Conditions: COPD
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: no

Brief summary:
Study to Evaluate the Effects of PT003 and Placebo MDI on Specific Image Based Airway Volumes and Resistance With Moderate to Severe COPD.

Detailed description:
Enrolled patients with COPD who were randomized to receive either PT003 MDI or Placebo MDI first and then crossed over to receive the opposite intervention. The study consisted of 2 treatment periods of 14 days separated by a washout period of 5-21 days.

Arms:
arm 1: Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI) arm 2: Placebo Metered Dose Inhaler (MDI)

Interventions: intervention 1: GFF MDI (PT003) 14.4/9.6μg intervention 2: Placebo MDI
Intervention descriptions: intervention 1: Glycopyrronium and Formoterol Fumarate intervention 2: Comparator: Placebo MDI which contains no active ingredients

Protocol document:
Prot_001.pdf: 
 
 
Revised Clinical Study Protocol 
Study Code 
PT003018 / FLUI-2015-139 
NCT #  
NCT02643082 
Date submitted: 
   02 MAY 2016 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Two Treatment, Two Period, Chronic 
Dosing (2 Weeks), Cross-Over, Single-Center Study to Evaluate the Effects 
of PT003 and Placebo MDI on Specific Image Based Airway Volumes and 
Resistance in Subjects With Moderate to Severe COPD 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) are included in this revised protocol: 
  
Amendment No.        
Date of Amendment           
Version 1 
15SEP2015 
Version 2,  Amendment 1 
16FEB2016 
Version 3,  Amendment 2  
02MAY2016 
 
 
 


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Title:
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Study Number:
37)/8,
Study Phase:
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Product Name:
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EudraCT 
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Investigators: 
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Sponsor:
Sponsor Contact: 
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Version Number
Date
Original 
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Confidentiality Statement
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Note: Confirm if patient meets stability 
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SYNOPSIS
Sponsor:
3HDUO7KHUDSHXWLFV,QF³3HDUO´
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Names of Finished Products:
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Name of Active Ingredients:
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Study Title:
$5DQGRPL]HG'RXEOH%OLQG7ZR7UHDWPHQW7ZR3HULRG&KURQLF'RVLQJ:HHNV&URVV
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Study Number:  37)/8,
Study Phase:,,,E
Study Objectives:
Primary Objectives:
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Secondary Objectives:
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Safety Objective:
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Table 5-4:  Prohibited Medications
Prohibited medications
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Table 6-5.  
Study Product Packaging Descriptions
Product name and 
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Study medications
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Table 6-6. Description of Boxes
Drug supplies
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Table 7-7:  
MMRC Dyspnea Scale
Grade
Description of Breathlessness
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Table 7-8:  
Lab Parameters
Hematology 
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Liver Enzyme and Other Function Tests
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Figure A1-1. Indicator at Top of Canister
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How to prime GFF MDI and Placebo MDI
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How to take a dose from GFF MDI and Placebo MDI 
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How to clean GFF MDI and Placebo MDI
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Figure A1-2. Wash Actuator through Top of Actuator 
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Figure A1-3. Wash Actuator through Mouthpiece
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If the actuator becomes blocked
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How to read the inhaler dose indicator
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Figure A1-4. Metered Dose Inhaler Parts
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Instructions for Use of Atrovent HFA Inhalation Aerosol Device 
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Instructions for Use of Ventolin HFA Inhaler
Instructions for Use
For Oral Inhalation Only 
Your VENTOLIN HFA inhaler
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Do not XVHWKHDFWXDWRUZLWKDFDQLVWHURIPHGLFLQHIURPDQ\RWKHULQKDOHU
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Do not XVHD9(172/,1+)$FDQLVWHUZLWKDQDFWXDWRUIURPDQ\RWKHULQKDOHU
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Before using your VENTOLIN HFA inhaler
Before you use VENTOLIN HFA for the first time, you must prime the inhaler so 
that you will get the right amount of medicine when you use it.
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VSUD\WKHLQKDOHUWLPHLQWRWKHDLUDZD\IURP\RXUIDFHSee )LJXUH&Avoid spraying 
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How to use your VENTOLIN HFA inhaler 
Follow these steps every time you use VENTOLIN HFA.
Step 1. 0DNHVXUHWKHFDQLVWHUILWVILUPO\LQWKHDFWXDWRU7KHFRXQWHUVKRXOGVKRZWKURXJK
WKHZLQGRZLQWKHDFWXDWRU
Shake the inhaler well EHIRUHHDFKVSUD\
7DNHWKHFDSRIIWKHPRXWKSLHFHRIWKHDFWXDWRU/RRNLQVLGHWKHPRXWKSLHFHIRUIRUHLJQ
REMHFWVDQGWDNHRXWDQ\\RXVHH
Step 2. +ROGWKHLQKDOHUZLWKWKHPRXWKSLHFHGRZQSee )LJXUH(
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Step 3. %UHDWKHRXWWKURXJK\RXUPRXWKDQGSXVKDVPXFKDLUIURP\RXUOXQJVDV\RXFDQ
3XWWKHPRXWKSLHFHLQ\RXUPRXWKDQGFORVH\RXUOLSVDURXQGLWSee )LJXUH)
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Step 5. $IWHUWKHVSUD\FRPHVRXWWDNH\RXUILQJHURIIWKHFDQLVWHU$IWHU\RXKDYHEUHDWKHG
LQDOOWKHZD\WDNHWKHLQKDOHURXWRI\RXUPRXWKDQGFORVH\RXUPRXWK
Step 6Hold your breath for about 10 seconds, RUIRUDVORQJDVLVFRPIRUWDEOHBreathe 
out slowly as long as you can. 
If your healthcare provider has told you to use more spraysZDLWPLQXWHDQGVKDNHWKH
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Step 7. 3XWWKHFDSEDFNRQWKHPRXWKSLHFHDIWHUHYHU\WLPH\RXXVHWKHLQKDOHU0DNHVXUHLW
VQDSVILUPO\LQWRSODFH
Cleaning your VENTOLIN HFA inhaler
&OHDQ\RXULQKDOHUDWOHDVWWLPHHDFKZHHN<RXPD\QRWVHHDQ\PHGLFLQHEXLOGXSRQWKH
LQKDOHUEXWLWLVLPSRUWDQWWRNHHSLWFOHDQVRPHGLFLQHEXLOGXSZLOOQRWEORFNWKHVSUD\See 
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Step 8. 7DNHWKHFDQLVWHURXWRIWKHDFWXDWRUDQGWDNHWKHFDSRIIWKHPRXWKSLHFH7KHVWUDS
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SAP_000.pdf: 
 
Statistical Analysis Plan 
Study Code 
PT003018 / FLUI-2015-139 
Edition Number 
1 
Date 
27 February 2017 
 
A Randomized, Double-Blind, Two Treatment, Two Period, Chronic 
Dosing (2 Weeks), Cross-Over, Single-Center Study to Evaluate the Effects 
of PT003 and Placebo MDI on Specific Image Based Airway Volumes and 
Resistance in Subjects With Moderate to Severe COPD. 
 
 
 
 
 
 
 






Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
4 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
SIGNATURE OF STUDY STATISTICIAN .......................................................... 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................... 3 
TABLE OF CONTENTS ......................................................................................... 4 
LIST OF ABBREVIATIONS .................................................................................. 6 
AMENDMENT HISTORY ..................................................................................... 8 
1. 
STUDY DETAILS ................................................................................................... 9 
1.1 
Study objectives ....................................................................................................... 9 
1.1.1 
Primary objectives ................................................................................................... 9 
1.1.2 
Secondary objectives ............................................................................................... 9 
1.1.3 
Safety Objective ....................................................................................................... 9 
1.2 
Study design ............................................................................................................. 9 
1.3 
Number of subjects ................................................................................................ 11 
2. 
ANALYSIS SETS ................................................................................................. 11 
2.1 
Definition of analysis sets ...................................................................................... 11 
2.1.1 
Intent-To-Treat (ITT) population ........................................................................... 11 
2.1.2 
Modified Intent-To-Treat (mITT) population ........................................................ 11 
2.1.3 
Safety population ................................................................................................... 11 
2.1.4 
Population for analyses .......................................................................................... 11 
2.2 
Violations and deviations ....................................................................................... 12 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 13 
3.1 
Efficacy Endpoints ................................................................................................. 13 
3.1.1 
Definition of baselines ........................................................................................... 13 
3.1.2 
Treatment periods and visit windows .................................................................... 13 
3.1.3 
Primary Efficacy Endpoints ................................................................................... 13 
3.1.4 
Secondary Efficacy Endpoints ............................................................................... 15 
3.1.4.1 
FRI Parameters ....................................................................................................... 15 
3.1.4.2 
Spirometry Parameters ........................................................................................... 15 
3.1.4.3 
Body Plethysmography Parameters ....................................................................... 16 
3.1.5 
Other Efficacy Endpoints ....................................................................................... 16 
3.1.5.1 
FRI Parameters ....................................................................................................... 16 
3.1.5.2 
Spirometry Parameters ........................................................................................... 18 
3.1.5.3 
Body Plethysmography Parameters ....................................................................... 18 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
5 
3.2 
Safety Endpoints .................................................................................................... 18 
3.3 
Handling of missing data ....................................................................................... 19 
4. 
ANALYSIS METHODS ....................................................................................... 19 
4.1 
General principles .................................................................................................. 19 
4.1.1 
Hypothesis testing .................................................................................................. 19 
4.1.2 
Control of Type I error ........................................................................................... 20 
4.1.3 
Software ................................................................................................................. 20 
4.2 
Analysis methods ................................................................................................... 20 
4.2.1 
Disposition, demographics and baseline characteristics ........................................ 20 
4.2.2 
Concomitant medications ....................................................................................... 21 
4.2.3 
Exposure and compliance ...................................................................................... 21 
4.2.4 
Analysis of FRI data .............................................................................................. 21 
4.2.5 
Spirometry / Body Plethysmography data ............................................................. 22 
4.2.6 
Assumptions Checks and Removal of Outliers in Sensitivity Analyses ................ 22 
4.2.7 
Exploratory analyses .............................................................................................. 23 
4.2.8 
Safety data .............................................................................................................. 23 
5. 
INTERIM ANALYSES (NOT APPLICABLE) .................................................... 24 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 24 
7. 
REFERENCES ...................................................................................................... 24 
8. 
APPENDIX ............................................................................................................ 25 
 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
6 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
ATC 
ATS 
BID 
CFD 
COPD 
CSR 
CT 
ECG 
eCRF 
ERS 
FEF25-75 
FEV1 
FRC 
FRI 
FVC 
GFF 
GOLD 
HFA 
IC 
IPD 
iRaw 
ITT 
iVaw 
iVlobe 
LUL 
LL 
LLL 
MDI 
mITT 
PFT 
Raw 
RLL 
RML 
RUL 
Adverse Event 
Anatomic Therapeutic Class 
American Thoracic Society 
Bis In Die, twice daily 
Computational Fluid Dynamics 
Chronic Obstructive Pulmonary Disease 
Clinical Study Report 
Computed Tomography 
Electrocardiograms 
electronic Case Report Form 
European Respiratory Society 
Forced Expiratory Flow between 25% to 75% of FVC 
Forced Expiratory Volume In 1 Second 
Functional Residual Capacity 
Functional Respiratory Imaging 
Forced Vital Capacity 
Glycopyrronium and Formoterol Fumarate 
Global initiative for chronic Obstructive Lung Disease 
Hydrofluoroalkane 
Inspiratory Capacity 
Important Protocol Deviation 
Image based Airway Resistance 
Intent-To-Treat 
Image based Airway Volume 
Image based Lobar Volume 
Left Upper Lobe 
Lower Lobe 
Left Lower Lobe 
Metered Dose Inhaler 
Modified Intent-To-Treat 
Pulmonary Function Test 
Airway Resistance 
Right Lower Lobe 
Right Middle Lobe 
Right Upper Lobe 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
7 
Abbreviation or 
special term 
Explanation 
RV 
sGaw 
siRaw 
siVaw 
sRaw 
TEAE 
TLC 
TP 
UA 
UL 
WHO-DD 
Residual Volume 
Specific Airway Conductance 
Specific Image based Airway Resistance 
Specific Image based Airway Volume 
Specific Airway Resistance 
Treatment Emergent Adverse Event 
Total Lung Capacity 
Treatment Period 
Upper Airway 
Upper Lobe 
World Health Organization Drug Dictionary 
 
 
 
 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
8 
AMENDMENT HISTORY 
Date 
Brief description of change 
 
N/A 
 
 
 
 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
9 
1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objectives 
x To assess the effect of treatment with Glycopyrronium and Formoterol Fumarate  
Metered Dose Inhaler (GFF MDI), twice daily (BID) compared with Placebo MDI on 
specific image-based airway volumes and resistance in subjects with moderate to 
severe chronic obstructive pulmonary disease (COPD) following chronic dosing after 
approximately two weeks treatment. 
1.1.2 
Secondary objectives 
x To compare the effects of GFF MDI on various Functional Respiratory Imaging (FRI) 
parameters. 
x To compare the effects of GFF MDI and Placebo MDI on pulmonary function test 
(PFT) parameters. 
1.1.3 
Safety Objective 
To assess the safety of GFF MDI in subjects with moderate to severe COPD based on adverse 
events (AEs), and any clinically relevant findings from vital sign measurements, 
electrocardiograms (ECGs), physical examination findings and clinical laboratory evaluations. 
1.2 
Study design 
This is a single center, double-blind, two treatment, two period, full cross-over, chronic dosing 
(2 weeks) study to assess the effects of GFF MDI (14.4/9.6 μg BID) compared with Placebo 
MDI BID on specific image-based airway volumes and resistance in subjects with moderate to 
severe COPD.  
Approximately 20 patients will be randomised to one of two sequences (GFF MDI followed 
by Placebo MDI or Placebo MDI followed by GFF MDI) 
The sensitivity of the study increases with the crossover design where each subject acts as 
his/her own control. In this study the calculation of airway dimension parameters between the 
active compound and the placebo will be compared within the same subject after the 
administration of both the active compound as well as the placebo.  
This single-center study will be conducted at one site in Belgium, with the site contributing 
approximately 20 randomized subjects with moderate to severe COPD.  
Study Duration:  
Each subject will receive in total study treatment for approximately 4 weeks in two separate 
treatment periods of two weeks. Between the Treatment Periods there will be a washout 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
10 
period of 5-21 days. The entire study is scheduled to take approximately 13 weeks for each 
individual subject. 
Study design chart 
 
Computed Tomography (CT)-scans during study:  
On Day 1 of each Treatment Period [Visit 2 and Visit 4] a baseline measurement inspiratory 
scan (total lung capacity [TLC] scan) and expiratory scan (functional residual capacity [FRC] 
scan) will be conducted.  During Visit 2 an additional scan of the upper airway (UA) will be 
taken. Post dose measurement inspiratory scan (total lung capacity [TLC] scan) will be taken 
after approximately 2 weeks of treatment with either GFF MDI or Placebo MDI on Day 15 (± 
5 days) (Visit 3 and Visit 5). Post dose activities should be started 1 hour after dosing on Visit 
3 and Visit 5 and should be concluded within 2.5 hours after dosing.  


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
11 
1.3 
Number of subjects 
Approximately 20 subjects with moderate to severe COPD will be randomized into the study 
In a double blind cross over study where 10 COPD Global Initiative for Chronic Obstructive 
Lung Disease (GOLD) III subjects received a budesonide/formoterol combination, FRI was 
able to quantify the effects of the active compound relative to placebo. A sample size 
calculation (power goal 90%, alpha 0.05) revealed that in order to have a well-powered study 
with change in imaging based airway volume as primary outcome parameter, a total of 7 
subjects would be required (De Backer, 2012). This is based upon powering for a difference of 
around 1 mL in iVaw and assuming a standard deviation of within subject differences of 
around 0.6 mL. Similarly, 17 subjects would be required for the image based airway 
resistance. If the significance level for the volume is set to 0.025 by the Hochberg's step-up 
procedure, 8 subjects would be required. It can be assumed that a good power will be obtained 
when including 20 subjects. 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
The following analysis populations are defined in this study: 
2.1.1 
Intent-To-Treat (ITT) population 
The ITT Population is defined as all subjects who are randomized to treatment. Data are 
analysed by randomized treatment regardless of the treatment actually received.  
2.1.2 
Modified Intent-To-Treat (mITT) population 
The modified Intent-to-Treat (mITT Population) is a subset of the ITT population including 
subjects who received treatment and have post treatment efficacy data from both Treatment 
Periods. Data judged to be impacted by important protocol deviations will be determined prior 
to unblinding and excluded. Statistical tabulations and analyses will be by randomized 
treatment, but data obtained after subjects receive an incorrect treatment will be excluded 
from the affected periods. 
2.1.3 
Safety population 
The Safety Population is defined as all subjects who are randomized to treatment and receive 
at least one dose of the study treatment. Statistical analyses and tabulations will be by the 
treatment actually received. 
2.1.4 
Population for analyses 
Analyses will be performed as follows: 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
12 
Demographics will be summarized for the ITT population. Extent of exposure will be 
summarized for the Safety Population. The Safety Population will be used to summarize 
safety data. 
Efficacy analyses will be performed for the ITT Population. If the mITT Population differs 
from the ITT Population it will be used to conduct sensitivity analyses for the co-primary 
endpoints. 
2.2 
Violations and deviations 
Only Important Protocol Deviations (IPDs) will be listed or tabulated. These are defined as 
those protocol deviations that may significantly affect the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a patient's rights, safety, or well-
being. These will be identified based upon blinded data, before database lock. 
The following will be considered important protocol deviations: 
x 
Patient randomized despite not meeting key inclusion criteria, including: 
o 
Patients not meeting COPD diagnosis (as defined by ATS/ERS) and severity 
criteria (FEV1/FVC ratio of <0.70 and post-bronchodilator FEV1 >30% and <80% 
of predicted normal) as per inclusion criteria 5 and 7. 
o 
Patients meeting exclusion criteria for other respiratory disease as per 
exclusion criteria 4, including diagnoses of asthma. 
x 
Patient received incorrect study drug 
x 
Prohibited concomitant COPD medication taken during the study, defined as the 
classes of medications listed in table 5-1 of the protocol, received after visit 2, other 
than those provided by the sponsor. 
x 
Developed discontinuation criteria but not withdrawn from study or discontinued 
investigational product  
 
Randomization errors 
If a subject is given a treatment pack for a different patient or is randomized out of 
chronological order, he will be included in the statistical analysis. If a subject would receive 
the same treatment twice, this will be considered an important protocol deviation and 
sensitivity analyses will be conducted using the mITT population. 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
13 
3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Efficacy Endpoints 
3.1.1 
Definition of baselines 
Efficacy baseline assessments are taken pre-dose at Day 1 of each Treatment Period (TP) 
(Visits 2 and 4). The mean of the available pre-dose assessments across both of these visits 
will be taken as the subject-average baseline. The mean of the available pre-dose assessments 
at each of Visit 2 and Visit 4 respectively will be taken as the period-dependent baseline for 
that respective TP.  
For spirometry and plethysmography endpoints the subject-average baseline will be used. 
That is the mean of all available pre-dose values conducted at Day 1 of each TP will be used 
to establish baseline. For spirometry the mean of the pre-dose -60 and -30 minute values at 
Visit 2 and Visit 4 will be averaged. In patients missing either of these assessments the single 
value from that visit will be used. Baselines for plethysmography endpoints will be based 
upon the -30 minute assessments.  
For FRI parameters subject-average baselines will be derived for each patient as the mean of 
the baselines across all lobes and periods. Similarly subject-by-period average baselines will 
be derived across lobes at the subject by period level. These will be used as covariates in 
sensitivity analyses, but the primary analysis will be conducted on absolute values at Day 15 
without using baseline covariates. 
3.1.2 
Treatment periods and visit windows 
There will be two treatment periods in this study. The first day on which a study treatment is 
received is Treatment Day 1 (for that study treatment and period). Treatment day is numbered 
sequentially thereafter until washout is begun or a subsequent study treatment is received. 
Each treatment period is intended to last until Day15. 
No study time windows will be derived for the reporting of data. Data will be reported 
according to the protocol-scheduled day. Efficacy data obtained during unscheduled visits 
after Day 1 will be allocated to Day 15 within the same treatment period if the Day 15 visit is 
missing. For analysis of spirometry data by time point, if multiple values are collected the last 
available assessment will be used for a given nominal time point. 
3.1.3 
Primary Efficacy Endpoints 
FRI Parameters: 
The co-primary endpoints of this study are as follows: 
x Specific Image based airway volume (siVaw):  Absolute value in Airway Volume 
(iVaw) relative to the lobar volume at Day 15.  


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
14 
x Specific Image based airway resistance (siRaw): Absolute value in Airway Resistance 
relative to the lobar volume at Day 15.  
For FRI parameters data is generated within each of the five lobes of the lung (right upper 
lobe, right middle lobe, right lower lobe, left upper lobe and left lower lobe). Only the 
trimmed iVaw values will be taken for the derivation of these parameters. 
For FRI parameters, only data generated from the scans taken at TLC level will be used for 
statistical analyses, but data generated at FRC will also be listed and will be summarised for 
selected parameters. 
Visible airway generations can be different in the pre-dose CT and the post-dose CT scans. 
For the primary outcome, the airways are trimmed until the same length for both visits. We 
thus only asses the generations of airways that are visible in the scans of both study visit days. 
This allows us to view the pure bronchodilation of the airways. 
The values of siVaw and siRaw are derived from iVaw and iRaw by dividing iVaw by the 
image based lobe volume (iVlobe) for siVaw and by multiplying iRaw by iVlobe for siRaw. 
See the definitions of iVaw, iRaw and iVlobe below. On a lobar scale (RUL: right upper lobe, 
RML: right middle lobe, RLL: right lower lobe, LUL: left upper lobe, LLL: left lower lobe), 
these calculations are: 
x siVaw LLL = iVaw LLL / iVlobe LLL 
x siVaw LUL = iVaw LUL / iVlobe LUL 
x siVaw RML = iVaw RML / iVlobe RML 
x siVaw RUL = iVaw RUL / iVlobe RUL 
x siVaw RLL = iVaw RLL / iVlobe RLL 
x siRaw LLL = iRaw LLL * iVlobe LLL 
x siRaw LUL = iRaw LUL * iVlobe LUL 
x siRaw RML = iRaw RML * iVlobe RML 
x siRaw RUL = iRaw RUL * iVlobe RUL 
x siRaw RLL = iRaw RLL * iVlobe RLL 
 
Similarly, values can be derived for the Lower Lobe (LL) by first summing iVaw values for 
LLL and RLL or for the Upper Lobe (UL) by first summing iVaw values for the LUL, RML 
and RUL. Distal totals can be derived using all 5 lobes. For airflow and resistance parameters 
a result from the central region of the lung is also provided and this combined with the distal 
total gives an overall total. For deriving resistance totals, parallel sums of iRaw should be 
used, by summing the inverse of iRaw values and then inverting again. 
 
For FRI parameters the values for each lobe, the lower lobe total, upper lobe total and overall 
total will be listed. 
 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
15 
3.1.4 
Secondary Efficacy Endpoints 
3.1.4.1 
FRI Parameters 
x Airway volume (iVaw): Absolute value at Day 15  
In the CT scans, the airways can be segmented up to the point where no distinction can 
be made between the intraluminal and alveolar air. This is where the airway diameter 
is around 1 – 2 mm, typically around the 5th to 10th bifurcation, depending mainly on 
the disease state of the individual patient. From the resulting model, the central and 
distal airway volumes can be assessed at individual airways or in different regions.  
The distal airway volume is defined as the segmented airway volume starting from the 
third bifurcation, that is from the 5 lung lobes without the central region. It is this 
distal region that will be used in the analyses in this study. 
Visible airway generations can be different in the pre-dose CT and the post-dose CT 
scans. The iVaw measurements can be performed in two ways: 1) measure of all the 
generation visible at certain study visit day 2) only asses the generations of airways 
that are visible in the scans of both pre-dose CT and the post-dose CT scans. The first 
parameter is called untrimmed iVaw and gives us an idea of the bronchodilation and 
bronchial recruitment, while the second parameter, called trimmed iVaw, allows us to 
view the pure bronchodilation. Both iVaw parameters will be analysed. 
x Airway resistance (iRaw): Absolute value at Day 15  
The airway resistance (iRaw) is determined using Computational Fluid Dynamics 
(CFD). During the CFD calculations, the outflow to each lobe is adjusted iteratively 
for each patient to match the internal flow rate distributions obtained from the 
segmentation of the CT scans hence iRaw accounts for the patient specific internal 
airflow distribution which might be greatly altered by the lung disease. Hence, the 
airflow distribution in the CFD calculation reflects the airflow distribution as derived 
from the expansion of the lung lobes from FRC to TLC. The iRaw is defined as the 
total pressure drop over an airway, divided by the flow rate through that airway. 
Visible airway generations can be different in the pre-dose CT and the post-dose CT 
scans. For iRaw, the airways are trimmed until the same length for both visits. We thus 
only asses the generations of airways that are visible in the scans of both study visit 
days. 
3.1.4.2 
Spirometry Parameters 
x Forced expiratory volume in one second (FEV1): Change from baseline to Day 15 in 
post-dose FEV1  
The volume of air exhaled under forced conditions in the first second. Post-dose 
results will be used. Change from baseline is calculated relative to the subject-average 
baseline. 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
16 
3.1.4.3 
Body Plethysmography Parameters 
x Functional residual capacity (FRC): Change from baseline to Day 15 in post-dose FRC 
The volume in the lungs at the end-expiratory position. Change from baseline is 
calculated relative to the subject-average baseline. 
3.1.5 
Other Efficacy Endpoints 
3.1.5.1 
FRI Parameters 
The following parameters will be analysed formally using scans at TLC with the exception of 
the mass of deposited particles, Internal Airflow Distribution and Air Trapping, which will be 
summarised descriptively only. 
x Image based Lobe volumes (iVlobe): Absolute value at Day 15  
By identifying and grouping the voxels that represent the air in the lungs the lung 
volume (L) can be determined from the scans. During segmentation, identifying the 
fissure planes on the CT images and using these surfaces as cutting objects can 
separate lung lobes. This means that not only the total lung volume is determined, but 
also the volume of each lobe individually. 
For each treatment, only scans at the TLC level are taken after the treatment. That 
means that analyses can only be performed on TLC lobar volumes but not for FRC. 
For the FRC level, only descriptive summary of baseline values will be presented. 
The percent predicted image based lobe volume (based upon age, sex and height) will 
also be derived. This will be analysed similarly to iVlobe using scans at the TLC level 
and summarised at baseline using scans at the FRC level.  
x Air trapping:  Descriptive summary of baseline results  
Air trapping is defined as all the intrapulmonary voxels with Hounsfield Units between 
-1024 and -850 using the expiratory scans at FRC. This parameter is given as 
percentage of iVlobe. 
Air Trapping is only valid on FRC scans, so because there are no FRC scans after 
treatment, no analyses can be done, only descriptive summary of baselines values. The 
air trapping will also be derived for the upper lobes, lower lobes and total by summing 
data from relevant individual lobes. 
x Internal lobar airflow distribution: Descriptive summary of baseline results 
By segmenting the lobes at FRC and TLC for each patient, the patient-specific airflow 
distribution can be established by assessing lobar volume expansion. 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
17 
Internal Airflow Distribution requires both FRC and TLC scans, so because there are 
no FRC scans after treatment no analyses can be done. Only descriptive summary of 
baselines values will be produced. 
x Low attenuation or emphysema score: Absolute value at Day 15  
Low attenuation score is defined as all the intrapulmonary voxels with Hounsfield 
Units between -1024 and -950 using the inspiratory scans at TLC. This parameter is 
given as percentage of iVlobe. 
x Blood vessel density or fibrosis score: Absolute value at Day 15  
Blood vessel density can be determined through segmentation and three-dimensional 
reconstruction of the blood vessels. The segmentation is based on a Hounsfield unit 
(HU) threshold between -600 and 600 and is performed on the TLC scan. The blood 
vessel density can be considered a surrogate for perfusion. This parameter is given as 
percentage of iVlobe. 
x Airway wall thickness: Absolute value at Day 15  
The airway wall volume consists of all visible tissue in the CT scan that encompasses 
the airway wall. The airway wall volume can typically be described to the same 
generation level as the volume description of the airway lumen, this is where the 
airway diameter is around 1 - 2 mm. This parameter can also be given relative to the 
lobar volume and is then called specific airway wall volume (siVaww). Visible airway 
generations can be different in the pre-dose CT and the post-dose CT scans. For airway 
wall thickness, the airways are trimmed until the same length for both visits. We thus 
only asses the generations of airways that are visible in the scans of both study visit 
days. 
x Mass of deposited particles per defined airway section:  Descriptive summary of 
baseline results 
Regional aerosol deposition is determined by simulating the flow in the patient 
specific geometries using patient specific boundary conditions by means of CFD. 
While solving the flow equations, simultaneously particles are released in the flow and 
the force mass balance of the individual particles is determined through additional 
discrete phase computations. When a calculated particle trajectory intersects with the 
airway wall, the particle is trapped in that location. This allows determining the 
regional concentration of inhaled aerosols and consequently the effective lung dose of 
inhaled medication. These are measured in the full airway tree.  
Mass of deposited particles is a useful way to see the particle deposition in each region 
of the lung. Data from the baseline TLC scan will be summarised. Distal and 
peripheral data will be summed. Upper lobe and lower lobe totals will also be derived. 


Statistical Analysis Plan  
Study Code PT003018 / FLUI-2015-139 
Edition Number 1  
Date 27 February 2017 
18 
3.1.5.2 
Spirometry Parameters 
The change from baseline at Day 15 will be assessed for the following parameters. Change 
from baseline is calculated relative to the subject-average baseline. 
x Forced vital capacity (FVC): the determination of the vital capacity from a maximally 
forced expiratory effort 
x Tiffeneau index (FEV1/FVC ratio): the proportion of a person's vital capacity that they 
are able to expire in the first second of forced expiration 
x Forced expiratory flow  25%-75% (FEF25-75): forced expiratory flow at 25–75% of 
forced vital capacity 
x Inspiratory capacity (IC): the amount of air that can be inhaled after the end of a 
normal expiration. The average of the available Day 15 post-dose assessments will be 
used. 
3.1.5.3 
Body Plethysmography Parameters 
The change from baseline at Day 15 will be assessed for the following parameters. Change 
from baseline is calculated relative to the subject-average baseline. 
x Residual volume (RV): the volume of air remaining in the lungs after a maximal 
exhalation 
x TLC: the volume in the lungs at maximal inflation 
x Airway resistance (Raw): the resistance of the respiratory tract to airflow during 
inspiration and expiration 
x Specific airway resistance (sRaw): airway resistance corrected for differences in lung 
volume. Specific airway conductance (sGaw): derived as the mathematical inverse of 
airway resistance corrected for differences in lung volume 
3.2 
Safety Endpoints  
The safety assessments include Adverse Events (AEs) and Serious Adverse Events (SAEs) 
during the study period. 
AEs experienced by the subjects will be collected throughout the entire study and will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Only treatment emergent adverse events from the time of randomization onwards will be 
summarised. AEs will be assigned to the treatment period in which they first occurred. AEs 
reported as starting during a Washout Period or follow-up period will be assigned to the last 
treatment received. If an AE has a missing or partial onset date, then unless the stop date of 
the AE indicates otherwise, this will be considered an on treatment event.  


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Clinically relevant findings from laboratory, ECG and vital sign parameters will be reported 
as adverse events. As such these assessments will not be further tabulated. 
3.3 
Handling of missing data 
Data for FRI parameters will be generated across each lobe of the lung. For an individual there 
may be missing data within certain lobes if for example the subject is missing that lobe or no 
airways lead to the lobe (giving a volume of zero and infinite airway resistance). If fissures 
between lobes cannot be distinguished then only a combined estimate across multiple lobes 
may be produced. Such results from combined lobes will not be used in the analyses. This will 
be consistent for both periods. Such combined lobe results may however enable totals and 
sub-totals to be calculated for a patient if the lobes which are combined coincide with those 
required for relevant regions. 
Data from all individually evaluable lobes will be used in the analysis to allow for the 
estimation of effects at the subject level across all lobes. For patients with lobes that cannot be 
distinguished the estimates for that lobe are not meaningful for the patient and so they will not 
contribute, but this will be the case for both periods. Where scans are not evaluable for a 
single assessment or period this data is assumed to be missing at random. 
Where Day 15 assessments are missing data from unscheduled post-baseline assessments will 
be used in their place, if available. No further imputation for missing values is planned. 
 
4. 
ANALYSIS METHODS 
The primary objective of this study is to assess the effect of treatment with GFF MDI, 14.4/9.6 
μg ex actuator, BID relative to Placebo MDI BID on specific image based airway volumes and 
resistance in subjects with moderate to severe COPD. 
4.1 
General principles 
4.1.1 
Hypothesis testing 
For the efficacy analyses, the null hypothesis for each pair-wise comparison will be that the 
mean GFF MDI treatment effect is equal to that of Placebo MDI; the alternative hypothesis is 
then that the GFF MDI treatment effect and that of Placebo MDI are not equal. P-values will 
thus be reported as two-sided. Statistical level of significance will be set to 0.05.  
For the co-primary endpoints and other FRI parameters the effect is defined using the absolute 
value at Day 15 of each TP. For the spirometry and plethysmography parameters the effect is 
defined in terms of the change from baseline, given that these parameters are commonly 
reported in those terms. 
The null (H0) and alternative (H1) hypotheses with μ representing the mean are: 


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H0: μGFF = μplacebo 
H1: μGFF ≠ μplacebo 
For each parameter in each group this null hypothesis will be tested. The different groups are:  
x Primary efficacy endpoints: FRI  
x Secondary efficacy endpoints: FRI; Spirometry and Body Plethysmography  
x Other efficacy endpoints: FRI parameters (except the mass of deposited particles, 
internal airflow distribution and air trapping); Spirometry and Body Plethysmography  
In order to gain extra insight into the mode of action of the product, additional exploratory 
analyses may be executed using (robust) linear regression or mixed-models if necessary and 
reported outside of the Clinical Study Report (CSR). 
The Intent-to-Treat (ITT) Population will be considered the primary analysis population for 
efficacy. 
Continuous efficacy variables will be summarized with descriptive statistics (the number of 
non-missing values, mean, standard deviation, median, minimum and maximum). Where data 
has been logarithmically transformed for analysis the summary statistics on the back-
transformed data will include the geometric mean and the coefficient of variation (calculated 
as 100x√[exp(s2)-1], where s is the standard deviation of the data on the log scale.  Categorical 
variables will be summarized with frequency counts and percentages, by treatment. 
Only data deemed to meet acceptability criteria, for example regarding the quality of 
spirometry procedures, will be listed and summarised. 
4.1.2 
Control of Type I error 
For the primary efficacy endpoints, Hochberg's step-up procedure will be used as multiplicity 
adjustment. No correction will be performed for the secondary and the other efficacy 
endpoints. 
4.1.3 
Software 
All statistical analysis will be conducted using R version 3.0.2 or higher (The R Foundation 
for Statistical Computing, Vienna, Austria), SAS version 9.2 or higher, or other validated 
software as appropriate. 
4.2 
Analysis methods 
4.2.1 
Disposition, demographics and baseline characteristics 
Descriptive summaries of disposition, demographics and baseline characteristics will be 
produced. Disposition tables will summarise the number of patients who received each 
treatment, the number who completed 1 or 2 treatment periods and the number of early 


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discontinuations. The number of patients in each analysis set will be summarised along with 
any reasons for exclusion. 
Demographics and baseline characteristics at screening will be summarised descriptively, 
including COPD disease duration and symptom severity scores. Baseline pre and post 
bronchodilator spirometry parameters and reversibility to Ventolin HFA will be summarised 
using descriptive statistics based upon the baseline assessments within each treatment period.  
4.2.2 
Concomitant medications 
Concomitant medications will be 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. Medications will be summarised according to whether they 
are COPD related or non-COPD related. Summaries will be presented for those medications 
started prior to the beginning of study treatment, those started during a treatment period and 
those started during the washout period. 
4.2.3 
Exposure and compliance 
The number of days of exposure to each treatment will be 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 across study 
days/total expected puffs taken across study days) across all days of a subject’s dosing 
between start of study treatment and last day on study treatment) x 100. 4 puffs a day are 
expected, with 2 puffs on the final day of treatment. 
Exposure to IP, number of puffs/inhalations of IP and % compliance will be summarized by 
treatment using the safety analysis set.  
4.2.4 
Analysis of FRI data 
The primary analyses will be conducted using the ITT population. Similar methods will be 
used for the analysis of each of siVaw and siRaw. 
The Day 15 value for each parameter in each period will be analysed using a linear mixed 
effect model. It is anticipated that the data will be logarithmically transformed prior to 
analysis. A multi-level model will be used to incorporate the repeated measurements from the 
lobes for each subject.  
The model will include fixed effects for period, treatment, lobe and treatment by lobe 
interaction. The model will not include treatment sequence unless that term is determined to 
be important (p<0.10). Lobe will be included as a random effect, within each subject. 
Heterogeneity across lobes (within subject) will be modelled using an unstructured variance-
covariance matrix, with independence assumed between subjects.  
If this model fit fails to converge a compound symmetry covariance structure will be 
considered to model correlation across lobes from the same patient. If necessary, a per-visit 


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composite from across all lobes may be formed in order to conduct analyses at the subject 
rather than the lobe level. This would be based upon a sum across all available lobes for a 
subject, scaled for the number of evaluable lobes. 
Estimates will be produced of the difference between treatments taken across all lobes. Where 
logarithmic transformations have been made, estimates will be exponentiated and treatment 
effects presented as ratios. Estimates and standard errors will be reported along with 2-sided 
95% confidence intervals and p-values. The Kenward-Roger approximation for degrees of 
freedom and correction of downward bias in the standard error of fixed effect parameters will 
be used. 
For the primary FRI endpoints only, line-plots will be produced displaying Day1 and Day 15 
absolute values by treatment and sequence at the individual patient level using the mean of 
data from available single lobes for each patient.  
For the primary endpoints only, the mITT population will be used to produce sensitivity 
analyses using only patients with data from both periods without important protocol 
deviations. Similar mixed models will be used. Should no patients require exclusion then these 
sensitivity analyses will not be required. 
For the primary endpoints only, a further model will be produced which includes covariates 
for baseline. The model will include fixed effects for period, treatment, lobe and treatment by 
lobe interaction, subject-average baseline by lobe and period-dependent baseline by lobe. Both 
versions of baseline are continuous covariates. The use of both subject-average and period-
dependent baselines allows for different coefficients for the between and within subject 
covariate regressions (Kenward and Roger 2010). Period-dependent baselines will be 
summarised for the primary endpoints. 
Similar analyses to the primary analysis will be conducted for secondary and other efficacy 
endpoints based upon FRI, with the exception of the mass of deposited particles, the Internal 
Airflow Distribution and Air Trapping. For these values, only descriptive summaries will be 
produced by showing the deposition in each region of the patient’s lungs at baseline. For the 
Internal Airflow Distribution, the presented values will consist of distance to normal values. 
4.2.5 
Spirometry / Body Plethysmography data 
For spirometry and body plethysmography parameters data will be at the subject level and not 
split by lobe. The change from baseline to Day 15 for each endpoint will be analysed using a 
linear mixed effect model including subject-average baseline as a continuous covariate and 
treatment and period as fixed effects. The model will not include treatment sequence unless 
that term is determined to be important (p<0.10). The ITT population will be used. It is 
expected that plethysmography endpoints may require logarithmic transformation, but that 
spirometry endpoints will not. 
4.2.6 
Assumptions Checks and Removal of Outliers in Sensitivity Analyses 
It is expected that logarithmic transformations will be required for most FRI and 
plethysmography endpoints, with the exception of the percent predicted lobe volume. Data 


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will be transformed via the natural logarithm prior to analysis and the adjusted mean estimates 
and confidence intervals from the linear models will be exponentiated back for presentation. 
As such the treatment effect for these endpoints will be presented as a ratio. 
Under certain circumstances, (eg, during a COPD exacerbation unrelated to treatment) 
extreme and atypical values can arise. Such values may disproportionately affect model-based 
estimates of the fixed effect and variance parameters. Depending on the plots of the 
standardized residuals versus fitted values of the mixed-effect models, other data 
transformations may be considered. If necessary, this may include the fifth root, adapted for 
positive and negative values: fifthroot (x) = sign (x) * ( abs (x) ) ^ (1/5). 
For resistance measures, outliers can occur that are real values but affect the model estimates 
extremely. In these cases, values that are larger than the third quantile + 3 times the 
interquartile range may be removed. Infinite values for resistance are possible and these will 
be listed, but will be removed from the data before statistical analysis. If erroneous values are 
detected, every effort will be made to correct them prior to database lock. However, if these 
values cannot be corrected, they will be considered for removal from the analysis. 
4.2.7 
Exploratory analyses 
In order to gain extra insights in the mode of action of the product, additional exploratory 
analyses may be executed and these may be reported outside of the CSR. These may entail 
post-hoc tests on the previously generated mixed-effect model. Contrasts for lobe by treatment 
interactions may be studied to examine the consistency of effects across the 5 lung lobes. 
Pearson or Spearman’s rank correlations between variables may be produced (depending upon 
behaviour of distributions). If appropriate, exploratory analyses of mixed-effect regressions or 
linear regression between parameters may be conducted to investigate associations between 
parameters, but these reported outside of the CSR. 
4.2.8 
Safety data 
Adverse events will be summarized by the number and percentage of subjects experiencing an 
event. Tables will show the overall incidence of AEs, and the incidence for each treatment. 
Treatment emergent adverse events from the time of randomization onwards will be 
summarised. AEs reported as starting during a Washout Period or follow-up period will be 
assigned to the last treatment received. 
AEs will be presented according to MedDRA preferred term and system organ class. 
Summaries will be produced by severity, seriousness, AEs leading to discontinuation, and by 
causality assessment to study drug. No hypothesis tests will be performed.  
Clinically relevant findings from laboratory, ECG and vital sign parameters will be reported 
as adverse events. As such these  assessments will not be further tabulated. 


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5. 
INTERIM ANALYSES (NOT APPLICABLE) 
No interim analyses are planned in this study. 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL  
The clinical study protocol stated that all FRI, spirometry and body plethysmography 
endpoints would utilise changes from baseline for statistical analyses. Effects were defined as 
differences between Day 15 and Day 1. As described in Kenward and Roger, conditioning on 
period-dependent baselines in a cross-over study has the potential to increase the variability of 
treatment effect estimates (Kenward and Roger 2010). For this reason statistical analyses will 
now be conducted either using absolute values or relative to subject-average (period 
independent) baselines.  
It is now planned that FRI endpoints will be analysed using their absolute values at Day 15 
rather than the change from baseline. This avoids the need to derive baselines across multiple 
lobes. In a cross-over study comparisons are driven by within-subject comparisons and the 
adjustment for baselines is not necessary as this adjusts for between patient variability.  
Spirometry and plethysmography endpoints will utilise change from a subject-average 
baseline. The use of the subject-average baseline covariate will not affect the treatment effect 
estimates, but will allow for the estimation of changes from baseline for each separate 
treatment.  
Given that the ITT, mITT and safety populations are expected to only differ slightly 
demographics and other characteristics will only be summarised for the ITT population. The 
mITT population will purely be used for sensitivity analyses of the primary endpoints should 
the ITT and mITT populations differ. 
7. 
REFERENCES 
R Core Team (2016). R: A language and environment for statistical computing. R Foundation 
for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/. 
De Backer L, Vos W, De Backer J, Van Holsbeke C, Vinchurkar S, De Backer W. The acute 
effect of budesonide/formoterol in COPD: a multi-slice computed tomography and lung 
function study. Eur Respir J. 2012 Aug 1;40(2):298–305. 
Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics 
(2010), 11, 1, 1–17 


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8. 
APPENDIX