Clinical trial NCT03250182
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Pearl Therapeutics, Inc.
Start date: 2017-08-11; Completion date: 2017-12-07
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase I open-label, single center study to assess the PK and safety of BGF MDI 320/14.4/9.6 µg in subjects with moderate to severe COPD. Pharmacokinetics will be assessed following a single dose administration on the first treatment day (Day 1) and will be assessed again after 7 days of repeat dosing. This study includes a Screening Period of up to 28 days and a single Treatment Period of 8 days. A follow-up phone call will be conducted at least 5 days but no longer than 7 days after the last dose of study drug.

Detailed description:

Arms: arm 1: PT010; Budesonide, Glycopyrrolate, and Formoterol Fumarate Inhalation Aerosol per protocol. Administered as 2 inhalations per use as instructed in the protocol.
Interventions: intervention 1: PT010
Intervention descriptions: intervention 1: PT010; Budesonide, Glycopyrrolate, and Formoterol Fumarate Inhalation Aerosol. Administered as 2 inhalations per use as instructed per the protocol.

Protocol documents:
Prot_000.pdf: 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc. 
Clinical Study Protocol: PT010018-00
Version 1.0 
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Clinical Study Protocol: PT010018-00
Study Title:
A Study to Assess the Pharmacokinetics and Safety of PT010 in
Subjects With Moderate to Severe COPD Following Single and Repeat 
Dose Administration
Study Number:
PT010018
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
14 June 2017
Confidentiality Statement 
Property of Pearl Therapeutics
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of Pearl Therapeutics Inc.


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SYNOPSIS 
Sponsor:
Pearl Therapeutics, Inc.
Name of Study Drug:
PT010: Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol, Metered 
Dose Inhaler (BGF MDI)
Name of Active Ingredients:
Budesonide, Glycopyrronium, and Formoterol Fumarate
Study Title:
A Study to Assess the Pharmacokinetics and Safety of PT010 in Subjects With Moderate to 
Severe COPD Following Single and Repeat Dose Administration
Study Protocol Number:PT010018-00
Study Phase: I
Primary Objective:
•
To assess the pharmacokinetic (PK) profile of BGF MDI in subjects with moderate 
to severe COPD after single dose administration on the first treatment day and after 7 
days of repeat dosing.
Safety Objective:
•
To assess the safety and tolerability of BGF MDI in subjects with moderate to severe 
COPD after single dose administration on the first treatment day and after 7 days of 
repeat dosing
Study Design:
This is a Phase I open-label, single center study to assess the PK and safety of BGF MDI 
320/14.4/9.6 μg in subjects with moderate to severe COPD. Pharmacokinetics will be 
assessed following a single dose administration on the first treatment day (Day 1) and will be 
assessed again after 7 days of repeat dosing. This study includes a Screening Period of up to 
28 days and a single Treatment Period of 8 days. A follow-up phone call will be conducted at 
least 5 days but no longer than 7 days after the last dose of study drug.
Subjects who provide informed consent before the conduct of any screening assessments will 
undergo screening procedures to determine eligibility to participate in the study.
To be considered eligible for the study, subjects must have a documented history (ie, within 
the past 12 months) of COPD defined as a post-bronchodilator forced expiratory volume in 1 
second (FEV1)/forced vital capacity (FVC) <0.70 and a post-bronchodilator FEV1 <80% 
predicted normal. Subjects without historical documentation must meet these criteria at the 


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Screening Visit. In addition, subjects must have a pre-bronchodilator FEV1 between ≥50 and 
<80% predicted normal during Screening after withholding all COPD medications and after 
withholding the use of albuterol for at least 6 hours prior to the assessment. All eligible 
subjects will receive Sponsor-provided Ventolin® hydrofluoroalkane (HFA; albuterol sulfate 
inhalation aerosol) for rescue use throughout the study. During the Screening Period, eligible 
subjects will continue the use of their regular COPD maintenance therapy. However, any 
medication containing any one or more of the components of BGF (all formulations of 
budesonide, glycopyrronium or formoterol fumarate) are prohibited a minimum of 4 weeks 
before Screening during the study. 
Subjects will be admitted to the clinic as an inpatient on Day -1, at which time continuing 
eligibility will be assessed and subjects will be instructed to discontinue all COPD therapy 
except study-provided rescue Ventolin HFA after their last dose for the day. Study subjects 
will use a Placebo MDI for training purposes only to demonstrate proper use of the MDI on 
Day -1, Day 1, Day 7, and Day 8. The Treatment Period of 8 days will start on Day 1. BGF 
MDI 320/14.4/9.6 μg will be administered as oral inhalation as follows: 
• Single dose administration on the morning of Day 1 (Visit 3) followed by serial 
blood draws for 24 hours  
• Twice daily (BID) dosing every morning and evening on Days 2 through Day 7 
approximately 12 hours apart  
• Single dose administration on the morning of Day 8 (Visit 5) followed by serial 
blood draws for 12 hours 
 
Subjects will be discharged on Day 2 of the Treatment Period after performing the last PK 
blood draw and will continue to administer BGF MDI BID at home on Days 2 through 7. 
Subjects will return to the clinic for inpatient admission on Day 7 (Visit 4) and administer the 
evening dose of study drug at the clinic. 
Subjects will undergo safety assessments and serial blood draws on Day 8 following the 
morning dose of study drug. After all protocol-specified assessments are completed and 
safety data have been reviewed by the Principal Investigator or designated staff, the subject 
will be discharged from the clinic on the evening of Day 8. 
Subjects will return to appropriate COPD maintenance medications after the final 
assessments on Day 8 are completed. 
Study Population: 
The planned study population will include approximately 30 male and female adult subjects 
with moderate to severe COPD who will be enrolled to provide approximately 24 subjects 
who will complete the study. 


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Study Drug, Dose, and Mode of Administration 
Product Name & Dose 
Product Strength 
Dosage Form/ 
Fill Count 
Administration 
BGF MDI 320/14.4/9.6 μg 
ex-actuator 
160/7.2/4.8 μg/actuation 
MDI/ 
120 inhalations 
2 inhalations BID 
Duration of Treatment:  
It is planned that each subject will receive study drug for 8 days. 
Duration of Study: 
The entire study period is scheduled to take approximately 7 weeks (expected range between 
2.5 to 7 weeks) for each individual subject. The study is anticipated to run for approximately 
4 to 6 months. 
PK Endpoints 
Pharmacokinetics 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 and Day 8. 
Primary PK Endpoints 
• Maximum plasma concentration (Cmax) 
• Area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) 
• Area under the plasma concentration-time curve from 0 to the time of the last 
measureable plasma concentration (AUC0-tlast) 
 
Secondary PK Endpoints 
• Time to maximum plasma concentration (tmax) 
• Area under the plasma concentration-time curve from 0 extrapolated to infinity 
(AUC0-∞)  
Safety Endpoints: 
• Adverse events (AEs) 
• 12-lead electrocardiograms (ECGs) 
• Clinical laboratory testing  
• Vital sign measurements 
Statistical Methods: 
Safety Analyses: Descriptive statistics will be provided for ECG, vital signs, and laboratory 
measurements as appropriate. The frequencies of AEs and the number and percentage of 
subjects with AEs will also be provided. 


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PK Analyses: The accumulation ratios for AUC0-12 and Cmax and the linearity ratio 
AUC0-12/AUC0-∞between Day 8 and Day 1 for budesonide, glycopyrronium, and formoterol 
will be analyzed using a mixed model with day as a fixed effect and subject as random effect. 
Descriptive statistics without model adjustment will be used to describe the other 
budesonide, glycopyrronium, and formoterol PK parameters after treatment with BGF MDI. 
The time to steady state for each analyte will be estimated using the effective rate of 
accumulation.
Sample Size: This study is descriptive in nature. The planned sample size of approximately 
30 enrolled subjects is selected to provide approximately 24 completers for assessment of the 
single- and multiple-dose PK of BGF MDI in subjects with COPD.
Date of Protocol:


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................6 
LIST OF IN-TEXT TABLES ..................................................................................................10 
LIST OF IN-TEXT FIGURES.................................................................................................11 
LIST OF APPENDICES ..........................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
TRADEMARK INFORMATION ...........................................................................................16 
1 
INTRODUCTION AND STUDY RATIONALE ...........................................................17 
2 
STUDY OBJECTIVES ....................................................................................................19 
2.1 
Primary Objective ..................................................................................................19 
2.2 
Safety Objective .....................................................................................................19 
3 
STUDY ENDPOINTS .....................................................................................................20 
3.1 
PK Endpoints .........................................................................................................20 
3.1.1 
Primary PK Endpoints .................................................................................20 
3.1.2 
Secondary PK Endpoints .............................................................................20 
3.1.3 
Other PK Endpoints .....................................................................................20 
3.2 
Safety Endpoints ....................................................................................................21 
4 
INVESTIGATIONAL PLAN ..........................................................................................22 
4.1 
Overall Study Design and Plan ..............................................................................22 
4.2 
Study Duration .......................................................................................................23 
5 
STUDY POPULATION SELECTION ...........................................................................24 
5.1 
Inclusion Criteria ...................................................................................................24 
5.2 
Exclusion Criteria ..................................................................................................25 
5.3 
Subject Identification .............................................................................................27 
5.4 
Prior, Concomitant, and Prohibited Medications ...................................................27 
5.4.1 
Prior, Concomitant, and Prohibited COPD Medications .............................27 
5.4.2 
Other Prohibited Medications ......................................................................29 
5.5 
Other Study Restrictions ........................................................................................30 
5.5.1 
Dietary Restrictions .....................................................................................30 
5.5.2 
Illicit Drugs and/or Drugs of Abuse Restriction ..........................................31 
5.6 
Study Withdrawal ..................................................................................................31 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES ....................................................................................................32 
6.1 
Description of Study Drug .....................................................................................32 
6.2 
Other Sponsor-Provided Medications Used in the Study ......................................32 
6.3 
Packaging and Labeling .........................................................................................33 


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6.4 
Storage Requirements ............................................................................................34 
6.5 
Instructions for Preparation of Study Drug for Administration .............................34 
6.6 
Study Drug Dosing ................................................................................................35 
6.7 
Emergency Unblinding of Treatment Assignment ................................................36 
6.8 
Study Drug Accountability/Return of Clinical Supplies .......................................36 
7 
STUDY PROCEDURES .................................................................................................37 
7.1 
Informed Consent...................................................................................................37 
7.2 
Subject Eligibility ..................................................................................................37 
7.3 
Subject Diary Data Collection ...............................................................................37 
7.4 
Pulmonary Function Tests .....................................................................................37 
7.4.1 
Lung Function Assessment ..........................................................................38 
7.4.2 
Pre- and Post-Bronchodilator Assessments .................................................38 
7.5 
PK Assessments .....................................................................................................39 
7.5.1 
Blood Sample Collection Schedule .............................................................39 
7.5.2 
Procedures for Shipping Samples ................................................................39 
7.5.3 
Storage and Destruction of PK Samples ......................................................39 
7.6 
Safety Assessments ................................................................................................40 
7.6.1 
Medical History ...........................................................................................40 
7.6.2 
Physical Examination...................................................................................40 
7.6.3 
Vital Signs ....................................................................................................40 
7.6.4 
12-Lead ECG ...............................................................................................40 
7.6.5 
Clinical Laboratory Tests .............................................................................41 
7.6.5.1 
Laboratory Sample Collection, Storage and Shipping .......................42 
7.7 
AEs .........................................................................................................................42 
7.7.1 
Performing AE Assessments........................................................................42 
7.7.2 
AE Definitions .............................................................................................42 
7.7.3 
Pre-Treatment AEs.......................................................................................43 
7.7.4 
TEAEs ..........................................................................................................43 
7.7.5 
Severity ........................................................................................................43 
7.7.6 
Relationship .................................................................................................44 
7.7.7 
COPD Exacerbations ...................................................................................44 
7.7.8 
AEs of Special Interest.................................................................................44 
7.7.8.1 
LABA and LAMA Effects .................................................................44 
7.7.8.2 
Local Steroid Effects..........................................................................44 
7.7.9 
Clinical Laboratory AEs ..............................................................................45 
7.7.10 
SAEs ............................................................................................................45 
7.7.10.1 
Reporting SAEs .................................................................................46 
7.7.10.2 
Supplemental Investigations of SAEs ................................................46 
7.7.10.3 
Post-Study Follow-up of AEs ............................................................46 


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7.7.10.4 
Notification of Post-Treatment SAEs ................................................47 
7.7.10.5 
IRB/IEC Notification of SAEs...........................................................47 
7.7.10.6 
Health Authority Safety Reports ........................................................47 
7.7.11 
Overdose ......................................................................................................47 
7.7.12 
Pregnancy .....................................................................................................47 
7.7.13 
Paternal Exposure ........................................................................................48 
7.8 
Termination of the Study .......................................................................................48 
8 
STUDY ACTIVITIES .....................................................................................................49 
8.1 
Screening Visit 1 (Screening, Day -28 to Day -2) .................................................55 
8.2 
Visit 2 (Admission to Clinic, Day -1) ....................................................................55 
8.3 
Visit 3 (Day 1/Day 2 of the Treatment Period)......................................................56 
8.4 
Telephone Contact (Days 2 to 7 of the Treatment Period) ....................................57 
8.5 
Visit 4 (Day 7) .......................................................................................................57 
8.6 
Visit 5 (Day 8) .......................................................................................................58 
8.7 
Follow-up Telephone Call .....................................................................................58 
9 
PLANNED STATISTICAL METHODS ........................................................................59 
9.1 
General Considerations ..........................................................................................59 
9.2 
Analysis Populations ..............................................................................................59 
9.3 
Demographics and Baseline Characteristics ..........................................................59 
9.4 
Analysis of PK Variables .......................................................................................59 
9.5 
Safety Analyses ......................................................................................................61 
9.6 
Randomization .......................................................................................................61 
9.7 
Determination of Sample Size ...............................................................................61 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................62 
10.1 
Regulatory Authority Approval .............................................................................62 
10.2 
Ethical Conduct of the Study and IRB or IEC Approval .......................................62 
10.3 
Subject Information and Consent...........................................................................62 
10.4 
Laboratory Accreditation .......................................................................................62 
10.5 
Confidentiality .......................................................................................................63 
10.5.1 
Confidentiality of Data ................................................................................63 
10.5.2 
Confidentiality of Subject/Patient Records ..................................................63 
10.6 
Quality Control and Assurance ..............................................................................63 
10.7 
Data Management ..................................................................................................63 
10.8 
Study Monitoring ...................................................................................................63 
10.9 
Retention of Data ...................................................................................................64 
10.10 Financial Disclosure...............................................................................................65 
10.11 Investigator’s Final Report ....................................................................................65 
10.12 Publication Policy ..................................................................................................65 


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11 REFERENCE LIST .........................................................................................................67 
12 APPENDICES .................................................................................................................68 
 


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LIST OF IN-TEXT TABLES 
Table 5-1 
Prohibited Budesonide, Glycopyrronium, and Formoterol Fumarate 
COPD Medications ......................................................................................................28 
Table 5-2  
Other Prohibited COPD Medications .....................................................28 
Table 5-3  
Other Prohibited Medications ................................................................29 
Table 6-1 
Study Drug Description..........................................................................32 
Table 6-2 
Other Medications Provided by Sponsor ...............................................33 
Table 7-1 
Laboratory Tests .....................................................................................41 
Table 8-1 
Schedule of Events for Screening, Treatment, and Follow-up ..............50 
Table 8-2 
Timing of Assessments on Day 1 (Visit 3) ............................................53 
Table 8-3 
Timing of Assessments on Day 8 (Visit 5) ............................................54 
Table A1-1.  
Recommended Minimal Scale Factors for Time, Volume and Flow 
on Graphical Output .....................................................................................................90 
Table A1-2  
Summary of Equipment Quality Control ...............................................91 
Table A1-3  
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers ..................................................................................................93 
 


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LIST OF IN-TEXT FIGURES 
Figure 4-1. 
Study Design ..........................................................................................23 
Figure A1-1  
Example of a Usable Spirogram ............................................................87 
 


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LIST OF APPENDICES 
Appendix 1 
Dose Indicator Reading ..........................................................................69 
Appendix 2 
Subject Instructions for Use of BGF MDI and Placebo MDI ................70 
Appendix 3 
Instructions for Use of Ventolin HFA Inhalation Aerosol Device ........79 
Appendix 4 
Spirometry Assessment Criteria .............................................................87 
Appendix 5 
Spirometry Performance Recommendations ..........................................89 
Appendix 6 
Sponsor Signatory ..................................................................................95 
Appendix 7 
Investigator’s Signature .........................................................................96 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-tlast 
Area under the plasma concentration-time curve from 0 the time of the last 
measureable 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 
BID 
Twice daily 
BP 
Blood pressure 
CI 
Confidence interval 
CL/F 
Apparent total body clearance 
Cmax 
Maximum plasma concentration 
COPD 
Chronic obstructive pulmonary disease 
CV% 
Coefficient of variation 
CYP3A4 
Cytochrome P450 3A4 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 


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hCG 
Human chorionic gonadotropin 
HFA 
Hydrofluoroalkane 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICS 
Inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISMPP 
International Society for Medical Publication Professionals 
LABA 
Long-acting β2-agonist 
LAMA 
Long-acting muscarinic antagonist 
λz 
Terminal elimination rate constant 
LSM 
Least square mean 
MDI 
Metered dose inhaler 
NHANES 
National Health and Nutrition Examination Survey 
PFT 
Pulmonary function test 
PK 
Pharmacokinetics 
PT009 
Budesonide and Formoterol Fumarate Inhalation Aerosol 
PT010 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol 
QTcF 
Fridericia-corrected QT interval 
RAC(Cmax) 
Accumulation ratio for Cmax 
RAC(AUC0-12) 
Accumulation ratio for AUC0-12 
Rlin 
Linearity ratio 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event 
SAMA 
Short-acting muscarinic antagonist 
SAP 
Statistical analysis plan 
t1/2 
Apparent terminal elimination half-life 


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TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma concentration 
US 
United States  
Vd/F 
Apparent volume of distribution 
 
 


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TRADEMARK INFORMATION 
Trademarks not owned by the Sponsor: 
Foradil 
Seebri 
Perforomist 
Symbicort 
Pulmicort 
Turbuhaler 
Rhinocort 
Xolair 
Robinul 
 
 
 
 


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1 
INTRODUCTION AND STUDY RATIONALE 
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 (Global Initiative for Chronic 
Obstructive Lung Disease [GOLD 2017]). 
Bronchodilator medications are central to the symptomatic management of COPD. The 
principal bronchodilator treatments are β2-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 of ICS may lead to exacerbations in some patients. When combined with a 
long-acting β2-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 Pearl) is developing a 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. Glycopyrronium, and Formoterol Fumarate 
Inhalation Aerosol MDI is approved in the United States (US) as a BID maintenance 
bronchodilator treatment in patients with COPD under the tradename Bevespi Aerosphere®. 
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 dihydrate (ie, Symbicort® [AstraZeneca, LP]) 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 


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in many countries in multiple formulations for different indications, including for the 
treatment of COPD. 
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® [AstraZeneca, LP]) for use in patients with 
asthma and COPD. When inhaled, formoterol fumarate acts locally in the lung as a 
bronchodilator. Formoterol fumarate stimulates β2-adrenoreceptors in the airways, inducing 
airway smooth muscle relaxation and reducing or preventing bronchoconstriction. 
The purpose of this study is to determine the pharmacokinetics (PK) of BGF MDI in subjects 
with COPD following single and repeat administration. This will allow determination of 
accumulation of each component of BGF MDI in plasma during steady-state administration. 
The plasma concentration data will also contribute to population PK modeling. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To assess the PK profile of BGF MDI in subjects with moderate to severe COPD 
after single dose administration on the first treatment day and after 7 days of repeat 
dosing 
 
2.2 
Safety Objective 
• To assess the safety and tolerability of BGF MDI in subjects with moderate to severe 
COPD after single dose administration on the first treatment day and after 7 days of 
repeat dosing 
 


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3 
STUDY ENDPOINTS 
3.1 
PK Endpoints 
Pharmacokinetics 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 and Day 8. 
3.1.1 
Primary PK Endpoints 
• Maximum plasma concentration (Cmax) 
• Area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) 
• Area under the plasma concentration-time curve from 0 to the time of the last 
measureable plasma concentration (AUC0-tlast) 
 
3.1.2 
Secondary PK Endpoints 
• Time to maximum plasma concentration (tmax) 
• Area under the plasma concentration-time curve from 0 extrapolated to infinity 
(AUC0-∞) 
 
3.1.3 
Other PK Endpoints 
The following PK parameters will be calculated at Day 1 only: 
• Apparent terminal elimination half-life (t1/2) 
• Apparent total body clearance (CL/F) 
• Apparent volume of distribution (Vd/F) 
• Terminal elimination rate constant (λz) 
 
The following will be derived based on ratios of Day 8 values to Day 1 values: 
• Accumulation ratio for Cmax (RAC [Cmax]) 
• Accumulation ratio for AUC0-12 (RAC [AUC0-12]) 
• Linearity ratio (Rlin [AUC0-12/AUC0-∞]) 
 
Other PK parameters may be calculated, as appropriate. 


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3.2 
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 open-label, single center study to assess the PK and safety of BGF MDI 
320/14.4/9.6 μg in subjects with moderate to severe COPD. Pharmacokinetics will be 
assessed following a single dose administration on the first treatment day (Day 1) and will be 
assessed again after 7 days of repeat dosing. This study includes a Screening Period of up to 
28 days and a single Treatment Period of 8 days. A follow-up phone call will be conducted at 
least 5 days but no longer than 7 days after the last dose of study drug.  
Subjects who provide informed consent before the conduct of any screening assessments will 
undergo screening procedures to determine eligibility to participate in the study. 
To be considered eligible for the study, subjects must have a documented history (ie, within 
the past 12 months) of COPD defined as a post-bronchodilator FEV1/forced vital capacity 
(FVC) <0.70 and a post-bronchodilator FEV1 <80% predicted normal. Subjects without 
historical documentation must meet these criteria at the Screening Visit. In addition, subjects 
must have a pre-bronchodilator FEV1 between ≥50 and <80% predicted normal during 
Screening after withholding all COPD medications and after withholding the use of albuterol 
for at least 6 hours prior to the assessment. All eligible subjects will receive Sponsor-
provided Ventolin® hydrofluoroalkane (HFA; albuterol sulfate inhalation aerosol) for rescue 
use throughout the study. During the Screening Period, eligible subjects will continue the use 
of their regular COPD maintenance therapy. However, any medication containing any one or 
more of the components of BGF (all formulations of budesonide, glycopyrronium, or 
formoterol fumarate) are prohibited a minimum of 4 weeks before Screening and during the 
study. 
Subjects will be admitted to the clinic as an inpatient on Day -1, at which time continuing 
eligibility will be assessed and subjects will be instructed to discontinue all COPD therapy 
except study-provided rescue Ventolin HFA after their last dose for the day. Study subjects 
will use a Placebo MDI for training purposes only to demonstrate proper use of the MDI on 
Day -1, Day 1, Day 7, and Day 8. The Treatment Period of 8 days will start on Day 1. BGF 
MDI 320/14.4/9.6 μg will be administered as oral inhalation as follows: 
• Single dose administration on the morning of Day 1 (Visit 3) followed by serial 
blood draws for 24 hours 
• BID dosing every morning and evening on Days 2 through Day 7 approximately 12 
hours apart  
• Single dose administration on the morning of Day 8 (Visit 5) followed by serial 
blood draws for 12 hours 
 
Subjects will be discharged on Day 2 of the Treatment Period after performing the last PK 
blood draw and will continue to administer BGF MDI BID at home on Days 2 through 7. 




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5 
STUDY POPULATION SELECTION 
Approximately 30 subjects with moderate to severe COPD will be enrolled in this study. 
Subjects who withdraw from the study after receiving at least 1 dose of study drug will not 
be replaced. Subjects who are enrolled but do not receive study will be replaced. Subjects 
who are re-evaluated will maintain 1 screening number throughout the study. 
5.1 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. Give their signed written informed consent to participate 
2. Are at least 40 and no older than 80 years of age at Visit 1 
3. 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]) 
Note: For purposes of this protocol, menopausal women are defined as women 
≥50 years old who are amenorrheic for 12 consecutive months or more following 
cessation of all exogenous hormonal treatment 
- 
Practice 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 informed 
consent form (ICF) is signed until 2 weeks after the final dose of study drug is taken: 
◦ 
Hormonal contraception (eg, oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive) 
◦ 
Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide or condom plus spermicide) 
◦ 
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 Visit 1 
- 
Males 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 their last dose, and must not donate sperm during their study 
participation period 
4. COPD Diagnosis: An established clinical history of COPD as defined by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) (Celli 2004) characterized 
by progressive airflow limitation associated with an abnormal inflammatory response of 
the lungs to noxious particles or gases, primarily caused by cigarette smoking. This 
includes demonstration (at the Screening Visit or within the past 12 months) of a post-
bronchodilator FEV1/FVC ratio of <0.70 and post-bronchodilator FEV1 of <80% 
predicted normal value. 


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5. Tobacco Use: Current or former smokers with a history of at least 10 pack-years of 
cigarette smoking. Number of pack-years= (number of cigarettes per day/20) × number of 
years smoked (eg, 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years 
represent 10 pack-years). 
6. COPD Severity: At Visit 1, pre-bronchodilator FEV1/FVC ratio must be <0.70 and 
pre-bronchodilator FEV1 must be ≥50% and <80% predicted normal value calculated 
using National Health and Nutrition Examination Survey (NHANES) III reference 
equations.  
7. Screening clinical laboratory tests must be acceptable to the Investigator. 
8. Screening ECG must be acceptable to the Investigator. 
9. Compliance: Must be willing to remain at the study center as required per protocol to 
complete all visit assessments. 
10. Demonstrate correct MDI administration technique. Spacer use is prohibited 
 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Pregnancy and Lactation: Women who are pregnant or lactating, or are planning to 
become pregnant during the course of the study, or women of childbearing potential who 
are not using an acceptable method of contraception. 
2. Asthma: Subjects who have a diagnosis of asthma. (Note: Subjects with a primary 
diagnosis of COPD but a prior history of asthma that is remote (ie, more than 10 years 
since it has been an active diagnosis) are eligible. 
3. Alpha-1 Antitrypsin Deficiency: Alpha-1 antitrypsin deficiency as the cause of COPD. 
4. Other Respiratory Disorders: Includes other active pulmonary disease such as active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary 
hypertension, interstitial lung disease and uncontrolled sleep apnea (ie, in the opinion of 
the Investigator, severity of the disorder would impact the conduct of the study). 
5. Lung Resection: Subjects who have undergone lung volume reduction surgery at any 
time in the past. 
6. Exacerbation: Subjects who have had a moderate or severe COPD exacerbation (ie, an 
exacerbation for which the subject was hospitalized or required systemic corticosteroids 
or antibiotics) within 3 months of Screening (Visit 1). 
7. Lower respiratory tract infections: Subjects who have had lower respiratory tract 
infections that required antibiotics within 3 months prior to Screening (Visit 1). 
8. Spirometry Performance: Subjects who cannot perform acceptable spirometry as per 
ATS/ERS criteria (Miller 2005). 
9. Other Diseases: Subjects who have clinically significant medical conditions, including 
but not limited to cardiovascular, neurological, psychiatric, hepatic, gastrointestinal, renal 
(creatinine clearance ≤30 mL/minute), immunological, glaucoma, symptomatic prostatic 
hypertrophy (if treated and asymptomatic, the subject is eligible for enrollment), 


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endocrine (including uncontrolled diabetes or thyroid disease), or hematological medical 
problems. 
10. Clinically significant abnormal ECG: Subjects who in the opinion of the Investigator 
have a clinically significant abnormal 12-lead ECG. A clinically significant abnormal 
ECG is defined as (but not limited to) any of the following: 
- 
Clinically significant conduction abnormalities (eg, complete left bundle branch 
block, Wolff-Parkinson-White syndrome) 
- 
Clinically significant arrhythmias (eg, atrial fibrillation, ventricular tachycardia) 
- 
Fridericia-corrected QT interval (QTcF) ≥500 msec in subjects with QRS <120 msec 
and QTcF ≥530 msec in subjects with QRS ≥120 msec 
- 
Ventricular rate <45 bpm 
- 
Evidence of second-degree (Mobitz Type II) or third-degree atrioventricular block 
- 
Pathological Q waves of 1 year or less 
- 
ST-T wave abnormalities deemed to be clinically significant by the Investigator. 
Note: Subjects with non-specific ST-T wave abnormalities that are not deemed 
clinically significant (per Investigator) are allowed. 
11. Uncontrolled Hypertension: Subjects who have clinically significant uncontrolled 
hypertension. 
12. Liver Function: Abnormal liver function tests defined as aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, or total bilirubin ≥1.5 
times upper limit of normal on repeat testing 
13. Cancer: Cancer that has not been in complete remission for at least 5 years 
Note: Subjects with squamous cell carcinoma and/or basal cell carcinoma of the skin or 
localized prostate cancer that in the opinion of the Investigator has been adequately 
worked up, is clinically controlled, and where the subject’s participation in the study 
would not represent a safety concern, are eligible. 
14. Drug Allergy: Subjects who have a history of hypersensitivity to any corticosteroid, 
β2-agonist, muscarinic anticholinergic, or any component of the MDI. 
15. Anemia: Subjects with anemia that is considered clinically significant by the Investigator 
16. History of blood donation within 90 days before Screening 
17. Surgery: Subjects with major surgical interventions within 4 weeks before Screening or 
minor surgical interventions within 2 weeks before Screening 
18. Substance Abuse: Subjects with a known or suspected history of alcohol or drug abuse 
within 1 year prior to Screening 
19. An abnormal clinically significant chest X-ray during Screening or within 6 months prior 
to Screening. If the subject is able to provide a report of a chest X-ray or computed 
tomography within 6 months prior to Screening to assess this criterion, a chest X-ray at 
Screening will not be required. 
20. Medication Prior to Spirometry: Subjects who are medically unable to withhold their 
short-acting bronchodilators for the 6-hour period required prior to spirometry 


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21. Prohibited COPD Medications: Unable to abstain from protocol-defined prohibited 
medications during Screening and Treatment Periods (Section 5.4) 
22. Oxygen: Requirement for oxygen therapy for >12 hours/day 
23. Non-compliance: Unable to comply with study procedures 
24. Affiliations with Investigator Site: Study Investigators, Sub-Investigators, study 
coordinators, employees of a participating Investigator, or immediate family members of 
the aforementioned are excluded from participation in this study. 
25. Questionable Validity of Consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation, substance abuse (including drug and alcohol), or 
other conditions that might limit the validity of informed consent to participate in the 
study. 
26. Investigational Drugs or Devices: Treatment with an investigational study drug or 
participation in another clinical trial or study within the last 30 days or 5 half-lives prior 
to Screening, whichever is longer. 
27. Previous treatment in a Pearl BGF MDI or BFF MDI study  
 
5.3 Subject Identification 
All subjects who undergo screening procedures will be assigned a unique subject 
identification number at Screening. Only subjects continuing to meet entry 
inclusion/exclusion criteria on Day 1 will be assigned a unique subject enrollment number. 
5.4 
Prior, Concomitant, and Prohibited Medications 
All prescription and over-the-counter medications taken by the subject within 30 days prior 
to Visit 1 will be recorded on the Prior/Concomitant Medications electronic case report form 
(eCRF). 
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications eCRF page with indication, total daily dose, and dates of drug administration. 
Any additions, deletions, or changes in the dose of these medications while in the study 
should be recorded on the eCRF. Any current ongoing medications, including over-the-
counter drugs and herbal supplements, will be allowed provided they are not prohibited by 
the protocol (see Section 5.4) and are approved by the Investigator. 
5.4.1 
Prior, Concomitant, and Prohibited COPD Medications 
All formulations of budesonide, glycopyrronium, or formoterol fumarate used as 
monotherapy or in combination to treat COPD or any other condition (eg, allergic rhinitis) 
are prohibited for a minimum of 4 weeks before Visit 1 and during the study. Examples of 
these medications are summarized in Table 5-1. 


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Table 5-1 
Prohibited Budesonide, Glycopyrronium, and Formoterol 
Fumarate COPD Medications 
Product 
Example Trade Names 
Budesonide-containing products 
Symbicort, Rhinocort®, Pulmicort® 
Glycopyrronium-containing products  
Seebri®, Robinul®, Bevespi 
Formoterol fumarate-containing products 
Symbicort, Foradil®, Perforomist®, Bevespi 
 
All subjects entering the study on allowed inhaled COPD maintenance therapies for the 
management of their COPD should have been maintained on a stable dose of this treatment 
for at least 4 weeks prior to Visit 1. These COPD maintenance medications will be withheld 
after their last dose for the day on Day -1 (Visit 2) and throughout the study.  
Additionally, short acting bronchodilators (eg, short-acting β2-agonists [SABAs] or short-
acting muscarinic antagonists [SAMAs] or their combinations) will be withheld 6 hours prior 
to spirometry assessment at the Screening Visit and throughout the study except study-
provided Ventolin HFA for use as needed for symptom relief. Additional prohibited COPD 
medications and associated cessation periods prior to Visit 1 are summarized in Table 5-2. 
Table 5-2  
Other Prohibited COPD Medications 
Prohibited COPD Medications 
Minimum Cessation Period Prior to 
Visit 1 
Parenteral, depot, and oral steroids 
3 months 
Nebulized albuterol and/or ipratropium COPD 
medications 
6 hours 
Oral β-agonists 
2 days 
Theophylline (total daily dose >400 mg/day)a 
7 days 
SAMA 
6 hours 
SABAb 
6 hours 
Fixed-dose combinations of SAMA/SABA 
6 hours 
Note: Subjects requiring chronic maintenance therapy with oral corticosteroids are excluded from participation 
in this study. 
Note: Subjects requiring maintenance therapy with roflumilast (or any phosphodiesterase 4 inhibitor) are 
excluded from participation in this study. 
a 
Theophylline ≤400 mg/day is permitted provided the subject has been on a stable dose of therapy for at 
least 4 weeks prior to Visit 1. 
b 
Discontinue and use Sponsor-provided Ventolin HFA 
 


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5.4.2 
Other Prohibited Medications 
Subjects requiring medications presented in Table 5-3 are prohibited from participating in 
this study. Subjects who recently discontinued use of these medications may be considered 
for study enrollment provided they have not received these medications for a minimum of 
4 weeks before Visit 1. These medications are prohibited throughout the course of the study.  
Table 5-3  
Other Prohibited Medications 
Any drug with potential to significantly prolong the QT interval (eg, quinidine, bepridil, sotalol, 
amiodarone, chlorpromazine, erythromycin, etc)a 
Non-selective beta-adrenergic antagonists 
Cardiac antiarrhythmics Class Ia, III 
Any drug that causes significant tachycardia (pseudoephedrine, appetite suppressants, etc) 
Other investigational drugsb 
CYP3A4 inhibitors, including amiodarone, diltiazem, cimetidine, erythromycin, itraconazole, 
norfloxacin, ciprofloxacin, fluconazole, ketoconazole, clarithromycin, fluvoxamine, mifepristone, 
nefazodone, and troleandomycin 
CYP3A4 inducers including barbiturates (eg, phenobarbital), carbamazepine, phenytoin, and rifampin 
Anticonvulsants (barbiturates, hydantoins, and carbamazepine) for the treatment of seizure disorderc 
Tricyclic antidepressantsd 
Antipsychotic drugs (phenothiazines)d 
Monoamine oxidase inhibitors 
Anti-tumor necrosis factor α antibodies (eg, infliximab and any other members of this class of drugs) 
Monoclonal antibodiese 
Systemic calcineurin inhibitors 
Protease inhibitors 
Systemic anticholinergicsf 
Chinese complementary and alternative bronchodilatory medicines, ie, herbal therapies (eg, 
Astragalus membranaceus [huáng qí], Panax ginseng [ginseng products], Cordyceps sinensis, and 
A. membranaceus [ghost moth caterpillar fungus]) 


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Table 5-3  
Other Prohibited Medications 
Abbreviation: CYP3A4=cytochrome P450 3A4. 
Note: Benzodiazepines are not exclusionary. 
a 
Subjects who are on medications that have the potential to prolong the QTc interval may be enrolled 
provided the dose has remained stable for at least 3 months prior to Screening, the subject meets all of the 
ECG inclusion criteria and none of the ECG exclusion criteria, and if, in the opinion of the Investigator, 
there are no safety concerns for the subject to participate in the study. Initiation of medications with the 
potential to significantly prolong the QT interval is prohibited throughout the study. 
b 
Investigational therapies are not permitted within 30 days or 5 half-lives (whichever is longer) prior to 
Screening. 
c 
Anticonvulsants for conditions other than seizures may be started and stopped at any time prior to the study 
and throughout the Treatment Period. 
d 
Antipsychotic agents and tricyclic antidepressants used for previously diagnosed underlying medical 
conditions are allowed if, in the opinion of the Investigator, there are no concerns regarding subject safety, 
and if the subject has been on a stable dose for at least 6 weeks. 
e 
Investigators should consult the Medical Monitor to determine the appropriateness and safety of continuing 
study drug on a case by case basis (eg, XOLAIR® [omalizumab] will not be allowed, whereas a monoclonal 
for another indication such as osteoporosis may be allowed after consultation). 
f 
If systemic anticholinergics are used for treatment of overactive bladder and the treatment has been 
constant for at least 1 month, they are allowed. 
 
Any other medication that is considered necessary for the subject’s safety and well-being 
may be given at the Investigator’s discretion. 
5.5 
Other Study Restrictions 
5.5.1 Dietary Restrictions 
Fasting (at least 6 hours) is required for clinical laboratory testing at Visit 1, Visit 2 (Day -1), 
and Visit 5 (Day 8). 
Fasting (at least 6 hours) is required prior to administration of BGF MDI on serial PK sample 
collection days (Days 1 and 8). Food may be consumed 4 hours after dosing. 
Standardized meals will be administered on Days 1, 2, and Day 8 at specified times after 
observation of fasting time for blood draws. There are no restrictions regarding clear fluid 
intake. 
Subjects are not allowed to consume grapefruits or grapefruit juice throughout the study. 
Subjects must not ingest xanthine (caffeine)-containing foods, beverages, or medications for 
at least 6 hours prior to study drug administration and for 4 hours post dose on the days of 
serial PK assessments (Day1 and Day 8). Examples of such products include coffee, tea, 
chocolate, and cola. Decaffeinated beverages are acceptable. 


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5.5.2 Illicit Drugs and/or Drugs of Abuse Restriction 
Illicit drugs and/or drugs of abuse will not be allowed from within 1 year of Screening to 
whenever the subject withdraws from or completes the study. If any illicit drugs or drugs of 
abuse are used by the subject during the study, the dates of use and the amount will be 
documented. 
5.6 Study Withdrawal 
The Investigator or medically qualified designee may withdraw a subject at the occurrence of 
any or all of the following: 
• Protocol deviation 
• AE 
• COPD exacerbation 
• Subject becomes pregnant 
• Clinically significant change in a laboratory parameter(s) 
• Termination of the study by the Sponsor or Investigator 
• Request by the subject to be discontinued from the study 
• Investigator’s discretion 


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6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES 
Study drug will be packaged to support enrollment of the study in an open-label fashion for 
the 8-day Treatment Period. Clinical supplies will be packaged according to a component 
schedule generated by the Sponsor or their designee. 
6.1 
Description of Study Drug 
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 [ICH] E6 R1). The 
study drug used in this study is described in Table 6-1. Instructions for use/priming are 
provided in Appendix 2. Subjects meeting all study eligibility criteria (Section 5) will be 
assigned to open-label study drug at Visit 3 to be administered as directed in Section 6.5. 
The BGF MDI active drug substances are budesonide, glycopyrronium, and formoterol 
fumarate. Study drug will be provided by Pearl. 
Table 6-1 
Study Drug Description 
Product Name & Dose 
Product Strength 
Dosage 
Form/Fill Count 
Administration 
BGF MDI 
320/14.4/9.6 μg 
ex-actuator 
160/7.2/4.8 μg/actuation 
MDI/120 
inhalations 
2 inhalations BID 
Note: Study drug will be administered by oral inhalation. A single dose of study drug will be administered on 
Day 1, and BID doses will be administered Day 2 through Day 7, with a final single administration of study 
drug occurring on the morning of Day 8. Administration of study drug should occur at approximately the same 
time of day approximately 12 hours apart.  
 
6.2 
Other Sponsor-Provided Medications Used in the Study 
Other Sponsor-provided medications used during the study are described in Table 6-2. The 
manufacturer’s instructions for administration, cleaning, and storage are provided in 
Appendix 2 and Appendix 3. 


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Table 6-2 
Other Medications Provided by Sponsor 
Product Name & 
Dose 
Product Strength 
Dosage Form/Fill 
Count 
Administration 
Albuterol sulfate  
inhalation aerosol 
90 μg 
ex-actuator 
Ventolin HFA 
Each inhalation 
contains 108 μg 
albuterol sulfate 
corresponding to 
90 μg albuterol base 
from the mouthpiece 
MDI/60 or 200 
actuations 
Taken as 2 
inhalations up to 4 
times daily as needed 
for symptom relief 
during the study and 
as 4 puffs for post-
bronchodilator 
testing at Visit 1 
Placebo MDIa 
Formulation does not 
contain active 
ingredient 
MDI 
120 inhalations 
Subjects will use the 
Placebo MDI for 
training purpose only 
to demonstrate 
proper use of the 
MDI on Day -1, 
Day 1, Day 7, and 
Day 8 
a 
All Placebos MDIs are identical in appearance to study drug; they have no active moieties and have a 
different labels because they are only used for training. 
 
6.3 Packaging and Labeling  
All clinical trial supplies will be packaged by the Sponsor. 
Study drug (BGF MDI) 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 # 
Space for entry of randomization # 
Fill Count & Dosage Form 
Visit # (Space for Entry of Interval ID) 
Storage Conditions 
Protocol # 
Country regulatory requirements 
Sponsor address  
Translation Key  
Abbreviations: #=number; ID=identification. 
 
Ventolin HFA will be provided as individually labeled MDIs with a single label on the 
actuator and canister. 


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Labels will be printed with black ink and may include the following text: 
Lot # (Packaging Lot Trace ID) 
Space for entry of screening # 
Component ID # 
Space for entry of randomization # 
Fill Count & Dosage Form 
Visit # (Space for Entry of Interval ID) 
Storage Conditions 
Protocol # 
Country regulatory requirements 
Sponsor address  
Translation Key  
 
Placebo MDI will be packaged in individual boxes and labeled for training purpose only. 
Inside the box will be a labeled foil pouch containing a labeled MDI canister and actuator 
6.4 Storage Requirements 
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 the 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 canisters 
into a fire or incinerator. Avoid spraying in eyes. 
BGF MDI and Placebo MDI should be stored below 25°C (77°F) in a dry place. Excursions 
permitted up to 30°C (86°F).  
Ventolin HFA should be stored between 15°C and 25°C (59°F and 77°F). Store the inhaler 
with the mouthpiece down. For best results, the inhaler should be at room temperature before 
use. 
6.5 
Instructions for Preparation of Study Drug for Administration 
Individual BGF MDI devices will be packaged in a foil pouch and contained in an individual 
visit treatment box. Both the visit treatment box and the foil overwrap will have a label with 
a component ID number. The visit treatment box is labeled with a 2-part label. Write the 
subject number and treatment visit number on each of the 2-part labels. 
All subjects will receive BGF MDI (320/14.4/9.6 μg). Site staff will instruct study subjects 
on the proper use of an MDI using a bulk-supplied MDI (placebo). Subjects must 
demonstrate correct use of the MDI at Screening, Day -1, and before study drug dosing on 
Day 1, Day 7, and Day 8. 
All MDIs must be primed before the first use. Priming involves releasing 4 sprays into the air 
before the first use of the inhaler. 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 must occur in a separate room away from the subject treatment area. 


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Designated study site staff will be responsible for priming the study drug. On Day 1 of the 
Treatment Period, prior to the first study drug administration, the MDI device will be primed 
by the site staff in a separate room, or under an externally vented hood away from the 
treatment area. Priming in the same room as subjects being dosed is strictly prohibited as this 
could lead to cross contamination of different subjects. 
Just prior to dosing, subjects will be trained again on the proper use of the MDI device so 
that they are able to use it correctly. 
Once primed and the subject demonstrates the proper use of the MDI, the first dose (2 puffs) 
of study drug should be taken by the subject in the clinic under site personnel supervision.  
The date and time of the second puff should be recorded as the time of dose administration in 
the source and eCRF. 
Refer to Appendix 2 for additional instructions on the administration and cleaning of the 
BGF MDI and Placebo MDI. 
On serial PK days (Day 1 and Day 8), administration of BGF MDI will take place in a room 
separate from the room where blood samples will be drawn. 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. The subjects will also wash their hands and 
faces with water and rinse and clean their mouths twice with 25 mL water (rinse and spit out) 
after the administration of BGF MDI. Each dose will consist of 2 puffs from the MDI. 
Study site personnel should clean and dry the inhaler for 12 hours overnight following the 
evening dose on Day 7. 
6.6 Study Drug Dosing 
Designated study staff will schedule the first dose of study drug administration in the clinic 
to occur in the morning, before approximately 10 am.  
On Day 2, before discharge, BGF MDI will be dispensed and the subject should be instructed 
that subsequent morning study drug dosing should occur BID (2 puffs in the morning and 2 
puffs in the evening) at approximately the same time every day, and that evening dosing 
should occur as close as possible to 12 hours from the time of morning dosing. Study drug 
dosing should continue until the subject returns to the clinic on Day 7. Site staff will contact 
the subject by telephone each morning and evening during the Treatment Period to ensure 
study drug dosing compliance. 
For each subject, treatment will comprise of single dose administration (Day 1), BID dosing 
(Day 2 through Day 7), and a single morning dose on Day 8. 


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6.7 Emergency Unblinding of Treatment Assignment  
Not applicable - this is an open-label study.  
6.8 Study Drug Accountability/Return of Clinical Supplies 
Under no circumstances will the Investigator allow the study drug to be used other than as 
directed by this protocol. 
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secure location to which only the 
Investigator and designated study 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 or designee is responsible for keeping accurate records of the clinical 
supplies received from the Sponsor, the amount dispensed to and returned by the subject, and 
the amount remaining at the conclusion of the study. Study drug should be handled in 
accordance with instructions provided in this section. The Clinical 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. 
Sites should check with the Pearl representative for appropriate documentation that needs to 
be completed for drug accountability. 
The Investigator or designee should not open the individual clinical supply containers until 
all pre-dose assessments have been completed and the subject is eligible to be enrolled in the 
study. Any deviation from this must be discussed with the with the Sponsor’s Medical 
Monitor or designee. 
For each subject, all used study drug materials will be collected. Used subject supplies will 
be kept at room temperature in a secure and locked cabinet until returned to the Sponsor or 
designee. 
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 and all study-related activities. The ICF 
must be approved by the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) that is reviewing the study documents. The ICF 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 
Investigator. 
7.2 Subject Eligibility 
Eligibility screening of COPD 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 visit. Subjects will be admitted to the clinic on 
Day -1 and discharged on Day 2 and return for clinic admission on the evening of Day 7, 
with discharge on Day 8 after all assessments are complete. Screen failure and the reason for 
screen failure will be documented in the study site source documents and captured in the 
eCRF. 
7.3 
Subject Diary Data Collection 
Subjects will be provided with a diary to be completed BID to record their at-home study 
drug dosing (refer to dose indicator instructions in Appendix 1). 
The subject is to return the completed diary at Day 7 (Visit 4). The study coordinator will be 
responsible for reviewing the diary for completeness and accuracy with the subject before 
dosing study drug in the clinic. All fields should be completed by the subject. The subject 
will sign (initial) and date each page of the diary on the day it was completed, and the study 
coordinator will initial and date each diary page at the site visit when the diary is returned to 
validate the authenticity of the entries. If discrepancies or omissions of data are observed at 
this review, the subject, not the study coordinator, should make the corrections. The subject 
should draw a single line through the error and initial and date all corrections. The subject 
should make all entries in the diary in blue or black ink. 
7.4 
Pulmonary Function Tests 
Forced expiratory maneuvers for derivation of FEV1 and FVC will be assessed using the 
site's spirometry equipment, which must comply with the ATS/ERS Task Forces 
recommendation for standardization of lung function testing (Miller 2005). All spirometry 
tests, including FEV1 and FVC maneuvers, will be performed according to the ATS/ERS 
criteria (Miller 2005) (Appendix 4). 
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 3 
flow ranges (ie, low, medium, and high flows), with temperature and barometric pressure 


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correction. The calibration syringe must meet ATS/ERS specifications and must not be used 
beyond the expiry date. Required accuracy is ±3% (ie, 3.09 L to 2.91 L) (ATS/ERS). The 
results will be printed and maintained in a calibration log, which will be monitored for 
compliance during the monitoring visits (Appendix 5). 
Spirometry assessments will be conducted at Screening Visit 1. 
7.4.1 
Lung Function Assessment 
A subject may be eligible to participate in this study if they have a confirmed diagnosis of 
COPD (defined as a post-bronchodilator FEV1 <80% of predicted normal [calculated using 
NHANES III reference equations] and a post-bronchodilator FEV1/FVC ratio of <0.70). 
Documentation of the COPD diagnosis (defined as FEV1 <80% predicted and FEV1/FVC 
<0.70) within the past 12 months is acceptable. If this is not available, the subject must 
undergo a post-bronchodilator assessment at Visit 1to confirm the COPD diagnosis as 
previously defined. All subjects must also have a pre-bronchodilator FEV1 at Visit 1 that is 
≥50% and <80% of predicted normal and a pre-bronchodilator FEV1/FVC ratio of <0.70.  
7.4.2 
Pre- and Post-Bronchodilator Assessments 
Post-bronchodilator testing to Ventolin HFA will only be conducted at Visit 1 for subjects 
who do not have documentation of a post-bronchodilator FEV1 <80% predicted and an 
FEV1/FVC <0.70 in the past 12 months: 
• Perform pre-bronchodilator pulmonary function tests (PFTs) (within 60 minutes) 
prior to administration of Ventolin HFA (all subjects) 
• Administer 4 puffs of Ventolin HFA (only subjects without documentation in the 
past 12 months) 
• Perform post-bronchodilator PFTs 30 minutes after the administration of Ventolin 
HFA (only subjects without documentation in the past 12 months) 
 
To determine study eligibility criteria for a study subject, the Investigator and/or designee 
will review the following: 
• Pre- and post-bronchodilator PFTs to ensure the maneuvers meet repeatability and 
acceptability criteria per ATS/ERS guidelines 
• Diagnosis of COPD is confirmed using historical or Visit 1 post-bronchodilator 
assessments 
• Pre-bronchodilator FEV1 is ≥50% and <80% predicted and pre-bronchodilator 
FEV1/FVC ratio is <0.70 
 


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7.5 
PK Assessments 
Pharmacokinetic sampling will occur during the Treatment Period. Sample collections will 
be scheduled for the nominal time point, and actual collection times will be recorded in the 
source documents. 
7.5.1 
Blood Sample Collection Schedule 
Approximately 10 mL of whole blood will be collected at each time point indicated below 
and within 60 minutes prior to the morning administration of study drug as referenced in 
Table 8-2 and Table 8-3. Subjects must fast for at least 6 hours prior to dosing on serial PK 
days (Day 1 and Day 8). Meals on Days 1 and 8 will be standard but will not begin until the 4 
hours post-dose blood samples are obtained. 
•
Pre-dose sample collection - Days 1 (morning dose), 7 (evening dose), and 8 
(morning dose) (Table 8-2 and Table 8-3) 
•
Post-dose sample collection 
-
Day 1 ONLY (Table 8-2) 
-
Day 8 ONLY (Table 8-3) 
•
The recommended time windows for post-dose PK assessments are as follows: 
Time points
Time windows
2 and 6 min  
±1 min 
20 and 40 min and 1 h  
±2 min 
2 and 4 h  
±5 min 
8, 10, 12, 18, and 24 h 
±10 min 
Collection and storage of PK samples will be detailed in the laboratory manual. 
7.5.2 
Procedures 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. 
7.5.3 
Storage and Destruction of PK Samples 
Samples for determination of study drug concentration in plasma will be analyzed by 
 on behalf of Pearl using an appropriate bioanalytical method. Full details of the 
analytical method used will be described in a separate bioanalytical report. 


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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. 
7.6 
Safety Assessments 
7.6.1 
Medical History 
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 include the 
subject’s family health history, history of hospitalization, and history of surgeries. 
7.6.2 
Physical Examination 
A complete physical examination including evaluation of the following will be performed at 
Screening and on Day -1 and Day 8: 
• General appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), 
lymph nodes, respiratory, cardiovascular, musculoskeletal, abdominal, extremities, 
neurological and dermatological. 
• Weight and height, assessed in ordinary indoor clothing with shoes removed, will 
also be recorded during Screening only 
 
7.6.3 
Vital Signs 
Vital signs including blood pressure (BP) and heart rate will be assessed after the subject has 
been supine for 5 minutes at the Screening Visit, Day -1, Day 7, and Day 8 (Table 8-1 and 
Table 8-3). 
7.6.4 12-Lead ECG 
Twelve-lead ECGs will be recorded at Screening, Day -1, and Day 8 (Table 8-1 and 
Table 8-3).  
Subjects should be supine and resting 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 


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abnormalities after the first dose of study drug throughout the Treatment Period until the 
follow-up telephone will be reported as treatment-emergent adverse events (TEAEs) and 
followed closely by the Investigator in order to assure the safety of the study subject. 
7.6.5 
Clinical Laboratory Tests 
Subjects must fast for at least 6 hours prior to any scheduled complete clinical laboratory 
assessment blood draw (chemistry and hematology). 
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 7-1 will be collected at Screening, Day -1, and Day 8. 
Standardized meals will be administered on Days 1, 2, and 8 at specified times after 
observing fasting times for blood draws. There are no restrictions regarding clear fluid 
intake. 
Table 7-1 
Laboratory Tests 
Hematology 
Chemistry 
Hematocrita 
Hemoglobin 
Serum iron 
Ferritin 
Platelet count 
Red blood cell count 
White blood cell count 
White blood cell differential 
Mean corpuscular volume 
Mean cell hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Creatinineb 
Potassium 
Sodium 
Chloride 
Magnesium 
Calcium 
Inorganic phosphate 
Glucose 
Urea 
Bilirubin (total) 
Blood urea nitrogen 
Bilirubin (direct) 
ALT 
AST 
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 
based on macroscopic results. 
Urine drug screen: A urine sample will be collected and analyzed (positive or negative) at 
Screening and on inpatient admission days for drugs of abuse including amphetamine, opiate, 
cocaine, barbiturates, benzodiazepines, and marijuana (tetrahydrocannabinol). 
Alcohol breathalyzer test: A breathalyzer test will be performed at Screening and on 
inpatient admission days for the presence of alcohol (positive or negative). 
For all females: A serum hCG test at Screening and urine hCG test on inpatient admission 
days. 


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Table 7-1 
Laboratory Tests 
Hematology 
Chemistry 
Abbreviations: hCG=human chorionic gonadotropin. 
a 
Packed cell volume 
b 
Estimated glomerular filtration rate will be calculated by the Chronic Kidney Disease Epidemiology 
Collaboration Equation 
 
7.6.5.1 Laboratory Sample Collection, Storage and Shipping 
Detailed instructions for laboratory sample collection, processing, and shipping instructions 
will be provided in the laboratory manual. 
Approximately 320 mL of blood will be collected per subject during the study. The exact 
blood volume collected may vary depending on laboratory procedures or changes in PK 
sampling. However, it will not exceed 400 mL per subject during the study. 
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. 
7.7 AEs 
7.7.1 Performing 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 7.7.10) 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 event, the Investigator and the Medical 
Monitor may discontinue the subject from study drug. 
7.7.2 AE Definitions 
The following definitions of terms are guided by the ICH, the US Code of Federal 
Regulations (21 Code of Federal Regulations 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 


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with another drug) and from any route of administration, formulation, or dose, including an 
overdose. 
Adverse events include, but are not limited to: 
• 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 leads to the procedure is an AE (eg, bleeding 
esophageal varices, dental caries) 
• 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 
 
For subjects discontinuing study drug and withdrawing from the study, all AEs/SAEs will be 
collected through the 5- to 7-day follow up telephone call. 
7.7.3 Pre-Treatment AEs 
Adverse events that occur between the time subject signs the ICF for the study and the time 
when that subject receives first dose of study drug will be summarized as medical history and 
not as an AE unless the event meets the definition of an SAE as defined in Section 7.7.10. 
7.7.4 
TEAEs 
All AEs that occur at the time of and following the first administration of study drug through 
the final telephone follow-up will be considered as being TEAEs. 
7.7.5 Severity 
The Investigator must categorize the severity of each AE according to the following 
guidelines: 


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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. 
7.7.6 Relationship 
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’. 
7.7.7 
COPD Exacerbations 
Subjects experiencing a COPD exacerbation will be discontinued from the study and treated 
with appropriate therapy. Chronic obstructive pulmonary disease exacerbations will be 
considered expected events, as a general part of the disease, and will not be reported as AEs 
unless considered an SAE. 
7.7.8 
AEs of Special Interest 
Certain AEs have been identified as adverse events of special interest (AESIs) due to the 
class of drugs being studied. These AEs will be captured through spontaneous reports and the 
reporting of these AESIs will be described in the statistical analysis plan (SAP). Some events 
are described below but this is not a comprehensive list of all AESIs. 
7.7.8.1 
LABA and LAMA Effects 
Known effects of LAMAs and LABAs include cardiovascular effects, ocular disorders, 
urinary retention, gastrointestinal disorders, and anticholinergic effects for LAMAs and 
cardiovascular, potassium, glucose and tremor effects for LABAs. 
7.7.8.2 
Local Steroid Effects 
Local steroid effects include oral candidiasis, hoarseness, dysphonia, and throat irritation. 


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7.7.9 
Clinical Laboratory AEs 
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). In such cases, the laboratory abnormality itself (eg, 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 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 (eg, 
concomitant medication or therapy) 
• 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. 
7.7.10 
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 
• In patient 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 judgment, they may 
jeopardize the subject or 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. 


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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. 
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. 
7.7.10.1 
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 Pearl Pharmacovigilance or designee. All SAEs must be reported to 
Pearl Pharmacovigilance or designee 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 Pearl Pharmacovigilance or designee within 2 working 
days after receiving the information. Follow-up information will be a detailed written report 
that may include copies of hospital records, case reports, autopsy reports, and other pertinent 
documents. 
For subjects discontinuing study drug and withdrawing from the study, all AEs/SAEs will be 
collected through the 5- to 7-day follow up telephone call. 
Post-study SAEs following the last dose of study drug must be reported to Pearl 
Pharmacovigilance as described in Section 7.7.10.4.  
The Investigator is responsible for continuing to report any new or relevant follow up 
information that s/he learns about the SAE. 
7.7.10.2 
Supplemental Investigations of SAEs 
The Investigator and supporting personnel responsible for subject care should discuss with 
the Sponsor Medical Monitor or designee any need for supplemental investigations of SAEs. 
If additional assessments are conducted, results must be reported to the Sponsor. If a subject 
dies during study participation and if a post mortem examination is performed, a copy of the 
autopsy report should be submitted to the Sponsor. 
7.7.10.3 
Post-Study Follow-up of AEs 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 


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eCRF. Pearl 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. 
7.7.10.4 
Notification of Post-Treatment SAEs 
Investigators are not obligated to actively follow subjects after 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, the SAE 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. 
7.7.10.5 
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 their 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. 
7.7.10.6 
Health Authority Safety Reports 
The Sponsor or its representatives will submit a safety report to the appropriate regulatory 
agencies for any suspected adverse reaction that is both serious and unexpected within the 
timeframe specified by each regulatory agency. 
The Sponsor or its representatives will send copies of each submitted safety report to 
Investigators actively participating in Pearl sponsored clinical studies. Safety reports must 
also be submitted to the appropriate IRBs/IECs as soon as possible. Documentation of 
submission to the IRB/IEC must be retained for each safety report. 
7.7.11 
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 
Medical Monitor 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. 
7.7.12 
Pregnancy 
To ensure subject safety, each pregnancy from Visit 1 until study completion must be 
reported to the Sponsor within 24 hours of learning of its occurrence. The pregnancy should 


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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 Pearl Pharmacovigilance or 
designee. 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. 
7.7.13 
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 
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. 
7.8 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 with the Sponsor. 
The Sponsor reserves the right to discontinue 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’ well-
being. 


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8 
STUDY ACTIVITIES 
A schedule of events is provided in Table 8-1. Detailed schedules of inpatient assessments on 
Visit 3 (Day 1) and Visit 5 (Day 8) are provided in Table 8-2 and Table 8-3, respectively. 
 


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Table 8-1 
Schedule of Events for Screening, Treatment, and Follow-up 
 
Screening 
Treatment Perioda 
Follow up 
Visit 1 
Visit 2 
Clinic Admission 
Visit 3 
Visit 4 
Clinic Admission 
Visit 5 
Telephone 
Follow up 
Procedure/Assessment 
Days -28 to -2 
Day -1 
Day 1 
Day 7 
Day 8 
5 to7 days post 
last dose 
Informed consent 
X 
 
 
 
 
 
Inpatient admission 
 
X 
 
X 
 
 
Medical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
Spirometry testing 
Xb 
 
 
 
 
 
Smoking status 
X 
X 
 
X 
 
 
Vital signs (BP, heart rate) 
X 
X 
 
X 
X 
 
Chest x-rayc 
X 
 
 
 
 
 
Eligibility reviewd 
X 
X 
X 
X 
X 
 
Subject enrollment number 
 
 
X 
 
 
 
Placebo MDI usage demonstration/practicee 
Xf 
Xf 
Xf 
Xf 
Xf 
 
12-lead ECG 
X 
X 
 
 
X 
 
Clinical laboratory testingg 
X 
X 
 
 
X 
 
AEs 
Xh 
Xh 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Urine drug screen 
X 
X 
 
X 
 
 
Alcohol breathalyzer test 
X 
X 
 
X 
 
 


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Table 8-1 
Schedule of Events for Screening, Treatment, and Follow-up 
 
Screening 
Treatment Perioda 
Follow up 
Visit 1 
Visit 2 
Clinic Admission 
Visit 3 
Visit 4 
Clinic Admission 
Visit 5 
Telephone 
Follow up 
Procedure/Assessment 
Days -28 to -2 
Day -1 
Day 1 
Day 7 
Day 8 
5 to7 days post 
last dose 
Pregnancy test (females only)i 
X 
X 
 
X 
 
 
PK assessmentj 
 
 
X 
X 
X 
 
Dispense/collect Ventolin HFAk 
X 
X 
X 
 
X 
 
Dispense/collect study drug MDI 
 
 
X 
 
X 
 
Study drug administrationl 
 
 
Xm 
X 
Xm 
 
Dispense/collect/review diaryn 
 
 
X 
X 
 
 
Clean study drug MDI deviceo 
 
 
 
X 
 
 
Inpatient discharge 
 
 
Xp 
 
Xq 
 
Abbreviations: AE=adverse event; BID=twice daily; BP=blood pressure; COPD=chronic obstructive pulmonary disorder; ECG=electrocardiogram; FEV1=forced 
expiratory volume in 1 second; FVC=forced vital capacity; hCG=human chorionic gonadotropin; HFA=hydrofluoroalkane; MDI=metered dose inhaler; 
PK=pharmacokinetic; SAE=serious adverse event. 
a 
Sites must call subjects for morning and evening study drug administration confirmation on Days 2 to 7. 
b 
Pre-bronchodilator FEV1 must be ≥50% and <80% predicted and pre-bronchodilator FEV1/FVC must be <0.70 in all subjects at Visit 1. Post–bronchodilator 
assessments to confirm the diagnosis of COPD (defined as FEV1 <80% predicted and FEV1/FVC<0.70) must be performed to confirm the diagnosis of 
COPD if not documented and available in the 12 months prior to Visit 1. 
c 
Chest x-ray to be completed if chest x-ray or computed tomography not available within the 6 months before Visit 1. 
d 
Confirm subjects continued eligibility to continue in the study. 
e 
Inhalation training tools may be utilized to ensure appropriate training of subjects for the correct use of an MDI. 
f 
Subjects will use the Placebo MDI for training purposes only to demonstrate proper use of the MDI. 
g 
Creatinine clearance calculated as described in Section 7.6.5. Subjects must fast for a minimum of 6 hours before clinical laboratory assessment blood draw. 
h 
Only SAEs will be recorded prior to first dose as defined in Section 7.7.10. All AEs prior to first dose will be recorded as medical history. 
i 
For all women, obtain serum hCG at Screening and urine hCG thereafter. 


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Table 8-1 
Schedule of Events for Screening, Treatment, and Follow-up 
 
Screening 
Treatment Perioda 
Follow up 
Visit 1 
Visit 2 
Clinic Admission 
Visit 3 
Visit 4 
Clinic Admission 
Visit 5 
Telephone 
Follow up 
Procedure/Assessment 
Days -28 to -2 
Day -1 
Day 1 
Day 7 
Day 8 
5 to7 days post 
last dose 
j 
PK samples will be collected predose on Days 1 (morning dose), 7 (evening dose), and 8 (morning dose). 
k 
Ventolin HFA will dispensed at Visits 1, 2, and 3 as needed and collected at Visit 5. 
l 
See Table 8-2 and Table 8-3 for details regarding times and events for the 12-lead ECG, vital signs, drug administration, and PK assessments during the 
Treatment Period. All study drugs will be administered by oral inhalation. A single dose of study drug will be administered on Day 1 and BID doses will be 
administered Day 2 through Day 7, with a final single-dose administration of study drug occurring on the morning of Day 8. Administration of study drug 
should occur at approximately the same time of day. 
m 
Refer to instructions in Section 6.5 for procedures to prevent possible cross-contamination. 
n 
Dispense diary on Day 2 prior to discharge. Subjects should be instructed to record their at-home BID study drug dosing. Site staff should collect the diary 
on Day 7 and review study drug dosing before admission to the clinic. 
o 
Clean study drug device on Day 7 after dosing in the evening and dry for approximately 12 hours overnight per instructions in Appendix 2. 
p 
Subjects will be discharged on Day 2 after all assessments have been completed. 
q 
Discharge will occur after completion of all assessments and subjects have been instructed about resuming appropriate COPD therapy. The site should 
schedule the subject’s follow-up phone call at least 5 days but no longer than 7 days after the date of last administration of study drug. 
 


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Table 8-2 
Timing of Assessments on Day 1 (Visit 3) 
 
Time Relative to Drug Administration 
Procedure 
-60 
min 
0 
hr 
2 
min 
6 
min 
20 
min 
40 
min 
1 
hr 
2 
hrs 
4 
hrs 
8 
hrs 
10 
hrs 
12 
hrs 
18 
hrs 
24 
hrsa 
PK blood draw  
Xb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Placebo MDI usage 
demonstration/practice 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of study drugc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Adverse events 
X 
X 
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 
X 
X 
a 
The 24-hour post-dose assessment occurs on Day 2. 
b 
Within 60 minutes prior to dosing. A pre-dose sample will be collected on Day 7 before the evening dose. 
c 
Study drug will be administered by oral inhalation. A single dose of study drug will be administered on Day 1. 
d 
Administer morning dose of study drug in the clinic on Day 2 after the 24-hour post-dose PK sample has been collected and before discharge from the clinic. 
 
 
 


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Table 8-3 
Timing of Assessments on Day 8 (Visit 5) 
Procedure 
Time Relative to Drug Administration 
-60 
min 
0 
hr 
2 
min 
6 
min 
20 
min 
40 
min 
1 
hr 
2 
hrs 
4 
hrs 
8 
hrs 
10 
hrs 
12 
hrs 
PK blood draw 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Placebo MDI usage demonstration/practice 
X 
 
 
 
 
 
 
 
 
 
 
 
Administration of study drugb 
 
X 
 
 
 
 
 
 
 
 
 
 
12-lead safety ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
 
 
Xd 
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 
a 
Within 60 minutes prior to dosing.  
b 
Study drug will be administered by oral inhalation. A final single-dose administration of study drug will occur on the morning of Day 8. 
c 
Complete clinical laboratory testing - chemistry and hematology (includes glucose and potassium) fasting required. 
d 
Complete any time prior to discharge. 
 
 


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8.1 
Screening Visit 1 (Screening, Day -28 to Day -2) 
After obtaining written and signed informed consent, the following procedures and 
assessments will be performed during the Screening period and results will be documented in 
the eCRF and/or source documents: 
• Obtain informed consent (obtain first, before other study procedures) 
• Record demographics and relevant medical history 
• Perform physical examination 
• Record smoking status 
• Obtain vital signs 
• Practice Placebo MDI usage and demonstrate proper technique 
• Conduct spirometry for all subjects and post-bronchodilator spirometry for subjects 
who do not have confirmation of COPD diagnosis (post-bronchodilator FEV1 <80% 
predicted and FEV1/FVC <0.70) in the past 12 months 
• Obtain 12-lead ECG 
• Collect blood and urine samples for clinical laboratory evaluations (hematology, 
chemistry, and urinalysis) 
• Document concomitant medications 
• Perform urine drug test 
• Perform alcohol breathalyzer test 
• Perform serum pregnancy test (women only) 
• Obtain chest x-ray if needed 
• Review eligibility criteria 
• Dispense Ventolin HFA 
• 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 7.7.10) 
 
8.2 Visit 2 (Admission to Clinic, Day -1) 
The following study activities and assessments will be performed on Day -1, and results will 
be documented in the eCRF and/or source documents: 
• Perform physical examination 
• Record smoking status 
• Obtain vital signs 


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• Obtain 12-lead ECG 
• Collect blood and urine samples for clinical laboratory evaluations (hematology, 
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 7.7.10) 
• Document concomitant medications 
• Perform urine drug test 
• Perform alcohol breathalyzer test 
• Perform urine pregnancy test (women only) 
• Review eligibility criteria 
• Admit subject to the clinic 
• Practice Placebo MDI usage and demonstrate proper technique 
• Dispense Ventolin HFA (if needed) 
 
8.3 
Visit 3 (Day 1/Day 2 of the Treatment Period) 
The following study activities and assessments will be performed on Day 1 and Day 2, and 
results will be documented in the eCRF and/or source documents: 
• Review eligibility criteria 
• Obtain subject enrollment number 
• Practice Placebo MDI usage and demonstrate proper technique 
• 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 7.7.10) 
• Document concomitant medications  
• Collect pre-dose PK samples per Table 8-2 
• Administer study drug; a single dose of study drug will be administered by oral 
inhalation (refer to Section 6.5 for details regarding study drug dispensing and 
administration). 
• Collect post-dose PK samples per Table 8-2. The 24-hour post-dose sample will be 
collected on the morning of Day 2. 
• Dispense study drug MDI and Ventolin HFA 
• Administer morning dose of study drug in the clinic on Day 2 after the 24-hour post-
dose PK sample has been collected and before discharge from the clinic 
• Schedule telephone calls with subjects for dose administration confirmation 


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• Schedule Visit 4 
• Dispense diary 
• Discharge subject on Day 2 after all assessments have been completed 
 
8.4 Telephone Contact (Days 2 to 7 of the Treatment Period) 
• Call subjects for morning and evening dose administration confirmation. 
Note: Dosing must be scheduled relative to the subject’s first morning dose in clinic 
on Day 1 (Visit 3). Subjects must be advised that subsequent morning study drug 
dosing must occur at approximately the same time every day and that evening dosing 
should occur as close as possible to 12 hours from the time of morning dosing. 
 
8.5 Visit 4 (Day 7) 
The following study activities and assessments will be performed on Day 7, and results will 
be documented in the eCRF and/or source documents: 
• Document AEs 
• Document concomitant medications 
• Collect diary and review with subject 
• Record smoking status 
• Obtain vital signs 
• Confirm subject’s eligibility to continue in the study 
• Practice Placebo MDI usage and demonstrate proper technique 
• Perform urine drug test 
• Perform alcohol breathalyzer test 
• Perform urine pregnancy test (women only) 
• Admit the subject to the clinic 
• Collect PK sample within 60 minutes prior to evening dose  
• Administer the evening dose of study drug as close as possible to 12 hours from the 
time of morning dose 
• After the evening dose, study site staff should wash the study drug device and dry for 
approximately 12 hours overnight per instructions in Appendix 2 
 


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8.6 
Visit 5 (Day 8) 
The following study activities and assessments will be performed on Day 8, and results will 
be documented in the eCRF and/or source documents: 
• Perform physical examination 
• Obtain vital signs 
• Obtain 12-lead ECG 
• Collect blood samples and urine for clinical laboratory evaluations (hematology, 
chemistry, and urinalysis) 
• Confirm subject’s eligibility to continue in the study 
• Document AEs 
• Document concomitant medications  
• Practice Placebo MDI usage and demonstrate proper technique 
• Collect pre-dose PK samples per Table 8-3 
• Administer study drug; a single dose of study drug will be administered by oral 
inhalation (refer to Section 6.5 for details regarding study drug dispensing and 
administration). 
• Collect post-dose PK samples per Table 8-3 
• Collect study drug MDI and Ventolin HFA 
• Restart subject’s COPD medications after all assessments are completed 
• Schedule follow-up telephone call 
 
After all scheduled protocol-specified assessments are complete, and safety data, including 
vital signs, have been reviewed by the Investigator, the subject will be discharged from the 
clinic. 
8.7 
Follow-up Telephone Call 
Upon completion of the study, a follow-up phone call will be completed at least 5 days but 
no longer than 7 days from the date of last administration on Visit 5 (Day 8). Subjects will be 
asked about any new or ongoing AEs, and any new concomitant medication. This will be 
documented appropriately in the subject source documents and eCRFs. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The general approach for the statistical analyses is provided below. A detailed SAP will be 
finalized prior to database lock. 
9.2 
Analysis Populations 
Two subject populations will be evaluated during this study and are defined as follows: 
• PK Population: All treated subjects who have sufficient data to reliably calculate at 
least 1 PK parameter and do not have major protocol deviations. Subjects will be 
analyzed according to treatment received. 
• Safety Population: All subjects who receive at least 1 dose of study drug. 
 
Safety and tolerability analyses will be performed on data from all subjects in the Safety 
Population. 
Pharmacokinetic analysis will be performed using the PK population. 
9.3 
Demographics and Baseline Characteristics 
Demographic information will include month/year of birth, 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. 
9.4 
Analysis of PK Variables 
Pharmacokinetic and statistical analysis will be performed using the PK population. The 
initial estimation of PK parameters will be performed using non-compartmental methods. 
Pharmacokinetic parameters calculated using pre-defined post dose serial blood draws over 
24 hours on the first day (Day 1) and using pre-defined post dose serial blood draws over 12 
hours after the last dose (Day 8) will include the following: 
• Cmax 
• AUC0-12 
• tmax 
 


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The following PK parameters will be calculated at Day 1 only: 
• AUC0-tlast 
• AUC0-∞ 
• t1/2 
• CL/F 
• Vd/F 
• λz 
 
The following will be derived based on ratios of Day 8 values to Day 1 values: 
• Accumulation ratio for Cmax (RAC [Cmax]) 
• Accumulation ratio for AUC0-12 (RAC [AUC0-12]) 
• Linearity ratio (Rlin [AUC0-12/AUC0-∞]) 
 
Other PK parameters may be calculated, as appropriate.  
Descriptive statistics for plasma concentrations of budesonide, glycopyrronium, and 
formoterol by day and nominal time point will be summarized on the raw and log-normal 
scales using the PK Population. Individual plasma concentration at each nominal and actual 
time point for each Day will be listed by subject using the Safety Population. 
All budesonide, glycopyrronium, and formoterol PK parameters will be presented by visit 
(Visit 3 [Day 1] or Visit 5 [Day 8]) with number of measurements, number of subjects with 
non-missing data (n), mean, standard deviation, coefficient of variation (CV%), median, 
minimum, maximum, geometric mean, and geometric CV%. For tmax, the geometric mean 
and the CV% will be omitted, and only the number of observations (n), median, minimum 
and maximum will be provided.  
To estimate the RAC values and Rlin, natural-log transformed AUC0-12, AUC0-∞, and Cmax of 
budesonide, glycopyrronium, and formoterol between Day 8 and Day 1, a mixed model with 
day as a fixed effect and subject as a random effect will be employed. A separate mixed 
model will be fit for each analyte and ratio type. For each analyte, the estimated ratio of 
geometric least square mean (LSM) for Day 8 to Day 1 and the corresponding 90% 
confidence interval (CI) will be determined by exponentiating the mean difference between 
Day 8 and Day 1 and the associated CI (on the logarithm scale). The estimated ratio of 
geometric LSM and its corresponding 90% CI will be an estimate of RAC or Rlin with the 
90% CI. The residual variance component from the model estimating Rlin will provide an 
estimate of intra-subject variability. 


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If the effective rate of drug accumulation is estimable, the time to reach steady state will be 
estimated for each analyte using the methodology of Panebianco and Maes 
(Panebianco 2009). 
9.5 
Safety Analyses 
Safety data will be summarized and listed. The safety of BGF MDI will be assessed from AE 
reporting including SAE reporting, vital signs (BP, heart rate), clinical laboratory values 
(hematology, chemistry, and urinalysis), and findings from 12-lead ECGs. The incidence of 
AEs and SAEs will be tabulated. Summary statistics of assessed laboratory values and vital 
signs by visit and change from baseline will be provided. Subjects with out-of-range values 
of 12-lead ECGs will be listed. 
9.6 
Randomization 
Not applicable. 
9.7 
Determination of Sample Size 
This study is descriptive in nature. The planned sample size of approximately 30 enrolled 
subjects is selected to provide approximately 24 completers for assessment of the single- and 
multiple-dose PK of BGF MDI in subjects with COPD. 


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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), Declaration 
of Helsinki, concerning medical research in humans (Ethical Principles for Medical Research 
Involving Human Subjects), and regulatory requirement if applicable.’ 
The Investigator (or The 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. 
The Investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and entry into the study. The subject will be 
provided with 2 original ICFs. One original will be retained by the study Investigator and the 
subject will retain the second original. 
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 


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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 data used and disclosed in 
connection with this study in accordance with all applicable laws, rules and regulations. 
10.6 Quality Control and Assurance 
The Sponsor or its designee is responsible for implementing and maintaining quality control 
and quality assurance systems with written standard operating procedures to ensure that trials 
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 the clinical study. 
10.7 Data Management 
Data management procedures and information for this protocol will be provided by the 
Sponsor or their designee. 
10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and the Sponsor 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 


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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 issues 
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 
files by the Sponsor’ 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' quality 
assurance auditors and by all applicable regulatory authorities. The period of time these 


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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 it’s designee should contact the site 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 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 an end of study summary 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 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 Publication Professionals 
(ISMPP), which provides guidance to the preparation of publications, 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 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 representative) is responsible 
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 


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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 first 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 and 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. 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 Trial Results: To provide transparency in the conduct and reporting 
of randomized clinical trials, the Sponsor reports clinical findings based on the guidance 
of The CONsolidated Standards of Reporting Trials Statement (Mohler 2012) and a 25-
item checklist, which is intended to improve the reporting of a randomized controlled 
study; facilitate reader understanding of the study design, conduct, analysis and 
interpretation; and 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. Per 
AstraZeneca policy, The Sponsor posts clinical study protocols for public viewing when 
a manuscript is published in a medical journal. Prior to being made public, the protocol is 
reviewed by AstraZeneca Intellectual Property. 
 


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11 REFERENCE LIST 
Celli B, MaNee W, Agusti A, et al. Standards for the diagnosis and treatment of subjects with 
COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946. 
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. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005;26:319 338. 
Mohler, D, Hopewell S, Schulz KF, et al. CONSORT 2010 Explanation and Elaboration: 
updated guidelines for reporting parallel group randomised trials. J Clin Epidemiolo 
2010;63:e1-37. Erratum in J Clin Epidemiolo. 2012;65:351. 
Panebianco DL, Maes A. Estimating time to steady state using the effective rate of drug 
accumulation. Pharm Stat. 2011;10:27-33. 
SYMBICORT® (budesonide and formoterol fumarate dehydrate) inhalation aerosol 
[package insert]. Wilmington, DE. AstraZeneca; 2017. 
 
 


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12 APPENDICES 


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Appendix 1 
Dose Indicator Reading 
130 Count (Actuation) Version Shown 
 
If your dose 
indicator 
display looks 
like this record 
120+  
 
If your dose 
indicator 
display looks 
like this record 
120 
 
If your dose 
indicator 
display looks 
like this record 
110 
 
If your dose 
indicator 
display looks 
like this record 
100 
 
If your dose 
indicator 
display looks 
like this record 
90 
 
If your dose 
indicator 
display looks 
like this record  
80 
 
If your dose 
indicator 
display looks 
like this record  
70 
 
If your dose 
indicator 
display looks 
like this record  
60 
 
If your dose 
indicator 
display looks 
like this record 
50 
 
If your dose 
indicator 
display looks 
like this record 
40 
 
If your dose 
indicator 
display looks 
like this record  
30 
 
If your dose 
indicator 
display looks 
like this record  
20 
 
If your dose 
indicator 
display looks 
like this record  
10 
 
If your dose 
indicator 
display looks 
like this record  
0  
 
 


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Appendix 2 
Subject Instructions for Use of BGF MDI and Placebo 
MDI 
How do I store the Inhaler? 
• 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. 
 
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. 


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• 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 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: 
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.   
 


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Figure 3 
 
 
• Prime the inhaler before you use it for the first time. 
 
Priming the Inhaler: 
• 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. 


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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. 
• 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. 
 


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Figure 5 
 
 
How to clean the Inhaler: 
It is very important to keep your inhaler clean so medicine will not build-up and block the 
spray through the Mouthpiece. See Figure 6. 


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Figure 6 
 
 
The Canister should be gently pulled from the top of the Actuator once a week and the 
Actuator cleaned. Do not clean the Canister or let it get wet. 
• Step 1: Pull the Canister out of the Actuator as shown in Figure 7. 
 


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Figure 7 
 
 
• Step 2: Set the Canister aside where it will not get wet. 
• Step 3: Take the Cap off the Mouthpiece. 
• Step 4: Rinse the Actuator through the top with warm running water for 30 seconds. 
Then rinse the Actuator again through the Mouthpiece (see Figure 8).  
 
Figure 8 
 
• Step 5: Shake all of the water droplets out of the Actuator. 


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• Step 6: Look in the Actuator and the Mouthpiece to make sure it is clean and clear. 
 
Repeat Step 4 through Step 6, until the Actuator and the Mouthpiece are clean and clear. 
• Step 7: Let the Actuator dry completely, such as overnight as shown in Figure 9. Do 
not put the Canister back into the Actuator if it is still wet. 
 
Figure 9 
 
 
Reassembly of the Inhaler and Instructions for Use after Cleaning: 
• After the Actuator is completely dry, gently press the Canister down in the 
Actuator as shown in Figure 10. It is not necessary to press down on the Canister 
hard enough to cause a puff to be released. 
 


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Figure 10 
 
• Re-prime your inhaler 2 times after each cleaning. 
• Hold the Actuator with the Mouthpiece pointing away from you and others as 
shown in Figure 4. 
• 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 until the Canister stops moving in the Actuator to release a puff from the 
Mouthpiece. 
• Repeat this re-priming step 1 more time for a total of 2 times. 
• After re-priming your inhaler 2 times, your inhaler is now ready to use. 
 
 


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Appendix 3 
Instructions for Use of Ventolin HFA Inhalation Aerosol 
Device  
Instructions for Use 
For Oral Inhalation Only 
Your VENTOLIN HFA inhaler 
The metal canister holds the medicine. See Figure A. 
Figure A 
 
 
Figure A 
The canister has a counter to show how many sprays of medicine you have left. The number 
shows through a window in the back of the actuator. See Figure B. 


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Figure B 
 
 
Figure B 
• The counter starts at either 204 or 064, depending on which size inhaler you have. 
The number will count down by 1 each time you spray the inhaler. The counter will 
stop counting at 000. 
• Do not try to change the numbers or take the counter off the metal canister. The 
counter cannot be reset, and it is permanently attached to the canister. 
• The blue plastic actuator sprays the medicine from the canister. The actuator has a 
protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on 
the mouthpiece when the canister is not in use. The strap keeps the cap attached to 
the actuator. 
• Do not use the actuator with a canister of medicine from any other inhaler. 
• Do not use a VENTOLIN HFA canister with an actuator from any other inhaler. 
 
Before you use VENTOLIN HFA for the first time, you must prime the inhaler so that 
you will get the right amount of medicine when you use it. 
To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well. Then spray 
the inhaler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes. 


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Figure C 
 
 
Figure C 
• Shake and spray the inhaler like this 3 more times to finish priming it. The counter 
should now read 200 or 060, depending on which size inhaler you have. See 
Figure D. 
 
Figure D 
 
 
Figure D 
You must prime your inhaler again if you have not used it in more than 14 days or if you 
drop it. Take the cap off the mouthpiece and shake and spray the inhaler 4 times into the air 
away from your face. 


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How to use your VENTOLIN HFA inhaler: 
Follow these steps every time you use VENTOLIN HFA. 
Step 1. Make sure the canister fits firmly in the actuator. The counter should show through 
the window in the actuator. 
Shake the inhaler well before each spray. 
Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign 
objects, and take out any you see. 
Step 2. Hold the inhaler with the mouthpiece down. See Figure E. 
Figure E 
 
 
Figure E 
Step 3. Breathe out through your mouth and push as much air from your lungs as you can. 
Put the mouthpiece in your mouth and close your lips around it. See Figure F. 


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Figure F 
 
 
Figure F 
Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly 
through your mouth. See Figure F. 
Step 5. After the spray comes out, take your finger off the canister. After you have breathed 
in all the way, take the inhaler out of your mouth and close your mouth. 
Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe 
out as slowly as long as you can. 
If your healthcare provider has told you to use more sprays, wait 1 minute and shake the 
inhaler again. Repeat Steps 2 through Step 6. 
Step 7. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it 
snaps firmly into place. 
Cleaning your VENTOLIN HFA inhaler: 
Clean your inhaler at least 1 time each week. You may not see any medicine build-up on the 
inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See 
Figure G. 


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Figure G 
 
 
Figure G 
Step 8. Take the canister out of the actuator, and take the cap off the mouthpiece. The strap 
on the cap will stay attached to the actuator. 
Step 9. Hold the actuator under the faucet and run warm water through it for about 30 
seconds. See Figure H. 
Figure H 
 
 
Figure H 
Step 10. Turn the actuator upside down and run warm water through the mouthpiece for 
about 30 seconds. See Figure I. 


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Figure I 
 
 
Figure I 
Step 11. Shake off as much water from the actuator as you can. Look into the mouthpiece to 
make sure any medicine build-up has been completely washed away. If there is any build-up, 
repeat Steps 9 and 10. 
Step 12. Let the actuator air-dry overnight. See Figure J. 
Figure J 
 
 
Figure J 
Step 13. When the actuator is dry, put the protective cap on the mouthpiece and then put the 
canister in the actuator and make sure it fits firmly. Shake the inhaler well, remove the cap, 


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and spray the inhaler once into the air away from your face. (The counter will count down by 
1 number.) Put the cap back on the mouthpiece. 
If you need to use your inhaler before the actuator is completely dry: 
• Shake as much water off the actuator as you can. 
• Put the cap on the mouthpiece and then put the canister in the actuator and make sure 
it fits firmly. 
• Shake the inhaler well and spray it 1 time into the air away from your face. 
• Take your VENTOLIN HFA dose as prescribed. 
• Follow cleaning Steps 8 through 13 above 
 
 


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Appendix 4 
Spirometry Assessment Criteria  
Acceptable Versus Usable Tests 
Acceptable tests must meet the following 7 criteria: 
1. Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and back 
extrapolation volume (EV) <5% of FVC or 0.150 L, whichever is the greater. (Refer to 
example in Figure A1-1) 
2. No cough during the first second. 
3. No valsalva maneuver. 
4. No leak. 
5. No obstruction of mouthpiece. 
6. No extra breaths. 
7. Plateau achieved, ie, the volume-time curve shows no change in volume (<0.025 L) for 
≥1 second, and the patient has tried to exhale for at least 6 seconds. 
 
An acceptable test meets all 7 criteria listed. This is to be considered the “gold standard”. 
Useable spirometry tracings are those that only meet criteria 1 and 2 (Figure A1-1). When 
this occurs, repeat testing up to 8 attempts in an effort to obtain 3 acceptable spirograms. If 
only usable tests are obtained, report results based on the 3 best usable results with observed 
limitations. 
Figure A1-1  Example of a Usable Spirogram 
 
The expanded version of the early part of a subject’s volume-time spirogram, illustrating 
back extrapolation through the steepest part of the curve, where flow is peak expiratory flow 
(PEF), to determine the new “time zero”. Forced vital capacity (FVC)-4.291 L; back 
extrapolated volume (EV) – 0.123 L (2.9% FVC): back extrapolation line through PEF. 


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Between-Maneuver Reproducibility Criteria 
After 3 acceptable spirograms have been obtained, apply the following tests: 
a. The 2 largest values of FVC must be within 0.150 L of each other 
b. The 2 largest values of FEV1 must be within 0.150 L of each other 
 
If these criteria are met, the spirometry testing for that time-point may conclude. The highest 
FEV1 and the highest FVC obtained at each testing time-point (even if from different 
reproducible tracings), will be collected.  
If acceptability criteria are not met, continue testing until they are met or the patient 
cannot/should not continue (maximum of 8 attempts). 


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Appendix 5 
Spirometry Performance Recommendations 
Spirometry data of the highest quality must be obtained for proper interpretation of the 
results of this protocol. To these ends, a standard spirometer will be used (provided by Pearl), 
central training provided, qualification will be required, and specific operating instruction 
will also be provided.  
The following instructions are supported by ATS/ERS defined criteria (Miller 2005). 
FEV1 AND FVC MANEUVERS 
Equipment Requirements 
The spirometer must be capable of accumulating volume for ≥15 s (longer times are 
recommended) and measuring volumes of ≥8 L (body temperature (ie, 37°C), ambient 
pressure, saturated with water vapor, body temperature and pressure saturated [BTPS]) with 
an accuracy of at least ±3% of reading or ±0.050 L, whichever is greater, with flows between 
0 and 14 L-s -1. The total resistance to airflow at 14.0 L-s -1 must be <1.5 cmH2O L-1 1s -1 
(0.15 kPa L-1 1s -1). The total resistance must be measured with any tubing, valves, pre filter, 
etc. included that may be inserted between the subject and the spirometer. Some devices may 
exhibit changes in resistance due to water vapor condensation, and accuracy requirements 
must be met under BTPS conditions for up to eight successive FVC maneuvers performed in 
a 10 minute period without inspiration from the instrument. 
Display 
For optimal quality control, both flow volume and volume time displays are useful, and test 
operators should visually inspect the performance of each maneuver for quality assurance 
before proceeding with another maneuver. This inspection requires tracings to meet the 
minimum size and resolution requirements set forth in this standard. Displays of flow vs. 
volume provide more detail for the initial portion (first 1 s) of the FVC maneuver. Since this 
portion of the maneuver, particularly the peak expiratory flow rate, is correlated with the 
pleural pressure during the maneuver, the flow–volume display is useful to assess the 
magnitude of effort during the initial portions of the maneuver. The ability to overlay a series 
of flow–volume curves registered at the point of maximal inhalation may be helpful in 
evaluating repeatability and detecting sub maximal efforts. However, if the point of maximal 
inhalation varies between blows, then the interpretation of these results is difficult because 
the flows at identical measured volumes are being achieved at different absolute lung 
volumes. In contrast, display of the FVC maneuver as a volume–time graph provides more 
detail for the latter part of the maneuver. A volume–time tracing of sufficient size also allows 
independent measurement and calculation of parameters from the FVC maneuvers. In a 
display of multiple trials, the sequencing of the blows should be apparent to the user. For the 
start of test display, the volume–time display should include >0.25 s, and preferably 1 s, 
before exhalation starts (zero volume). This time period before there is any change in volume 
is needed to calculate the back extrapolated volume (EV) and to evaluate effort during the 
initial portion of the maneuver. Time zero, as defined by EV, must be presented as the zero 


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point on the graphical output. The last 2 s of the maneuver should be displayed to indicate a 
satisfactory end of test. 
When a volume–time curve is plotted as hardcopy, the volume scale must be ≥10 mm L-1 
(BTPS). For a screen display, 5 mm L-1 is satisfactory (Table A1-1). 
Table A1-1.  Recommended Minimal Scale Factors for Time, Volume and 
Flow on Graphical Output 
Parameter 
Instrument Display 
Hardcopy Graphical 
Output 
 
Resolution Required 
Scale Factor 
Resolution Required 
Volume* 
0.050 L 
5 mm-L-1 
0.050 L 
Flow* 
0.200 L-s-1 
2.5 mm L-1 s-1 
0.200 L-s-1 
Time 
0.2 s 
10 mm-s-1 
0.2 s 
*The correct aspect ratio for flow versus volume display is two units of flow per one unit of volume 
 
The time scale should be ≥20 mm-s -1, and larger time scales are preferred (≥30 mm-s -1) 
when manual measurements are made. When the volume–time plot is used in conjunction 
with a flow–volume curve (ie, both display methods are provided for interpretations and no 
hand measurements are performed), the time scale requirement is reduced to 10 mm-s -1 from 
the usually required minimum of 20 mm-s -1 (Table A1-1). The rationale for this exception is 
that the flow–volume curve can provide the means for quality assessment during the initial 
portion of the FVC maneuver. The volume–time curve can be used to evaluate the latter part 
of the FVC maneuver, making the time scale less critical. 
Validation 
It is strongly recommended that spirometry systems should be evaluated using a computer 
driven mechanical syringe or its equivalent, in order to test the range of exhalations that are 
likely to be encountered in the test population. Testing the performance of equipment is not 
part of the usual laboratory procedures. 
Quality Control 
Attention to equipment quality control and calibration is an important part of Good 
Laboratory Practice. At a minimum, the requirements are as follows: 1) a log of calibration 
results is maintained; 2) the documentation of repairs or other alterations which return the 
equipment to acceptable operation; 3) the dates of computer software and hardware updates 
or changes; and 4) if equipment is changed or relocated (eg, industrial surveys), calibration 
checks and quality control procedures must be repeated before further testing begins. 
Key aspects of equipment quality control are summarized in Table A1-2. 


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Table A1-2  Summary of Equipment Quality Control 
Test 
Minimal Interval 
Action 
Volume 
Daily 
Calibration check with a 3 L syringe 
Leak 
Daily 
2 cmH2O (0.3 kPa) constant pressure for 1 minute 
Volume 
Linearity 
Quarterly 
1 L increments with a calibrating syringe measured over the 
entire volume range 
Flow 
Linearity 
Weekly 
Test at least three different flow ranges 
Time 
Quarterly 
Mechanical recorder check with stop watch 
Software 
New versions 
Log installation date and perform test using “known” subject 
 
Calibration is the procedure for establishing the relationship between sensor determined 
values of flow or volume and the actual flow or volume. A calibration check is different from 
calibration and is the procedure used to validate that the device is within calibration limits, 
eg, ±3% of true. If a device fails its calibration check, then new calibration procedure or 
equipment maintenance is required. Calibration checks must be undertaken daily, or more 
frequently, if specified by the manufacturer. The syringe used to check the volume 
calibration of spirometers must have an accuracy of ±15 mL or ±0.5% of the full scale (15 
mL for a 3 L syringe), and the manufacturer must provide recommendations concerning 
appropriate intervals between syringe calibration checks. Users should be aware that a 
syringe with an adjustable or variable stop may be out of calibration if the stop is reset or 
accidentally moved. Calibration syringes should be periodically (eg, monthly) leak tested at 
more than one volume up to their maximum; this can be done by attempting to empty them 
with the outlet corked. A dropped or damaged syringe should be considered out of calibration 
until it is checked. 
With regard to time, assessing mechanical recorder time scale accuracy with a stopwatch 
must be performed at least quarterly. An accuracy of within 2% must be achieved. 
Quality Control for Volume Measuring Devices 
The volume accuracy of the spirometer must be checked at least daily, with a single 
discharge of a 3 L calibrated syringe. Daily calibration checking is highly recommended so 
that the onset of a problem can be determined within 1 day and also to help define day to day 
laboratory variability. More frequent checks may be required in special circumstances, such 
as: 1) during industrial surveys or other studies in which a large number of subject 
maneuvers are carried out, the equipment’s calibration should be checked more frequently 
than daily; and 2) when the ambient temperature is changing (eg, field studies), volume 
accuracy must be checked more frequently than daily and the BTPS correction factor 
appropriately updated.  


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Page 92 of 96 
The accuracy of the syringe volume must be considered in determining whether the measured 
volume is within acceptable limits. For example, if the syringe has an accuracy of 0.5%, a 
reading of ±3.5% is appropriate. 
The calibration syringe should be stored and used in such a way as to maintain the same 
temperature and humidity of the testing site. This is best accomplished by keeping the 
syringe in close proximity to the spirometer, but out of direct sunlight and away from heat 
sources. 
Volume type spirometer systems must be evaluated for leaks every day. The importance of 
undertaking this daily test cannot be overstressed. Leaks can be detected by applying a 
constant positive pressure of ≥3.0 cmH2O (0.3 kPa) with the spirometer outlet occluded 
(preferably at or including the mouthpiece). Any observed volume loss of 0.30 mL after 1 
minute indicates a leak and needs to be corrected. 
At least quarterly, volume spirometers must have their calibration checked over their entire 
volume range using a calibrated syringe or an equivalent volume standard. The measured 
volume should be within ±3.5% of the reading or 65 mL, whichever is greater. This limit 
includes the 0.5% accuracy limit for a 3-L syringe. The linearity check procedure provided 
by the manufacturer can be used if it is equivalent to one of the following procedures: 
1) consecutive injections of 1-L volume increments while comparing observed volume with 
the corresponding cumulative measured volume (eg, 0–1,1–2, 2–3,…6–7 and 7–8 L, for an 8-
L spirometer); and 2) injection of a 3-L volume starting at a minimal spirometer volume, then 
repeating this with a 1-L increment in the start position (eg, 0–3, 1–4, 2–5, 3–6, 4–7, and 5–
8 L, for an 8-L spirometer). The linearity check is considered acceptable if the spirometer 
meets the volume accuracy requirements for all volumes tested. 
Quality Control for Flow Measuring Devices 
With regards to volume accuracy, calibration checks must be undertaken at least daily, using 
a 3-L syringe discharged at least three times to give a range of flows varying between 0.5 and 
12 L-s -1 (with 3-L injection times of 6 s and 0.5 s). The volume at each flow should meet the 
accuracy requirement of ±3.5%. For devices using disposable flow sensors, a new sensor 
from the supply used for subject tests should be tested each day. 
For linearity, a volume calibration check should be performed weekly with a 3-L syringe to 
deliver three relatively constant flows at a low flow, then three at a mid-range flow and 
finally three at a high flow. The volumes achieved at each of these flows should each meet 
the accuracy requirement of ±3.5%. 
VITAL CAPACITY AND INSPIRATORY CAPACITY MANEUVERS 
Equipment 
For measurements of vital capacity (VC) and inspiratory capacity, the spirometer or flow 
meter must comply with the requirements for FVC (as described previously) and be capable 
of accumulating volume for >30 s. Expiratory maneuvers or, ideally, both inspiratory and 


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Clinical Study Protocol: PT010018-00 
Version 1.0 
 
 
 
Confidential and Proprietary 
Page 93 of 96 
expiratory maneuvers should be included in the display of VC maneuver. Regardless of 
whether the inspiratory or expiratory maneuver is used for deriving measurements, a display 
of the entire recorded VC maneuver must be provided. The maximal expiratory volume must 
be assessed to determine whether the subject has obtained a plateau in the expiratory effort. 
For display of the slow VC, the time scale may be reduced to 5 mm-s -1. 
TECHNICAL CONSIDERATIONS 
Minimal Recommendations for Spirometry Systems 
Accurate results require accurate equipment. Spirometer equipment recommendations apply 
to all spirometers and are minimal requirements. In some circumstances, it may be 
appropriate to exceed these requirements (ie, in some research/surveillance applications). 
Instrumentation recommendations should be followed to provide accurate spirometric data 
and information that is comparable from laboratory to laboratory and from one time period to 
another. The accuracy of a spirometry system depends on characteristics of the entire system, 
from the volume or flow transducer and the use of an in line filter, to the recorder, display or 
processor. Changes in any aspect of the equipment or errors at any step in the process can 
affect the accuracy of the results. For example, if the BTPS correction factor is wrong, an 
accurately measured FVC will be incorrectly reported. Spirometers are not required to 
measure all of the indices in Table A1-3, but must meet the recommendations for those that 
are measured. Accuracy and repeatability recommendations apply over the entire volume 
range of the instrument. 
Table A1-3  Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers 
Test 
Range/Accuracy 
(BTPS) 
Flow 
Range 
(L-s-1) 
Resistance and 
Back Pressure 
Test Signal 
VC 
0.5–8 L, ±3% of reading or 
±0.050 L, whichever is greater 
0-14 
 
3-L Calibration syringe 
FVC 
0.5–8 L, ±3% of reading or 
±0.050 L, whichever is greater 
0-14 
<1.5 cmH2O L-1 s-1 
(0.15 kPa L-1s-1) 
24 ATS waveforms, 3-L 
Cal Syringe 
FEV1 
0.5–8 L, ±3% of reading or 
±0.050 L, whichever is greater 
0-14 
<1.5 cmH2O L-1 s-1 
(0.15 kPa L-1s-1) 
24 ATS waveforms 
Time 
Zero 
The time point from which all 
FEVt measurements are taken 
 
Back extrapolation 
 
FEVt: forced expiratory volume in t seconds 
 
BTPS correction 
All spirometry values should be reported at BTPS by any method (measuring temperature 
and barometric pressure) proven effective by the manufacturer. For volume-type spirometers, 


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Pearl Therapeutics, Inc. 
Clinical Study Protocol: PT010018-00 
Version 1.0 
 
 
 
Confidential and Proprietary 
Page 94 of 96 
the temperature inside the spirometer should be measured for each breathing maneuver. 
Regardless of the BTPS correction technique used, the ambient temperature must always be 
recorded with an accuracy of ±1°C. In situations where the ambient air temperature is 
changing rapidly (>3°C in <30 min), continuous temperature corrections may be necessary. 
Spirometer users should be aware of potential problems with testing performed at lower 
ambient temperatures: 17°C is the lower limit for ambient temperature, unless a manufacturer 
states that their spirometer will operate accurately at lower ambient temperatures. If 
barometric pressure is not used in calculating the BTPS correction factor, the range of 
barometric pressures over which the BTPS correction factor is valid must be published. 
 
 
 




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Clinical Study Protocol: PT010018-00
Version 1.0 
Confidential and Proprietary 
Page 96 of 96
Appendix 7 
Investigator’s Signature
Study Title:
A Study to Assess the Pharmacokinetics and Safety of PT010 in 
Subjects With Moderate to Severe COPD Following Single and 
Repeat Dose Administration
Study Number:
PT010018
Final Date:
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:  
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 1 of 41) 
 
 
STATISTICAL ANALYSIS PLAN FOR 
STUDY PT010018 
 
 
 
Protocol Number: 
PT010018 
 
Investigational Drug 
and Drug Number: 
BGF MDI; PT010 
 
Indication: 
COPD 
Dosage Form/Dose: 
x BGF MDI 320/14.4/9.6 μg ex-actuator 
 
PT010018 Protocol Title: A Study to Assess the Pharmacokinetics and Safety of PT010 in 
Subjects With Moderate to Severe COPD Following Single and Repeat Dose Administration 
 
 
Date of Issue: 
18 Dec 2017 
 
Version: 
Version 1.3 
 
 
 






Statistical Analysis Plan
Protocol Nos.:  PT010018
Date:  18 Dec 2017
                                        (Page 4 of 41)
Change Log
Version No.
Effective Date
Reason for the Change / Revision
Supersedes
1.1
1.2
1.3
12-Dec-2017
15-Dec-2017
18-Dec-2017
Page 29: changed “AUC0-t, AUC0-12, and AUC0-∞,
will be calculated using linear log trapezoidal 
method.” to “AUC0-t, AUC0-12, and AUC0-∞, will be 
calculated using the linear up/log down method.”
Page 31: 1st paragraph deleted ‘in the Safety 
Population’ at the end.
Page 35: added “Figure 2.1.1.1”
Page 36: added “Figure 2.2.1.1” and “Figure 
2.3.1.1”
Page 39: deleted “(PCS)” in “Table 3.5.2” title
Page 41: changed to “Safety Population” in 
“Listing 8.1” subtitle
Page 29: Adjusted r2 value reported in 
must be ≥ 0.8.
“For all subjects in the PK Population” added to the 
below statement: “In addition, all calculated PK 
parameters for each subject for each analyte will be 
listed (Listing 8.2) for all subjects in the PK 
Population.”
SAP text updated to address comments following 
delivery of Dry Run 1.
Removal of reference to randomized treatment to 
indicate study treatment.
Abbreviations for Cmin and Cav added to list of 
abbreviations.
T90 added
V1.0
V1.1
V1.2


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 5 of 41) 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................................... 11 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 11 
2.1 
STUDY OBJECTIVES ............................................................................................................................ 11 
2.1.1 
Primary Objective ............................................................................................................... 11 
2.1.2 
Safety Objective ................................................................................................................. 11 
2.2 
STUDY ENDPOINTS ............................................................................................................................. 11 
2.2.1 
Pharmacokinetic Endpoints ................................................................................................ 11 
2.2.1.1 
Primary PK Endpoints ....................................................................................... 11 
2.2.1.2 
Secondary PK Endpoints ................................................................................... 12 
2.2.1.3 
Other PK Endpoints ........................................................................................... 12 
2.2.2 
Safety Endpoints ................................................................................................................. 12 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ............................................................. 12 
3.1 
STUDY DESIGN ................................................................................................................................... 12 
3.1.1 
Overall Study Design and Plan ........................................................................................... 13 
3.1.2 
Prior, Concomitant, Prohibited Medications ...................................................................... 14 
3.2 
RANDOMIZATION AND BLINDING ....................................................................................................... 14 
3.3 
HYPOTHESIS TESTING ........................................................................................................................ 14 
3.4 
SAMPLE SIZE ...................................................................................................................................... 14 
3.5 
STUDY PROCEDURES .......................................................................................................................... 14 
3.6 
SCHEDULE OF ASSESSMENTS.............................................................................................................. 14 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ........................................................................ 15 
5. 
ANALYSIS POPULATIONS ................................................................................................................... 15 
5.1 
POPULATION DEFINITIONS ................................................................................................................. 15 
5.1.1 
Safety Population ................................................................................................................ 15 
5.1.2 
Pharmacokinetic (PK) Population ...................................................................................... 15 
5.2 
POPULATIONS FOR ANALYSES ............................................................................................................ 16 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES ..................................................................... 16 
6.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................................... 16 
6.2 
PHARMACOKINETICS .......................................................................................................................... 16 
6.3 
SAFETY ASSESSMENTS ....................................................................................................................... 16 
6.3.1 
Physical Examination ......................................................................................................... 16 
6.3.2 
Vital Signs .......................................................................................................................... 17 
6.3.3 
12-Lead Electrocardiogram ................................................................................................ 18 
6.3.4 
Clinical Laboratory Tests ................................................................................................... 19 
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.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 6 of 41) 
 
7.3.2 
Prior and Concomitant Medications/Treatments ................................................................ 25 
7.3.3 
Extent of Exposure to Study Medication and Compliance ................................................. 26 
7.4 
PHARMACOKINETIC ASSESSMENTS .................................................................................................... 27 
7.5 
SAFETY ASSESSMENTS ....................................................................................................................... 30 
7.5.1 
Physical Examination ......................................................................................................... 30 
7.5.2 
Vital Signs .......................................................................................................................... 30 
7.5.3 
12-Lead Electrocardiogram ................................................................................................ 30 
7.5.4 
Clinical Laboratory Tests ................................................................................................... 31 
7.5.5 
Adverse Events ................................................................................................................... 32 
7.5.6 
Urine Drug Screening and Alcohol Breath Testing ............................................................ 32 
7.5.7 
Pregnancy Test ................................................................................................................... 32 
7.5.8 
Prior/Concomitant Medications/Treatments ....................................................................... 32 
8. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE ......................................................... 33 
9. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................... 33 
10. STATISTICAL SOFTWARE ................................................................................................................... 33 
11. REFERENCES .......................................................................................................................................... 33 
APPENDIX 1: DATA HANDLING RULES .................................................................................................... 33 
APPENDIX 2: TABLE OF CONTENTS FOR END-OF-TEXT TABLES, LISTINGS, AND FIGURES . 33 
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES ..................................................................... 41 
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .... 41 
 
 
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 7 of 41) 
 
 
List of Tables 
 
Table 1 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ............................................................................................... 18 
Table 2 
Potentially Clinically Significant Criteria for Heart Rate Parameters ................... 18 
Table 3 
Criteria for PCS ECG Values................................................................................. 18 
Table 4                   List of Laboratory Tests ......................................................................................... 19 
Table 5                   Potentially Clinically Significant (PCS) Laboratory Parameter Criteria ............... 20 
 
 
List of Figures 
 
Figure 1 
Study Design .......................................................................................................... 13 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 8 of 41) 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ATC 
Anatomic Therapeutic Class 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours 
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 
BGF MDI 
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose 
Inhaler 
BID 
Bis in die, twice daily 
BLOQ 
Below Limit of Quantification 
BP 
Blood Pressure 
Cav 
Average concentration during a dosing interval 
CL/F 
Apparent Total Body Clearance 
Cmax 
Maximum Observed Plasma Concentration 
Cmin 
Lowest concentration in the dosing interval 
COPD 
Chronic Obstructive Pulmonary Disease  
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 
IEC 
Independent Ethics Committee  
IRB 
Institutional Review Board  


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 9 of 41) 
 
λz 
Apparent Terminal Elimination Rate Constant  
LLOQ 
Lower Limit of Quantification 
MDI 
Metered dose inhaler 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
μg 
Microgram 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
NCA 
Non-Compartmental Analysis 
PCS 
Potentially Clinically Significant 
PK 
Pharmacokinetics  
PT 
Preferred Term 
PT010 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol 
QTcF 
QT Corrected Using Fridericia’s Formula 
RAC(Cmax) 
Accumulation ratio for Cmax 
RAC(AUC0-12) 
Accumulation ratio for AUC0-12 
Rlin 
Linearity ratio 
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 of last measurable (positive) concentration 
tmax 
Time To Maximum Observed Plasma Concentration  


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 10 of 41) 
 
Vd/F 
Apparent Volume of Distribution 
WHO 
World Health Organization 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 11 of 41) 
 
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 PT010018. 
The SAP should be read in conjunction with the study protocol and the electronic Case Report 
Forms (eCRFs) for the study. This version of the SAP has been developed using the PT010018-
00 Protocol (Version 1.0 dated 14 June 2017) and the CRF Revision 02 dated 11 September, 
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, open label, single center study to assess the pharmacokinetics (PK) and safety 
of BGF MDI 320/14.4/9.6 μg in subjects with moderate to severe chronic obstructive pulmonary 
disease (COPD) following a single administration and after repeat dose administration for 7 
days. 
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  
x To assess the PK profile of BGF MDI in subjects with moderate to severe COPD after single 
dose administration on the first treatment day and after 7 days of repeat dosing. 
 
2.1.2 
Safety Objective 
x To assess the safety and tolerability of BGF MDI in subjects with moderate to severe COPD 
after single dose administration on the first treatment day and after 7 days of repeat dosing. 
 
2.2 
Study Endpoints 
2.2.1 
Pharmacokinetic Endpoints 
Pharmacokinetics 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 and Day 8.  
2.2.1.1 
Primary PK Endpoints 
x Maximum plasma concentration (Cmax) 
x Area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) 
x Area under the plasma concentration-time curve from 0 to the time of the last measurable 
plasma concentration (AUC0-tlast) (Day 1 only) 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010018 
Date:  18 Dec 2017 
 
                                        (Page 12 of 41) 
 
2.2.1.2 
Secondary PK Endpoints 
x Time to maximum plasma concentration (tmax) 
x Area under the plasma concentration-time curve from 0 extrapolated to infinity (AUC0-∞) 
2.2.1.3 
Other PK Endpoints 
The following PK parameters will be calculated at Day 1 only: 
x Apparent terminal elimination half-life (t1/2) 
x Apparent total body clearance (CL/F) 
x Apparent volume of distribution (Vd/F) 
x Terminal elimination rate constant (λz) 
The following will be derived based on ratios of Day 8 values to Day 1 values: 
x Accumulation ratio for Cmax (RAC [Cmax]) 
x Accumulation ratio for AUC0-12 (RAC [AUC0-12]) 
x Linearity ratio (Rlin [AUC0-12/AUC0-∞]) 
2.2.2 
Safety Endpoints 
The safety and tolerability of BGF MDI will be assessed from AE (adverse event) reporting 
including serious adverse event (SAE) reporting, vital signs (blood pressure [BP] and heart rate 
[HR]), clinical laboratory values (hematology, chemistry, and urinalysis), findings from 12-lead 
safety electrocardiograms (ECG) and physical examination findings incorporated in the adverse 
events tabulation.  
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS 
3.1 
Study Design 
This is a Phase I, single-center, open-label, study to assess the PK and safety and tolerability of 
BGF MDI in subjects with moderate to severe COPD. Pharmacokinetics will be assessed 
following a single administration and after repeat dose administration for 7 days. Safety will be 
assessed during the 8-day treatment period and throughout the entire study until subjects are 
released from participation. The study drug will be administered by oral inhalation. It is planned 
that the study will enroll an estimated 30 eligible subjects to have approximately 24 completers 
for the assessment of single and multiple dose PK of BGF MDI 320/14.4/9.6 μg in subjects with 
COPD.  


 
 
 
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This study includes a Screening Period of up to 28 days and a single Treatment Period of 8 days. 
A follow-up phone call will be conducted at least 5 days, but no longer than 7 days after 
completion of the last dose. The maximum participation in the study for each subject is up to 7 
weeks, with an expected range of participation between 2.5 to 7 weeks. 
3.1.1 
Overall Study Design and Plan 
The overall study design is summarized and illustrated in Figure 1. 
Figure 1 
Study Design 
 
Note: All study drugs are administered by oral inhalation. A single dose of study drug will be administered on Day 1 
(Visit 3) and BID doses will be administered Day 2 through Day 7 of the Treatment Period, with a final single 
administration of study drug occurring on the morning of Day 8 (Visit 5). Administration of study drug should occur 
at approximately the same time of day for all morning dosing and at the same time of day for all evening dosing. 
Subjects who provide informed consent, will be provided a unique subject number at Screening 
and undergo Screening procedures. Only subjects continuing to meet entry inclusion/exclusion 
criteria on Day 1 will be assigned a unique subject enrollment number and will be dosed in the 
study.  
Subjects will be admitted to the clinic on Day -1 and discharged on Day 2 and return for clinic 
admission on the evening of Day 7, with discharge on Day 8 after all assessments are complete.  
During the inpatient treatment period, study specified procedures will be performed and will 
include safety assessments and pre-, post-dose serial blood draws as defined in Protocol Section 
7.5 and in Table 8-1, Table 8-2, and Table 8-3 of the study protocol. Upon completion of the 
study, a follow-up phone call will be conducted at least 5 days but no longer than 7 days from the 
date of last administration on Visit 5 (Day 8). 


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3.1.2
Prior, Concomitant, Prohibited Medications 
Investigational therapies are not permitted within 30 days or five half-lives (whichever is longer) 
prior to beginning the Screening Period. 
All formulations of budesonide, glycopyrronium, or formoterol fumarate used as monotherapy or 
in combination to treat COPD or any other condition are prohibited for a minimum of 4 weeks 
before Visit 1 and during the study. 
All subjects entering the study on allowed inhaled COPD maintenance therapies for the 
management of their COPD should have been maintained on a stable dose of this treatment for at 
least 4 weeks prior to Visit 1. These COPD maintenance will be withheld after their last dose for 
the day on Day -1 (Visit 2) and throughout the study. 
Short acting bronchodilators will be withheld 6 hours prior to spirometry assessment at the 
Screening Visit and throughout the study except study-provided Ventolin HFA for use as needed 
for symptom relief. Additional prohibited COPD medications and associated cessation periods 
prior to Visit 1 are summarized in Table 5-2 of the study protocol. Other prohibited medications 
are summarized in Section 5.4.2 of the study protocol.
3.2
Randomization and Blinding 
This study is open-label, single arm study so no blinding or randomization occurred in the study. 
3.3
Hypothesis Testing 
No formal hypothesis tests will be performed for this study. 
3.4
Sample Size 
This study is descriptive in nature. 
3.5
Study Procedures 
Study procedures are contained in Table 8-1, Table 8-2, and Table 8-3 and detailed in Sections 7 
and Section 8 of the study protocol. 
3.6
Schedule of Assessments 
A schedule of events is provided in Table 8-1 of the study protocol. Detailed schedules of 
inpatient assessments on Visit 3 (Day 1) and Visit 5 (Day 8) are provided in Table 8-2 and Table 
8-3, respectively, of the study protocol. 


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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 
.
Detailed data management procedures are documented in the study Data Management Plan, and
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 violations 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. 
5.
ANALYSIS POPULATIONS 
5.1
Population Definitions 
5.1.1
Safety Population  
The Safety Population is defined as all treated subjects who receive at least one dose of study 
drug.
Safety 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 treated subjects who have sufficient data to reliably 
calculate at least one PK parameter for at least one analyte and who do not have major protocol
deviations which affect the PK analysis. Major protocol deviations can result in exclusion of all 
data collected for 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 upon by the study team and 
documented prior to database lock.
Steady state is expected to be achieved within 3 days for all analytes (budesonide, 
glycopyrronium, and formoterol). If a subject has missed any of the scheduled doses in the 3 
days prior to Day 8, the Day 8 concentration data for that subject will be excluded from the PK 
Population and will not contribute to the non-compartmental analysis. 
Reasons for exclusion from the PK Population will documented in the Blinded Data Review 
meeting minutes prior to database lock; these minutes will be included in an appendix to the 
Clinical Study Report. 


 
 
 
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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 after treatment with BGF MDI. The 
Safety Population will be used to summarize safety. Safety and tolerability analyses will be 
based on descriptive statistics for vital signs, ECG, 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. 
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 will be assessed using plasma concentrations of budesonide, 
glycopyrronium, and formoterol pre-dose and at various times post-dose on Day 1 and Day 8 
(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) 


 
 
 
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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 
6.3.2 
Vital Signs 
Vital sign determinations, including BP and heart rate will be performed after the subject has 
been supine for a 5-minute period at the Screening Visit, on the day of clinic admission (Day -1; 
Visit 2), and on the day of clinic admission (Day 7, Visit 4), and Visit 5 (Day 8) within 60 
minutes prior to administration of study drug and 12 hours post administration of study drug 
(Day 8 only).  
Potentially clinically significant (PCS) changes in systolic and diastolic blood pressure will 
be defined based on the following criteria provided by Pearl, Inc.: 
 


 
 
 
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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 (PCS) changes in heart rate 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 Adverse Event 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. 
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 
Potentially clinically significant ECG parameter values will be identified based on criteria listed 
in Table 3.  


 
 
 
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6.3.4 
Clinical Laboratory Tests 
Laboratory testing (hematology with differential, chemistry and urinalysis) will be performed 
using standard methods.  
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.  
Table 4 List of Laboratory Tests 
Hematology 
Blood Chemistry 
Hematocrita 
Hemoglobin 
Serum Iron 
Ferritin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential 
Mean corpuscular volume (MCV) 
Mean cell haemoglobin (MCH) 
MCH concentration (MCHC) 
Creatinineb 
Potassium (K+) 
Sodium (Na+) 
Chloride (Cl-) 
Magnesium (Mg++) 
Calcium 
Inorganic phosphate 
Glucosec 
Uric Acid 
Bilirubin (Total) 
Blood Urea Nitrogen (BUN) 
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 and analyzed (positive or negative) at 
Screening and at inpatient admission days for drugs of abuse including amphetamine, opiate, 
cocaine, barbiturates, benzodiazepines, and marijuana [tetrahydrocannabinol (THC)]. 
Alcohol Breathalyzer Test: A breathalyzer test will be performed at Screening and at inpatient 
admission days for the presence of alcohol (positive or negative). 
For all females: A serum hCG test at Screening and urine hCG test on inpatient admission days. 
a Packed cell volume (PCV). 
b eGFR will be calculated by the Chronic Kidney Disease Epidemiology Collaboration Equation 
  
 
 
 


 
 
 
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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 
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 adverse 
event 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 an SAE. 
All AEs that occur at the time of and following the first administration of study drug through the 
final telephone follow-up will be considered as being Treatment-Emergent Adverse Events 
(TEAEs).  


 
 
 
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An AE is considered as On-Treatment if the onset date of the adverse event is on or after the first 
day of dose of study treatment, and up to and including the date completion of study treatment or 
the last day of premature discontinuation from study treatment +1 day.  An adverse event that 
begins on the same date as the first dose of study treatment is On-treatment if the AE begins after 
the time of first dose or if the time of AE onset is unknown.  
An AE is considered as Post-treatment if the onset date of the adverse event is after the date 
completion of study treatment or on or after the last day of premature discontinuation from study 
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  


 
 
 
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• A life-threatening AE  
• In patient 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 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 discontinuation)  
• A laboratory abnormality that results in any therapeutic intervention (e.g., concomitant 
medication or therapy)  


 
 
 
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• Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion) 
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 
A serum hCG test at Screening and a urine hCG test on inpatient admission days will be 
conducted for all females.  
6.3.8 
Concomitant Medications/Treatments 
Concomitant medications will be collected 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 pharmacokinetic 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.  
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 screened will be provided (Table 1.1). This tabulation will 
include the number and percentage of subjects who were treated with the study treatment, who 
discontinued treatment prematurely, who withdrew from the study prematurely, and who 
completed the study. The number and percentage of subjects included in the Safety and PK 
Populations will also be tabulated (Table 1.3). Informed consent is listed in Listing 1.1.  
A summary of reasons for withdrawal 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). Baseline information and 
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 Status (including number of years smoked, time in years since last smoked, 
average number of cigarettes smoked per day) 
x
Weight  
x
Height 
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 Enhanced (WHO-DDE) + WHO HD 
3Q2017 (September 2017) or later, and C3 format coding will be used.
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 discontinuation from study treatment for the subject. A medication with an 
onset date on or after the date of discontinuation from or completion of 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. 
Prior, concomitant, and post-treatment medications will be listed (Listing 10.1.1).  
7.3.3 
Extent of Exposure to Study Medication and Compliance 
Subject’s exposure to study treatment will be determined by the duration of time (days) for 
which the doses were administered, defined as “((End date of treatment – Date of first dose of 
treatment) + 1)”. Percent compliance is defined as (total number of puffs of study treatment 
taken on a study day/total expected puffs taken on a study day) averaged across all days of a 
subject’s dosing between start day of study treatment and last day on study treatment) x 100. The 
expected number of puffs will be 2 on Day 1 and Day 8, and the expected number of puffs will 
be 4 on Day 2 through Day 7.  
 
The number of days of exposure to study treatment will be summarized for the Safety 
Population. The tabulation will include the number and percentage of subjects with 1, 2, 3, 4, 5, 
6, 7, and 8 days of exposure. The total person-years of exposure, defined as the total exposure in 
the study across all subjects, will also be provided (Table 1.6 for the Safety Population).  
In addition, treatment compliance will be provided in this summary. The treatment compliance 
will be categorized into 7 different groups depending on the degree of compliance: 0 – <20%, 
≥20 – <40%, ≥40 – <60%, ≥60 – <80%, ≥80 – ≤100%, >100 – ≤120%, and >120%. Also 
provided in this summary will be descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum) for percent compliance (Table 1.6). Treatment compliance will be 
reported in Listing 6.1. 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). 


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7.4
Pharmacokinetic Assessments 
For the single dose administration, time points for PK blood sample collection will be pre-dose 
within 60 minutes and post-dose at 2, 6, 20, and 40 minutes, and at 1, 2, 4, 8, 10, 12, 18, and 24 
hours. 
Following 7 days of repeat dosing BID, time points for PK blood sample collection will be pre-
dose within 60 minutes and post-dose at 2, 6, 20, and 40 minutes, and at 1, 2, 4, 8, 10, and 12 
hours starting on the morning of the 8th day. 
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 
 
 
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 the
treatment period: 
AUC0-tlast
Area under the plasma concentration-time curve from 0 to the time of the last 
measurable plasma concentration
AUC0-12
Area under the plasma concentration-time curve from time 0 to 12 hours post dose
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 
minutes
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 of last measurable (positive) concentration
From the plasma budesonide, glycopyrronium and formoterol concentration-time data, AUC0-12,
Cmax and tmax will be estimated for each subject where possible on Day 8 during the treatment 


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period. In addition, Fluctuation, Swing, Cav, and Cmin will be estimated and reported where 
feasible on Day 8. 
Fluctuation 
Degree of fluctuation [(Cmax-Cmin)/Cav]
Swing 
[(Cmax-Cmin)/Cmin]
Cav
Average concentration during a dosing interval. 
Cmin
The lowest concentration in the dosing interval, expressed in concentration units 
AUC0-t, AUC0-12, and AUC0-∞, will be calculated using the linear up/log down 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 limit of 
quantification (BLOQ) 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 BLOQ will be set to zero (per 
 SOP) for the NCA. Concentrations measured after the Day 1 dose of study medication 
that are BLOQ 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 that are 
BLOQ 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). 
In addition to the above PK parameters to be calculated on Day 1 and Day 8, accumulation ratios 
for AUC0-12 (RAC [AUC0-12]) and Cmax (RAC [Cmax]) will be calculated by taking subject level 
ratios of Day 8 values to Day 1 values. 
Steady state is expected to be achieved after 3 consecutive days of dosing for budesonide, 
glycopyrronium, and formoterol. 


 
 
 
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The linearity ratio (Rlin [AUC0-12/AUC0-∞]) will also be calculated, for which the AUC0-12 on 
Day 8 is divided by the AUC0-∞ on Day 1. 
To estimate the RAC values and Rlin, natural-log transformed AUC0-12, AUC0-∞, and Cmax of 
budesonide, glycopyrronium, and formoterol between Day 8 and Day 1, will be analyzed using a 
mixed model with day as a fixed effect and subject as a random effect. A separate mixed model 
will be fit for each analyte and ratio type. For each analyte, the estimated ratio of geometric least 
square mean (LSM) for Day 8 to Day 1 and the corresponding 90% confidence interval (CI) will 
be determined by exponentiating the mean difference between Day 8 and Day 1 and the 
associated CI (on the logarithm scale). The estimated ratio of geometric LSM and its 
corresponding 90% CI will be an estimate of RAC or Rlin with the 90% CI.  
The residual variance component from the model estimating Rlin will provide an estimate of 
intra-subject variability. The model-based geometric coefficient of variation for the model which 
estimates Rlin is calculated as 100*sqrt[(exp[residual_variance_component])-1], where sqrt is 
the square root function and residual_variance_component is the residual variance component 
from the model estimating Rlin. This model-based geometric coefficient of variation will be 
displayed. 
If the effective rate of drug accumulation is estimable, the time to reach steady state will be 
estimated for each analyte using the methodology of Panebianco and Maes (Panebianco and 
Maes 2009). T90 will be reported. 
Descriptive statistics for plasma concentrations of budesonide, glycopyrronium, and formoterol,  
by day and time point will be summarized using the Safety 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 day. 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 parameter tmax, 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. 
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 


 
 
 
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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) for all 
subjects in the PK Population. 
7.5 
Safety Assessments 
Safety data will be summarized and listed. The safety assessments for BGF MDI included 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 
Vital sign measurements (PR, BP) as collected on eCRFs (see Section 6.3.2) during the study 
will be displayed in a vital sign listing, as well as weight and height (collected at the Screening 
visit) (Listing 10.2).  
Summary statistics (n, mean, median, standard deviation, minimum and maximum) of pre-dose 
(in the respective period) and post-dose values (in the respective period) as well as changes from 
baseline values for systolic blood pressure, diastolic blood pressure and heart rate will be 
tabulated (Table 3.4.1). Baseline is defined (computationally) as the mean of all available pre-
dose measurements taken on Day 1 prior to the start of dosing with study drug. 
The percentage of subjects with potentially clinically significant values for vital signs at any time 
post-dose at a visit will be summarized based on the criteria in Table 1 and Table 2 (Table 3.4.2). 
They will also be listed (Tables 3.4.3 and 3.4.4).  
7.5.3 
12-Lead Electrocardiogram 
The QTcF is defined as [QT/(RR1/3)]. Heart rate (bpm) is estimated as 60,000/RR, where RR is 
in units of ms. These assessments will be tabulated for each assessment time.  
A Clinically Significant Abnormality for a 12-Lead ECG measurement identified by the 
investigator as a clinically significant abnormality will be recorded as an Adverse Event if it 
occurred after the start of study treatment. These adverse events will be included in the AE 
summaries. 


 
 
 
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All 12-Lead ECG measurements for the Safety Population will be listed (Listing 10.6). Summary 
statistics (mean, median, standard deviation and range) for raw values in Heart Rate, PR Interval, 
QRS Axis, QRS Interval, QT Interval and QTcF interval will be calculated. These assessments 
will be tabulated for each scheduled timepoint at each visit (Table 3.5.1). Data from unscheduled 
visits will not be used for the by-visit summaries. Data from both scheduled and unscheduled 
visits will be listed. ECG data from subjects with pacemakers will not be included in analyses, 
but will be listed. 
Data from unscheduled visits will not be used for the by-visit summaries but both scheduled-visit 
data and unscheduled-visit data are candidates for clinically significant values. 
Potentially clinically significant ECG parameter values will be identified based on listed criteria. 
The number and percentage of subjects who had such values observed any time post-dose will be 
tabulated (Table 3.5.2) and listed (Table 3.5.3).  
7.5.4 
Clinical Laboratory Tests 
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) of 
assessment values for laboratory testing (hematology with differential (Table 3.3.1), serum 
chemistry including estimated eGFR (Table 3.3.2) will be tabulated at each time point and at 
each visit. Urinalysis results will be listed (Listing 9.3) and tabulated (Table 3.3.3). Changes 
from baseline will also be summarized at Day 8 (Visit 5). Baseline is the last assessment during 
the screening period.  
Individual clinical laboratory variables for hematology, serum chemistry including estimated 
eGFR and urinalysis will be provided in listings (Listings 9.1 - 9.3). 
Shifts from baseline to Visit 5 (Day 8), based on reference ranges (Low, Normal, High), will be 
presented for hematology and serum chemistry (Table 3.3.4) and for urinalysis (Table 3.3.5). 
Baseline is the last assessment during the screening period for all laboratory assessments. 
 
Many laboratory abnormalities observed during the course of a study will be included under a 
reported AE describing a clinical syndrome (e.g., 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. 
Potentially clinically significant laboratory values will be identified based on listed criteria. 
Since a reduction in potassium and an increase in blood glucose are known class effects of 
beta-agonists, all potassium or glucose assessments for subjects who experienced newly 
occurring or worsening potentially clinically significant values after start of the study treatment 
will be provided in separate listings (Tables 3.3.7 and 3.3.8). For all laboratory parameters other 
than glucose and potassium, all laboratory data for the parameter identified as potentially 
clinically significant for a subject will be listed (Table 3.3.9). 


 
 
 
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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 
7.1 and 7.2). All AEs whether treatment-emergent or not, will be included in the Listings. 
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 
discontinuation from study treatment, with SAEs leading to early withdrawal from study 
treatment, 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) for the Safety Population (Table 
3.1.2). 
On-treatment AEs will be summarized by (maximum) severity, with respect to SOC and 
preferred terms (Table 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, Table 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 listing (Listing 10.1). 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 


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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).
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 PT010018, Version 1.0 dated 14 June 2017.
10.
STATISTICAL SOFTWARE 
or later in the UNIX environment will be used for all statistical analyses.  
will be used for all PK parameter 
calculations. 
11.
REFERENCES 
 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 Screened)  
 Table 1.2 Analysis Populations 


 
 
 
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                  (Analysis Set: Safety Population)  
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)  
Table 1.6 Study Treatment Exposure and Compliance 
                  (Analysis Set: Safety Population)  
1.2 Pharmacokinetic Data 
Table 2.1.1 Descriptive Statistics for Plasma Concentrations of Budesonide (unit) by Visit and Timepoint 
                  (Analysis Set: PK Population)  
Figure 2.1.1 Mean (+/- SE) Plasma Budesonide Concentration-Time Profile after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (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 on Day 1 and Repeat Dose Administration on Day 8 (Linear-Linear Scale) 
(Analysis Set: PK Population) 
Figure 2.1.2 Mean Plasma Budesonide Concentration-Time Profile after Single Dose Administration on 
Day 1 and Repeat Dose Administration on Day 8 (Log-Linear Scale) 
(Analysis Set: PK Population)  
Table 2.1.2  Descriptive Statistics for Pharmacokinetic Parameters of Budesonide by Visit 
(Analysis Set: PK Population)  
Table 2.2.1 Descriptive Statistics for Plasma Concentrations of Glycopyrronium (unit) by Visit and 
Timepoint 


 
 
 
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                  (Analysis Set: PK Population)  
Figure 2.2.1 Mean (+/- SE) Plasma Glycopyrronium Concentration-Time Profile after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8  (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.2.1.1 Mean (+/- SE) Plasma Glycopyrronium Concentration-Time Profile within 2 hours after 
Single Dose Administration on Day 1 and Repeat Dose Administration on Day 8  (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.2.2 Mean Plasma Glycopyrronium Concentration-Time Profile after Single Dose Administration 
on Day 1 and Repeat Dose Administration on Day 8  (Log-Linear Scale) 
(Analysis Set: PK Population) 
Table 2.2.2  Descriptive Statistics for Pharmacokinetic Parameters of Glycopyrronium by Visit 
(Analysis Set: PK Population)  
Table 2.3.1 Descriptive Statistics for Plasma Concentrations of Formoterol (unit) by Visit and Timepoint 
               (Analysis Set: PK Population)  
Figure 2.3.1 Mean (+/- SE) Plasma Formoterol Concentration-Time Profile after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Linear-Linear Scale) 
(Analysis Set: PK Population) 
Figure 2.3.1.1 Mean (+/- SE) Plasma Formoterol Concentration-Time Profile within 2 hours after Single 
Dose Administration on Day 1 and Repeat Dose Administration on Day 8 (Linear-Linear Scale) 
(Analysis Set: PK Population)  
Figure 2.3.2 Mean Plasma Formoterol Concentration-Time Profile after Single Dose Administration on 
Day 1 and Repeat Dose Administration on Day 8  (/Log-Linear Scale) 
(Analysis Set: PK Population)  
Table 2.3.2  Descriptive Statistics for Pharmacokinetic Parameters of Formoterol by  Visit 
(Analysis Set: PK Population)  


 
 
 
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Figure 2.4.1  Individual Plasma Concentration-Time Profile of Budesonide after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Linear-Linear Scale) 
                  (Analysis Set: PK Population)  
Figure 2.4.2  Individual Plasma Concentration-Time Profile of Budesonide after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Log-Linear Scale) 
                  (Analysis Set: PK Population)  
Figure 2.5.1  Individual Plasma Concentration-Time Profile of Glycopyrronium after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Linear-Linear Scale) 
                  (Analysis Set: PK Population)  
Figure 2.5.2  Individual Plasma Concentration-Time Profile of Glycopyrronium after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Log-Linear Scale) 
                  (Analysis Set: PK Population)  
Figure 2.6.1 Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Linear-Linear Scale) 
                  (Analysis Set: PK Population)  
Figure 2.6.2  Individual Plasma Concentration-Time Profile of Formoterol after Single Dose 
Administration on Day 1 and Repeat Dose Administration on Day 8 (Log-Linear Scale) 
                  (Analysis Set: PK Population)  
1.3 Safety Data 
1.3.1 Adverse Events 
Table 3.1.1 Summary of Subjects With At Least One 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-discontinuation Follow-up Adverse Events by System Organ 
Class and Preferred Term 


 
 
 
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                  (Analysis Set: Safety Population)  
Table 3.2.1 Summary of On-Treatment Adverse Events by SOC, Preferred Term and Highest Severity – 
BGF MDI 320/14.4/9.6 μg 
                  (Analysis Set: Safety Population)  
Table 3.2.2 Summary of Post-treatment-discontinuation Follow-up Adverse Events by SOC, Preferred 
Term and Highest Severity – BGF MDI 320/14.4/9.6 μg 
                  (Analysis Set: Safety Population)  
1.3.2 Laboratory Data 
Table 3.3.1 Summary of Laboratory Results by Time of Assessment – Hematology 
                  (Analysis Set: Safety Population)  
Table 3.3.2 Summary of Laboratory Results by Time of Assessment – Chemistry 
                  (Analysis Set: Safety Population)  
Table 3.3.3 Summary of Laboratory Results by Time of Assessment – Urinalysis 
                  (Analysis Set: Safety Population)  
Table 3.3.4 Shift Table for Laboratory Hematology Data: NCI-CTC Grading 
                  (Analysis Set: Safety Population)  
Table 3.3.5 Shift Table for Laboratory Chemistry Data: NCI-CTC Grading  
                  (Analysis Set: Safety Population)  
Table 3.3.6 Shift Table for Laboratory Urinalysis Data: NCI-CTC Grading  
                  (Analysis Set: Safety Population)  
Table 3.3.7 All Potassium Records for Subjects with Newly Occurring or Worsening Potentially Clinically 
Significant Potassium Values Post-Baseline 
                  (Analysis Set: Safety Population)  
Table 3.3.8 All Glucose Records for Subjects With Newly Occurring or Worsening Potentially Clinically 
Significant Glucose Values Post-Baseline  


 
 
 
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                  (Analysis Set: Safety Population)  
Table 3.3.9 All Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant 
Laboratory Values Post-Baseline Other Than Those for Glucose and Potassium  
                  (Analysis Set: Safety Population)  
1.3.3 Vital Signs 
Table 3.4.1 Summary of Vital Sign Measurements by Time of Assessment 
                  (Analysis Set: Safety Population)  
Table 3.4.2 Post-Baseline Potentially Clinically Significant Vital Sign Values 
                  (Analysis Set: Safety Population)  
Table 3.4.3 Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure Increases and 
Decreases 
                   (Analysis Set: Safety Population)  
Table 3.4.4 Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events 
                  (Analysis Set: Safety Population)  
1.3.4 Electrocardiogram (ECG) 
Table 3.5.1 ECG Parameters by Visit and Time of Assessment 
                     (Analysis Set: Safety Population)  
Table 3.5.2 Post-Baseline Potentially Clinically Significant ECG Values 
                      (Analysis Set: Safety Population ) 
Table 3.5.3 Listing of ECGs Meeting QTcF Interval Prolongation Criteria 
                  (Analysis Set: All Subjects Screened) 
2 DATA LISTINGS 
2.1.1 Subject Disposition and Demographics 
Listing 1.1 Listing of Subject Disposition and Demographic Data 


 
 
 
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                  (Analysis Set: All Subjects Screened)  
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 Screened)  
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)  
Listing 6.1 Compliance and Exposure to Study Treatment 
                  (Analysis Set: Safety Population)  
2.1.6 Adverse Events 
Listing 7.1 Listing of Reported Adverse Events by Subject, SOC, Preferred Term and Onset Day 
                  (Analysis Set: Safety Population)  
Listing 7.2 Listing of Reported Serious Adverse Events by Subject, SOC, Preferred Term and Onset Day 
                  (Analysis Set: All Screened Subjects)  


 
 
 
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2.1.7 Pharmacokinetic Data 
Listing 8.1 Plasma Concentrations of Budesonide, Glycopyrronium, and Formoterol by Visit, Subject ID, 
and Timepoint 
(Analysis Set: Safety Population)  
Listing 8.2 Derived Pharmacokinetic Parameters of Budesonide, Glycopyrronium, and Formoterol by Visit 
and Subject ID 
(Analysis Set: PK Population)  
2.1.8 Laboratory Data 
Listing 9.1 Listing of Laboratory Test Results - Hematology 
                  (Analysis Set: Safety Population)  
Listing 9.2 Listing of Laboratory Test Results - Chemistry 
                  (Analysis Set: Safety Population)  
Listing 9.3 Listing of Laboratory 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) 
                  (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 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 


 
 
 
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                  (Analysis Set: All Subjects Screened)  
Listing 10.5 Listing of Comments 
                  (Analysis Set: All Subjects Screened) 
Listing 10.6 12-Lead Electrocardiogram (ECG) 
                  (Analysis Set: All Subjects Screened)  
APPENDIX 3: SAS 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.