Clinical trial NCT03262012
Conditions: COPD
Sponsor: Pearl Therapeutics, Inc.
Start date: 2016-08-09; Completion date: 2018-06-15
Enrollment: 416 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Randomized, Double-Blind, Parallel Group, 28-Week Chronic Dosing, Multi-Center Long-term Extension Study to Assess the Safety and Efficacy in Japanese Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) compared with Symbicort® Turbohaler®

Detailed description:
This is a multicenter, randomized, double-blind, parallel group, chronic dosing, active-controlled, 28-week, safety extension of Study PT010006 to assess the safety and efficacy of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH as an active control over a 52-week period in Japanese subjects with moderate to very severe COPD who remain symptomatic on maintenance treatment with either an ICS and one or more bronchodilator(s) or two or more maintenance bronchodilators.

Arms: arm 1: Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol, BGF MDI, PT010 arm 2: Glycopyrronium and Formoterol Fumarate Inhalation Aerosol, GFF MDI, PT003 arm 3: Budesonide and Formoterol Fumarate Inhalation Aerosol, BFF MDI, PT009 arm 4: Budesonide and Formoterol Fumarate Inhalation Powder, Symbicort® Turbohaler® Inhalation Powder, Symbicort Turbohaler
Interventions: intervention 1: BGF MDI (PT010) intervention 2: GFF MDI (PT003) intervention 3: BFF MDI (PT009) intervention 4: Symbicort® Turbohaler® Inhalation Powder
Intervention descriptions: intervention 1: Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol, BGF MDI, PT010 intervention 2: Glycopyrronium and Formoterol Fumarate Inhalation Aerosol, GFF MDI, PT003 intervention 3: Budesonide and Formoterol Fumarate Inhalation Aerosol, BFF MDI, PT009 intervention 4: Budesonide and Formoterol Fumarate Inhalation Powder, Symbicort® Turbohaler® Inhalation Powder, Symbicort Turbohaler

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Trial Protocol: PT010007-01 
Study Title: 
A Randomized, Double-Blind, Parallel-Group, 28-Week, Chronic-
Dosing, Multi-Center, Extension Study to Assess the Safety and 
Efficacy of PT010, PT003, and PT009 in Japanese Subjects with 
Moderate to Very Severe Chronic Obstructive Pulmonary Disease 
(COPD) compared with Symbicort® Turbuhaler® as an Active Control 
Study Number: 
PT010007-01 
Study Phase: 
III 
Product Name: 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol, PT010 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol, PT003 
Budesonide and Formoterol Fumarate Inhalation Aerosol, PT009 
Indication: 
COPD 
Investigators: 
Multi-center 
Sponsor: 
Pearl Therapeutics, Inc. 
 
 
 
 
 
Sponsor Contact: 
 
 
 
Version Number 
Date 
Original Protocol: 
Version 1.0 
05 July 2015 
Amended Protocol: 
Version 2.0 
17 March 2017 
 
Confidentiality Statement 
Property of Pearl Therapeutics Inc. 
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of Pearl Therapeutics Inc. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 2 of 123 
SUMMARY OF CHANGES TO ORIGINAL PROTOCOL VERSION 1.0, 
DATED 05 JULY 2015 
The amended study protocol, PT010007-01(Version 2.0), includes the following edits: 
Location(s) and Description of Change 
Rationale 
Global  
Administrative changes to correct and/or 
clarify protocol language 
Administrative changes include edits for: 
• Consistency 
• Grammar 
• Typographical errors 
 
Changed Sponsor Contact on Title and 
Sponsor Signature Page 
Revised to reflect named Clinical Program 
Head 
Synopsis and Section 9.5.1.1 Statistical 
Methods-Efficacy Analysis 
Added baseline eosinophil count as 
continuous covariate. 
Baseline eosinophil count is included as a 
continuous covariate as higher blood 
eosinophils may be predictive of the response 
to ICS. 
Synopsis and Sections 7.3.6.3, 7.3.7, 7.3.15, 
9.4.2, and 9.4.3 
Clarified that there is a single Clinical 
Endpoint Committee with charters evaluating 
cardiovascular and cerebrovascular events, 
cause-specific mortality, and pneumonia. 
Section 4.1 Overall Study Design and Plan, 
Figure-1 
Corrected study schematic to reflect Visit 10a 
as the last visit of PT010006, added a note to 
clarify that Visit 10a and 10b occur on the 
same day, and indicated the 14-day follow-up 
applies for all study treatment arms. 
Section 5.4.1 Allowed Medications to Treat 
a COPD Exacerbation 
Additional details to clarify treatment of 
COPD exacerbations. 
Added details to clarify treatment of COPD 
exacerbations during the treatment period 
including guidance for treatment as deemed 
appropriate by the health care provider. This 
change also provides the guidance that 
subjects should be returned to their pre-
exacerbation regimen as soon as practical. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 3 of 123 
Section 5.4.2 Prohibited COPD 
Medications, Table 5-1 
Moved Roflumilast from footnote “b” to a 
Note and added “(or any PDE4 inhibitor)” 
Revised to include the PDE4 medication class, 
use of other medications, and clarified use of 
theophylline if subjects received in Study 
PT010006.  
Section 5.4.3 Other Prohibited Medications, 
Table 5-3, and footnote “a” 
Revision clarifies that if a subject is 
required to use any of the prohibited 
medications listed in Table 5-4, the subject 
should be discontinued from randomized 
treatment but continued in the study. 
Added exception for Carvedilol to treat 
subjects who may have Class I/II failure 
where use of this medication is appropriate. 
Clarified use of anticonvulsants for seizure 
disorders and allowed anticonvulsants for 
other indications.  
Antipsychotic agents and tricyclic 
antidepressants are allowed if, in the 
opinion of Investigator, there are no safety 
concerns and if the patient was on a stable 
dose during PT010006. 
Allowed systemic anticholinergic if used in 
Study PT010006 and dose remains 
unchanged. 
This section is revised to align with criteria 
used in prior and ongoing studies in subjects 
with COPD in the Pearl COPD development 
program. This will maintain consistency 
across studies and avoid confusion for 
investigators participating in more than 1 Pearl 
COPD study. 
Sections 4.1 and 5.5.2 Dietary Restrictions 
Added caffeine containing medications to 
list. 
Added to have a more comprehensive list of 
caffeine sources. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 4 of 123 
Section5.5 Other Restrictions, Illicit 
Dangerous Drugs and Section 5.5.1 Illicit 
Dangerous Drugs 
Replaced the term ‘Illicit’ with ‘dangerous’ 
in these sections. 
Clarification change based on local preference 
of terminology. 
Section 5.6 Smoking Status: Deleted 
medical marijuana.  
Correction 
Section 5.7 Reasons for Treatment 
Discontinuation or Study Withdrawal 
Revised this section to define reasons for 
study treatment discontinuation that are 
required by the protocol versus Investigator 
discretion and emphasize that treatment 
discontinuation does not also mean study 
withdrawal. 
Revised to discontinue treatment consistently 
across sites based on defined safety 
parameters, and to emphasize continued study 
participation after treatment discontinuation. 
Section 7.1.1 Pulmonary Function Tests 
Deleted single spirometry assessment at 
Visit 14. 
Revised to indicate 2 pre-dose spirometry 
assessments prior to return to appropriate 
COPD medication in order to align with other 
visits in PT010007. 
Section 7.3.1 Performing Adverse Events 
Assessment 
Added language specifying email and fax 
for paper SAE form. 
Contingency wording added in case of an 
unanticipated situation, such as electronic data 
capture system failure. 
Sections 7.3.9.1 thru 7.3.9.5 
Added “Head of the Medical Institution”  
Addition of the Head of the Medical 
Institution as a recipient of SAE notifications 
and associated safety reporting. 
Section 7.3.9.6 Health Authority Safety 
Reports 
Added Pharmaceuticals and Medical 
Devices Agency (PMDA) 
Clarified safety reporting by adding PMDA. 
Section 7.3.11 Pregnancy 
Added Email addresses and fax number for 
reporting using the Paper Pregnancy Report 
Clarification by providing email addresses and 
fax number in protocol. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 5 of 123 
Form. 
Section 7.2.4.2 Clinical Chemistry, Table 7-
1: Corrected timing of serum and urine hCG 
tests 
Correction 
New Section 7.3.12 Paternal Exposure 
Added for consistent evaluation across the 
PT010 studies. 
New Section 7.3.13 and Appendix 7 -Hy’s 
Law 
Added Hy’s Law for continued assessment of 
liver safety from Study PT010006. 
Section 8, Table 8-1, footnote “e”- In-clinic 
dosing time is recorded as time of the 
second puff/inhalation. The in-clinic dosing 
time should be timed to be within 12±2 
hours of the prior evening dosing time. if 
assigned to blinded treatment or 24±2 hours 
of the prior morning dosing time if assigned 
to Symbicort. Record/document the dose 
indicator readings of the used device and 
the replacement device; this applies to all 
the study medications including Symbicort 
TBH. 
Correction/Consistency 
Section 8.7 Vital Status Confirmation at 
Week 52: Deleted “After the fifth attempt, 
the study site will contact the national death 
registries (if available) to confirm date and 
cause of death.” 
Correction. 
Sections 9.3, 9.4, and 9.41: Deleted 
PT010007 Safety Population 
Removed to simplify the number of study 
populations for analysis and to remove any 
redundancy with the Japanese Safety 
Population. 
Section 10.2 Ethical Conduct of the Study 
and Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) 
Approval: Added Japan specific 
requirements 
Further clarified and added references to 
additional ordinances, related laws and 
regulations. 
Section 10.9 Retention of Data: Added the 
Head of the Medical Institution 
Clarified data retention responsibilities and 
timings. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 6 of 123 
responsibilities for data retention. 
Section 10.11 Investigator’s Final Report 
Replaced “Investigator” with “Head of 
Medical Institution” 
Clarified/corrected responsible party. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 7 of 123 
SYNOPSIS 
Sponsor: 
Pearl Therapeutics, Inc. (“Pearl”) 
 
 
 
 
Names of Finished Products: 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol (PT010, 
BGF metered dose inhaler [MDI])  
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol (PT003, GFF MDI)  
Budesonide and Formoterol Fumarate Inhalation Aerosol (PT009, BFF MDI)  
Symbicort® Turbuhaler® (TBH) Inhalation Powder 
Names of Active Ingredients: 
Budesonide, Glycopyrronium, and Formoterol Fumarate 
Glycopyrronium and Formoterol Fumarate 
Budesonide and Formoterol Fumarate 
Study Title: 
A Randomized, Double-Blind, Parallel-Group, 28-Week, Chronic-Dosing, Multi-Center 
Extension Study to Assess the Safety and Efficacy of PT010, PT003, and PT009 in Japanese 
Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) 
compared with Symbicort® Turbuhaler® as an Active Control 
Study Number: PT010007-01 
Study Phase: III 
Primary Objective:  
• The primary objective of this extension study is to evaluate the long-term safety and 
tolerability of BGF MDI, GFF MDI, BFF MDI, and Symbicort Turbuhaler (TBH) in 
Japanese subjects with moderate to very severe COPD 
 
Other Objectives: 
• To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on lung 
function 
• To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on COPD 
exacerbations 
• To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on 
symptoms using the change in rescue medication use as an indirect measure of symptom 
control 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 8 of 123 
Study Design: 
This is a randomized, double-blind, parallel-group, 28-week, chronic-dosing, multi-center, 
active-controlled, safety extension of Study PT010006 to assess the safety of BGF MDI, GFF 
MDI, BFF MDI, and Symbicort TBH twice-daily (BID) as an active control over a 52-week 
period in Japanese subjects with moderate to very severe COPD who completed participation 
in Study PT010006. Efficacy assessments will also be measured. 
All Japanese sites that participated in Study PT010006 will be eligible to contribute subjects 
to this study. It is planned that approximately 324 Japanese subjects with moderate to very 
severe COPD will continue into this study to provide approximately 300 subjects to complete 
the study.  Based on the randomization ratio from the original lead in Study PT010006, this 
study will evaluate approximately 100 completed Japanese subjects in the BGF MDI and 
GFF MDI arms, and approximately 50 completed Japanese subjects in the BFF MDI and 
Symbicort TBH arms.   
Study PT010007 will be initiated as a double-blind study as patients begin to enroll after 
completion of Study PT010006. Once patient participation has completed in Study PT010006 
and that study is unblinded for reporting purposes, investigational sites and study patients 
will remain blinded to treatment assignment. Subjects will remain on the same therapy that 
they were receiving in Study PT010006 so that subjects completing Study PT010007 will 
have been exposed to treatment for 1 year. The entire study period, including Study 
PT010006, is scheduled to take approximately 58 weeks for most subjects. 
Study Population:  
Approximately 324 subjects with moderate to very severe COPD will be enrolled to provide 
approximately 300 subjects to complete the study. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 9 of 123 
Test Product, Dose, and Mode of Administration:  
Investigational materials will be provided by Pearl, as shown below: 
 
Product Name & Dose 
Product Strength 
Dosage Form/ 
Fill Count 
Administration 
Study Medications 
BGF MDI (PT010)  
320/14.4/9.6 µg ex-
actuator 
160/7.2/4.8 µg per 
actuation 
MDI/ 
120 inhalations 
Taken as 2 inhalations 
BID 
GFF MDI (PT003) 
14.4/9.6 µg ex-actuator 
7.2/4.8 µg per actuation 
MDI/ 
120 inhalations 
Taken as 2 inhalations 
BID 
BFF MDI (PT009)  
320/9.6 µg ex-actuator 
160/4.8 µg per actuation 
MDI/ 
120 inhalations 
Taken as 2 inhalations 
BID 
Open-Label Product 
Budesonide and 
formoterol 
fumarate inhalation 
powder (Symbicort 
Turbuhaler) † 
 400/12 µg 
EU Source: Symbicort® 
Turbuhaler® 
200/6 µg per actuation 
Each metered dose 
contains: budesonide 
200 µg per inhalation 
and formoterol fumarate 
dihydrate 6 µg which 
corresponds to a 
delivered dose of 160 µg 
budesonide and 4.5 µg 
formoterol fumarate 
dihydrate per inhalation 
DPI/ 
60 inhalations 
Taken as 
2 inhalations BID 
Supplies are open-label 
Albuterol Sulfatea 
inhalation aerosol 90 μg 
ex-actuator 
US source: Ventolin® 
HFA 
HFA inhalation aerosol 
will be the US-supplied 
product.”  Albuterol 
sulfate inhalation 
aerosol.  Each inhalation 
contains 108 μg 
corresponding to 90 µg 
albuterol base from the 
mouthpiece 
MDI/ 
60 or 200 actuations 
Taken as directed 
Supplies are open-label 
BGF MDI = Budesonide, Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; GFF MDI = 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; BFF MDI = Budesonide and Formoterol 
Fumarate Inhalation Aerosol; MDI = metered-dose inhaler; DPI = dry powder inhaler; BID = twice daily; 
HFA= hydrofluouroalkane; µg = microgram. 
† Active control 
a Rescue medication. Albuterol sulfate is also known as salbutamol sulfate in some countries. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 10 of 123 
Duration of Treatment:  
In this long-term extension study, each subject will receive study treatment for 28 weeks.  
The entire study participation, including participation in Study PT010006, from Screening to 
Follow-up, is scheduled to take approximately 58 weeks for each individual subject. 
The data from this 28-week study will be combined with the 24 weeks of data obtained from 
the lead-in Study PT010006 to provide safety and efficacy data over 52 weeks of treatment. 
The baseline for all subjects will remain the original baseline (Visit 4 Randomization) of 
Study PT010006. 
Safety Endpoints: 
Overall safety and tolerability will be evaluated over 52 weeks using:  
• Adverse events (AEs) 
• 12-lead electrocardiograms (ECG): Change from baseline in heart rate (HR), PR interval, 
QRS axis, QRS interval, QT interval, and QTcF (Fridericia Corrected QT) interval 
• Clinical laboratory testing 
• Vital sign measurements 
 
Efficacy Endpoints (over 52 weeks unless otherwise stated):  
• Change from baseline in morning pre-dose trough FEV1 over 52 weeks (Weeks 4 to 52) 
and at each post-randomization visit 
• Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use. 
• Percentage of days with no rescue Ventolin HFA use 
• Rate of moderate or severe COPD exacerbations  
• Rate of COPD exacerbations of any severity 
• Change from baseline in morning pre-dose trough for forced vital capacity (FVC), peak 
expiratory flow rate (PEFR), and forced expiratory flow 25-75% (FEF25-75) over 52 
weeks (Weeks 4 to 52) and at each post randomization visit 
• Change from baseline in: the EXACT total score, the 11-item EXACT Respiratory 
Symptoms (E-RS) Total Score (RS-Total Score), as well as 3 subscale scores symptom 
(RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 52 weeks 
and over each 4-week interval of the 52-week Treatment Period  
Statistical Methods:  
Safety Analyses (Primary): 
The incidence (number and percentage) of subjects experiencing each adverse event will be 
tabulated for each treatment group using the coded MedDRA preferred term, and the 
MedDRA System Organ Class. Tabulations will be created by severity, by relationship to 
study drug, and AEs leading to withdrawal. Vital signs, clinical laboratory findings, and ECG 
results will all be tabulated by treatment group. No inferential analyses will be performed. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 11 of 123 
 
Efficacy Analyses:  
The change from baseline in pre-dose trough FEV1 over 52 weeks will be analyzed using a 
linear model with repeated measures. The model will include baseline trough FEV1, baseline 
eosinophil count, and percent reversibility to Ventolin HFA as continuous covariates and 
visit, treatment, treatment by visit, and ICS use at Screening as categorical covariates.  An 
unstructured covariance matrix will be used to model additional autocorrelation within 
subject. If this model fails to converge, a first order autoregressive [AR (1)] structure will be 
used instead; for this model subject will be considered a random effect.  Two-sided p-values 
and point estimates with two-sided 95% confidence intervals will be produced for each 
treatment difference.   
Sample Size:  
The sample size of approximately 324 subjects (108 per arm in the BGF MDI and GFF MDI 
groups and 54 per arm in the BFF MDI and Symbicort TBH groups) includes all Japanese 
subjects who were enrolled in Study PT010006.  No statistical power calculations were 
performed to arrive at this number. The sample size was selected to provide approximately 
100 completing subjects in the BGF MDI and GFF MDI arms. 
Data Monitoring and Clinical Endpoint Committees: 
Data Monitoring Committee:  
An external Data Monitoring Committee (DMC) that was initiated in Study PT010006 will 
continue to provide systematic and unbiased assessments of safety. Members of the DMC 
will review data at predetermined intervals. If significant safety issues arise in between 
scheduled meetings, ad hoc meetings will be scheduled to review the data.  Based on the 
safety implications of the data, the DMC may recommend modification or termination of the 
study. 
Clinical Endpoint Committee: 
An independent, external clinical endpoint committee (CEC) that was initiated in Study 
PT010006 will continue to adjudicate for this study. The committee will consist of experts 
who will provide a centralized review functioning independently of Pearl. Three Clinical 
Endpoint Adjudication Charters will outline the clinical endpoints for adjudication. 
• Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter 
• Cause-Specific Mortality Clinical Endpoint Adjudication Charter 
• Pneumonia Clinical Endpoint Adjudication Charter 
Date of Original Approved Protocol: 05 July 2015 
Date of Protocol Amendment 1.0 (Version 2.0): 17 March 2017 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 12 of 123 
TABLE OF CONTENTS 
SUMMARY OF CHANGES TO ORIGINAL PROTOCOL VERSION 1.0, DATED 05 
JULY 2015 .........................................................................................................................2 
SYNOPSIS .................................................................................................................................7 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF IN-TEXT TABLES ..................................................................................................16 
LIST OF IN-TEXT FIGURES.................................................................................................16 
LIST OF APPENDICES ..........................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
TRADEMARK INFORMATION ...........................................................................................21 
1 
INTRODUCTION AND STUDY RATIONALE ...........................................................22 
1.1 
Study Rationale ......................................................................................................23 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Primary Objective ..................................................................................................24 
2.2 
Other Objectives ....................................................................................................24 
3 
STUDY ENDPOINTS .....................................................................................................24 
3.1 
Safety Endpoints ....................................................................................................24 
3.2 
Efficacy Endpoints (over 52 weeks unless otherwise stated): ...............................24 
4 
INVESTIGATIONAL PLAN ..........................................................................................25 
4.1 
Overall Study Design and Plan ..............................................................................25 
5 
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA .................29 
5.1 
Inclusion Criteria ...................................................................................................29 
5.2 
Exclusion Criteria ..................................................................................................29 
5.3 
Subject Identification .............................................................................................29 
5.4 
Prior, Concomitant, and Prohibited Medications ...................................................29 
5.4.1 
Allowed Concomitant Medications to Treat a COPD Exacerbation ...........29 
5.4.2 
Prohibited COPD Medications ....................................................................30 
5.4.3 
Other Prohibited Medications ......................................................................31 
5.5 
Other Restrictions, Dangerous Drugs or Drugs of Abuse......................................33 
5.5.1 
Dangerous Drugs .........................................................................................33 
5.5.2 
Dietary Restrictions .....................................................................................33 
5.6 
Smoking Status ......................................................................................................33 
5.7 
Reasons for Treatment Discontinuation or Study Withdrawal ..............................33 
5.7.1 
Reasons for Treatment Discontinuation.......................................................33 
5.7.2 
Reasons for Study Withdrawal ....................................................................34 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES ....................................................................................................35 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 13 of 123 
6.1 
Subject Information ...............................................................................................35 
6.2 
Product Descriptions ..............................................................................................35 
6.3 
Primary Packaging and Labeling Information .......................................................37 
6.4 
Secondary Packaging and Labeling Information (Box) .........................................37 
6.5 
Emergency Unblinding of treatment assignment ...................................................38 
6.6 
Storage Requirements ............................................................................................38 
6.7 
Instructions for Preparation of Treatments for Administration and Dispensing....39 
6.7.1 
BGF MDI, GFF MDI, and BFF MDI ..........................................................39 
6.7.2 
Symbicort® Turbuhaler® ..............................................................................39 
6.7.3 
Ventolin HFA® ............................................................................................39 
6.8 
Drug Accountability/Return of Clinical Supplies ..................................................40 
7 
STUDY PROCEDURES .................................................................................................41 
7.1 
Efficacy Assessments.............................................................................................41 
7.1.1 
Pulmonary Function Tests ...........................................................................41 
7.1.2 
Subject Electronic Diary (eDiary) Data Collection .....................................42 
7.1.2.1 
Rescue Medication Usage ..................................................................42 
7.1.2.2 
Medication Compliance .....................................................................42 
7.1.2.3 
Recording of Dose Indicator Reading................................................42 
7.1.2.4 
Major/minor Symptom Worsening Assessment and Alert System ...43 
7.1.3 
COPD Exacerbations ...................................................................................43 
7.1.3.1 
Severity of COPD Exacerbation ........................................................44 
7.1.3.2 
Duration of COPD Exacerbation .......................................................44 
7.1.3.3 
Approach for Capturing COPD Exacerbations ..................................45 
7.1.3.4 
Other Information ..............................................................................45 
7.1.3.5 
Investigator-Judged COPD Exacerbations ........................................45 
7.1.4 
Subject Questionnaire ..................................................................................45 
7.2 
Safety Assessments ................................................................................................46 
7.2.1 
Medical/Surgical History and Physical Examination ..................................46 
7.2.2 
Vital Sign Measurements .............................................................................46 
7.2.3 
12-Lead Electrocardiogram .........................................................................46 
7.2.4 
Clinical Laboratory Tests .............................................................................47 
7.2.4.1 
Hematology ........................................................................................48 
7.2.4.2 
Clinical Chemistry .............................................................................48 
7.2.4.3 
Urinalysis ...........................................................................................50 
7.2.4.4 
Pregnancy Test ...................................................................................50 
7.3 
Adverse Events ......................................................................................................50 
7.3.1 
Performing Adverse Events Assessments ....................................................50 
7.3.2 
Adverse Event Definitions ...........................................................................50 
7.3.3 
Severity ........................................................................................................51 
7.3.4 
Relationship .................................................................................................52 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 14 of 123 
7.3.5 
Chronic Obstructive Pulmonary Disease Exacerbations .............................52 
7.3.6 
Adverse Events of Special Interest ..............................................................52 
7.3.6.1 
LABA and LAMA Effects .................................................................53 
7.3.6.2 
Local Steroid Effects..........................................................................53 
7.3.6.3 
Pneumonia..........................................................................................53 
7.3.6.4 
Paradoxical Bronchospasm ................................................................54 
7.3.7 
Major Adverse Cardiovascular Events (MACE) .........................................54 
7.3.8 
Clinical Laboratory Adverse Events ............................................................54 
7.3.9 
Serious Adverse Events ...............................................................................54 
7.3.9.1 
Reporting Serious Adverse Events ....................................................55 
7.3.9.2 
Supplemental Investigations of SAEs ................................................56 
7.3.9.3 
Post-Study Follow-Up of Adverse Events .........................................56 
7.3.9.4 
Notification of Post-Study Serious Adverse Events ..........................56 
7.3.9.5 
Investigational Research Board/Independent Ethics Committee 
Notification of Serious Adverse Events .............................................56 
7.3.9.6 
Health Authority Safety Reports ........................................................57 
7.3.10 
Overdose ......................................................................................................57 
7.3.11 
Pregnancy .....................................................................................................57 
7.3.12 
Paternal Exposure ........................................................................................58 
7.3.13 
Hy's Law ......................................................................................................58 
7.3.14 
Use of Steroids during the Trial ...................................................................58 
7.3.15 
Clinical Endpoint Committee ......................................................................58 
7.3.15.1 
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint 
Adjudication Charter ..........................................................................59 
7.3.15.2 
Cause-Specific Mortality Clinical Endpoint Adjudication Charter ...59 
7.3.15.3 
Pneumonia Clinical Endpoint Adjudication Charter .........................59 
7.3.16 
Data Monitoring Committee ........................................................................59 
7.4 
Termination of the Study .......................................................................................59 
8 
STUDY ACTIVITIES .....................................................................................................60 
8.1 
Visit 10b (Week 24 Safety Extension Entry Visit) ................................................63 
8.2 
Visit 11 (Week 28) and Visit 13 (Week 44) ..........................................................64 
8.3 
Visit 12 (Week 36) .................................................................................................65 
8.4 
Visit 14 (Week 52) Final Visit ...............................................................................66 
8.5 
Unscheduled Visit/Premature Discontinuation Visit .............................................67 
8.6 
Follow-Up Telephone Call ....................................................................................68 
8.7 
Vital Status Confirmation at Week 52 ...................................................................68 
8.8 
Completion of the Study ........................................................................................68 
9 
PLANNED STATISTICAL METHODS ........................................................................70 
9.1 
Introduction ............................................................................................................70 
9.2 
Protocol Variables ..................................................................................................70 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 15 of 123 
9.2.1 
Safety Endpoints ..........................................................................................70 
9.2.2 
Efficacy Endpoints (over Week 52 unless otherwise stated) .......................71 
9.3 
Study Populations ..................................................................................................71 
9.4 
Safety Analyses ......................................................................................................71 
9.4.1 
Adverse Events ............................................................................................72 
9.4.2 
Cardio- and Cerebrovascular Events Determined by Adjudication 
Committee ....................................................................................................72 
9.4.3 
Pneumonia Events Determined by Adjudication Committee ......................72 
9.4.4 
Clinical Laboratory Measurements ..............................................................72 
9.4.5 
Vital Signs ....................................................................................................73 
9.4.6 
Electrocardiograms ......................................................................................73 
9.4.7 
Exposure ......................................................................................................73 
9.5 
Efficacy Analyses ..................................................................................................73 
9.5.1 
Efficacy Analysis .........................................................................................73 
9.5.1.1 
Change from Baseline in Morning Pre-dose Trough FEV1 ...............73 
9.5.1.2 
Rescue Ventolin HFA Use .................................................................74 
9.5.1.3 
Percentage of Days with No Rescue Ventolin HFA Use over the 
Treatment Period ................................................................................74 
9.5.1.4 
Chronic Obstructive Pulmonary Disease Exacerbations ...................74 
9.5.1.5 
Other Spirometry Analyses ................................................................75 
9.5.1.6 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) .........75 
9.5.2 
Type I Error Control ....................................................................................75 
9.6 
Randomization .......................................................................................................76 
9.7 
Experimental Design ..............................................................................................76 
9.8 
Sample Size Consideration ....................................................................................76 
9.9 
Data Validation and Transformation .....................................................................76 
9.10 
Analysis Plan .........................................................................................................76 
9.11 
Handling of Missing Data ......................................................................................76 
9.12 
Statistical Software ................................................................................................76 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................77 
10.1 
Regulatory Authority Approval .............................................................................77 
10.2 
Ethical Conduct of the Study and Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) Approval ....................................................77 
10.3 
Subject Information and Consent...........................................................................78 
10.4 
Laboratory Accreditation .......................................................................................78 
10.5 
Confidentiality .......................................................................................................78 
10.5.1 
Confidentiality of Data ................................................................................78 
10.5.2 
Confidentiality of Subject/Patient Records ..................................................78 
10.6 
Quality Control and Assurance ..............................................................................79 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 16 of 123 
10.7 
Data Management ..................................................................................................79 
10.8 
Study Monitoring ...................................................................................................79 
10.9 
Retention of Data ...................................................................................................80 
10.10 Financial Disclosure...............................................................................................80 
10.11 Investigator's Final Report .....................................................................................81 
10.12 Publication Policy ..................................................................................................81 
11 REFERENCE LIST .........................................................................................................83 
12 APPENDICES .................................................................................................................86 
 
LIST OF IN-TEXT TABLES 
Table 5-1 
Prohibited COPD Medications ...............................................................30 
Table 5-2 
Other Prohibited Respiratory/Nasal Medications: .................................31 
Table 5-3  
Non-COPD Medications Allowed Under Certain Conditions ...............31 
Table 5-4 
Prohibited Medications ..........................................................................32 
Table 6-1 
Product, Dose, and Mode of Administration: ........................................36 
Table 6-2 
Description of Boxes ..............................................................................37 
Table 7-1.  
Clinical Laboratory Tests .......................................................................49 
Table 8-1 
Schedule of Events .................................................................................61 
Table A1-1 
Recommended Minimal Scale Factors for Time, Volume and Flow 
on Graphical Output .....................................................................................................88 
Table A1-2 
Summary of Equipment Quality Control ...............................................89 
Table A1-3 
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers ..................................................................................................91 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..........................................................................................28 
Figure A2-1 
Example of a Usable Spirogram ............................................................93 
 
LIST OF APPENDICES 
Appendix 1 
Spirometry Performance Recommendations ..........................................87 
Appendix 2 
Spirometry Assessment Criteria .............................................................93 
Appendix 3 
Subject Instructions for Use of BGF MDI, GFF MDI, and BFF MDI ..95 
Appendix 4 
Instructions for Use of Symbicort Turbuhaler® Inhalation Powder 
Device 
 ..............................................................................................................104 
Appendix 5 
Instructions for Use of Ventolin HFA Inhalation Aerosol Device ......106 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 17 of 123 
Appendix 6 
Exacerbations of Chronic Obstructive Pulmonary Disease Tool 
(EXACT) - Patient-Reported Outcomes ....................................................................113 
Appendix 7 
Hy’s Law ..............................................................................................118 
Appendix 8 
Dose Indicator Reading ........................................................................121 
Appendix 9 
Sponsor Signatory ................................................................................122 
Appendix 10 
Investigator’s Agreement and Signature Page .....................................123 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 18 of 123 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
Adverse Event of Special Interest 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
AP 
alkaline phosphatase 
AR (1) 
first order autoregressive 
AST 
aspartate aminotransferase (SGOT) 
ATS 
American Thoracic Society 
BD 
budesonide 
BDI 
baseline dyspnea index 
BFF 
budesonide and formoterol fumarate 
BGF 
budesonide, glycopyrronium, and formoterol fumarate 
BID 
bis in die, twice daily 
BMP 
basic metabolic panel 
BP 
blood pressure 
BPM 
beats per minute 
BUN 
blood urea nitrogen 
CEC 
Clinical endpoint committee 
CCV 
cardio- and cerebro-vascular 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
chronic obstructive pulmonary disease 
CRF 
case report form 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 19 of 123 
DPI 
dry powder inhalation 
ECG 
electrocardiogram 
ex actuator 
dose delivered from the actuator (ie., mouthpiece) of the metered dose 
inhaler 
EXACT 
Exacerbations of Chronic Obstructive Pulmonary Disease Tool 
FDA 
Food and Drug Administration 
FEF 
forced expiratory flow 
FEV1 
forced expiratory volume in 1 second 
FF 
formoterol fumarate 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GFF 
glycopyrronium and formoterol fumarate 
GGT 
gamma glutamyl transferase 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
hCG 
human chorionic gonadotropin 
HFA 
hydrofluoroalkane 
HR 
Heart Rate 
HL 
Hy’s Law 
ICF 
Informed Consent Form 
ICS 
Inhaled corticosteroid 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
JRS 
Japan Respiratory Society 
LABA 
long acting β2 agonist 
LAMA 
long acting antimuscarinic agents 
mITT 
modified intent-to-treat 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 20 of 123 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
mL 
milliliter 
PEFR 
peak expiratory flow rate 
PFT 
Pulmonary function test 
PHL 
Potential Hy’s Law 
PIN 
Personal identification number 
QID 
four times daily 
SABA 
short acting β2 agonist 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
standard error  
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
TBH 
Turbuhaler 
TBL 
Total bilirubin 
µg 
micrograms 
ULN 
upper limit of normal 
US 
United States 
 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 21 of 123 
TRADEMARK INFORMATION  
Trademarks Not Owned By Pearl Therapeutics, Inc. 
KoKo Spirometer 
Ventolin 
Oxis 
Turbuhaler 
Spiriva 
 
Symbicort 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 22 of 123 
1 
INTRODUCTION AND STUDY RATIONALE 
Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable 
disease characterized by persistent airflow limitation that is usually progressive and 
associated with an enhanced chronic inflammatory response in the airways and the lung to 
noxious particles or gases. 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 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, 2014); Japanese 
Respiratory Society (JRS, 2013)]. 
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, quality of life, and reducing exacerbations in subjects with 
moderate to very severe COPD [GOLD, 2014]. 
Pearl Therapeutics, Inc. (hereinafter referred to as Pearl) is developing the fixed-dose ICS/ 
long-acting anti-muscarinic agent (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 (PT003) 
hereinafter referred to as glycopyrronium and formoterol fumarate (GFF) MDI is being 
developed as a BID maintenance bronchodilator treatment in patients with COPD. 
Budesonide is a well-established corticosteroid approved worldwide in monotherapy and 
combination therapies for 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® is approved for use in patients with asthma 
and COPD.  
Glycopyrronium is a LAMA which exerts its bronchodilatory effect via muscarinic receptors 
located on smooth muscle cells within the trachea and bronchi. Glycopyrronium is approved 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 23 of 123 
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 
(e.g., Symbicort® MDI, Symbicort® Turbuhaler® (TBH [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. 
In clinical studies, Symbicort MDI 320/9 µg administered BID demonstrated significant 
improvements in lung function compared with Budesonide MDI 320 µg BID or formoterol 
fumarate (Oxis® Turbuhaler) 9 µg BID in patients with COPD. In the clinical studies, 
improvements in secondary endpoints of morning and evening peak expiratory flow and 
reduction in rescue medication use were supportive of the efficacy of Symbicort MDI 
320/9 µg [Rennard, 2009; Tashkin, 2008]. 
1.1 
Study Rationale 
This is the 28-week extension of the Study PT010006 with the purpose to assess the long-
term safety and tolerability of BGF MDI, GFF MDI, BFF MDI, and Symbicort Turbuhaler 
(TBH) in Japanese subjects with moderate to very severe COPD. 
This study is intended to provide the long-term 1-year safety data to support registration of 
these investigational products in Japan. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 24 of 123 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
• The primary objective of this extension study is to evaluate the long-term safety and 
tolerability of BGF MDI, GFF MDI, BFF MDI, and Symbicort Turbuhaler (TBH) in 
Japanese subjects with moderate to very severe COPD 
 
2.2 
Other Objectives  
• To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on lung 
function 
• To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on COPD 
exacerbations 
• To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on 
symptoms using the change in rescue medication use as an indirect measure of symptom 
control 
 
3 
STUDY ENDPOINTS 
The data from this 28-week study will be combined with the 24 weeks of data obtained from 
the lead-in Study PT010006 to provide safety and efficacy data over 52 weeks of treatment.  
Baseline for all subjects will remain the original baseline (Visit 4 Randomization) from 
Study PT010006. 
3.1 
Safety Endpoints 
Overall safety and tolerability will be evaluated over 52 weeks using: 
• Adverse Events (AEs) 
• 12-Lead ECG: Change from baseline in heart rate, PR interval, QRS axis, QRS interval, 
QT interval, and QTcF (Fridericia Corrected QT) interval 
• Clinical laboratory testing 
• Vital sign measurements 
 
3.2 
Efficacy Endpoints (over 52 weeks unless otherwise stated): 
• Change from baseline in morning pre-dose trough FEV1 over 52 weeks (Weeks 4 to 52) 
and at each post-randomization visit 
• Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 25 of 123 
• Percentage of days with no rescue Ventolin HFA use 
• Rate of moderate or severe COPD exacerbations 
• Rate of COPD exacerbations of any severity 
• Change from baseline in morning pre-dose trough for forced vital capacity (FVC), peak 
expiratory flow rate (PEFR), and forced expiratory flow 25-75% (FEF25-75) over 52 
weeks (Weeks 4 to 52) and at each post randomization visit 
• Change from baseline in: the EXACT total score, the 11-item EXACT Respiratory 
Symptoms (E-RS) Total Score (RS-Total Score), as well as 3 subscale scores symptom 
(RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 52 weeks 
and over each 4-week interval of the 52-week Treatment Period 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a randomized, double-blind, parallel-group, 28-week, chronic-dosing, multi-center, 
active-controlled, safety extension of Study PT010006 to assess the safety of BGF MDI, GFF 
MDI, BFF MDI, and Symbicort TBH (BID) as an active control over a 52-week period in 
Japanese subjects with moderate to very severe COPD who completed participation in Study 
PT010006. 
All Japanese sites that participated in Study PT010006 will be eligible to contribute subjects 
to this study. It is planned that approximately 324 Japanese subjects with moderate to very 
severe COPD will continue into this study to provide approximately 300 subjects to complete 
the study. This study will evaluate approximately 100 completed Japanese subjects in the 
BGF MDI and GFF MDI arms, and approximately 50 completed Japanese subjects in the 
BFF MDI and Symbicort TBH arms.   
Study PT010007 will be initiated as a double-blind study as patients begin to enroll after 
completion of Study PT010006. Once patient participation has completed in Study PT010006 
and that study is unblinded for reporting purposes, investigational sites and study patients 
will remain blinded to treatment assignment. 
There are 10 scheduled visits in the lead-in Study PT010006. The tenth visit comprises the 
last visit of the lead-in Study PT010006 and the first visit of the PT010007 extension study.  
In order to differentiate, assessments conducted at the completion of the lead-in study (Study 
PT010006) will be captured in Visit 10a and the initial assessment conducted in the extension 
study (Study PT010007) will be captured in Visit 10b. Visit 10b will begin immediately 
following completion of Visit 10a procedures. 
At Visit 10b, all subjects who are eligible for participation in and agree to participate in 
Study PT010007 will sign an informed consent form prior to the conduct of any study 
assessments specific to Study PT010007. Subjects will be reminded to not use certain 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 26 of 123 
prohibited COPD medications and to maintain their maintenance COPD therapy as adjusted 
for participation in Study PT010006. 
Subjects who meet all entry criteria will undergo Visit 10b procedures will be maintained on 
the same treatment assignment from Study PT010006. Subjects will then be discharged from 
the clinic and will continue to administer study medication for 4 weeks at home until Visit 
11. 
Following enrollment (Visit 10b) into this safety extension study, subjects will be examined 
at Visit 11 (Week 28), Visit 12 (Week 36), Visit 13 (Week 44), and Visit 14 (Week 52). In 
total each completed subject will attend 5 scheduled visits in this study. For assessments at 
each visit refer to the schedule of events in Table 8-1.  
Subjects will be required to take their study medication twice a day and will inhale 2 puffs in 
the morning between 06:00 and 10:00 AM (Breakfast time) and in the evening between 
06:00 and 10:00 PM (Dinner time). 
Subjects who complete (Visit 14) of this safety extension study will be scheduled for a post-
study follow-up telephone call at least 14 days from Visit 14. 
All visits will be scheduled relative to Visit 4 (Treatment Day 1, Randomization) of Study 
PT010006. Thus Visits 11, 12, 13, and 14, will be scheduled 28, 36, 44, and 52 weeks ± 7 
days of Visit 4 of Study PT010006 respectively. Sites should make every effort to maintain 
subjects within the scheduled visit window (particular attention should be made to schedule 
the final visit as close to 52 weeks as possible). If a visit falls outside the expected visit 
window the subsequent visit should still be scheduled as planned relative to Visit 4. 
General Considerations for Treatment Visits 10b through Visit 14: 
• At the start of each study visit, prior to any study procedures being performed, site 
personnel must confirm the subject withheld all COPD medications, including study 
medication, rescue Ventolin HFA, and maintenance medications (ICS, theophylline or 
PDE4s) for at least 6 hours, by confirming the last time of dosing for all COPD 
medication(s). Note: Subjects who inadvertently took COPD medication(s) within 6 
hours of the start of study procedures must be rescheduled as soon as is practical but 
within the specified visit window. In addition, before the in-clinic dose is administered, 
the site must confirm the subject met all other protocol specified requirements (e.g. 
completion of Visit 10a) 
• Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods, 
beverages, or medications for at least 6 hours prior to each study visit and for the duration 
of each study visit. Examples of such products include coffee, tea, chocolate, and cola. 
Decaffeinated beverages are acceptable 
• Subjects will be required to refrain from smoking (nicotine gums or patches are allowed) 
for at least 4 hours prior to each study visit and throughout the duration of each study 
visit 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 27 of 123 
• In order to minimize diurnal variance, sites should make every effort to assess subjects at 
the same time throughout the study and to discuss the importance of dosing in a timely 
manner every 12 hours 
• Subjects will be required to return to the clinic at approximately the same time as Visit 4 
of the lead-in study (Study PT010006) for all treatment visits (± 2 hours) but not to 
exceed 10:00 AM and will be required to remain at the clinic until completion of all 
protocol-defined assessments 
• Sites should make every effort to ensure that the in-clinic dosing time is before 10:00 AM 
and within 12±2 hours of the prior at home evening dosing time 
• The in-clinic dosing time will be recorded as the time of administration of the second 
puff. 
• To ensure standardization of dosing times, it is recommended that sites encourage 
subjects to maintain a dosing schedule consistent with their in-clinic dosing time and that 
sites call the subject on the day before a scheduled visit to remind the subject of the 
following: 
- 
To take their last dose the evening before the scheduled visit; 
- 
To bring their study medications and eDiary with them to the clinic and to withhold 
all COPD medications (including ICS and phosphodiesterase inhibitors) for at least 6 
hours prior to pulmonary function tests (PFTs); 
- 
Refrain from ingesting xanthine and/or xanthine analogue (caffeine)-containing 
foods, beverages, or medications for at least 6 hours prior to each study visit and for 
the duration of each study visit. Examples of such products include coffee, tea, 
chocolate, and cola. Decaffeinated beverages are acceptable; 
- 
Refrain from smoking for at least 4 hours prior to the study visit and throughout the 
duration of each study visit; 
• Site personnel will instruct subjects not to take any COPD medications, without site 
personnel permission, during a visit until all study procedures have been completed, and 
the subject is discharged. Site personnel should take every precaution to prevent subject 
use of COPD medications during test day. Site personnel may request the subject to 
surrender all COPD medications prior to the start of the visit before performing any study 
procedures and return the COPD medications to the subject at the end of the visit when 
all study procedures are completed. Subjects will be asked to abstain wherever possible 
from using rescue Ventolin HFA during study visits. If a subject is experiencing severe 
symptoms and requires Ventolin HFA for relief of COPD symptoms at any time during a 
test day, site personnel must note the time and justification of use in the subject’s chart 
and all subsequent spirometry assessments should be stopped. However, safety 
assessments should be continued at the discretion of the Investigator. 
 
 
 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 29 of 123 
5 
STUDY POPULATION SELECTION AND WITHDRAWAL 
CRITERIA 
5.1 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Give their signed written informed consent to participate. 
2. Completion of the treatment phase of the lead-in Study PT010006. 
3. Compliance with Study PT010006 study procedures and study drug dosing. 
4. No medical contraindication as judged by the principle investigator. 
 
5.2 
Exclusion Criteria 
1. Requiring and currently being administered contraindicated medications refer to Sections 
5.4.2and 5.4.3. 
Note: Participation in observational studies is not exclusionary. 
2. Discontinuation of treatment in Study PT010006. 
 
5.3 
Subject Identification 
All subjects who participate in this study will maintain the unique screening identification 
number and unique subject randomization number assigned to them for participation in Study 
PT010006. 
5.4 
Prior, Concomitant, and Prohibited Medications 
Any additions, deletions, or changes in the dose of medications while in the study should be 
entered on the CRF.  Any current ongoing medications, including OTC drugs and herbal 
supplements, will be allowed provided they are not prohibited by the protocol (refer to 
Sections 5.4.2 and 5.4.3) and are approved by the investigator.  Subjects should also be 
instructed to contact the investigator if they develop any illnesses.  
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications CRF page with indication, total daily dose, and dates of drug administration. 
5.4.1 
Allowed Concomitant Medications to Treat a COPD Exacerbation 
Medications to treat an exacerbation should not be used for more than 14 days. Recent data 
have suggested that treatment with systemic steroids for shorter periods of time results in 
similar outcomes with less systemic steroid exposure. Therefore, it is recommended that 
subjects are treated with a 5 day course of steroids (Leuppi, 2013) and no longer than 14 
days. During a COPD exacerbation, it is important for subjects to be treated as deemed 
appropriate by the treating health care provider. However, subjects should return to their pre-
exacerbation medication regimen as soon as practical. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 30 of 123 
In the instance a subject is hospitalized for a severe COPD exacerbation and study drug is 
interrupted to allow COPD medications to be prescribed, the subject may be able to restart 
study drug upon stopping the COPD medications. If a subject is not able to discontinue 
prescribed COPD medications during the exacerbation treatment (Table 5-1) within 14 days, 
then the subject must be permanently discontinued from the study drug and encouraged to 
complete the remaining study visits. 
5.4.2 
Prohibited COPD Medications 
The following medications used for the treatment of COPD are not permitted during this 
study.  These medications must have been discontinued during the Screening Period of Study 
PT010006 and are also not permitted during this extension study, refer to Table 5-1. 
Table 5-1 
Prohibited COPD Medications 
Class of Medication 
LAMAs 
Short acting muscarinic antagonists (SAMA)   
LABAs (inhaled) 
Fixed combinations of LABA/LAMA 
Fixed combinations of LABA/ICS 
Fixed combinations of SABAs and SAMAs 
SABAsa 
Oral β-agonists 
Theophylline (total daily dose >400 mg/day)b 
Abbreviations:  COPD=chronic obstructive pulmonary disease; HFA=hydrofluoroalkane; ICS=inhaled 
corticosteroid; LABA=long acting β2 agonist; LAMA=long acting muscarinic antagonist  
SABA=short-acting β2 agonist; SAMA=short-acting muscarinic antagonist 
a Other than sponsor-provided open-label Ventolin HFA 
b Theophylline is allowed if the total daily dose is ≤400 mg\ and the subject was receiving theophylline in 
Study PT010006. 
 
Notes:  
• During the Treatment Period (Visit 10b to Visit 14), subjects may be treated with 
systemic corticosteroids, if required as described in Section 5.4.1. 
• Subjects who are steroid dependent and maintained on an equivalent of ≤5 mg oral 
prednisone per day or ≤10 mg oral prednisone every other day are permitted to enroll in 
the study provided they have been on a stable dose of therapy during participation in 
Study PT010006 
• Roflumilast (or any PDE4 inhibitor) is allowed provided the subject has been on stable 
dose of therapy during participation in Study PT010006. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 31 of 123 
 
The following respiratory medications are not permitted during this study (Table 5-2). 
Table 5-2 
Other Prohibited Respiratory/Nasal Medications: 
Class of Medication 
Leukotriene antagonists (e.g., zafirlukast, montelukast, and zilueton) 
Cromoglycate or other mast cell inhibitors (e.g., Intal and Tilade) 
Nedocromil 
Ketotifen * 
*Ketotifen eye drops are allowed 
 
5.4.3 
Other Prohibited Medications 
Table 5-3 lists certain non-COPD medications that can be used under the stated conditions 
during this study.  
Table 5-3  
Non-COPD Medications Allowed Under Certain Conditions 
Medications 
Condition 
Selective serotonin reuptake inhibitors 
(SSRIs), serotonin-norepinephrine reuptake 
inhibitors (SNRIs), and noradrenergic and 
specific serotonergic antidepressants 
(NaSSAs) 
Subject was receiving a stable dose in Study 
PT010006 
Intranasal corticosteroids, intranasal 
antihistamines, intranasal anticholinergics, or 
any combination thereof 
Subject was receiving a stable dose Study 
PT010006 
Note: Use of cutaneous topical medications, including cutaneous topical corticosteroids, is 
permitted provided these medications are not applied to more than 20% of the subject’s body 
surface area. 
Subjects requiring medications presented in Table 5-4 are prohibited from participating in 
this study as specified below.  These medications are prohibited throughout the course of the 
study, and should a subject require use of any of the listed medications, the subject should be 
discontinued from randomized treatment and resume the appropriate COPD maintenance 
therapy and be encouraged to complete the remaining study visits.   
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 32 of 123 
Table 5-4 
Prohibited Medications 
Prohibited Medications 
Any drug with potential to significantly prolong the QT interval 
Other investigational drugs 
Non-selective beta-blocking agentsa  
Cardiac antiarrhythmics Class Ia, III 
Anticonvulsants for seizure disorderb 
Anticonvulsants for other indicationsc 
Tricyclic antidepressantsd 
Monoamine oxidase inhibitors 
Anti-tumor necrosis factor α (TNF α) antibodies (e.g.infliximab and any other members of 
this class of drugs) 
Monoclonal antibodiese 
Antipsychotic drugsd 
Systemic calcineurin inhibitors, systemic antifungal agents, protease inhibitors and 
cimetidine 
Systemic anticholinergicsf 
Illicit drugs or drugs of abuse 
Chinese complementary and alternative bronchodilatory medicines (CAM), ie, herbal therapies 
(eg, Astragalus membranaceus [huáng qí], Panax ginseng [ginseng products] and Cordyceps sinensis. A. 
membranaceus [ghost moth caterpillar fungus])c 
Note: Benzodiazepines are not exclusionary. 
a 
Carvedilol is allowed for the treatment of Class I/II congestive heart failure where use of this medication is 
appropriate 
b 
Anticonvulsants for seizure disorders are allowed if the subject has been receiving a stable dose and the 
subject was free of seizures during Study PT010006 
c 
 Anticonvulsants for other indications are allowed at any time throughout the study 
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 patient safety 
e 
Investigators should contact 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 
antibody for another indication, such as osteoporosis, may be allowed after consultation with the Medical 
Monitor) 
f 
Systemic anticholinergics are allowed providing the patient was treated with this class of medications 
during Study PT010006 and the dose remains unchanged 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 33 of 123 
5.5 
Other Restrictions, Dangerous Drugs or Drugs of Abuse 
5.5.1 
Dangerous Drugs 
Dangerous drugs or drugs of abuse will not be allowed during the study from Visit 10b to 
Visit 14 or to whenever the subject discontinues the study.  If any dangerous drugs or drugs 
of abuse are used by the subject during the study, the dates of use and the amount will be 
documented and the subject will be discontinued at the discretion of the investigator. 
5.5.2 
Dietary Restrictions 
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods, 
beverages, or medications for at least 6 hours prior to and for the duration of each study visit.  
Examples of such products include coffee, tea, chocolate, and cola.  Decaffeinated beverages 
are acceptable. 
5.6 
Smoking Status 
Changes in a subject’s smoking status (e.g., stopping or re-starting smoking) may have an 
impact on the efficacy outcome measures. At all visits the subject will be asked about any 
recent change in their smoking status (i.e. whether a subject’s status has changed from 
smoker to non-smoker or vice versa). Smoking status changes during the 28-week Treatment 
Period will be captured in the eCRF, but the subject will be permitted to continue in the 
study. Subjects will be required to refrain from smoking (including electronic cigarettes) for 
at least 4 hours prior to each study visit and throughout the duration of each study visit. Study 
participants may utilize various nicotine replacement treatments such as chewing gum and 
patches (PRN), in accordance with recommendations from the Investigator during the entire 
study visit. 
Note: Use of electronic cigarettes will be viewed and managed in the same manner as 
traditional smoking. 
5.7 
Reasons for Treatment Discontinuation or Study Withdrawal 
5.7.1 
Reasons for Treatment Discontinuation 
Subjects may be withdrawn from the study at any time at their own request, upon request of 
the Investigator, or by Pearl at any time or for any reason. A subject who withdraws consent 
will always be asked about the reason(s) and the presence of any adverse events (AE). For all 
subjects who discontinue for any reason, they, their family or healthcare providers, will be 
contacted 52 weeks post-randomization to determine vital status, and if appropriate, cause of 
death (Section 8.7). The subject may voluntarily discontinue treatment at any time without 
prejudice to further treatment.  
If a subject experiences any of the changes of concern listed below, a repeat assessment 
should be obtained, and if confirmed, the subject must be discontinued from randomized 
treatment but can continue in the study. The changes of concern include: 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 34 of 123 
• Calculated QTcF intervals >500 msec, and have increased by 60 msec or more over test 
day baseline value 
• Hepatic impairment defined as abnormal liver function test of AST, ALT or total 
bilirubin ≥3 times upper limit of normal on repeat testing 
 
If a subject experiences any of the changes of concern listed below, a repeat assessment 
should be obtained, and if confirmed, the Investigator or designee needs to make a 
determination as to the suitability of continuing the subject on randomized treatment in the 
study. The changes of concern include: 
• Following dosing, a heart rate increase of >40 bpm from the pre-dose value obtained on 
that specific test day and the measured value is also >120 bpm 
• Following dosing, a systolic blood pressure increase of >40 mmHg from the pre dose 
value obtained on that specific test day and the measured value is also >160 mmHg 
• Decrease in creatinine clearance to a value ≤30 mL/minute using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) formula or a clinically relevant change 
from baseline as determined by the Investigator 
 
Subjects requiring any of the prohibited medications listed in Section 5.4 (other than study-
provided medication or COPD medications used during the treatment of a severe COPD 
exacerbation as described in Section 5.4.1) should be withdrawn from randomized study drug 
but encouraged to continue in the study and complete all study visits. 
NOTE: Subjects who suffer a COPD exacerbation (regardless of severity) will remain in the 
study and continue to take their assigned study drug unless the Investigator decides that it is 
in the best interest of the subject to discontinue randomized treatment and/or withdraw from 
the study (see Section 8). 
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 (Section 
7.3.12). 
5.7.2 
Reasons for Study Withdrawal 
If a female subject becomes pregnant during the course of the study, the subject will be 
withdrawn from the study and the pregnancy will be followed through delivery or final 
outcome (Section 7.3.11).  
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 35 of 123 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES 
6.1 
Subject Information 
Clinical supplies will be packaged to support enrollment of the study. Study personnel will 
have access to an Interactive Web Response System (IWRS) to allocate subjects, to assign 
drug to subjects and to manage the distribution of clinical supplies. Clinical supplies will be 
packaged according to a component schedule generated by the Sponsor. Each person 
accessing the IWRS system must be assigned an individual unique personal identification 
number (PIN). They must use only their assigned PIN to access the system and they must not 
share their assigned PIN with anyone. 
6.2 
Product Descriptions 
Investigational materials will be provided by Pearl as summarized in Table 6-1. 
Ventolin HFA will be supplied as open-label MDI. Additionally, Symbicort TBH will also be 
supplied as open-label DPI. 
Ventolin HFA will be a US-sourced product.  The EU-sourced Symbicort TBH must be used 
for the active control, and a locally available product cannot be substituted for the sponsor-
provided Symbicort TBH. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 36 of 123 
Table 6-1 
Product, Dose, and Mode of Administration: 
Investigational materials will be provided by Pearl Therapeutics (Pearl), as shown below: 
Product Name & Dose 
Product Strength 
Dosage Form/ 
Fill Count 
Administration 
BGF MDI (PT010)  
320/14.4/9.6 µg ex-
actuator 
160/7.2/4.8 µg per 
actuation 
MDI/ 
120 inhalations 
Taken as 2 inhalations 
BID 
GFF MDI (PT003) 
14.4/9.6 µg ex-actuator 
7.2/4.8 µg per actuation 
MDI/ 
120 inhalations 
Taken as 2 inhalations 
BID 
BFF MDI (PT009)  
320/9.6 µg ex-actuator 
160/4.8 µg per actuation 
MDI/ 
120 inhalations 
Taken as 2 inhalations 
BID 
Open-Label Product 
Budesonide and 
formoterol 
fumarate inhalation 
powder (Symbicort 
Turbuhaler) † 
 400/12 µg 
EU Source: Symbicort® 
Turbuhaler® 
200/6 µg per actuation 
Each metered dose 
contains: budesonide 200 
µg per inhalation and 
formoterol fumarate 
dihydrate 6 µg which 
corresponds to a 
delivered dose of 160 µg 
budesonide and 4.5 µg 
formoterol fumarate 
dihydrate per inhalation 
DPI/ 
60 inhalations 
Taken as 
2 inhalations BID 
Supplies are open-label 
Albuterol Sulfatea 
inhalation aerosol 90 μg 
ex-actuator 
US source: Ventolin® 
HFA 
HFA inhalation aerosol 
will be the US-supplied 
product.”  Albuterol 
sulfate inhalation aerosol.  
Each inhalation contains 
108 μg corresponding to 
90 µg albuterol base from 
the mouthpiece 
MDI/ 
60 or 200 actuations 
Taken as directed 
Supplies are open-label 
BGF MDI = Budesonide, Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; GFF MDI = 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; BFF MDI = Budesonide and Formoterol 
Fumarate Inhalation Aerosol; MDI = metered-dose inhaler; DPI = dry powder inhaler; BID = twice-daily; 
HFA= hydrofluouroalkane; µg = microgram 
†  Active control 
a Rescue medication. Albuterol sulfate is also known as salbutamol sulfate in some countries. 
Note: All study drugs will be administered by oral inhalation. Glycopyrronium 14.4 µg in GFF MDI is 
equivalent to 18 µg of glycopyrronium bromide. 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 37 of 123 
Open-label Symbicort TBH DPIs will be provided from commercial supplies. 
Manufacturer’s instructions for study drug administration are provided in Appendix 4. 
Open-label Ventolin HFA with dose counters will be provided from commercial supplies.  
Manufacturer’s instructions for study drug administration are provided in Appendix 5 
6.3 
Primary Packaging and Labeling Information 
Investigational materials will be packaged by the Sponsor.  Symbicort TBH will be supplied 
as open-label DPI.  Ventolin HFA will be supplied as open-label MDI. 
Blinded Supplies: Each MDI will be labeled with a single label. The MDI actuator will be 
labeled with a single label.  The foil pouch will be labeled with a single label.  
Open-label Supplies: Symbicort TBH will be supplied as open-label DPI.  The DPI actuator 
will be labeled with a single label. Open-label Ventolin HFA will be provided as an 
individually-labeled MDI.  The MDI will contain a single label.  The MDI actuator will be 
labeled with a single label. 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 
ID = identification; # = number 
6.4 
Secondary Packaging and Labeling Information (Box) 
Blinded investigational drug and open-label supplies (Symbicort TBH and Ventolin HFA) 
will be packaged in individual boxes as outlined in Table 6-2.  Box configuration is subject 
to change as a result of packaging constraints. 
Table 6-2 
Description of Boxes 
Drug Supplies 
Individual Box Contents 
Blinded 
Symbicort Turbuhaler  
Ventolin (albuterol sulfate) HFA 
1 MDI 
1 DPI 
1 MDI 
DPI=dry powder inhaler; HFA=Hydrofluoroalkane; MDI=metered dose inhaler 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 38 of 123 
Each box will be labeled with a 2-part label printed with black ink and may include the 
following text: 
Packaging Lot ID # 
Space for entry of screening # 
Component ID # 
Space for entry of randomization # 
Kit Contents (1 MDI) 
Space for entry of Interval ID 
Re-evaluation/Expiration date (if applicable) 
Dosing Instructions (if applicable) 
Storage Conditions 
Compound ID - Protocol # 
Country regulatory requirements 
Sponsor address (if applicable) 
Translation Key (if applicable) 
ID = identification; # = number 
6.5 
Emergency Unblinding of treatment assignment 
The IWRS should be used in order to unblind subjects and to unmask drug identity. When 
the Investigator contacts the system to unblind a subject, he/she must provide the requested 
subject identifying information and confirm the necessity to unblind the subject. Pearl will 
not provide a disclosure envelope with the clinical supplies. 
The Investigator or treating physician may unblind a subject’s treatment assignment only in 
the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject. 
Whenever possible, the Investigator must first discuss options with the Medical Monitor or 
appropriate study personnel before unblinding the subject’s treatment assignment. If this is 
impractical, the Investigator must notify Pearl as soon as possible, but without revealing the 
treatment assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. The date and reason for the unblinding must be 
recorded in the appropriate data collection tool. 
6.6 
Storage Requirements 
Blinded Supplies should be kept in a secured location.  BGF MDI, GFF MDI, and BFF MDI 
should be stored below 25° C (77° F) in a dry place. Excursions permitted up to 30°C (86°F). 
Symbicort® Turbuhaler® supplies: Do not store above 30°C (84° F). Keep the container 
tightly closed, in order to protect from moisture. 
Ventolin® HFA supplies: Store 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. Do not use or store near heat or open flame. Exposure to temperatures above 120°F 
(49°C) may cause bursting. Never throw into a fire or incinerator. 
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 39 of 123 
accordance with the product label. Documentation of temperature monitoring should be 
maintained. 
6.7 
Instructions for Preparation of Treatments for Administration and 
Dispensing 
6.7.1 
BGF MDI, GFF MDI, and BFF MDI 
Individual BGF MDI, GFF MDI, and BFF MDI 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. Confirm that the identifier given by 
IWRS and the component ID number written on the label are the same. 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. The ‘tear-off’ part of the label is to be placed onto the IWRS 
confirmation report. 
All MDIs must be primed before the first use. Priming involves releasing a certain number of 
sprays (4) 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. 
The MDI must be primed in a separate room, away from the subject treatment area.  
Each dose will consist of 2 puffs from the MDI. Subjects will be dispensed the MDI and 
instructed to continue taking study medication twice daily, 2 puffs in the morning and 2 puffs 
in the evening approximately 12 hours apart, until subject returns to the clinic. The MDI 
should be stored at room temperature by the subject, to avoid temperature extremes, and the 
products should not be stored in direct sunlight. Refer to Appendix 3 for instructions on 
administration and cleaning of BGF MDI, GFF MDI, and BFF MDI.   
6.7.2 
Symbicort® Turbuhaler®  
Refer to Appendix 4 for instructions on the administration and cleaning of Symbicort® 
Turbuhaler®. 
6.7.3 
Ventolin HFA® 
Refer to Appendix 5 for the manufacturer’s instructions on the administration and cleaning of 
Ventolin HFA. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 40 of 123 
6.8 
Drug Accountability/Return of Clinical Supplies 
Under no circumstances will the Investigator(s) 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 assistants 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 Pearl, the amount 
dispensed to and returned by the subject, and the amount remaining at the conclusion of the 
study. Study medication should be handled in accordance with applicable local guidelines 
(i.e., gloves should always be worn by study personnel if directly handling tablets or capsules 
that are returned). 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 Pearl. 
Sites should check with the Pearl representative for appropriate documentation that needs to 
be completed for drug accountability. 
The Investigator or designated assistant should not open individual clinical supply containers 
until all pre-dose assessments have been completed and the subject is eligible to be 
randomized/continue with the study. Any deviation from this must be discussed with the 
Clinical Monitor. 
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 Pearl or 
designee. Please refer to Section 6.6. 
Note: Used study drug will be stored separately from unused study drug. 
All product complaints (including device malfunctions) must be reported to Pearl using the 
Product Complaints Form provided in each site’s regulatory binder. Pearl will contact the site 
as needed to evaluate the nature of the complaint and determine what further action may be 
required. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 41 of 123 
7 
STUDY PROCEDURES 
A schedule of events is provided in Table 8-1. 
7.1 
Efficacy Assessments 
7.1.1 
Pulmonary Function Tests  
Forced expiratory spirometry maneuvers for derivation of FEV1, FVC, and PEFR will be 
assessed using a spirometer that meets or exceeds minimum performance recommendations 
of the ATS (See Appendix 1). 
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 3 
flow ranges i.e., low, medium and high flows, with temperature and barometric pressure 
correction. The calibration syringe must meet ATS specifications and must not be used 
beyond the expiry date. Required accuracy is ± 3%, i.e., 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 (Refer to Appendix 2). 
All pulmonary function tests including FEV1, FVC, and PEFR as defined in ATS/ERS 
guidelines will be performed in accordance with ATS criteria (Miller, 2005). 
To standardize spirometry, all sites will be provided with identical spirometry systems 
(KoKo Spirometer, nSpire Health, Inc., Longmont, CO, USA) with customized, study-
specific software. All study staff responsible for performing pulmonary function testing will 
receive standardized training at the investigator meetings. All technicians are required to 
demonstrate proficiency in the use of the equipment and the ability to perform technically 
acceptable pulmonary function tests (ATS criteria, Miller, 2005) prior to performing testing 
on study subjects. After each test is performed, the spirometry software will provide 
immediate feedback to the technician indicating whether the effort meets ATS acceptability 
and repeatability standards. All efforts will be stored electronically. After completion of 
testing, the study staff will electronically transmit the spirometric measurements for 
centralized quality assurance review (nSpire Health, Inc., Longmont, CO, USA). Feedback 
on the quality of the measurements will be provided to the investigational site and to Pearl 
Therapeutics or designee for central data management. 
Spirometry assessments will be obtained at the conclusion of Study PT010006 (Visit 10a) 
and will not be obtained during Visit 10b of this study.  
Spirometry assessments will be conducted 60 minutes and 30 minutes prior to study drug 
administration at Visit 11 through Visit 13. Spirometry assessments will be conducted at 
approximately 60 minutes and 30 minutes prior to receiving the appropriate COPD 
maintenance therapy at Visit 14. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 42 of 123 
7.1.2 
Subject Electronic Diary (eDiary) Data Collection 
Subjects will continue to use their eDiary provided during participation in Study PT010006 
to continue to record time of study medication administration, morning and evening 
symptoms, use of rescue albuterol (Ventolin HFA), and dose indicator reading (if assigned to 
BGF MDI, GFF MDI or BFF MDI only). 
Electronic Diary Compliance Requirement: Subject participation may be terminated at any 
time during the study for the following reason: 
• Chronic failure, in the judgment of the investigator, to comply with diary compliance, 
despite documentation at the site of repeated efforts to reinforce compliance. As defined 
for this study, compliance requires >70% subject completion of diary assessments. The 
sponsor may also instruct a site to discontinue a subject based on consistent 
noncompliance 
 
In-clinic dosing times and dose indicator readings will be documented by the site staff and 
will not be entered by the subject into their eDiary. 
The eDiary data report will be available to site personnel through the vendor's server.  The 
eDiary data report should be reviewed by the study personnel at each visit. The review 
should verify that morning and evening diary entries have been recorded by the subject for 
compliance requirements. The subject should be reinstructed, as appropriate, on the 
importance of recording twice daily entries if missing entries are observed. 
7.1.2.1 
Rescue Medication Usage 
The subject will record the total number of “puffs” of rescue Ventolin HFA used on a daily 
basis in the electronic diary. The number of “puffs” of rescue Ventolin HFA to be recorded is 
the number of actuations of the canister.  For example, when rescue Ventolin HFA is 
required and 2 actuations are inhaled, this should be recorded as 2 “puffs.” In the event the 
subject requires 4 actuations, this should be recorded as 4 “puffs”. Subjects requiring more 
than 8 puffs per day on 3 consecutive days with worsening symptoms should contact the site. 
7.1.2.2 
Medication Compliance 
Time of dosing with study medication will be recorded in the subject’s eDiary for each day 
of treatment (except the in-clinic dosing time). Study medication compliance will be checked 
at all visits, and any issues identified will be documented in the appropriate study files.  
7.1.2.3 
Recording of Dose Indicator Reading 
The BGF MDI, GFF MDI and BFF MDI will be fitted with a dose indicator to track in life 
use of the MDI. 
Subjects will be instructed to record the dose indicator reading from the MDI in their eDiary. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 43 of 123 
Prior to dosing at Visits 11 to 13 and at the final Visit 14, site personnel will observe the dose 
indicator reading on the study drug returned by the subject and record the dose indicator 
reading in the source. 
Note: The dose indicator reading recorded by the site staff will be dose indicator reading 
observed prior to subject dosing. For new MDIs the recorded count will be the count 
following the priming of the MDI but before the subject dose.  
At each visit, the site staff will compare the dose indicator reading from the prior evening 
entered in the subject eDiary with the dose indicator reading recorded by the site staff. For 
major discrepancies (i.e. >20 puff difference) the site staff will review the major discrepancy 
with the subject and document reason for the major discrepancy. If appropriate, site staff will 
retrain the subject on the proper recording of dose indicator reading and/or proper use of the 
MDI. 
7.1.2.4 
Major/minor Symptom Worsening Assessment and Alert System 
All major and minor symptoms of a worsening event will be captured once each morning for 
the purposes of a symptom worsening alert. The purpose of this alert is to notify both the 
subject and the site of a potential symptom worsening event that warrants contact between 
the subject and site for further evaluation. 
All questions will have a 24-hour recall period. Questions pertaining to the severity of 
symptoms versus their usual state will have 3 response options (e.g., How breathless have 
you been in the last 24 hours? Less breathlessness than usual, Usual level of breathlessness, 
More breathless than usual) whereas questions related to the presence or absence of a 
symptom will have a dichotomous response (e.g., Have you had a sore throat in the last 24 
hours? No, Yes, I had a sore throat). 
An alert will be triggered if 2 or more major symptoms (dyspnea, sputum volume, and 
sputum color) worsen for 2 consecutive days or if 1 major symptom and 1 minor symptom 
(sore throat, cold, fever without other cause, cough, and wheeze) worsen for at least 2 
consecutive days. When either of these criteria is met, the subject will be alerted via the 
eDiary to contact the site as soon as possible for further evaluation. Likewise, the study site 
will be alerted to contact the subject within approximately 24 to 72 hours if he/she has not 
yet contacted the study site for further evaluation. 
7.1.3 
COPD Exacerbations 
A COPD exacerbation will be defined as a change in the subject’s usual COPD symptoms 
that lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may 
warrant a change in regular medication. The change in symptoms must include at least one 
major COPD symptom and at least one other major or minor symptom from the list below: 
• Major COPD symptoms: dyspnea, sputum volume, and sputum color 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 44 of 123 
• Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhea or nasal 
congestion), and fever without other cause   
 
If symptoms are acute or have progressed rapidly and require treatment less than two days 
from onset of symptoms, the investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF.  
If the subject’s symptoms and the overall clinical findings support the diagnosis of a COPD 
exacerbation, but the subject has not experienced a worsening of at least one major COPD 
symptom and at least one other major or minor symptom, the investigator will have to justify 
the decision for defining the event as an exacerbation and record it in the eCRF. 
7.1.3.1 
Severity of COPD Exacerbation 
COPD exacerbations will be classified as mild, moderate or severe based on the following 
criteria: 
Exacerbations will be considered moderate if they result in: 
• Use of systemic corticosteroids and/or antibiotics for at least 3 days; a single depot 
injectable dose of corticosteroids will be considered equivalent to a 3-day course of 
systemic corticosteroids 
 
Exacerbations will be considered severe if they result in: 
• An inpatient COPD-related hospitalization (documentation stating that the subject was 
hospitalized for the COPD exacerbation or a record of the subject being admitted for ≥24 
hours to  an observation area, the emergency department, or other equivalent healthcare 
facility depending on the country and healthcare system). 
• COPD-related death 
 
Exacerbations will be considered mild if they do not meet the requirements to be classified as 
moderate or severe but otherwise fulfill the definition of COPD exacerbation. 
7.1.3.2 
Duration of COPD Exacerbation 
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment, whereas for mild exacerbations, the duration is defined by the length of symptoms. 
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date 
will be defined as the last day of prescribed treatment with a systemic corticosteroid or 
systemic antibiotic. In order to ensure that the same event is not counted twice, concurrent 
moderate or severe COPD exacerbations with start and stop dates equal to or less than 7 days 
apart will be considered the same event and assigned the maximum severity between the two.   


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 45 of 123 
For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms 
as recorded by the subject in the eDiary, and the stop date will be defined as the last day of 
worsened symptoms. In order to ensure that the same event is not counted twice, mild COPD 
exacerbations with start and stop dates equal to or less than 7 days apart will be considered 
the same event. 
7.1.3.3 
Approach for Capturing COPD Exacerbations 
All moderate or severe COPD exacerbations must be captured using the COPD Exacerbation 
eCRF. Mild COPD exacerbations will be captured based on symptoms as recorded by the 
subject in the eDiary. COPD exacerbations of any severity will be considered expected study 
endpoints and will not be reported as AEs unless considered a serious AE (SAE). 
7.1.3.4 
Other Information 
Pearl Therapeutics will be using an eDiary to capture daily symptom reporting. If symptoms 
meet a specific threshold (i.e., one major COPD symptom and at least one other major or 
minor symptom for 2 consecutive days), the eDiary generates alerts to the subject and the 
clinical site. This alert is intended to generate a contact between the subject and the clinical 
investigator. The clinical investigator makes the decision to escalate or initiate treatment 
(steroids and/or antibiotics and/or hospitalizations). 
Circumstances will occur where symptoms are not captured in the eDiary (e.g. technical 
difficulties, rapid deterioration, or sudden death).  In these cases, the investigator or designee 
will enter the information into the eCRF to capture the symptoms related to a COPD 
exacerbation. 
7.1.3.5 
Investigator-Judged COPD Exacerbations 
For events which do not meet the outlined symptom criteria and/or when symptoms have a 
shorter duration, the investigator can justify the decision for considering the event an 
exacerbation. Exacerbations could be defined by an investigator when symptoms of COPD 
warranted urgent treatment due to rapid onset or rapidly progressive symptoms. Such a 
situation does not allow enough time to strictly fulfill the criteria for symptom duration (≥2 
consecutive days). In these cases, the investigator may define such an event as a COPD 
exacerbation. As clinical presentations may vary among patients with COPD, exacerbations 
defined by an investigator can be supported by respiratory symptoms that may not strictly 
fulfill all symptom requirements defined above. Since the investigator will need to document 
the symptoms that justify his or her decision to begin treatment defining a COPD 
exacerbation event, all exacerbations in the study will have documented symptoms justifying 
their clinical relevance. 
7.1.4 
Subject Questionnaire 
The exacerbations of chronic pulmonary disease tool (EXACT) questionnaire will be 
captured via the subject eDiary (see Appendix 6). 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 46 of 123 
7.2 
Safety Assessments 
The safety assessments include physical examination findings, vital signs, ECGs, clinical 
laboratory tests in addition to recording of AEs and SAEs. 
7.2.1 
Medical/Surgical History and Physical Examination 
Medical history and history of COPD exacerbation will be taken at Screening in Study 
PT010006. A complete physical examination will be performed at the conclusion of Study 
PT010006 (Visit 10a) and will not be obtained during Visit 10b of this study. A complete 
physical examination will be conducted at the Final Visit (Visit 14) or at the Treatment 
Discontinuation/Withdrawal Visit. A complete physical examination will include the 
following: general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), 
lymph nodes, chest, heart, abdomen, extremities, and nervous system. Weight, assessed in 
ordinary indoor clothing with shoes removed, will be recorded at Visit 14. 
7.2.2 
Vital Sign Measurements 
Vital signs, including Heart rate (HR) and systolic and diastolic blood pressure (DBP), and 
temperature will be assessed as outlined below; assessments may be obtained while the 
subject is resting for 5 minutes in either the supine or seated position. 
Vital signs will be obtained at the conclusion of the lead-in study PT010006 (Visit 10a) and 
will not be obtained during Visit 10b of this study. 
At Visits 11 to 13: 
• Pre-dose vital signs will be obtained within 60 minutes prior to study drug dosing 
• Post-dose vital signs will be obtained at 30 minutes post study drug dosing 
 
A single set of vital signs will also be obtained at a Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable. 
Note: Temperature will be obtained pre-dose at all visits and will not be repeated post-dose 
at subsequent time points unless clinically indicated. 
7.2.3 
12-Lead Electrocardiogram  
ECGs will be obtained at the conclusion of Study PT010006 (Visit 10a) and will not be 
obtained during Visit 10b of this study. 
At Visit 12 (Week 36) only, an ECG will be obtained within 60 minutes prior to study drug 
dosing. 
An ECG will also be obtained at Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 47 of 123 
To standardize ECG collection, all sites will be provided with identical ECG equipment 
(Global Instrumentation M12R recorder, Global Instrumentation, Syracuse, NY, USA) with 
customized study-specific software. All study staff responsible for performing ECG 
collection will receive identical, detailed training at the investigator meetings as well as site 
phone training sessions. Each site is required to demonstrate proficiency in the use of the 
equipment and the ability to perform technically acceptable ECGs prior to performing testing 
on study subjects. After each test is performed, the ECG data will be transmitted 
electronically for centralized quality assurance review (iCardiac Technologies, Rochester, 
NY, USA). Feedback on the quality of the ECGs will be provided to the investigational site 
via a site qualification form. 
The ECG parameters that will be assessed include heart rate, PR interval, QRS axis, QRS 
interval, and QT/QTcF interval.   
QT intervals and calculated QTcF intervals will be reviewed and checked for gross 
inaccuracies by the investigator or designated ECG reviewer. If the calculated QTcF intervals 
are greater than 500 msec, and have increased by 60 msec or more over test day baseline 
value, the investigator will make a determination on the suitability of continuing the subject 
in the study. If QTcF interval prolongation exceeding these limits is verified during 
treatment, the subject’s medical history should be examined closely for risk factors that may 
have contributed to the event, including evidence of prior genotyping for hereditary long QT 
syndromes, if appropriate. 
Any sign of arrhythmia should be noted. During treatment, any indication of Torsade de 
Pointes, a polymorphic ventricular tachyarrhythmia that appears on the ECG as continuous 
twisting of the vector of the QRS complex around the isoelectric baseline, must be recorded 
as an AE and reported to the Pearl Therapeutics Medical Monitor.  
All such subjects, including subjects with cardiac arrhythmias, should be monitored closely.  
If appropriate, ECG monitoring should be performed until the QT and QTcF interval and 
waveform morphology have returned to normal. If the prolongation or abnormal rhythm 
persists, the Pearl Therapeutics Medical Monitor must be contacted immediately. 
7.2.4 
Clinical Laboratory Tests 
Clinical safety laboratory tests will be analyzed by a central laboratory according to 
standardized, validated assays. The laboratory will supply detailed instructions and all 
containers for blood and urine investigations. Blood sample volumes will meet the 
laboratory’s specification. Clinical laboratory tests will be obtained prior to dosing at the 
final visit of Study PT010006 (Visit 10a), and will not be obtained during Visit 10b of this 
study. During the course of this study, clinical laboratory tests will be obtained prior to 
dosing at Visit 12 (Week 36) only. Clinical laboratory tests will also be obtained at Visit 14 
(Week 52) or at the Treatment Discontinuation/Withdrawal Visit, if applicable. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 48 of 123 
7.2.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured prior to dosing at the final visit of Study PT010006 (Visit 
10a), and will not be obtained during Visit 10b of this study. During the course of this study, 
hematology assessments will be obtained prior to dosing at Visit 12 (Week 36). Hematology 
assessments will also be obtained at Visit 14 (Week 52) or at the Treatment 
Discontinuation/Withdrawal Visit, if applicable. 
7.2.4.2 
Clinical Chemistry 
A comprehensive chemistry panel will be measured prior to dosing at the final visit of Study 
PT010006 (Visit 10a), and will not be obtained during Visit 10b of this study. During the 
course of this study, clinical chemistry assessments will be obtained prior to dosing at Visit 
12 (Week 36) only. Clinical chemistry assessments will be obtained at Visit 14 (Week 52) or 
at the Treatment Discontinuation/Withdrawal Visit, if applicable.  
Refer to Table 7-1 for a list of study-associated laboratory tests. The central laboratory will 
supply procedures for the preparation and collection of these samples. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 49 of 123 
Table 7-1.  
Clinical Laboratory Tests 
Hematology 
Hemoglobin 
Mean corpuscular hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin concentration 
White blood cell count with differential 
Mean corpuscular volume 
Red blood cell count 
Eosinophils 
Clinical Blood Chemistry 
Liver Enzyme and Other Liver Function Tests 
Other Clinical Blood Chemistry 
Alanine aminotransferase 
Albumin 
Aspartate aminotransferase 
Blood Urea Nitrogen (BUN) 
Alkaline phosphatase 
Calciuma 
Bilirubin, total 
Chloridea 
Gamma glutamyl transferase 
Cholesterol 
 
Bicarbonate 
 
Creatininea 
 
Glucosea 
 
Magnesium 
 
Potassiuma 
 
Phosphate 
 
Protein, total 
 
Sodiuma 
 
Triglycerides 
Urinalysis 
Macroscopic examination including specific gravity, pH, protein, glucose, ketones, blood, and  
urobilinogen 
Other Tests: 
Pregnancy test (women of child-bearing potential only): serum [human chorionic gonadotropin (hCG)] at Visit 
14 or Treatment Discontinuation/Withdrawal visit only and urine hCG at Visits 11, 12, and 13 
Creatinine clearance will be estimated by the CKD EPI formula [Levey, 2009]. 
Abbreviations: CKD EPI=Chronic Kidney Disease Epidemiology Collaboration; hCG=human chorionic  
gonadotropin 
a Parameters included in the Basic Metabolic Panel. 
 
 
 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 51 of 123 
can be any unfavorable and unintended sign (e.g., 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 (e.g., off-label use, use in combination 
with another drug) and from any route of administration, formulation, or dose, including an 
overdose. 
Adverse events include, but are not limited to: 
• 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: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that leads to the procedure are an AE (e.g., bleeding 
esophageal varices, dental caries) 
• Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms 
• Non-clinically significant abnormal laboratory values.  (If accompanied by 
signs/symptoms, the signs or symptoms are considered an AE.) 
 
7.3.3 
Severity 
The Investigator must categorize the severity of each AE according to the following 
guidelines: 
Mild: Associated with no limitation of usual activities or only slight discomfort; generally not 
requiring alteration or cessation of study drug administration; and/or not needing therapeutic 
intervention. 
Moderate: Associated with limitation of usual activities or significant discomfort; generally 
requiring alteration or cessation of study drug administration; and/or requiring therapeutic 
intervention. 
Severe: Associated with inability of subject to carry out usual activities or very marked 
discomfort; considered to be life-threatening; resulting in significant disability or incapacity; 
and requiring therapeutic intervention. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 52 of 123 
7.3.4 
Relationship 
The relationship of each AE to the study drug administration will be assessed by the 
Investigator after careful consideration, and according to the following guidelines: 
Definitely: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; it disappears 
or decreases on cessation or reduction in study drug dose; and/or it reappears or worsens 
when the study drug is administered. 
Probably: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; and/or that 
could not be reasonably explained by other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatments. 
Possibly: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug, but that 
could reasonably have been produced by a number of other factors including underlying 
disease, complications, concomitant drugs, or concurrent treatments. 
Not Related: A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
7.3.5 
Chronic Obstructive Pulmonary Disease Exacerbations 
All moderate or severe COPD exacerbations must be captured using the COPD Exacerbation 
eCRF. Mild COPD exacerbations will be captured based on symptoms as recorded by the 
subject in the eDiary. COPD exacerbations of any severity will be considered expected study 
endpoints and will not be reported as AE unless considered an SAE.  
Exacerbation(s) of COPD is expected to occur as a progression of disease despite 
standardized drug treatment, or treatment(s) with combination therapies. As a result, the 
Sponsor has classified this event as a protocol specified criteria expected event. Any 
individual case safety reports received related to exacerbation of COPD will not be submitted 
on an expedited basis as a Suspected Unexpected Serious Adverse Reaction (SUSAR) unless 
otherwise required as per the Sponsor’s medical assessment. 
7.3.6 
Adverse Events of Special Interest 
Certain AEs have been identified as adverse events of special interest (AESIs) due to the 
class of drugs being studied. These adverse events will be captured through spontaneous 
reporting and the reporting of these AESIs will be described in the SAP. Some events are 
described below but this is not a comprehensive list of all AESIs. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 53 of 123 
7.3.6.1 
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 and tremor effects for LABAs. 
7.3.6.2 
Local Steroid Effects  
Local steroid effects include oral candidiasis, hoarseness candidiasis, oropharyngeal 
candidiasis, dysphonia, and throat irritation. 
7.3.6.3 
Pneumonia 
In order to adequately assess and characterize the risk of pneumonia in patients in a non-
biased manner, a Clinical Endpoint Committee (CEC) will review all AEs reported as 
pneumonia to ensure appropriate pre-defined and clinically consistent pneumonia criteria are 
met. 
To standardize the diagnosis of pneumonia a clinically consistent definition of pneumonia 
will be implemented, which will require the following: 
1. Clinical diagnosis of pneumonia by the Investigator 
2. Documentation of chest imaging obtained within 14 days of the diagnosis of pneumonia 
that is compatible with the diagnosis of pneumonia 
3. Treatment with antibiotics (and/or if appropriate antiviral and/or antifungal agents) 
4. At least 2 of the following clinical signs, symptoms, or laboratory findings: 
• Increased cough  
• Increased sputum purulence or production  
• Adventitious breath sounds on auscultation  
• Dyspnea or tachypnea 
• Fever 
• Elevated white blood cell counts 
• Hypoxemia 
 
The CEC will be empowered to request any additional information, including copies of chest 
X-rays or CT scans if needed, to confirm the pneumonia diagnosis.   
Radiographs will be evaluated locally and the results (infiltrate compatible with pneumonia 
(yes/no) will be entered in the eCRF. If the Investigator becomes aware that a diagnosis of 
pneumonia was made without a chest image having been performed, he or she should obtain 
a chest image (frontal and lateral) up to 10 to 14 days after the date of pneumonia diagnosis. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 54 of 123 
7.3.6.4 
Paradoxical Bronchospasm 
Monitoring for paradoxical bronchospasm will occur through spontaneous reporting. 
7.3.7 
Major Adverse Cardiovascular Events (MACE) 
Due to the prevalence of cardiovascular diseases in patients with COPD, MACE will be 
evaluated according to pre-defined criteria as described in the Clinical Endpoint Adjudication 
Charters. The CEC will review potential clinical events to determine if the events meet the 
following MACE criteria: 
• Cardiovascular death 
• Non-fatal myocardial infarction (MI) 
• Non-fatal stroke 
 
The Clinical Endpoint Adjudication Charters will be established to govern these processes as 
described in Section 7.3.15 Clinical Endpoint Committee. 
7.3.8 
Clinical Laboratory Adverse Events 
Many laboratory abnormalities observed during the course of a study will be included under 
a reported AE describing a clinical syndrome (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). 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 (i.e., concomitant 
medication or therapy) 
• Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion) 
 
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 clinically significant or not clinically significant for the subject. 
 
7.3.9 
Serious Adverse Events 
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes: 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 55 of 123 
• 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. 
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 or 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. 
7.3.9.1 
Reporting Serious Adverse Events 
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 Therapeutics no later than 24 hours after the Investigator recognizes/classifies the event 
as an SAE. 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 (e.g., 
SAE Report Form). After the initial report, as necessary, the Investigator must provide any 
additional information on a SAE to Pearl Pharmacovigilance within 2 working days after 
he/she receives that information. This follow-up information will be a detailed written report 
that may include copies of hospital records, case reports, and autopsy reports, and other 
pertinent documents. 
Post-study SAEs following the last dose of study drug must be reported to Pearl as described 
in Section 7.3.9.4. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 56 of 123 
The Investigator is responsible for continuing to report any new or relevant follow-up 
information that he/she learns about the SAE. 
The Principle Investigator will report SAEs to Pearl and to the Head of the Medical 
Institution during the performance of this protocol. 
7.3.9.2 
Supplemental Investigations of SAEs 
The Investigator and supporting personnel responsible for subject care should discuss with 
the Medical Monitor any need for supplemental investigations of SAEs. The results of these 
additional assessments conducted must be reported to Pearl and to the Head of the Medical 
Institution. If a subject dies during participation in the study and a post-mortem examination 
is performed, a copy of the autopsy report must be submitted to Pearl and to the Head of the 
Medical Institution. 
7.3.9.3 
Post-Study Follow-Up of Adverse Events 
Investigators are not obligated to actively follow subjects after the completion of the study.  
However, if the Investigation becomes aware of a post-study SAEs occurring up to 14 days 
following the last dose of study drug must be reported to Pearl, whether or not the event is 
attributable to study drug. All SAEs must be reported to Pearl no later than 24 hours after the 
Investigator recognizes/classifies the event as an SAE.  The Principle Investigator will report 
SAEs to Pearl and to the Head of the Medical Institution during the performance of this 
protocol. 
7.3.9.4 
Notification of Post-Study Serious Adverse Events 
Investigators are not obligated to actively follow subjects after the completion of the study.  
However, if the Investigation becomes aware of a post-study SAEs occurring up to 14 days 
following the last dose of study drug must be reported to Pearl, whether or not the event is 
attributable to study drug. All SAEs must be reported to Pearl no later than 24 hours after the 
Investigator recognizes/classifies the event as an SAE.  The Principle Investigator will report 
SAEs to Pearl and to the Head of the Medical Institution during the performance of this 
protocol. 
7.3.9.5 
Investigational Research Board/Independent Ethics Committee Notification of 
Serious Adverse Events 
The Investigator is responsible for promptly notifying her/his Investigational Research 
Board/Independent Ethics Committee (IRB/IEC) of all SAEs, including any follow-up 
information, occurring at her/his site and any SAE regulatory report, including any follow-up 
reports that he/she receives from Pearl. Documentation of the submission to the IRB/IEC 
must be retained for each safety report. The Investigator is also responsible for notifying 
Pearl if their IRB/IEC requires revisions to the ICF or other measures based on its review of 
an SAE report.  Notifications of Serious Adverse Events to the IRB/IEC including any 
follow-up reports should also be provided to the Head of the Medical Institution. 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 58 of 123 
7.3.12 
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 randomized treatment 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. 
7.3.13 
Hy's Law 
Cases where a subject shows an AST or ALT ≥ 3x Upper Limit of Normal (ULN) with Total 
Bilirubin (TBL) ≥ 2x ULN may need to be reported as SAEs. Please refer to Appendix 7 for 
further instructions in cases of combined increase of aminotransferase and TBL. 
7.3.14 
Use of Steroids during the Trial 
At each visit, subjects will be asked whether they have been administered oral, intramuscular, 
or intravenous corticosteroids since last visit. Use of oral, intramuscular, or intravenous 
corticosteroids for the management of COPD exacerbations or other condition is not a reason 
for early treatment discontinuation or study withdrawal. Use of corticosteroids should be 
documented. Subjects who are being treated for a COPD exacerbation with oral 
corticosteroids or have been treated for a COPD exacerbation with oral corticosteroids within 
14 days of the scheduled visit will be allowed to perform PFTs under close medical 
supervision. The Investigator can decide to stop PFTs if subject safety is at risk or symptoms 
make it difficult for the subject to continue. 
Subjects treated with oral, intramuscular, or intravenous corticosteroids for other indications 
will follow their visit schedule. If a subject requires intraocular corticosteroids, this should be 
fully documented and the Investigator should make a determination as to the suitability of the 
subject continuing on randomized treatment. 
7.3.15 
Clinical Endpoint Committee 
An external CEC that was initiated in Study PT010006 will continue to adjudicate for this 
study.  The CEC will provide systematic and unbiased assessment of pre-defined, 
Investigator reported adverse events. The committee will consist of experts who will provide 
a centralized review functioning independently of Pearl. Three Clinical Endpoint 
Adjudication Charters will outline the clinical endpoints for adjudication. 
• Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter 
• Cause-Specific Mortality Clinical Endpoint Adjudication Charter 
• Pneumonia Clinical Endpoint Adjudication Charter 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 59 of 123 
7.3.15.1 
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication 
Charter 
A CCV Clinical Endpoint Adjudication Charter will be referenced for the review and 
assessment of non-fatal serious CCV events and classification of MACE. The CEC will 
review potential events to determine if the event meets MACE criteria. 
7.3.15.2 
Cause-Specific Mortality Clinical Endpoint Adjudication Charter 
A Cause-Specific Mortality Clinical Endpoint Adjudication Charter will be referenced for the 
review and assessment of the cause of deaths. The CEC will review fatal reports to determine 
if the event meets MACE criteria. Cardiovascular deaths will be classified as MACE. 
7.3.15.3 
Pneumonia Clinical Endpoint Adjudication Charter 
A Pneumonia Clinical Endpoint Adjudication Charter will be referenced for the review and 
assessment of all pneumonia-related events to ensure appropriate pre-defined and clinically 
consistent pneumonia criteria are met. 
7.3.16 
Data Monitoring Committee 
An external Data Monitoring Committee (DMC) that was initiated in Study PT010006 will 
continue to provide systematic and unbiased assessments of safety for Study PT010007. 
Members of the DMC will review data at predetermined intervals. If significant safety issues 
arise in between scheduled meetings, ad hoc meetings will be scheduled to review the data. 
Based on the safety implications of the data, the DMC may recommend modification or 
termination of the study. 
7.4 
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 Pearl. 
Pearl 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 Pearl, in a time frame that is compatible with the subjects’ wellbeing. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0  
 
 
 
 
Confidential and Proprietary 
Page 60 of 123 
8 
STUDY ACTIVITIES 
A time and events schedule is provided in Table 8-1.   


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 61 of 123 
Table 8-1 
Schedule of Events 
Procedures 
Treatment Period 
Follow-Up 
Visit 10b 
Visit 11 
Visit 12 
Visit 13 
Visit 14 
14 Days 
Post-Dose 
Study Day/Week a 
Week 24 ±7 
Days 
Week 28 ±7 
Daysa 
Week 36 ±7 
Daysa 
Week 44 
±7 Daysa 
Week 52 ±7 
Daysa 
Week 54 ±7 
Daysa 
Obtain Informed Consent 
X 
 
 
 
 
 
Review Incl/Excl Criteria 
X 
 
 
 
 
 
Verify Continued Eligibility 
 
X 
X 
X 
X 
 
Smoking Status 
 
X 
X 
X 
X 
 
Physical Examination 
 
 
 
 
X 
 
Prior/Concomitant Medicationsb 
 
X 
X 
X 
X 
X 
COPD Exacerbations and Adverse Events 
 
X 
X 
X 
X 
X 
Adjust COPD Medicationsc 
 
 
 
 
X 
 
Vital Signsd 
 
X 
X 
X 
X 
 
Urine Pregnancy Testd 
 
X 
X 
X 
 
 
Serum Pregnancy Testd 
 
 
 
 
X 
 
12-Lead ECGd 
 
 
X 
 
X 
 
Clinical Laboratory Testingd 
 
 
X 
 
X 
 
Spirometryd 
 
X 
X 
X 
X 
 
Study Drug Dispensing/Collection 
X 
X 
X 
X 
X 
 
Review of Electronic Diary Datad 
 
X 
X 
X 
X 
 
Study Drug Administratione 
 
X 
X 
X 
 
 
Record Dose Indicator Readinge 
X 
X 
X 
X 
X 
 
Telephone Contactf 
 
Xf 
Xf 
Xf 
Xf 
Xg 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 62 of 123 
a. 
Scheduling visits: All visits will be scheduled relative to Visit 4 (Treatment Day 1, Randomization) of the lead-in study (PT010006).  
b. 
At all visits, note time of last dose of short-acting bronchodilator and other COPD medications (if <6 hours, visit should be rescheduled). 
c. 
At the end of Visit 14, return subject to pre-study or other appropriate inhaled maintenance COPD medications. 
d. 
Refer to Section 7 for specific assessments and specific time points to be performed at each treatment visit. 
e. 
In-clinic dosing time is recorded as time of the second puff/inhalation. The in-clinic dosing time should be timed to be within 12±2 hours of the prior evening dosing time.  Record/document 
the dose indicator readings of the used device and the replacement device; this applies to all the study medications including Symbicort TBH. 
f. 
It is recommended that sites call the subject on the day before a scheduled visit and remind the subject of the expectations for the upcoming visit (e.g. Dosing appropriately the day before the 
visit, withholding COPD medications the morning of the scheduled visit, bring all study drug and eDiary to the visit, etc.). 
g. 
Refer to Section 8.6for details of the follow-up telephone call. 
Note: Refer to Section 8.5for procedures that may be required at a premature discontinuation visit. Treatment Discontinuation/Withdrawal Visits will be captured as unscheduled visits. 
Note: Where data collection time-points are concurrent, variables should be collected in the following order: vital signs, ECG, clinical laboratory assessments, and spirometry. 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 63 of 123 
8.1 
Visit 10b (Week 24 Safety Extension Entry Visit) 
There are 10 scheduled visits in Study PT010006; the tenth visit is the last visit of the Study 
PT010006 and the first visit of the extension study (PT010007). In order to differentiate, 
assessments conducted at the completion of the Study PT010006 will be captured in Visit 
10a and procedures conducted in the extension study will be captured in Visit 10b. Visit 10b 
will be completed following completion of all Visit 10a study procedures. A reminder 
phone contact should be made prior to Visit 11. 
Note: All subjects in Japan who completed and were compliant with all study procedures in 
Study PT010006 will be invited to participate in Study PT010007. Visit 10b will be 
completed only in subjects who consent to participate in the safety extension study. 
• Obtain informed consent 
• Review safety extension inclusion/exclusion criteria and confirm subject eligibility to 
enroll into the safety extension study 
• Confirm all visit 10a procedures have been completed before proceeding to register 
subjects in IWRS 
• Register subject in IWRS to confirm participation in the safety extension study 
• Return electronic diary to subjects and provide retraining if appropriate 
• When assigned blinded study drug site personnel will complete priming in the clinic 
before dispensing to the subject for at home use 
• Refer to Section 6.7for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits 
• Record/document the dose indicator reading. The dose indicator count recorded by the 
site staff will be dose indicator count observed after priming but prior to subject dosing. 
Refer to Section 7.1.2for more details 
• Subject will administer first dose of safety extension study drug at home in the evening. 
Note: During the extension study subjects will continue on the same treatment that they 
were assigned in Study PT010006 
• Subjects will be instructed to bring their eDiary and all study medication (including used 
study drug, replacement MDI kit if assigned to blinded study drug and sponsor-provided 
rescue Ventolin HFA) to the next scheduled clinic visit 
• Schedule next visit and ensure subject has adequate supply of study drug including a 
replacement MDI kit if assigned to blinded study drug and sponsor-provided rescue 
Ventolin HFA 
 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 64 of 123 
8.2 
Visit 11 (Week 28) and Visit 13 (Week 44) 
• Confirm subject eligibility to continue 
• Collect study drug including sponsor-provided Ventolin HFA  
• Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, the visit must be rescheduled) 
• Confirm the subject took their last dose of randomized study medication as scheduled. If 
the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled   
• Review subject diary for data collection compliance 
• Review smoking status  
• Record COPD exacerbations and adverse events (if any) 
• Review all prior/concomitant medications and ensure adherence to COPD regimen 
• Obtain vital signs within 60 minutes prior to dosing 
• Perform urine pregnancy test 
• Obtain pre-dose spirometry at -60 and -30 minutes prior to dosing 
• Return electronic diary to subjects and provide retraining if appropriate 
• Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in-clinic dosing and to continue dosing at home until the next scheduled visit 
• Refer to Section 6.7 for detailed instructions for preparation of treatments for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits 
• Record/document the dose indicator readings of the used device and the replacement 
device.  This applies to all the study drugs, including Symbicort TBH.  
• For new MDIs, the recorded count will be the count following the priming of the device 
but before the subject doses. Refer to Section 7.1.2for more details 
• Administer in-clinic study drug dosing from the new kit assigned at the visit 
• Obtain vital signs 30 minutes post study drug dosing 
• Subjects will be instructed to track study drug dosing in their electronic diary between 
study clinic visits 
• Subject assigned to blinded study drug will be instructed to dose while at home from the 
site-primed MDI only, unless all of the following replacement conditions are met: 
- 
Dose indicator is in the red zone (See Appendix 8 for dose indicator reading 
instructions),  
- 
If the dose indicator registers ≤10 puffs remaining, and their next scheduled study 
clinic visit is not the following day. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 65 of 123 
- 
If these replacement conditions are met, subjects will be instructed to open one of 
their replacement kits, prime the MDI and start using for at home dosing until the 
next scheduled study clinic visit. 
- 
Subjects will be instructed to bring their eDiary and all study medication (including 
used study drug, replacement MDI kit if assigned to blinded study drug and sponsor-
provided rescue Ventolin HFA) to the next scheduled clinic visit. 
• Schedule next visit and ensure subject has adequate supply of study drug including two 
replacement MDI kits if assigned to blinded study drug and sponsor-provided rescue 
Ventolin HFA 
• Perform reminder phone contact prior to the next visit 
 
8.3 
Visit 12 (Week 36) 
• Confirm subject eligibility to continue 
• Collect study drug including sponsor-provided Ventolin HFA  
• Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, the visit must be rescheduled) 
• Confirm the subject took their last dose of randomized study medication as scheduled. If 
the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled  
• Review subject diary for data collection compliance 
• Review smoking status 
• Record COPD exacerbations and adverse events (if any) 
• Review all prior/concomitant medications and ensure adherence to COPD regimen 
• Obtain vital signs within 60 minutes prior to dosing 
• Perform urine pregnancy test 
• Obtain 12-lead ECG within 60 minutes prior to study drug dosing 
• Obtain clinical laboratory samples prior to study drug dosing 
• Obtain pre-dose spirometry at -60 and -30 minutes prior to dosing 
• Return electronic diary to subjects and provide retraining if appropriate 
• Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in-clinic dosing and to continue dosing at home until the next scheduled visit 
• Refer to Section 6.7 for detailed instructions for preparation of treatments for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits 
• Record/document the dose indicator readings of the used device and the replacement 
device.  This applies to all the study drugs, including Symbicort TBH.   


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 66 of 123 
• For new MDIs, the recorded count will be the count following the priming of the device 
but before the subject doses. Refer to Section 7.1.2for more details 
• Administer in-clinic study drug dosing from the new kit assigned at the visit 
• Obtain vital signs 30 minutes post study drug dosing 
• Subjects will be instructed to track study drug dosing in their electronic diary between 
study clinic visits 
• Subject assigned to blinded study drug will be instructed to dose while at home from the 
site-primed MDI only, unless all of the following replacement conditions are met: 
- 
Dose indicator is in the red zone (See Appendix 8 for dose indicator reading 
instructions),  
- 
If the dose indicator registers ≤10 puffs remaining, and their next scheduled study 
clinic visit is not the following day. 
- 
If these replacement conditions are met, subjects will be instructed to open one of 
their replacement kits, prime the MDI and start using for at home dosing until the 
next scheduled study clinic visit. 
- 
Subjects will be instructed to bring their eDiary and all study medication (including 
used study drug, replacement MDI kit if assigned to blinded study drug and sponsor-
provided rescue Ventolin HFA) to the next scheduled clinic visit. 
• Schedule next visit and ensure subject has adequate supply of study drug including two 
replacement MDI kits if assigned to blinded study drug and sponsor-provided rescue 
Ventolin HFA 
• Perform reminder phone contact prior to the next visit 
 
8.4 
Visit 14 (Week 52) Final Visit 
• Confirm subject eligibility to continue 
• Collect study drug including sponsor-provided Ventolin HFA 
• Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, the visit must be rescheduled) 
• Confirm the subject took their last dose of randomized study medication as scheduled.  If 
the time of dosing was not in accordance with the protocol, then the visit must be 
rescheduled  
• Review subject diary for data collection compliance 
• Review smoking status  
• Perform physical examination, including weight 
• Record COPD exacerbations and adverse events (if any) 
• Review all prior/concomitant medications and ensure adherence to COPD regimen 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 67 of 123 
• Obtain vital signs measurements 
• Perform serum pregnancy test 
• Obtain 12-lead ECG measurements 
• Obtain clinical laboratory samples 
• Obtain pre-dose spirometry at -60 and -30 minutes prior to dosing with appropriate 
COPD maintenance therapy 
• Return subject to pre-study or appropriate maintenance COPD medications 
• Collect subject eDiary 
• Record/document the dose indicator readings of the used device and the replacement 
device.  This applies to all the study drugs, including Symbicort TBH.   
• Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug 
• Schedule the follow-up telephone call at least 14 days from Visit 14 
 
8.5 
Unscheduled Visit/Premature Discontinuation Visit 
Repeat assessments, if needed, will be captured in unscheduled visits. 
Premature discontinuations visits will be captured as unscheduled visits.  The following 
minimum procedures should be completed at the Premature Discontinuation Visit: 
• Collect all study drugs 
• Record COPD exacerbations and adverse events (if any) 
• Review concomitant medications 
• Conduct a physical examination, including vital signs. 
• Perform ECG and collect urine and blood samples for hematology and chemistry 
• Collect a blood sample for pregnancy test for women of child bearing potential 
• Collect subject eDiary 
• Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug 
• Return subject to pre-study or appropriate maintenance COPD medications 
• Capture the subject discontinuation reason 
• Schedule a follow-up telephone call (TC) 14 days post last study drug dosing. If the 
discontinuation visit is performed > 14 days post last study drug dosing a follow-up TC 
will not be required 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 68 of 123 
8.6 
Follow-Up Telephone Call 
Subjects will be followed-up through a TC 14 days post last study drug dosing. The 
following information will be requested: 
• Review previously on-going COPD exacerbations and adverse events and record any new 
AEs (if any) 
• Review concomitant medications 
 
8.7 
Vital Status Confirmation at Week 52 
All subjects who discontinue study treatment post-Visit 10b but prior to Visit 14 will have 
their vital status confirmed at 52 weeks post- randomization. 
To confirm the vital status and cause of death, if appropriate, the following attempts will be 
made: 
• The first and second attempts may be conducted as telephone follow-up call to the subject 
within 2 weeks after 52 weeks post- randomization 
• The third attempt will be by certified mail to the subject's address provided at the time of 
informed consent within 3 weeks after 52 weeks post- randomization 
• The fourth attempt will be made as a telephone follow-up call to the next of 
kin/emergency contact provided at the time of informed consent within 4 weeks after 52 
weeks post- randomization 
• A fifth attempt will be made through a certified letter to the next of kin/emergency 
contact provided at the time of informed consent within 5 weeks after 52 weeks post- 
randomization 
 
8.8 
Completion of the Study 
The investigator will document the completion or the reason for early withdrawal/premature 
discontinuation from the study by a subject in the eCRF.  The following categories should be 
used to describe these events in the eCRF: 
• Subject discretion (document reason) 
• Investigator considers it to be in the best interest of the subject 
• Adverse events(s) 
• Administrative reasons (e.g., early termination of the study) 
• Subject lost-to-follow-up 
• Lack of efficacy 
• Major protocol violation 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 69 of 123 
• Death 
• Completion of the study 
• Protocol specified criteria such as heart rate, systolic or diastolic blood pressure, or use of 
prohibited medications (see Section 5.7) 
 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 70 of 123 
9 
PLANNED STATISTICAL METHODS 
9.1 
Introduction 
This study will be conducted as a double-blind, parallel-group study evaluating the following 
treatments in approximately 324 subjects: 
• BGF MDI (320/14.4/9.6 µg BID) 
• GFF MDI (14.4/9.6 µg BID) 
• BFF MDI (320/9.6 µg BID) 
• Symbicort Turbuhaler (200/6 µg) 
 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
BGF MDI, GFF MDI, BFF MDI, and Symbicort Turbuhaler (TBH) in Japanese subjects with 
moderate to very severe COPD. 
This study will include a 28-week treatment period that will immediately follow an initial 24-
week treatment period from Study PT010006. Analyses will include data from subjects 
enrolled in Japan in Study PT010006 whenever applicable in order to minimize the impact of 
bias caused by dropout and in order to allow inferences to be made over 52 weeks. Baseline 
for all subjects will remain the original baseline from Study PT010006. For clinic measured 
values, the baseline is the assessment obtained prior to initial dosing at Visit 4. Specifically 
for the primary efficacy measure, baseline is the average of the -60 min and -30 min 
assessments. For diary data, the baseline is the average of the values obtained during the 
seven days prior to Visit 4 including the morning of Visit 4 prior to initial dosing. 
9.2 
Protocol Variables 
The data from this 28-week study will be combined with the 24 weeks of data obtained from 
Study PT010006 to provide safety and efficacy data over 52 weeks of treatment. 
9.2.1 
Safety Endpoints 
The safety endpoints (over 52-weeks) for this study include: 
• Adverse events (AEs) 
• 12-lead electrocardiograms (ECG): Change from baseline in heart rate (HR), PR interval, 
QRS axis, QRS interval, QT interval, and QTcF (Fridericia Corrected QT) interval 
• Clinical laboratory testing 
• Vital sign measurements 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 71 of 123 
9.2.2 
Efficacy Endpoints (over Week 52 unless otherwise stated) 
• Change from baseline in morning pre-dose trough FEV1 over 52 weeks (Weeks 4 to 52) 
and at each post-randomization visit 
• Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use 
• Percentage of days with no rescue Ventolin HFA use 
• Rate of moderate or severe COPD exacerbations 
• Rate of COPD exacerbations of any severity 
• Change from baseline in morning pre-dose trough for FVC, PEFR, and FEF25-75 over 52 
weeks (Weeks 4 to 52) and at each post randomization visit 
• Change from baseline in: the EXACT total score, the 11-item EXACT Respiratory 
Symptoms (E-RS) Total Score (RS-Total Score), as well as 3 subscale scores symptom 
(RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 52 weeks 
and over each 4-week interval of the 52-week Treatment Period 
 
9.3 
Study Populations 
• The Japanese Modified Intent-To-Treat (mITT) Population is defined as the subgroup 
of Japanese mITT subjects from Study PT010006, regardless of participation in 
PT010007. Subjects will be analyzed according to the active treatment they were 
assigned to at randomization in Study PT010006. (Note that a subject who used a study 
treatment, but took less than one full dose of treatment will qualify for this population).  
Data from both Study PT010006 and Study PT010007 will be included. 
• The Japanese Safety Population is defined as all Japanese subjects who received any 
amount of study medication in Study PT010006, regardless of participation in PT010007. 
Subjects will be analyzed according to the actual treatment they received. 
 
Analyses will be performed as follows: 
Demographics will be summarized for the Japanese mITT population and the Japanese 
Safety Populations. Extent of exposure and safety will be summarized for the Japanese 
Safety Population. Efficacy Analyses will be performed for the Japanese mITT Population. 
9.4 
Safety Analyses 
Safety data will be summarized cumulatively over 52 weeks using data observed during 
Study PT010006 and this 28-week extension Study PT010007. Analyses involving change 
from baseline will use baseline values from Study PT010006. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 72 of 123 
9.4.1 
Adverse Events 
All AEs will be summarized for the Japanese Safety Population. The version of the Medical 
Dictionary for Regulatory Activities (MedDRA) that is current at the time of database lock 
will be used to code verbatim terms for AEs for final analysis of the data. The incidence 
(number and percentage) of subjects experiencing adverse events, serious adverse events, 
adverse events of special interest by category, confirmed AEs of pneumonia, and study drug 
discontinuations due to adverse events will be summarized by treatment group. They will be 
tabulated at the level of the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term and the MedDRA system organ class. Tabulations will be broken down by 
severity, by relationship to study drug, and AEs leading to treatment discontinuation. No 
hypothesis tests will be performed. 
9.4.2 
Cardio- and Cerebrovascular Events Determined by Adjudication 
Committee 
The CEC will review and adjudicate serious CCV events as MACE. MACE events are 
defined as the following: 
• Cardiovascular death 
• Non-fatal myocardial infarction (MI) 
• Non-fatal stroke  
 
The CEC will review and assess these non-fatal serious CCV events and all deaths as to 
whether or not they fulfill criteria (based on adjudication committee working practices) for 
MACE. 
MACE events will be summarized by treatment group. 
9.4.3 
Pneumonia Events Determined by Adjudication Committee 
All AEs/SAEs with preferred terms that could relate to pneumonia will be adjudicated by the 
CEC to provide a more complete assessment of all physician-reported pneumonias. The 
assessment of pneumonia events will include the overall rates of pneumonia. 
9.4.4 
Clinical Laboratory Measurements  
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for the 
baseline assessment (Day 1) and for the pre-dose value and change from baseline at pre-dose 
value of post-baseline visits with scheduled lab assessments of continuous laboratory 
variables, including serum potassium and glucose, will be tabulated. 
Shift tables relative to the normal reference ranges will be produced using the categories 
defined by the CTCAE Version 4.03 grades. For these shift tables, for each treatment, the 
subject’s pre-dose grade will be cross-tabulated by the subject’s maximum post-baseline 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 73 of 123 
grade during the treatment; also, the subject’s maximum post-baseline grade during treatment 
will be tabulated for all baseline grades combined. 
The number and percent of subjects with potentially clinically significant (PCS) lab values 
will be summarized. PCS values for serum potassium are < 3.0 mmol/L or > 6.0 mmol/L and 
for blood glucose < 2.2 mmol/L or > 13.9 mmol/L. PCS values for additional labs will be 
defined in the SAP. No hypothesis tests will be performed. 
9.4.5 
Vital Signs  
Summary statistics (mean, median, standard deviation and range) for absolute values and 
change from baseline values will be tabulated for each treatment and assessment time. For 
vital signs, baseline values will be defined as the average of the values prior to dosing at the 
randomization visit (Visit 4). PCS values for vital signs will be defined in the SAP and the 
percentage of subjects with PCS values will be summarized. No hypothesis tests will be 
performed. 
9.4.6 
Electrocardiograms 
Summary statistics (mean, median, standard deviation and range) for raw values and change 
from baseline values in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and 
QTcF interval will be calculated, where baseline is defined as the average of the pre-dose 
measurements taken prior to the start of treatment at the randomization visit (Visit 4). The 
QTcF is defined as (QT/ (RR 1/3)). Heart rate (bpm) is estimated as 60,000/RR. These 
assessments will be tabulated for each treatment and assessment time. PCS values for ECG 
parameters will be defined in the SAP, and the percentage and number of subjects with PCS 
ECG values will be tabulated. No hypothesis tests will be performed. 
9.4.7 
Exposure 
The duration of exposure to study medication (in days), the person-years of exposure, the 
mean number of doses, and number and percentage of subjects who are compliant will be 
summarized by treatment group. All exposure summaries will be generated for the safety 
population by actual treatment received. 
9.5 
Efficacy Analyses 
9.5.1 
Efficacy Analysis 
For the comparisons, the null hypothesis for each pair-wise comparison will be that the mean 
treatment difference is zero (mean treatment effects are equal). The alternative hypothesis is 
that the mean treatment difference is greater (less than) zero (mean treatment effects are not 
equal). P-values will be reported as 2-sided. 
9.5.1.1 
Change from Baseline in Morning Pre-dose Trough FEV1 
The change from baseline in morning pre-dose trough FEV1 will be analyzed using a linear 
model with repeated measures (RM). The model will include treatment, visit, and treatment 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 74 of 123 
by visit, and ICS use at Screening as categorical covariates and baseline trough FEV1, 
baseline eosinophil count, and percent reversibility to Ventolin HFA as continuous 
covariates.  Baseline is defined as the average of the non-missing 60 minute and 30 minute 
values obtained prior to dosing at Visit 4. An unstructured covariance model will be used to 
model variability across time within each subject. If this model fails to converge, an AR (1) 
structure will be used instead; for this model, subject will be included as a random effect. 
Two-sided p-values and point estimates with two-sided 95% confidence intervals will be 
produced for each treatment difference. The analysis will assess the treatment effects over the 
entire 52 weeks of treatment, i.e. subject data from the first 24 weeks of Study PT010006 
will be included in the analyses.   
Additional supportive analyses of morning pre-dose trough FEV1 will include treatment 
differences at individual time points estimated by the RM model. 
9.5.1.2 
Rescue Ventolin HFA Use 
The number of puffs of rescue Ventolin HFA taken in the previous 12 hours will be recorded 
in the subject diary in the morning and evening. For every period of time for which the mean 
number of puffs of rescue will be calculated, missing values will be ignored in both the 
numerator and denominator. As such, the denominator will be adjusted based on the number 
of days (including half days) with non-missing values. 
The mean change from baseline in rescue use will be summarized by treatment group over 52 
weeks and over each post-randomization 4-week interval (Interval 1 to Interval 13). 
9.5.1.3 
Percentage of Days with No Rescue Ventolin HFA Use over the Treatment 
Period 
As a supportive analysis, percentage of days with ‘no rescue Ventolin HFA use’ over 52 
weeks will be summarized using descriptive statistics. A ‘day with no rescue use’ is defined 
using rescue Ventolin HFA usage data from days where rescue Ventolin HFA usage data is 
non-missing as any day where the subject reported no puffs of rescue Ventolin HFA. 
9.5.1.4 
Chronic Obstructive Pulmonary Disease Exacerbations 
The rate of moderate or severe COPD exacerbations will be summarized by treatment group.  
Chronic obstructive pulmonary disease exacerbations will be considered separate events 
provided that 7 or more days are between the recorded stop date of the earlier event and start 
date of the latter. For moderate or severe COPD exacerbations, the start date is be defined as 
the start date of prescribed treatment with a systemic corticosteroid or systemic antibiotic and 
the stop date will be defined as the last day of prescribed treatment with a systemic 
corticosteroid or systemic antibiotic. The rate of COPD exacerbations of any severity will be 
presented in a similar manner. 
Duration of COPD Exacerbation 
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment, whereas for mild exacerbations, the duration is defined by the length of symptoms. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 75 of 123 
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date 
will be defined as the last day of prescribed treatment with a systemic corticosteroid or 
systemic antibiotic. In order to ensure that the same event is not counted twice, concurrent 
moderate or severe COPD exacerbations with start and stop dates equal to or less than 7 days 
apart will be considered the same event and assigned the maximum severity between the two.  
For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms 
as recorded by the subject in the eDiary, and the stop date will be defined as the last day of 
worsened symptoms. In order to ensure that the same event is not counted twice, mild COPD 
exacerbations with start and stop dates equal to or less than 7 days apart will be considered 
the same event. 
In addition, in order to not double count exacerbations that are moderate or severe, eDiary 
data from dates within 7 days of a moderate or severe exacerbation will not be included as 
additional mild COPD exacerbations. This implies that continuing worsened symptoms that 
meet the definition of a mild exacerbation would need to be present at least 2 days prior to 
the 7-day period immediately preceding the start date of a moderate or severe COPD 
exacerbation in order to be considered a separate event. Similarly, worsened symptoms 
would need to be present for at least 2 days after the 7-day period immediately following a 
moderate or severe COPD exacerbation to be considered a separate event. 
9.5.1.5 
Other Spirometry Analyses 
The analysis of the other between-treatment comparisons for changes in morning pre-dose 
trough FEV1 at each post-dose time point has already been described in Section 9.5.1.  
Treatment differences in the change from baseline in pre-dose trough FVC, PEFR, and 
FEF25-75 will be evaluated in a similar manner to the pre-dose trough FEV1. 
9.5.1.6 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
The EXACT is a 14-item PRO daily diary which will be used to measure the effect of 
treatment on exacerbations, and on the severity of respiratory symptoms. The E-RS is an 11-
item subset which will be used to measure the effect of treatment on the severity of 
respiratory symptoms. Mean change from baseline in: the daily EXACT Total Score, the 
daily total symptom score (RS-Total Score), as well as 3 subscale scores, RS-Breathlessness, 
RS-Cough and Sputum, and RS-Chest Symptoms, will be calculated over each 4-week 
interval of the 52-week Treatment Period. The last 7 days of the Screening Period from lead-
in Study PT010006 will be used to calculate the baseline. The mean change from baseline in 
RS-Total Score, RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms will be 
summarized by treatment group over 52 weeks and over each post-randomization 4-week 
interval (Interval 1 to Interval 13). 
9.5.2 
Type I Error Control 
Since the primary objective of this extension study is the evaluation of safety, no additional 
controls of type I error are planned. 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 77 of 123 
10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Regulatory Authority Approval 
Pearl 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 Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) Approval 
This clinical study complies with: 
• the standards described in Article 14, Paragraph 3, and Article 80-2 of the Law for 
Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices (commonly 
called the Drugs and Medical Devices Law), 
• the ordinances and related laws and regulations regarding good clinical practices 
(J-GCP), and 
• the Good Clinical Practice (GCP) prescribed by the International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH), 
• and it will be conducted in accordance with the ethical principles of the EU Directive 
(2001/20/EC), U.S. Code of Federal Regulations Title 21, Part 50 (21CFR50), and the 
J-GCP. 
 
The clinical study will be conducted in accordance with GCP.  These standards respect the 
following guidelines:  
• Guideline for GCP E6 (R1): Consolidated Guideline [ICH of Technical Requirements for 
the Registration of Pharmaceuticals for Human Use, May 1996]. 
• US CFR dealing with clinical studies (21 CFR parts 50, 54, 56, and 312). 
• Declaration of Helsinki, concerning medical research in humans (Ethical Principles for 
Medical Research Involving Human Subjects) 
[http://www.wma.net/en/10home/index.html]. 
• Any additional regulatory requirements. 
 
The Investigator (or Pearl, 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 78 of 123 
Pearl 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 Pearl 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 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. A copy of the signed 
ICF will be provided to the subject. The original will be retained by the Investigator. 
10.4 Laboratory Accreditation 
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations in that state and/or country. Reference values and/or 
normal ranges for the test results must be provided to Pearl. Pearl 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 Pearl that information furnished to the 
Investigator by Pearl will be maintained in confidence and such information will be divulged 
to the IRB, 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 Pearl (or representative), IRB, or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/CRF 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/CRF information, the subject/patient will be identified by unique code only; full 
names/initials will be masked prior to transmission to Pearl. In addition, the Investigator 
agrees to treat all subject data used and disclosed in connection with this study in accordance 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 79 of 123 
with all applicable privacy laws (i.e., Health Insurance Portability and Accountability Act; 
Unlawful Disclosure of Confidential Information), rules, and regulations. 
10.6 Quality Control and Assurance 
Pearl is responsible for implementing and maintaining quality control and quality assurance 
systems with written SOPs to ensure that Studies are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of GCP, and 
all applicable federal, state, and local laws, rules and regulations relating to the conduct of 
the clinical study. 
10.7 Data Management 
Data management procedures and information for this protocol will be provided by Pearl 
Therapeutics. 
10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and Pearl Therapeutics procedures, clinical 
monitors will contact the site prior to the subject enrollment to review the protocol and data 
collection procedures with site staff. In addition, the monitor will periodically contact the 
site, including conducting on-site visits. The extent, nature, and frequency of on-site visits 
will be based on such considerations as the study objective and/or endpoints, the purpose of 
the study, study design complexity, and enrollment rate. 
During these contacts, the monitor will: 
• Check the progress of the study 
• Review study data collected 
• Conduct source document verification 
• Identify any issues and address their resolution 
 
This will be done in order to verify that the: 
• Data are authentic, accurate, and complete 
• Safety and rights of subjects are being protected 
• Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements 
 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 80 of 123 
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 Pearl Therapeutics 
• 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 Pearl Therapeutics’ Quality Assurance auditors, and authorized representatives of the 
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 Pearl’s quality 
assurance auditors and by all applicable regulatory authorities. The period of time these 
documents must be maintained is governed by applicable regulations. Pearl or its designee 
will inform the Investigator when these documents may be destroyed. Pearl or its designee 
must be notified in writing at least 6 months prior to the intended date of disposal of any 
study record related to this protocol to allow Pearl to make alternate storage arrangements. 
The Head of the Medical Institution implementing the clinical study shall appropriately retain 
documents and records related to the study that should be retained, including records and 
source documents, for three years following the date the marketing and manufacturing 
approval for the pharmaceutical related to the test drug is received or the date that the study 
is terminated or ends, whichever is latest. Moreover, based on the Law for Ensuring the 
Quality, Efficacy, and Safety of Drugs and Medical Devices, if the pharmaceutical related to 
the test drug receives approval, the study sponsor shall retain these records appropriately for 
five years from the date that the recipient of the approval received the approval (in the case 
of a review which exceeds five years from the date the approval was received, until the time 
the review ends), and shall retain the records for a period decided upon with the sponsor. 
10.10 Financial Disclosure 
The Principal Investigator or sub-Investigators named on the Form FDA 1572 or the locally 
accepted alternate Investigator Statement form, 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 81 of 123 
10.11 Investigator's Final Report 
Shortly after completion of the Investigator's participation in the study, the Head of the 
Medical Institution will submit a written report to Pearl. 
10.12 Publication Policy 
Pearl 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 
Pearl -sponsored studies should fairly recognize the activities of those that have made a 
significant contribution to the study. Thus, it is anticipated that authorship will reflect the 
contribution made by Pearl 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, Pearl 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. Pearl (or its representatives) 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 
activities. All manuscripts will be reviewed and agreed upon before submission for 
publication by all authors. 
3. Sponsor Review of External Manuscripts: Consistent with the previous bullet point, 
drafts of any and all publications or presentations that may arise from this study must be 
submitted at least 30 days prior to submission for publication or presentation to Pearl for 
review, approval, and to ensure consistency with the policy in this protocol. Pearl 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 Pearl 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 Pearl to publish the study in a 
fair and accurate manner, Pearl 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 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 82 of 123 
evaluate and audit, e.g., 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 Pearl 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, Pearl reports clinical findings based on the 
guidance of The CONSORT (Consolidated Standards of Reporting Trials) Statement 
(CONSORT, 2010) and a 25 item checklist which is intended to improve the reporting of 
a randomized controlled Study, and to facilitate reader understanding of the Study design, 
conduct, analysis and interpretation, and to support their ability to assess the validity of 
its results. 
7. Internet Clinical Trial Listing: In addition, also consistent with the recommendations of 
the ICMJE, Pearl 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, and other clinical trial 
listings as appropriate (e.g., EUdraCT; https://eudract.ema.europa.eu). Per AstraZeneca 
policy, Pearl 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 83 of 123 
11 REFERENCE LIST 
Albers R, Ayres J, Backer V, et al. Formoterol in patients with chronic obstructive 
pulmonary disease: a randomized, controlled, 3-month trial. European Respiratory Journal 
2002; 19:936–943. 
Anderson GP. Formoterol: pharmacology, molecular basis of agonism, and mechanism of 
long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. 
Life Science. 1993;52(26):2145-2160. 
Calverley P, Lee A, Towse L, et al. Effect of tiotropium bromide on circadian variation in 
airflow limitation in chronic obstructive pulmonary disease. Br Medical J. 2003;58(10):855– 
860. 
Calverley P, Anderson J, Celli B, Ferguson G, Jenkins C, Jones P, Yates J, and Vestbo J, 
Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary 
Disease: New England Journal of Medicine 2007;356:775-89. 
Campbell M, Elias A, Johansson G, et al. Formoterol for maintenance and as-needed 
treatment of chronic obstructive pulmonary disease. Respiratory Medicine 2005; 99:1511–
1520. 
Campbell SC, Crier, GJ, Levine, BE, Simon, SJ, Smith, JS, Orevillo, C. et al. Cardiac safety 
of formoterol 12 µg twice daily in patients with chronic obstructive pulmonary disease. 
Pulmonary Pharmacology and Therapeutics 2007; 20:571-579. 
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. 
Consolidated Standards of Reporting Trials (CONSORT) Statement 2010.  Accessed on 17 
July 2014.  Available online at: http://www.consort-statement.org/consort-2010 
Dahl R, Greefhorst LA, Nowak D, et al. Inhaled formoterol dry powder versus ipratropium 
bromide in chronic obstructive pulmonary disease. American Journal of Respiratory and 
Critical Care Medicine 2001; 164:778–84. 
D’Urzo A, Salvo M D, Ramirez-Rivera A, et al. In subjects with copd, treatment with a 
combination of formoterol and ipratropium is more effective than a combination of 
salbutamol and ipratropium a 3-week, randomized, double-blind, within-subject, multicenter 
study. Chest. 2001;119(5):1347–1356. 
Eakin EG, Sassi-Dambron DE, Ries AL, Kaplan RM. Reliability and validity of dyspnea 
measures in patients with obstructive lung disease. Int J Behav Med. 1995;2(2):118-34. 
Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders analysis 
graph to present pain data over a range of cut-off points: Making clinical trial data more 
understandable. J Pain Symptom Manage 2006; 31:369-377. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 84 of 123 
Feenstra TL, van Genugten ML, Hoogenveen RT, et al. The impact of aging and smoking on 
the future burden of chronic obstructive pulmonary disease: a model analysis in the 
Netherlands. Am J Respir Crit Care Med 2001;164:590-596. 
Ferrer, Alonso J,Morera J, et al. Chronic obstructive pulmonary disease Part and health 
related quality of life. Ann Intern Med. 1997;127:1072-1079. 
Fletcher CM, Elmes PC, Fairbairn MB, et al. The significance of respiratory symptoms and 
the diagnosis of chronic bronchitis in a working population. Br Med J. 1959; 2:257-266. 
GOLD (Global Initiative for Chronic Obstructive Lung Disease). Global strategy for the 
diagnosis, management, and prevention of chronic obstructive pulmonary disease. National 
Institutes of Health, updated 2014 (www.goldcopd.com). Accessed December 10, 2014. 
Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is 
the true burden of disease? Chest 2003;123:1684-1692. 
Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systemic review and meta-
analysis. Eur Respir J 2006;28:523-532. 
Hochberg Y, A sharper Bonferroni procedure for multiple tests of significance. Biometrika 
1988; 75, 4, pp. 800-2. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data.  Second Edition. Wiley-
Interscience. 2002. 
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The Measurement of Dyspnea 
Contents, Interobserver Agreement, and Physiologic Correlates of Two New Clinical 
Indexes. Chest 1984;85:751-758. 
Mahler DA, Witek TJ. The MCID of the transition dyspnea index is a total score of one unit.  
COPD 2005:2(1):99-103. 
Mahler DA, Buhl R, Lawrence D, and McBryan D. of indacaterol and tiotropium in COPD 
patients according to dyspnoea severity.  Pulmonary Pharmacology & Therapeutics 2013; 26: 
348-355. 
Miller MR, Crapo R, Hankinson J, et al. ATS/ERS Task Force. General considerations for 
lung function testing. Eur Respir J. 2005; 26:153-61 Eur Respir J. 2005; 26:153-61. 
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-
2020: Global Burden of Disease Study. Lancet 1997;349:1498-1504. 
R Development Core Team, 2003] R Development Core Team (2003). R: A language and 
environment for statistical computing. R Foundation for Statistical Computing, Vienna, 
Austria. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 85 of 123 
Rennard SI, Tashkin DP, McElhattan J, et al.  Efficacy and tolerability of 
budesonide/formoterol in one HFA pressurized metered-dose inhaler in patients with chronic 
obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial.  
Drugs. 2009;69(5):549-65. 
Rossi A, Kristufek P, Levine B, Thomson MH, Till D, Kottakis J, Cioppa GD.  Comparison 
of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release 
theophylline in the treatment of COPD. Chest 2002; 121:1058-1069. 
Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000;117:5S-9S. 
Symbicort Turbuhaler Data Sheet 040313. CDS 191007. Astra Zeneca Limited. Auckland, 
New Zealand. March 2013. Available at: 
http://www.medsafe.govt.nz/profs/Datasheet/s/Symbicortinh.pdf. Accessed 12 January, 
2015. 
Tashkin DP, Rennard SI, Martin P, et al.  Efficacy and safety of budesonide and formoterol 
in one pressurized metered-dose inhaler in patients with moderate to very severe chronic 
obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008; 
68(14):1975 2000. 
van Noord JA. Comparison of tiotropium once daily, formoterol twice daily and both 
combined once daily in subjects with COPD. European Respiratory Journal. 2005; 
26(2):214–222. 
van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJG. 
Effects of Tiotropium With and Without Formoterol on Airflow Obstruction and Resting 
Hyperinflation in Patients With COPD. Chest 2006;129;509-517. 
Vogelmeier C, Kardos P, Harari S, Gans SJM,Stenglein S, Thirlwell J. Formoterol mono- 
and combination therapy with tiotropium in patients with COPD: A 6-month study. 
Respiratory Medicine. 2008;102:1511-1520. 
Witek TJ, Mahler DA, Minimal important difference of the transition dyspnoea index in a 
multinational clinical trial. European Respiratory Journal. 2003; 21: 267–272. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 86 of 123 
12 APPENDICES 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 87 of 123 
Appendix 1 
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 
Therapeutics), central training provided, qualification will be required, and specific operating 
instruction will also be provided. 
Series “ATS/ERS Task Force: Standardization of Lung Function Testing:  Number 2 in 
Series.  European Respiratory Journal 2005;26(2):319-338. 
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 (i.e., 37°C), ambient 
pressure, saturated with water vapor, 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-1s-1 (0.15 kPa L-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 
8 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 versus 
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 (PEF), 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 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 88 of 123 
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 (i.e., 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 (e.g., 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 89 of 123 
Table A1-2 Summary of Equipment Quality Control 
Test 
Minimal 
Interval 
Action 
Volume 
Daily 
Calibration check with a 3 L syringe 
Leak 
Daily 
2 cm H2O (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, 
e.g., +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 (e.g., 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 (e.g., field studies), volume 
accuracy must be checked more frequently than daily and the BTPS correction factor 
appropriately updated.   


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 90 of 123 
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, e.g., 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, e.g., 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 patient 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%. 
VC AND IC MANEUVERS 
Equipment 
For measurements of VC and IC, 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 expiratory maneuvers should be 
included in the display of VC maneuver. Regardless of whether the inspiratory or expiratory 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 91 of 123 
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 (i.e., 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) 
Time 
(s) 
Resistance and Back 
Pressure 
Test Signal 
VC 
0.5–8 L, +3% of reading 
or +0.050 L, whichever 
is greater 
0-14 
30 
 
3-L Calibration 
syringe 
FVC 
0.5–8 L, +3% of reading 
or +0.050 L, whichever 
is greater 
0-14 
15 
<1.5 cm H2O 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 
<1.5 cm H2O 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 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01  
 
Version 2.0 
 
 
 
Confidential and Proprietary 
Page 92 of 123 
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, 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 93 of 123 
Appendix 2 
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. (See 
example in Figure A2-1 below) 
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, i.e., the volume-time curve shows no change in volume (<0.025 L) for 
≥1s, 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. 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 trials with observed limitations. 
Figure A2-1 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. 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 94 of 123 
Between-Maneuver Reproducibility Criteria 
After three acceptable spirograms have been obtained, apply the following tests: 
• The two largest values of FVC must be within 0.150 L of each other 
• The two 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). 
 
 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 96 of 123 
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 2d 
20 puffs 
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. 
 
 
Figure 2a 
120 puffs 
Figure 2b 
110 puffs 
Figure 2c 
100 puffs 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 97 of 123 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 98 of 123 
 
 
 
Figure 4a  
 
 
 
 
 
Figure 4b 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 99 of 123 
 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 100 of 123 
 
 
 
 
 
 
 
 
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. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 101 of 123 
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. 
• 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 102 of 123 
• 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. 
 
 
 
 
 
 
 
 
 
  
Figure 10 
• Re-prime your inhaler 2 times after each cleaning. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 103 of 123 
• 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. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 104 of 123 
Appendix 4 
Instructions for Use of Symbicort Turbuhaler® 
Inhalation Powder Device  
Preparing your new Symbicort Turbuhaler: 
Before using your new Symbicort Turbohaler for the first time, you need to prepare it for 
use as follows: 
• Unscrew the cover and lift it off. You may hear a rattling sound. 
• Hold your Turbohaler upright with the red grip at the bottom. 
• Turn the red grip as far as it will go in one direction. Then turn it as far as it will go in the 
other direction (it does not matter which way you turn it first). You should hear a click 
sound. 
 
• Do this again, turning the red grip in both directions. 
• Your Turbohaler is now ready for use. 
 
How to take an inhalation: 
Every time you need to take an inhalation, follow the instructions below. 
1. Unscrew the cover and lift it off. You may hear a rattling sound. 
2. Hold your Turbohaler upright with the red grip at the bottom.  
3. Do not hold the mouthpiece when you load your Turbohaler. To load your Turbohaler 
with a dose, turn the red grip as far as it will go in one direction. Then turn it as far as it 
will go in the other direction (it does not matter which way you turn it first). You should 
hear a click sound. Your Turbohaler is now loaded and ready to use. Only load your 
Turbohaler when you need to use it.  
4. Hold your Turbohaler away from your mouth. Breathe out gently (as far as is 
comfortable). Do not breathe out through your Turbohaler.  


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 105 of 123 
5. Place the mouthpiece gently between your teeth. Close your lips. Breathe in as deeply 
and as  hard as you can through your mouth. Do not chew or bite on the mouthpiece. 
 
6. Remove your Turbohaler from your mouth. Then breathe out gently. The amount of 
medicine that is inhaled is very small. This means you may not be able to taste it after 
inhalation.  If you have followed the instructions, you can still be confident that you have 
inhaled the dose and the medicine is now in your lungs. 
 
7. If you are to take a second inhalation, repeat steps 2 to 6.  
8. Replace the cover tightly after use.  
9. Rinse your mouth with water after your daily morning and/or evening doses, and spit it 
out. 
Do not try to remove or twist the mouthpiece. It is fixed to your Turbohaler and must not be 
taken off. Do not use your Turbohaler if it has been damaged or if the mouthpiece has come 
apart from your Turbohaler. 
Cleaning your Turbohaler: 
Wipe the outside of the mouthpiece once a week with a dry tissue. Do not use water or 
liquids. 
How to store Symbicort Turbohaler: 
• Keep this medicine out of the sight and reach of children.  
• Do not use this medicine after the expiry date that is stated on the carton or on the label 
of  your inhaler after EXP. The expiry date refers to the last day of that month.  
• Do not store above 30°C.  
• Keep the container/cap tightly closed, in order to protect from moisture.  
• Do not throw away any medicines via wastewater or household waste. Ask your 
pharmacist how to throw away medicines you no longer use. These measures will help 
protect the environment. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 106 of 123 
Appendix 5 
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 
 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 107 of 123 
 
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 using your VENTOLIN HFA 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 108 of 123 
 
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 
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.


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 109 of 123 
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 
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. 
 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 110 of 123 
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. 
 
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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 111 of 123 
 
Figure H 
Step 10. Turn the actuator upside down and run warm water through the mouthpiece for 
about 30 seconds. See 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. 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 112 of 123 
 
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, 
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 
 
 
 












Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 118 of 123 
Appendix 7 
Hy’s Law 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Pearl clinical representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. 
Hy’s Law criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug-Induced Liver Injury (DILI) caused by study drug.  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
DEFINITIONS 
• Potential Hy's Law 
The levels of AST or ALT ≥3x ULN with TBL ≥2x ULN at any point during the study 
irrespective of an increase in alkaline phosphatase (ALP).  The elevations do not have to 
occur at the same time or within a specified time frame. 
• Hy's Law 
The levels of AST or ALT ≥3x ULN with TBL ≥2x ULN, where no other reason, other 
than the study drug, can be found to explain the combination of increases, eg, elevated 
ALP indicating cholestasis, viral hepatitis, or another drug. The elevations do not have to 
occur at the same time or within a specified time frame. 
 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
• ALT ≥3x ULN 
• AST  ≥3x ULN 
• TBL ≥2x ULN 
 
When a subject meets any of the identification criteria in combination, the central laboratory 
will immediately send an alert to the Investigator and Pearl representative.  
The Investigator will also remain vigilant for any laboratory reports where the identification 
criteria are met, the Investigator will: 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 119 of 123 
• Request a repeat of the test (new blood draw) by the central laboratory 
When the identification criteria are met from central laboratory results the Investigator will 
without delay: 
• Determine whether the subject meets PHL criteria by reviewing all laboratory reports 
including previous visits. 
• Notify the Pearl representative. 
• Promptly enter the laboratory data into the laboratory CRF. 
 
FOLLOW-UP 
Potential Hy’s Law Criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• Notify the Pearl representative who will then inform the central Study Team. 
 
The Medical Monitor contacts the Investigator, to provide guidance, discuss, and agree on 
method of follow up and the continuous review of data.  Subsequent to this contact, the 
Investigator will: 
• Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
• Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Pearl Medical Monitor. 
• If at any time (in consultation with the Pearl Medical Monitor) the PHL case meets 
serious criteria, report the event as an SAE using standard reporting procedures. 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 2 weeks after the biochemistry abnormality was initially detected, the Pearl 
Medical Monitor contacts the Investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI caused 
by the study drug. The Pearl Medical Monitor and other subject matter experts (as 
appropriate) will collaborate in the review and assessment of these cases. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE: 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 120 of 123 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
• If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the standard reporting procedures. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study drug: 
• Report as an SAE (report term "Hy's Law case") according to Pearl standard processes.  
• The "Medically Important" serious criterion should be used if no other serious criteria 
apply. 
• As there is no alternative explanation for the HL case, a causality assessment of "related" 
should be assigned. 
 
If, there is an unavoidable delay of over 2 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation. Until an informed decision can be made, the following procedure 
should be followed: 
• Report as an SAE (report term "Potential Hy's Law") applying serious criteria and 
causality assessment as per above. 
 
Continue follow up and review according to the agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE Report Form according to the outcome of the 
review. 
 
 


Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 121 of 123 
Appendix 8 
Dose Indicator Reading  
For the purposes of this study, when recording the dose indicator display value, review the 
indicator display at the top of the MDI and record the number of inhalations remaining that 
matches the chart below: 
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  
 
 
 




Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics, Inc.  
Clinical Trial Protocol: PT010007-01 
 
Version 2.0,  
 
 
 
Confidential and Proprietary 
Page 123 of 123 
Appendix 10 
Investigator’s Agreement and Signature Page 
Study Title: 
A Randomized, Double-blind, Parallel Group, 28-Week Chronic Dosing, Multi-
Center Extension Study to Assess the Safety and Efficacy of PT010, PT003, and 
PT009 in Japanese Subjects with Moderate to Very Severe Chronic Obstructive 
Pulmonary Disease (COPD) compared with Symbicort® Turbuhaler® as an 
Active Control 
Study Number: 
PT010007-01 
Final Date: 
17 March 2017 
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 
• 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 comply with good clinical practices (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 the Sponsor 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 Therapeutic 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 Therapeutics 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 Therapeutics 
• 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 case report forms 
(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 Therapeutics 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 
•  
Signature: 
___________________________________  
Date: 
_____________________________ 
 
Name:  
___________________________________ 
 
Site Name: ___________________________________ 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study Code 
PT010006 
NCT#  
NCT02497001 
Date 
09JANUARY2018 
 
 
 
 
 
 
 
 
 
 
  A Randomized, Double-Blind, Parallel-Group, 24-Week, Chronic-Dosing, 
Multi-Center Study to Assess the Efficacy and Safety of PT010, PT003, and 
PT009 Compared with Symbicort® Turbuhaler® as an Active Control in 
Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary 
Disease 
 
 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 1 of 355
 
 
 
 
STATISTICAL ANALYSIS PLAN FOR 
STUDY PT010006 AND STUDY PT010007 
 
 
Protocol Numbers: 
PT010006 and PT010007 
Investigational Drug 
and Drug Number: 
BGF MDI; PT010 
GFF MDI; PT003 
BFF MDI; PT009 
Symbicort® Turbuhaler®
Indication:
COPD 
Dosage Form/Dose: 
x
BGF MDI 320/14.4/9.6 ȝg ex-actuator BID 
x
GFF MDI 14.4/9.6 ȝg ex-actuator BID 
x
BFF MDI 320/9.6 ȝg ex-actuator BID 
x
Symbicort® Turbuhaler® 400/12 ȝg BID 
 
PT010006 Protocol Title: A Randomized, Double-Blind, Parallel-Group, 24-Week, Chronic-
Dosing, Multi-Center Study to Assess the Efficacy and Safety of PT010, PT003, and PT009 
Compared with Symbicort® Turbuhaler® as an Active Control in Subjects with Moderate to Very 
Severe Chronic Obstructive Pulmonary Disease 
 
PT010007 Protocol Title: A Randomized, Double-Blind, Parallel-Group, 28-Week, Chronic-
Dosing, Multi-Center, Extension Study to Assess the Safety and Efficacy of PT010, PT003, and 
PT009 in Japanese Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary 
Disease (COPD) compared with Symbicort® Turbuhaler® as an Active Control 
 
Date of Issue: 
09 Jan 2018 
 
Version:
Version 2.0 
 




BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 3 of 355
 
 
Change Log
Version No. 
Effective Date 
Reason for the Change / Revision 
Supersedes 
2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
09 Jan 2018 
 
x
Non-inferiority margins for are provided for 
the following secondary endpoints: TDI, 
MCID in SGRQ, peak change from baseline in 
FEV1, and E-RS Total Score. 
x
The definition of ICS use at screening has 
been clarified. 
x
Have clarified the definitions of the on-
treatment and post-treatment periods. 
x
Have clarified that subjects with premature 
treatment discontinuation are to be considered 
to be non-responders for the responder 
analyses. 
x
Have specified how to estimate the 
attributable estimand for the SGRQ responder 
analysis. 
x
Have provided more detail about the statistical 
analysis of the EuroQOL EQ-5D 
questionnaire. 
x
Have clarified the baseline Exacerbation 
History categories to be using for sub-group 
analyses. 
x
Have specified correlation analyses for 
subgroups. 
x
Have clarified that the Attributable Estimand 
is considered to be secondary. 
x
Minor edits have been made for clarity and 
grammatical correctness. 
 
1.0 
 
 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 4 of 355
 
 
TABLE OF CONTENTS 
1.
INTRODUCTION ..................................................................................................................................... 14
2.
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 14
2.1
STUDY OBJECTIVES ............................................................................................................................ 14
2.2
OBJECTIVES FOR PT010006: .............................................................................................................. 14
2.2.1
Primary Objective ............................................................................................................... 14
2.2.2
Secondary Objectives ......................................................................................................... 14
2.2.3
Safety Objectives ................................................................................................................ 15
2.2.4
Healthcare Resource Utilization Objective ......................................................................... 15
2.3
OBJECTIVES FOR SUB-STUDIES IN PT010006 ..................................................................................... 15
2.3.1
12-Hour Pulmonary Function Test (PFT) Sub-study Objective ......................................... 15
2.3.2
Pharmacokinetic Sub-study Objective ................................................................................ 15
2.3.3
HPA Axis Sub-study Objective .......................................................................................... 15
2.4
OBJECTIVES FOR PT010007: .............................................................................................................. 15
2.4.1
Primary Objective ............................................................................................................... 15
2.4.2
Other Objectives ................................................................................................................. 15
2.5
STUDY ENDPOINTS ............................................................................................................................. 16
2.5.1
Efficacy Endpoints for PT010006 ...................................................................................... 16
2.5.1.1
Primary Efficacy Endpoints ............................................................................... 16
2.5.1.2
Secondary Efficacy Endpoints ........................................................................... 16
2.5.1.3
Other Efficacy Endpoints ................................................................................... 17
2.5.1.4
Efficacy Endpoints for PT010007:..................................................................... 18
2.5.2
Safety Endpoints ................................................................................................................. 19
2.5.3
Sub-Study Endpoints (for PT010006) ................................................................................ 19
2.5.3.1
12-hour PFT Sub-Study ..................................................................................... 19
2.5.3.2
Pharmacokinetic Sub-study Endpoints: ............................................................. 20
2.5.3.3
HPA Axis Sub-study Endpoints: ........................................................................ 20
2.5.4
Health Care Resource Utilization Endpoints (for Study PT010006) .................................. 20
3.
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ............................................................. 21
3.1
STUDY DESIGNS ................................................................................................................................. 21
3.1.1
Overall Study Designs and Plan ......................................................................................... 21
3.1.2
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other Restrictions (if 
applicable) .......................................................................................................................... 25
3.2
HYPOTHESIS TESTING ........................................................................................................................ 25
3.3
INTERIM ANALYSIS ............................................................................................................................ 25
3.4
SAMPLE SIZE ...................................................................................................................................... 25
4.
DATA AND ANALYTICAL QUALITY ASSURANCE ........................................................................ 26
5.
ANALYSIS POPULATIONS ................................................................................................................... 27
5.1
POPULATION DEFINITIONS ................................................................................................................. 27
5.1.1
Intent-to-Treat (ITT) Population (PT010006 only) ............................................................ 27
5.1.2
Modified Intent-to-Treat (mITT) Population (PT010006 only) .......................................... 27
5.1.3
Japanese Modified Intent-to-Treat (mITT) Population ....................................................... 27
5.1.4
Rescue Ventolin User Population (RVU) (PT010006 Only) .............................................. 27
5.1.5
Per-Protocol (PP) Population (PT010006 only) ................................................................. 27
5.1.6
Safety Population (PT010006 only) ................................................................................... 28
5.1.7
Japanese Safety Population ................................................................................................. 29
5.1.8
PT010007 Safety Population .............................................................................................. 29


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 5 of 355
 
 
5.1.9
PK Population ..................................................................................................................... 29
5.1.10
HPA Axis Population ......................................................................................................... 29
5.2
POPULATIONS FOR PRIMARY AND SENSITIVITY ANALYSES ................................................................ 29
6.
STATISTICAL ANALYSIS ..................................................................................................................... 30
6.1
DATA HANDLING RULES AND DEFINITIONS, INCLUDING HANDLING OF MISSING DATA .................... 30
6.2
SUBJECT DISPOSITION AND ANALYSIS POPULATIONS ........................................................................ 31
6.3
DEMOGRAPHIC AND BASELINE CHARACTERISTICS AND EXTENT OF EXPOSURE ................................. 32
6.3.1
Demography, Physical Characteristics, CAT ..................................................................... 32
6.3.2
COPD History, Screening/Baseline Spirometry, and Reversibility .................................... 33
6.3.3
Medical and Surgical History at Screening, Reproductive Status and Pregnancy Testing . 34
6.3.4
Prior, Concomitant, and Post-Treatment Medications/Treatments ..................................... 35
6.3.5
Extent of Exposure to Study Medication and Compliance ................................................. 36
6.4
EFFICACY ANALYSES ......................................................................................................................... 36
6.4.1
Estimands ........................................................................................................................... 37
6.4.2
Baselines and Baseline Covariates for Analysis ................................................................. 38
6.4.3
Visits and Time Windows for Visit-Based Efficacy Assessments ..................................... 39
6.4.4
Primary Efficacy Analyses ................................................................................................. 40
6.4.4.1
Change from Baseline in Morning Pre-Dose Trough FEV1 ............................... 40
6.4.4.2
FEV1 AUC0-4 ...................................................................................................... 42
6.4.4.3
Assumptions Checks and Removal of Outliers in Sensitivity Analyses ............ 43
6.4.4.4
Sensitivity Analyses for Missing Data ............................................................... 44
6.4.5
Analysis of Secondary Efficacy Variables ......................................................................... 47
6.4.5.1
Transition Dyspnea Index .................................................................................. 48
6.4.5.2
Peak FEV1 .......................................................................................................... 49
6.4.5.3
St. George’s Respiratory Questionnaire ............................................................. 51
6.4.5.4
Rescue Ventolin HFA Use ................................................................................. 55
6.4.5.5
RS-Total Score ................................................................................................... 58
6.4.5.6
Time to Onset of Action Assessed Using FEV1 on Day 1 ................................. 59
6.4.5.7
Other Spirometry Endpoints .............................................................................. 59
6.4.5.8
Rate of COPD Exacerbations ............................................................................. 60
6.4.6
Time to Clinically Important Deterioration ........................................................................ 68
6.4.7
Analysis of Other Endpoints ............................................................................................... 69
6.4.7.1
Percentage of Days with “No Rescue Ventolin HFA Use” Over the Treatment 
Period ................................................................................................................. 69
6.4.7.2
Time to First COPD Exacerbation ..................................................................... 69
6.4.7.3
Time to Treatment Failure ................................................................................. 70
6.4.7.4
European Quality-of-Life-5 Dimension-5 Level Questionnaire ........................ 70
6.4.8
12-Hour Pulmonary Function Tests .................................................................................... 71
6.4.9
Subgroup Analyses ............................................................................................................. 72
6.4.9.1
China and Asia Subgroups ................................................................................. 75
6.4.9.2
Subgroup Analyses China and Asia ................................................................... 75
6.4.10
Correlations ........................................................................................................................ 76
6.4.11
Control of Type I Error ....................................................................................................... 76
6.4.11.1 Japan/China Approach: ...................................................................................... 76
6.4.11.2 EU/Canada Approach ........................................................................................ 78
6.4.11.3 US Approach ...................................................................................................... 81
6.5
SAFETY ANALYSIS ............................................................................................................................. 83
6.5.1
Adverse Events ................................................................................................................... 83
6.5.1.1
Adverse Events of Special Interest .................................................................... 86
6.5.1.2
MACE Events Determined by Clinical Endpoint Committee ............................ 88
6.5.1.3
Pneumonia Events Determined by Adjudication Committees ........................... 88
6.5.1.4
Cause of Death Determined by Adjudication Committees ................................ 88


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 6 of 355
 
 
6.5.2
Clinical Laboratory Measurements ..................................................................................... 89
6.5.3
Vital Signs .......................................................................................................................... 93
6.5.4
12-Lead Electrocardiogram Measurements ........................................................................ 95
6.5.5
Healthcare Resource Utilization ......................................................................................... 97
6.5.6
Pharmacokinetic Analysis .................................................................................................. 99
6.5.7
HPA Axis Analysis ........................................................................................................... 101
6.5.8
Physical Examination ....................................................................................................... 102
7.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................. 103
8.
STATISTICAL SOFTWARE ................................................................................................................. 103
9.
REFERENCES ........................................................................................................................................ 103
APPENDIX 1: DATA HANDLING RULES .................................................................................................. 105
APPENDIX 2: ANALYSIS DATASET SPECIFICATIONS ........................................................................ 113
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES ................................................................... 113
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .. 114
APPENDIX 5: STANDARD MEDDRA QUERIES ...................................................................................... 114
APPENDIX 6: STATISTICAL DETAILS ..................................................................................................... 114
APPENDIX 7: TABLE OF CONTENTS END-OF-TEXT TLFS ................................................................ 114
APPENDIX 8: TABLE OF CONTENTS FOR POST-TEXT TLFS IN THE CHINA SUBGROUP ........ 211
APPENDIX 9: TABLE OF CONTENTS POST-TEXT TLFS IN THE ASIA SUBGROUP ..................... 224
APPENDIX 10: EQ-5D CROSSWALK SPSS AND SAS CODE FOR STATISTICAL ANALYSES OF 
INDEX SCORE ...................................................................................................................................... 236
 
List of Tables
Table 1
Analysis Study Time Window for Spirometry Assessments ................................. 40
Table 2
Sensitivity Analyses for Morning Pre-dose Trough FEV1 and FEV1 AUC0-4 ....... 45
Table 3
Sensitivity Analyses for Peak Change from Baseline in FEV1 .............................. 51
Table 4
Sensitivity Analyses for Percentage of Subjects Achieving an MCID of 4 Units or 
More in SGRQ Total Score at Week 24 ................................................................ 54
Table 5
Sensitivity Analyses for Rescue Ventolin HFA Use .............................................. 57
Table 6
Sensitivity Analyses for Rate of Moderate or Severe COPD Exacerbations ......... 62
Table 7
Adverse Events of Special Interest ........................................................................ 86
Table 8
Lab Parameters ....................................................................................................... 90
Table 9
Analysis Study Time Window for Clinical Lab Assessments ............................... 91
Table 10
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria ............... 93
Table 11
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ............................................................................................... 94
Table 12
Potentially Clinically Significant Criteria for Heart Rate Parameters ................... 94
Table 13
Analysis Study Time Windows for Vital Signs Assessments ................................ 95
Table 14
Analysis Study Time Window for ECG Assessments ........................................... 96
Table 15
Criteria for PCS ECG Values ................................................................................. 97


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 7 of 355
 
 
List of Figures 
 
Figure 1
Study Design .......................................................................................................... 24
Figure 2 
Overarching Intervals of Moderate-or-Severe (QMS) and Severe (QS) COPD 
Exacerbations ......................................................................................................... 65
Figure 3 
Overarching Intervals (I) of Mild-Moderate-or-Severe COPD Exacerbation Events 
Based on eDiary Symptom Data ............................................................................ 66
Figure 4 
Overarching Intervals (QQ) of Mild-Moderate-or-Severe COPD Exacerbation 
Events Incorporating Both CRF Data and eDiary Symptom Data ......................... 66
Figure 5
Type I Error Control: Japan/China Approach ........................................................ 78
Figure 6
Type I Error Control: EU Approach ...................................................................... 80
Figure 7
Type I Error Control: US Approach ...................................................................... 82


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 8 of 355
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AR(1) 
Autoregressive order 1 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
BDI 
Baseline Dyspnea Index 
BFF MDI 
Budesonide and Formoterol Fumarate Metered Dose Inhaler 
BGF MDI 
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose 
Inhaler 
BID 
Bis in die, twice daily 
bpm 
Beats per minute 
BMI 
Body mass index 
CAT 
Chronic Obstructive Pulmonary Disease Assessment Test 
CCU 
Coronary care unit 
CCV 
Cardio- and cerebrovascular 
CD 
Compact disc 
CI 
Confidence interval 
CID 
Clinically important deterioration 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
cm 
Centimeter 
Cmin 
The minimum observed plasma concentration, expressed in concentration 
units 
Cmax 
The maximum observed plasma concentration, expressed in concentration 
units 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 9 of 355
 
 
Cavg 
Average concentration during a dosing interval 
COPD 
Chronic obstructive pulmonary disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
į 
Non-inferiority margin 
DMC 
Data monitoring committee 
E-RS 
Evaluating Respiratory Symptoms 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic Diary 
e.g. 
Exempli gratia; for example 
eGFR 
Estimated glomerular filtration rate 
EQ-5D 
EuroQol 5 Dimensions Questionnaire 
EQ-5D-5L 
EuroQol 5 Dimensions Questionnaire 5-level  
ER 
Emergency room 
EU 
European Union 
ex-actuator 
Dose delivered from the actuator (i.e., mouthpiece) of the MDI  
EXACT 
Exacerbations of Chronic Pulmonary Disease Tool – Patient Reported 
Outcomes 
FEV1 
Forced expiratory volume in the first second 
FEF25-75 
Forced expiratory flow between 25% and 75% of FVC 
FVC 
Forced vital capacity 
GFF MDI 
Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler 
H0 
Null Hypothesis 
H1 
Alternative hypothesis 
hCG 
Human chorionic gonadotropin 
HCRU 
Health Care Resource Utilization 
HFA 
Hydrofluoroalkane 
HLGT 
High-Level Group Term 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 10 of 355
 
 
HLT 
High-Level Term 
HPA 
Hypothalamic-pituitary-adrenal 
ICF 
Informed consent form 
ICS 
Inhaled corticosteroid 
ICU 
Intensive care unit 
i.e. 
Id est; that is 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
JRS 
Japanese Respiratory Society 
Ȝz 
The terminal elimination rate constant, calculated from the slope of the 
terminal portion of the ln(drug concentration) versus time curve 
L 
Liter 
LABA 
Long-acting ȕ2 agonist 
LAMA 
Long-acting muscarinic antagonist 
LLQ 
lower limit of quantification 
MACE 
Major adverse cardiovascular event 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MCMC 
Markov chain Monte Carlo 
MCID 
Minimal clinically important difference 
MDI 
Metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MNAR 
Missing not at random 
μg 
Microgram 
mITT 
Modified intent-to-treat  
mL 
Milliliter 
mm 
Millimeter 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 11 of 355
 
 
mmHg 
Millimeter of mercury 
msec (ms) 
Millisecond 
NHANES 
National Health and Nutrition Examination Survey 
OTC 
Over-the-counter 
PCS 
Potentially clinically significant 
PEFR 
Peak expiratory flow rate 
PFT 
Pulmonary function test 
PK 
Pharmacokinetic 
PMM 
Pattern mixture model  
PP 
Per-protocol 
PT 
Preferred Term 
PT003 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol 
PT009 
Budesonide and Formoterol Fumarate Inhalation Aerosol 
PT010 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol 
QoL 
Quality of life 
QTcF 
QT corrected using Fridericia’s formula 
RM 
Repeated measures 
ROM 
Read-only memory 
SABA 
Short-acting ȕ2-agonist 
SAE 
Serious adverse event 
SAMA 
Short-acting muscarinic antagonist 
SAP 
Statistical analysis plan 
SC 
Serum cortisol 
SD 
Standard deviation 
SGRQ 
St. George’s Respiratory Questionnaire 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 12 of 355
 
 
t1/2 
The apparent terminal elimination half-life, expressed in hours. 
TBH 
Turbuhaler 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, listings, and figures 
tmax 
The time to reach maximum observed plasma concentration (Cmax), 
expressed in hours 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog score 
WAVE 
Weighted average 
WHO-DD 
World Health Organization Drug Dictionary 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 13 of 355
 
 
Trademark Information 
Trademarks Not Owned By Pearl 
Atrovent
SAS
Ventolin 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 14 of 355
 
 
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 PT010006, 
and its extension sub-study, PT010007, in Japanese subjects. Pearl Therapeutics is a member of 
the AstraZeneca group of companies. Sponsor means either Pearl or AstraZeneca. The SAP 
should be read in conjunction with the study protocol. This version of the SAP has been 
developed using the PT010006-01 Amended Protocol (Version 3.0 dated 25 August 2017) and 
the PT010006 CRF (Version 02 dated 19 February 2016) as well as the PT010007 Protocol 
(Version 2.0 dated 17 March 2017) and the PT010007 CRF (Version Revision 01 dated 25 May 
2017). 
2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1
Study Objectives 
The overall objective of PT010006 is to assess the efficacy and safety of treatment with BGF 
MDI 320/14.4/9.6 ȝg (micrograms) (budesonide, glycopyrronium, and formoterol fumarate 
metered dose inhaler), GFF MDI 14.4/9.6 ȝg (glycopyrronium and formoterol fumarate metered 
dose inhaler), BFF MDI 320/9.6 ȝg (budesonide and formoterol fumarate metered dose inhaler), 
and Symbicort® Tubuhaler® (TBH) 400/12 ȝg over 24 weeks in subjects with moderate to very 
severe chronic obstructive pulmonary disease (COPD).  
The objective of the Japanese extension sub-study PT010007 is to assess the long term safety 
and tolerability of treatment with BGF MDI 320/14.4/9.6 ȝg, GFF MDI 14.4/9.6 ȝg, BFF MDI 
320/9.6 ȝg, and Symbicort® Turbuhaler® 400/12 ȝg over 52 weeks in Japanese subjects with 
moderate to very severe COPD. 
2.2
Objectives for PT010006: 
2.2.1
Primary Objective 
x
To assess the effects of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on lung 
function. 
 
2.2.2
Secondary Objectives 
x
To assess the effects of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on dyspnea. 
x
To assess the effects of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on quality of 
life (QoL). 
x
To assess the effects of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on symptoms 
of COPD. 
x
To assess the effects of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on COPD 
exacerbations. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 15 of 355
 
 
x
To determine the time to onset of action of BGF MDI, GFF MDI, BFF MDI, and Symbicort 
TBH. 
2.2.3
Safety Objectives 
x
To assess the safety of BGF MDI, GFF MDI, BFF, and Symbicort TBH. 
 
2.2.4
Healthcare Resource Utilization Objective 
x
To assess overall and COPD-specific Healthcare Resource Utilization (HCRU) of BGF MDI, 
GFF MDI, BFF MDI, and Symbicort TBH. 
2.3
Objectives for Sub-studies in PT010006 
2.3.1
12-Hour Pulmonary Function Test (PFT) Sub-study Objective 
x
To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on PFT 
parameters over 12 hours. 
2.3.2
Pharmacokinetic Sub-study Objective 
x
To characterize the steady state pharmacokinetics of budesonide, glycopyrronium, and 
formoterol based on pharmacokinetic (PK) assessments. 
2.3.3
HPA Axis Sub-study Objective 
To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on hypothalamic-
pituitary-adrenal (HPA) axis function.
2.4
Objectives for PT010007: 
2.4.1
Primary Objective 
x
To evaluate the long-term safety and tolerability of BGF MDI, GFF MDI, BFF MDI, and 
Symbicort TBH in Japanese subjects with moderate to very severe COPD. 
2.4.2
Other Objectives 
x
To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on lung 
function. 
x
To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on COPD 
exacerbations. 
x
To assess the effect of BGF MDI, GFF MDI, BFF MDI, and Symbicort TBH on symptoms 
using the change in rescue medication use as an indirect measure of symptom control. 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 16 of 355
 
 
2.5
Study Endpoints 
2.5.1
Efficacy Endpoints for PT010006 
The primary endpoints, treatment comparisons of interest, and analysis timeframes may differ by 
country or region due to local regulatory agency requirements. The 3 different registration 
approaches will be called: (1) Japan/China, (2) Europe (EU)/Canada, and (3) United States (US). 
Countries not specifically mentioned will be decided by regulatory requirements and included in 
one of the three defined registration approaches. The delineation of multiplicity controls for the 
primary and secondary measures will be separated by approach. 
2.5.1.1
Primary Efficacy Endpoints
Primary Endpoint (Japan/China Approach) 
x
Change from baseline in morning pre-dose trough FEV1 (forced expiratory volume in the 
first second) over Weeks 12 to 24 (BGF MDI versus BFF MDI, BGF MDI versus GFF MDI, 
and BFF MDI versus Symbicort TBH) 
 
Primary Endpoints (European Union [EU] and Canada Approaches) 
x
FEV1 area under the curve from 0 to 4 hours (AUC0-4) over 24 weeks (BGF MDI versus BFF 
MDI and BGF MDI versus Symbicort TBH) 
x
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BGF MDI versus 
GFF MDI and BFF MDI versus Symbicort TBH [non-inferiority]) 
 
Primary Endpoints (United States [US] Approach) 
x
FEV1 AUC0-4 at Week 24 for the comparison of BGF MDI to BFF MDI 
x
Change from baseline in morning pre-dose trough FEV1 at Week 24 for the comparison of 
BGF MDI to GFF MDI 
 
2.5.1.2
Secondary Efficacy Endpoints 
Endpoints that are not considered primary for a specific approach or region have been included 
under secondary endpoints for that region; as a result, secondary endpoints may differ between 
approaches. 
Secondary Endpoints (Japan/China Approach): 
x
Change from baseline in morning pre-dose trough FEV1 over 24 weeks 
x
FEV1 AUC0-4 over Weeks 12 to 24 
x
Change from baseline in St. George Respiratory Questionnaire (SGRQ) total score over 
Weeks 12 to 24 
x
Transition dyspnea index (TDI) focal score over Weeks 12 to 24 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 17 of 355
 
 
x
Change from baseline in average daily rescue Ventolin Hydrofluoroalkane (HFA) use over 
24 weeks 
x
Peak change from baseline in FEV1 within 4 hours post-dosing over Weeks 12 to 24 
x
Time to clinically important deterioration (CID) 
x
Time to onset of action on Day 1 
 
Secondary Endpoints (Europe [EU] and Canada Approach):  
x
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BGF MDI versus 
BFF MDI) 
x
TDI focal score over 24 weeks (EU only) 
x
Change from baseline in SGRQ total score over 24 weeks 
x
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks 
x
Peak change from baseline in FEV1 within 4 hours post-dosing over 24 weeks 
x
Rate of Moderate or Severe COPD Exacerbations 
x
Change from baseline in the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) 
total score (RS-Total Score) over 24 weeks (EU only) 
x
Time to CID 
x
Time to onset of action on Day 1 
 
Secondary Endpoints (US Approach):  
x
Change from baseline in morning pre-dose trough FEV1 over 24 weeks  
x
Percentage of subjects achieving an minimal clinically important difference (MCID) of 4 
units or more in SGRQ total score (SGRQ responders) at Week 24 
x
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks. 
x
Peak change from baseline in FEV1 within 4 hours post-dosing at Week 24 
x
Rate of Moderate or Severe COPD Exacerbations 
x
Time to onset of action on Day 1 
 
2.5.1.3
Other Efficacy Endpoints 
Wherever stated, analyses of an endpoint at each post-randomization visit will be performed only 
at time points where the endpoint will be assessed per the schedule of assessments. 
 
Day 1 Assessments: 
x
Change from baseline at each post-dose time point in FEV1, forced vital capacity (FVC), 
peak expiratory flow rate (PEFR), and forced expiratory flow between 25% to 75% (FEF25-
75)  
x
Proportion of subjects achieving an improvement from baseline in FEV1 using different 
thresholds (e.g., 10%, 12%, 100 mL [milliliter], 200 mL; and 12% and 200 mL) 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 18 of 355
 
 
Assessments Over 24 Weeks (Unless Otherwise Stated): 
x
Rate of moderate or severe COPD exacerbations 
x
Rate of COPD exacerbations of any severity 
x
Rate of severe COPD exacerbations 
x
Time to treatment failure (treatment discontinuation for any cause, moderate or severe 
exacerbation, or death) 
x
Time to first moderate or severe COPD exacerbation 
x
Time to first COPD exacerbation of any severity 
x
Time to first severe COPD exacerbation 
x
Time to CID 
x
Time to sustained CID  
x
Additional spirometry assessments over 24 weeks, over Weeks 12 to 24, and at each post-
randomization visit: 
í
Change from baseline in morning pre-dose trough for FEV1, FVC, PEFR, and  
FEF25-75 
í
Peak change from baseline within 4 hours in FEV1, FVC, PEFR, and FEF25-75 
í
FEV1 AUC0-4, FVC AUC0-4, PEFR AUC0-4, and FEF25-75 AUC0-4 
x
Change from baseline in: the EXACT total score, E-RS: COPD total score (RS-Total Score), 
as well as 3 subscale scores symptom (RS-Breathlessness, RS-Cough and Sputum, and RS-
Chest Symptoms over each 4-week interval of the 24-week Treatment Period 
x
TDI focal score at each post-randomization visit 
x
Individual components of the TDI: functional impairment, magnitude of task, and magnitude 
of effort over 24 weeks, over Weeks 12 to 24, and at each post-randomization visit 
x
Percentage of subjects achieving an MCID threshold of 1 unit or more on average in TDI 
focal score over 24 weeks and separately over Weeks 12 to 24 
x
Changes from baseline at each post-randomization visit for SGRQ total score 
x
Change in individual domain scores of SGRQ: Symptoms, Activity, and Impacts over 24 
weeks, over Weeks 12 to 24, and at each post-randomization visit 
x
Percentage of subjects achieving an MCID of 4 units or more in SGRQ total score at Week 
24, over 24 weeks, and separately over Weeks 12 to 24 
x
Quality-of-Life Endpoints: European Quality-of-Life-5 Dimensions (EQ-5D-5L) scored at 
randomization and each post-randomization visit 
 
 
2.5.1.4
Efficacy Endpoints for PT010007: 
All efficacy endpoints for PT010007 are exploratory. The data from this 28-week study will be 
combined with the 24 weeks of data obtained from Study PT010006 to provide safety and 
efficacy data over 52 weeks of treatment. 
x
Change from baseline in morning pre-dose trough FEV1 over 52 weeks and at each post-
randomization visit 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 19 of 355
 
 
x
Change from baseline in average daily rescue Ventolin HFA (albuterol sulfate) use 
x
Percentage of days with no rescue Ventolin HFA use 
x
Rate of moderate or severe COPD exacerbations 
x
Rate of COPD exacerbations of any severity 
x
Change from baseline in morning pre-dose trough over 52 weeks, and at each post-
randomization visit for: 
o
FVC 
o
PEFR 
o
FEF25-75 
x
Change from baseline over 52 weeks and over each 4-week interval of the 52-week 
Treatment Period in: 
o
the EXACT total score 
o
the RS-Total Score 
o
3 subscale scores symptom (RS-Breathlessness, RS-Cough and Sputum, and RS-
Chest Symptoms) 
 
2.5.2
Safety Endpoints 
The safety endpoints for both PT010006 and PT010007 include: 
x
Adverse events (AEs), Treatment-emergent AEs, serious adverse events (SAEs), adverse 
events of special interest (AESIs) 
x
Major Adverse Cardiovascular Events (MACE) 
x
Confirmed cases of pneumonia 
x
12-lead electrocardiograms (ECGs): Change from baseline in heart rate, PR interval, QRS 
axis, QRS interval, QT interval, and QTcF (Fridericia Corrected QT) interval 
x
Clinical laboratory testing 
x
Vital signs measurements 
 
Safety endpoints for PT010006 are observed over 24 weeks, and those for PT010007 over 52 
weeks. 
 
2.5.3
Sub-Study Endpoints (for PT010006) 
2.5.3.1
12-hour PFT Sub-Study 
The primary 12-hour PFT endpoint is: 
x
FEV1 AUC0-12 at Week 24 
 
Additional assessments at Week 24: 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 20 of 355
 
 
x
FEV1 at each time point 
x
Serial spirometry parameters including FEV1 AUC0-6, FEV1 AUC6-12, and time to peak 
FEV1 
x
FVC, PEFR, and FEF25-75 will be evaluated using AUC0-12 
 
2.5.3.2
Pharmacokinetic Sub-study Endpoints: 
The PK endpoints at Week 24 (i.e. steady-state, where “i.e.” denotes “id est; that is”) include: 
x
Area under the plasma concentration-time curve from time 0 to 12 hours post dose  
(AUC0-12) 
x
Time to reach maximum observed plasma concentration (tmax) 
x
Maximum observed plasma concentration (Cmax) 
x
Terminal elimination rate constant (Ȝz) 
x
Terminal elimination half-life (t1/2) 
x
Minimum observed plasma concentration (Cmin) 
x
Time-average concentration during a dosing interval (Cavg) 
x
%Fluctuation 
x
%Swing 
 
2.5.3.3
HPA Axis Sub-study Endpoints: 
Primary Endpoint: 
x
Ratio to Baseline of the 0- to 24-hour weighted mean serum cortisol (SC) concentration 
curve at Visit 10a (Week 24) 
 
2.5.4
Health Care Resource Utilization Endpoints (for Study PT010006) 
x
The number of days missed from work due to COPD 
x
The number of days that primary caregivers of subjects missed from work as a result of the 
subject’s COPD 
x
The percentage of subjects with telephone calls to health-care providers 
o Call to any health-care provider (physician or other) 
o Calls to physician 
o Calls to other healthcare provider 
x
The mean number of telephone calls to health-care providers 
o Call to any health-care provider (physician or other) 
o Calls to physician 
o Calls to other healthcare provider 
x
The percentage of subjects with visits to health-care providers 
o Visits to any health-care provider (general practitioner [GP], specialist, or other) 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 21 of 355
 
 
o Visits to GP 
o Visits to specialist 
o Visits to other health-care provider 
x
The mean number of visits to health-care providers 
o  Visits to any health-care provider (GP, specialist, or other) 
o
Visits to GP 
o
Visits to specialist 
o
Visits to other health-care provider 
x
The percentage of subjects with Emergency Room (ER) visits 
x
The mean number of visits to ERs 
x
The percentage of subjects hospitalized 
x
The mean number of subject hospitalizations 
x
The mean number of days in the hospital 
x
The mean number of hospitalizations in which subject spent some time in the Intensive Care 
Unit (ICU) or the Coronary Care Unit (CCU) 
x
The percentage of subjects hospitalized with some time spent in the ICU or CCU 
x
The mean number of days in the hospital with some time spent in the ICU or CCU 
x
The mean number of hospitalizations in which subject spent No time in the ICU or the CCU 
x
The percentage of subjects hospitalized with No time in the ICU or CCU 
x
The mean number of days in the hospital with No time spent in the ICU or CCU 
x
The mean number of days in ICU 
x
The percentage of subjects in the ICU 
x
The mean number of days in CCU 
x
The percentage of subjects in the CCU 
x
The percentage of subjects who required ambulance transport 
x
The mean number of times ambulance transport was required 
 
3.
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS 
3.1
Study Designs 
3.1.1
Overall Study Designs and Plan 
PT010006 study is a multi-center, randomized, double-blind, parallel-group, chronic-dosing (24 
weeks), active-controlled study to assess the efficacy and safety of BGF MDI, GFF MDI, BFF 
MDI, and open-label Symbicort TBH as an active control in subjects with moderate to very 
severe COPD that remain symptomatic (COPD Assessment Test [CAT]10) on two or more 
inhaled maintenance treatments. 
This study will be conducted at approximately 160 sites, contributing approximately 10 to 20 
subjects per site. Subject participation in the PT010006 study and all sub-studies will be 
determined at Screening, prior to any study procedures. Approximately 1800 subjects with 
moderate to very severe COPD will be randomized in a 2:2:1:1 scheme into the study to provide 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 22 of 355
 
 
approximately 1600 subjects to complete the study. Approximately 600 subjects each will be 
randomized to the BGF MDI and GFF MDI treatment groups, and 300 subjects each will be 
randomized to the BFF MDI and Symbicort TBH treatment groups. Randomization will be 
stratified by reversibility to Ventolin HFA, country, and disease severity. 
All Japanese sites that participated in Study PT010006 will be eligible to contribute subjects to 
extension study PT010007. It is planned that approximately 324 Japanese subjects with moderate 
to very severe COPD will continue into study PT010007 for an additional 28 weeks to provide 
approximately 300 subjects to complete the study. Based on the randomization ratio from the 
Study PT010006, PT010007 will evaluate approximately 100 completed Japanese subjects in the 
BGF MDI and GFF MDI arms, and approximately 50 completed Japanese subjects in the BFF 
MDI and Symbicort TBH arms. 
In PT010006, subjects who discontinue study treatment prior to Week 24 (Visit 10a) will be 
encouraged to remain in the study to complete all remaining study visits during the 24 week 
treatment period. Subjects who agree to continue to be followed post treatment discontinuation 
will sign an informed consent form (ICF) addendum. All subjects who agree to continue study 
participation beyond treatment discontinuation will complete a Treatment 
Discontinuation/Withdrawal Visit prior to transitioning back to regularly scheduled study visits. 
Subjects participating in a sub-study who choose to discontinue from treatment will only 
complete regularly scheduled visits and not complete any remaining sub-study assessments. 
Treatment discontinuation subjects will return to appropriate maintenance COPD medications, 
per the investigators discretion.  
If a subject chooses not to continue with study assessments, at a minimum the subject will complete 
the Treatment Discontinuation/Withdrawal Visit (refer to the Schedule of Events in the Study 
Protocol). These subjects will return to appropriate maintenance COPD medications, per the 
investigators discretion. A follow-up telephone call will be performed at least 14 days after the last 
study drug dose. In the event the Treatment Discontinuation/Withdrawal Visit is performed >14 days 
post last study drug dosing, a follow-up TC will not be required. These subjects will be followed for 
vital status at 24 weeks post randomization in accordance with the informed consent. 
Sub-Studies: 
The PT010006 study will include the following 3 sub-studies: 
12-Hour PFT Sub-study (US sub-study only): Serial PFTs will be conducted over 12 hours in 
a subset of approximately 600 randomized subjects (200 subjects from each of BGF MDI and 
GFF MDI treatment groups, and 100 subjects from each of the BFF MDI and Symbicort TBH 
treatment groups) at Visit 10a (Week 24). On the test day, additional serial spirometry will be 
obtained at 6, 8, 10, 11.5 and 12 hours post-dose.  
Pharmacokinetic Sub-study: PK assessments will be performed in a subset of subjects who 
participate in the PFT sub-study. Approximately 240 randomized subjects (80 subjects from each 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 23 of 355
 
 
of the BGF MDI and GFF MDI treatment groups, and 40 subjects from each of the BFF MDI 
and Symbicort TBH treatment groups) will be assessed at Visit 10a (Week 24).  
HPA Axis Sub-study: Adrenocorticosteroid activity will be assessed in a subset of subjects in 
the PK sub-study. SC will be measured in approximately 108 randomized subjects (36 subjects 
from each of the BGF MDI and GFF MDI treatment groups, and 18 subjects from each of the 
BFF MDI and Symbicort TBH treatment groups) over 24 hours, between Visits 3 and 4 prior to 
dosing at Randomization and Visit 10a (Week 24).  
The Schedules of Events and Timed Assessments are in the study protocols. 
 
The overall study design is summarized and illustrated in Figure 1. 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 24 of 355
 
 
Figure 1 
Study Design 
PT010006 24-Week Study 
 
 
Abbreviations: BFF = Budesonide and Formoterol Fumarate; BGF = Budesonide, Glycopyrronium, and Formoterol Fumarate; 
GFF = Glycopyrronium and Formoterol Fumarate; MDI = metered dose inhaler; TBH = Tubuhaler; V = visit. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 25 of 355
 
 
3.1.2
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other 
Restrictions (if applicable) 
All prescription and over-the-counter (OTC) medications taken by the subject within 30 days 
before Visit 1 (Screening) 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, dose regimen, and dates 
of drug administration. 
3.2
Hypothesis Testing 
For the primary comparisons, the null hypothesis for each pair-wise comparison will be that the 
mean treatment difference is zero (mean treatment effects are equal). The alternative hypothesis 
is that the mean treatment difference is greater than (less than) zero (mean treatment effects are 
not equal). All comparisons will be for superiority except that the comparison of BFF MDI to 
Symbicort TBH will be for non-inferiority and will use margins (įs) of -50 mL for the lower 
bound of a 2-sided 95% CI for the treatment difference for morning pre-dose trough FEV1 and -
75 mL for FEV1 AUC0-4. Margins for secondary endpoints are provided with their descriptions 
below in Section 6.4. P-values will be reported as 2-sided.  
The primary null (H0) and alternative (H1) hypotheses with μ representing the mean are: 
x
H0: μBGF = μGFF 
H1: μBGF  μGFF 
x
H0: μBGF = μBFF 
H1: μBGF  μBFF  
x
H0: μBFF  μSymbicort í 50 mL for morning pre-dose trough FEV1 
H1: μBFF > μSymbicort í 50 mL for morning pre-dose trough FEV1 
Secondary and other efficacy analyses will involve the above hypotheses applied to secondary 
efficacy endpoints. The directionality – being “< “or “>” -- of H1 will depend on the endpoint. 
3.3
Interim Analysis 
No interim efficacy analyses are planned for this study. 
A Data Monitoring Committee (DMC) will review safety data approximately every 6 months. 
Further detail is given in the DMC Charter.  
3.4
Sample Size 
For Study PT010006, it is estimated that a sample size of 1800 subjects (600 per arm in the BGF 
MDI and GFF MDI groups and 300 per arm in the BFF MDI and Symbicort TBH groups) will 
provide the following power estimates, all assuming Type I error control at a 2-sided alpha level 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 26 of 355
 
 
of 0.05 unless specified otherwise: 99% power to detect a difference of 75 mL between BGF 
MDI and BFF MDI in FEV1 AUC0-4 over 24 weeks; 96% power to detect a difference of 35 mL 
between BGF MDI and GFF MDI in morning pre-dose trough FEV1 over 24 weeks and 
approximately 92% power over Weeks 12 to 24; 97% power to detect a difference of 50 mL 
between BGF MDI and BFF MDI in morning pre-dose trough FEV1 over Weeks 12 to 24; and 
96% power to demonstrate non-inferiority of BFF MDI to Symbicort TBH in morning pre-dose 
trough FEV1 over 24 weeks and approximately 92% power over Weeks 12 to 24 based on a 
margin of 50 mL (one-sided, alpha=0.025) assuming no true difference.  
Assumptions regarding variability for the primary endpoint are based on Pearl’s experience with 
Phase IIb and III clinical studies. A composite value standard deviation (SD) of 200 mL for the 
change from baseline at each visit has been assumed for trough FEV1 and 220 mL for FEV1 
AUC0-4. Dropout is anticipated to be approximately 12% by the end of the study. Based on the 
repeated measures (RM) analysis, an effective SD for the change over 24 weeks of 157 mL and 
173 mL for trough FEV1 and FEV1 AUC0-4, respectively, is assumed. For Weeks 12 to 24, an 
effective SD for trough FEV1 of 171 mL is assumed. 
For Study PT010007, the sample size of 324 (108 per arm in the BGF MDI and GFF MDI 
groups and 54 per arm in the BFF MDI and Symbicort TBH groups) includes all Japanese 
subjects who were enrolled in Study PT010006. The sample size was not calculated to achieve 
statistical power but was selected to provide approximately 100 completing subjects in the BGF 
MDI and GFF MDI arms. 
4.
DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance procedures for the study data, statistical programming and analyses 
are described in Standard Operating Procedures (SOPs) of Everest Clinical Research. Detailed 
data management procedures are documented in the study Data Management Plan, 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. 
Transfer of PFT data from the central PFT laboratory (iCardiac PFT Global) to Everest Clinical 
Research will be defined in the iCardiac DMP (Data Management Plan), and data handling rules 
related to this data are included in Appendix 1 of this SAP. The quality of all PFTs obtained at 
each time point will be graded independently at iCardiac by qualified personnel. Quality grading 
assessments will be based on ATS (American Thoracic Society)/ERS criteria and will be 
included in data transfers. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 27 of 355
 
 
5.
ANALYSIS POPULATIONS 
5.1
Population Definitions 
5.1.1
Intent-to-Treat (ITT) Population (PT010006 only) 
The ITT Population is defined as all subjects who are randomized to treatment and receive any 
amount of the study treatment in Study PT010006. Subjects will be analyzed according to 
randomized treatment group. Data obtained after discontinuation of treatment, but prior to 
withdrawal from the study, will be included. The ITT population will be used for sensitivity 
analyses. 
5.1.2
Modified Intent-to-Treat (mITT) Population (PT010006 only) 
The mITT Population is a subset of the ITT Population, defined as all subjects with post-
randomization data obtained prior to discontinuation from treatment in Study PT010006. Any 
data collected after completion of or discontinuation from randomized study medication will be 
excluded. Subjects will be analyzed according to randomized treatment group. (Note that a 
subject who used a study treatment, but took less than one full dose of treatment will qualify for 
this population). The mITT Population will be the primary population for all efficacy analyses 
except for the non-inferiority analyses. Note: The knowledge that a subject did not have a COPD 
exacerbation constitutes an efficacy assessment. 
5.1.3
Japanese Modified Intent-to-Treat (mITT) Population 
The Japanese mITT Population is defined as the subgroup of the mITT Population who are 
Japanese subjects (enrolled at sites in Japan) from Study PT010006, regardless of participation in 
Study PT010007. Subjects will be analyzed according to the active treatment they were assigned 
to at randomization in Study PT010006. Data from both Study PT010006 and Study PT010007 
will be included. 
5.1.4
Rescue Ventolin User Population (RVU) (PT010006 Only) 
Regional differences in rescue Ventolin HFA usage are expected with subjects in some countries 
using virtually no rescue medication at study entry. Therefore, the RVU Population is defined as 
all subjects in the ITT Population with mean baseline Rescue Ventolin use of  1.0 puff/day. 
5.1.5
Per-Protocol (PP) Population (PT010006 only) 
The PP Population is a subset of the ITT Population, defined as all subjects with post-
randomization data obtained prior to any major protocol deviations in Study PT010006. Data 
obtained after any major protocol deviation or discontinuation from treatment will be excluded. 
Since receiving the wrong treatment is a major protocol deviation, data after the deviation from 
such subjects will be excluded from the PP Population. If the first treatment received is the 
wrong treatment then the subject will be excluded entirely from the PP population. Any 
evaluability criteria with a potential impact on efficacy results will be identified during Blinded 
Data Review Meeting (BDRM) prior to database lock. Major protocol deviations, therefore, can 
result in exclusion of all data from a particular subject from the PP Population or require 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 28 of 355
 
 
exclusion of data from a specific time point and/or subsequent time points for an endpoint. The 
PP Population will be the main population for all non-inferiority analyses.  
Protocol deviations and criteria for exclusion from the PP Population will be established at a 
BDRM prior to database lock. Reasons for exclusion from the PP Population will include, but 
are not limited to, the following: 
1. An incorrect diagnosis of COPD. 
2. Subjects who do not have an established clinical history of COPD and severity where 
an established clinical history of COPD and severity is to be identified at the BDRM. 
3. For those subjects who use rescue Ventolin HFA less than 6 hours before study visit, 
all data post-Ventolin HFA administration will be considered missing for that day. 
4. For subjects who take any protocol-prohibited medication that would affect 
spirometry assessments on the date of an assessment, spirometry measurements taken 
at that assessment will be excluded.  
5. For spirometry endpoints, the subject will not be eligible for the endpoint-specific, 
visit-specific PP Population if the subject did not take study medication in the 
evening prior to the visit day. 
6. Subjects are also excluded from the PP Population for PFT endpoints if the following 
condition is true: 
-
Subjects who cannot meet protocol-specified baseline stability criteria. FEV1 baseline 
stability is defined as the mean of the -60 minute and -30 minute pre-dose FEV1 
assessments at Visit 4 being within ±20% or 200 mL of the mean of the pre-
bronchodilator FEV1 assessments obtained at the 2 preceding visits (average of pre-
dose FEV1 assessments obtained at Visit 2 and Visit 3). 
Subjects who fail to meet any of the three restriction criteria prior to spirometry will be 
handled as follows. The 3 restrictions are (1) subject was not to smoke for at least 4 
hours prior to study visit and throughout the duration of each study visit, (2) subject 
was not to use xanthine-containing products (i.e., coffee, tea, cola and chocolate) for 
at least 6 hours prior to study visit and for the duration of each study visit, and (3) 
subject was not to have COPD bronchodilator medications for at least 6 hours prior to 
study visit. Spirometry data for these subjects at the affected visits will be removed 
from the PP Population for PFT endpoints. Such restrictions will be applied only if 
data pertaining to the meeting of the criteria (including the timing) were collected. 
 
5.1.6
Safety Population (PT010006 only) 
The Safety Population is defined as all subjects who are randomized to treatment and receive at 
least one dose of the study treatment in Study PT010006. However, subjects will be analyzed 
according to treatment received rather than randomized. If a subject received more than one 
randomized treatment, they will be analyzed and included in summaries according to the 
treatment they received the most. Subjects receiving no study treatment will be excluded, as will 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 29 of 355
 
 
subjects who have no post-dose safety assessments. Note: The statement that a subject had no 
AEs also constitutes a safety assessment. 
5.1.7
Japanese Safety Population 
The Japanese Safety Population is a subset of the Safety Population that is defined as all 
Japanese subjects (enrolled at sites in Japan) who received any amount of study medication in 
Study PT010006, regardless of participation in Study PT010007. Subjects will be analyzed 
according to the actual treatment they received. Data from both Study PT010006 and Study 
PT010007 will be included. 
5.1.8
PT010007 Safety Population 
The PT010007 Safety Population is defined as all subjects who received any amount of study 
medication in Study PT010007. Subjects will be analyzed according to the actual treatment they 
received. Data from both Study PT010006 and Study PT010007 will be included. 
5.1.9
PK Population 
The PK Population is defined as all randomized and treated subjects who have sufficient data to 
reliably calculate at least one PK parameter in Study PT010006. Subjects will be analyzed 
according to treatment received rather than randomized. 
The PK Population will be determined after review of the clinical study data (e.g., concomitant 
medications, dosing information from the subject diary, and adverse events). Prior to the final 
PK analysis, subject data as well as protocol deviations will be reviewed in a blinded manner by 
Everest and Pearl at the BDRM for inclusion/exclusion into the PK Population. 
5.1.10
HPA Axis Population 
The HPA Axis Population is defined as all subjects who participated in the HPA axis sub-study. 
The HPA Axis Population is a subset of the Safety Population without protocol deviations which 
could affect SC endpoint and whose serum samples did not have confounding factors that would 
affect the interpretation of the results. Exclusion from the HPA Axis Population will be 
established at a blinded data review meeting prior to database lock. Subjects will be analyzed 
according to treatment received rather than randomized. 
5.2
Populations for Primary and Sensitivity Analyses 
PT010006: 
Demographics will be summarized for the mITT, PP, Safety, and Non-randomized Populations 
as well as for subjects participating in the 12-hr PFT, PK, and HPA Axis sub-studies.  
Extent of exposure will be summarized for the Safety Population. The Safety Population will be 
used to summarize safety.  


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 30 of 355
 
 
Efficacy Analyses will be performed for the ITT, mITT, and PP Populations. The mITT 
Population will be used for the primary efficacy analyses, with the ITT and PP populations being 
considered supportive with one exception. The PP Population will be primary for the non-
inferiority comparisons of BFF MDI vs. Symbicort TBH.  
PK will be summarized for the PK Population. HPA Axis results will be summarized for the 
HPA Axis Population.  
Selected analyses will be performed for specified sub-populations. See the Subgroup Analyses 
section (Section 6.4.9). 
PT010007:  
When the final database for PT010007 becomes available, selected safety and efficacy results 
will be generated using the Japanese Safety and Japanese mITT populations respectively. 
Selected AE summaries will be repeated on the PT010007 Safety Population. 
 
6.
STATISTICAL ANALYSIS 
Study PT010006 analyses will be performed when the PT010006 final database is available, with 
PT010007 analyses to be performed later once the PT010007 final database is available. 
All data collected contributing to the analysis will be provided in listings. Data for all subjects 
who are randomized will be included in the subject data listings. Data for non-randomized 
subjects will be listed where available. 
All safety and efficacy parameters will be summarized by treatment unless specified otherwise. 
Continuous variables will be summarized with descriptive statistics (the number of non-missing 
values, mean, standard deviation, median, minimum, and maximum). Additionally, the 25th and 
75th percentiles will be presented when appropriate based on historical knowledge of the 
normality or non-normality of the distribution of underlying data. 
Categorical variables will be summarized with frequency counts and percentages (where 
appropriate). 
6.1
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. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 31 of 355
 
 
Data Imputation for Adverse Events Summaries by Severity and Relationship to Study Drug 
For the AE summaries by severity (mild, moderate, or severe), an AE with missing severity will 
be deemed as severe. For the AE summaries by relationship to study drug, an AE with a missing 
relationship to study drug will be deemed as definitely related. Imputed values will not be listed 
in data listings. 
Data Imputation for Laboratory, Vital Sign, and ECG Summaries (Continuous Parameters) 
Data from unscheduled visits will not be used for by-visit summaries. Data from both scheduled 
and unscheduled visits will be used for the end-of-treatment summary, 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. 
On-treatment COPD exacerbations 
An exacerbation will be considered “on-treatment” if its start date is before or on the last 
treatment date. For treatment discontinuations, this definition is extended to include 
exacerbations starting one day after the last treatment date. (If it is decided during a clinic visit to 
discontinue study drug and to switch to a treatment for the ongoing exacerbation symptoms, the 
subject typically would not take the morning dose of study drug at that visit, and their 
exacerbation start date will be one day after the last treatment date. Such exacerbations will still 
be considered “on-treatment”). 
6.2
Subject Disposition and Analysis Populations 
A disposition table for PT010006 for all subjects randomized will be provided (Table 1.1.1.1). 
This tabulation will include the number of subjects in each randomized treatment who were not 
treated, who received the study treatment, who discontinued treatment prematurely, who 
discontinued treatment prematurely but completed the study, who discontinued treatment 
prematurely and withdrew from the study, who withdrew from the study prematurely, and who 
completed the study. The number and percentage of randomized subjects included in the mITT, 
Japanese mITT, ITT, PP, Safety, Japanese Safety, 12-hr PFT Sub-study, PK, and HPA Axis 
Populations will also be tabulated (Table 1.1.1.1). A disposition table for subjects in PT010006 
and PT010007 will also be provided (Table 1.1.1.2). Informed consent is listed in Listing 9.7. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 32 of 355
 
 
The numbers of subjects randomized and in the analysis populations will be provided by country, 
center, and treatment in Table 1.1.2. The number of subjects randomized by stratification factor 
and cross-classification of reversibility to Ventolin HFA and disease severity, using interactive 
web response system (IWRS) data and Clinical data for the stratification-factor levels, will be 
tabulated in Tables 1.1.5.1, 1.1.5.2, 1.1.6.1, and 1.1.6.2, respectively. If there are any subjects 
who took study treatment other than what was randomized during the study, both the treatment 
assigned at randomization and actual treatment(s) received during the Treatment Period will be 
listed (Listing 1.3). The duration of actual treatment will also be listed (Listing 1.3). A list of the 
discrepancies between IWRS-based and clinical-data-based stratification factors will be provided 
(Listing 1.6). 
A summary of reasons subjects were not randomized will be provided for all subjects not 
randomized (Table 1.1.3). A listing of reasons subjects were not randomized will also be 
provided (Listing 1.4). Subjects excluded from the ITT, mITT, PP, Safety, PK and HPA Axis 
analysis populations will be summarized (Table 1.1.4) for all subjects randomized. Reasons for 
premature discontinuation from study treatment will be summarized for the Safety Population 
and for the Japanese Safety Population (Table 1.2.1 and Table 1.2.2 respectively).
The number and percentage of subjects in the ITT Population who withdrew from the study will 
be tabulated by reason for withdrawal (Table 1.2.3).
The reason for exclusion from the PP Population will be tabulated by study treatment for all 
mITT subjects (Table 1.3.1). The reason for exclusion of a subject from the ITT, mITT, PP, 
Safety, PK and HPA Axis Populations or exclusion of partial data (at some but not all time 
points) for a subject will be listed for all randomized subjects (Table 1.1.4). A listing of subjects 
who did not comply with restrictions on smoking, use of rescue medication, and xanthine-
containing products (protocol deviations requiring removal of data from the PP Population 
analysis) just prior to spirometry will be provided in Listing 6.1.1. Use of rescue medication at 
pre-dose or during the post-dose assessments on each specific test day (yes/no), will be tabulated 
in Listing 6.1.3. In addition, the eligibility information (inclusion/exclusion criteria with any 
waivers granted) of all subjects who are randomized will be listed (Listing 2.1). 
The number and percentage of subjects with changes in smoking status after the start of study 
treatment will be tabulated by randomized treatment, by visit and overall during the study, in 
Table 1.13 (Safety Population) and Table 1.14 (Japanese Safety Population) (Listing 1.5).
6.3
Demographic and Baseline Characteristics and Extent of Exposure 
The definitions for the derived demographic or baseline characteristic variables can be found in 
Appendix 1. 
6.3.1
Demography, Physical Characteristics, CAT 
Subject demographics, total CAT score, use of inhaled corticosteroids (ICS) at screening, and 
smoking status/history will be summarized for the mITT, PP, and Safety Populations and for 
Non-Randomized subjects (Tables 1.4.1.1 through 1.4.5.1, respectively, and Listing 1.2). The 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 33 of 355
 
 
ITT population does not need to be tabulated because it is the same as the mITT population for 
demographics. If the Safety Population has the same treatment assignment as the mITT, then it 
will be identical as well and hence not produced. Use of ICS (yes/no) will be summarized for all 
populations except for the Non-Randomized subjects. Demographics will also be summarized for 
the subjects in the 12-hr PFT sub-study (Tables 1.4.6.1 through 1.4.6.4), HPA Axis Population 
(Tables 1.4.6.5 through 1.4.6.8), and PK Population (Tables 1.4.6.9 through 1.4.6.12). 
Demographics and baseline characteristics will also be summarized for subjects in the Japanese 
mITT, Japanese Safety, and PT010007 Safety Populations (Tables 1.4.7.1, 1.4.7.2, 1.4.7.3). 
Demographic and baseline characteristic variables summarized will include the following: 
x
Age 
x
Age Group 
x
Gender 
x
Race 
x
Ethnicity (Hispanic or Non-Hispanic) 
x
The CAT total score and total score category (<10, 10, <15, 15, <20, 20, Missing) 
x
Used ICSs at Screening (all populations except for Non-Randomized subjects) 
x
Baseline eosinophil count (<150 cells per mm3 vs. 150 cells per mm3) 
x
Baseline exacerbation history (0, 1, 2) 
x
Smoking status (current vs. former smoker) 
x
Number of years smoked 
x
Average number of cigarettes smoked per day 
x
Number of pack years smoked, calculated as (number of cigarettes per day/20) x number of 
years smoked 
x
Weight 
x
Height 
x
Body mass index (BMI) 
 
Screening and pre-treatment CAT data will be listed (Listing 4.2). 
6.3.2
COPD History, Screening/Baseline Spirometry, and Reversibility 
Duration of COPD and the number of years prior to the start of study medication that COPD was 
first diagnosed (calculated as [Date of First Dose of Study treatment in the study – Date COPD 
First Diagnosed] /365.25) will be summarized by treatment and for all subjects for the mITT, 
Safety, Japanese mITT, and Japanese Safety Populations and listed (Tables 1.5.1, 1.5.4, 1.5.5, 
and 1.5.8 and Listing 4.1). Severity of COPD at Screening Visit 2 post-Ventolin HFA will also 
be included in these summaries. History of moderate or severe COPD exacerbations within the 
past 12 months will be summarized and listed for subjects in the Safety, Japanese Safety, 
PT010007, mITT and Japanese mITT Populations (Table 1.9.4, Table 1.9.5, Table 1.9.6, Table 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 34 of 355
 
 
1.9.7 and Listing 4.3). Severity of COPD is defined in terms of baseline FEV1, as found in the 
Data Handling Rules (Appendix 1). 
Descriptive statistics will be provided for screening period pre-bronchodilator and 
post-bronchodilator and baseline spirometry parameters (Tables 1.6.1, 1.6.2, 1.6.3, 1.6.4, and 
1.6.5, for the mITT, ITT, PP, Japanese mITT Populations, and 12-hr PFT Sub-study, 
respectively, and Listings 2.2 and 2.3). 
Characterization of Reversibility: 
Reversibility to Ventolin HFA (short-acting ȕ2-agonist, SABA) will be evaluated at Visit 2. 
Reversibility to Atrovent HFA (short-acting anticholinergic) will be evaluated at Visit 3. 
Reversibility to Ventolin HFA (obtained at Visit 2) will be used as a stratification variable at 
randomization to ensure an even distribution of reversibility across the treatment arms. 
Reversibility to Atrovent HFA will be used to characterize the population.  
Reversibility (%) to a bronchodilator is defined as 100 x (the change from pre-bronchodilator 
HFA to post-bronchodilator HFA for FEV1)/pre-bronchodilator HFA FEV1. Reversible (Yes/No) 
is defined as improvement in FEV1 post-bronchodilator HFA administration compared to pre-
bronchodilator HFA of >=12% and >=200mL. 
Reversibility to Ventolin HFA at Screening Visit 2 and reversibility to Atrovent HFA at 
Screening Visit 3 will be summarized for the mITT, 12-hr PFT Sub-study, and Japanese mITT 
Populations and listed (Tables 1.7.1 to 1.7.5, and Tables 1.8.1 to 1.8.5 for Ventolin HFA and 
Atrovent HFA reversibility, respectively, and Listings 2.2 and 2.3 for Ventolin HFA reversibility 
and Atrovent HFA reversibility respectively, and Listing 5.2 for Atrovent HFA and Ventolin 
HFA dispensing). The number and percentage of subjects reversible will be included in these 
summaries. A summary of the change in FEV1 from pre-dose FEV1 to post-bronchodilator 
assessment will also be included. If multiple time points are available post-bronchodilator, then 
the one with the highest FEV1 will be used. 
Additionally, the number and percentage of subjects meeting each of the following response 
criteria will be summarized for both Ventolin HFA and Atrovent bronchodilators: 
x
12% improvement post-bronchodilator in FEV1 from pre-bronchodilator 
x
150 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator 
x
200 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator 
 
6.3.3
Medical and Surgical History at Screening, Reproductive Status and Pregnancy 
Testing
Medical and Surgical History at Screening will be summarized for the Safety Population and 
Japanese Safety Population and listed for all randomized subjects (Table 1.9.1.1, Table 1.9.1.2, 
and Listing 4.4). Cardiovascular medical history of interest at Screening will be summarized for 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 35 of 355
 
 
the Safety Population and Japanese Safety Population and listed for all randomized subjects 
(Table 1.9.2.1 and Table 1.9.2.2 and Listing 4.5). 
Screening Reproductive Status and Pregnancy Testing Results will be listed (Listing 4.6). 
Subjects’ history of moderate or severe COPD exacerbations within the past 12 months will be 
summarized for the Safety, Japanese Safety, PT010007 Safety, mITT, and Japanese mITT 
Populations (Tables 1.9.3 through 1.9.7). 
6.3.4
Prior, Concomitant, and Post-Treatment Medications/Treatments 
All prescription and OTC medications taken by the subject during 30 days before Screening will 
be recorded on the Concomitant Medications case report form (CRF) page. 
Coding: Verbatim medication/treatment terms will be coded by Everest Clinical Research and 
will be assigned a preferred term (PT) and an ATC (anatomic therapeutic class) term using the 
latest version of the World Health Organization Drug Dictionary (WHO-DD) available (version: 
3Q2016 or later). 
Multiple ATC assignments: If there are multiple ATC codes assigned to the same concomitant 
medication, the “primary” one based on a Pearl medical evaluation will be used. All 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 randomized study treatment in the study and being taken on or before the date 
prior to the last dose of study treatment for the subject. A medication with an onset date on or 
after the date of discontinuation from or completion of randomized study treatment for the 
subject will not be considered concomitant, but will be considered a Post-Treatment
medication/treatment. 
Any medication/treatment which cannot be identified as Prior, Concomitant, or Post-Treatment 
will be considered as being in each of the categories that are possible from the available 
information. 
Concomitant COPD-related, COPD exacerbation-related, and Non-COPD related 
medications/treatments will be summarized by preferred term and actual treatment received for 
the Safety Population (Tables 1.11.1, 1.11.1b, 1.11.2, 1.11.5.1 to 1.11.8) and Japanese Safety 
Population (Tables 1.11.3, 1.11.4). COPD-related summaries will not include the COPD-
exacerbation medications. Prior, concomitant/post-treatment COPD, COPD exacerbation, and 
Non-COPD medications will be displayed in separate listings (Listings 4.7 and 4.8, respectively).  


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 36 of 355
 
 
Reported prior medications for COPD and non-COPD-related medications will be tabulated for 
the Safety Population (Tables 1.10.1.1 and 1.10.2) and the Japanese Safety Population (Tables
1.10.3 and 1.10.4) and listed separately (Listings 4.7 and 4.8, respectively). 
Prior COPD Medications will be tabulated (for the Safety population) for subjects having 
received any one, two, all three, or none of the following treatments whether in fixed 
combination products or separate are used at the time of screening and separately for post-
treatment (for any duration): (1) a muscarinic antagonist, (2) a ȕ2 agonist, and (3) an ICS (Table
1.10.1.2). For this purpose, scheduled SAMA (Short-acting muscarinic antagonist) or SABA 
treatments are included. In addition, tabulations for long-acting muscarinic antagonists (LAMA) 
and long-acting ȕ2 agonists (LABA) will also be included. 
Post-treatment medications will be tabulated for subjects having received any one, two, all three, 
or none of the following treatments: (1) a muscarinic antagonist, (2) a ȕ2 agonist, and (3) an ICS 
(Table 1.11.5.2). 
6.3.5
Extent of Exposure to Study Medication and Compliance 
Subject’s exposure to a 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 of study treatment and last day on study treatment x 100. The 
expected number of puffs for a test day which is the last date of treatment will be 2, and the 
expected number of puffs for the last date of treatment which is not a test day will be 4 when a 
PM dose is taken but will be 2 otherwise; the expected number of puffs on dates prior to the last 
date of treatment will be 4. 
 
The number of days of exposure to study treatment will be summarized for each treatment for the 
Safety Population and Japanese Safety Population. The total person-years of exposure for a 
treatment group, defined as the total exposure in the study across all subjects in the treatment, 
will also be provided by treatment (Table 1.12.1 for the Safety Population, Table 1.12.2 for the 
Japanese Safety Population, Table 1.12.3 for PT010007 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%. Descriptive 
statistics (n, mean, standard deviation, median, minimum and maximum) for percent compliance 
will also be provided by treatment. Treatment compliance will be reported in Listing 5.3. 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 9.6). 
 
6.4
Efficacy Analyses 
For study PT010006, there are four pairwise comparisons of treatments of interest, namely,  


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 37 of 355
 
 
x
BGF MDI vs. BFF MDI,  
x
BGF MDI vs. GFF MDI,  
x
BGF MDI vs. Symbicort TBH, and  
x
BFF MDI vs. Symbicort TBH.  
However, summary statistics will be provided by randomized treatment and for each treatment 
difference for all comparisons. All comparisons will be performed for testing superiority except 
that the comparison of BFF MDI to Symbicort TBH will be for non-inferiority. Superiority 
comparisons will chiefly use the mITT population. Non-inferiority analyses will chiefly use the 
PP population, unless specifically stated otherwise. In order for non-inferiority to be met, the 
confidence bound (on the side of lower efficacy for BFF) from a 95% two-sided confidence 
interval (for the treatment difference or treatment ratio [as applicable]) must be less extreme than 
the non-inferiority margin. 
6.4.1
Estimands 
 
The primary estimand of interest is called the efficacy estimand and is the effect of the 
randomized treatments in all subjects assuming continuation of randomized treatments for the 
duration of the study regardless of actual compliance. There are three additional estimands of 
interest. One is called the attributable estimand and is the effect of treatment in subjects 
attributable to the randomized treatment. For this estimand, discontinuation of randomized 
medication for reasons such as tolerability or lack of efficacy are considered unfavorable 
outcomes. Another estimand of interest is called the treatment policy estimand. This estimand is 
the effect of randomized treatment over the study period regardless of whether randomized 
treatment is continued. The final estimand of interest is called the per protocol estimand. This 
estimand is the effect of treatment on subjects who are compliant with the protocol (i.e. no major 
protocol deviations), including the use of randomized medication. 
The primary analysis for the efficacy estimand will be conducted using the mITT Population 
where only data obtained prior to subjects discontinuing from randomized treatment will be 
utilized. This assumes that efficacy observed on treatment is reflective of what would have 
occurred after discontinuation of randomized treatment had they remained on treatment.  
The second estimand of interest is the attributable estimand. Analyses of the attributable 
estimand will be conducted in the mITT Population. Data that are missing due to treatment 
discontinuation will be imputed based on the 5th percentile of the reference arms’ distribution if 
the reason is reasonably attributable to tolerability or lack of efficacy. The 5th percentile applies 
to an endpoint for which a higher value is a better outcome; however the 95th percentile applies 
to an endpoint for which a lower value is a better outcome. Other missing data are to be imputed 
using the observed data model, i.e. assumed to be missing at random (MAR). The number of 
imputations used for the derivation of the attributable estimand will be between 100 and 1000. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 38 of 355
 
 
More detail about the computation of the attributable estimand will be provided in subsequent 
sections (especially 6.4.4.1) and in the Details Appendix to this SAP. 
Treatment discontinuations reasonably attributable to tolerability or lack of efficacy will be 
identified during the BDRM and documented in the minutes prior to unblinding. 
Discontinuations will be attributed to tolerability if the subject had an adverse event determined 
by the investigator to be possibly, probably, or definitely related to study drug, and for which 
study drug was permanently discontinued. Discontinuations will be attributed to lack of efficacy 
if ‘lack of efficacy’ is indicated to be the primary reason for discontinuation from study drug. For 
the remaining discontinuation categories, where specific reasons or criteria frequently need to be 
considered, decisions will be made and documented at the BDRM. Once these subjects are 
identified, post-treatment discontinuation FEV1 values for each patient will be imputed based on 
the 5th percentile of the reference arms’ distribution.  
The third estimand of interest is the treatment policy estimand. Analyses of the treatment policy 
estimand will be conducted in the ITT Population, in which all observed data will be utilized 
regardless of whether subjects remain on randomized treatment.  
Finally, the last estimand of interest is the per protocol estimand. Analysis of this estimand will 
use the PP Population. 
6.4.2
Baselines and Baseline Covariates for Analysis 
The mean of all evaluable 60- and 30-minute pre-dose spirometry assessments conducted at 
Day 1 (Visit 4) will be used to establish baseline for all FEV1, FVC, FEF25-75, and PEFR 
parameters. 
For the diary symptom score parameters and rescue medication usage, baseline will be the mean 
of the non-missing values from the diary data collected in the last seven days of the Screening 
Period. 
For the SGRQ scores, baseline will be the value of the score calculated using the Day 1 
questionnaire data collected prior to the start of randomized study treatment. 
Baseline COPD exacerbation history is set to 0, 1, or  2 moderate or severe exacerbations in the 
last 12 months (from the Visit 1 CRF page).  
Baseline percent predicted FEV1 is the mean of the 30 minute and 60 minute values of FEV1 
prior to dosing on Day 1 (Visit 4). 
ICS use at screening (Yes or No) is to be defined as follows. A subject was considered to have 
had “ICS Use at Screening” if: 
x
the subject was taking a medication that contained a component (active ingredient) that is 
in the WHODRUG SDG (standardized drug grouping) of “CORTICOSTEROIDS”, and 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 39 of 355
 
 
x
the route of administration was “INHALED”, and the medication was used at any time 
during the screening period (or in the 30 days prior to the screening period). Medications 
may be but are not necessarily ongoing medications. 
 
Baseline blood eosinophil count is the mean of non-missing blood eosinophil count values prior 
to the first dose of study medication. 
Baseline age is the age in years at the time of Informed Consent. 
Baseline post-bronchodilator FEV1 is the highest value of FEV1 obtained approximately 30 
minutes after dosing with Ventolin (or later if there are repeated assessments) at Visit 2 unless it 
is missing, in which case the post-Atrovent value at Visit 3 will be used.  
The baseline post-bronchodilator percent predicted FEV1 is the baseline post-bronchodilator 
FEV1 divided by the predicted FEV1 and multiplied by 100. 
Baseline percent reversibility to Ventolin is 100 x (POST-PRE)/PRE, where POST is the highest 
value of FEV1 obtained 30 minutes (or later if there are repeated assessments) after dosing with 
Ventolin at Visit 2 and PRE is the mean of the 30 minute and 60 minute values of FEV1 prior to 
dosing with Ventolin at Visit 2. 
6.4.3
Visits and Time Windows for Visit-Based Efficacy Assessments 
Efficacy data obtained during unscheduled visits will not be used for any of the pre-defined 
efficacy analyses. Efficacy from scheduled and unscheduled visits will be listed.  
For efficacy analysis or derivation of AUC based on time points, the change from baseline in 
PFT assessments will be allocated to derived nominal collection time windows using the time 
intervals specified for each below. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 40 of 355
 
 
Table 1 
Analysis Study Time Window for Spirometry Assessments 
Calculated 
Study Time Window 
Time Interval for the Study 
Time Window 
Pre-dose 60 min. 
45 minutes prior to dose
Pre-dose 30 min. 
0 to <45 minutes prior to dose
Post-dose 5 min. 
>0 to 9 min. post-dose
Post-dose 15 min. 
10 to 22 min. post-dose
Post-dose 30 min. 
23 to 44 min. post-dose
Post-dose 1 hr. 
45 to 89 min. post-dose
Post-dose 2 hrs. 
90 to 179 min. post-dose
Post-dose 4 hrs. 
3 to <5 hrs. post-dose
Post-dose 6 hrs. 
5 to <7.5 hrs. post-dose 
Post-dose 8 hrs. 
7.5 to <9 hrs. post-dose 
Post-dose 10 hrs. 
9 to <10.75 hrs. post-dose 
Post-dose 11.5 hrs. 
10.75 to <11.75 hrs. post-dose 
Post-dose 12 hrs. 
11.75 to < 14 hrs. post-dose, but 
must be prior to any subsequent 
dose of study medication or 
maintenance medication. 
Note: The minutes are rounded to the nearest whole number 
before applying time windows. 
If there are multiple spirometry values for the same parameter within the same post-baseline 
study time window on the same day, the last value will be chosen for analysis. 
Analyses for the efficacy endpoints are presented in sections 6.4.4 to 6.4.7.  
6.4.4
Primary Efficacy Analyses 
Analyses for the primary endpoint are presented in this section along with analyses for any of the 
secondary or other efficacy endpoints related to the primary endpoint. Calculation of FEV1 
AUC0-4 for the efficacy, treatment policy, and per protocol estimands will require at least one 
non-missing post-dose value. 
6.4.4.1
Change from Baseline in Morning Pre-Dose Trough FEV1
PT010006: 
Change from baseline in morning pre-dose trough FEV1 at each visit is defined as the mean of 
the 60 and 30 minute pre-dose values minus baseline. In subjects missing either of these pre-dose 
assessments, the value will be calculated from the single measurement. In subjects missing both 
pre-dose values, morning pre-dose trough FEV1 at that visit will not be calculated. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 41 of 355
 
 
The change from baseline in morning pre-dose trough FEV1 will be analyzed using an RM linear 
mixed model. The model will include treatment, visit, treatment by visit interaction, and ICS use 
at Screening as categorical covariates and baseline FEV1, baseline eosinophil count, and percent 
reversibility to Ventolin HFA as continuous covariates. Baseline FEV1 is defined as the mean of 
the non-missing -60 minute and -30 minute values obtained prior to dosing at Visit 4, and 
baseline eosinophil count is defined as the mean of non-missing eosinophil counts prior to the 
first dose of study treatment. An unstructured correlation (UN) matrix will be used to model 
correlation within a subject. If the UN model fails to converge, then a first-order autoregressive 
(AR(1)) structure will be used instead. In the AR(1) model, subject will be included as a random 
effect. 
Contrasts will be used to obtain estimates of the treatment differences over Weeks 12 to 24 
(primary for Japan/China), over 24 weeks (i.e. Weeks 4 to 24) (primary for EU and Canada; 
secondary for Japan/China; secondary for US), at Week 24 (primary for US), and at each post-
randomization visit (“other” endpoint). Subject data from the first 24 weeks post-randomization 
will be included in the analyses. Two-sided p-values and point estimates with two-sided 95% 
confidence intervals (CIs) will be produced for each treatment difference.  
All comparisons will be for superiority except that the comparison of BFF MDI to Symbicort 
TBH will be for non-inferiority and will use a margin of -50 mL for the lower bound of a 2-sided 
95% CI for the treatment difference. The primary analysis will be conducted using the efficacy 
estimand except for the non-inferiority comparisons of BFF MDI vs. Symbicort TBH, for which 
the per protocol estimand will be primary treatment (Tables and Figures 2.1.1, 2.1.3, 2.1.5, and
Figures 2.1.6.1, to 2.1.6.10 for the efficacy estimand, the attributable estimand, the treatment 
policy estimand, and the per protocol estimand, respectively). Efficacy data from unscheduled 
visits will not be used for this analysis. Additional figures will display the change from baseline 
in morning pre-dose trough FEV1 by completion vs. discontinuation patterns for the efficacy 
estimand, the attributable estimand, and the treatment policy estimand (Figures 2.1.6.11 to 
2.1.6.14). 
The attributable estimand will use the mITT Population but then impute missing post-treatment 
discontinuation data based on the 5th percentile of the reference arms’ (BFF’s and GFF’s 
combined) distribution if the reason for discontinuation is attributable to lack of efficacy 
or/tolerability. All other missing data will be imputed using the observed data model. The 
variance used for the multiple imputation is described in the Details Appendix to this SAP 
(Appendix 6). The number of imputations used for the derivation of the attributable estimand 
will be between 100 and 1000. Work by Seaman, White and Leacy (2014) and Cro (2017) show 
that Rubin’s rules can be validly used in conjunction with so called control-based multiple 
imputation methods, of which our attributable analysis is one type. Given these results we 
believe the attributable analysis to be conservative from a Type I error control perspective. 
Sensitivity analyses will be conducted to assess robustness of the analyses to missing data (See 
Section 6.4.4.4). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 42 of 355
 
 
PT010007: 
The change from baseline in morning pre-dose trough FEV1 over 52 weeks (Weeks 4 to 52) and 
at each post-baseline visit will be analyzed for the efficacy estimand with the Japanese mITT 
Population using an RM linear mixed model. The model will include treatment, visit, and 
treatment by visit interaction, and ICS use at screening as categorical covariates and baseline 
FEV1, baseline eosinophil count, and percent reversibility to Ventolin HFA as continuous 
covariates. Baseline is defined as the mean of the non-missing -60 minute and -30 minute values 
obtained prior to dosing at Visit 4. An unstructured correlation matrix will be used to model 
variability across time within each subject. If the UN model fails to converge, then an AR(1) 
structure will be used instead. In an AR(1) model, subject will be included as a random effect. 
Two-sided p-values and point estimates with two-sided 95% CIs will be produced for each 
treatment difference. The analysis will assess the treatment effects over the entire 52 weeks of 
treatment, i.e. subject data from the first 24 weeks of Study PT010006 will be included in the 
analyses (Table and Figure 2.1.2 and Figures 2.1.2.1 and 2.1.2.2 for the Japanese mITT 
Population). 
6.4.4.2
FEV1 AUC0-4
FEV1 AUC0-4 will be analyzed for PT010006.  
FEV1 AUC0-4 is the area under the curve for the change from baseline for FEV1 and is calculated 
using the trapezoidal rule. The AUC will be normalized by converting it into a weighted average, 
which will be accomplished through dividing by the time in hours from dosing to the last 
measurement included (typically 4 hours). Only one non-missing post-dose value is required for 
the calculation of AUC. Actual time from dosing will be used if available; otherwise scheduled 
time will be used.  
The differences between treatment groups in FEV1 AUC0-4 over 24 weeks (i.e. Weeks 4 to 24) 
(primary for EU/ Canada), over Weeks 12 to 24 (secondary for Japan/China), at Week 24 
(primary for US), and at Day 1 and each post-randomization visit (“other” endpoint), will be 
evaluated using an RM linear mixed model with baseline FEV1, percent reversibility to Ventolin 
HFA, and baseline eosinophil count as continuous covariates and treatment, visit, treatment by 
visit interaction, and ICS use at Screening as categorical covariates. Two-sided p-values and 
point estimates with two-sided 95% CIs will be produced for each treatment difference of 
interest (Tables and Figures 2.1.8 to 2.1.11, and Figures 2.1.12.1to 2.1.12.8 for the efficacy, 
attributable, treatment policy, and per protocol estimands, respectively). Additional figures will 
display FEV1 AUC0-4 by completion vs. discontinuation patterns for the efficacy estimand, the 
attributable estimand, and the treatment policy estimand (Figures 2.1.12.9 to 2.1.12.12). 
All comparisons will be for superiority except that the comparison of BFF MDI to Symbicort 
TBH will be for non-inferiority and will use a margin of -75 mL for the lower bound of the 95% 
CI for the treatment difference. The primary analysis will be conducted using the efficacy 
estimand except for the non-inferiority comparisons of BFF MDI vs. Symbicort TBH, for which 
the per protocol estimand will be the primary population. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 43 of 355
 
 
For the attributable estimand of FEV1 AUC0-4 (for the analysis at Week 24, the analysis over 
Weeks 12-24, and the analysis over 24 weeks), data that are missing due to treatment 
discontinuation will be imputed in a similar manner as in the attributable estimand for morning 
pre-dose trough FEV1 in Section 6.4.4.1 above. 
Sensitivity analyses will be conducted to assess robustness of the analyses to missing data (See 
Section 6.4.4.4). 
Study PT010007 did not have post-dose spirometry and therefore the analysis of FEV1 AUC0-4 is 
not possible. 
6.4.4.3
Assumptions Checks and Removal of Outliers in Sensitivity Analyses 
In general, the distribution of spirometry measures is well-approximated by a normal 
distribution. Under some circumstances (for example during a COPD exacerbation unrelated to 
treatment), atypical values can arise. Such values may disproportionately affect model-based 
estimates of the fixed effect and variance parameters. Prior to database lock and unblinding, the 
change from baseline values for efficacy endpoints will be examined as part of data quality 
management. This may include production of normal probability plots, kernel density estimates, 
and normal order outlier statistics. Based on this blinded evaluation, if atypical values are 
identified, nonparametric methods or data transformations (e.g. logarithmic or normal rank 
transformation) will be considered. If erroneous values are detected, every effort will be made to 
correct them prior to database lock. If these values cannot be corrected, they will be considered 
for removal from analysis. These analyses will be conducted if warranted to demonstrate the 
robustness of the primary and secondary results and reported in the Statistical Methods Appendix 
to the clinical study report (CSR). 
The assumption of normality in the change from baseline in the morning trough FEV1 data will 
be checked by visually inspecting the distribution of the residuals. Also, model fit and the 
assumption of homogeneity of variance will be verified by inspection of scatter plots of predicted 
vs. residuals, residuals vs. treatment, residuals vs. ICS use (yes/no), and by box plots of residuals 
for model variables with a potential effect on variance (treatment, visit, and ICS use). Plots for 
scaled (marginal) residuals will be prepared (option=VCIRY on the model statement and ODS 
graphics option allows the production of plots using these residuals). As a sensitivity analysis, if 
appropriate, the linear RM model analysis will be conducted by allowing for heterogeneity of 
variance between treatments, visits (if unstructured correlation matrix fail to converge), and/or 
ICS use categories (yes/no). Note that the unstructured correlation matrix structure allows for 
heterogeneity among the visits. 
 
Some further assumptions checks are mentioned in the Details Appendix to this SAP. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 44 of 355
 
 
6.4.4.4
Sensitivity Analyses for Missing Data 
Sensitivity analyses will be conducted for FEV1 and AUC0-4 to evaluate the robustness of the 
primary analysis findings to missing data.  
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013).  
For the attributable estimand for morning pre-dose trough FEV1 and FEV1 AUC0-4, data that are 
missing due to treatment discontinuation will be imputed based on the 5th percentile of the GFF 
and BFF reference arms’ distribution if the reason is reasonably attributable to tolerability or lack 
of efficacy (see Sections 6.4.4.1 and 6.4.4.2). Other missing data are to be imputed using the 
observed data model. 
 
Analyses of the treatment policy estimand will be conducted in the ITT Population where all 
observed data will be utilized regardless of whether subjects remain on randomized treatment. A 
sensitivity analysis will be conducted where missing data in the treatment arm are imputed with 
the benefit of treatment decremented by up to 500 mL until the p-value  0.05. 
The following table summarizes the multiple imputation-based sensitivity analyses under the 
PMM (pattern mixture model) framework that will be undertaken, 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 45 of 355
 
 
Table 2 
Sensitivity Analyses for Morning Pre-dose Trough FEV1 and FEV1 AUC0-4 
Efficacy Estimand 
Attributable Estimand 
Treatment Policy Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis 
#1: 
 
All missing data are 
imputed using the 
observed data model 
except that for 
subjects in the 
treatment arm (not the 
comparator arm) 
values that are 
considered MNAR 
are imputed with the 
change from baseline 
in the treatment arm 
decremented by up to 
500 mL until the p-
value  0.05.  
 
Tipping point 
analysis #2: 
  
All missing data are 
imputed using the 
observed data model 
except that for 
subjects in the 
treatment arm (not 
the comparator arm) 
values are imputed 
with the change from 
baseline in the 
treatment arm 
decremented by up 
to 500 mL until the 
p-value  0.05. 
 
 
Tipping point  
analysis: 
 
MI based on the 5th 
percentile of the reference 
arms’ distribution if 
treatment discontinuation 
is due to tolerability or 
lack of efficacy of study 
drug (as in the primary 
analysis of this estimand). 
Otherwise, all missing data 
are imputed using the 
observed data model 
except that for subjects in 
the treatment arm (not the 
comparator arm), values 
are imputed with the 
change from baseline in 
the treatment arm 
decremented by up to 500 
mL until the p-value  
0.05.
 
Tipping point analysis: 
 
All missing data are 
imputed using the observed 
data model except that for 
subjects in the treatment 
arm (not the comparator 
arm) values are imputed 
with the change from 
baseline in the treatment 
arm decremented by up to 
500 mL until the p-value  
0.05. 
 
MNAR = Missing not at random. Missingness determined to be potentially MNAR will be defined and documented 
in the BDRM minutes prior to unblinding. The tipping point will be shown to at least a precision of 10 mL. Imputed 
values may not be impossible values – i.e. changes from baseline that would imply a negative FEV1 value. Thus the 
values will be imputed from a truncated distribution. 
The primary analysis is for the efficacy estimand, which includes data collected up until the time 
of discontinuation of treatment. The efficacy estimand quantifies the difference in outcomes for 
all patients as if they continued on their initially randomized treatment. The primary analysis 
uses a linear mixed model and assumes that all missing data are MAR or MCAR (missing 
completely at random).  
Although the analysis for the attributable estimand starts with the same amount of missingness, 
less remains after imputation for missingness deemed attributable to the treatments is performed. 
These remaining missing data are imputed using the observed data model in the main analysis 
under the assumption of MAR. More detail about the computation of the attributable estimand is 
provided in subsequent sections and in the Details Appendix to this SAP. 
Tipping-point analyses will be conducted to examine the impact of varying the treatment mean 
for missing data in subjects who discontinue BGF MDI. Multiple imputation (MI) techniques 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 46 of 355
 
 
will be used to impute the missing data for these patients by varying the mean in the treatment 
arm. The change from baseline in the treatment arm will be decremented by up to 500 mL until 
the p-value for the comparison of treatment to comparator becomes  0.05. A total of 10 
imputations will be used for each set of tipping point analyses. This imputation technique will be 
applied in sensitivity analyses as described below. 
Tipping Point Analyses of the Primary Estimand: 
Tipping Point #1: this first set of analyses will impute diminished effects only for 
subjects on BGF MDI whose missing data are determined to be MNAR.  
Tipping Point #2: this analysis will impute diminished effects for all missing data in the 
BGF MDI arm.  
Note that for both tipping point analyses, all other missing data will be imputed using the 
observed data model. 
Tipping Point Analysis of the Attributable Estimand: 
For the attributable estimand, by definition, missing data in all arms due to tolerability and lack 
of efficacy are already imputed based on the 5th percentile of the reference arms’ distribution, 
therefore the remaining missing data imputed using the observed data model in the main analysis 
are likely MAR or MCAR. Hence, there is no need to conduct a tipping analysis like #1 planned 
for the efficacy estimand. A tipping point analysis like #2 will be conducted where the non-
attributable missing data will be imputed using progressively diminished effects. 
Tipping Point Analysis of the Treatment Policy Estimand: 
For the treatment policy estimand, a tipping point analysis like #2 will be conducted where 
missing data in the treatment arm will be imputed using progressively diminished effects. 
In all of these analyses, the imputed values that would have been seen are then combined with 
the observed values to provide a complete dataset. These data are then analyzed using the same 
linear mixed model used for the primary analysis. This analysis is repeated multiple times and 
the results are combined using Rubin’s formulae [Rubin, 1987].  
For the tipping point analyses, tables giving results for each progressively diminished effect will 
be produced. Figures of delta (decrement in treatment effect) versus p-values will also be 
produced. Details of the sensitivity analyses are discussed in the Statistical Methods Appendix to 
the CSR. 
Cumulative Responder Analysis 
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
(Farrar et al., 2006) for the change from baseline in morning pre-dose trough FEV1 over Weeks 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 47 of 355
 
 
12-24, over 24 weeks, and at Week 24 (Tables 2.1.14.1 to 2.1.14.3 for the efficacy estimand, 
Tables 2.1.14.1a to 2.1.14.3a for treatment policy estimand), and change from baseline in FEV1 
AUC0-4 over 24 weeks and at Week 24 (Tables 2.1.14.4 and 2.1.14.5 for the efficacy estimand 
and Tables 2.1.14.4b and 2.1.14.5b for the treatment policy estimand). A cumulative distribution 
plot by treatment arm will also be produced. The observed change from baseline in morning pre-
dose trough FEV1 over Weeks 12-24 (over 24 weeks and at Week 24) will be plotted on the X 
axis, while the proportion of responders (subjects that equal or exceed that level of change) will 
be plotted on the Y axis (Figures 2.1.14.1 to 2.1.14.3 for the efficacy estimand, Figures 
2.1.14.1a and 2.1.14.3a for the treatment policy estimand), and a cumulative proportion of 
responders plot for change from baseline in FEV1 AUC0-4 over 24 weeks and at Week 24 
(Figures 2.1.14.4 and 2.1.14.5 for the efficacy estimand and Figures 2.1.14.4a and 2.1.14.5a for 
the treatment policy estimand). Subjects without post-baseline data or who discontinue treatment 
for any reason will be considered non-responders in the analysis. For display purposes only, the 
range of the X axis will be from -1 to +1 liters [L] by increments of 0.01 liters in order to avoid 
the undue influence of outlying values. The cumulative responder curves for each treatment will 
then be compared pairwise using Kolmogorov-Smirnov tests. Cumulative responder analyses for 
the attributable estimand will not be performed because they are not well defined: methodology 
to apply Rubin’s rules for combining multiply imputed data for such an analysis is not readily 
available. 
6.4.5
Analysis of Secondary Efficacy Variables 
The following variables appear as secondary for 1 or more registration approaches: morning pre-
dose trough FEV1 over 24 Weeks, FEV1 AUC0-4 over Weeks 12-24, peak FEV1, TDI focal score 
(at Week 24, over Weeks 12-24, and over 24 weeks), rescue Ventolin HFA usage over 24 weeks, 
SGRQ total score over Weeks 12-24 and over 24 weeks, percentage of subjects achieving an 
MCID of 4 units or more in SGRQ total score at Week 24, RS-Total score over 24 weeks, time 
to CID, the rate of moderate or severe COPD exacerbations, and time to onset. Multiplicity will 
be controlled for the secondary variables as described in Section 6.4.11. The main analysis for 
secondary endpoints will use the efficacy estimand. The treatment policy estimand will include 
all post-treatment discontinuation data and will serve as a sensitivity analysis. The attributable 
estimand will also be estimated as a sensitivity analysis for the secondary endpoints with the 
exception of time of onset on Day 1.  
For the attributable estimand for continuous variables, namely, rescue Ventolin use, the SGRQ 
total score, and the RS-Total Score, missing data are imputed based on the 95th percentile of the 
reference arms’ distribution if the reason for discontinuation is attributable to lack of efficacy 
or/tolerability, while for TDI and Peak FEV1, missing data are imputed based on the 5th 
percentile of the reference arms’ distribution if the reason for discontinuation is attributable to 
lack of efficacy or/tolerability. All other missing data will be imputed using the observed data 
model. The variance used for the multiple imputation is described in the Details Appendix to this 
SAP. Time to onset on Day 1 is excluded since there is anticipated to be very little missing data 
at this early time point. The imputation for the rate of moderate or severe COPD exacerbations 
and time to CID is described in the respective sections below.  


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 48 of 355
 
 
The non-inferiority margins will be set to 0.75 for TDI, 10% for achievement of MCID in 
SGRQ, 75 mL for peak change from baseline in FEV1, and -1.5 for E-RS total score. 
6.4.5.1
Transition Dyspnea Index 
The TDI is collected in Study PT010006 only. 
 
Assessments of dyspnea will be obtained using the BDI/TDI (where BDI is the Baseline Dyspnea 
Index). The BDI/TDI questionnaire can be found in Protocol Appendix 10.  
 
At Randomization (Visit 4), the severity of dyspnea at baseline will be assessed using the BDI. 
BDI components are functional impairment, magnitude of task, and magnitude of effort (Listing 
6.1.6). The possible range of values for each BDI component score is 0 (very severe impairment) 
to 4 (no impairment). The BDI component scores are summed to determine the BDI focal score 
(0 to 12) (i.e., the lower the score, the worse the severity of dyspnea). 
At subsequent visits (as per Schedule of Events: see of the Schedule of Events in the PT010006 
protocol), change from baseline will be assessed using the TDI. TDI components include: 
Change in Functional Impairment, Change in Magnitude of Task, and Change in Magnitude of 
Effort (Listing 6.1.6). The TDI component score ranges from -3 (major deterioration) to +3 
(major improvement). The sum of all component scores yields the TDI focal score (-9 to +9) 
(i.e., the lower the score, the more deterioration from baseline).  
The difference between treatment groups in TDI focal score over Weeks 12-24 and over 24 
weeks and at each post-randomization visit will be analyzed using a similar RM approach as for 
the primary endpoint, but using BDI instead of baseline FEV1 in the model, and adding baseline 
post-bronchodilator percent predicted FEV1 as a continuous covariate. Thus, the model will 
include treatment, visit, treatment by visit interaction, and ICS use at Screening as categorical 
covariates and BDI, baseline eosinophil count, percent reversibility to Ventolin HFA and 
baseline post-bronchodilator percent predicted FEV1 as continuous covariates. The treatment 
comparisons at each visit are considered to be “other” endpoints. Data from all study treatments 
will be included in the modeling. Scoring and handling of missing items will be conducted in 
accordance with the user’s guide for the TDI score. Two-sided p-values and point estimates with 
2-sided 95% CIs will be produced for each treatment difference (Tables and Figures 2.2.1 for the 
efficacy estimand).  
Analyses in the attributable estimand, the treatment policy estimand, and the per protocol 
estimand over Weeks 12-24 and over 24 Weeks will be conducted as supportive (Tables and 
Figures 2.2.2, 2.2.3 and 2.2.5, respectively). 
The attributable estimand will be computed in a similar manner as the attributable estimand is 
computed for change from baseline in morning pre-dose trough FEV1 at Week 24 as described in 
Section 6.4.4.1. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 49 of 355
 
 
All comparisons will be for superiority except that the comparison of BFF MDI to Symbicort 
TBH will be for non-inferiority rather than superiority and will use a margin of -0.75 for the lower 
bound of the two sided 95% CI for the treatment difference. The main analysis will be conducted 
using the efficacy and attributable estimands except for the non-inferiority comparisons of BFF 
MDI vs. Symbicort TBH, for which the per protocol estimand analysis will be main analysis. 
In addition, the difference between treatments for the individual components of the TDI (as 
“other” endpoints): functional impairment, magnitude of task, and magnitude of effort will each 
be analyzed over 24 weeks, over Weeks 12-24, and at each post-baseline visit using the same 
modeling approach as for the TDI total score (Table 2.2.7 and Figures 2.2.7.1-2.2.7.3 for the 
functional impairment, magnitude of task, and magnitude of effort for the efficacy estimand).  
Furthermore, as supportive analyses, responder analyses will be performed (for the TDI focal 
score) where responders are defined as subjects with a response of 1.0 point or more 
(corresponding to at least a minor improvement) on average over 24 weeks and on average over 
Weeks 12-24. Logistic regression with SAS PROC GENMOD will be used to compare the 
treatment groups with BDI, baseline eosinophil count, post-bronchodilator percent predicted 
FEV1, and percent reversibility to Ventolin HFA as continuous covariates and treatment, and ICS 
use at Screening as categorical covariates. P-values and odds ratios with 95% CIs will be 
produced for each of the four treatment comparisons (Table 2.2.13 for the efficacy estimand). 
For the TDI, at each visit, if a response to any of the three questions is missing, then the focal 
score will also be considered missing. For the TDI responder analyses, subjects without post-
baseline data or who discontinue treatment for any reason will be considered to be non-
responders. 
TDI and BDI data will be listed in Listing 6.1.6. 
6.4.5.2
Peak FEV1
Peak FEV1 will be included in the analyses of the efficacy, attributable, treatment policy, and per 
protocol estimands as long as there is at least one non-missing post-dose value. 
Peak FEV1 will be analyzed for Study PT010006. 
The peak change from baseline in FEV1 within 4 hours post-dosing (assessed within a visit) over 
Weeks 12-24 (Japanese/China Approach), over 24 weeks (EU and Canada approaches), and at 
Week 24 (US Approach) will be analyzed and summarized similarly to morning pre-dose trough 
FEV1. The peak change from baseline on Day 1 and at each post randomization visit will also be 
analyzed. Peak FEV1 will be included in efficacy, attributable, and treatment policy estimand 
analyses as long as there is at least one non-missing post-dose value during the first 4 hours post-
dose. For the per protocol estimand analysis, Peak FEV1 will be calculated if there are at least 
two non-missing FEV1 data-points during the first 4 hours post-dose (Tables and Figures 2.3.1,
2.3.2, 2.3.3, and 2.3.5 for the efficacy, attributable, treatment policy, and per protocol estimands, 
respectively). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 50 of 355
 
 
The attributable estimand will be computed in a similar manner as the attributable estimand is 
computed for change from baseline in morning pre-dose trough FEV1 at Week 24 as described in 
Section 6.4.4.1.  
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in Farrar 2006 for the peak change from baseline in FEV1 within 4 hours post-dose 
over 24 Weeks (Table 2.3.4 for the efficacy estimand). A cumulative distribution plot by 
treatment arm (Farrar et al., 2006) will also be produced. The observed peak change from 
baseline in FEV1 will be plotted on the X axis, while the proportion of responders (subjects that 
equal or exceed that level of change) will be plotted on the Y axis (Figure 2.3.4 for the efficacy 
estimand). Subjects without post-baseline data or who discontinue treatment for any reason will 
be classified as non-responders. For display purposes only, the range of the X axis will be from -
1 to +1 liters [L] by increments of 0.01 liters in order to avoid the undue influence of outlying 
values. The cumulative responder curves for each treatment will then be compared pairwise 
using Kolmogorov-Smirnov tests. Cumulative responder analyses for the attributable estimand 
will not be performed because they are not well defined: methodology to apply Rubin’s rules for 
combining multiply imputed data for such an analysis is not readily available. 
Tipping Point Analyses for Peak Change from Baseline in FEV1 within 4 hours Post-Dose at 
Week 24  
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). A brief overview of the approach is summarized in the table below. Details of the 
methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in Sections 6.4.4.4 and in 
the Details Appendix to this SAP), but with the model for peak change from baseline in FEV1 
described above. Multiple-imputation results will be combined using Rubin’s formulae [Rubin, 
1987]. Details of the methods may be found in the Details Appendix to this SAP. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 51 of 355
 
 
Table 3 
Sensitivity Analyses for Peak Change from Baseline in FEV1
Efficacy Estimand 
Attributable Estimand 
Treatment Policy 
Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis 
#1: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values that are 
considered MNAR are 
imputed with the 
change from baseline in 
the treatment arm 
decremented by up to 
500 mL until the p-
value  0.05. 
 
Tipping point analysis 
#2: 
  
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the 
change from baseline 
in the treatment arm 
decremented by up to 
500 mL until the p-
value  0.05. 
 
 
Tipping point  
analysis: 
 
MI based on the 5th 
percentile of the 
reference arms’ 
distribution if treatment 
discontinuation is due to 
tolerability or lack of 
efficacy of study drug 
(as in the primary 
analysis of this 
estimand). Otherwise all 
missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm (not 
the comparator arm) 
values are imputed with 
the change from 
baseline in the treatment 
arm decremented by up 
to 500 mL until the p-
value  0.05. 
Tipping point analysis: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm (not 
the comparator arm) 
values are imputed with 
the change from 
baseline in the treatment 
arm decremented by up 
to 500 mL until the p-
value  0.05. 
MNAR = Missing not at random. The tipping point will be shown to at least a precision of 10 
mL. Imputed values may not be impossible values – i.e. changes from baseline that would imply 
a negative FEV1 value. Thus the values will be imputed from a truncated distribution. 
6.4.5.3
St. George’s Respiratory Questionnaire 
The SGRQ is collected in Study PT010006. 
The SGRQ will be used to provide the health status/health-related QoL measurements in this 
study (see PT010006 Protocol Appendix 10). The SGRQ contains 50 rated items divided into 
three domains: "Symptoms" concerned with respiratory symptoms, their frequency, and severity; 
"Activity" concerned with activities that cause or are limited by breathlessness; and "Impacts" 
which covers a range of aspects concerned with social functioning and psychological 
disturbances resulting from airway disease. Individual items of SGRQ data will be listed 
(Listings 6.1.7 for All Subjects Randomized). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 52 of 355
 
 
A score will be calculated for each component and a "Total" score will also be calculated 
(Listings 6.1.9 for All Subjects Randomized). In each case, the lowest possible value is zero and 
the highest is 100. Higher values correspond to greater impairment of QoL. 
The difference between treatment groups in the change from baseline in SGRQ over 24 weeks 
and over Weeks 12 to 24 will be evaluated using a similar RM approach as for TDI focal score, 
but adding country as a covariate, and with baseline SGRQ score replacing BDI in the model. 
Thus the model will include treatment, visit, treatment by visit interaction, ICS use at Screening, 
and country as categorical covariates and baseline SGRQ score, baseline eosinophil count, 
percent reversibility to Ventolin HFA and baseline post-bronchodilator percent predicted FEV1 
as continuous covariates. Scoring and handling of missing items will be conducted in accordance 
with the user’s guide for the SGRQ. Each response is to be given a unique empirically derived 
weight between 0 and 100, the weights of all responses are then summed up and divided by the 
maximum possible score and expressed as a percentage. Missing SGRQ total scores will not be 
imputed. Two-sided p-values and point estimates with 2-sided 95% CIs will be produced for 
each treatment difference. The comparison of BFF MDI to Symbicort TBH will be for 
non-inferiority rather than superiority and will use a margin of 3 units for the upper bound of the two 
sided 95% CI for the treatment difference. 
The main analysis of the SGRQ will be for the efficacy estimand. Supportive analyses will use 
the attributable estimand, the treatment policy estimand, and per protocol estimand over Weeks 
12-24 and over 24 Weeks (Tables and Figures 2.4.1, 2.4.3, 2.4.4, and 2.4.5 for the efficacy, 
attributable, treatment policy, and per protocol estimands, respectively).  
The attributable estimand (for the analysis of the change from baseline in total SGRQ score) will 
be computed in a similar manner as the attributable estimand is computed for change from 
baseline in morning pre-dose trough FEV1 at Week 24 as described in Section 6.4.4.1 except that 
the 95th percentile will be used instead of the 5th percentile. 
As additional supportive analyses (i.e. as other efficacy endpoints), the difference between 
treatments at each of the individual visits will be evaluated and summarized (Tables and Figures
2.4.1, 2.4.4, and 2.4.5). Individual domains of the SGRQ (as “other” endpoints) will also be 
analyzed in a similar fashion as the total score (Tables 2.4.7 for the efficacy estimand).  
Responder analyses will be performed where responders are defined as subjects with an 
improvement of (i.e. a decrease in the total SGRQ score of) 4.0 points at Week 24 (secondary 
endpoint for US Approach), and on average over 24 weeks (EU and Canada Approaches) and 
Weeks 12-24 (Japan/China Approach). For the SGRQ responder analyses, subjects without post-
baseline data or who discontinue treatment for any reason will be considered non-responders. 
Logistic regression will be used to compare the treatment groups with baseline SGRQ Score, 
baseline eosinophil count, baseline post-bronchodilator percent predicted FEV1, and percent 
reversibility to Ventolin HFA as continuous covariates, and treatment, country, and ICS use at 
Screening as categorical covariates. P-values and odds ratios with 95% CIs will be produced for 
each treatment comparison (Table 2.4.13 for the efficacy estimand and Tables 2.4.14, 2.4.15, and 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 53 of 355
 
 
2.4.16 for the attributable estimand, the treatment policy estimand, and the per protocol 
estimand, respectively). 
The attributable estimand (for responder analysis of SGRQ) will be computed as follows. First, 
multiple imputations will be performed on the continuous total SGRQ scores in a similar manner 
as for the attributable estimand that is computed for change from baseline in morning pre-dose 
trough FEV1 (Section 6.4.4.1), except that the 95th percentile will be used instead of the 5th 
percentile. After that, it will be determined whether the subject has attained the MCID. The 
analysis will proceed using logistic regression as described above, followed by combining of 
results across the multiple imputations using the formulae of Rubin [Rubin, 1987]. 
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in Farrar 2006 for the change from baseline in SGRQ score over 24 weeks (Table
2.4.2 for the efficacy estimand). A cumulative distribution plot by treatment arm (Farrar et al., 
2006) will also be produced. The observed change from baseline in SGRQ over 24 weeks will be 
plotted on the X axis, while the proportion of responders (subjects that equal or exceed that level 
of change) will be plotted on the Y axis (Figure 2.4.2 for the efficacy estimand). Subjects 
without post-baseline data or who discontinue treatment for any reason will not be considered 
non-responders at all values. For display purposes only, the range of the X axis will be from -8 to 
+8 by increments of 0.1 in order to avoid the undue influence of outlying values. The cumulative 
responder curves for each treatment will then be compared pairwise using Kolmogorov-Smirnov 
tests. Cumulative responder analyses for the attributable estimand will not be performed because 
it is not well defined. 
Tipping Point Analyses for Percentage of Subjects achieving an MCID of 4 Units or More in 
SGRQ Total Score at Week 24  
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). A brief overview of the approach is summarized in the table below. Details of the 
methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in Section 6.4.4.4 and in 
the Details Appendix to this SAP), but with the model for SGRQ total score described above. 
Multiple-imputation results will be combined using Rubin’s formulae [Rubin, 1987]. Details of 
the methods may be found in the Details Appendix to this SAP. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 54 of 355
 
 
Table 4 
Sensitivity Analyses for Percentage of Subjects Achieving an MCID of 4 Units or More 
in SGRQ Total Score at Week 24 
Efficacy Estimand 
Attributable Estimand 
Treatment Policy 
Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis #1: 
 
All missing data are 
imputed using the observed 
data model except that for 
subjects in the treatment 
arm (not the comparator 
arm) values that are 
considered MNAR are 
imputed with the SGRQ 
total score in the treatment 
arm increased by a 
maximum of 16 units until 
the p-value  0.05. 
Tipping point analysis 
#2: 
  
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the 
SGRQ total score in 
the treatment arm 
increased by a 
maximum of 16 units 
until the p-value  
0.05. 
 
Tipping point  
analysis: 
 
MI based on the 95th 
percentile of the 
reference arms’ 
distribution if 
treatment 
discontinuation is due 
to tolerability or lack 
of efficacy of study 
drug (as in the primary 
analysis of this 
estimand). Otherwise 
all missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the 
SGRQ total score in 
the treatment arm 
increased by a 
maximum of 16 units 
until the p-value  
0.05. 
Tipping point analysis: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the 
SGRQ total score in 
the treatment arm 
increased by a 
maximum of 16 units 
until the p-value  
0.05. 
MNAR = Missing not at random. The tipping point will be shown to at least a precision of 0.01 
units. Imputed values may not be impossible values – i.e. a negative SGRQ total score. Thus the 
values will be imputed from a truncated distribution. 
The multiple imputation will be applied to the continuous total SGRQ scores within the already-
stated repeated-measures analysis framework for total SGRQ score. Missing values will first be 
imputed for the missing total SGRQ scores prior to the computation of whether the subject has 
attained the MCID (for the sensitivity analysis). The analysis using the imputed data will proceed 
using logistic regression as described above, followed by a combining of results across the 
multiple imputations using the formulae of Rubin [Rubin, 1987]. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 55 of 355
 
 
6.4.5.4
Rescue Ventolin HFA Use 
PT010006: 
The number of puffs of rescue Ventolin HFA taken in the previous 12 hours since the previous 
(AM or PM) dose will be recorded in the subject diary in the morning and evening. The mean 
daily number of puffs of rescue Ventolin HFA used by subjects during the study will be 
calculated overall and for each of the 4-week intervals during the treatment period and provided 
in a diary data listing (Listing 6.1.3 for All Subjects Randomized). Diary data recorded during 
the last 7 days of the 10- to 14-day Screening Period will be used to calculate the baseline. For 
every interval of time over which the mean number of puffs of rescue will be calculated, records 
with missing values will be ignored in both the numerator and denominator. As such, the 
denominator will be adjusted based on the number of days (including half days) with 
non-missing values. 
That is, the mean daily number of puffs of daytime rescue use (M_DT) will be set to the total 
number of daytime puffs divided by the number of half-days when daytime rescue use was 
recorded. The mean daily number of puffs of nighttime rescue use (M_DN) will be set to the 
total number of nighttime puffs divided by the number of half-days when the nighttime rescue 
use was recorded. The mean daily rescue use (puffs) is then two multiplied by the mean of 
M_DT and M_DN. 
The difference between treatment groups in the change from baseline in rescue Ventolin HFA 
usage over 24 weeks will be evaluated using a linear RM analysis of covariance (ANCOVA) 
model which will include treatment, 4-week time interval (Interval 1 – Interval 6), treatment by 
time-interval interaction, and ICS use at Screening as categorical covariates, and baseline rescue 
Ventolin HFA use, baseline eosinophil count, percent reversibility to Ventolin HFA, and 
baseline post-bronchodilator percent predicted FEV1 as continuous covariates. A UN matrix will 
be used to model additional autocorrelation within subject. If the UN model fails to converge, an 
AR(1) structure will be used instead. In the AR(1) model, subject will be included as a random 
effect. Contrasts will be used to obtain estimates of the treatment differences over the entire 
24 weeks. Two-sided p-values and point estimates with two-sided 95% CIs will be produced for 
each of the four treatment differences. The comparison of BFF MDI to Symbicort TBH will be for 
non-inferiority rather than superiority and will use a margin of 0.75 puffs/day for the upper bound of 
the two sided 95% CI for the treatment difference. The main analysis will be conducted using the 
efficacy estimand (Table and Figure 2.5.1) restricted to the Rescue Ventolin User (RVU) 
Population. Supportive analyses will use the attributable, the treatment policy estimand, and the 
per protocol estimand (Tables and Figures 2.5.3 and 2.5.5) restricted to the RVU Population. 
Other supportive analyses will use the efficacy estimand not restricted to the RVU Population 
and the treatment policy estimand not restricted to the RVU Population (Tables and Figures
2.5.6 and 2.5.7).  
The attributable estimand (for the analysis of average daily rescue Ventolin HFA use) will be 
computed in a similar manner as the attributable estimand is computed for change from baseline 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 56 of 355
 
 
in morning pre-dose trough FEV1 at Week 24 as described in Section 6.4.4.1 except that the 95th 
percentile will be used instead of the 5th percentile. 
As supportive analyses, the treatment difference for each 4-week interval and over Weeks 12 to 
24 will be evaluated and summarized. Additionally, as supportive analyses, daytime rescue 
Ventolin® HFA use and night-time rescue Ventolin HFA use will be evaluated and summarized 
in a similar fashion. Two-sided p-values and point estimates with 2-sided 95% CIs will be 
produced for each treatment difference (Tables and Figures 2.5.9 and 2.5.13 for the efficacy 
estimand restricted to the RVU Population).  
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in Farrar 2006 for the change from baseline in average daily rescue medication over 
24 weeks (Table 2.5.1a for the efficacy estimand). A cumulative distribution plot by treatment 
arm (Farrar et al., 2006) will also be produced. The observed change from baseline in average 
daily rescue medication over 24 weeks will be plotted on the X axis, while the proportion of 
responders (subjects that equal or exceed that level of change) will be plotted on the Y axis 
(Figure 2.5.1a for the efficacy estimand. Subjects without post-baseline data or who discontinue 
treatment for any reason will be considered non-responders for all values. For display purposes 
only, the range of the X axis will be from the 1st percentile to the 99th percentile irrespective of 
treatment in order to avoid the undue influence of outlying values. The cumulative responder 
curves for each treatment will then be compared pairwise using Kolmogorov-Smirnov tests. 
Cumulative responder analyses for the attributable estimand will not be performed because they 
are not well defined. 
Tipping Point Analyses for Rescue Ventolin HFA Use Over 24 Weeks  
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). A brief overview of the approach is summarized in the table below. Details of the 
methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in Sections 6.4.4.4 and in 
the Statistical Methods Appendix to this SAP), but with the model for rescue Ventolin HFA use 
described above. Multiple-imputation results will be combined using Rubin’s formulae [Rubin, 
1987]. Details of the methods may be found in the Details Appendix to this SAP (Appendix 6). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 57 of 355
 
 
Table 5 
Sensitivity Analyses for Rescue Ventolin HFA Use 
Efficacy Estimand 
Attributable Estimand 
Treatment Policy 
Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis 
#1: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values that are 
considered MNAR are 
imputed with the 
number of puffs in the 
treatment arm increased 
by up to 4 puffs per day 
until the p-value  0.05.  
 
Tipping point analysis 
#2: 
  
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the 
number of puffs in the 
treatment arm 
increased by up to 4 
puffs per day until the 
p-value  0.05.  
 
 
Tipping point  
analysis: 
 
MI based on the 95th 
percentile of the 
reference arms’ 
distribution if treatment 
discontinuation is due to 
tolerability or lack of 
efficacy of study drug 
(as in the primary 
analysis of this 
estimand). Otherwise all 
missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm (not 
the comparator arm) 
values are imputed with 
the number of puffs in 
the treatment arm 
increased by up to 4 
puffs per day until the p-
value  0.05. 
Tipping point analysis: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects in 
the treatment arm (not the 
comparator arm) values 
are imputed with the 
number of puffs in the 
treatment arm increased 
by up to 4 puffs per day 
until the p-value  0.05.  
MNAR = Missing not at random. The tipping point will be shown to at least a precision of 0.02 
puffs/day. Imputed values may not be impossible values – i.e. a negative number of puffs of 
rescue Ventolin HFA. Thus the values will be imputed from a truncated distribution. 
PT010007: 
The mean change from baseline in rescue use will be summarized by treatment group over 52 
weeks and over each post-randomization 4-week interval (Interval 1 to Interval 13) (Table and
Figure 2.5.2 for the efficacy estimand with the Japanese mITT Population). Listing 6.1.3 in 
PT010006 will be generated for Japanese Randomized subjects and updated with information 
through 52 weeks. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 58 of 355
 
 
6.4.5.5
RS-Total Score 
PT010006: 
The EXACT is a 14-item patient reported outcome (PRO) instrument from the daily diary which 
will be used to measure the effect of treatment on exacerbations, and on the severity of 
respiratory symptoms. Mean change from baseline in the daily EXACT Total Score, the 11-item 
RS-Total Score, as well as 3 subscale scores, RS-Breathlessness, RS-Cough and Sputum, and 
RS-Chest Symptoms, will be calculated over each post-randomization 4-week interval of the 24-
week Treatment Period. Higher scores indicate a more severe condition. The last 7 days of the 10 
to 14 day Screening Period will be used to calculate the baseline. The mean change from 
baseline in the EXACT Total Score, RS-Total Score, RS-Breathlessness, RS-Cough and Sputum, 
and RS-Chest Symptoms over each 4-week interval will be analyzed using a similar RM model 
as for TDI to estimate treatment effects over 24 weeks and over Weeks 12 to 24, but using the 
corresponding baseline mean score instead of the BDI as a covariate (Tables and Figures 2.6.1, 
2.6.3, 2.6.4, and 2.6.5 for the efficacy estimand, the attributable estimand, and the treatment 
policy estimand, and Tables 2.6.13 and 2.6.14 for the efficacy estimand and the efficacy 
estimand in the Japanese mITT Population). The analyses on the attributable estimand, treatment 
policy estimand, and per protocol estimand will pertain to the RS-Total Score only. Instead of 
visit, the number of the relevant respective 4-week interval (Interval 1 to Interval 6) will be used 
as a categorical covariate in the model. Thus the model will include treatment, time interval, 
treatment by time-interval interaction, and ICS use at Screening as categorical covariates and 
baseline score, baseline eosinophil count, percent reversibility to Ventolin HFA and baseline 
post-bronchodilator percent predicted FEV1 as continuous covariates. An unstructured 
correlation matrix will be used to model additional autocorrelation within subject. If the UN 
model fails to converge, then an AR(1) structure will be used instead. In the AR(1) model, 
subject will be included as a random effect. The RS-Total score over 24 weeks is a secondary 
efficacy endpoint. The EXACT Total score, RS-Total score and the RS subscale scores are 
“other” endpoints. EXACT data will be listed in Listing 6.1.5. The analysis of RS-Total score 
will be secondary for the EU only. 
The attributable estimand (for the analysis of RS-Total score) will be computed in a similar 
manner as the attributable estimand is computed for change from baseline in morning pre-dose 
trough FEV1 at Week 24 as described in Section 6.4.4.1 except that the 95th percentile will be 
used instead of the 5th percentile. 
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in Farrar 2006 for the change from baseline in daily RS-Total Score over 24 weeks 
(Table 2.6.1a for the efficacy estimand). A cumulative distribution plot by treatment arm (Farrar 
et al., 2006) will also be produced. The observed change from baseline in mean daily RS-Total 
score over 24 weeks will be plotted on the X axis, while the proportion of responders (subjects 
that equal or exceed that level of change) will be plotted on the Y axis (Figure 2.6.1a for the 
efficacy estimand). Subjects without post-baseline data or who discontinue treatment for any 
reason will be considered non-responders for all values. For display purposes only, the range of 
the X axis will be from the 1st percentile to the 99th percentile irrespective of treatment in order 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 59 of 355
 
 
to avoid the undue influence of outlying values. The cumulative responder curves for each 
treatment will then be compared pairwise using Kolmogorov-Smirnov tests. Cumulative 
responder analyses for the attributable estimand will not be performed because they are not well 
defined. 
PT010007: 
The mean change from baseline in RS-Total Score, EXACT Total Score, RS-Breathlessness, RS-
Cough and Sputum, and RS-Chest Symptoms will be summarized by treatment group over 52 
weeks and over each post-randomization 4-week interval (Interval 1 to Interval 13) (Tables and
Figures 2.6.2 and 2.6.8 and Table 2.6.14)  
6.4.5.6
Time to Onset of Action Assessed Using FEV1 on Day 1 
This analysis will be conducted for PT010006. 
The onset of action will be determined for each treatment using the post-dosing FEV1 
assessments from Day 1. The onset of action for each product (BGF MDI, GFF MDI, and BFF 
MDI) will be defined as the first time point where the mean change from baseline exceeds 100 
mL. Supportive analyses may be conducted using alternatively definitions of onset of action. The 
resulting tables and figures are Table and Figure 2.7.1 for the efficacy estimand. 
6.4.5.7
Other Spirometry Endpoints 
Analyses of other endpoints will be performed for the efficacy estimand only.  
PT010006: 
The analysis for between-treatment comparisons of changes from baseline in morning pre-dose 
trough FEV1 over 24 weeks, over Weeks 12-24 and at each post-randomization visit through 
Week 24 has already been described in Section 6.4.4.1 (Tables and Figures 2.1.1, and 2.1.3). 
Analyses for FEV1 AUC0-4 over 24 weeks, over Weeks 12-24, and at each post-randomization 
visit have been described in a similar manner in Section 6.4.4.2 (Table and Figure 2.1.9 for 
efficacy estimand). Peak change from baseline within 4 hours in FEV1 over 24 weeks, over 
Weeks 12 to 24, and at Day 1 and at each post-randomization visit where measured through 
Week 24 will be estimated and compared between treatment groups using a linear mixed RM 
model with the same model as pre-dose trough FEV1 (Table and Figure 2.3.1 for the efficacy).  
Similar analyses will be conducted for FVC, PEFR, and FEF25-75 over 24 weeks, over Weeks 12 
to 24, and at each post-randomization visit where measured for the mITT and ITT Populations, 
respectively. The baseline covariate for each model will be endpoint-specific (Tables and 
Figures 2.8.1 to 2.8.14 for change from baseline in morning pre-dose trough FVC, PEFR, and 
FEF25-75; Tables and Figures 2.9.1 to 2.9.14 for peak change from baseline within 4 hours for 
FVC, PEFR, and FEF25-75; Tables and Figures 2.10.1 to 2.10.14 for FVC AUC0-4, PEFR AUC0-4, 
and FEF25-75 AUC0-4). The analyses for change from baseline at each post-dose time point in 
FEV1, FVC, PEFR, and FEF25-75 on Day 1 will be provided (Tables and Figures 2.7.1 and 2.7.3 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 60 of 355
 
 
for FEV1 and 2.11.7 to 2.11.19 for FVC, PEFR, and FEF25-75, respectively; Listings 6.3.1 to 6.3.7 
for the efficacy estimand). 
On Day 1 during the first four hours post-dosing and by time point, the proportion of subjects 
achieving an improvement from baseline in FEV1 using different thresholds (i.e., 10%, 12%, 
100 mL, 200 mL, and “12% and 200 mL”) will be estimated for each treatment. Subjects 
without post-baseline data will not be considered in the analysis. Logistic regression, performed 
with SAS PROC GENMOD, will be used to compare the treatments, adjusting for baseline 
FEV1, reversibility to Ventolin HFA, and baseline eosinophil count as continuous covariates, and 
ICS use at Screening as a categorical covariate. The odds ratio for treatment will be determined, 
along with the Wald two-sided 95% CI. The Wald chi-square test will be used to calculate p-
values for comparisons between treatments (Tables and Figures 2.12.1, 2.12.3, 2.12.4, 2.12.5, 
and 2.12.7 for the efficacy estimand). 
PT010007: 
The analysis for changes from baseline in morning pre-dose trough FEV1 over 52 weeks (Weeks 
4 to 52) and at each post-randomization visit has been described in Section 6.4.4.1 (Table 2.1.2 
and Figures 2.1.2, 2.1.2.1, and 2.1.2.2 for the Japanese mITT Population). 
Similar analyses will be performed on Change from baseline in morning pre-dose trough for 
FVC, PEFR, and FEF25-75 over 52 weeks (Weeks 4 to 52), and at each post randomization visit 
measured for the Japanese mITT Populations (Tables and Figures 2.8.2, 2.8.8, and 2.8.14 for
FVC, PEFR, and FEF25-75).  
6.4.5.8
Rate of COPD Exacerbations 
COPD Exacerbations 
A COPD exacerbation will be defined as a change in the subject’s usual COPD symptoms that 
lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may warrant a 
change in regular medication. The change in symptoms must include at least one major COPD 
symptom and at least one other major (dyspnea, sputum volume, and sputum color) or minor 
symptom (cough, wheeze, sore throat, cold symptoms, and fever without other cause). 
Exacerbations will be considered moderate if they result in:  
 
•
Use of systemic corticosteroids and/or antibiotics for at least 3 days; a single depot injectable 
dose of corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids. 
Exacerbations will be considered severe if they result in:  
•
An inpatient COPD-related hospitalization (documentation stating that the subject was 
hospitalized for the COPD exacerbation or a record of the subject being admitted for 24 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 61 of 355
 
 
hours to an observation area, the emergency department, or other equivalent healthcare 
facility depending on the country and healthcare system). 
•
COPD-related death. 
Moderate-or-severe COPD exacerbations will be entered in the eCRF.  
Additionally, the investigator may identify certain events (recorded on the same CRF page) 
which don’t entirely meet the criteria above as exacerbations; the justifications supporting the 
investigator’s judgment will be recorded on a separate page on the eCRF. 
COPD exacerbations not meeting the criteria for moderate or severe COPD exacerbations will be 
considered to be mild COPD exacerbations. For more detail about moderate-or-severe, severe, 
and any-severity COPD exacerbation events (and their start and end dates) and how they are 
operationally defined, see the subsections titled “Duration of COPD Exacerbation”, “Moderate-
or-Severe Exacerbation and Severe Exacerbation: Operational Definitions:”, and “Exacerbation 
of any Severity: Operational Definition:”. 
Tipping Point Analyses for Rate of Moderate or Severe COPD Exacerbations  
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). A brief overview of the approach is summarized in the table below. Details of the 
methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in Sections 6.4.4.4 and in 
the Details Appendix to this SAP), but with the negative binomial model for rate of moderate or 
severe COPD exacerbations described below. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 62 of 355
 
 
Table 6 
Sensitivity Analyses for Rate of Moderate or Severe COPD Exacerbations  
Efficacy Estimand 
Attributable Estimand 
Treatment Policy 
Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis 
#1: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values that are 
considered MNAR are 
imputed with rate in the 
treatment arm increased 
by up to 1.5 
exacerbations/year until 
the p-value  0.05. 
 
Tipping point analysis 
#2: 
  
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the rate 
in the treatment arm 
increased by up to 1.5 
exacerbations/year 
until the p-value  
0.05. 
 
 
Tipping point  
analysis: 
 
MI based on the 95th 
percentile of the 
reference arms’ 
distribution if treatment 
discontinuation is due to 
tolerability or lack of 
efficacy of study drug 
(as in the primary 
analysis of this 
estimand). Otherwise all 
missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm (not 
the comparator arm) 
values are imputed with 
rate in the treatment arm 
increased by up to 1.5 
exacerbations/year until 
the p-value  0.05. 
Tipping point analysis: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects in 
the treatment arm (not the 
comparator arm) values 
are imputed with the rate 
in the treatment arm 
increased by up to 1.5 
exacerbations/year until 
the p-value  0.05. 
MNAR = Missing not at random. The tipping point will be shown to at least a precision of 0.02 
exacerbations/year. 
Duration of COPD Exacerbation PT010006: 
x
The rate of moderate or severe COPD exacerbations will be analyzed using negative 
binomial regression as implemented in SAS PROC GENMOD. Treatments will be 
compared adjusting for baseline post-bronchodilator percent predicted FEV1 and baseline 
eosinophil count as continuous covariates and baseline COPD exacerbation history (0, 1, 
>=2), country, and ICS use at Screening (yes/no) as categorical covariates. COPD 
exacerbations will be considered separate events provided that there are more than 7 days 
between the recorded stop date of the earlier event and the start date of the later event. 
Time at risk of experiencing an exacerbation will be used as an offset variable in the 
model.  
x
For the efficacy estimand, the time at risk is defined as time of exposure to randomized 
treatment – not during or within 7 days after an exacerbation (of equal or greater severity) 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 63 of 355
 
 
– until the last dosing date. More precisely, this is the amount of time between the date of 
first dose of study medication and the date of premature discontinuation from study 
medication plus + 1 day or the date of completion of study medication minus the number 
of days while the subject was experiencing any exacerbation and minus the seven days 
subsequent to any exacerbation. Any days subsequent to the date of premature 
discontinuation from study medication + 1 day or the date of completion of study 
medication are not subtracted. For the treatment policy estimand, time at risk is defined 
as follow-up time (equivalently, the total exposure to randomized medication and post-
treatment follow-up for efficacy) – not during or within 7 days after an exacerbation (of 
equal or greater severity) – up to the last recorded date (of any assessment or contact) for 
the subject (including telephone contact) (Tables 2.13.1.1 and 2.13.4.1 for the efficacy 
estimand, and the treatment policy estimand, respectively). The per protocol estimand is 
not applicable for this endpoint. 
x
Any imputed COPD exacerbation events for the attributable estimand or for sensitivity 
analyses will have an assumed duration of 10 days. 
x
For moderate-or-severe COPD exacerbations that were identified apart from an electronic 
diary (eDiary) alert, the symptom information is listed in Listing 6.1.2.2. 
x
The rate (and number of) exacerbations and the percentage of subjects who experience 
exacerbations will be summarized for moderate-or-severe exacerbations (Tables 2.13.1, 
2.13.3, and 2.13.4 for the efficacy, attributable and treatment policy estimands, 
respectively). 
x
The rate of moderate or severe COPD exacerbations for subjects with 1 exacerbation in 
the previous year will be summarized for the efficacy estimand (Tables 2.13.6). 
x
 
x
The rate of moderate or severe COPD exacerbations for completers vs. discontinuations 
(Table 2.13.1b). 
PT010007: 
x
The rate of moderate-or-severe COPD exacerbations and the percentage of subjects who 
experience exacerbations will be summarized by treatment group (Table 2.13.2 for the 
efficacy estimand with the Japanese mITT Population).  


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 64 of 355
 
 
Duration of COPD Exacerbation  
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment (using the eCRF COPD exacerbation page), whereas for mild exacerbations, the 
duration is defined by the length of symptoms.  
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date will 
be defined as the latter of the last day of prescribed treatment with a systemic corticosteroid or 
systemic antibiotic (if applicable). In order to ensure that the same event is not counted twice, 
consecutive or concurrent moderate or severe COPD exacerbations with equal to or fewer than 7 
days between the recorded stop date of the earlier event and start date of the later event will be 
considered the same event and assigned the maximum severity between the two. 
For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms as 
recorded by the subject in the eDiary, and the stop date will be defined as the last day of 
worsened symptoms. In order to ensure that the same event is not counted twice, consecutive or 
concurrent mild COPD exacerbations with equal to or fewer than 7 days between the recorded 
stop date of the earlier event and start date of the later event will be considered the same event.  
In addition, in order to not double-count exacerbations, eDiary data from dates within 7 days 
prior to or after a moderate or severe exacerbation will not be counted as an additional mild 
COPD exacerbations. This implies that continuing worsened symptoms that meet the definition 
of a mild exacerbation would need to be present at least 2 days prior to the 7-day period 
immediately preceding the start date of a moderate or severe COPD exacerbation in order to be 
considered a separate event. Similarly, worsened symptoms would need to be present for at least 
2 days after the 7-day period immediately following a moderate or severe COPD exacerbation to 
be considered a separate event.  
Analyses of each severity of exacerbation will account for the time that subjects are at risk of 
having an exacerbation of that severity or greater. Time during or immediately following – i.e. 
within 7 days of – an exacerbation will not be considered as part of the time that the subject was 
at risk. However, time during or immediately following an exacerbation of lower severity will be 
included since, for example, a subject experiencing a mild exacerbation is still at risk of the event 
increasing in severity and becoming a moderate exacerbation. Moderate and severe COPD 
exacerbations occurring within 7 days of one another will be coalesced into a single COPD 
exacerbation event with the severity of “severe” (see details below).  
Moderate-or-Severe Exacerbation and Severe Exacerbation: Operational Definitions: 
x
Moderate exacerbations and severe exacerbations will be defined based on information 
from the COPD Exacerbation eCRF page. A time interval from a single COPD 
exacerbation eCRF page will be designated as being during an event of a moderate-or-


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 65 of 355
 
 
severe COPD exacerbation if for that interval, either antibiotics or oral corticosteroids 
were administered for the exacerbation. 
 
Call this time interval a “P-Interval”. The start date of the P-Interval is the earliest start date 
of the above, and the stop date will be defined as the last stop day of the above. If the subject 
was hospitalized due to the exacerbation or if the exacerbation led to a COPD-related death, 
then the severity of “severe” will be assigned to this P-interval; otherwise the severity of 
“moderate” will be assigned. The later of the stop date of the treatment with a systemic 
corticosteroid and the stop date of the treatment with an antibiotic will be the end date of the 
COPD exacerbation (i.e. the end of the P-Interval).  
An overarching interval of (any number of) such P-Intervals – including any P-Intervals with 
an end date not more than 7 days prior to the start date of some other P-Interval or with a 
start date not more than 7 days after the end date of some other P-Interval – and including the 
days in any gaps between them – will be called an “QMS-Interval”. This QMS-interval will 
represent the consolidated duration of several exacerbations recorded on different CRF 
pages. This QMS-Interval will be considered to be a single event of a moderate-or-severe 
COPD exacerbation. See Figure 2. 
x
A P-interval of severe COPD exacerbation is called a “severe” P-Interval. Any QMS 
interval that contains at least one “severe” P-Interval will also be called a “QS-Interval”. 
This QS-Interval will be considered to be a single event of a severe COPD exacerbation. 
See Figure 2.
Figure 2  
Overarching Intervals of Moderate-or-Severe (QMS) and Severe (QS) COPD 
Exacerbations
P 
(Severe) 
Å3 daysÆ 
P 
(Severe) 
Å 8  days  Æ
P 
Å5 daysÆ 
P 
(Severe) 
QMS 
 
QMS 
QS 
 
QS 
A P-interval is a moderate-or-severe COPD exacerbation instance from a single CRF page. 
In a “Severe” P-Interval [denoted in the figure as “P (severe)”], the maximum severity of the COPD 
exacerbation is “severe”. 
A QMS interval is an overarching moderate-or-severe COPD exacerbation event encompassing multiple 
CRF pages. 
A QS interval is an overarching severe COPD exacerbation event encompassing multiple CRF pages. 
 
Exacerbation of any Severity: Operational Definition: 
x
Using eDiary data, a day will be designated as being during an event of a COPD 
exacerbation of some severity if (1) there was at least one major symptom and there was 
at least one other major or minor symptom and if (2) on an adjacent day there was at least 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 66 of 355
 
 
one major symptom and there was at least one other major or minor symptom. Denote 
such a day as a “Category-D” day.  
x
An interval of (any number of) such Category-D days – including any Category-D days 
not more than 7 days apart from some other Category-D day – and including the days in 
any gaps between them – will be called an “I-Interval”. See Figure 3. 
x
An overarching interval coalescing (any number of) P-Intervals and I-Intervals – 
including any such P-or-I-intervals with an end date not more than 7 days prior to the 
start date of some other P-or-I-Interval or with a start date not more than 7 days after the 
end date of some other P-or-I-interval – and including the days in any gaps between them 
– will be called a “QQ-Interval”. This QQ-interval will represent the consolidated 
duration of several exacerbations recorded on different CRF pages or identified from 
subject diary data. This QQ-Interval will be considered to be a single event of an any-
severity COPD exacerbation. See Figure 4.
Figure 3  
Overarching Intervals (I) of Mild-Moderate-or-Severe COPD Exacerbation Events 
Based on eDiary Symptom Data 
D D D D D D D D Å 5 days Æ D D D D D D Å 9 days  Æ D D D Å     10 days    Æ D D
I 
 
I 
 
I 
A Category-D day is a day with mild-moderate-or-severe COPD exacerbation based on e-diary symptom 
data. 
An I-Interval is an overarching mild-moderate-or-severe COPD exacerbation event encompassing 
multiple clusters of e-diary symptom days. 
 
Figure 4  
Overarching Intervals (QQ) of Mild-Moderate-or-Severe COPD Exacerbation 
Events Incorporating Both CRF Data and eDiary Symptom Data  
P 
Å2 daysÆ 
I 
Å3 daysÆ
I 
Å 10 days Æ 
P
QQ 
 
QQ 
A P-Interval is a moderate-or-severe COPD exacerbation instance from a single CRF page. 
An I-Interval is an overarching mild-moderate-or-severe COPD exacerbation event based on e-diary 
symptom data. 
A QQ-Interval is an overarching mild-moderate-or-severe COPD exacerbation event – encompassing 
multiple P-Intervals and I-Intervals – incorporating both CRF data and e-diary symptom data. 
 
In summary, we combine CRF-based moderate-or-severe COPD exacerbation events if they are 
close enough together in time (Figure 2). We also combine severe COPD exacerbation events 
with other severe COPD exacerbation events or with moderate-or-severe COPD exacerbation 
events if they are close enough together in time (Figure 2) – thus forming a single severe COPD 
exacerbation event. We also combine mild-moderate-or-severe COPD exacerbations if they are 
close enough together in time; this coalescing is done first within-data-source (CRF [Figure 2] or 
diary [Figure 3]) and then between the two sources (Figure 4). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 67 of 355
 
 
Time-at-Risk for COPD Exacerbations of Various Severities: Operational Definition 
x
During a time when a subject is not experiencing a severe COPD exacerbation (i.e. QS 
interval) – and is not in the seven days following a severe COPD exacerbation – a subject 
is considered to be at risk of having a severe exacerbation. During a time when a subject 
is not experiencing a moderate-or-severe COPD exacerbation (i.e. QMS interval) – and is 
not in the seven days following a moderate-or-severe COPD exacerbation – a subject is 
considered to be at risk of having a moderate-or-severe exacerbation. During a time when 
a subject is not experiencing an any-severity COPD exacerbation (i.e. QQ interval) – and 
is not in the seven days following an any-severity COPD exacerbation – a subject is 
considered to be at risk of having an any-severity exacerbation. 
Overarching coalesced intervals (i.e. events) of COPD exacerbation will be listed for severe 
exacerbations, moderate -to-severe exacerbations, and any-severity exacerbations (Listing
6.1.2.3). A severe COPD exacerbation event must be classified also as a moderate-or-severe 
event and also as an any-severity event. A moderate-or-severe COPD exacerbation event must be 
classified also as an any-severity event. 
PT010006: 
x
Rate of COPD exacerbations of any severity will be analyzed in a manner similar to the 
rate of moderate or severe COPD exacerbations (Table 2.13.11.1 for the efficacy 
estimand). 
x
Rate of severe COPD exacerbations will be analyzed in a manner similar to the rate of 
moderate or severe COPD exacerbations (Table 2.13.12.1 for the efficacy estimand). 
PT010007: 
x
Rate of COPD exacerbations of any severity will be analyzed in a manner similar to the 
rate of moderate or severe COPD exacerbations (Table 2.13.11.2 for the efficacy 
estimand with the Japanese mITT Population). 
x
Rate of severe COPD exacerbations will be analyzed in a manner similar to the rate of 
moderate or severe COPD exacerbations (Table 2.13.12.2 for the efficacy estimand with 
the Japanese mITT Population). 
The count of COPD exacerbations of any severity is the number of QQ-Intervals (for a subject) 
as defined previously. Time at risk of experiencing an exacerbation will be used as an offset 
variable in the model. Time during an exacerbation (of any severity) or in the 7 days following 
an exacerbation (of any severity) will not be included in the calculation of exposure (i.e. time at 
risk). Data related to COPD exacerbations of any severity are listed in Listings 6.1.2.1, 6.1.2.2, 
6.1.2.3, and 6.1.4. For moderate-or-severe COPD exacerbations that were identified apart from 
an eDiary alert, the symptom information is listed in Listing 6.1.2.2. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 68 of 355
 
 
6.4.6
Time to Clinically Important Deterioration 
Time to CID will be analyzed for PT010006. 
Two definitions of CID will be used: 
x
CID: is  100 mL decrease (from baseline) in trough FEV1, or  4 points increase (from 
baseline) in SGRQ total score, or a TDI focal score of -1 point or less, or treatment-
emergent moderate-or-severe COPD exacerbation occurring up to Week 24. 
x
Sustained CID: is  100 mL decrease (from baseline) in trough FEV1, or  4 points 
increase (from baseline) in SGRQ total score, or a TDI focal score of -1 point or less, any 
of which is occurring on two consecutive analysis visits or for  50% of all available 
subsequent analysis visits, or a treatment emergent moderate-or-severe COPD 
exacerbation occurring up to Week 24 
Time to CID analysis will be performed for each CID definition using the Cox regression model. 
The model will include baseline post-bronchodilator percent predicted FEV1, baseline eosinophil 
count, baseline COPD exacerbation history (0, 1, >=2), country, and ICS use at Screening 
(yes/no). Time to a CID event will be based on the component event which occurs first. Subjects 
who do not have a CID event will be censored at the earliest day among the component 
censoring times. COPD exacerbations happening after Week 24 will not be counted as CID 
events. Estimated adjusted hazard ratios will be displayed along with associated 95% CI and p-
values (Tables 2.60.1, to 2.60.5). Time to CID will be displayed for each treatment group using a 
Kaplan-Meier curve (Figures 2.60.1 to 2.60.5). Time to CID will be analyzed for the efficacy 
estimand, the attributable estimand, the treatment policy estimand, and the per protocol estimand. 
The comparison of BFF MDI to Symbicort TBH will be for non-inferiority with the per protocol 
estimand rather than superiority and will use a margin of 1.1 for the upper bound of the two sided 
95% CI for the hazard ratio. 
For the analysis of the attributable estimand, missing data that have been reasonably attributed to 
tolerability or lack of efficacy will be imputed based on either the 5th or the 95th percentile (see 
below) of the reference arms’ distribution. The attributable estimand for time to CID will employ 
multiple by-visit imputation of pre-dose trough FEV1 and the SGRQ total score (at visits for 
which they are missing) (as described in Sections 6.4.4.1 and 6.4.5.3, respectively) and multiple 
imputation of time to first moderate-or-severe COPD exacerbation. A complete dataset for the 
COPD exacerbation count will be created analogously to that described in the analysis of Rate of 
Moderate or Severe Exacerbations in Section 6.4.5.8; however, the timing of imputed events is 
also needed. These will be obtained for each imputed event by randomly drawing a value from 
the uniform distribution over the interval that starts with time of treatment discontinuation + 1 
day (in study days) and ends at 24 weeks. The attributable estimand for time to CID will also 
employ multiple by-visit imputation of the TDI focal score in a manner similar to that for SGRQ. 
The application of the percentile penalty to the attributable estimand will be carried out for the 
four component variables simultaneously. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 69 of 355
 
 
6.4.7
Analysis of Other Endpoints 
6.4.7.1
Percentage of Days with “No Rescue Ventolin HFA Use” Over the Treatment 
Period 
PT010006: 
As a supportive analysis, percentage of days with “no rescue Ventolin HFA use” over 24 weeks 
will be analyzed. A “day with no rescue use” is defined as any day where the subject reported 
zero puffs of rescue Ventolin HFA. The rescue Ventolin HFA usage diary data from days where 
rescue Ventolin HFA usage data is non-missing will be used to ascertain the days with “no 
rescue Ventolin HFA use”. The percentage of days with no rescue use will be calculated as 100 x 
(number of days no rescue Ventolin use over the entire treatment period / number of days with 
non-missing rescue Ventolin use over the entire treatment period). The percentage of days with 
“no rescue use” will be summarized by treatment and analyzed using ANCOVA with baseline 
average daily rescue Ventolin HFA use, percent reversibility to Ventolin HFA, baseline post-
bronchodilator percent predicted FEV1, baseline blood eosinophil count as continuous covariates 
and ICS use at Screening as a categorical covariate. Two-sided p-values and point estimates with 
2-sided 95% CIs will be produced for each treatment difference (Tables 2.15.1 for the efficacy 
estimand).  
For the efficacy estimand, the analyses of Percentage of Days with “No Rescue Ventolin HFA 
Use” will be restricted to the Rescue Ventolin User Population. 
PT010007: 
Percentage of days with “no rescue Ventolin HFA use” over 52 weeks (PT010007) will be 
summarized descriptively (Table 2.15.2 for the efficacy estimand with the Japanese mITT 
Population). 
6.4.7.2
Time to First COPD Exacerbation 
Time to First COPD Exacerbation will be analyzed for PT010006. 
Time to first COPD exacerbation of any severity is the time from first dose of study medication 
(or from randomization for any subjects randomized but not treated) to the time of onset of the 
first COPD exacerbation (mild, moderate, or severe). Time to first severe COPD exacerbation is 
the time from first dose of study medication (or from randomization for any subjects randomized 
but not treated) to the time of onset of the first COPD exacerbation (severe). Time to first 
moderate or severe COPD exacerbation is the time from first dose of study medication (or from 
randomization for any subjects randomized but not treated) to the time of onset of the first COPD 
exacerbation (moderate or severe).  
The time to first COPD exacerbation of any severity will be analyzed up through Week 24 using 
a Cox regression model. Treatment comparisons will be performed using the model, adjusting 
for baseline percent predicted FEV1 and baseline eosinophil count as continuous covariates and 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 70 of 355
 
 
baseline COPD exacerbation history (0, 1, 2), country, and ICS use at Screening (Yes/No) as 
categorical covariates. Estimated adjusted hazard ratios relative to the comparator for each 
treatment comparison will be displayed along with the associated Wald two-sided 95% CIs and 
p-values (Table 2.13.13 for the efficacy estimand).  
Time to first COPD exacerbation of any severity will be displayed graphically for each treatment 
using a Kaplan-Meier curve (Figure 2.13.13 for the efficacy estimand). Subjects who do not 
experience a COPD exacerbation over treatment period will be censored at the Week 24 visit. 
Subjects who withdraw from the study without experiencing a COPD exacerbation will be 
censored at the date of withdrawal or the last date of treatment, whichever is later. Time to first 
moderate or severe COPD exacerbation will be analyzed and displayed similarly to the time to 
first COPD exacerbation of any severity (Table and Figure 2.13.19 for the efficacy estimand and 
Listing 6.1.2.3). 
Time to first severe COPD exacerbation will be analyzed similarly to the analysis for time to first 
COPD exacerbation of any severity (Table 2.13.20 and Figure 2.13.19).  
6.4.7.3
Time to Treatment Failure 
Time to Treatment Failure will be analyzed for PT010006. 
Treatment failure is defined as a moderate or severe COPD exacerbation or premature 
discontinuation from treatment for any reason or death. Time to treatment failure will be 
displayed graphically for each treatment group using a Kaplan-Meier curve and analyzed using a 
log-rank test to compare the curves between the treatments (Figure 2.14.1). Subjects who do not 
experience a treatment failure will be censored at their Week 24 Visit. The time to treatment 
failure will be analyzed using the efficacy estimand. The model will include treatment, baseline 
post-bronchodilator percent predicted FEV1, baseline eosinophil count, baseline COPD 
exacerbation history (0, 1, >=2), country, and ICS use at Screening (yes/no). Estimated adjusted 
hazard ratios will be displayed along with associated 95% CI and p-values (Table 2.14.1). 
6.4.7.4
European Quality-of-Life-5 Dimension-5 Level Questionnaire 
Data from the EQ-5D-5L will be analyzed for PT010006. 
The data will be weighted to calculate an index score based upon subjects’ responses to the 5 
dimensions. The visual analogue scale (VAS) will be scored from 0 (worst imaginable health 
state) through 100 (best imaginable health state) to represent the subject’s self-report concerning 
how bad or how good their health was during that day. 
EQ-5D will be presented in three different ways:  
1. Presenting results from the EQ-5D-5L descriptive system as a health profile at baseline, at all 
visits, and at EoT (%, n) by domain  
2. Presenting results of the VAS as a measure of overall self-rated health status - baseline scores, 
scores at each visit, changes from baseline at each visit, and mean VAS score over the treatment 
period 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 71 of 355
 
 
3. Presenting results from the EQ-5D-5L index score (using UK value set) baseline, each visit, 
changes from baseline to each visit, and the mean index score over the treatment period.  
 
The percentage of subjects’ categorical responses to each of the 5-dimensions will be 
summarized (Table 2.16.1 for the efficacy estimand). Descriptive statistics for the index score 
(Table 2.16.7 for the efficacy estimand) and VAS (Table 2.16.13 for the efficacy estimand) will 
be presented by treatment group. VAS scores over 24 weeks may be analyzed using a similar 
RM model as is used for the TDI, but using baseline EQ-5D VAS score as a covariate instead of 
BDI (Table and Figure 2.16.7 for the index score and Table 2.16.13 for VAS for the efficacy 
estimand). EQ-5D data are listed in Listing 6.1.11. 
For calculations of index score, the method recommended by the national institute for health and 
care excellence (NICE) August 2017 will be applied. Cross-walk between EQ-5D-3L value set 
and EQ-5D-5L descriptive system have been developed by Van Hout et al 2012 (Van Hout et al. 
2012) and this cross-walk value set for EQ-5D-5L will be used to calculate the index score (Van 
Reenan 2015). Appendix 10 contains the SAS/SPSS codes for crosswalk between 5L and 3L for 
calculation of index score. 
 
No imputation will be made for missing data in either the EQ-5D-5L or VAS responses.  
 
The compliance of completing the EQ-5D-5L questionnaires is a critical issue in the QoL and 
health-state evaluation, and will be described by post-randomization visit, by displaying the 
number and percentage of subjects who were assessed (per subject, at least 1 question answered) 
at each visit (Table 2.16.19 for the efficacy estimand).
  
6.4.8
12-Hour Pulmonary Function Tests 
12-Hour PFTs will be analyzed for PT010006. 
FEV1 AUC0-12 will be measured in a subset of approximately 600 randomized subjects at Day 1 
(Visit 4) and Week 24 (Visit 10a). Area under the curve at Week 24 will be calculated using the 
trapezoidal rule, after first subtracting the baseline FEV1 value, and transformed into a weighted 
average by dividing by the time in hours from dosing of the last measurement included (typically 
12 hours). Spirometry data are listed in Listings 6.2, 6.3.9 for FEV1, 6.3.12 for FVC, 6.3.15 for 
PEFR, and 6.3.18 for FEF25-75 for the efficacy estimand). Participation in the 12-hr PFT Sub-
study is listed in Listing 9.7. 
At least one non-missing post-dose value is required for the calculation of AUC. Actual time 
from dosing will be used if available; otherwise scheduled time will be used. The differences 
between treatments in FEV1 AUC0-12 at Day 1 and Week 24 will be evaluated using an 
ANCOVA with baseline FEV1, baseline eosinophil count, and percent reversibility to Ventolin 
HFA as continuous covariates and treatment and ICS use at Screening as categorical covariates. 
Two-sided p-values and point estimates with two-sided 95% CIs will be produced for each 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 72 of 355
 
 
treatment difference (Table 2.17.1 to 2.17.4 for the efficacy, attributable, treatment policy, and 
per protocol estimands for FEV1 AUC0-12, and Table 2.17.7 and Figure 2.17.7 for FEV1 over 12 
hours post-dose for the efficacy estimand). The comparison of BFF MDI to Symbicort TBH will 
be for non-inferiority rather than superiority and will use a margin of -75 mL for the lower bound 
of the two sided 95% CI for the treatment difference; for that comparison, the analysis on the per 
protocol estimand will be the main analysis. As additional supportive analyses, FEV1 AUC0-4, 
FEV1 AUC0-6, and FEV1 AUC6-12 will be calculated and analyzed in a similar fashion as FEV1 
AUC0-12 (Tables 2.17.28 for AUC0-4, 2.17.31 for AUC0-6, and 2.17.34 for AUC6-12, for the efficacy 
estimand). Similar analyses (as for AUC0-4 and AUC0-12) will be performed for FVC, PEFR, and 
FEF25-75 (Tables 2.17.37 for FVC AUC0-4, 2.17.40 for FVC AUC0-12, 2.17.43 for PEFR AUC0-4,
2.17.46 for PEFR AUC0-12, 2.17.49 for FEF25-75 AUC0-4, 2.17.52 for FEF25-75 AUC0-12, for efficacy 
estimand). The baseline covariate will be endpoint-specific.
Treatments will be compared using change from baseline at each post-dose time point over 
12 hours at Week 24 (Visit 10a) for the following variables: FEV1, FVC, PEFR, and FEF25-75. 
The differences between treatments will be evaluated using an ANCOVA with baseline of the 
respective endpoint, baseline eosinophil count, and percent reversibility to Ventolin HFA as 
continuous covariates and treatment and ICS use at Screening as categorical covariates (Tables 
and Figure 2.17.7 and Listing 6.3.9 for FEV1, 2.17.13 and Listing 6.3.12 for FVC, 2.17.19 and
Listing 6.3.15 for PEFR, and 2.17.25 and Listing 6.3.18 for FEF25-75 for the efficacy estimand).
The 12-hour post-dose trough is defined as the average of the 11.5 and 12 hour post-dose values. 
In subjects missing either of these assessments, the value will be calculated from the single 
measurement. In subjects missing both values, this value will be missing. 
The attributable estimand (for the analysis of FEV1 AUC0-12) will be computed in a similar 
manner as the attributable estimand is computed for change from baseline in morning pre-dose 
trough FEV1 at Week 24 as described in Section 6.4.4.1.
6.4.9
Subgroup Analyses 
Selected tabulations will be provided within the following subgroups for the primary endpoints: 
x
China  
x
Japan and Non-Japan  
x
Asia (Asia is defined by country rather than by race and includes China and Japan.) 
x
Each Individual Country (i.e. US, Canada, China, and Japan) 
x
Severity of COPD (based on FEV1): 
o
Moderate 
o
Severe 
o
Very Severe 
x
GOLD Categories (based on CAT, FEV1, and Exacerbations per year): 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 73 of 355
 
 
o
B, which is defined as: (% predicted FEV1 post-bronchodilator  50% AND no 
COPD hospitalizations AND at most one COPD exacerbation in the last 12 
months) AND CAT  10 
o
D, which is defined as: (% predicted FEV1 post-bronchodilator < 50% OR at least 
one COPD hospitalizations OR at least two COPD exacerbations in the last 12 
months) AND CAT  10 
x
Reversibility to Ventolin HFA: 
o
No 
o
Yes 
x
Baseline Eosinophil Count: 
o
<150 cells per mm3  
o
150 cells per mm3 
x
Racial groups (for the primary efficacy and the below safety endpoints only): 
o
 Black  
o
 White 
o
 Native Hawaiian or Pacific Islander (for safety only) 
o
 American Indian or Alaska Native (for safety only) 
o
 Asian 
o
 Other (for safety only) 
x
Age groups (for the primary efficacy and the below safety endpoints only): 
o
Age < 65 years 
o
Age  65 years 
x
Sex groups (for the primary efficacy and the below safety endpoints only): 
o
Male 
o
Female 
x
ICS Use at Screening: 
o
Yes 
o
No 
x
Post-bronchodilator FEV1 (<50%, 50% Predicted) 
x
Exacerbation history (0, 1 in the last year) 
 
The distribution of baseline characteristics used in the primary model – ICS use at screening, 
baseline FEV1, baseline eosinophil count, and percent reversibility to Ventolin HFA – will be 
summarized within subgroups, both overall and by treatment group. 
The following tables and figures will be provided by subgroup: 
x
Change from Baseline in Trough FEV1 (excluding the exacerbation history subgroups). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 74 of 355
 
 
x
FEV1 area under the curve from 0 to 4 hours, except Japan (no post-dose spirometry 
assessments collected) and Asia and the exacerbation history subgroups.  
x
Rate of Moderate or Severe COPD exacerbations (for country, baseline eosinophil count, and 
exacerbation history [0, 1 in the last year] subgroups only). 
 
 
 
In addition, the following subgroup analyses will be presented for the efficacy estimand for the 
China (Tables and Figures 8.X.X.X.X), Japan/non-Japan (Tables and Figures 6.X.X.X.X), and 
Asia (Tables and Figures 9.X.X.X.X) subgroups, unless indicated otherwise (see also Section 
6.4.9.1 and 6.4.9.2): 
x
TDI Focal Score  
x
TDI Responder (China and Asia only) 
x
Change from Baseline in Average Daily Rescue Ventolin HFA Use  
x
Change from Baseline in Average Daily Daytime Rescue Ventolin HFA Use (China only) 
x
Change from Baseline in Average Daily Nighttime Rescue Ventolin HFA Use (China only) 
x
Change from Baseline in SGRQ Total Score  
x
SGRQ Responder (China and Asia only) 
x
Peak Change from Baseline in FEV1 (L) within 4 hours post-dosing (China only) 
x
Change from Baseline in FEV1 (L) at 5-Min Post-Dose on Day 1 (China only) 
x
Change from Baseline in FEV1 (L) at 15-Min Post-Dose on Day 1 (China only) 
x
RS-Total Score 
x
EXACT Total Score (China and Asia only) 
x
Time to CID  
x
Change from Baseline in Trough FVC (China and Asia only) 
x
Percent responders analyses for Day 1 (China only) 
x
Rate of Moderate or Severe COPD Exacerbations 
x
Rate of Severe COPD exacerbations (China and Asia only) 
x
EuroQoL 5 Dimensions categorical responses (China and Asia only) 
 
In the notation X.X.X.X used above, X can refer to any integer. 
 
Additional analyses for China and Asia subgroups may be found in Appendix 8 and Appendix 9, 
respectively.  
 
Each subgroup will be analyzed separately using the same model that was used for the overall 
(combined subgroups) analysis. Estimates for the treatment effect and for the treatment 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 75 of 355
 
 
differences will be displayed in the efficacy endpoint tables for each subgroup (Tables 6.1.1 to
6.11.40). 
 
For each subgroup analysis, a test for the treatment-by-subgroup interaction will be performed 
using the same model that was used for the overall (combined subgroups) analysis but with the 
addition of terms for subgroup and the treatment-by-subgroup interaction. A table will be 
provided with the p-value for the test of the treatment-by subgroup interaction (Table 6.13 for the 
efficacy estimand). Should any country/region effects be identified, shrinkage estimates may be 
generated in order to further understand the impact of these effects (Carroll and Fleming, 2013). 
Subgroup analyses of the trough FEV1 will be conducted in the baseline eosinophil count-high 
(150 cells per mm3) and the baseline eosinophil count-low (<150 cells per mm3) subgroups. It is 
acknowledged 150 cells per mm3 may not ultimately be the appropriate threshold for evaluation 
of treatment benefit. Thus, additional analyses will evaluate alternative thresholds, and the 
results from these analyses could then inform thresholds for future clinical studies. This 
exploration will include using additive mixed models that combine nonparametric regression for 
the relationship of eosinophil levels to trough FEV1 as well as potentially using subgroups 
defined by different cut points. 
6.4.9.1
China and Asia Subgroups 
The China subgroup is defined as all subjects enrolled in sites in China. The Asia subgroup is 
defined as all subjects enrolled in sites located in Japan and China. 
Corresponding ITT, mITT, RVU, PP and Safety analysis populations, as well as other relevant 
analysis sets, for the China and Asia subgroups are defined as described in Section 5.1 and 
restricted to the China/Asia subgroups. Populations described for primary analyses in Section 5.2 
are applied to China/Asia subgroups. 
6.4.9.2
Subgroup Analyses China and Asia 
To support registration in China, a separate Clinical Study Report will be written to present the 
study results in the China and Asia subgroups with the objective of demonstrating consistency 
with the overall Study PT010006 population. Select subject disposition, demographic and 
baseline characteristics, extent of exposure, prior and concomitant medications, efficacy, and 
safety analyses will be repeated for the China/Asia subgroups. Appendix 8 and Appendix 9 
contain the table of contents for Post-Text TFLs in the China and Asia subgroups, respectively. 
Analyses in the China and Asia subgroups will proceed as described in Section 6.4.9. All 
analyses based on the China and Asia subgroups will be considered exploratory. No adjustment 
for multiplicity will be made; thus the hierarchical testing detailed in Section 6.4.11 to control 
the Type I error will not be employed directly to the China and Asia subgroups. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 76 of 355
 
 
6.4.10
Correlations
Pearson correlation coefficients will be generated between the primary and secondary continuous 
endpoints (from Japan/China Approach, EU/Canada Approach, US Approach). SGRQ total score 
will be used in place of the SQRQ responder. The mITT population will be used.  
Note that for morning trough FEV1, AUC0-4 FEV1, TDI, and change from baseline in SGRQ, the 
estimates over 24 weeks were obtained as LS means from MMRM analyses, and were not 
derived at the subject level. For the purpose of the correlation analysis, the endpoints over 24 
weeks will be represented by simple averages of available data over 24 weeks. 
The correlations will be organized in a matrix, with its upper triangle filled with pairwise 
Pearson correlation coefficients. All treatment groups will be pooled (Table 2.61.1 to 2.61.3). 
6.4.11
Control of Type I Error 
There are 3 separate plans for control of Type I error, corresponding to each of the 3 registration 
approaches for Japan/China, EU/Canada, and US. Each of the plans will test the primary 
endpoint using the efficacy estimand first for superiority comparisons, followed by the 
attributable estimand, which is considered a secondary endpoint. Additional secondary endpoints 
will only be tested using the efficacy estimand for Type I error control. Non-inferiority 
comparisons will be made using the per-protocol estimand. All secondary endpoints with the 
exception of time to onset are included in the Type I error control plans described below.  
6.4.11.1
Japan/China Approach: 
The comparisons of interest for the Japan/China approach are BGF MDI versus BFF MDI and 
BGF MDI versus GFF MDI, both for superiority, and BFF MDI versus Symbicort TBH for non-
inferiority. 
Strong control of the Type I error rate will be maintained at the 2-sided 0.05 level for the primary 
endpoint across key treatment comparisons using a sequential approach across comparisons, and 
then for the secondary measures, Type I error control will be maintained within comparison 
using a combination of sequential and simultaneous approaches as detailed below. Based on 
positive dependence of the test statistics (Sarkar, 2008; Sarkar and Chang 1997), simultaneous 
control of Type I error for the relevant secondary measures will be achieved using the Hochberg 
procedure (Hochberg, 1988).  
The following 3 between-treatment comparisons will be conducted, in the order stated, for 
morning pre-dose trough FEV1 over Weeks 12 to 24: BGF MDI versus BFF MDI, BGF MDI 
versus GFF MDI, using the efficacy estimand, and BFF MDI versus Symbicort TBH (non-
inferiority) using the per-protocol estimand. Each comparison will be made only if the preceding 
comparison in the sequence is statistically significant.  
If the comparisons for BGF MDI versus BFF MDI and BGF MDI versus GFF MDI are both 
statistically significant at a 2-sided alpha level of 0.05, testing will proceed to comparison of the 
respective attributable estimands in the same order. If the comparisons of the attributable 
estimands are also significant, then the secondary measures within each comparison will be 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 77 of 355
 
 
tested using the efficacy estimand. Type I error will be controlled at 0.05 within each comparison 
(BGF MDI versus BFF MDI, BGF MDI versus GFF MDI) for the remaining secondary 
endpoints through simultaneous testing under the Hochberg procedure with a 2-sided alpha of 
0.05. 
If non-inferiority is established for the comparison of trough FEV1 between BFF MDI and 
Symbicort TBH, then tests of the additional secondary measures for this comparison will be 
interpreted without any additional control of Type I error. Non-inferiority margins appear 
throughout the document in description and analyses of the endpoints as applicable. 
  




BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 79 of 355
 
 
x
Trough FEV1 for BGF MDI versus GFF MDI using the efficacy estimand 
x
FEV1 AUC0-4 for BGF MDI versus BFF MDI using the attributable estimand 
x
Trough FEV1 for BGF MDI versus GFF MDI using the attributable estimand 
All subsequent comparisons below will use only the efficacy estimand. 
If the comparison of FEV1 AUC0-4 between BGF MDI and BFF MDI using the attributable 
estimand above is statistically significant, testing will proceed to the secondary comparison of 
BGF MDI versus BFF MDI for change in morning pre-dose trough FEV1 using a 2-sided 0.05 
level test. If this test is also significant, testing will proceed to the remaining secondary 
endpoints. BGF MDI versus BFF MDI will be simultaneously compared among these secondary 
endpoints using the Hochberg procedure with a 2-sided alpha of 0.05.  
If the comparison of BGF MDI versus GFF MDI for change in morning pre-dose trough FEV1 
using the attributable estimand is statistically significant, testing will proceed to the remaining 
secondary endpoints for BGF MDI vs. GFF MDI using the efficacy estimand. BGF MDI versus 
GFF MDI will be simultaneously compared among the secondary endpoints using the Hochberg 
procedure with a 2-sided alpha of 0.05. 
If the comparison of FEV1 AUC0-4 for BGF MDI versus BFF MDI is statistically significant 
using the attributable estimand, testing will also proceed to a comparison of BGF MDI versus 
Symbicort TBH for of FEV1 AUC0-4 using the efficacy estimand. If statistically significant, the 
remaining secondary endpoints for BGF MDI versus Symbicort TBH will be simultaneously 
compared among the secondary endpoints using the Hochberg procedure with a 2-sided alpha of 
0.05. 
Finally, if the comparison of FEV1 AUC0-4 over 24 weeks for BGF MDI versus BFF MDI is 
statistically significant, testing will proceed to the non-inferiority comparisons of BFF MDI 
versus Symbicort TBH. If non-inferiority is established, tests of the additional secondary 
measures for this comparison will be interpreted without any additional control of Type I error. 
Non-inferiority margins appear throughout the document in description and analyses of the 
endpoints as applicable. 
 
 




BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 81 of 355
 
 
6.4.11.3
US Approach 
The comparisons of interest for the US approach are: BGF MDI versus GFF MDI and BGF MDI 
versus BFF MDI, both for superiority, and at Week 24 unless stated otherwise. Statistical 
significance for nominal comparisons will be at alpha=0.05. 
Strong control of the Type I error rate will be maintained at the 2-sided 0.05 level for the key 
comparisons using a sequential approach for the primary endpoints and then for the secondary 
measures Type I error control will be maintained within comparison using a combination of 
sequential and simultaneous approaches as detailed below. 
The following 4 comparisons will be conducted first, in the order they appear below: 
x
FEV1 AUC0-4 for BGF MDI versus BFF MDI using the efficacy estimand 
x
Trough FEV1 for BGF MDI versus GFF MDI using the efficacy estimand 
x
FEV1 AUC0-4 for BGF MDI versus BFF MDI using the attributable estimand 
x
Trough FEV1 for BGF MDI versus GFF MDI using the attributable estimand 
 
If the comparison of FEV1 AUC0-4 between BGF MDI versus BFF MDI using the attributable 
estimand is statistically significant, the remaining secondary endpoints for BGF MDI versus BFF 
MDI will be compared simultaneously using the efficacy estimand, and using the Hochberg 
procedure with a 2-sided alpha of 0.05. 
If the comparison of trough FEV1 AUC0-4 between BGF MDI versus GFF MDI for the 
attributable estimand is statistically significant, the secondary endpoints for BGF MDI versus 
GFF MDI will be simultaneously compared using the Hochberg procedure with a 2-sided alpha 
of 0.05. 




BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 83 of 355
 
 
 
6.5
Safety Analysis 
All safety analyses for PT010006 are based on the Safety Population. Most safety analyses for 
PT010007 employ the Japanese Safety Population. A few analyses for PT010007 employ the 
PT010007 Safety Population. Hypothesis testing will not be performed for any safety analyses. 
For PT010006, all AE data, clinically significant laboratory values, vital signs, and ECG values 
will be categorized according to their onset date into the following study periods: 
x
Events occurring during the Treatment Period are events with an onset date on or after 
the first date of dose and up to and including the date of completion of study treatment or 
the day after the date of premature discontinuation from study treatment. Events known 
to have occurred before the time of the first dose of study treatment are not included.  
x
Events occurring during the Post-treatment-discontinuation Follow-up are events with an 
onset date on [or after] the day after the dateof completion of study treatment or on or 
after the day after the day after (i.e. 2 days after) the date of premature discontinuation of 
study treatment. The exception is that deaths are still considered to be during the 
Treatment Period if any adverse event that led to that death is during the Treatment 
Period. 
 
Any AEs, clinically significant laboratory values, vital signs, and ECG values during the 
Treatment Period will be tabulated and listed. Beginning on the day after the date of 
discontinuation from or completion of study medication, any new clinically significant ECGs, 
laboratory values, and vital signs will not be included in the tabulation or the computation of 
incidence rates, but will still be listed. Any new AEs, SAEs, and deaths during the Post- 
treatment-discontinuation Follow-up will be tabulated and listed. Tabulations of the incidence of 
deaths, AEs by system organ class (SOC), and SAEs by SOC will be provided using information 
collected after treatment discontinuation (as alternative tables). 
6.5.1
Adverse Events 
The version of the Medical Dictionary for Regulatory Activities (MedDRA) that is current at the 
time of database lock will be used to code verbatim terms for AEs for final analysis of the data. 
A glossary of MedDRA preferred terms used for adverse events reported in the study along with 
the associated Investigator’s verbatim term will be provided in Listing 7.2. 
An adverse event is considered on-treatment (i.e. treatment-emergent) if an event occurs after the 
first dose of study medication in the study, or if the AE worsened during the study after the first 
dose of study medication in the study (intensity and/or severity changed to a worsened grade) 
and the event onset is on or before the date of discontinuation from or completion of study 
medication. An adverse event that begins on the same date as the first dose of study medication 
is treatment-emergent if the AE begins after the time of first dose or if the time of AE onset is 
unknown. Adverse events with onset after the date of premature discontinuation from study 
treatment plus one day or after the date of completion of study treatment will not be considered 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 84 of 355
 
 
treatment-emergent, but will be tabulated separately (Table 3.2.1.18) and listed in adverse event 
data listings (Listing 7.1). . Adverse events that occur between the time the subject signs the 
informed consent form (ICF) for the study and the time when that subject is randomized are to be 
recorded as medical history unless the event met the definition of an SAE. Additionally, if an AE 
has an onset date on treatment and has an outcome of death, that death will be considered on 
treatment even if the date of death is after the last date of treatment+1.  
 
The incidence of an AE will be defined as the number and percentage of subjects experiencing 
an event. Adverse events will be tabulated at the level of the MedDRA preferred term and the 
MedDRA SOC for the Safety Population and for the Japanese Safety Population. These will also 
be summarized by duration of exposure for the Japanese Safety Population for both Studies 
PT010006 and PT010007 (using the combined data from both studies). No hypothesis tests will 
be performed. 
An overview table will be prepared for the Safety Population, for the Japanese Safety Population, 
and for the PT010007 Safety Population with the incidences of subjects with at least one TEAE, 
at least one serious TEAE, at least one TEAE related to study treatment, at least one serious 
TEAE related to study treatment, at least one TEAE leading to premature discontinuation, at 
least one serious TEAE leading to premature discontinuation, and a report of death (Tables 3.1, 
3.1.13, and 3.1.14). This overview table will also be presented by duration of exposure for the 
Japanese Safety Population (Tables 3.1.15 to 3.1.18). 
The following will be done for events with irregular onset dates. All treatment-emergent adverse 
events (TEAEs) will be included in the data listings regardless of the completeness of the onset 
dates. Partial dates will be imputed in order to determine if an AE is treatment-emergent using 
the imputation rules in Appendix 1; however, imputed dates will not be provided in the data 
listings. 
All adverse events, whether treatment-emergent or not, will be included in the listings. Reported 
adverse events by SOC, preferred term, treatment, country, center, subject and onset day will be 
provided (Listing 7.1). Reported adverse events by treatment, country, center, subject, and onset 
date will be presented in Listing 7.3. SAE-specific report information will be listed in Listing 7.7. 
The listing of adverse events will provide the severity, maximum severity, relationship to study 
drug, action taken and outcome for each adverse event. Adverse events leading to permanent 
discontinuation of study treatment will be listed for the Safety Population and for the Japanese 
Safety Population (Table 3.6.1, Table 3.6.2). A listing of any reported deaths during the study 
(prior to randomization, during the Treatment Period, or during the Post- treatment-
discontinuation Follow-up) will be provided (Table 3.15.2.1); study treatment taken prior to the 
death and the number of days since the last dose of this study treatment at the time of the death 
will be included in the listing.  
Summary tabulations of the following will be prepared for all subjects in the Safety Population, 
for each treatment, for each primary SOC, and for each preferred term within an SOC: 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 85 of 355
 
 
1. The incidence of all TEAEs (Tables 3.2.1.1, 3.2.1.2, Table 3.2.1.3) 
2. The incidence of all TEAEs by the duration of exposure for the Japanese Safety 
Population (Tables 3.2.1.4 to 3.2.1.7) 
3. The incidence of subjects with adverse events by SOC during the Post-treatment-
discontinuation Follow-up (Tables 3.2.1.18, 3.2.1.19) 
4. The incidence of TEAEs occurring in SMQs (Standard MedDRA Queries)/groupings 
of interest (Tables 3.2.3.1, 3.2.3.2) 
5. The incidence of non-serious TEAEs occurring in 5% of subjects in a treatment 
(Tables 3.2.4.1, 3.2.4.2) 
6. The incidence of all treatment-related TEAEs (Tables 3.4.1, 3.4.2) 
7. The incidence of discontinuation from study treatment due to a TEAEs (Tables 3.5.1, 
3.5.2) 
8. The incidence of treatment-emergent serious adverse events (Tables 3.7.1.1.1, 
3.7.1.1.2, 3.7.1.1.3) 
9. The incidence of subjects with SAEs by SOC during the Post-treatment-
discontinuation Follow-up (Tables 3.7.2.3, 3.7.2.4) 
10. The incidence of all treatment-related treatment-emergent serious adverse events 
(Tables 3.9.1, 3.9.2) 
11. The incidence of all TEAEs by highest severity to treatment (Tables 3.11.1.1 through
3.11.4.2 for the four treatments) 
12. A summary tabulation will also be prepared for the incidence of TEAEs occurring in 
at least 2% of subjects in any treatment (Tables 3.2.2.1, 3.2.2.2 sorted by descending 
frequency of events in a preferred term).
13. In addition, to control for possible differences in exposure between the treatments, the 
following AE and SAE summaries will be presented with the frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, 
primary SOC, and preferred term: 
a) Frequency and rate of AEs (Tables 3.3.1, 3.3.2) 
b) Frequency and rate of SAEs (Tables 3.8.3.1, 3.8.3.2) 
c) Frequency and rate of neoplasms (Tables 3.10.3.1 and 3.10.3.2 – All Cancer, 
3.10.4.1 and 3.10.4.2 - Excluding Non-Melanoma Skin Cancer). 
 
Safety summaries will be performed for AEs (overall summary of AEs and incidence of AEs by 
MedDRA SOC and preferred term in Tables 7.1.1 to 7.2.1.17f), SAEs (Tables 7.3.1.2 to 
7.3.1.13f), and AEs of special interest (Tables 7.7.1 to 7.7.3) for China, Asia, and Japan 
subgroups. 
In addition to AE, SAE, and AEs of special interest summaries for the Japan subgroup described 
above, treatment-related AEs and AEs leading to discontinuation will also be summarized for the 
Japan subgroup (Tables 7.4 to 7.6) for PT010006. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 86 of 355
 
 
Safety summaries will be performed for AEs (overall summary of AEs and incidence of AEs by 
MedDRA SOC and preferred term, and SAEs) for age, sex, and race subgroups. 
6.5.1.1
Adverse Events of Special Interest 
AESIs have been defined based on known effects of s LAMAs, LABAs, and ICS. These include 
but are not limited to cardiovascular effects, ocular disorders, urinary retention, gastrointestinal 
disorders, and anticholinergic effects for LAMAs; cardiovascular, tremor effects, hyperglycemia, 
and hypokalemia for LABAs; and local (e.g., candidiasis and voice effects) and systemic (e.g., 
bone and skin effects, diabetes control, ocular and taste effects, adrenal suppression) steroid class 
effects and lung infection for ICS.  
SMQs will be utilized when possible, and a selection of high-level group terms (HLGTs), high-
level terms (HLTs), and preferred terms (PTs) will be utilized to represent other situations. The 
terms proposed to be used in the assessment of AESIs associated with ICS, LAMAs, and LABAs 
are listed in Table 7. Standardized MedDRA queries will be utilized when possible and a 
selection of preferred terms in other situations (Appendix 5). 
Table 7 
Adverse Events of Special Interest 
Medical Concept 
Selection of MedDRA Terms 
Adrenal suppression 
Adrenal cortical hypofunctions HLT 
Agitation or anxiety 
Collection of PTs 
Anticholinergic effectsa 
Anticholinergic syndrome SMQ 
Dry mouth PT 
Bone fracture 
Collection of HLGTs, HLTs, and PTs. 
Candidiasis  
Collection of PTs 
Cardiovascular 
Cardiac arrhythmias SMQ 
Cardiac failure SMQ 
Ischemic heart disease SMQ 
Torsades de Pointe/QT prolongation SMQ 
Cardiovascular death 
Collection of PTs 
Cerebrovascular condition 
CNS haemorrhages and cerebrovascular conditions 
SMQ 
Diabetes mellitus 
Hyperglycaemia/new onset diabetes mellitus SMQ 
Dysgeusia or ageusia 
Collection of PTs 
Dysphonia or aphonia 
Collection of PTs 
Gastrointestinal 
Gastrointestinal perforation, ulceration, haemorrhage 
or obstruction SMQ 
Gastrointestinal obstruction SMQ 
Headache  
Headache (PT) 
Hypercortisolism 
Collection of PTs 
Hypertension 
Blood pressure ambulatory increased (PT) 
Blood pressure increased (PT) 
Blood systolic increased (PT) 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 87 of 355
 
 
Medical Concept 
Selection of MedDRA Terms 
Hypokalemia 
Collection of PTs 
Lower respiratory tract infections other than 
pneumonia 
Bronchitis (PT) 
Bronchitis viral (PT) 
Bronchitis bacterial (PT) 
Lower respiratory tract infection (PT) 
Lower respiratory tract infection viral (PT) 
Lower respiratory tract infection bacterial (PT) 
Infective exacerbation of chronic obstructive airway 
disease (PT) 
Ocular effects 
Visual disorders HLT 
Glaucoma SMQ 
increased intraocular pressure collection of PTs 
Cataract collection of PTs 
Osteoporosis and osteopenia 
Osteoporosis/osteopenia (SMQ) 
Palpitation 
Palpitations PT 
Paradoxical bronchospasm 
Collection of PTs 
Pneumonia  
Collection of PTs 
Psychiatric effect 
Collection of PTs 
Skin effects 
Skin atrophy (PT) 
Skin striae (PT)  
Acne (PT)  
Contusion (PT)  
Ecchymosis (PT)  
Increased tendency to bruise (PT)  
Petechiae (PT)  
Purpura (PT)  
Malassezia folliculitis (collection of PTs)  
Hypertrichosis (collection of PTs)  
Alopecia (collection of PTs) 
Sleep effects 
Initial insomnia (PT) 
Insomnia (PT) 
Sleep disorder (PT) 
Sudden death 
Collection of PTs 
Throat irritation 
Collection of PTs 
Tremor 
Tremor HLT 
Urinary retention 
Collection of PTs 
Weight gain 
Collection of PTs 
Abbreviations: CNS=central nervous system. 
a
This medical concept is uniquely associated with LAMAs. 
 
Appendix 5 (which will be based on the latest version of MedDRA available at the time of 
database lock) provides detail on selection of terms (narrow/wide designations for preferred 
terms are provided). 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 88 of 355
 
 
The incidence of adverse Events in MedDRA SMQs/Groupings of Interest by Term will be 
tabulated for the Safety Population, and the Japanese Safety Population (Tables 3.2.3.1 and 
3.2.3.2), as well as for the China, Asia, and Japan Subgroups of the Safety Population (Tables
7.7.1 to 7.7.3). 
6.5.1.2
MACE Events Determined by Clinical Endpoint Committee 
The clinical endpoint committee (CEC) will review and adjudicate serious cardio- and 
cerebrovascular (CCV) events as MACE. MACE events are defined as the following: 
 
• Cardiovascular death 
 
• Non-fatal myocardial infarction (MI) 
 
• Non-fatal stroke 
 
The CEC will review and assess these non-fatal serious CCV events and all deaths as to whether 
or not they fulfill criteria (based on CEC working practices) for MACE. 
MACE events will be summarized by adjudicated CRF category and treatment group (Tables
3.13.1.1, 3.13.1.2). The assessment of MACE events will include the rate of confirmed MACE 
events (Tables 3.13.2.1, 3.13.2.2). Adjudicated MACE events will be listed in Listing 7.4. 
The incidence of subjects with adjudicated MACE AEs by category will be summarized in Table
3.13.3.1 and Table 3.13.3.2. 
6.5.1.3
Pneumonia Events Determined by Adjudication Committees 
All AEs/SAEs with preferred terms that could relate to pneumonia will be adjudicated to provide 
a more complete assessment of all physician-reported pneumonias. The incidence of confirmed 
pneumonia events will be tabulated (Tables 3.13.3.1, 3.13.3.2). The assessment of pneumonia 
events will include the rate of confirmed pneumonia events (Tables 3.14.2.1, 3.14.2.2). 
Adjudicated pneumonia events will be listed in Listing 7.4. 
 
In order to account for specific patient risk factors, data permitting, time to first pneumonia will 
be compared between treatments using Cox proportional hazards (Tables 3.14.3.1, 3.14.3.2). 
Specific patient risk factors (baseline FEV1, age, and medical history of pneumonia in the last 5 
years [Yes or No]) will be evaluated for inclusion. 
The incidence of subjects with adjudicated pneumonia AEs by category will be summarized in 
Table 3.13.3.1 and Table 3.13.3.2. 
6.5.1.4
Cause of Death Determined by Adjudication Committees 
Causes of death will be listed by subject and summarized by treatment for (1) all-cause mortality, 
(2) mortality of probable cardiovascular cause, (3) mortality of probable respiratory cause and 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 89 of 355
 
 
(4) mortality of probable other causes using the Safety Population based on (A) cases reported 
during the active Treatment Period and (B) cases reported during the active Treatment Period 
plus the Post-treatment-discontinuation Follow-up (Tables 3.15.2.1 and 3.15.2.2). The incidence 
of subjects with a death event will be tabulated by adjudicated CRF category and treatment 
during the Treatment Period (Tables 3.15.1.1, 3.15.1.2) and during the Post-treatment-
discontinuation Follow-up (Tables 3.15.1.3 and 3.15.1.4). To control for possible differences in 
exposure between treatments, the death will be summarized with frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, primary 
SOC, and preferred term (Tables 3.15.3.1, 3.15.3.2). Adjudicated death events will be listed in 
Listing 7.4. 
6.5.2
Clinical Laboratory Measurements 
Lab parameters collected include the following: 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 90 of 355
 
 
Table 8 
Lab Parameters 
Hematology 
Hemoglobin 
Mean corpuscular 
hemoglobin  
Hematocrit 
Mean corpuscular 
hemoglobin concentration 
White blood cell count with differential 
Mean corpuscular 
volume  
Red blood cell count  
Eosinophils 
Platelet count 
Clinical Blood Chemistry 
 
Liver Enzyme and Other Liver Function Tests 
Other Clinical Blood 
Chemistry
Alanine aminotransferase  
Albumin 
Aspartate aminotransferase  
Blood Urea Nitrogen 
(BUN) 
Alkaline phosphatase  
Calciuma 
Bilirubin, total  
Chloridea 
Gamma-glutamyl transferase  
Cholesterol  
 
Bicarbonate 
 
Creatininea 
 
Glucosea 
 
Magnesium  
 
Potassiuma 
 
Phosphate 
 
Protein, total  
 
Sodiuma 
 
Triglycerides  
Urinalysis 
Macroscopic examination including specific gravity, pH, protein, glucose, ketones, blood, and  
urobilinogen. 
Other Tests: 
PT010006 
Pregnancy test (women of childbearing potential only): serum hCG at Visit 1 (Screening) and 
Final Visit in PT010006 (Visit 10a) or Treatment Discontinuation Visit; urine hCG at Visit 7 (Week 12) 
PT010007 
Pregnancy test (women of childbearing potential only): serum hCG at Visit 14 only and urine hCG at Visit 
12 (Week 36) or Treatment Discontinuation Visit.  
Creatinine clearance will be estimated by the CKD-EPI formula [Levey, 2009]. 
Abbreviations: CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; hCG=human chorionic  
gonadotropin 
a
Parameters included in the Basic Metabolic Panel. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 91 of 355
 
 
Hematology 
 
 
A Clinically Significant Laboratory Abnormality as identified by the investigator after the 
start of study treatment will be recorded as an Adverse Event and tabulated as an AE in the AE 
analysis. Abnormalities occurring prior to the start of treatment will be noted in medical history 
and presented in a data listing. Per protocol, the criteria for a "clinically significant" laboratory 
abnormality are: 
a.
A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension or discontinuation) 
b. A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy) 
c.
Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion) 
All laboratory data will be stored in the database with the units in which they were originally 
reported. Laboratory data not reported in International System of Units (SI units; Système 
International d’Unités) will be converted to SI units before data analysis. 
Individual clinical laboratory variables for hematology and clinical chemistry and kidney 
function, including creatinine clearance, will be provided in listings (Listing 8.1 for hematology, 
Listing 8.2 for blood chemistry and kidney function, Listing 8.3 for urinalysis, and Listing 4.6 for 
pregnancy test results at screening and after the start of treatment). Data will be listed in SI units 
where available. Comments for laboratory testing will be listed (Listing 8.4). For listings, 
laboratory values will be flagged as Low or High based on the reference ranges provided by the 
central laboratory, LabCorp Laboratories (Appendix 4). 
The baseline measurement for a laboratory parameter will be the last available measurement 
prior to the start of dosing. 
Table 9 
Analysis Study Time Window for Clinical Lab Assessments 
Calculated Study Time Window 
Time Interval for the Study Time 
Window
Pre-dose 1 hr. 
0 min. prior to dose 
Post-dose 30 min. 
>0 to <75 min. post-dose 
Post-dose 2 hrs. 
75 min. to <4 hrs. post-dose 
               Note: The minutes are rounded to the nearest whole number before applying time windows. 
The laboratory-value windows will be applied only for calcium, chloride, glucose, potassium, 
and sodium (i.e. the laboratory parameters that are sometimes assessed post-dose) and these 
windows will be applied only at the following visits: Visit 4 (Day 1), Visit 5 (Week 4), and Visit 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 92 of 355
 
 
10a (Week 24). For other laboratory parameters and other visits, windows will not be applied. 
The rationale is that for other laboratory parameters and other visits, post-dose assessments are 
not to be assessed. 
If there are multiple laboratory values for the same parameter at pre-dose of a visit or within the 
same post-dose study time window (if applicable) at a visit, the last value will be chosen for 
analysis.  
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for the 
baseline assessment and for the pre-dose value and change from baseline at each post-baseline 
visit and end of treatment for scheduled lab assessments of continuous laboratory variables 
including serum potassium and glucose will be tabulated. “End of Treatment” is defined as the 
last non-missing assessment during the treatment period. Data from unscheduled visits will not 
be used for the by-visit summaries but both scheduled-visit values and unscheduled-visit values 
are candidates for the end-of-treatment summary. Data from both scheduled and unscheduled 
visits will be listed. The summaries will be provided by treatment (Tables 3.16.1.1 through 
3.16.4.2, for hematology, blood chemistry, kidney function, and urinalysis, respectively). 
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, for the end-of-
treatment summary, and for shift tables. Shift tables will be produced using the categories 
defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grades 
for the Safety Population (Tables 3.16.5.1, 3.16.6.1, and Table 3.16.7.1) for hematology, 
chemistry, kidney function and urinalysis, respectively) and the Japanese Safety Population 
(Tables 3.16.5.2, Table 3.16.6.2, Table 3.16.7.2 and Table 3.16.8.2 for hematology, chemistry, 
kidney function and urinalysis, respectively). For these shift tables, for each treatment, the 
subject’s pre-dose grade will be cross-tabulated by the subject’s maximum post-baseline grade 
during the treatment; also, the subject’s maximum post-baseline grade during treatment will be 
tabulated for all baseline grades combined. Percentages of subjects in each maximum post-
baseline grade for a treatment will be calculated for each pre-dose grade for the treatment and 
also for all baseline grades combined. Laboratory abnormal values on-treatment will be flagged 
as High or Low values based on laboratory reference ranges provided by LabCorp Laboratories 
(found in Appendix 4) as per Pearl, Inc. These flags along with the reference ranges will be 
provided in the laboratory data listings. 
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 
following thresholds: 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 93 of 355
 
 
Table 10 
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 
(upper limit of normal) 
White Blood Cell Count 
<2000/μL  
 
>35,000/μL 
Platelet Count 
<50,000/μL 
 
>999,000/μL  
Chemistry
 
eGFR-EPI (where eGFR denotes 
estimated glomerular filtration rate) 
<30 mL/min/1.73 m2 
AST (aspartate aminotransferase) >3 x ULN 
ALT (alanine aminotransferase) 
>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 or equal to 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. 
Clinically significant laboratory values will be tabulated for the Safety Population (Table 3.16.9). 
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 3.16.10.1, 3.16.10.2, 3.16.11.1, and 3.16.11.2). For 
all laboratory parameters other than glucose and potassium noted in Table 8, all laboratory data 
for the parameter identified as potentially clinically significant for a subject will be listed (Table
3.16.12.1- Safety Population and 3.16.12.2- Japanese Safety Population). 
6.5.3
Vital Signs 
Changes from Baseline in on-treatment supine or seated systolic blood pressure, supine or 
seated diastolic blood pressure, and heart rate will be evaluated, where baseline is defined as the 
mean of all available pre-dose measurements taken prior to the start of dosing at the 
Randomization Visit (Visit 4). If there are no Visit 4 pre-dose values, the baseline will be defined 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 94 of 355
 
 
as the mean of pre-bronchodilator values at Visit 2 and Visit 3. No Hypothesis testing will be 
performed. 
A Clinically Significant Abnormality in vital signs identified by the investigator will be 
recorded as an Adverse Event if it occurs after the start of treatment. These adverse events will 
be included in the AE summaries; abnormalities prior to the start of treatment will be noted in 
medical history and listed. 
Potentially clinically significant changes in systolic and diastolic blood pressure will be 
defined based on the following criteria provided by Pearl, Inc.:
Table 11 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood Pressure 
Parameters 
Parameter (mmHg) 
Post-Baseline Criteria 
Systolic Blood Pressure, increase 
180 and increase from baseline 20  
Systolic Blood Pressure, decrease 
90 and decrease from baseline 20 
Diastolic Blood Pressure, increase 
105 and increase from baseline 15 
Diastolic Blood Pressure, decrease 
50 and decrease from baseline 15 
mmHG = millimeter of mercury. 
Potentially clinically significant changes in heart rate will be assessed as follows: 
Table 12 
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 
bpm = beats per minute. 
Vital sign measurements (Heart rate, systolic blood pressure, diastolic blood pressure and body 
temperature, weight, height) during the study will be displayed in a vital signs listing 
(Listing 9.1). 
A summary of baseline weight, height, and BMI will be presented by treatment (Tables 1.4.1.1, 
1.4.3.1, 1.4.4.1 and 1.4.5.1 for the mITT, PP, and Safety Populations, and all subjects not 
randomized respectively). The ITT Population does not need to be summarized because it is the 
same as the mITT Population at baseline. The Safety Population may not be needed either. 
Summary statistics (n, mean, median, standard deviation and range) of the absolute value and 
change from baseline for systolic blood pressure, diastolic blood pressure, and heart rate, will be 
tabulated by treatment, visit, and time point. Baseline will be defined as the mean of the values 
prior to dosing at Visit 4 (Day 1). These summaries (Table 3.17.1.1, Table 3.17.1.2) will be 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 95 of 355
 
 
prepared for baseline and each scheduled post-baseline nominal time point at each scheduled 
post-baseline visit and end of treatment. “End of Treatment” will be summarized for each 
scheduled post-baseline time point (pre-dose 1 hr, and post-dose 30 minutes and 2 hour). “End of 
Treatment” for each of these assessment points is defined as the last non-missing on-treatment 
assessment available for the time point. 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 the 
end-of-treatment summary. Data from both scheduled and unscheduled visits will be listed. Time 
windows will be derived for each post-baseline visit using the time intervals for the study time 
windows detailed in Table 13. No hypothesis tests will be performed. 
Table 13 
Analysis Study Time Windows for Vital Signs Assessments 
Calculated Study Time Window 
Time Interval for the Study Time Window 
Pre-dose 
0 min. prior to dose 
Post-dose 30 min. 
>0 to <75 min. post-dose 
Post-dose 2 hr 
 75 min. to < 4 hrs. post-dose 
Post-dose 12 hrs. 
8 hrs. to <16 hrs. post-dose 
Note that minutes are rounded to the nearest whole number before applying time 
windows. 
If there are multiple vital sign values for the same parameter at pre-dose assessments after Visit 4 
or within the same post-dose study time window at a visit, the last value will be chosen for 
analysis. 
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 and for the end-of-
treatment summary. 
The percentage of subjects with potentially clinically significant values for vital signs at any time 
post-dose at a visit will be summarized by treatment based on the criteria in Table 11 and Table 
12 (Table 3.17.2.1- Safety Population, Table 3.17.2.2- Japanese Safety Population).All vital sign 
assessments for subjects with potentially clinically significant values will be listed (Tables
3.17.3.1, 3.17.3.2, 3.17.4.1, Table 3.17.4.2). 
6.5.4
12-Lead Electrocardiogram Measurements 
Changes from baseline in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and 
QTcF interval will be calculated where baseline is defined as the mean of the pre-dose 
measurements taken prior to the start of treatment at the randomization visit (Visit 4). If there are 
no Visit 4 pre-dose values, the baseline will be defined as the mean of the pre-bronchodilator 
values at Visit 2 and Visit 3. The QTcF (Fridericia Corrected QT) 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 treatment and assessment time.  


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 96 of 355
 
 
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 (Listing 9.2). Summary 
statistics (mean, median, standard deviation and range) for raw values and change from baseline 
values in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and QTcF interval will 
be calculated, where baseline is defined as the mean of the pre-dose measurements taken prior to 
the start of treatment at Visit 4 (Day 1). These assessments will be tabulated for each treatment 
and each scheduled nominal time point (derived using the time intervals for the study time 
windows detailed below in Table 14) at each visit and at end of treatment (Table 3.18.1, Table 
3.18.2). “End of Treatment” will be summarized for each scheduled post-baseline time point 
(pre-dose 1 hour, post-dose 30 minutes, and post-dose 2 hours). End of Treatment for each of 
these assessment points is defined as the last non-missing on-treatment assessment available for 
the time point. 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 the end-of-treatment summary. 
Data from both scheduled and unscheduled visits will be listed. Mean pre-dose change from 
baseline for heart rate and QTcF will be plotted across post-baseline visits by treatment (Figure
3.18.1a and Figure 3.18.1e). ECG data from subjects with pacemakers will not be included in 
analyses, but will be listed. 
Table 14 
Analysis Study Time Window for ECG Assessments 
Calculated Study Time Window 
Time Interval for the Study Time 
Window
Pre-dose 1 hr. 
0 min. prior to dose 
Post-dose 30 min. 
>0 to <75 min. post-dose 
Post-dose 2 hrs. 
75 min. to <4 hrs. post-dose 
Post-dose 12 hrs. 
8 hrs. to <16 hrs. post-dose 
               Note: The minutes are rounded to the nearest whole number before applying time windows. 
If there are multiple ECG values for the same parameter at pre-dose of a visit date (other than for 
Visit 4) or within the same post-dose study time window on a visit date, the last value will be 
chosen for analysis. 
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 and for the end-of-
treatment summary. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 97 of 355
 
 
Table 15 
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 15. The number and percentage of subjects who had such values observed any time 
post-dose will be tabulated for each treatment (Table 3.18.3, 3.18.4) and listed (Tables 3.18.5, 
3.18.6 for QTcF prolongation). No hypothesis tests will be performed. 
6.5.5
Healthcare Resource Utilization 
Data on HCRU will be collected at all visits post-baseline and summarized by treatment group. 
The following variables will be calculated unadjusted (per subject) over the entire Treatment 
Period and tabulated by actual treatment received for those subjects for whom they or one or 
more of their family members missed work: 
x
The number of days missed work due to COPD. 
x
The number of days that caregivers of subjects missed from work as a result of the subject’s 
COPD. 
 
The following variables will be tabulated by actual treatment received and relationship to COPD 
(COPD-related, not COPD-related, and combined). The mean and the mean per person-year will 
be calculated across all subjects in a treatment. 
x
The percentage of subjects with telephone calls to health-care providers: 
o
Calls to any health-care provider (physician or other) 
o
Calls to physician 
o
Calls to other healthcare provider 
x
The mean number of telephone calls to health-care providers: 
o
Calls to any health-care provider (physician or other) 
o
Calls to physician 
o
Calls to other healthcare provider 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 98 of 355
 
 
x
The percentage of subjects with visits to health-care providers: 
o
Visits to any health-care provider (GP, specialist, or other) 
o
Visits to GP 
o
Visits to specialist 
o
Visits to other health-care provider 
x
The mean number of visits to health-care providers: 
o
Visits to any health-care provider (GP, specialist, or other) 
o
Visits to GP 
o
Visits to specialist 
o
Visits to other health-care provider 
x
Ambulance Transport 
o
The percentage of subjects who required ambulance transport 
o
The mean number of times ambulance transport was required 
x
ER Visits 
o
The percentage of subjects with ER visits 
o
The mean number of visits to ERs 
x
Hospitalizations 
o
The percentage of subjects hospitalized 
o
The mean number of subject hospitalizations  
o
The mean number of days in the hospital 
x
Hospitalizations with some time spent in the ICU or CCU 
o
The percentage of subjects hospitalized with some time spent in the ICU or CCU 
o
The mean number of subject hospitalizations with some time spent in the ICU or 
CCU 
o
The mean number of days in the hospital with some time spent in the ICU or CCU 
x
Hospitalizations with No time spent in the ICU or CCU 
o
The percentage of subjects hospitalized with No time spent in the ICU or CCU 
o
The mean number of subject hospitalizations with No time spent in the ICU or 
CCU 
o
The mean number of days in the hospital with No time spent in the ICU or CCU 
x
ICU 
o
The percentage of subjects in the ICU 
o
The mean number of days in ICUs 
x
CCU 
o
The percentage of subjects in the CCU 
o
The percentage of subjects who required ambulance transport 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 99 of 355
 
 
 
Analyses will be performed using the mITT Population. 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
provided by actual treatment received for the number of days missed from work, the number of 
days that family members of subjects missed from work per year overall during the study (Table
3.20.1 and Listing 9.4). 
Also, descriptive statistics will be provided by actual treatment received and relationship to 
COPD (related, not-related, and total) overall during the entire Treatment Period for the 
following variables: the number of telephone calls to health-care providers, the number of visits 
to health-care providers, the number of ER visits, the number of number of times ambulance 
transport was required, the number of subject hospitalizations, the number of days in the 
hospital, the number of days in the ICU, and the number of days in the CCU (Table 3.20.2 and 
Listings 9.4 and 9.5).  
6.5.6
Pharmacokinetic Analysis 
Blood samples for PK assessments will be taken prior to administration of study drug at Week 24 
and at 2, 5, and 20 minutes, and at 1, 2, 4, 8, 10, and 12 hours post-dose. Actual sampling time 
points relative to dosing will be used for PK assessments and analysis where available. If the 
actual sampling time is unknown, the scheduled protocol time may be used for the calculation of 
derived PK parameters. 
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 
Phoenix® WinNonlin® (Pharsight Corporation, US). From the plasma budesonide, 
glycopyrronium and formoterol concentration-time data, the following PK parameters will be 
estimated for each subject where possible: 
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 100 of 355
 
 
AUC0-12 
The area under the plasma concentration-time curve from time 0 to 12 hours 
post dose 
Cmax 
The maximum observed plasma concentration, expressed in concentration 
units 
tmax 
The time to reach Cmax, expressed in hours 
Ȝz
The terminal elimination rate constant, calculated from the slope of the 
terminal portion of the ln(drug concentration) versus time curve 
t1/2 
The apparent terminal elimination half-life, expressed in hours, calculated as 
ln2/ Ȝz 
Cmin 
The minimum observed plasma concentration, expressed in concentration 
units 
Cavg 
Average concentration during a dosing interval 
Fluctuation 
Degree of fluctuation [(Cmax-Cmin)/Cavg]  
Swing 
[(Cmax-Cmin)/Cmin] 
 
AUC0-12 will be calculated using the linear-log trapezoidal method. 
The PK parameters Cmax, Cmin and time to Cmax (tmax) will be obtained from the observed values. 
A 12-hour post-dose sampling schedule may not permit adequate estimation of Ȝz considering the 
known PK of the products. However, Ȝz 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 Ȝz for 
each subject for each treatment 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 the lower limit of quantification (LLQ) should be used in the 
estimation. 
x
Cmax must not be used in the estimation. 
 
In order for the selection to take place the adjusted r2 value reported in Phoenix® WinNonlin® 
must be above 0.7. 
Fluctuation, swing and t1/2 will be calculated using the formulas listed above. 
For the purposes of parameter estimation, plasma concentration values below the LLQ will be set 
to missing in 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. 
All concentration-time data reported by the bioanalytical laboratory, for each analyte, for each 
treatment, will be listed for subjects participating in the PK sub-study. Actual sample collection 
times will be detailed in the listing along with the scheduled nominal sample collection times. In 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 101 of 355
 
 
addition, all calculated PK parameters for each treatment for each analyte will be listed for 
subjects participating in the PK sub-study. 
Descriptive statistics for plasma concentrations of budesonide, formoterol, and glycopyrronium, 
by treatment, visit and time point will be summarized. 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 4.1 – 4.3). 
Descriptive statistics for PK parameters of budesonide, glycopyrronium, and formoterol, will be 
summarized by treatment and visit. Descriptive statistics will include the number of observations 
(n), mean (CV %), SD, median, minimum, maximum, 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 4.4-4.6). 
The plasma concentration-time profiles for individual and mean plasma concentrations of 
budesonide, formoterol, and glycopyrronium, will be presented for each treatment 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 individual plots (Figures 4.1.1 through 4.6.2). 
Non-compartmental parameter estimates for budesonide, formoterol, and glycopyrronium  
AUC0-12 and Cmax will be natural-log transformed and analyzed using mixed effect models 
(Tables and Figures 4.7 – 4.9). 
The relative bioavailability of budesonide, formoterol, and glycopyrronium delivered via BGF 
MDI to delivery via GFF MDI, BFF MDI, or Symbicort TBH will be evaluated and summarized. 
Separate analysis of variance (ANOVA) models with fixed effects for treatment, will be fit for 
each analyte (Tables 4.7 – 4.9). 
6.5.7
HPA Axis Analysis 
Twenty-four-hour SC levels will be obtained in a subset of PK sub-study subjects over 24 hours 
between Visits 3 and 4 prior to dosing at Randomization and Visit 10a (Week 24). 
Cortisol sampling will occur 30 minutes pre-dose, and 1, 2, 4, 8, 10, 12, 14, 16, 20, 22, and 24 
hours post-dose. All SC concentrations reported will be listed. 
The data reported by the bioanalytical laboratory will be evaluated for inclusion in the HPA Axis 
analysis dataset. 
The HPA Axis analysis will be performed for subjects in the HPA Axis Population. 
The following parameters will be estimated for each subject where possible: 
x
0-24 hour weighted mean SC concentration  
 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 102 of 355
 
 
The 24-hour SC weighted mean concentration (AUC/t) will be obtained by dividing the AUC by 
the sample collection time interval within 24 hours; t is the difference in hours between last non-
missing time minus first non-missing time included in the AUC. The AUC will be calculated 
using the trapezoidal rule from the first non-missing time point to the last non-missing time 
point.  
Baseline is defined as the weighted mean 0-24 h from Day -1/1. If only one time point is 
available at either baseline or at Week 24, time-weighted average will use the single 
concentration value at that time point; in this case, baseline time-weighted average is just the 
single concentration value collected at baseline. 
Concentrations below the assay’s LLQ will be imputed with a value of LLQ/2 when deriving the 
weighted mean and AUC. If an observation is missing between 2 non-missing observations, the 
AUC will be calculated using the reported values at the adjacent time points.  
The primary analysis will be performed on the log-transformed ratio from baseline of the 
weighted mean SC for subjects in the HPA Axis Population. An ANCOVA model with baseline 
(log-transformed) value, gender, age, and treatment group as covariates will be used to draw 
comparisons between BGF MDI versus GFF MDI, BFF MDI versus GFF MDI, and Symbicort 
TBH versus GFF MDI. Estimated ratios and their 90% confidence intervals will be presented 
(Table 5.1).  
SC concentration values will be listed (Listing 11.1). Baseline and Week 24 weighted mean SC 
concentration will be listed for each subject (Listing 11.2). 
The ratio from baseline to Week 24 (Visit 10a) in the 0-24 hour weighted mean SC concentration 
at will be summarized by treatment group (Table 5.1).  
Descriptive statistics (n, mean, SD, median, minimum, maximum, geometric mean, and 
geometric coefficient of variation) for SC concentration by time point (for both Screening and 
Week 24) will be tabulated (Table 5.2). SC concentration profiles over 24 hours will be 
graphically presented by treatment group using box plots over time, at baseline and at Week 24 
(Figures 5.2.1 – 5.2.4).  
The percentage of subjects observing an at least 30% increase from baseline in 0- to 24-hour 
weighted mean SC concentration will be summarized by treatment group. The percentage of 
subjects observing an at least 30% decrease from baseline in 0- to 24-hour weighted mean SC 
concentration will also be summarized by treatment group. 
6.5.8
Physical Examination 
Any physical examination abnormality reported after the start of treatment for a subject is to be 
reported as an adverse event. Thus, these will be included in listings of adverse events and 
summarized in adverse event summaries. Abnormalities seen at the Screening physical 
examinations will be recorded as Medical History and listed. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 103 of 355
 
 
7.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
Any further refinements to methods planned in this SAP will be identified in the BDRM minutes. 
8.
STATISTICAL SOFTWARE 
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using SAS (Version 9.2 or higher). Graphs may also be produced 
using R (R Development Core Team, 2003). 
9.
REFERENCES 
Anzures-Cabrera J, Higgens PT. Graphical displays for meta-analysis: An overview with 
suggestions for practice. Research Synthesis Methods, Published online on 23 Mar 2010 (Wiley 
Interscience). 
Carroll KJ, Fleming TR. Statistical Evaluation and Analysis of Regional Interactions: The 
PLATO Trial Case Study. Statistics in Biopharmaceutical Research, 2013; 5:2, 91-101. DOI: 
10.1080/19466315.2013.783878 
COPD Assessment Test (CAT) (http://www.catestonline.org/) 
Cro, S (2017) Relevant Accessible Sensitivity Analysis for Clinical Trials with Missing Data. 
PhD thesis, London School of Hygiene & Tropical Medicine. DOI: 10.17037/PUBS.03817571 
(http://researchonline.lshtm.ac.uk/3817571/1/2017 EPH PhD CRO S.pdf). 
Devlin N, Shah K, Feng Y, Mulhern B, van Hout B. (2016), Valuing Health-Related Quality of 
Life: An EQ-5D-5L Value Set for England. Office of Health Economics, Research Paper 16/01.  
EuroQol Group. EQ-5D. Accessed at www.euroqol.org/about-eq-5d/how-to-use-eq-5d.html 
(November, 2014). 
Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders analysis graph 
to present pain data over a range of cut-off points: Making clinical trial data more 
understandable. J Pain Symptom Manage 2006; 31:369-377 
Hochberg Y, A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988; 
75, 4, pp. 800-2. 
Japanese Respiratory Society (JRS). Guidelines for the Diagnosis and Treatment of COPD, 4th 
edition, 2013. 
Jennison C, Turnbull BW. Group Sequential Methods: Applications to Clinical Trials. Chapman 
and Hall/CRC: Florida, 2000. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150(9):604-612. 


BGF MDI/GFF MDI/BFF MDI 
Protocols PT010006 and PT010007 
Version 2.0 
09 Jan 2018
Page 104 of 355
 
 
Little RJA, Rubin DB. Statistical analysis with missing data, (2nd edn.). John Wiley and Sons, 
Inc.: New York, 2002. 
Molenberghs G, Kenward MG. Missing data in clinical studies. John Wiley and Sons, Inc.: New 
York, 2007. 
National Center for Health Statistics. 1996. NHANES III Reference Manuals and Reports. Data 
Dissemination Branch, Hyattsville, MD. CD-ROM No. 6-0178 (1096). 
National Research Council. Panel on Handling Missing Data in Clinical Trials. Committee on 
National Statistics, Division of Behavioral and Social Sciences and Education. The prevention 
and treatment of missing data in clinical trials. The National Academies Press: Washington, DC, 
2010. 
R Development Core Team. R: A language and environment for statistical computing, 2003. R 
Foundation for Statistical Computing, Vienna, Austria. 
Ratitch B, O’Kelley M, and Tosiello R. Missing data in clinical trials: from clinical assumptions 
to statistical analysis using pattern mixture models. Pharmaceutical Statistics, 2013; 12: 337-347. 
Rubin DB. M. Multiple imputation for nonresponse in surveys. John Wiley and Sons, Inc.: New 
York, 1987. 
SAS Institute Inc. 2008. SAS/STAT 9.2 User’s Guide. Cary, NC: SAS Institute Inc.  
Seaman SR, White IR, Leacy FP. Comment on “Analysis of Longitudinal Trials With Protocol 
Deviations: A Frameword for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation,” by Carpenter, Roger, and Kenward. Journal of Biopharmaceutical Statistics, 2014; 
24(6):1358-1362. 
Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value in Health 15, 2012 (708-715). 
van Reenan M, Janssen B. EuroQol Group EQ-5D-5L User Guide: Basic information on how to 
use the EQ-5D-5L instrument. https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L UserGuide 2015.pdf (April 2015) 
White IR, Royston P, and Wood AM. Multiple imputation using changed equations: issues and 
guidance for practice. Statistics in Medicine, 2011; 30: 377-399.