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
Phase: PHASE3
Conditions: COPD
Sponsor: Pearl Therapeutics, Inc.

 
 
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. 
 
 

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Clinical Trial Protocol: PT010007-01  
 
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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. 

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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. 

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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. 

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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. 

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responsibilities for data retention. 
Section 10.11 Investigator’s Final Report 
Replaced “Investigator” with “Head of 
Medical Institution” 
Clarified/corrected responsible party. 

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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 

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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. 
 
 

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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. 

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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. 

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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 
 
 

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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 

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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 

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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 

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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 

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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 

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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 
 
 

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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 

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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 

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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 
 
 
 

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TRADEMARK INFORMATION  
Trademarks Not Owned By Pearl Therapeutics, Inc. 
KoKo Spirometer 
Ventolin 
Oxis 
Turbuhaler 
Spiriva 
 
Symbicort 
 

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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 

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in many countries in multiple formulations for different indications, including for the 
treatment of COPD. 
Formoterol fumarate is a selective LABA approved worldwide for use in asthma and COPD.  
In addition, formoterol fumarate is also approved worldwide in combination with budesonide 
(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. 

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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 

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• 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 

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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 

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• 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. 
 
 
 

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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. 

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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. 

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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.   
 
 

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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 
 

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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: 

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• 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).  
 

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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. 
 
 

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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. 
 

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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 
 

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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 

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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. 
 
 

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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. 
 
 

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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. 
 
 

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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. 

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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 

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• 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.   

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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). 

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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. 

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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. 
 
 

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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. 
 
 

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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. 
 
 
 

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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. 

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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. 

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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. 

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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: 

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• 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. 

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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. 

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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 
 

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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. 
 
 

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8 
STUDY ACTIVITIES 
A time and events schedule is provided in Table 8-1.   

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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 

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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. 
 

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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 
 
 
 

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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. 

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- 
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.   

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• 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 

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• 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 
 

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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 

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• 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) 
 
 
 

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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 
 

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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. 

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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 

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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 

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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. 

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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. 

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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. 

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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 

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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. 

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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. 

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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 

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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. 

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long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. 
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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 
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Campbell M, Elias A, Johansson G, et al. Formoterol for maintenance and as-needed 
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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 
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Dahl R, Greefhorst LA, Nowak D, et al. Inhaled formoterol dry powder versus ipratropium 
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D’Urzo A, Salvo M D, Ramirez-Rivera A, et al. In subjects with copd, treatment with a 
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Eakin EG, Sassi-Dambron DE, Ries AL, Kaplan RM. Reliability and validity of dyspnea 
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Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders analysis 
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Ferrer, Alonso J,Morera J, et al. Chronic obstructive pulmonary disease Part and health 
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Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systemic review and meta-
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Rennard SI, Tashkin DP, McElhattan J, et al.  Efficacy and tolerability of 
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obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial.  
Drugs. 2009;69(5):549-65. 
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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, 
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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. 
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12 APPENDICES 
 
 

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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 

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point on the graphical output. The last 2 s of the maneuver should be displayed to indicate a 
satisfactory end of test. 
When a volume–time curve is plotted as hardcopy, the volume scale must be >10 mm L-1 
(BTPS). For a screen display, 5 mm L-1 is satisfactory (Table A1-1). 
Table A1-1 Recommended Minimal Scale Factors for Time, Volume and Flow 
on Graphical Output 
Parameter 
Instrument Display 
Hardcopy Graphical 
Output 
 
Resolution Required 
Scale Factor 
Resolution Required 
Volume* 
0.050 L 
5 mm-L-1 
0.050 L 
Flow* 
0.200 L-s-1 
2.5 mm L-1 s-1 
0.200 L-s-1 
Time 
0.2 s 
10 mm-s-1 
0.2 s 
*The correct aspect ratio for flow versus volume display is two units of flow per one unit of volume 
 
The time scale should be >20 mm-s-1, and larger time scales are preferred (>30 mm-s-1) when 
manual measurements are made. When the volume–time plot is used in conjunction with a 
flow–volume curve (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. 

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Table A1-2 Summary of Equipment Quality Control 
Test 
Minimal 
Interval 
Action 
Volume 
Daily 
Calibration check with a 3 L syringe 
Leak 
Daily 
2 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.   

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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 

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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 
 

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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. 

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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. 
 

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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). 
 
 

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left (see Figure 2b).  After 10 more puffs are used, the Dose indicator pointer will move 
to the number 100.  This means that there are 100 puffs of medicine left (see Figure 2c). 
The Dose indicator number will continue to change after every 20 puffs. 
 
 
 
 
 
 
 
 
• When the number in the Dose indicator window changes to 20 and the color behind the 
number changes to red, this means that there are only 20 puffs left in your inhaler. See 
Figure 2d 
 
Figure 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 

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Figure 3 
 
Prime the inhaler before you use it for the first time. 
Priming the Inhaler: 
• Check inside the Mouthpiece for objects before use. 
• Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4a. 
• Shake the inhaler well before each puff. 
• Push down fully on the center (not 'off center') of the Dose indicator on top of the 
Canister (see Figure 1) until the Canister stops moving in the Actuator to release a 
puff from the Mouthpiece as shown in Figure 4b.  Note:  It is normal to hear a soft click 
from the dose indicator as it counts down during use. 
• Repeat this priming step 3 more times for a total of 4 times, shaking the inhaler each time 
before you press it. 
• After completing the 4 priming puffs, your inhaler is now primed ready to use for the first 
time. 
 
You must re-prime your inhaler again if you have not used it in more than 7 days.  Take the 
cap off the mouthpiece and shake and spray the inhaler 2 times into the air away from your 
face. 

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Figure 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. 

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

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

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

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• 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. 

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• Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4. 
• Shake the inhaler well before each puff. 
• Push down fully on the center (not 'off center') of the Dose indicator on top of the 
Canister until the Canister stops moving in the Actuator to release a puff from the 
Mouthpiece. 
• Repeat this re-priming step 1 more time for a total of 2 times. 
After re-priming your inhaler 2 times, your inhaler is now ready to use. 
 
 

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Appendix 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.  

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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. 

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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. 

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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. 

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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.

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How to use your VENTOLIN HFA inhaler: 
Follow these steps every time you use VENTOLIN HFA. 
Step 1. Make sure the canister fits firmly in the actuator. The counter should show through 
the window in the actuator. 
Shake the inhaler well before each spray. 
Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign 
objects, and take out any you see. 
Step 2. Hold the inhaler with the mouthpiece down. See Figure E. 
 
Figure E 
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. 

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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. 

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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. 

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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 
 
 
 

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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: 

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• 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: 

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• 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. 
 
 

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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  
 
 
 

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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: ___________________________________