinical studies that it sponsors in 
compliance with the Declaration of Helsinki (http://www.wma.net/en/10home/index.html). 
Consistent with the recommendations of the editors of several leading medical journals, the 
International Committee of Medical Journal Editors (ICMJE), authorship of publications 
resulting from the Sponsor sponsored studies should fairly recognize the activities of those 
that have made a significant contribution to the study. In addition, the Sponsor recognizes 
and adheres to the precepts of the International Society for Medical Publications 
Professionals (ISMPP) that provide guidance to the preparation of publications, providing
disclosure of conflicts of interest, and the protection of intellectual property. Thus, it is 
anticipated that authorship will reflect the contribution made by the Sponsor’s personnel, the 
Investigators and others involved, such as statisticians.
In recent years, issues about conflicts of interest and accuracy of the study data have been
raised in the medical press. Accordingly, the Sponsor has developed publication guidelines as 
described below:
1. Responsibility: Each Principal Investigator is responsible for the accuracy and 
completeness of all data from their site. the Sponsor (or its representatives) is responsible 


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for the accuracy of the data entered into the study databases and for the accuracy of the 
analyses conducted.
2. Authorship and Publication Committee: The Sponsor, in collaboration with the 
Investigators, will establish the appropriate authorship and responsibility for drafting 
study documents in accordance with the principles of the ICMJE and ISMPP. It is 
anticipated that a publication committee will be formed to assume oversight of these 
activities. All manuscripts will be reviewed and agreed upon before submission for 
publication by all authors.
3. Sponsor Review of External Manuscripts: Consistent with the previous bullet point, 
drafts of any and all publications or presentations that may arise from this study must be 
submitted at least 30 days prior to submission for publication or presentation to the 
Sponsor for review, approval, and to ensure consistency with the policy in this protocol. 
The Sponsor will have the right to request appropriate modification to correct facts and to 
represent its opinions, or the opinions of the publication committee, if these differ with 
the proposed publication.
4. Confidentiality: Investigators will conduct all interactions with the Sponsor and with 
third parties consistent with the executed confidentiality agreements. While publication, 
by intention, presents the critical scientific data in a public forum, some information 
(such as future plans, results of nonclinical studies, or chemical formulae) may still need 
to remain confidential.
5. Medical Journal Review: Consistent with the intention of the Sponsor to publish the 
study in a fair and accurate manner, the Sponsor supports diligence in the publication 
review process of medical journals. Accordingly, upon request, all pertinent study data 
and information will be made available as supplemental information for journal editors 
and reviewers to evaluate and audit, eg, protocol and amendments, data tabulations, etc. 
The journal and reviewers will need to make arrangements to maintain the confidentiality 
of such supplemental information, where relevant, and the Sponsor will make suitable 
arrangements to ensure that the identity of journal reviewers is kept confidential. Records 
will be maintained of reviewers and the respective documents and datasets that were 
reviewed by each of them.
6. Reporting of Clinical Trials Results: To provide transparency in the conduct and 
reporting of randomized clinical trials, the Sponsor reports clinical findings based on the 
guidance of The CONSORT (CONsolidated Standards of Reporting Trials) Statement 
and a 25 item checklist which is intended to improve the reporting of a randomized 
controlled trial, and to facilitate reader understanding of the trial design, conduct, analysis 
and interpretation, and to support their ability to assess the validity of its results. 
7. Internet Clinical Trial Listing: In addition, also consistent with the recommendations of 
the ICMJE, the Sponsor will make available appropriate information regarding the study 
via the internet. This will include registration and listing of the study on 
www.clinicaltrials.gov, the US National Institutes of Health listing of clinical trials.


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11 REFERENCE LIST
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for 
Diagnosis, Management, and Prevention of COPD-2017. http://www.goldcopd.org/. 
Accessed 31 January 2017.
SYMBICORT® (budesonide and formoterol fumarate dehydrate) inhalation aerosol 
[package insert]. Wilmington, DE. AstraZeneca; 2017.


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Appendix 1
Instructions for Use of BGF MDI
How do I store the inhaler (to be stored by study site personnel)?
•
The inhaler should be stored below 25°C (77°F) in a dry place. Excursions permitted up 
to 30°C (86°F). 
•
The contents of the canister are under pressure. Do not puncture or throw the canister into 
a fire or incinerator. Do not use or store it near heat or open flame. Storage above 120ºF 
may cause the canister to burst.
•
Keep the product and all medicines out of the reach of children.
For Oral Inhalation Only
Parts of the Inhaler:
•
The parts of your inhaler are seen in Figure 1.
•
The Dose indicator lets you know about how many puffs are left in your inhaler and is 
the part of the inhaler that is pressed to dispense a puff of medication. See Figure 1.
•
The Dose indicator should be pointing just to the right of 120 when your inhaler is new. 
See Figure 1.
•
The Dose indicator has numbers for every 20 puffs. The Dose indicator display will 
move after every tenth puff. 
•
For example, if the Dose indicator is pointing to 120 (see Figure 2a) and you take 10 
puffs it will move between 120 and 100. This means that there are 110 puffs of medicine 


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left (see Figure 2b). After 10 more puffs are used, the Dose indicator pointer will move 
to the number 100. This means that there are 100 puffs of medicine left (see Figure 2c).
•
The Dose indicator number will continue to change after every 20 puffs.
•
When the number in the Dose indicator window changes to 20 and the color behind the 
number changes to red, this means that there are only 20 puffs left in your inhaler. See
Figure 2d.
Figure 2
Preparing the Inhaler for Use (To be conducted by study site personnel):
The inhaler comes in a foil pouch that contains a drying packet (desiccant).
•
Take the inhaler out of the foil pouch.
•
Throw away the pouch and the drying packet. Do not eat or inhale the contents of the 
drying packet. 
•
Remove the Cap from the Mouthpiece as shown in Figure 3.
Figure 3
Prime the inhaler before you use it for the first time.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
Confidential and Proprietary
Page 57 of 62
Priming the Inhaler (To be conducted by study site personnel):
•
Check inside the Mouthpiece for objects before use.
•
Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4a.
•
Shake the inhaler well before each puff.
•
Push down fully on the center (not ‘off center’) of the Dose indicator on top of the 
Canister (see Figure 1) until the Canister stops moving in the Actuator to release a 
puff from the Mouthpiece as shown in Figure 4b. Note: It is normal to hear a soft click 
from the dose indicator as it counts down during use.
•
Repeat this priming step 3 more times for a total of 4 times, shaking the inhaler each time 
before you press it.
•
After completing the 4 priming puffs, your inhaler is now primed ready to use for the first 
time.
You must re-prime your inhaler again if you have not used it in more than 7 days. Take the 
cap off the mouthpiece and shake and spray the inhaler 2 times into the air away from your 
face.
Figure 4
Using the Inhaler:
Your dose of medicine comes from 2 puffs from the inhaler.
Refer to Figure 5 for Step 1 through Step 8.
•
Step 1: Remove the Cap from the Mouthpiece.
•
Step 2: Shake the inhaler well before each puff.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
Confidential and Proprietary
Page 58 of 62
•
Step 3: While holding the inhaler with the Mouthpiece pointing towards you breathe out 
through your mouth to empty as much air from your lungs as possible.
•
Step 4: Close your lips around the Mouthpiece and tilt your head back slightly to make 
sure your tongue is away from the Mouthpiece.
•
Step 5: Take a deep breath in (inhale) slowly through your mouth while pressing down 
firmly on the center (not ‘off center’) of the Dose indicator until the Canister stops 
moving in the Actuator and a puff has been released. Then, stop pressing the Dose
indicator.
•
Step 6: When you have finished breathing in, remove the Mouthpiece from your mouth 
and hold your breath for 10 seconds or as long as comfortable. 
•
Step 7: Then, breathe out normally. 
Take your second puff of medicine by repeating Step 2 through Step 7. 
•
Step 8: Replace the Cap back on the Mouthpiece.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
Confidential and Proprietary
Page 59 of 62
Figure 5


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011 
Version 1.0
Confidential and Proprietary
Page 60 of 62
Appendix 2 
Aerochamber Plus Flow-Vu Instructions for Use 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc
Clinical Trial Protocol: PT010011
Version 1.0
Confidential and Proprietary
Page 62 of 62
Appendix 4
Investigator’s Signature
Study Title:
A Randomized, Open-label, Single-dose, Single-center, Crossover 
Study in Healthy Subjects to Assess the Relative Bioavailability of 
PT010 Administered With and Without a Spacer, and With and 
Without Oral Charcoal
Study Number:
PT010011
Final Date:
11 September 2017
I have read the protocol described above. I agree to comply with all applicable regulations and to conduct the 
study as described in the protocol. I agree:
•
To assume responsibility for the proper conduct of the study at this site.
•
To conduct the study in compliance with the protocol and with any other study conduct procedures 
provided by Pearl Therapeutics, Inc. (hereafter referred to as Pearl).
•
Not to implement any changes to the protocol without agreement from the Sponsor and prior review and 
written approval from the IRB/IEC, except where necessary to eliminate an immediate hazard to the 
subjects, or for administrative aspects of the study (where permitted by all applicable regulatory 
requirements).
•
That I am aware of, and will fully comply with GCP and all applicable regulatory requirements.
•
That I am thoroughly familiar with the appropriate use of the investigational product(s), and other 
information provided by Pearl including, but not limited to, the following: the protocol and the current 
Investigator’s Brochure (IB).
•
To ensure that all persons assisting me with the study are qualified, adequately informed about the 
investigational product(s) and of their study related duties and functions.
•
To supply Pearl with any necessary information regarding ownership interest and financial ties; to promptly 
update this information if any relevant changes occur during the course of the study and for 1 year 
following completion of the study; and agree that Pearl may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.
•
I agree to report all information or data in accordance with the protocol and any other study conduct 
procedures provided by Pearl. 
•
That since the information in this protocol and IB is confidential, I understand that its disclosure to any 
third parties, other than those involved in approval, supervision or conduct of the study is prohibited.
•
To accurately transfer all required data from each subject’s source document to the CRFs. The CRFs will 
be provided to the Sponsor in a timely manner at the completion of the study, or as otherwise specified by 
the Sponsor.
•
To allow authorized representatives of Pearl or regulatory authority representatives to conduct on site visits 
to review, audit and copy study documents. I will personally meet with these representatives to answer any 
study related questions.
Signed:
Date:
Name:
Site Name:

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Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 1 of 40) 
 
 
STATISTICAL ANALYSIS PLAN FOR 
STUDY PT010011 
 
 
Protocol Number: 
PT010011 
 
Investigational Drug 
and Drug Number: 
BGF MDI; PT010 
 
Indication: 
COPD 
Dosage Form/Dose: 
x BGF MDI 320/28.8/9.6 μg ex-actuator 
 
PT010011 Protocol Title: A Randomized Open-label, Single-dose, Single-center, Crossover 
Study in Healthy Subjects to Assess the Relative Bioavailability of PT010 Administered With 
and Without a Spacer, and With and Without Oral Charcoal 
 
 
Date of Issue: 
16 Jan 2018 
 
Version: 
Version 1.0 
 
 
 


Statistical Analysis Plan
Protocol Nos.:  PT010011
Date:  16 Jan 2018
                                        (Page 2 of 40)
Signed Agreement on Statistical Analysis Plan 
FINAL SIGN-OFF SIGNATURES 
Primary Biostatistician 
and Peer Reviewer:
Author:
Approved by:
Approved by:


Statistical Analysis Plan
Protocol Nos.:  PT010011
Date:  16 Jan 2018
                                        (Page 3 of 40)
Approved by:
Approved by:


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 4 of 40) 
 
Change Log 
Version No. 
Effective Date 
Reason for the Change / Revision 
Supersedes 
 
 
 
 
 
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 5 of 40) 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................................... 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 9 
2.1 
STUDY OBJECTIVES .............................................................................................................................. 9 
2.1.1 
Primary Objective ................................................................................................................. 9 
2.1.2 
Secondary Objective ............................................................................................................. 9 
2.2 
STUDY ENDPOINTS ............................................................................................................................... 9 
2.2.1 
Pharmacokinetic Endpoints .................................................................................................. 9 
2.2.1.1 
Primary PK Endpoints ....................................................................................... 10 
2.2.1.2 
Secondary PK Endpoints ................................................................................... 10 
2.2.1.3 
Other PK Endpoints ........................................................................................... 10 
2.2.2 
Safety Endpoints ................................................................................................................. 10 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ........................................................... 10 
3.1 
STUDY DESIGN ................................................................................................................................... 10 
3.1.1 
Overall Study Design and Plan ........................................................................................... 11 
3.1.2 
Prior, Concomitant, Prohibited Medications ...................................................................... 12 
3.2 
RANDOMIZATION AND BLINDING ....................................................................................................... 12 
3.3 
HYPOTHESIS TESTING ........................................................................................................................ 13 
3.4 
SAMPLE SIZE ...................................................................................................................................... 13 
3.5 
STUDY PROCEDURES .......................................................................................................................... 13 
3.6 
SCHEDULE OF ASSESSMENTS.............................................................................................................. 13 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ...................................................................... 13 
5. 
ANALYSIS POPULATIONS ................................................................................................................. 14 
5.1 
POPULATION DEFINITIONS ................................................................................................................. 14 
5.1.1 
Safety Population ................................................................................................................ 14 
5.1.2 
Pharmacokinetic (PK) Population ...................................................................................... 14 
5.2 
POPULATIONS FOR ANALYSES ............................................................................................................ 14 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES ................................................................... 14 
6.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................................... 14 
6.2 
PHARMACOKINETICS .......................................................................................................................... 15 
6.3 
SAFETY ASSESSMENTS ....................................................................................................................... 15 
6.3.1 
Physical Examination ......................................................................................................... 15 
6.3.2 
Vital Signs .......................................................................................................................... 16 
6.3.3 
12-Lead Electrocardiogram ................................................................................................ 17 
6.3.4 
Clinical Laboratory Tests ................................................................................................... 18 
6.3.5 
Adverse Events ................................................................................................................... 20 
6.3.6 
Urine Drug Screening/Alcohol Breath Testing ................................................................... 23 
6.3.7 
Pregnancy Test ................................................................................................................... 23 
6.3.8 
Concomitant Medications/Treatments ................................................................................ 23 
7. 
STATISTICAL ANALYSIS ................................................................................................................... 23 
7.1 
DATA HANDLING RULES AND DEFINITIONS, INCLUDING HANDLING OF MISSING DATA .................... 24 
7.2 
SUBJECT DISPOSITION AND ANALYSIS POPULATIONS ........................................................................ 24 
7.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................................ 25 
7.3.1 
Medical and Surgical History at Screening, Reproductive Status, and Pregnancy Testing 25 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 6 of 40) 
 
7.3.2 
Prior and Concomitant Medications/Treatments ................................................................ 25 
7.3.3 
Extent of Exposure to Study Medication ............................................................................ 26 
7.4 
PHARMACOKINETIC ASSESSMENTS .................................................................................................... 26 
7.5 
SAFETY ASSESSMENTS ....................................................................................................................... 29 
7.5.1 
Physical Examination ......................................................................................................... 29 
7.5.2 
Vital Signs .......................................................................................................................... 29 
7.5.3 
12-Lead Electrocardiogram ................................................................................................ 29 
7.5.4 
Clinical Laboratory Tests ................................................................................................... 29 
7.5.5 
Adverse Events ................................................................................................................... 29 
7.5.6 
Urine Drug Screening and Alcohol Breath Testing ............................................................ 30 
7.5.7 
Pregnancy Test ................................................................................................................... 30 
7.5.8 
Prior/Concomitant Medications/Treatments ....................................................................... 30 
8. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE ....................................................... 31 
9. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................. 31 
10. 
STATISTICAL SOFTWARE ................................................................................................................. 31 
11. 
REFERENCES ........................................................................................................................................ 31 
APPENDIX 1: DATA HANDLING RULES .................................................................................................... 31 
APPENDIX 2: TABLE OF CONTENTS FOR END-OF-TEXT TABLES, LISTINGS, AND FIGURES . 31 
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES ..................................................................... 40 
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .... 40 
 
List of Tables 
 
Table 1 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ............................................................................................... 17 
Table 2 
Potentially Clinically Significant Criteria for Heart Rate Parameters ................... 17 
Table 3 
Criteria for PCS ECG Values................................................................................. 18 
 
 
List of Figures 
 
Figure 1 
Study Design .......................................................................................................... 11 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 7 of 40) 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ATC 
Anatomic Therapeutic Class 
AUC0-tlast 
Area under the plasma concentration-time curve from 0 to the Time of the 
Last Measurable Plasma Concentration 
AUC0-∞ 
Area under the plasma concentration-time curve from 0 Extrapolated to 
Infinity 
BDRM 
Blinded Data Review Meeting 
BGF MDI 
Budesonide, Glycopyrronium, and Formoterol Metered Dose Inhaler 
BLOQ 
Below Limit of Quantification 
BP 
Blood Pressure 
CI 
Confidence Interval 
CL/F 
Apparent Total Body Clearance 
Cmax 
Maximum Observed Plasma Concentration 
COPD 
Chronic Obstructive Pulmonary Disease  
CRF 
Case Report Form 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eg 
Exempli gratia; for example 
GFR 
Glomerular Filtration Rate 
HR 
Heart Rate 
IB 
Investigators Brochure  
ICF 
Informed Consent Form 
i.e. 
Id Est; That Is 
λz 
Apparent Terminal Elimination Rate Constant  
LLOQ 
Lower Limit of Quantification 
MDI 
Metered dose inhaler 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 8 of 40) 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
μg 
Microgram 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
NCA 
Non-Compartmental Analysis 
OTC 
Over-the Counter 
PCS 
Potentially Clinically Significant 
PK 
Pharmacokinetics  
PT 
Preferred Term 
PT010 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol 
QTcF 
QT Corrected Using Fridericia’s Formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure  
t1/2 
Apparent Terminal Elimination Half-life  
TEAE 
Treatment-emergent adverse event 
tlast 
Time to last measurable plasma concentration 
tmax 
Time To Maximum Observed Plasma Concentration  
Vd/F 
Apparent Volume of Distribution 
VS 
Vital signs 
WHO 
World Health Organization 
WHO-DD 
World Health Organization-Drug Dictionary 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
WHO-HD 
World Health Organization-Herbal Dictionary 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 9 of 40) 
 
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and 
analysis of data to be performed at the end of Pearl Therapeutics, Inc. (Pearl) Study PT010011. 
The SAP should be read in conjunction with the study protocol. This version of the SAP has 
been developed using the PT010011 Protocol (Version 1.0 dated 11 September 2017) and the 
CRF Revision 01 dated 07 November, 2017. This is the main SAP, describing the statistical 
analyses that will be carried out at the end of the study.  
This is a phase I, randomized, open label, single-dose, single center, crossover study to assess the 
pharmacokinetics (PK) and safety of budesonide, glycopyrronium, and formoterol metered dose 
inhaler (BGF MDI) in healthy subjects. 
The definitions of data sets will be described in separate documents called SDTM specifications 
and ADaM specifications.  
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective  
The primary objectives of this study are the following: 
x To assess the total systemic exposure of budesonide, glycopyrronium, and formoterol 
administered as BGF MDI with and without a spacer device 
x To assess the lung exposure of budesonide, glycopyrronium, and formoterol administered as 
BGF MDI with and without oral activated charcoal 
 
2.1.2 
Secondary Objective 
The secondary objectives of this study are the following: 
x To characterize the PK profiles of budesonide, glycopyrronium, and formoterol administered 
as BGF MDI, with and without a spacer device, and with and without oral charcoal 
x To assess the safety of single doses of BGF MDI in healthy subjects 
 
2.2 
Study Endpoints 
2.2.1 
Pharmacokinetic Endpoints 
Pharmacokinetics after single-dose administration of BGF MDI will be assessed using plasma 
concentrations of budesonide, glycopyrronium, and formoterol for each regimen.  


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 10 of 40) 
 
2.2.1.1 
Primary PK Endpoints 
x Maximum observed plasma concentration (Cmax) 
x Area under the plasma concentration-time curve from 0 to the time of the last measurable 
plasma concentration (AUC0-tlast) 
2.2.1.2 
 Secondary PK Endpoints 
x Time to maximum observed plasma concentration (tmax) 
x Area under the plasma concentration-time curve from 0 extrapolated to infinity (AUC0-∞) 
2.2.1.3 
Other PK Endpoints 
x Apparent terminal elimination half-life (t1/2) 
x Apparent total body clearance (CL/F) 
x Apparent volume of distribution (Vd/F) 
x Apparent terminal elimination rate constant (λz) 
x Time to last measurable plasma concentration (tlast) 
2.2.2 
Safety Endpoints 
x Adverse events (AEs) 
x 12-lead electrocardiograms (ECGs) 
x Clinical laboratory testing 
x Vital sign (VS) measurements 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS 
3.1 
Study Design 
This is a Phase I, randomized, open-label, single-dose, single-center, crossover study to assess 
the PK and safety of BGF MDI in healthy subjects (male or female). The PK profiles of each 
active ingredient (budesonide, glycopyrronium, and formoterol), will be determined after 
administration of BGF MDI with a spacer device (test) and without a spacer device (reference), 
and with and without concomitant administration of activated oral charcoal to estimate lung 
exposure and total systemic exposure, respectively. 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 11 of 40) 
 
Approximately 56 healthy male or female subjects will be randomized in this study in order to 
ensure approximately 48 subjects complete all 4 Treatment Periods. Subjects who withdraw from 
the study after receiving at least 1 dose of study drug will not be replaced. Subjects who are re-
screened will maintain 1 screening number throughout the study. The study will be conducted at 
a single center in the US. 
This study includes a Screening Period of up to 28 days and four single-dose Treatment Periods 
during which subjects will be resident from the afternoon before dosing with BGF MDI until at 
least 24 hours after dosing and discharged on the morning of Day 2 of each Treatment Period. 
There will be a washout period of 5 to 14 days after Treatment Periods 1, 2, and 3. A follow-up 
phone call will take place within 5 to 7 days following the last administration of BGF MDI. 
3.1.1 
Overall Study Design and Plan 
The overall study design is summarized and illustrated in Figure 1. 
Figure 1 
Study Design 
 
 
After providing informed consent, subjects will undergo screening procedures. Subjects meeting 
eligibility criteria will be enrolled into the study and admitted to the study site as an inpatient on 
Day -1 of Treatment Period 1, at which time continuing eligibility will be assessed. Device 
training will be conducted during screening, on admission to each Treatment Period, and prior to 
dosing on Day 1 of each Treatment Period. In addition to training with a placebo MDI device, 
additional inhalation training tools may be used to help ensure the subjects are able to use the 
MDI device correctly. 
Study drug will be administered, under fasted conditions, on the morning of Day 1 of each 
Treatment Period, at approximately the same time of day throughout the study (± 30 minutes). 
Eligible subjects will receive a single dose of BGF MDI 320/28.8/9.6 μg administered as 
follows: 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 12 of 40) 
 
x Without a spacer device and without charcoal (regimen A) 
x With a spacer device and without charcoal (regimen B) 
x Without a spacer device and with charcoal (regimen C) 
x With a spacer device and with charcoal (regimen D) 
Subjects will receive all 4 regimens (1 regimen per Treatment Period) in 1 of 8 possible regimen 
sequences: AB CD, AB DC, BA CD, BA DC, CD AB, CD BA, DC AB, or DC BA. 
The regimen sequences allow for subjects who might drop out after completing only 2 Treatment 
Periods to be included in the PK statistical analysis.  
Randomization will be performed on the morning of first dosing (Day 1, Treatment Period 1). 
Randomization codes will be assigned strictly sequentially in ascending order as subjects become 
eligible. 
During their inpatient stay, subjects will undergo safety assessments and have an indwelling 
intravenous cannula for serial PK blood draws. Subjects will be discharged on the morning of 
Day 2 of each Treatment Period after all protocol-specified assessments are completed. There 
will be a washout period of 5 to 14 days after Treatment Periods 1, 2 and 3. 
A follow-up phone call will be conducted 5 to 7 days after Treatment Period 4 dosing or after the 
last dose of study drug, whichever comes first. 
3.1.2 
Prior, Concomitant, Prohibited Medications 
Apart from paracetamol/acetaminophen, hormone replacement therapy and systemic 
contraceptives, no concomitant medication or therapy will be allowed. The subjects should be 
instructed that no other medication is allowed, including herbal remedies, vitamin supplements 
and over the counter (OTC) products, without the consent of the Investigator. 
When any medication is required, it should be prescribed by the Investigator. Following 
consultation with the Medical Monitor, the Investigator must determine whether or not the 
subject should continue in the study. 
The Investigator or designated qualified personnel will assess and record concomitant 
medication usage on the eCRF. Concomitant medication usage will be assessed at screening and 
throughout the study. 
3.2 
Randomization and Blinding 
This study will be conducted as a 4-period, 8-sequence, 4-regimen, crossover design. The 
experimental design was chosen to be balanced with respect to period, sequence and first-order 


Statistical Analysis Plan
Protocol Nos.:  PT010011
Date:  16 Jan 2018
                                        (Page 13 of 40)
carryover effects. Thus eligible subjects will be equally randomized to 1 of the following 8 
regimen sequences: AB CD, AB DC, BA CD, BA DC, CD AB, CD BA, DC AB, or DC BA. 
3.3
Hypothesis Testing 
No formal hypothesis tests will be performed for this study. 
3.4
Sample Size 
This study is being conducted for estimation purposes. 
 a sample size of 48 subjects completing the study will provide 
 probability to observe a 1-sided 
 lower confidence bound for the geometric mean ratio 
(D/C) that is greater than 
 
3.5
Study Procedures 
Study procedures are contained in Table 8-1, Table 8-2, and Table 8-3 and detailed in Section 7 
and Section 8 of the study protocol. 
3.6
Schedule of Assessments 
A schedule of events for screening, treatment, and follow-up is provided in Table 8-1 of the 
study protocol. Detailed schedules of inpatient assessments on Day 1 during inpatient treatment 
periods 1, 2, and 3 are provided in Table 8-2 and inpatient assessments on Day 1 during inpatient 
treatment period 4 are provided in Table 8-3, of the study protocol. 
4.
DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance (QA) procedures for the study data, statistical programming and 
analyses are described in Standard Operating Procedures (SOPs) of Everest Clinical Research. 
Detailed data management procedures are documented in the study Data Management Plan 
(DMP), Data Validation Check Specifications, and Integrated Safety Data Review Plan. Detailed 
statistical and programming quality control and quality assurance procedures are documented in 
the Statistical Analysis and Programming QC/QA Plan. 
The study endpoints and analytic approaches are both prospectively defined and documented in 
the protocol and in this SAP. The SAP will be finalized, and protocol deviations will be 
identified and decisions for inclusion and exclusion of subjects from the PK Population will be 
made at the Blinded Data Review Meeting (BDRM) prior to the database lock and data analysis. 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 14 of 40) 
 
5. 
ANALYSIS POPULATIONS 
5.1 
Population Definitions 
5.1.1 
Safety Population  
The Safety Population is defined as all randomized subjects who receive at least one dose of 
BGF MDI.  
Safety and tolerability analyses will be performed on data from all subjects in the Safety 
Population. Analyses will be according to treatment received.  
5.1.2 
Pharmacokinetic (PK) Population 
The PK Population is defined as all subjects in the Safety Population set for whom at least one 
of the primary PK parameters for a given analyte can be calculated and who have no important 
protocol deviations thought to impact the analysis of the PK data. Major protocol deviations can 
result in exclusion of all data from a particular subject from the PK Population or require 
exclusion of data from a specific analyte, timepoint and/or subsequent timepoints for an 
endpoint. Protocol deviations for exclusion of subjects or data from the PK Population will be 
agreed by the study team and documented prior to database lock. 
Reasons for exclusion from the PK Population will documented in the BDRM minutes prior to 
database lock; these minutes will be included in an appendix to the Clinical Study Report. 
 
Pharmacokinetic analyses will be performed on data from all subjects in the PK Population. 
Analyses will be according to treatment received.  
5.2 
Populations for Analyses 
Demographics and baseline characteristics will be summarized descriptively for both the PK and 
Safety Populations. Extent of exposure will also be summarized for the Safety Population. For 
the PK Population, descriptive statistics without model adjustment will be used to describe the 
budesonide, glycopyrronium, and formoterol PK parameters by regimen. The Safety Population 
will be used to summarize safety. Safety and tolerability analyses will be based on descriptive 
statistics for vital signs, and laboratory measurements as appropriate, and also on frequencies of 
AEs (including any AEs based on ECG findings) as well as the number and proportion of 
subjects with AEs.  
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES 
6.1 
Demographics and Baseline Characteristics 
General demographic information such as age, race, ethnicity, gender, weight, and height will be 
collected at the Screening visit. Age will be calculated as the integer part of (Informed Consent 
date – Birth date)/365.25. For additional details please refer to the Data Handing rules outlined in 
Appendix 1. 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010011 
Date:  16 Jan 2018 
 
                                        (Page 15 of 40) 
 
Medical/surgical history will be collected on the eCRF during the Screening period. Medical 
history will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(currently MedDRA 20.1).  
The definitions for the derived demographic or baseline characteristic variables can be found in 
Appendix 1. 
6.2 
Pharmacokinetics 
Pharmacokinetics of BGF MDI with and without spacer and with or without oral charcoal will be 
assessed using plasma concentrations of budesonide, glycopyrronium, and formoterol pre-dose 
and at various times post-dose on Day 1 of each treatment period. See Section 7.4. 
6.3 
Safety Assessments 
6.3.1 
Physical Examination 
Any clinically significant physical examination abnormality reported after the start of study 
medication will be reported as an adverse event. These adverse events will be included in the AE 
summaries.  
The physical examination will include:  
x Documentation of height (Screening only) 
x Documentation of weight (Screening only) 
x General appearance 
x Head, eyes, ears, nose, throat, and neck (including thyroid),  
x Respiratory 
x Cardiovascular 
x Musculoskeletal 
x Abdominal 
x Neurologic 
x Extremities 
x Dermatologic 
x Lymph nodes 


 
 
 
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6.3.2 
Vital Signs 
Vital sign determinations, including blood pressure (BP) and heart rate (HR) will be performed 
after the subject has been supine for a 5-minute period at the Screening Visit, on the day of each 
clinic admission (Day -1), on Day 1 prior to study drug administration, and on Day 2 of 
Treatment Period 4.  
Potentially clinically significant (PCS) changes in systolic and diastolic blood pressure will 
be defined based on the criteria listed in Table 1.  
 


 
 
 
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Table 1 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood Pressure 
Parameters 
Parameter (mmHg) 
Post-Baseline Criteria 
Systolic Blood Pressure, increase 
≥180 mmHg and increase from 
baseline ≥20 mmHg 
Systolic Blood Pressure, decrease 
≤90 mmHg and ≥20 mmHg decrease 
from baseline 
Diastolic Blood Pressure, increase 
≥105 mmHg and increase from 
baseline ≥15 mmHg 
Diastolic Blood Pressure, decrease 
≤50 mmHg and ≥15 mmHg decrease 
from baseline 
 
Potentially clinically significant changes in HR will be assessed as follows: 
Table 2 
Potentially Clinically Significant Criteria for Heart Rate Parameters 
Parameter 
Post-Baseline Criteria 
Tachycardia Event 
≥110 bpm and increase ≥15% from baseline 
Bradycardia Event 
≤50 bpm and decrease ≥15% from baseline 
 
6.3.3 
12-Lead Electrocardiogram 
A Clinically Significant Abnormality for a 12-Lead ECG measurement identified by the 
investigator as a clinically significant abnormality will be recorded as an AE if it occurred after 
the start of study treatment. These adverse events will be included in the AE summaries. 
All 12-Lead ECG measurements for the Safety Population will be listed. 
Potentially clinically significant ECG parameter values will be identified based on criteria listed 
in Table 3.  


 
 
 
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Table 3 
Criteria for PCS ECG Values 
Parameter 
Post-Baseline Criteria 
QTcF Prolongation 
(1) ≥ 500 msec if < 500 msec at study baseline and ≥ 15 msec 
change from study baseline 
 
 
(2) ≥ 530 msec if ≥ 500 msec at study baseline and ≥ 15 msec 
change from study baseline 
 
(3) ≥ 500 msec and ≥ 15 msec change from study baseline 
 
(4) Change of ≥60 msec from study baseline regardless of initial 
value 
msec = millisecond 
6.3.4 
Clinical Laboratory Tests 
Laboratory testing (hematology with differential, chemistry and urinalysis) will be performed 
using standard methods. The laboratory parameters to be assessed in this study are listed below 
in Table 4. 
Potentially Clinically Significant Laboratory Values Above/Below a Clinically Relevant 
Threshold on-treatment, based on CTCAE 4.03 and other criteria, will be identified based on the 
thresholds in Table 5. 
 
 


 
 
 
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Table 4 
List of Laboratory Tests 
Hematology 
Blood Chemistry 
Hematocrita 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential 
Mean corpuscular volume (MCV) 
MCH concentration (MCHC) 
Creatinineb 
Potassium (K+) 
Sodium (Na+) 
Chloride (Cl-) 
Magnesium (Mg++) 
Calcium 
Inorganic phosphate 
Glucose 
Urea 
Bilirubin (Total) 
 
Bilirubin (direct) 
 Alanine aminotransferase 
    (ALT) 
 Aspartate aminotransferase   
    (AST) 
Gamma- 
   Glutamyltransferase 
   (GGT) 
Alkaline phosphatase 
Total Protein 
Albumin 
 
Urinalysis: Macroscopic examination routinely including specific gravity, pH, protein, glucose, 
ketones, blood and urobilinogen. A microscopic examination will be performed if warranted based 
on macroscopic results. 
Urine drug screen: A urine sample will be collected at screening and Day-1 of each treatment 
period and analyzed (positive or negative) for drugs of abuse including amphetamine, opiate, 
cocaine, barbiturates, benzodiazepines, cotinine, and marijuana [tetrahydrocannabinol (THC)]. 
Alcohol Breathalyzer Test: A breathalyzer test will be performed at screening and Day -1 of each 
treatment period for the presence of alcohol (positive or negative). 
Serology: Testing for HbsAg, Hepatitis C antibody, and HIV will be performed at screening only. 
Results of each serology test will be reported as either positive or negative.  
For females who are not post-menopausal: A serum hCG test at screening and urine hCG test at 
admission will be performed during each of the 4 Treatment Periods.  
For females of non-childbearing potential: A serum hCG test at screening will be performed. In 
addition, a serum FSH test for confirmation of non-childbearing status will be performed at 
screening.  
a Packed cell volume (PCV). 
b Serum creatinine value will be used to calculate eGFR using Chronic Kidney Disease Epidemiology 
Collaboration Equation (according to National Kidney Disease Education Program) - CKD-EPI.  
 
Table 5 
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria 
Parameter 
Post-Baseline Criteria 
Hematology 
Hemoglobin  
<8.0 g/dL (<80 g/L) 
 
Increase of >40 g/L to a value above the 
ULN 
White Blood Cell Count 
<2000/μL 
 
>35,000/μL 


 
 
 
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Parameter 
Post-Baseline Criteria 
Platelet Count 
<50,000/μL 
>999,000/μL 
Chemistry 
eGFR-EPI  
<30 mL/min/1.73 m2 
AST 
>3 x ULN 
ALT 
>3 x ULN 
Alkaline Phosphatase 
>5 x ULN 
Total Bilirubin 
>2 x ULN 
Blood Glucose* (random values) 
<2.2 mmol/L (<39.6 mg/dL) 
 
>13.9 mmol/L (>250 mg/dL) if baseline 
is below 10.0 mmol/L (180 mg/dL), > 
16.7 mmol/L (>300 mg/dL) if baseline 
is greater than 10.0 mmol/L (180 
mg/dL) 
Serum Potassium 
<3.0 mmol/L 
 
>6.0 mmol/L 
*CTCAE 4.03 criteria are based on fasting glucose values. However, subjects were not required 
to fast prior to obtaining blood glucose values. 
6.3.5 
Adverse Events 
Adverse events (AEs) will be collected from the time of administration of the first dose of study 
drug to the time of the Follow-Up Telephone Call Visit, study termination, or study exit. AEs 
will be characterized by severity and relationship to study drug. The incidence of an AE will be 
defined by the number of subjects experiencing an event.  
Adverse events will be collected and coded using the latest version of MedDRA available at the 
time of database lock for this study. The study physician will review the adverse event coding. 
Adverse events that occur between the time the subject signs the informed consent form for the 
study and the time when that subject receives the first dose of study drug will be summarized as 
medical history and not as an AE unless the event meets the definition of a serious adverse event 
(SAE). 
 
An AE is considered as On-Treatment if the onset date of the adverse event is on or after the day of 
the first dose of randomized treatment, and up to and including the date completion of randomized 
treatment or the last day of premature withdrawal from randomized treatment +1 day.  An adverse 
event that begins on the same date as the first dose of randomized treatment is On-treatment if 
the AE begins after the time of first dose or if the time of AE onset is unknown. All on-treatment 
AEs are refered to as treatment emergent adverse events (TEAEs). 


 
 
 
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An AE is considered as Post-treatment if the onset date of the adverse event is after the date 
completion of randomized treatment or on or after the last day of premature withdrawal from 
randomized treatment +2 days. 
 
Adverse events will be listed in adverse event data listings (Listing 7.1).  
Events with Irregular Start Dates: All adverse events will be included in the tabulations 
regardless of the completeness of the onset dates. 
Adverse events include, but are not limited to:  
x Any symptom or condition not previously reported by the subject (medical history).  
x An exacerbation of a pre-existing symptom or condition.  
x A significant increase in frequency or intensity of a pre-existing episodic event or 
condition.  
x A drug interaction.  
x A condition first detected or diagnosed after study drug administration even though it 
may have been present prior to the start of the study.  
An AE does not include the following: 
x Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that results in the procedure is considered an AE (e.g., 
bleeding esophageal varices, dental caries).  
x Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms.  
x Abnormal laboratory values that are not clinically significant. (If accompanied by 
signs/symptoms, the signs or symptoms are considered an AE).  
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any of 
the following outcomes:  
• Death  
• A life-threatening AE  
• In patient hospitalization or prolongation of existing hospitalization  


 
 
 
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• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in subject hospitalization, or the development of drug 
dependency or drug abuse.  
Hospitalization for a pre-existing condition, including elective procedures, which has not 
worsened, does not constitute an SAE. 
An AE is considered “life-threatening’ if, in the view of the Investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an adverse reaction 
or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death.  
An AE or suspected adverse reaction is considered unexpected if it is not listed in the current 
investigator brochure or is not listed at the specificity or severity that has been observed. 
Many laboratory abnormalities observed during the course of a study will be included under a 
reported AE describing a clinical syndrome (e.g., elevated BUN and creatinine in the setting of 
an AE of renal failure, or decreased hemoglobin in a case of bleeding esophageal varices). In 
such cases, the laboratory abnormality itself (e.g., elevated creatinine in a setting of renal failure) 
does not need to be recorded as an AE. However, isolated laboratory abnormalities should be 
reported as AEs if they are considered to be clinically significant by the Investigator.  
Criteria for a "clinically significant" laboratory abnormality are:  
• A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension, or study withdrawal)  
• A laboratory abnormality that results in any therapeutic intervention (e.g., concomitant 
medication or therapy)  
• Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion) 


 
 
 
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For laboratory abnormalities that do not meet the above criteria but are outside of normal range 
(e.g., < or > normal reference range), the Investigator should indicate whether the value is 
potentially clinically significant or not clinically significant for the subject. 
6.3.6 
Urine Drug Screening/Alcohol Breath Testing 
A urine sample will be collected and analyzed (positive or negative) for drugs of abuse including 
amphetamine, opiate, cocaine, barbiturates, benzodiazepines, and marijuana 
[tetrahydrocannabinol (THC)]. A breathalyzer test will be performed for the presence of alcohol 
(positive or negative). Both tests will be conducted at Screening and at inpatient admission days. 
6.3.7 
Pregnancy Test 
For females who are not post-menopausal, a serum hCG test at screening and urine hCG test at 
admission will be performed during each of the 4 Treatment Periods. For females of non-
childbearing potential, a serum hCG test at screening will be performed. In addition, a serum 
FSH test for confirmation of non-childbearing status will be performed at screening.  
 
6.3.8 
Concomitant Medications/Treatments 
Concomitant medications will be collected for for all visits of the study. 
Any medications that were being taken prior to signing the ICF will be documented as prior 
study medications and must be stopped prior to entry. 
Concomitant medications will be coded using the latest version of the World Health 
Organization (WHO) Drug Dictionary Enhanced (WHO DDE) and the WHO Herbal Dictionary 
(WHO-HD). 
7. 
STATISTICAL ANALYSIS 
All data collected on the CRF and contributing to the analysis will be provided in listings, except 
for data collected only for confirmation of study entry criteria and for study management 
purposes.  
All PK and safety parameters will be summarized unless specified otherwise.  
Continuous variables will be summarized with descriptive statistics: the number of non-missing 
values, mean, standard deviation, median, minimum, and maximum.  
Categorical variables will be summarized with frequency counts and percentages (where 
appropriate). 


 
 
 
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7.1 
Data Handling Rules and Definitions, Including Handling of Missing Data 
Missing data will be maintained as missing in the analysis datasets, unless specified otherwise. 
For variables where missing data are imputed, the analysis dataset will contain a new variable 
with the imputed value, and the original variable value will be maintained as missing. 
Data imputation for PK summaries is detailed in Section 7.4. 
Data Imputation for Adverse Events Summaries by Severity and Relationship to Study Drug 
For the AE summaries by severity, an AE with missing severity will be deemed as severe. For 
AEs that could be associated with any study procedure the causal relationship is implied as ‘yes’. 
Imputed values will not be listed in data listings.  
Data Imputation for Laboratory, Vital Sign, and ECG Summaries (Continuous Parameters) 
By-visit and by-timepoint summaries will be based on scheduled visits and/or timepoints (i.e. no 
time windows), as applicable. Data from unscheduled visits and/or timepoints will not be used 
for by-visit or by-timepoint summaries but will be included in the listings. Data from both 
scheduled and unscheduled visits will be used for shift tables and for determining incidence of 
clinically significant values. End-of-treatment refers to the last visit during study treatment when 
an assessment was made. 
Data Imputation (All Laboratory Summaries) 
Laboratory values of ‘>=x’ or ‘<=x’ will be taken as the value of x in the analyses. If a 
laboratory value is prefixed with‘>’: the available original value +0.001 will be used for table 
summaries; if a laboratory value is prefixed with ‘<’, then the original value –0.001 will be used 
in table summaries. 
Study Dates and Day of Assessment or Event 
Study Day and Day of Assessment or Event definitions are provided in Appendix 1, Data 
Handling Rules. 
7.2 
Subject Disposition and Analysis Populations 
A disposition table for all subjects randomized will be provided (Table 1.1). This tabulation will 
include the number and percentage of subjects who were treated with the study treatment, who 
completed the study, who withdrew from the study prematurely (early termination) along with 
the reason for study withdrawal. The number and percentage of subjects included in the Safety 
and PK Populations will also be tabulated by regimen (Table 1.3). Informed consent is listed in 
Listing 1.1.  
A summary of reasons for withdrawal from study treatment by regimen sequence will be 
summarized for the Safety Population (Table 1.2). These reasons will be listed in Listing 1.2.  


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7.3
Demographic and Baseline Characteristics 
Demographic data will be summarized for both the Safety and PK Populations (Tables 1.4.1 and 
1.4.2). Continuous demographic and baseline variables will be summarized by tabulating the 
number of subjects, mean, standard deviation (SD), median, minimum, and maximum values. 
For categorical demographic and baseline variables, the frequency and percentage of subjects 
will be tabulated. Demographic data will be listed (Listing 1.1). Medical and Surgical History 
(Listing 4.2) will be listed.  
Demographic variables summarized will include the following: 
x
Age 
x
Gender 
x
Race  
x
Ethnicity 
x
Smoking Classification (Smoking status - including number of years smoked, time in years 
since last smoked, average number of cigarettes smoked per day) 
x
Weight (kg) 
x
Height (cm) 
x
BMI (body mass index, derived from weight and height, equal to weight in kg divided by the 
square of height in m) 
7.3.1
Medical and Surgical History at Screening, Reproductive Status, and Pregnancy 
Testing 
Relevant medical history, based on the opinion of the Investigator, will be obtained from the 
subject at Screening, and recorded on the source document. Medical history will capture the 
subject’s family health history, history of hospitalization, and history of surgeries. 
Medical and Surgical History at Screening will be listed for all subjects (Listing 4.2).  
Screening Reproductive Status and Pregnancy Testing Results will be listed (Listing 10.4). 
7.3.2
Prior and Concomitant Medications/Treatments
Coding: Verbatim medication/treatment terms will be coded by 
 and 
will be assigned a preferred term and an ATC (anatomic therapeutic class) term using the latest 
version of the World Health Organization Drug Dictionary (WHO-DD) available (version: 3Q 
2017 or later). 
Multiple ATC assignments: If there are multiple ATC codes assigned to the same concomitant 
medication, the “primary” one based on medical evaluation by study physician will be used. All 


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prior medication taken by the subject within 30 days of Screening for the study and all 
concomitant therapy taken by the subject while on study will be recorded in the eCRF. 
Prior medication/treatment is any medication/treatment taken prior to study treatment, even if 
this medication continued to be taken on the day of the start of study treatment in the study or 
afterward (Appendix 1).
Concomitant medication/treatment is any medication/treatment reported as being taken after 
the start of the study treatment in the study and being taken on or before the date prior to 
completion of or withdrawal from study treatment for the subject. A medication with an onset 
date on or after the date of study withdrawal from or completion of randomized study treatment 
for the subject will not be considered concomitant, but will be considered a Post-Treatment 
medication/treatment.
Any medication/treatment which cannot be identified as Prior, Concomitant, or Post-Treatment 
will be considered as being in each of the categories that are possible from the available 
information. 
Reported prior, concomitant, and post-treatment medications will be listed (Listing 10.1.1 and 
Listing 10.1.2).
7.3.3
Extent of Exposure to Study Medication 
A listing of treatment dosing and dispensing information will be provided in Listing 5.1. Any 
comments related to study medication or any other additional study comments will be listed 
(Listing 10.5).
7.4
Pharmacokinetic Assessments 
Time points for PK blood sample collection will be pre-dose within 60 minutes prior to dosing 
and post-dose at 2, 6, 20, and 40 minutes, and at 1, 2, 4, 8, 12, and 24 hours. 
Actual sampling time points relative to dosing will be used for PK assessments and analysis 
where available. It is expected that the actual sampling time will generally be available. In any 
(likely rare) cases when the actual sampling time was not recorded, the scheduled time may be 
used. This is considered preferable to ignoring a valid concentration measurement. 
The concentration-time data reported by the bioanalytical laboratory will be evaluated for 
inclusion in the PK analysis dataset. 
The PK analysis will be performed for subjects in the PK Population. 
PK parameters will be estimated by non-compartmental analysis (NCA) using the software 
 
 


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From the plasma budesonide, glycopyrronium and formoterol concentration-time data, the 
following PK parameters will be estimated for each subject where possible on Day 1 of each 
treatment period: 
AUC0-tlast
Area under the plasma concentration-time curve from 0 to the time of the last 
measurable plasma concentration
AUC0-∞
Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity
Cmax
Maximum observed plasma concentration, expressed in concentration units
tmax
Time to reach maximum observed plasma concentration (Cmax), expressed in hours
λz
Terminal elimination rate constant, calculated from the slope of the terminal 
portion of the ln(drug concentration) versus time curve
t1/2
Apparent terminal elimination half-life, expressed in hours, calculated as ln2/ λz
CL/F
Apparent total body clearance
Vd/F
Apparent volume of distribution
tlast
Time to last measurable plasma concentration
AUC0-tlast, and AUC0-∞, will be calculated using the linear up/log down trapezoidal method. 
The PK parameters Cmax and time to Cmax (tmax) will be obtained from the observed values. 
λz will be estimated for each subject where feasible by linear regression analysis, calculated from 
the slope of the terminal portion of the ln(drug concentration) versus time curve. Selection of 
data points to include in the estimation of λz for each subject for each analyte will be based on 
the following criteria: 
x
All samples used should preferably fall in the log-linear elimination phase. 
x
At least 3 samples above lower limit of quantification (LLOQ) should be used in the 
estimation. 
x
Cmax must not be used in the estimation. 
x
Adjusted r2 value reported in 
 
 must be ≥ 0.8.
For the purposes of parameter estimation, plasma concentration values below the LLOQ will be 
set to missing in the NCA with the exception of those values reported at Day 1 pre-dose. Day 1 
pre-dose concentrations that are below the limit of quantification (BLOQ) will be set to zero (per 
 SOP) for the NCA. Concentrations measured after the Day 1 dose of study medication 
that are below the lower limit of quantification will set to missing values (per 
SOP) for 
the NCA. Missing values (e.g., no blood sample collected, no value obtained at analysis) will be 
treated as missing and excluded from the NCA. If there are ≥2 consecutive missing concentration 
values, the estimation of PK parameters will be evaluated on a case-by-case basis. 
For descriptive statistics for concentrations and for the concentration figures, all values below 
LLOQ will be assigned a value of ½ LLOQ except for Day 1 pre-dose which will be assigned a 
value of 0 (no geometric mean will be calculated for Day 1 pre-dose). 


 
 
 
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Descriptive statistics for plasma concentrations of budesonide, glycopyrronium, and formoterol, 
by regimen and nominal time point will be summarized using the PK Population. Descriptive 
statistics will include the number of observations (n), mean (CV%), SD, standard error (SE), 
median, minimum (min), maximum (max), geometric mean, and geometric coefficient of 
variation (Tables 2.1.1, 2.2.1, and 2.3.1). The geometric coefficient of variation is calculated as 
GEOCV(y) (%) = 100*sqrt[(exp[var(ln[y])])-1], where sqrt is the square root function and 
“var(ln[y])” is natural-log scale variance.  
Descriptive statistics for PK parameters of budesonide, glycopyrronium, and formoterol, will be 
summarized by regimen. Descriptive statistics will include the number of observations (n), mean 
(CV%), SD, median, min, max, geometric mean, and geometric coefficient of variation. For the 
PK parameters tmax and tlast, only the number of observations (n), mean, median, minimum (min), 
and maximum (max) will be presented (Tables 2.1.2, 2.2.2, and 2.3.2). 
The plasma concentration-time profiles for individual and mean plasma concentrations of 
budesonide, glycopyrronium, and formoterol will be plotted for each treatment and each visit on 
the linear/linear scale and on the linear/log-linear scale for the Safety Population. 
Mean and individual plots will be separate for each analyte. Nominal sampling time points 
relative to dosing will be used for all mean plots. Actual sampling time points will be used for all 
individual plots (mean plots in Figures 2.1.1 through 2.3.2 and individual plots in Figures 2.4.1 
through 2.6.2). 
All concentration-time data reported by the bioanalytical laboratory, for each analyte, will be 
listed for subjects in the Safety Population (Listing 8.1). Actual sample collection times will be 
detailed in the listing along with the scheduled nominal sample collection times. In addition, all 
calculated PK parameters for each subject for each analyte will be listed (Listing 8.2). 
The treatment ratio of each of the test formulations (regimen B or regimen D) will be compared 
to the reference formulations (regimen A or regimen C) for budesonide, glycopyrronium, and 
formoterol. 
The statistical analysis will be conducted separately for the following: 
x Total systemic exposure: regimen B versus regimen A (Table 2.1.3, Table 2.2.3, Table 
2.3.3) 
x Lung exposure: regimen D versus regimen C (Table 2.1.4, Table 2.2.4, Table 2.3.4) 
Treatment comparisons of primary PK parameters will be assessed on the difference of log-
transformed Cmax, AUC0-tlast, and AUC0-∞ of budesonide, glycopyrronium, and formoterol using a 
2-sided 90% CI approach based on an analysis of variance model including period, sequence, 
regimen, and subject within sequence as fixed effects. Estimated geometric mean ratios with 
90% CIs will be provided. 


 
 
 
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Only the data for the comparison under investigation will be included in the statistical analysis, 
e.g., when comparing regimen B and regimen A, the data for the other regimens will be removed 
from the dataset. Subjects must have a primary PK parameter available for both regimens for a 
given analyte under consideration in order to be included in a specific analysis. A subject may 
therefore be included in the analysis for one parameter and not for another. 
To investigate the effect of the spacer on the PK parameters (AUC0-tlast, AUC0-∞ and Cmax), 
summaries of the budesonide, glycopyrronium, and formoterol AUC0-tlast, AUC0-∞ and Cmax 
pararmeters by exposure quartiles will be presented. The quartiles are established based on 
values from without spacer only; then the AUC and Cmax values and the ratios for with:without 
spacer are summarized for each of the quartiles. 
Data will be divided into quartiles based on AUC0-tlast reported during treatment without the 
spacer. 
7.5 
Safety Assessments 
Safety data will be summarized by regimen and listed for the Safety Population. The safety 
assessments for BGF MDI  will include AEs and SAEs, vital signs (BP, HR), clinical laboratory 
values (hematology, chemistry, and urinalysis), and findings from 12-lead ECGs. The incidence 
of on-treatment AEs and SAEs will be tabulated. Summary statistics of assessed laboratory 
values will also be tabulated. 
7.5.1 
Physical Examination 
Any clinically significant physical examination abnormality reported after the start of study 
medication was to be reported as an adverse event. Thus, these will be included in listings of 
adverse events and summarized in adverse event summaries. 
7.5.2 
Vital Signs 
Subjects with out-of-range values will be listed (Listing 10.2). All clinically significant 
abnormalities after administration of randomized study drug will be reported as AEs. 
7.5.3 
12-Lead Electrocardiogram 
Subjects with out-of-range values will be listed  (Listing 10.6). All clinically significant 
abnormalities after administration of randomized study drug will be reported as AEs. 
7.5.4 
Clinical Laboratory Tests 
Subjects with out-of-range hematology, chemistry, and urinalysis results will be listed  (Listings 
9.1 - 9.3). All clinically significant abnormalities after administration of randomized study drug 
will be reported as AEs. 
7.5.5 
Adverse Events 
On-treatment AEs will be included in tabular format, for subjects who meet the criteria for the 
Safety Population. Listings for AEs will present all AEs in the database for all subjects (Listings 


 
 
 
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7.1 and 7.2). All AEs, whether on-treatment or not, will be included in the Listings. Pre-
treatment SAEs will also be listed (Listing 7.3). 
Analysis endpoints for AEs include both the numbers of treatment-emergent AEs as observed by 
the investigational team or reported by the subject, and the numbers of subjects experiencing 
treatment-emergent adverse events. The incidence of an on-treatment AE will be defined as the 
number of subjects experiencing an event. 
An overall summary of subjects with at least one on-treatment AE, with AEs related to study 
treatment, with SAEs, with SAEs related to study treatment, with AEs leading to early 
withdrawal from the study, with SAEs leading to early withdrawal from the study, and with 
deaths will be presented (Table 3.1.1). 
The frequency and percentage of subjects experiencing a specific on-treatment AE will be 
tabulated by system organ class (SOC) and preferred term (PT) by regimen for the Safety 
Population (Table 3.1.2). 
On-treatment AEs will be summarized by (maximum) severity, with respect to SOC and 
preferred terms by regimen (Tables 3.2.1). 
If applicable, deaths (PT) will be included as part of AE/SAE analysis, including appropriate 
information such as date where available. 
Post-treatment AEs will be listed separately (Table 3.1.3 and Tables 3.2.2). 
7.5.6 
Urine Drug Screening and Alcohol Breath Testing 
Urine Drug Screening/Alcohol Breath Testing conducted during the study will be provided in a 
listing (Listing 10.3). 
7.5.7 
Pregnancy Test 
Pregnancy testing results conducted during the study will be provided in a listing (Listing 10.4). 
7.5.8 
Prior/Concomitant Medications/Treatments 
Prior and concomitant medications will be provided in a listing (Listing 10.1.1 and Listing 
10.1.2). Information from both complete and partial dates will be utilized. Medications with end 
date of ‘Ongoing’ are considered concomitant. Should there not be sufficient information to 
determine whether a medication is prior or concomitant the status will be considered to be both 
prior and concomitant. 
Concomitant medications and treatments will be summarized for the Safety Population. 
Frequency tables will present the frequency and proportion of subjects having received at least 
one concomitant medication during the course of the trial. Results will also be summarized with 
respect to subjects’ receiving medications by coded preferred term (Table 1.5.1). 


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8.
ANALYSES PERFORMED BEFORE DATABASE CLOSURE
Not applicable. 
9.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
This SAP outlines the statistical methods for the display, summary and analysis of data collected 
within the scope of Pearl Therapeutics Inc. Protocol PT010011, Version 1.0 dated 11 September 
2017.
10.
STATISTICAL SOFTWARE 
 environment will be used for all statistical analyses.  
 will be used for all PK parameter 
calculations. 
11.
REFERENCES 
 will be used for all PK parameter 
calculations. 
APPENDIX 1: DATA HANDLING RULES 
This appendix is provided in a separate document. 
APPENDIX 2: TABLE OF CONTENTS FOR END-OF-TEXT TABLES, LISTINGS, AND 
FIGURES 
1 TABLES AND FIGURES 
1.1 Summary of Subject Disposition, Demographics, and Baseline Characteristics 
Table 1.1 Subject Disposition 
 (Analysis Set: All Subjects Randomized)  
Table 1.1.1 Subject Disposition 
 (Analysis Set: All Subjects Screened)  
Table 1.2 Reasons for Withdrawal by Regimen 
 (Analysis Set: Safety Population)  


 
 
 
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Table 1.3 Analysis Populations by Regimen 
 (Analysis Set: All Subjects Randomized)  
Table 1.4.1 Summary of Demographic Data 
 (Analysis Set: Safety Population)  
Table 1.4.2 Summary of Demographic Data 
 (Analysis Set: PK Population)  
Table 1.5.1 Summary of Concomitant Medications 
 (Analysis Set: Safety Population)  
1.2 Pharmacokinetic Data 
Table 2.1.1 Descriptive Statistics for Plasma Concentrations of Budesonide (unit) by Regimen and 
Timepoint 
 (Analysis Set: PK Population)  
Figure 2.1.1 Mean (+/- SE) Plasma Budesonide Concentration-Time Profile after Single Dose 
Administration on Day 1 of each Treatment Period (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.1.1.1 Mean (+/- SE) Plasma Budesonide Concentration-Time Profile within 2 hours after Single 
Dose Administration (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.1.2 Mean Plasma Budesonide Concentration-Time Profile after Single Dose Administration (Log-
Linear Scale) 
(Analysis Set: PK Population) 
Table 2.1.2  Descriptive Statistics for Pharmacokinetic Parameters of Budesonide by Regimen 
(Analysis Set: PK Population)  
Table 2.1.3  Statistical Comparison of Budesonide PK Parameters – Total Systemic Exposure (Without 
Charcoal) 
(Analysis Set: PK Population)  


 
 
 
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Table 2.1.4  Statistical Comparison of Budesonide PK Parameters – Lung Exposure  (With Charcoal) 
(Analysis Set: PK Population)  
Table 2.1.5 Summary of Plasma Pharmacokinetic Parameters of Budesonide by Exposure Quartile 
(Analysis Set: PK Population)  
Table 2.2.1 Descriptive Statistics for Plasma Concentrations of Glycopyrronium (unit) by Regimen and 
Timepoint 
 (Analysis Set: PK Population)  
Figure 2.2.1 Mean (+/- SE) Plasma Glycopyrronium Concentration-Time Profile after Single Dose 
Administration (Linear-Linear Scale) 
(Analysis Set: PK Population) 
Figure 2.2.1.1 Mean (+/- SE) Plasma Glycopyrronium Concentration-Time Profile with 2 hours after 
Single Dose Administration (Linear-Linear Scale) 
(Analysis Set: PK Population) 
Figure 2.2.2 Mean Plasma Glycopyrronium Concentration-Time Profile after Single Dose Administration 
(Log-Linear Scale) 
(Analysis Set: PK Population)  
Table 2.2.2  Descriptive Statistics for Pharmacokinetic Parameters of Glycopyrronium by Regimen and 
Treatment Period 
(Analysis Set: PK Population)  
Table 2.2.3  Statistical Comparison of Glycopyrronium PK Parameters – Total Systemic Exposure 
(Without Charcoal) 
(Analysis Set: PK Population)  
Table 2.2.4  Statistical Comparison of Glycopyrronium PK Parameters – Lung Exposure (With Charcoal) 
(Analysis Set: PK Population)  
Table 2.2.5  Summary of Plasma Pharmacokinetic Parameters of Glycopyrronium by Exposure Quartile 
(Analysis Set: PK Population)  


 
 
 
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Table 2.3.1 Descriptive Statistics for Plasma Concentrations of Formoterol (unit) by Regimen and 
Timepoint 
 (Analysis Set: PK Population)  
Figure 2.3.1 Mean (+/- SE) Plasma Formoterol Concentration-Time Profile after Single Dose 
Administration (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.3.1.1 Mean (+/- SE) Plasma Formoterol Concentration-Time Profile with 2 hours after Single 
Dose Administration (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.3.2 Mean Plasma Formoterol Concentration-Time Profile after Single Dose Administration (Log-
Linear Scale) 
(Analysis Set: PK Population)  
Table 2.3.2  Descriptive Statistics for Pharmacokinetic Parameters of Formoterol by Regimen and 
Treatment Period 
(Analysis Set: PK Population)  
Table 2.3.3  Statistical Comparison of Formoterol PK Parameters – Total Systemic Exposure (Without 
Charcoal) 
(Analysis Set: PK Population)  
Table 2.3.4  Statistical Comparison of Formoterol PK Parameters – Lung Exposure (With Charcoal) 
(Analysis Set: PK Population)  
Table 2.3.5  Summary of Plasma Pharmacokinetic Parameters of Formoterol by Exposure Quartile 
(Analysis Set: PK Population)  
Figure 2.4.1  Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration (Linear-Linear Scale) 
 (Analysis Set: PK Population)  
Figure 2.4.2  Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration (Log-Linear Scale) 


 
 
 
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 (Analysis Set: PK Population)  
Figure 2.4.3  Invidual Budesonide AUC0-tlast after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.4.3.1  Invidual Budesonide AUC0-tlast after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.4.4  Invidual Budesonide Cmax after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.4.4.1  Invidual Budesonide Cmax after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.4.5  Invidual Budesonide AUC0-∞ after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.4.5.1  Invidual Budesonide AUC0-∞ after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.5.1  Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration (Linear-Linear Scale) 
 (Analysis Set: PK Population)  
Figure 2.5.2  Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration (Log-Linear Scale) 
 (Analysis Set: PK Population)  
Figure 2.5.3  Invidual Glycopyrronium AUC0-tlast after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.5.3.1  Invidual Glycopyrronium AUC0-tlast after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.5.4  Invidual Glycopyrronium Cmax after Single-Dose Administration with Charcoal 


 
 
 
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(Analysis Set: PK Population)  
Figure 2.5.4.1  Invidual Glycopyrronium Cmax after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.5.5  Invidual Glycopyrronium AUC0-∞ after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.5.5.1  Invidual Glycopyrronium AUC0-∞ after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.6.1 Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration (Linear-Linear Scale) 
 (Analysis Set: PK Population)  
Figure 2.6.2  Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration (Log-Linear Scale) 
 (Analysis Set: PK Population)  
Figure 2.6.3  Invidual Formoterol AUC0-tlast after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.6.3.1  Invidual Formoterol AUC0-tlast after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.6.4  Invidual Formoterol Cmax after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.6.4.1  Invidual Formoterol Cmax after Single-Dose Administration without Charcoal 
(Analysis Set: PK Population)  
Figure 2.6.5  Invidual Formoterol AUC0-∞ after Single-Dose Administration with Charcoal 
(Analysis Set: PK Population)  
Figure 2.6.5.1  Invidual Formoterol AUC0-∞ after Single-Dose Administration without Charcoal 


 
 
 
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(Analysis Set: PK Population)  
 
1.3 Safety Data 
1.3.1 Adverse Events 
Table 3.1.1 Summary of Subjects With At Least One Treatment Emergent Adverse Event 
 (Analysis Set: Safety Population)  
Table 3.1.2 Summary of On-treatment Adverse Events by System Organ Class and Preferred Term 
 (Analysis Set: Safety Population)  
Table 3.1.3 Summary of Post-treatment Adverse Events by System Organ Class and Preferred Term 
(Analysis Set: Safety Population)  
Table 3.2.1 Summary of On-treatment Adverse Events by SOC, Preferred Term and Highest Severity by 
Regimen 
 (Analysis Set: Safety Population)  
Table 3.2.2 Summary of Post-treatment- Adverse Events by SOC, Preferred Term and Highest Severity by 
Regimen 
 (Analysis Set: Safety Population)  
 
 


 
 
 
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2 DATA LISTINGS 
2.1.1 Subject Disposition and Demographics 
Listing 1.1 Listing of Subject Disposition and Demographic Data 
 (Analysis Set: All Subjects Randomized)  
Listing 1.2 Listing of Early Withdrawals 
 (Analysis Set: Safety Population)  
2.1.2 Protocol Deviations 
Listing 2.1 Listing of Major Protocol Deviations 
 (Analysis Set: Safety Population)  
Listing 2.2 Violation of Inclusion/Exclusion Criteria 
 (Analysis Set: All Subjects Treated)  
2.1.3 Subjects Excluded from the Analysis Populations 
Listing 3.1 Listing of Subjects Excluded From Analysis Populations 
 (Analysis Set: Safety Population)  
2.1.4 Baseline Characteristics 
Listing 4.2 Listing of Medical and Surgical History 
 (Analysis Set: Safety Population)  
2.1.5 Dosing and Compliance 
Listing 5.1 Listing of Study Drug Dosing 
 (Analysis Set: Safety Population)  
  
2.1.6 Adverse Events 
Listing 7.1 Listing of Reported Adverse Events by Subject, System Organ Class, Preferred Term and Onset 
Day 


 
 
 
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 (Analysis Set: Safety Population)  
Listing 7.2 Listing of Reported Serious Adverse Events by Subject, System Organ Class, Preferred Term 
and Onset Day 
 (Analysis Set: All Screened Subjects)  
Listing 7.3 Listing of Reported Pre-treatment Serious Adverse Events by Subject, System Organ Class, 
Preferred Term and Onset Day 
 (Analysis Set: Safety Population)  
2.1.7 Pharmacokinetic Data 
Listing 8.1 Plasma Concentrations of Budesonide, Glycopyrronium, and Formoterol by SubjectID, 
Regimen, Period, Study Day, and Timepoint 
(Analysis Set: PK Population)  
Listing 8.2 Derived Pharmacokinetic Parameters of Budesonide, Glycopyrronium, and Formoterol by Visit 
and Subject ID 
(Analysis Set: PK Population)  
Listing 8.3 Derived Pharmacokinetic Parameters of Budesonide, Glycopyrronium, and Formoterol by 
Subject ID 
(Analysis Set: PK Population)  
2.1.8 Laboratory Data 
Listing 9.1 Listing of Laboratory Test Out-of-Range Test Results - Hematology 
 (Analysis Set: Safety Population)  
Listing 9.2 Listing of Laboratory Test Out-of-Range Test Results - Chemistry 
 (Analysis Set: Safety Population)  
Listing 9.3 Listing of Laboratory Test Out-of-Range Test Results - Urinalysis 
(Analysis Set: Safety Population)  
2.1.9 Other Clinical Observations and Measurements 
Listing 10.1.1 Listing of Reported Prior, Concomitant, and Post-Treatment Medication (COPD Related) 


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 (Analysis Set: All Subjects Screened)  
Listing 10.1.2 Listing of Reported Prior, Concomitant, and Post-Treatment Medication (Non-COPD 
Related) 
 (Analysis Set: All Subjects Screened)  
Listing 10.2 Listing of Out-of-Range Vital Signs, Weight, and Height 
 (Analysis Set: All Subjects Screened)  
Listing 10.3 Listing of Urine Drug Screening / Alcohol Breath Testing 
 (Analysis Set: All Subjects Screened)  
Listing 10.4 Listing of Pregnancy Testing 
 (Analysis Set: All Subjects Screened)  
Listing 10.5 Listing of Comments 
 (Analysis Set: All Subjects Screened) 
Listing 10.6 Out-of-Range 12-Lead Electrocardiogram (ECG) 
 (Analysis Set: All Subjects Screened)  
APPENDIX 3: 
 CODE FOR STATISTICAL ANALYSES 
This appendix is provided in a separate document. 
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND 
CENTRAL LABORATORY REFERENCE RANGES FOR USE IN FLAGGING 
ABNORMAL VALUES 
This appendix is provided in a separate document.