Conditions: Chronic Obstructive Pulmonary Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: yes

Brief summary:
A study to assess the pharmacokinetics and safety of two doses of PT010 and a single dose of PT003 in healthy Chinese adult subjects

Detailed description:
A Phase I, Randomized, Double-Blind, Parallel Group, Study to Assess the Pharmacokinetics and Safety of Two Doses of PT010 and a Single Dose of PT003 in Healthy Chinese Adult Subjects Following a Single Administration and After Chronic Administration for 7 Days

Arms:
arm 1: PT010 Budesonide, Glycopyrronium and Formoterol Fumurate Metered Dose Inhaler (BGF MDI) 320/14.4/9.6 µg arm 2: PT010 (BGF MDI) 160/14.4/9.6 µg arm 3: PT003 (GFF MDI) 14.4/9.6 µg

Interventions: intervention 1: PT010 (BGF MDI) 320/14.4/9.6 µg intervention 2: PT010 (BGF MDI) 160/14.4/9.6 µg intervention 3: PT003 (GFF MDI) 14.4/9.6 µg
Intervention descriptions: intervention 1: A single dose of study drug will be administered on Day 1 and BID doses will be administered Day 2 through Day 7 of the Treatment Period, with a final single administration of study drug occurring on the morning of Day 8. intervention 2: A single dose of study drug will be administered on Day 1 and BID doses will be administered Day 2 through Day 7 of the Treatment Period, with a final single administration of study drug occurring on the morning of Day 8. intervention 3: A single dose of study drug will be administered on Day 1 and BID doses will be administered Day 2 through Day 7 of the Treatment Period, with a final single administration of study drug occurring on the morning of Day 8.

Protocol document:
Prot_001.pdf: 
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SAP_000.pdf: 
 
 
Statistical Analysis Plan 
Study Code 
PT010010 
NCT #  
NCT03075267 
Version 
Ver. 1.0 
Date  
24 August 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 A Phase I, Randomized, Double-Blind, Parallel-Group Study to Assess 
the Pharmacokinetics and Safety of Two Doses of PT010 and a Single 
Dose of PT003 in Healthy Chinese Adult Subjects Following A Single 
Administration and After Chronic Administration for 7 Days  
 
 
 
  
 
 
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 1 of 42)
 
 
STATISTICAL ANALYSIS PLAN FOR 
STUDY PT010010 
 
 
Protocol Number: 
PT010010 
 
Investigational Drug 
and Drug Number: 
BGF MDI; PT010 
GFF MDI; PT003 
 
Indication:
COPD 
Dosage Form/Dose: 
x
BGF MDI 320/14.4/9.6 ȝg ex-actuator  
x
BGF MDI 160/14.4/9.6 ȝg ex-actuator  
x
GFF MDI 14.4/9.6 ȝg ex-actuator  
 
PT010010 Protocol Title: A Phase I, Randomized, Double-Blind, Parallel-Group, Study to 
Assess the Pharmacokinetics and Safety of Two Doses of PT010 and a Single Dose of PT003 in 
Healthy Chinese Adult Subjects Following A Single Administration and After Chronic 
Administration for 7 Days 
 
 
Date of Issue: 
24 Aug 2017 
 
Version:
Version 1.0 
 






 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 4 of 42)
 
Change Log
Version No. 
Effective Date 
Reason for the Change / Revision 
Supersedes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 5 of 42)
 
TABLE OF CONTENTS 
1.
INTRODUCTION ..................................................................................................................................... 12
2.
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 12
2.1
STUDY OBJECTIVES ............................................................................................................................ 12
2.1.1
Primary Objective ............................................................................................................... 12
2.1.2
Secondary Objective ........................................................................................................... 12
2.2
STUDY ENDPOINTS ............................................................................................................................. 12
2.2.1
Pharmacokinetic Endpoint .................................................................................................. 12
2.2.2
Secondary Endpoint ............................................................................................................ 13
3.
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ............................................................. 13
3.1
STUDY DESIGN ................................................................................................................................... 13
3.1.1
Overall Study Design and Plan ........................................................................................... 14
3.1.2
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other Restrictions ...... 15
3.1.2.1
Surgical Procedure/Intervention Restrictions ..................................................... 15
3.1.2.2
Dietary Restrictions ........................................................................................... 16
3.1.2.3
Illicit Drugs and/or Drugs of Abuse Restriction ................................................ 16
3.1.2.4
Smoking Restrictions ......................................................................................... 16
3.2
RANDOMIZATION AND BLINDING ....................................................................................................... 16
3.3
HYPOTHESIS TESTING ........................................................................................................................ 17
3.4
INTERIM ANALYSIS ............................................................................................................................ 17
3.5
SAMPLE SIZE ...................................................................................................................................... 17
3.6
STUDY PROCEDURES .......................................................................................................................... 17
3.7
SCHEDULE OF ASSESSMENTS.............................................................................................................. 17
4.
DATA AND ANALYTICAL QUALITY ASSURANCE ........................................................................ 17
5.
ANALYSIS POPULATIONS ................................................................................................................... 17
5.1
POPULATION DEFINITIONS ................................................................................................................. 17
5.1.1
Safety Population ................................................................................................................ 17
5.1.2
Pharmacokinetic (PK) Population ...................................................................................... 18
5.2
POPULATIONS FOR ANALYSES ............................................................................................................ 18
6.
SPECIFICATION OF ENDPOINTS AND VARIABLES ..................................................................... 18
6.1
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................................... 18
6.2
PHARMACOKINETICS .......................................................................................................................... 18
6.3
SAFETY ASSESSMENTS ....................................................................................................................... 19
6.3.1
Physical Examination ......................................................................................................... 19
6.3.2
Vital Signs .......................................................................................................................... 19
6.3.3
12-Lead Electrocardiogram ................................................................................................ 20
6.3.4
Clinical Laboratory Tests ................................................................................................... 20
6.3.5
Adverse Events ................................................................................................................... 22
6.3.6
Urine Drug Screening/Alcohol Breath Testing ................................................................... 25
6.3.7
Pregnancy Test ................................................................................................................... 25
6.3.8
Concomitant Medications/Treatments ................................................................................ 25
7.
STATISTICAL ANALYSIS ..................................................................................................................... 25
7.1
DATA HANDLING RULES AND DEFINITIONS, INCLUDING HANDLING OF MISSING DATA .................... 25
7.2
SUBJECT DISPOSITION AND ANALYSIS POPULATIONS ........................................................................ 26


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 6 of 42)
 
7.3
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................................ 27
7.3.1
Medical and Surgical History at Screening, Reproductive Status, and Pregnancy Testing 27
7.3.2
Prior and Concomitant Medications/Treatments ................................................................ 27
7.3.3
Extent of Exposure to Study Medication and Compliance ................................................. 28
7.4
PHARMACOKINETIC ASSESSMENTS .................................................................................................... 29
7.5
SAFETY ASSESSMENTS ....................................................................................................................... 31
7.5.1
Physical Examination ......................................................................................................... 31
7.5.2
Vital Signs .......................................................................................................................... 32
7.5.3
12-Lead Electrocardiogram ................................................................................................ 32
7.5.4
Clinical Laboratory Tests ................................................................................................... 32
7.5.5
Adverse Events ................................................................................................................... 33
7.5.6
Urine Drug Screening and Alcohol Breath Testing ............................................................ 33
7.5.7
Pregnancy Test ................................................................................................................... 34
7.5.8
Prior/Concomitant Medications/Treatments ....................................................................... 34
8.
ANALYSES PERFORMED BEFORE DATABASE CLOSURE ......................................................... 34
9.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................... 34
10. STATISTICAL SOFTWARE ................................................................................................................... 34
11. REFERENCES .......................................................................................................................................... 34
APPENDIX 1: DATA HANDLING RULES .................................................................................................... 34
APPENDIX 2: TABLE OF CONTENTS FOR END-OF-TEXT TABLES, LISTINGS, AND FIGURES . 35
APPENDIX 3: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .... 42
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 7 of 42)
 
List of Tables 
Table 1
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ............................................................................................... 20
Table 2
Potentially Clinically Significant Criteria for Heart Rate Parameters ................... 20
Table 3
List of Laboratory Tests ......................................................................................... 21
Table 4
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria ............... 22
List of Figures 
Figure 1
Study Design .......................................................................................................... 14


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 8 of 42)
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ATC 
Anatomic Therapeutic Class 
AUC0-12 
Area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-t 
Area under the plasma concentration-time curve from 0 to the Time of the 
Last Measurable Plasma Concentration 
AUC0- 
Area under the plasma concentration-time curve from 0 Extrapolated to 
Infinity 
BGF MDI 
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose 
Inhaler 
BID 
Bis in die, twice daily 
BLOQ 
Below Limit of Quantification 
BP 
Blood Pressure 
CL/F 
Apparent Total Body Clearance 
Cmax 
Maximum Plasma Concentration 
COPD 
Chronic Obstructive Pulmonary Disease  
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic Acid  
eCRF 
Electronic Case Report Form 
eg 
Exempli gratia; for example 
FSH 
Follicle Stimulating Hormone  
GFF MDI 
Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler 
GFR 
Glomerular Filtration Rate 
HbsAg  
Hepatitis B Surface Antigen  
hCG 
Human chorionic gonadotropin 
HIV 
Human Immunodeficiency Virus  
HR 
Heart Rate 
IB 
Investigators Brochure  


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 9 of 42)
 
ICF 
Informed Consent Form 
i.e. 
Id Est; That Is 
IEC 
Independent Ethics Committee  
IRB 
Institutional Review Board  
Ȝz 
Apparent Terminal Elimination Rate Constant  
LLQ 
Lower Limit of Quantification 
MDI 
Metered dose inhaler 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
μg 
Microgram 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
msec (ms) 
Millisecond 
NCA 
Non-Compartmental Analysis 
PCS 
Potentially Clinically Significant 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetics  
PR 
Pulse Rate  
PT 
Preferred Term 
PT003 
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol 
PT010 
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation 
Aerosol 
QTcF 
QT Corrected Using Fridericia’s Formula 
RAC(Cmax) 
Accumulation ratio for Cmax 
RAC(AUC0-12) 
Accumulation ratio for AUC0-12 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 10 of 42)
 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure  
t1/2 
Apparent Terminal Elimination Half-life  
TEAE 
Treatment-emergent adverse event 
TFL 
Table, Figure, Listing 
tmax 
Time To Maximum Plasma Concentration  
Vd/F 
Apparent Volume of Distribution 
WHO 
World Health Organization 
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 11 of 42)
 
Trademark Information 
Trademarks Not Owned By Pearl 
Oxis 
Pulmicort 
Respules
Spiriva
Symbicort
Turbuhaler
Vacutainer
Ziploc 
 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 12 of 42)
 
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and 
analysis of data to be performed at the end of Pearl Therapeutics, Inc. (Pearl) Study PT010010. 
The SAP should be read in conjunction with the study protocol and the electronic Case Report 
Forms (eCRFs) for the study. This version of the SAP has been developed using the PT010010-
03 Amended Protocol (Version 4.0 dated 12 May 2017) and the CRF Revision 2 dated 2 March, 
2017. This is the main SAP, describing the statistical analyses that will be carried out at the end 
of the study.  
This is a phase I, randomized, double-blind, parallel-group, study to assess the pharmacokinetics 
(PK) and safety of two dosage strengths of PT010 (BGF MDI 320/14.4/9.6 ȝg ex-actuator and 
(BGF MDI 160/14.4/9.6 ȝg ex-actuator) and a single dosage strength of PT003 (GFF MDI 
14.4/9.6 ȝg ex-actuator) in healthy Chinese adult subjects following a single administration and 
after chronic administration for 7 days. 
The definitions of data sets will be described in separate documents called SDTM specifications 
and ADaM specifications. A prototype SAS code appendix will not be necessary for this study 
because the statistics are descriptive in nature, without modeling or hypothesis testing. 
2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1
Study Objectives 
2.1.1
Primary Objective  
x
To assess the pharmacokinetic profile of two dosage strengths of BGF MDI (BGF MDI 
320/14.4/9.6 ȝg ex-actuator and (BGF MDI 160/14.4/9.6 ȝg ex-actuator) and a single dosage 
strength of GFF MDI (GFF MDI 14.4/9.6 ȝg ex-actuator) in healthy Chinese adult subjects 
after a single administration and after chronic administration for 7 days.  
 
2.1.2
Secondary Objective 
x
To assess the safety and tolerability of two dosage strengths of BGF MDI and a single dosage 
strength of GFF MDI in healthy Chinese adult subjects after single administration and after 
chronic administration for 7 days. 
 
2.2
Study Endpoints 
2.2.1
Pharmacokinetic Endpoint 
Pharmacokinetics of BGF MDI and GFF MDI will be assessed and compared using plasma 
concentrations of budesonide, glycopyrronium, and formoterol. For the single dose 
administration, time points for PK blood sample collection will be pre-dose within 60 minutes 
and post-dose at 2, 6, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12, and 24 hours. Following 7 days 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 13 of 42)
 
of chronic dosing BID, time points for PK blood sample collection will be pre-dose within 60 
minutes and post-dose at 2, 6, 20, and 40 minutes and at 1, 2, 4, 8, 10, 12 and 24 hours.  
Pharmacokinetic parameters calculated at the first day (Day 1) and last dose (Day 8) during the 
Treatment Period will include the following:  
• Maximum plasma concentration (Cmax)  
• Area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12)  
• Time to maximum plasma concentration (tmax)  
The following PK parameters will be calculated at Day 1 only:  
• Area under the plasma concentration-time curve from 0 to the time of the last measureable 
plasma concentration (AUC0-t) 
• Area under the plasma concentration-time curve from 0 extrapolated to infinity (AUC0-)  
• Elimination half-life (t½) 
• Apparent total body clearance (CL/F) 
• Apparent volume of distribution (Vd/F) 
• Apparent terminal elimination rate constant (Ȝz) 
The following will be derived by taking subject level ratios of Day 8 values to Day 1 values:  
• Accumulation ratio for Cmax (RAC [Cmax]) 
• Accumulation ratio for AUC0-12 (RAC [AUC0-12]) 
2.2.2
Secondary Endpoint 
The safety and tolerability of BGF MDI and GFF MDI will be assessed from physical 
examination findings, AE (adverse event) reporting including serious adverse event (SAE) 
reporting, vital signs (blood pressure [BP], pulse rate [PR], respiratory rate, and body 
temperature), clinical laboratory values (hematology, chemistry, and urinalysis), and findings 
from 12-lead safety electrocardiograms (ECG) incorporated in the adverse events tabulation.  
3.
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS 
3.1
Study Design 
This is a Phase I, single-center, randomized, double-blind, parallel-group, study to assess the PK 
and safety and tolerability of two doses of BGF MDI and a single dose of GFF MDI in healthy 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 14 of 42)
 
Chinese adult subjects. Pharmacokinetics will be assessed following a single administration and 
after chronic administration for 7 days. Safety will be assessed during the 8-day treatment period 
and throughout the entire study until subjects are released from participation. All study drugs 
will be administered by oral inhalation. It is planned that the study will enroll and randomize an 
estimated 96 eligible subjects to one of three treatment groups in a 1:1:1 ratio to have 
approximately 90 completed subjects. Subjects will receive one of the following three 
treatments:  
BGF MDI 320/14.4/9.6 ȝg  
BGF MDI 160/14.4/9.6 ȝg  
GFF MDI 14.4/9.6 ȝg  
This study includes a Screening Period of up to 28 days and a single Treatment Period of 8 days. 
A follow-up phone call will be conducted at least 5 days, but no longer than 7 days after 
completion of the last dose. The maximum participation in the study for each subject is not 
expected to exceed approximately 43 days.  
3.1.1
Overall Study Design and Plan 
The overall study design is summarized and illustrated in Figure 1. 
Figure 1 
Study Design 
 
 
Note: All study drugs are administered by oral inhalation. A single dose of study drug will be administered on Day 1 
and BID doses will be administered Day 2 through Day 7 of the Treatment Period, with a final single administration 
of study drug occurring on the morning of Day 8. Administration of study drug should occur at approximately the 
same time of day. 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 15 of 42)
 
Subjects who provide informed consent, undergo Screening procedures, and qualify for the study 
will be randomized in a 1:1:1 ratio to one of three treatments: BGF MDI (320/14.4/9.6 ȝg), BGF 
MDI (160/14.4/9.6 ȝg), or GFF MDI (14.4/9.6 ȝg). Approximately 32 subjects will be 
randomized to each treatment arm.  
Subjects will be admitted as inpatients to the Clinical Research Unit (hereinafter referred to as 
“clinic”) during the Treatment Period. For the Treatment Period, subjects will be admitted to the 
clinic on Visit 2 (the day prior to dosing), at which time, continuing eligibility will be assessed. 
At in-clinic Visit 3 (Day 1 of Treatment), if the subject continues to meet eligibility criteria, the 
subject will be randomized into the study, admitted into the inpatient study unit and administered 
their first single dose of study drug. 
During the inpatient treatment period, study specified procedures will be performed and will 
include safety assessments, baseline and pre-, post-dose serial blood draws as defined in Protocol 
Section 7.3 and in Table 8—1, 8—2, and Table 8—3 of the study protocol. After all protocol 
specified assessments are completed and safety data has been reviewed by the Principal 
Investigator (Investigator) or designated staff, the subjects will be discharged from the clinic on 
Day 9. A follow-up phone call will be conducted 5 days, but no later than 7 days, after the last 
dose on Day 8. 
3.1.2
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other 
Restrictions
Investigational therapies are not permitted within 30 days or five half-lives (whichever is longer) 
prior to beginning the Screening Period. 
The use of prescription or over-the counter medications are not permitted within 30 days or five 
half-lives (whichever is longer) prior to Visit 3 (Day 1). 
Acetaminophen will be permitted at doses of 2 grams/day as determined to be necessary by the 
Investigator or medically qualified designee. 
With the exception of, contraceptives in female subjects, or need for medication during an 
emergency ongoing treatment for chronic conditions will not be allowed. Any medications that 
were being taken prior to signing the informed consent form (ICF) will be documented as prior 
study drugs and must be stopped prior to entry. 
3.1.2.1
Surgical Procedure/Intervention Restrictions 
Major surgical interventions are not permitted within 4 weeks of study drug administration (Visit 
3) and minor surgical interventions are not allowed within 2 weeks of study drug administration 
(Visit 3). 


 
 
 
Statistical Analysis Plan 
Protocol Nos.:  PT010010 
Date:  24 Aug 2017 
 
                                        (Page 16 of 42)
 
3.1.2.2
Dietary Restrictions 
Fasting (at least 8 hours) is required for scheduled complete clinical laboratory testing – 
chemistry and hematology (including glucose and potassium), at Screening Visit 1, Visit 2 (Day 
-1) and for the 24 hours post-dose sample collection on Day 9.  
Fasting is not required for glucose and potassium only blood sample collections on Visit 3 (Day 
1) at 30 min and at 2 hours post-dose and on Visit 4 (Day 8) at 30 min, 2 hours and 12 hours 
post-dose. 
Standardized meals will be administered at specified times after observation of fasting time for 
blood draws. There are no restrictions regarding clear fluid intake. 
Subjects are not allowed to consume grapefruits or grapefruit juice throughout the study. 
Subjects must not ingest xanthine (caffeine)-containing foods, beverages or medications for at 
least 6 hours prior to 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. 
3.1.2.3
Illicit Drugs and/or Drugs of Abuse Restriction 
Illicit drugs and/or drugs of abuse will not be allowed from within 1 year of Screening to 
whenever the subject discontinues the study. If any illicit drugs or drugs of abuse are used by the 
subject during the study, the dates of use and the amount will be documented.  
3.1.2.4
Smoking Restrictions 
Smoking is prohibited throughout the duration of the study and 3 months prior to screening. 
Electronic cigarettes and nicotine supplements will be treated the same way as smoking is 
considered in the protocol. 
3.2
Randomization and Blinding 
Following determination of study eligibility, subjects will be randomized in a 1:1:1 ratio to one 
of the three treatment groups: BGF 320/14.4/9.6 ȝg, BGF 160/14.4/9.6 ȝg, or GFF MDI 14.4/9.6 
ȝg. 
All treatment arms will be double-blinded. 
Randomization numbers will be generated off-site, to ensure allocation concealment, using a 
permutated block randomization design. The randomization numbers will be printed on sealed 
envelopes and corresponding component ID codes will be provided within the envelopes. The 
sealed envelopes are given out sequentially (i.e. there are serially numbered opaque sealed 
envelopes). Sealed emergency unblinding envelopes will also be provided separately. 
Subjects, investigators and the sponsor will be blinded to the treatment administered as described 
above until the study database is locked. The pharmacist will have access to the unblinded 
randomized treatment sequence. 


 
 
 
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3.3
Hypothesis Testing 
No formal hypothesis tests will be performed for this study. 
3.4
Interim Analysis 
There is no interim analysis planned for this study. 
3.5
Sample Size 
Previous studies with BGF MDI suggest that the inter-subject variability of glycopyrronium after 
single-dose administration may be as high as 
 
 
 
3.6
Study Procedures 
Study procedures are contained in Table 8—1, 8—2, and Table 8—3 of the study protocol. 
3.7
Schedule of Assessments 
A schedule of events is provided in Table 8—1 of the study protocol. Detailed schedules of 
inpatient assessments on Visit 3 (Day 1) and Visit 4 (Day 8) are provided in Table 8—2 and 
Table 8—3, respectively, of the study protocol. 
4.
DATA AND ANALYTICAL QUALITY ASSURANCE 
The overall quality assurance (QA) procedures for the study data, statistical programming and 
analyses are described in Standard Operating Procedures (SOPs) of 
. 
Detailed data management procedures are documented in the study Data Management Plan, and 
Data Validation Check Specifications, and Integrated Safety Data Review Plan. Detailed 
statistical and programming quality control and quality assurance procedures are documented in 
the Statistical Analysis and Programming QC/QA Plan. 
The study endpoints and analytic approaches are both prospectively defined and documented in 
the protocol and in this SAP. The SAP will be finalized, and protocol violations will be identified 
and decisions for inclusion and exclusion of subjects from the PK Population will be made at the 
Blinded Data Review Meeting (BDRM) prior to the database lock and data analysis. 
5.
ANALYSIS POPULATIONS 
5.1
Population Definitions 
5.1.1
Safety Population
The Safety Population is defined as all subjects who receive at least one dose of any blinded 
study drug.  


 
 
 
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Safety analyses will be performed on data from all subjects in the Safety Population. Analyses 
will be according to treatment received.  
5.1.2
Pharmacokinetic (PK) Population 
The PK Population is defined as all subjects in the Safety Population who have sufficient data 
to reliably calculate at least one PK parameter and do not have major protocol deviations (to be 
determined at the BDRM prior to unblinding). A major protocol deviation is a protocol deviation 
which can affect membership in an analysis population. 
Pharmacokinetic analyses will be performed on data from all subjects in the PK Population. 
Analyses will be according to treatment received.  
5.2
Populations for Analyses 
Demographics and baseline characteristics will be summarized descriptively for the PK and 
Safety Populations. Extent of exposure will also be summarized for the Safety and PK 
Populations. For the PK Population, descriptive statistics without model adjustment will be used 
to describe the budesonide, glycopyrrolate and formoterol PK parameters after treatment with 
two dosage strengths of BGF MDI and single dosage strength of GFF MDI. The Safety 
Population will be used to summarize safety. Safety and tolerability analyses will be based on 
descriptive statistics for vital signs, physical examination and laboratory measurements as 
appropriate, and also on frequencies of AEs (including any AEs based on ECG findings) as well 
as the number and proportion of subjects with AEs.  
6.
SPECIFICATION OF ENDPOINTS AND VARIABLES 
6.1
Demographics and Baseline Characteristics 
General demographic information such as age, race/ethnicity, gender, weight, and height will be 
collected at the Screening visit. Age will be calculated as the integer part of (Informed Consent 
date – Birth date)/365.25. 
Medical/surgical history will be collected on the eCRF during the Screening period. Medical 
history will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(currently MedDRA 19.1). Serology testing for HIV, HBsAg, Syphilis Ab, and Hepatitis C 
antibody will be conducted at the Screening visit. 
The definitions for the derived demographic or baseline characteristic variables can be found in 
Appendix 1. 
6.2
Pharmacokinetics
See Section 7.4. 


 
 
 
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6.3
Safety Assessments 
6.3.1
Physical Examination 
Any clinically significant physical examination abnormality reported after the start of study 
medication will be reported as an adverse event. These adverse events will be included in the AE 
summaries.  
The physical examination will include:  
x
Documentation of height (Screening only) 
x
Documentation of weight (Screening only) 
x
General appearance 
x
Head, eyes, ears, nose, and throat 
x
Respiratory 
x
Cardiovascular 
x
Musculoskeletal 
x
Abdominal 
x
Neurologic 
x
Extremities 
x
Dermatologic 
x
Lymph nodes 
6.3.2
Vital Signs 
Vital sign determinations, including BP, PR, respiratory rate, and body temperature will be 
performed after the subject has been supine for a 5-minute period at the Screening Visit, on the 
day of clinic admission Visit 2 (Day -1), Days 2 through Day 7, and on Visit 3 (Day 1) and Visit 
4 (Day 8) within 120 minutes (on Day 1; within 60 minutes on Day 3) prior to administration of 
study drug and 30 minutes, 2 hours, 4 hours, 12 hours, and 24 hours post administration of study 
drug.  
Potentially clinically significant (PCS) changes in systolic and diastolic blood pressure will 
be defined based on the following criteria provided by Pearl, Inc.: 


 
 
 
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Table 1 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood Pressure 
Parameters 
Parameter (mmHg) 
Post-Baseline Criteria 
Systolic Blood Pressure, increase 
180 mmHg and increase from 
baseline 20 mmHg 
Systolic Blood Pressure, decrease 
90 mmHg and 20 mmHg decrease 
from baseline 
Diastolic Blood Pressure, increase 
105 mmHg and increase from 
baseline 15 mmHg 
Diastolic Blood Pressure, decrease 
50 mmHg and 15 mmHg decrease 
from baseline 
 
Potentially clinically significant (PCS) changes in heart rate will be assessed as follows: 
Table 2 
Potentially Clinically Significant Criteria for Heart Rate Parameters 
Parameter 
Post-Baseline Criteria 
Tachycardia Event 
110 bpm and increase 15% from baseline 
Bradycardia Event 
50 bpm and decrease 15% from baseline 
 
6.3.3
12-Lead Electrocardiogram 
 Any clinically significant abnormality noted post-randomization based on twelve-lead safety 
ECGs will be recorded as adverse events. 
Machine-read ECG parameter data will be provided to the Investigator by local ECG lab(s).  
 
6.3.4
Clinical Laboratory Tests 
Laboratory testing (hematology with differential, chemistry and urinalysis) will be performed 
using standard methods.  
Standardized meals will be administered at specified times after observing fasting times for 
blood draws. 
Potentially Clinically Significant Laboratory Values Above/Below a Clinically Relevant 
Threshold on-treatment, based on CTCAE 4.03 and other criteria, will be identified based on the 
thresholds in Table 4. 
 
 


 
 
 
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Table 3 
List of Laboratory Tests 
Hematology 
Blood Chemistry 
Hematocrita 
Hemoglobin 
Serum Iron 
Ferritin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential 
Mean corpuscular volume (MCV) 
Mean cell haemoglobin (MCH) 
MCH concentration (MCHC) 
Creatinineb 
Potassium (K+)c 
Sodium (Na+) 
Chloride (Cl-) 
Magnesium (Mg++) 
Calcium 
Inorganic phosphate 
Glucosec 
Uric Acid 
Bilirubin (Total) 
Blood Urea Nitrogen (BUN) 
Bilirubin (direct) 
 Alanine aminotransferase 
    (ALT) 
 Aspartate aminotransferase   
    (AST) 
Gamma- 
   Glutamyltransferase 
   (GGT) 
Alkaline phosphatase 
Total Protein 
Albumin 
 
Urinalysis: Macroscopic examination routinely including specific gravity, pH, protein, glucose, 
ketones, blood and urobilinogen. A microscopic examination will be performed if warranted based 
on macroscopic results.
Urine drug screen: A urine sample will be collected and analyzed (positive or negative) for drugs 
of abuse including amphetamine, opiate, cocaine, barbiturates, benzodiazepines, and marijuana 
[tetrahydrocannabinol (THC)]. 
Breathalyzer Test: A breathalyzer test will be performed for the presence of alcohol (positive or 
negative). 
Serology: Testing for HbsAg, Hepatitis C antibody and HIV will be performed at screening only. 
Results of each serology test will be reported as either positive or negative. 
For females who are not post-menopausal: A serum hCG test at the screening visit and urine 
hCG test at admission. 
For females of non-childbearing potential: A serum hCG test at the screening visit and urine hCG 
test at admission. In addition, a serum, follicle-stimulating hormone (FSH) test for confirmation of 
non-childbearing status will be performed at screening only. 
Abbreviations: eGFR=estimated glomerular filtration rate; HbsAg=hepatitis B surface antigen; hCG=human 
chorionic gonadotropin; HIV=human immunodeficiency virus; FSH=follicle-stimulating hormone.  
a Packed cell volume (PCV). 
b eGFR will be calculated by the Modification of Diet in Renal Disease (MDRD) equation following :  
   http://www.columbiamedicine.org/divisions/gharavi/calc_egfr.php 
   C-MDRD (modified for Chinese) equation:  
   eGFR = 175 × (Serum Creatinine)-1.234 × (Age)-0.179 × (0.79 if Female)  
c Additionally, within 60 minutes prior to dosing and at 30 min, 2 hours, and 12 hours (Visit 4 only)  
  post-dose of Treatment. 
 


 
 
 
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Table 4 
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria 
Parameter 
Post-Baseline Criteria 
Hematology 
 
Hemoglobin  
<8.0 g/dL (<80 g/L) 
 
Increase of >40 g/L to a value above the 
ULN 
White Blood Cell Count 
<2000/μL 
 
>35,000/μL 
Platelet Count 
<50,000/μL 
 
>999,000/μL 
Chemistry
 
eGFR-EPI  
<30 mL/min/1.73 m2 
AST 
>3 x ULN 
ALT 
>3 x ULN 
Alkaline Phosphatase 
>5 x ULN 
Total Bilirubin 
>2 x ULN 
Blood Glucose* (random values) 
<2.2 mmol/L (<39.6 mg/dL) 
 
>13.9 mmol/L (>250 mg/dL) if baseline 
is below 10.0 mmol/L (180 mg/dL), > 
16.7 mmol/L (>300 mg/dL) if baseline 
is greater than 10.0 mmol/L (180 
mg/dL) 
Serum Potassium 
<3.0 mmol/L 
 
>6.0 mmol/L 
*CTCAE 4.03 criteria are based on fasting glucose values. However, subjects were not required 
to fast prior to obtaining blood glucose values. 
 
6.3.5
Adverse Events 
Adverse events (AEs) will be collected from the time of administration of the first dose of study 
drug to the time of the Follow-Up Telephone Call Visit, study termination, or study exit. AEs 
will be characterized by severity and relationship to study drug. The incidence of an adverse 
event will be defined by the number of subjects experiencing an event.  
Adverse events will be collected and coded using the latest version of MedDRA available at the 
time of database lock for this study. The study physician will review the adverse event coding. 
Adverse events that occur between the time the subject signs the informed consent form for the 
study and the time when that subject is randomized will be summarized as medical history and 
not as a treatment-emergent adverse event (TEAE). 


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


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


 
 
 
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For laboratory abnormalities that do not meet the above criteria but are outside of normal range 
(e.g., < or > normal reference range), the Investigator should indicate whether the value is 
potentially clinically significant (Table 4) or not clinically significant for the subject. 
6.3.6
Urine Drug Screening/Alcohol Breath Testing 
A urine sample will be collected and analyzed (positive or negative) for drugs of abuse including 
amphetamine, opiate, cocaine, barbiturates, benzodiazepines, and marijuana 
[tetrahydrocannabinol (THC)]. A breathalyzer test will be performed for the presence of alcohol 
(positive or negative). Both tests will be conducted at the Screening Visits 1 and 2. 
6.3.7
Pregnancy Test 
A serum hCG test and a urine hCG test at the Screening visit will be conducted for all females.  
6.3.8
Concomitant Medications/Treatments 
Concomitant medications will be collected for all visits of the study. 
Any medications that were being taken prior to signing the ICF will be documented as prior 
study medications and must be stopped prior to entry. 
Concomitant medications will be coded using the latest version of the World Health 
Organization (WHO) Drug Dictionary Enhanced (WHO DDE) and the WHO Herbal Dictionary 
(WHO-HD). 
7.
STATISTICAL ANALYSIS 
All data collected on the CRF and contributing to the analysis will be provided in listings, except 
for data collected only for confirmation of study entry criteria and for study management 
purposes. Data for all subjects who are randomized will be included in the subject data listings. 
Data for non-randomized subjects will be listed where available. 
All PK and safety parameters will be summarized by treatment unless specified otherwise.  
Continuous variables will be summarized with descriptive statistics: the number of non-missing 
values, mean, standard deviation, median, minimum, and maximum.  
Categorical variables will be summarized with frequency counts and percentages (where 
appropriate). 
7.1
Data Handling Rules and Definitions, Including Handling of Missing Data 
Missing data will be maintained as missing in the analysis datasets, unless specified otherwise. 
For variables where missing data are imputed, the analysis dataset will contain a new variable 
with the imputed value, and the original variable value will be maintained as missing. 


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


 
 
 
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7.3
Demographic and Baseline Characteristics 
Demographic data will be summarized by treatment group for both the Safety and PK 
Populations (Tables 1.4.1 and 1.4.2). Continuous demographic and baseline variables will be 
summarized by tabulating the number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum values in each treatment group. For categorical demographic and 
baseline variables, the frequency and percentage of subjects in each treatment group will be 
tabulated. Demographic data will be listed (Listing 1.1). Baseline information (including 
Serology Testing (Listing 4.1) and Medical and Surgical History (Listing 4.2)) will be listed.  
Demographic variables summarized will include the following: 
x
Age 
x
Gender 
x
Race  
x
Ethnicity 
x
Smoking Status (including number of years smoked, time in years since last smoked) 
x
Weight  
x
Height 
x
BMI (body mass index, derived from weight and height, equal to weight in kg divided by the 
square of height in m) 
7.3.1
Medical and Surgical History at Screening, Reproductive Status, and Pregnancy 
Testing
Relevant medical history, based on the opinion of the Investigator, will be obtained from the 
subject at Screening, and recorded on the source document. Medical history will capture the 
subject’s family health history, history of hospitalization, and history of surgeries.  
Medical and Surgical History at Screening will be listed for all randomized subjects (Listing 4.2).  
Screening Reproductive Status and Pregnancy Testing Results will be listed (Listing 10.4). 
7.3.2
Prior and Concomitant Medications/Treatments 
Coding: Verbatim medication/treatment terms will be coded by 
 and 
will be assigned a preferred term and an ATC (anatomic therapeutic class) term using the latest 
version of the World Health Organization Drug Dictionary (WHO-DD) available (version: 3Q 
2016 or later). 
Multiple ATC assignments: If there are multiple ATC codes assigned to the same concomitant 
medication, the “primary” one based on medical evaluation by study physician will be used. All 


 
 
 
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prior medication taken by the subject within 30 days of Screening for the study and all 
concomitant therapy taken by the subject while on study will be recorded in the eCRF. 
Prior medication/treatment is any medication/treatment taken prior to study treatment, even if 
this medication continued to be taken on the day of the start of study treatment in the study or 
afterward (Appendix 1).
Concomitant medication/treatment is any medication/treatment reported as being taken after 
the start of the study treatment in the study and being taken on or before the date prior to 
completion of or discontinuation from study treatment for the subject. A medication with an 
onset date on or after the date of discontinuation from or completion of randomized study 
treatment for the subject will not be considered concomitant, but will be considered a Post-
Treatment medication/treatment. 
Any medication/treatment which cannot be identified as Prior, Concomitant, or Post-Treatment 
will be considered as being in each of the categories that are possible from the available 
information. 
Prior, concomitant, and post-treatment medications will be listed (Listing 10.1).  
7.3.3
Extent of Exposure to Study Medication and Compliance 
Subject’s exposure to a study treatment will be determined by the duration of time (days) for 
which the doses were administered, defined as “((End date of treatment – Date of first dose of 
treatment) + 1)”. Percent compliance is defined as (total number of puffs of study treatment 
taken on a study day/total expected puffs taken on a study day) averaged across all days of a 
subject’s dosing between start day of study treatment and last day on study treatment) x 100. For 
BGF MDI and GFF MDI, the expected number of puffs for a test day which is the last date of 
treatment will be 2, and the expected number of puffs for the last date of treatment which is not a 
test day will be 4 when a PM dose is taken but will be 2 otherwise; the expected number of puffs 
on dates prior to the last date of treatment will be 4.  
 
The number of days of exposure to study treatment will be summarized for each treatment for the 
Safety Population. The tabulation will include the number and percentage of subjects with 1, 2, 
3, 4, 5, 6, 7, and 8 days of exposure. The total person-years of exposure for a treatment group, 
defined as the total exposure in the study across all subjects in the treatment, will also be 
provided by treatment (Table 1.6 for the Safety Population).  
In addition, treatment compliance will be provided in this summary. The treatment compliance 
will be categorized into 7 different groups depending on the degree of compliance: 0 – <20%, 
20 – <40%, 40 – <60%, 60 – <80%, 80 – 100%, >100 – 120%, and >120%. Also 
provided in this summary will be descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum) for percent compliance by treatment. Treatment compliance will be 
reported in Listing 6. A listing of treatment dosing and dispensing information will be provided 


 
 
 
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in Listing 5. Any comments related to study medication or any other additional study comments 
will be listed (Listing 10.5). 
7.4
Pharmacokinetic Assessments 
For the single dose administration, time points for PK blood sample collection will be pre-dose 
within 60 minutes and post-dose at 2, 6, 20, and 40 minutes, and at 1, 2, 4, 8, 10, 12 and 24 
hours. 
Following 7 days of chronic dosing BID, time points for PK blood sample collection will be pre-
dose within 60 minutes and post-dose at 2, 6, 20, and 40 minutes, and at 1, 2, 4, 8, 10, 12 and 24 
hours starting on the morning of the 8th day. 
Actual sampling time points relative to dosing will be used for PK assessments and analysis 
where available. It is expected that the actual sampling time will generally be available. In any 
(likely rare) cases when the actual sampling time was not recorded, the scheduled time may be 
used. This is considered preferable to ignoring a valid concentration measurement. 
The concentration-time data reported by the bioanalytical laboratory will be evaluated for 
inclusion in the PK analysis dataset. 
The PK analysis will be performed for subjects in the PK Population. 
PK parameters will be estimated by non-compartmental analysis (NCA) using the software 
 
From the plasma budesonide, glycopyrronium and formoterol concentration-time data, the 
following PK parameters will be estimated for each subject where possible on Day 1 of the 
treatment period: 
AUC0-t 
Area under the plasma concentration-time curve from 0 to the time of the last 
measurable plasma concentration 
AUC0-12 
Area under the plasma concentration-time curve from time 0 to 12 hours post dose 
AUC0- 
Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity 
Cmax 
Maximum observed plasma concentration, expressed in concentration units 
tmax 
Time to reach maximum observed plasma concentration (Cmax), expressed in 
minutes 
Ȝz
Terminal elimination rate constant, calculated from the slope of the terminal 
portion of the ln(drug concentration) versus time curve 
t1/2 
Apparent terminal elimination half-life, expressed in hours, calculated as ln2/ Ȝz 
CL/F 
Apparent total body clearance 
Vd/F 
Apparent volume of distribution 
 


 
 
 
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From the plasma budesonide, glycopyrronium and formoterol concentration-time data, the 
following PK parameters will be estimated for each subject where possible on Day 8 during the 
treatment period: 
AUC0-12 
Area under the plasma concentration-time curve from time 0 to 12 hours post dose 
Cmax 
Maximum observed plasma concentration, expressed in concentration units 
tmax 
Time to reach maximum observed plasma concentration (Cmax), expressed in hours 
 
AUC0-t, AUC0-12, and AUC0-, will be calculated using the linear-log trapezoidal method. 
 
The PK parameters Cmax and time to Cmax (tmax) will be obtained from the observed values. 
Ȝz will be estimated for each subject where feasible by linear regression analysis, calculated from 
the slope of the terminal portion of the ln(drug concentration) versus time curve. Selection of 
data points to include in the estimation of Ȝz for each subject for each treatment for each analyte 
will be based on the following criteria: 
x
All samples used should preferably fall in the log-linear elimination phase. 
x
At least 3 samples above lower limit of quantification (LLQ) should be used in the 
estimation. 
x
Cmax must not be used in the estimation. 
 
In order for the selection to take place the adjusted r2 value reported in 
 
must be above 0.7. 
t1/2 will be calculated as ln2/Ȝz. 
For the purposes of parameter estimation, plasma concentration values below the LLQ will be set 
to missing in the NCA with the exception of those values reported at Day 1 pre-dose. Day 1 pre-
dose concentrations that are below the limit of quantification (BLOQ) will be set to zero (per 
SOP) for the NCA. Concentrations measured after the Day 1 dose of study medication 
that are BLOQ will set to missing values (per 
SOP) for the NCA. Missing values (e.g., 
no blood sample collected, no value obtained at analysis) will be treated as missing and excluded 
from the NCA. If there are 2 consecutive missing concentration values, the estimation of PK 
parameters will be evaluated on a case-by-case basis. 
For descriptive statistics for concentrations and for the concentration figures, all values below 
LLQ will be assigned a value of ½ LLQ except for Day 1 pre-dose which will be assigned a 
value of 0 (no geometric mean will be calculated for Day 1 pre-dose). 
In addition to the above PK parameters to be calculated on Day 1 and Day 8, accumulation ratios 
for AUC0-12 (RAC [AUC0-12]) and Cmax (RAC [Cmax]) will be calculated by taking subject level 
ratios of Day 8 values to Day 1 values. 


 
 
 
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All concentration-time data reported by the bioanalytical laboratory, for each analyte, for each 
treatment, will be listed for subjects in the PK Population (Listing 8.1). Actual sample collection 
times will be detailed in the listing along with the scheduled nominal sample collection times. In 
addition, all calculated PK parameters for each treatment for each analyte will be listed (Listing
8.2). 
Descriptive statistics for plasma concentrations of budesonide, formoterol, and glycopyrronium, 
by treatment, visit and time point will be summarized. Descriptive statistics will include the 
number of observations (n), mean (CV%), SD, standard error (SE), median, minimum (min), 
maximum (max), geometric mean, and geometric coefficient of variation (Tables 2.1.1, 2.2.1, 
and 2.3.1). The geometric coefficient of variation (of a statistic y) is calculated as GEOCV(y) 
(%) = 100*sqrt[(exp[var(ln[y])])-1], where sqrt is the square root function and “var” is variance.  
Descriptive statistics for PK parameters of budesonide, glycopyrronium, and formoterol, will be 
summarized by treatment and visit. Descriptive statistics will include the number of observations 
(n), mean (CV%), SD, median, min, max, geometric mean, and geometric coefficient of 
variation. For the PK parameter tmax, only the number of observations (n), mean, median, 
minimum (min), and maximum (max) will be presented (Tables 2.1.2, 2.2.2, and 2.3.2). 
The plasma concentration-time profiles for individual and mean plasma concentrations of 
budesonide, formoterol, and glycopyrronium, will be presented for each treatment and each visit 
on the linear/linear scale and on the linear/log-linear scale. 
 
 Mean and individual plots will be separate for each analyte. Nominal sampling time points 
relative to dosing will be used for all mean plots. Actual sampling time points will be used for all 
individual plots (mean plots in Figures 2.1.1 through 2.3.2 and individual plots in Figures 2.4.1 
through 2.6.2). 
7.5
Safety Assessments 
Safety data will be summarized by treatment and listed. The safety of BGF MDI and GFF MDI 
will be assessed from physical examination findings, AE reporting including SAE reporting, vital 
signs (BP, PR, respiratory rate, and body temperature), clinical laboratory values (hematology, 
chemistry, and urinalysis), and findings from 12-lead ECGs. The incidence of AEs and SAEs 
will be tabulated by treatment. Summary statistics of assessed laboratory values will be tabulated 
by treatment. 
7.5.1
Physical Examination 
Any clinically significant physical examination abnormality reported after the start of study 
medication was to be reported as an adverse event. Thus, these will be included in listings of 
adverse events and summarized in adverse event summaries. 


 
 
 
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7.5.2
Vital Signs 
Vital sign measurements (PR, BP, body temperature, and respiratory rate) as collected on eCRFs 
(see Section 6.3.2) during the study will be displayed in a vital sign listing, as well as weight and 
height (collected at the Screening visit) (Listing 10.2).  
Summary statistics (n, mean, median, standard deviation, minimum and maximum) of pre-dose 
(in the respective period) and post-dose values (in the respective period) as well as changes from 
baseline values for systolic blood pressure, diastolic blood pressure and pulse rate will be 
tabulated by treatment group (Table 3.4.1). Baseline is defined (computationally) as the mean of 
all available pre-dose measurements taken on Day 1 prior to the start of dosing with study drug. 
The percentage of subjects with potentially clinically significant values for vital signs at any time 
post-dose at a visit will be summarized by treatment based on the criteria in Table 1 and Table 2 
(Table 3.4.2). They will also be listed (Tables 3.4.3 and 3.4.4).  
7.5.3
12-Lead Electrocardiogram 
All clinically significant abnormalities after the first dosing through the treatment period until 
follow-up telephone will be reported as TEAEs and followed closely by the Investigator in order 
to assure the safety of the study subject. 
7.5.4
Clinical Laboratory Tests 
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) of 
assessment values for laboratory testing (hematology with differential (Table 3.3.1), serum 
chemistry including estimated eGFR (Table 3.3.2 and 3.3.3) will be tabulated by treatment group 
at each time point and at each visit. Urinalysis results will be listed (Listing 9.3) and tabulated 
(Table 3.3.5). Changes from baseline will also be summarized by treatment group at 24 hours 
post-dose at Day 8 (Visit 4). Baseline is the last assessment during the screening period (e.g. 
Visit 2).  
Individual clinical laboratory variables for hematology, serum chemistry including estimated 
eGFR and urinalysis will be provided in listings (Listings 9.1 - 9.3). 
Glucose and potassium will also be collected within 30 minutes and 2 hours post-dose at Visit 3, 
and 60 minutes pre-dose, and 30 minutes, 2 hours, 12 hours, and 24 hours post-dose at Visit 4. 
The values as well as the changes from baseline for each visit and time point will be summarized 
by treatment (Table 3.3.4). Baseline is the last assessment prior to the first dose of study 
treatment. Glucose and potassium are also included into the complete laboratory assessment at 
Visit 2. 
For glucose and potassium, the frequency and percentage of potentially clinically significant 
values will be summarized by treatment group, at each post-dose timepoint (Table 3.3.4). 
Potentially clinically significant values for serum potassium and blood glucose may be found in 
Table 4 (CTCAE Version 4.03). Potentially clinically significant laboratory values for 
potassium, glucose, and other laboratory parameters will be listed (Tables 3.3.6, 3.3.7, and 
3.3.8).  


 
 
 
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Shifts from baseline to 24 hours post-dose at Visit 4 (Day 9), based on reference ranges (Low, 
Normal, High), will be presented by treatment group for hematology and serum chemistry (Table
3.3.9) and for urinalysis (Table 3.3.10). Baseline is the last assessment during the screening 
period (e.g. Visit 2) for all laboratory assessments. 
 
Many laboratory abnormalities observed during the course of a study will be included under a 
reported AE describing a clinical syndrome (e.g., decreased hemoglobin in a case of bleeding 
esophageal varices). In such cases, the laboratory abnormality itself (e.g., elevated creatinine in a 
setting of renal failure) does not need to be recorded as an AE. However, isolated laboratory 
abnormalities should be reported as AEs if they are considered to be clinically significant by the 
investigator. 
7.5.5
Adverse Events 
Treatment-emergent AEs (TEAEs) will be included in tabular format, for subjects who meet the 
criteria for the Safety Population. Listings for AEs will present all AEs in the database for all 
subjects (Listings 7.1 and 7.2). All AEs, whether treatment-emergent or not, will be included in 
the Listings. 
Analysis endpoints for AEs include both the numbers of treatment-emergent AEs as observed by 
the investigational team or reported by the subject, and the numbers of subjects experiencing 
treatment-emergent adverse events. The incidence of a TEAE will be defined as the number of 
subjects experiencing an event. 
An overall table of subjects with at least one TEAE will be summarized by treatment group, for 
subjects with AEs related to study treatment, with SAEs, with SAEs related to study treatment, 
with AEs leading to early discontinuation from study treatment, with SAEs leading to early 
withdrawal from study treatment, and with deaths (Table 3.1.1). 
The frequency and percentage of subjects experiencing a specific AE will be tabulated by system 
organ class (SOC) and preferred term (PT) by treatment group for the Safety Population (Table
3.1.2). 
TEAEs will be summarized by (maximum) severity, with respect to SOC and preferred terms by 
treatment group (Tables 3.2.1 – 3.2.3). 
If applicable, deaths (PT) will be included as part of AE/SAE analysis, including appropriate 
information such as date where available. 
7.5.6
Urine Drug Screening and Alcohol Breath Testing 
Urine Drug Screening / Alcohol Breath Testing conducted during the study will be provided in a 
listing (Listing 10.3). 


 
 
 
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7.5.7
Pregnancy Test 
Pregnancy testing results conducted during the study will be provided in a listing (Listing 10.4). 
7.5.8
Prior/Concomitant Medications/Treatments 
Prior and concomitant medications will be provided in listings (Listing 10.1). Information from 
both complete and partial dates will be utilized. Medications with end date of ‘Ongoing’ are 
considered concomitant. Should there not be sufficient information to determine whether a 
medication is prior or concomitant the status will be considered to be both prior and concomitant. 
Concomitant medications and treatments will be summarized for the Safety Population, as well 
as presented by treatment group (Table 1.5.1). Frequency tables will present the frequency and 
proportion of subjects having received at least one concomitant medication during the course of 
the trial. Results will also be summarized with respect to subjects’ receiving medications by 
coded preferred term. 
8.
ANALYSES PERFORMED BEFORE DATABASE CLOSURE 
Not applicable. 
9.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
This SAP outlines the statistical methods for the display, summary and analysis of data collected 
within the scope of Pearl Therapeutics Inc. Protocol PT010010, Version 2.1 dated 15 Nov 2016. 
10.
STATISTICAL SOFTWARE 
 environment will be used for all statistical analyses.  
 will be used for all PK parameter calculations. 
11.
REFERENCES 
 
  
  
 will be used for all PK parameter calculations. 
 APPENDIX 1: DATA HANDLING RULES 
This appendix is provided in a separate document. 


 
 
 
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APPENDIX 2: TABLE OF CONTENTS FOR END-OF-TEXT TABLES, LISTINGS, AND 
FIGURES 
1TABLESANDFIGURES
1.1SummaryofSubjectDisposition,Demographics,andBaselineCharacteristics
Table1.1SubjectDisposition
(AnalysisSet:AllSubjectsScreened)
Figure1.1FlowChartofSubjectDistribution
(AnalysisSet:AllSubjectsScreened)
Table1.2ReasonsforWithdrawalbyTreatment
(AnalysisSet:SafetyPopulation)
Table1.3AnalysisPopulationsbyTreatment
(AnalysisSet:AllSubjectsRandomized)
Table1.4.1SummaryofDemographicDatabyTreatment
(AnalysisSet:SafetyPopulation)
Table1.4.2SummaryofDemographicDatabyTreatment
(AnalysisSet:PKPopulation)
Table1.5.1SummaryofConcomitantMedications
(AnalysisSet:SafetyPopulation)
Table1.6StudyTreatmentExposureandCompliance
(AnalysisSet:SafetyPopulation)
1.2PharmacokineticData
Table2.1.1DescriptiveStatisticsforPlasmaConcentrationsofBudesonide(unit)byTreatment,Visit,and
Timepoint
(AnalysisSet:PKPopulation)


 
 
 
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Figure2.1.1Mean(+/ͲSE)PlasmaBudesonideConcentrationͲTimeProfileafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LinearͲLinearScale)
AnalysisSet:PKPopulation
Figure2.1.2MeanPlasmaBudesonideConcentrationͲTimeProfileafterSingleDoseAdministrationon
Day1andChronicDoseAdministrationonDay8(LogͲLinearScale)
AnalysisSet:PKPopulation
Table2.1.2DescriptiveStatisticsforPharmacokineticParametersofBudesonidebyTreatmentandVisit
AnalysisSet:PKPopulation
Table2.2.1DescriptiveStatisticsforPlasmaConcentrationsofGlycopyrronium(unit)byTreatment,Visit,
andTimepoint
(AnalysisSet:PKPopulation)
Figure2.2.1Mean(+/ͲSE)PlasmaGlycopyrroniumConcentrationͲTimeProfileafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LinearͲLinearScale)
AnalysisSet:PKPopulation
Figure2.2.2MeanPlasmaGlycopyrroniumConcentrationͲTimeProfileafterSingleDoseAdministration
onDay1andChronicDoseAdministrationonDay8(LogͲLinearScale)
AnalysisSet:PKPopulation
Table2.2.2DescriptiveStatisticsforPharmacokineticParametersofGlycopyrroniumbyTreatmentand
Visit
AnalysisSet:PKPopulation
Table2.3.1DescriptiveStatisticsforPlasmaConcentrationsofFormoterol(unit)byTreatment,Visit,and
Timepoint
(AnalysisSet:PKPopulation)
Figure2.3.1Mean(+/ͲSE)PlasmaFormoterolConcentrationͲTimeProfileafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LinearͲLinearScale)
AnalysisSet:PKPopulation


 
 
 
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Figure2.3.2MeanPlasmaFormoterolConcentrationͲTimeProfileafterSingleDoseAdministrationon
Day1andChronicDoseAdministrationonDay8(/LogͲLinearScale)
AnalysisSet:PKPopulation
Table2.3.2DescriptiveStatisticsforPharmacokineticParametersofFormoterolbyTreatmentandVisit
AnalysisSet:PKPopulation
Figure2.4.1IndividualPlasmaConcentrationͲTimeProfileofBudesonideafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LinearͲLinearScale)
(AnalysisSet:PKPopulation)
Figure2.4.2IndividualPlasmaConcentrationͲTimeProfileofBudesonideafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LogͲLinearScale)
(AnalysisSet:PKPopulation)
Figure2.5.1IndividualPlasmaConcentrationͲTimeProfileofGlycopyrroniumafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LinearͲLinearScale)
(AnalysisSet:PKPopulation)
Figure2.5.2IndividualPlasmaConcentrationͲTimeProfileofGlycopyrroniumafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LogͲLinearScale)
(AnalysisSet:PKPopulation)
Figure2.6.1IndividualPlasmaConcentrationͲTimeProfileofFormoterolafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LinearͲLinearScale)
(AnalysisSet:PKPopulation)
Figure2.6.2IndividualPlasmaConcentrationͲTimeProfileofFormoterolafterSingleDose
AdministrationonDay1andChronicDoseAdministrationonDay8(LogͲLinearScale)
(AnalysisSet:PKPopulation)
1.3SafetyData
1.3.1AdverseEvents
Table3.1.1SummaryofSubjectsWithAtLeastOneAdverseEvent


 
 
 
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(AnalysisSet:SafetyPopulation)
Table3.1.2SummaryofTreatmentEmergentAdverseEventsbySystemOrganClassandPreferredTerm
(AnalysisSet:SafetyPopulation)
Table3.2.1SummaryofTreatmentEmergentAdverseEventsbySOC,PreferredTermandHighest
Severity–BGFMDI320/14.4/9.6μg
(AnalysisSet:SafetyPopulation)
Table3.2.2SummaryofTreatmentEmergentAdverseEventsbySOC,PreferredTermandHighest
Severity–BGFMDI160/14.4/9.6μg
(AnalysisSet:SafetyPopulation)
Table3.2.3SummaryofTreatmentEmergentAdverseEventsbySOC,PreferredTermandHighest
Severity–GFFMDI14.4/9.6μg
(AnalysisSet:SafetyPopulation)
1.3.2LaboratoryData
Table3.3.1SummaryofLaboratoryResultsbyTimeofAssessment–Hematology
(AnalysisSet:SafetyPopulation)
Table3.3.2SummaryofLaboratoryResultsbyTimeofAssessment–Chemistry
(AnalysisSet:SafetyPopulation)
Table3.3.3SummaryofLaboratoryResultsbyTimeofAssessment–GlucoseandPotassium
(AnalysisSet:SafetyPopulation)
Table3.3.4SummaryofPotentiallyClinicallySignificantLaboratoryResultsPostͲbaseline–Glucoseand
Potassium
(AnalysisSet:SafetyPopulation)
Table3.3.5SummaryofLaboratoryResultsbyTimeofAssessment–Urinalysis
(AnalysisSet:SafetyPopulation)
Table3.3.6AllPotassiumRecordsforSubjectswithNewlyOccurringorWorseningPotentiallyClinically
SignificantPotassiumValuesPostͲBaseline


 
 
 
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Table3.3.7AllGlucoseRecordsforSubjectsWithNewlyOccurringorWorseningPotentiallyClinically
SignificantGlucoseValuesPostͲBaseline
Table3.3.8AllRecordsforSubjectsWithNewlyOccurringorWorseningPotentiallyClinicallySignificant
LaboratoryValuesPostͲBaselineOtherThanThoseforGlucoseandPotassium
Table3.3.9ShiftsfromBaseline[a]toDay8PreͲDoseLaboratoryData–HematologyandChemistry
(AnalysisSet:SafetyPopulation)
Table3.3.9ShiftsfromBaseline[a]toDay8PreͲDoseLaboratoryData–HematologyandChemistry
(AnalysisSet:SafetyPopulation)
1.3.3VitalSigns
Table3.4.1SummaryofVitalSignMeasurementsbyTimeofAssessment
(AnalysisSet:SafetyPopulation)
Table3.4.2PostͲBaselinePotentiallyClinicallySignificantVitalSignValues
(AnalysisSet:SafetyPopulation)
Table3.4.3ListingofPotentiallyClinicallySignificantSystolicandDiastolicBloodPressureIncreasesand
Decreases
(AnalysisSet:SafetyPopulation)
Table3.4.4ListingofPotentiallyClinicallySignificantTachycardiaandBradycardiaEvents
(AnalysisSet:AllSubjectsRandomized)
2DATALISTINGS
2.1.1SubjectDispositionandDemographics
Listing1.1ListingofSubjectDispositionandDemographicData
(AnalysisSet:AllSubjectsScreened)
Listing1.2ListingofEarlyWithdrawalsbyTrialTreatment
(AnalysisSet:AllSubjectsRandomized)
2.1.2ProtocolDeviations


 
 
 
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Listing2.1ListingofMajorProtocolDeviations
(AnalysisSet:AllSubjectsRandomized)
Listing2.2ViolationofInclusion/ExclusionCriteriaandWaivers
(AnalysisSet:AllSubjectsRandomized)
2.1.3SubjectsExcludedfromtheAnalysisPopulations
Listing3.1ListingofSubjectsExcludedFromAnalysisPopulations
(AnalysisSet:AllSubjectsRandomized)
2.1.4BaselineCharacteristics
Listing4.1ListingofSerology
(AnalysisSet:AllSubjectsRandomized)
Listing4.2ListingofMedicalandSurgicalHistory
(AnalysisSet:AllSubjectsRandomized)
2.1.5DosingandCompliance
Listing5.1ListingofStudyDrugDosing
(AnalysisSet:AllSubjectsRandomized)
Listing5.2ComplianceandExposuretoStudyTreatment
(AnalysisSet:AllSubjectsRandomized)
2.1.6AdverseEvents
Listing7.1ListingofReportedAdverseEventsbySubject,SOC,PreferredTermandOnsetDay
(AnalysisSet:AllSubjectsRandomized)
Listing7.2ListingofReportedSeriousAdverseEventsbySubject,SOC,PreferredTermandOnsetDay
(AnalysisSet:AllScreenedSubjects)
2.1.7PharmacokineticData


 
 
 
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Listing8.1PlasmaConcentrationsofBudesonide,FormoterolandGlycopyrroniumbyTreatment,Visit,
SubjectID,andTimepoint
AnalysisSet:PKPopulation
Listing8.2DerivedPharmacokineticParametersofBudesonide,Formoterol,andGlycopyrroniumby
Treatment/VisitandSubjectID
AnalysisSet:PKPopulation
2.1.8LaboratoryData
Listing9.1ListingofLaboratoryTestResultsͲHematology
(AnalysisSet:AllSubjectsRandomized)
Listing9.2ListingofLaboratoryTestResultsͲChemistry
(AnalysisSet:AllSubjectsRandomized)
Listing9.3ListingofLaboratoryTestResultsͲUrinalysis
(AnalysisSet:AllSubjectsRandomized)
2.1.9OtherClinicalObservationsandMeasurements
Listing10.1ListingofReportedPrior,Concomitant,andPostͲTreatmentMedication
(AnalysisSet:AllSubjectsRandomized)
Listing10.2ListingofVitalSigns,Weight,andHeight
(AnalysisSet:AllSubjectsRandomized)
Listing10.3ListingofUrineDrugScreening/AlcoholBreathTesting
(AnalysisSet:AllSubjectsRandomized)
Listing10.4ListingofPregnancyTesting
(AnalysisSet:AllSubjectsRandomized)
Listing10.5ListingofComments
(AnalysisSet:AllSubjectsRandomized)


 
 
 
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APPENDIX 3: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND 
CENTRAL LABORATORY REFERENCE RANGES FOR USE IN FLAGGING 
ABNORMAL VALUES 
This appendix is provided in a separate document. 
 


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Date:   24 August 2017 
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APPENDIX 1: DATA HANDLING RULES
Programming of the tables, listings and figures will be performed using 
 or a 
more recent version. The following table presents the algorithms to be used in
 to calculate 
the derived variables, including rules for handling other missing data or partial dates, or 
irregular/unexpected data issues.
Category 
Description
Data Handling Rule 
1. Age (years)
Age (years)
Age = integer part of ( [Informed Consent date 
– Birth date + 1]/365.25)
2. Smoking 
History
Former smoker
Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to 
Screening (Visit 1).
Months Since a Former 
Smoker Quit 
(Date of Screening Visit 1 – Date Former 
Smoker Quit)/30.4375. 
3. Medical 
History 
Medical History Begin 
Date of Condition 
Begin date of condition will be imputed for all 
subjects as the 1st of the month for the purpose 
of computing the onset day. 
4. Surgical 
History 
Surgical History Date 
of Surgery 
Date of surgery will be imputed for all subjects 
as the 1st of the month for the purpose of 
computing the onset day.
5. First and Last 
Treatment 
Dates
date/time of first and 
last dose of a study 
treatment
The date and time (24 hr. clock) of the first 
dose of study treatment will be taken from the 
Dosing eCRF. The date of the last dose of 
study treatment will be the last date of dosing 
from the Dosing eCRF for the treatment.
6. Last Visit 
Date
Date of Last Visit
Date of last visit according to the Visit eCRF.
7. Last Study 
Participation 
Date (STDM 
variable, 
typically 
named 
RFPENDTC)
Last Study 
Participation Date 
(STDM variable, 
RFPENDTC), where 
SDTM denotes Study 
Data Tabulation Model 
Last study participation date is defined as last 
known date of contact which would be the 
later of the following dates: last visit date, date 
of the last dose, date of last contact if lost-to-
follow-up, date of telephone follow-up, or 
death date.
8. Study Day 
Definitions
Study Day for 
assessment/event which 
occurs on or after the 
start of study treatment
Study Day = Date of assessment/event – date 
of the first dose of study treatment + 1. 
Study Day for 
assessments/events on 
Study Day for assessments/events on days 
prior to the first dose of study treatment in the 


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 2 of 8)
Category
Description
Data Handling Rule
days prior to the first 
dose of study treatment 
in the study
study
Study Day Post-
Treatment of 
Assessment or event 
which occurs after 
study treatment
Study Day = ‘P’ concatenated with the number 
of days post-treatment that the assessment or 
event occurred which is defined as Date of 
assessment/event – date of last dose of study 
treatment.
Study Day of 
Randomization
Study Day of Randomization = date of 
randomization – date of the first dose of study 
treatment in the study + 1. Study Day is 1 if 
baseline day is on the day of randomization.
First Dose Day
First Dose Day in the study is defined as the 
study day of the first dose of study treatment in 
the study (Study Day 1).
Last Dose Day
Last Dose Day in the study is defined as the 
study day of the last dose of study treatment in 
the study (defined as the last date of dosing 
from the Dosing CRF pages).
Last Study Day
For subjects who did not receive study 
treatment in the study (e.g., Non-
Randomized subjects), Last Study Day is 
defined as (the later of the last visit date and 
the date of last contact for subjects 
lost-to-follow-up from the Study 
Completion/Early Discontinuation CRF) –
Date of Screening Visit + 1.
For subjects who received study treatment 
in the study, Last Study Day is defined as (the 
later of the last visit date and the date of last 
contact for subjects lost-to-follow-up from the 
Study Completion/Early Discontinuation CRF) 
– first dose date in the study + 1.
Days Since Last Dose 
for event (e.g., Death)
Days Since Last Dose is defined as date of 
event – date of last dose of study treatment.
The duration of any 
event 
The duration of any event is defined as (stop 
date – start date + 1).
9. Duration of 
event 
The duration of any 
event 
The duration of any event is defined as (stop 
date – start date + 1).


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 3 of 8)
Category
Description
Data Handling Rule
10. Multiple 
assessments 
for the same 
visit
Vital Signand 
Laboratory assessments
x
All data will be listed in data listings.
x
The last of multiple valid assessments 
within a post-baseline study time window 
will be used for summaries and statistical 
testing.
x
If there are multiple laboratory values for 
the same parameter at post-baseline pre-
dose of a visit, the last value will be chosen 
for analysis.
The mean of all available pre-dose vital sign 
measurements for a vital sign parameter taken 
prior to the start of dosing for the Treatment 
Period will be used for calculation of baseline 
for a parameter.
11. Special Lab 
Value 
Handling (not 
including PK 
values)
Lab values with a 
prefix such as: ‘>’, ‘<’, 
‘+’ and ‘Less than’ Etc.
x
‘>’: use the available original value +0.001 
in the analyses.
x
‘<’: use the available original value –0.001
in the analyses.
x
‘+’: use the available original value 
without the prefix in the analyses.
x
‘>=’: use the available original value in the 
analyses.
x
‘<=’: use the available original value in the 
analyses.
12. Prior. 
concomitant, 
and post-
treatment 
medication / 
treatment
Prior, concomitant, and 
post-treatment 
medication/treatment
1. Prior medication/treatment: is any 
medication/treatment taken prior to the first 
dose of study medication in the study (or 
the date of the randomization visit, Visit 3,
if the date of the start of study medication 
is missing), even if this 
medication/treatment continued into the 
study medication treatment period. A 
medication/treatment will be considered 
prior if the start date of the 
medication/treatment is missing or the 
medication/treatment start date is before 


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 4 of 8)
Category
Description
Data Handling Rule
first dose date of study medication in the 
study (or the date of the randomization 
visit, Visit 3, if the date of the start of study 
medication is missing).
2. A medication/treatment will be identified 
as a concomitant medication/treatment if 
any of the following are true: 
o
The start date is on or after the date 
of the start of study treatment (or 
the date of randomization, Visit 3,
if missing), but prior to the date of 
completion of study medication (for 
subjects not having discontinued 
treatment early) or the date of 
discontinuation of study medication
(for subjects who discontinued 
treatment early).
o
The end date is prior to the date of 
completion of study medication (for 
subjects not having discontinued 
treatment early) or the date of the 
discontinuation of study medication 
(for subjects who discontinued 
treatment early), but the end date is 
on or after the start of study 
medication in the study (or the date 
of the randomization visit, Visit 3,
if missing). The 
medication/treatment is checked as 
‘Ongoing’, and the start date of the 
medication/treatment is prior to the 
date of completion of study 
medication (for subjects not having 
discontinued treatment early) or the 
date of the discontinuation of study 
medication (for subjects who 
discontinued treatment early). 
3. A medication with an onset date on or after 
the date of completion of study medication 
(for subjects not having discontinued 


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 5 of 8)
Category
Description
Data Handling Rule
treatment early) or on or after the date of 
discontinuation of study medication (for 
subjects who discontinued treatment early)
will not be considered concomitant, but 
will be considered a Post-Treatment 
medication.
4. Any medication/treatment which cannot be 
identified as Prior, Concomitant, or Post-
Treatment will be considered as being in 
each of the possible categories depending 
on available information
13. Adverse 
event
Missing severity
For the AE summary by severity, an AE with 
missing severity will be deemed as Severe. 
Imputed values will not be listed in data 
listings.
Missing relationship to 
study drug
For AE summary by relationship, an AE with a 
missing relationship to study drug will be 
deemed as Definitely related. Imputed values 
will not be listed in data listings. 
Treatment-emergent 
adverse event 
An adverse event is considered treatment-
emergent if an event occurs (or if there was a 
worsening [intensity and/or severity changed 
to worsened grades]) after the first dose of 
randomized study medication and on or before 
the date of discontinuation from or completion 
of randomized study medication. An adverse 
event that begins on the same date as the first 
dose of randomized study medication is 
treatment-emergent if the AE begins after the 
time of first dose or if the time of AE onset is 
unknown. A non-serious adverse event will not 
be considered to be treatment-emergent if its 
date of onset is after the date of completion of 
study medication (for subjects not having 
discontinued treatment early) or after the date 
of discontinuation from study medication (for 
subjects who discontinued treatment early). An
SAE will not be considered to be treatment-
emergent if its date of onset is after the date of 
completion of study medication (for subjects 


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 6 of 8)
Category
Description
Data Handling Rule
not having discontinued treatment early) or 
after the date of discontinuation from study 
medication (for subjects who discontinued 
treatment early).
If the AE start date is partial/missing, then
x
If AE start date is completely missing, then 
the AE is considered as treatment-
emergent.
x
If both AE start month and day are missing 
and AE start year is the same or after the 
first dose year, then the AE is considered 
as treatment-emergent.
x
If AE start day is missing and AE start year 
and month are the same or after the first 
dose year and month, then the AE is 
considered as treatment-emergent.
Missing/incomplete (partial) AE start and end 
dates will not be imputed for data listings.
14. Treatment 
Duration
Treatment |Duration
Treatment duration is defined as Date of last 
dose of a study treatment - Date of first dose of 
a study treatment +1. 
15. Total Years 
of Exposure
Total years of exposure 
to study treatment
Total exposure (years) for a treatment as a 
whole is defined as the sum of all days of 
exposure for a treatment /365.25.
16. Exposure 
(days)
Exposure (days)
Exposure is defined as (Date of the last dose of 
the study treatment – Date of first dose of the 
study treatment + 1). 
17. Total 
Expected 
Puffs
Total expected number 
of puffs taken of a 
study treatment
The expected number of puffs for a test day 
which is the first date of treatment or the last 
date of treatment will be 2, the expected 
number of puffs for the last date of treatment 
which is not a test day will be 4 when a PM 
dose has been taken and then 2 otherwise, and 
the expected number of puffs on dates after the 
first date of treatment and prior to the last date 
of treatment will be 4. Thus, for test 
treatments, the total expected number of puffs 
will be 4 x (treatment end date – treatment start 


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 7 of 8)
Category
Description
Data Handling Rule
date-1) + expected number of puffs on last day 
of treatment + expected number of puffs on 
first day of treatment.
18. Treatment 
Compliance 
(%)
Treatment Compliance 
(%) for a treatment 
Percent compliance is defined as (total number 
of puffs of study treatment taken on a study 
day/total expected puffs taken on a study day) 
averaged across all days of a subject’s dosing 
between start of study treatment and last day 
on study treatment) x 100. For MDI test 
treatments, the expected number of puffs for a 
test day which was the first or the last date of 
treatment is 2, the expected number of puffs 
for the last date of treatment which was not a 
test day is 4 when a PM dose was taken and 
then 2 otherwise; the expected number of 
doses on dates after the first date of treatment 
and prior to the last date of treatment is 4. 
19. Hard coding
Hard coding for data 
analysis
Hard Coding is not allowed during data 
analysis unless if agreed in writing by the 
Sponsor.
20. PK analysis 
Considerations to be 
made in the calculation 
of AUC and Ȝz and for 
descriptive statistics
The following considerations will be made in 
WKHFDOFXODWLRQRI$8&DQGȜz and descriptive 
statistics:
x
AUC will be calculated by the 
linear-log trapezoidal method
x
The final selection of samples for 
calculation of Oz will be based on 
visual inspection of individual log-
concentration-time profiles.
x
The time range of samples used to 
estimate Oz should preferably exceed 
the derived terminal half-life t½ (= ln 
2/Oz). This consideration may affect the 
interpretability of the estimated Oz and 
t½.
x
All the samples used to calculate Oz
should ideally fall in the log-linear 
elimination phase.  PK modeling may 


Statistical Analysis Plan
Protocol Nos.:  PT010010
Date:   24 August 2017
                                        (Page 8 of 8)
Category
Description
Data Handling Rule
be used as a complementary tool to 
determine the start of the elimination 
phase, i.e., where the decline in plasma 
concentration is mainly due to 
elimination.
x
At least three samples above LLQ 
obtained during the log-linear 
elimination phase will be included in 
WKHFDOFXODWLRQRIWKHȜz . If there are 
not at least three samples above the 
LLQ in the log linear elimination 
SKDVHȜz will not be estimated.
x
All values below LLQ will be ignored 
(set to missing) in the non-
compartmental analysis for computing 
pharmacokinetic parameters except that 
Day 1 pre-dose concentrations below 
the LLQ will be set to 0.  For 
descriptive statistics for concentrations
and for the concentration figures, all 
values below LLQ will be assigned a 
value of ½ LLQ except for Day 1 pre-
dose which will be assigned a value of 
0 (no geometric mean will be 
calculated for Day 1 pre-dose).


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APPENDIX 3
CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL
LABORATORY REFERENCES RANGES FOR USE IN FLAGGING ABNORMAL VALUES
Trial Sponsor: 
Pearl Therapeutics, Inc.
Protocol Number:
PT010010-01
Investigational Drug:
Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol 
(PT010, BGF metered dose inhaler [MDI])
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
(PT003, GFF MDI)
Indication:
COPD
Drug Number:
PT010
Dosage Form/Strength:
x
BGF MDI 320/14.4/9.6 μg ex-actuator BID
x
BGF MDI 160/14.4/9.6 μg ex-actuator BID
x
GFF MDI 14.4/9.6 μg ex-actuator BID
Protocol Title: A Phase I, Randomized, Double-Blind, Parallel-Group, Study to Assess the Pharmacokinetics and Safety of Two Doses of 
PT010 and a Single Dose of PT003 in Healthy Chinese Adult Subjects Following A Single Administration and After Chronic 
Administration for 7 Days


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CTCAE LABORATORY TEST CRITERIA
Investigations
Grade
Adverse Event
1
2
3
4
Alanine 
aminotransferase 
increased
>ULN – 3.0 x ULN
>3.0 – 5.0 x ULN
>5.0 – 20.0 x ULN
>20.0 x ULN
Alkaline phosphatase 
increased
>ULN – 2.5 x ULN
>2.5 – 5.0 x ULN
>5.0 – 20.0 x ULN
>20.0 x ULN
Aspartate 
aminotransferase 
increased
>ULN – 3.0 x ULN
>3.0 – 5.0 x ULN
>5.0 – 20.0 x ULN
>20.0 x ULN
Blood bilirubin 
increased
>ULN – 1.5 x ULN
>1.5 – 3.0 x ULN
>3.0 – 10.0 x ULN
>10.0 x ULN
Cholesterol high
>ULN – 300 mg/dL; 
>ULN –7.75 mmol/L
>300 – 400 mg/dL; >7.75 
–10.34 mmol/L
>400 – 500 mg/dL; 
>10.34 –12.92 mmol/L
>500 mg/dL; >12.92 
mmol/L
Creatinine increased
>1 – 1.5 x baseline; 
>ULN -1.5 x ULN
>1.5 – 3.0 x baseline; 
>1.5 -3.0 x ULN
>3.0 baseline; >3.0 – 6.0 
xULN
>6.0 x ULN
Chloride
GGT increased
>ULN – 2.5 x ULN
>2.5 – 5.0 x ULN
>5.0 – 20.0 x ULN
>20.0 x ULN
Hematocrit
n/a
n/a
n/a
n/a


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Investigations
Grade
Adverse Event
1
2
3
4
Hemoglobin increased
Increase in >0 – 2
gm/dL above ULN or 
above baseline if 
baseline is above 
ULN 
Increase in >2 – 4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN
Increase in >4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN
n/a
Anemia (hemoglobin 
decreased)
Hemoglobin (Hgb) 
<LLN– 10g/dL; 
<LLN – 6.2 mmol/L; 
<LLN – 100 g/L
Hgb <10.0 – 8.0 g/dL; 
<6.2 – 4.9 mmol/L; 
<100 – 80g/L
Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L; 
transfusion indicated
Life-threatening 
consequences; urgent 
intervention indicated
Serum Iron
n/a
n/a
n/a
n/a
Ferritin
n/a
n/a
n/a
n/a
Red blood cells 
(erythrocytes)
n/a
n/a
n/a
n/a
Leukocytosis (White 
blood cell increased) 
(a)
n/a
n/a
>100,000/mm3
Clinical 
manifestations of 
leucostasis; urgent 
intervention indicated


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Investigations
Grade
Adverse Event
1
2
3
4
White blood cell 
decreased
<LLN – 3000/mm3;
<LLN – 3.0 x 109/L
<3000 – 2000/mm3;
<3.0 – 2.0 x 109 /L
<2000 – 1000/mm3;
<2.0 – 1.0 x 109 /L
<1000/mm3;
<1.0 x 109 /L
White blood cell 
differential
n/a
n/a
n/a
n/a
Platelet count 
decreased
<LLN –
75,000/mm3; 
<LLN – 75.0 x 109/L
<75,000–- 50,000/mm3; 
<75.0 – 50.0 x 109/L
<50,000 – 25,000/mm3; 
<50.0 – 25.0 x 109/L
<25,000/mm3;
<25.0 x 109/L
Mean corpuscular 
volume
n/a
n/a
n/a
n/a
Mean cell hemoglobin 
(MCH)
n/a
n/a
n/a
n/a
MCH concentration
n/a
n/a
n/a
n/a


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Metabolism and Nutrition Disorders
Grade
Adverse Event
1
2
3
4
Acidosis
pH <normal, but 
>=7.3
-
pH <7.3
Life-threatening 
consequences
Alkalosis
pH >normal, but 
<=7.5
-
pH >7.5
Life-threatening 
consequences
Urea
n/a
n/a
n/a
n/a
Blood Urea Nitrogen (BUN)
n/a
n/a
n/a
n/a
Proteinuria
1+ proteinuria; 
urinary protein 
<1.0g/24 hrs
Adults: 2+ 
proteinuria; urinary 
protein 1.0 – 3.4 
g/24 hrs.
Pediatric: urin P/C 
(protein/creatinine) 
ratio 0.5 - 1.9
Adults: urinary protein 
>=3.5 g/24 hrs; Pediatric: 
urine P/C >1.9
n/a
Hypercalcemia
Corrected serum 
calcium of >ULN -
11.5 mg/dL; >ULN -
2.9 mmol/L; Ionized 
calcium >ULN - 1.5
mmol/L
Corrected serum 
calcium of >11.5 -
12.5 mg/dL; >2.9 -
3.1 mmol/L; Ionized 
calcium >1.5 - 1.6
mmol/L; 
symptomatic
Corrected serum calcium 
of >12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L; 
Ionized calcium >1.6 -
1.8 mmol/L; 
hospitalization indicated
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 
mmol/L; Ionized 
calcium >1.8 
mmol/L; life-
threatening 
consequences


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Metabolism and Nutrition Disorders
Grade
Adverse Event
1
2
3
4
Hyperglycemia
Fasting glucose 
value >ULN - 160
mg/dL; Fasting 
glucose value >ULN 
- 8.9 mmol/L
Fasting glucose 
value >160 - 250
mg/dL; Fasting 
glucose value >8.9 -
13.9 mmol/L
>250 - 500 mg/dL; >13.9 
- 27.8 mmol/L; 
hospitalization indicated
>500 mg/dL; >27.8 
mmol/L; life-
threatening 
consequences
Hyperkalemia
(Potassium Increased)
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L; 
hospitalization indicated
>7.0 mmol/L; life-
threatening
consequences
Hypermagnesemia
(Magnesium Increased)
>ULN - 3.0 mg/dL; 
>ULN - 1.23
mmol/L
n/a
>3.0 - 8.0 mg/dL; >1.23 -
3.30 mmol/L
>8.0 mg/dL; >3.30 
mmol/L; life-
threatening 
consequences
Hypernatremia (Sodium 
Increased)
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L; 
hospitalization indicated
>160 mmol/L; life-
threatening 
consequences
Hypertriglyceridemia
150 mg/dL - 300
mg/dL; 1.71 mmol/L 
- 3.42 mmol/L
>300 mg/dL - 500
mg/dL;  >3.42 
mmol/L - 5.7
mmol/L
>500 mg/dL - 1000
mg/dL;  >5.7 mmol/L -
11.4 mmol/L
>1000 mg/dL; 
>11.4 mmol/L;  life-
threatening 
consequences
Hypoalbuminemia (Albumin 
Decreased)
<LLN - 3 g/dL; 
<LLN - 30 g/L
<3 - 2 g/dL; <30 -
20 g/L
<2 g/dL; <20 g/L
Life-threatening 
consequences; 
urgent intervention 
indicated


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Metabolism and Nutrition Disorders
Grade
Adverse Event
1
2
3
4
Hypocalcemia (Calcium 
Decreased)
Corrected serum 
calcium of <LLN -
8.0 mg/dL; <LLN -
2.0 mmol/L; Ionized 
calcium<LLN - 1.0
mmol/L
Corrected serum 
calcium of  <8.0 -
7.0 mg/dL; <2.0 -
1.75 mmol/L; 
Ionized calcium 
<1.0- 0.9 mmol/L; 
symptomatic
Corrected serum calcium 
of  <7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L; 
Ionized calcium <0.9- 0.8
mmol/L; 
hospitalizationindicated
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L;Ionized 
calcium <0.8 
mmol/L;life-
threatening 
consequences
Hypoglycemia (Glucose 
Decreased)
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L
<40 - 30 mg/dL; <2.2 -
1.7 mmol/L
<30 mg/dL; <1.7 
mmol/L; life-
threatening 
consequences; 
seizures
Hypokalemia (Potassium 
Decreased)
<LLN - 3.0 mmol/L
<LLN - 3.0
mmol/L; 
symptomatic; 
intervention 
indicated
<3.0 - 2.5 mmol/L; 
hospitalization indicated
<2.5 mmol/L; life-
threatening 
consequences
Hypomagnesemia 
(Magnesium Decreased)
<LLN - 1.2 mg/dL; 
<LLN - 0.5 mmol/L
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L
<0.9 - 0.7 mg/dL; <0.4 -
0.3 mmol/L
<0.7 mg/dL; <0.3 
mmol/L; life-
threatening 
consequences
Hyponatremia (Sodium 
Decreased)
<LLN - 130 mmol/L
n/a
<130 - 120 mmol/L
<120 mmol/L; life-
threatening 
consequences


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Metabolism and Nutrition Disorders
Grade
Adverse Event
1
2
3
4
Hypophosphatemia 
(Phosphate Decreased)
<LLN - 2.5 mg/dL; 
<LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 -
0.3
mmol/L
<1.0 mg/dL; <0.3 
mmol/L; life-
threatening 
consequences
Renal and Urinary 
Disorders
Grade
Adverse Event
1
2
3
4
Chronic kidney disease
eGFR (estimated 
Glomerular
Filtration Rate) or CrCl 
(creatinine clearance) 
<LLN -60 ml/min/1.73 
m2 or proteinuria 2+ 
present; urine 
protein/creatinine >0.5
eGFR or CrCl 59 -
30 ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 
ml/min/1.73 m2;
dialysis or renal 
transplant indicated


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Acute kidney injury
Creatinine level 
increase of >0.3 
mg/dL; creatinine 1.5 -
2.0 x above baseline
Creatinine 2 – 3 x 
above baseline
Creatinine >3 x baseline 
or >4.0 mg/dL; 
hospitalization indicated
Life-threatening 
consequences; organ 
failure; urgent 
operative intervention 
indicated
(a) Grade 1 and Grade 2 not categorized in CTCAE4; Grade 1 and 2 based on reference laboratory alert criteria of 40,000 /mm3
(LabCorp)


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Protocol Reference Range Definitions
For reference range definitions, refer to the document pt010010 lab range site 001 20170405.pdf