Observational Study in Healthy Subjects and Patients With COPD to Assess the Relationship Between Clinical, Imaging and Biomarker Measurements, and Progression of Emphysema Over Three Years [FOOTPRINTS®].
Conditions: Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema
Sponsor: Boehringer Ingelheim

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CLINICAL STUDY PROTOCOL
TITLE PAGE
Document Number:
c02362157-07
EudraCT No.:
n/a
BI Study No.:
352.2069
BI Investigational 
Product(s):
n/a
Title:
Observational study in healthy subjects and patients with COPD 
to assess the relationship between clinical, imaging and 
biomarker measurements, and progression of emphysema over 
three years [FOOTPRINTS®].
Brief Title:
Emphysema Progression Biomarker Study
Clinical Phase:
n/a
Trial Clinical 
Monitor:
Phone: +
Fax: +
Project Advisor:
Status:
Final Protocol (Revised Protocol (based on Global Amendment
5))
Version and Date:
Version: 6.0
Date: 24 Feb 2020
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2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL STUDY PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
n/a
Name of active ingredient:
n/a
Protocol date:
02 Sep 2015
Study number:
352.2069
Revision date:
24 Feb 2020
Title of study:
Observational study in healthy subjects and patients with COPD to assess the 
relationship between clinical, imaging and biomarker measurements, and 
progression of emphysema over three years [FOOTPRINTS®].
Coordinating
Investigator:
n/a
Study site(s):
Multi-center, multi-national study, ~ 12 participating countries, 50 sites.
Clinical phase:
n/a
Objective(s):
The overall objective of this study is to explore, if any of the biomarkers 
(soluble, functional imaging and physiological) assessed within healthy subjects, 
patients with COPD and patients with COPD and A1ATdeficiency are 
correlated to COPD disease progression, particularly emphysema progression
over 156 weeks.
Methodology:
Prospective, longitudinal study.
No. of subjects: 
total entered:
Up to 455 subjects entered including:

60 Healthy subjects without airflow limitation

125 patients with COPD GOLD 1

125 patients with COPD GOLD 2

125 patients with COPD GOLD 3

Up to 20 patients with COPD and A1AT deficiency (ZZ genotype)
Diagnosis:

Healthy Subjects

COPD GOLD grade 1, 2, 3

COPD and A1AT deficiency (ZZ genotype)

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Name of company:
Boehringer Ingelheim 
Name of finished product:
n/a
Name of active ingredient:
n/a
Protocol date:
02 Sep 2015
Study number:
352.2069
Revision date:
24 Feb 2020
Main criteria
for inclusion:

COPD and healthy subjects of both sex aged ≥ 40 and ≤ 70 years

COPD with A1ATD of both sex aged ≥30 and ≤ 70 years

COPD and healthy ex-smokers with a smoking history ≥ 20 pack years

COPD with A1ATD ex-smokers with a smoking history ≥10 pack years

Body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2 (≤30 kg/m2 in the MRI 
substudy)
Duration of
observation:
156 weeks (~ 3 years)
Assessments:
Clinical assessments:

Spirometry

Body plethysmography

Pulse oximetry

Diffusing capacity of the lung for carbon monoxide

Questionnaires: mMRC, CAT, SGRQ 

BODE index

6 minute walk test (6 MWT)

Medical Events of Special Interest (MESI)

Adverse Events
Biofluids:

Blood

Induced Sputum (at selected sites)
Imaging assessments:

Chest CT (inspiratory/expiratory)

Magnetic Resonance Imaging (MRI) (in a subset of healthy subjects and 
patients with COPD without A1ATD)
Biobanking:
Unspecified biomarker testing in blood in all subjects and sputum in a subset of 
subjects
Safety criteria:
Vital signs, physical examination, safety laboratory, urine pregnancy testing, 12-
lead electrocardiogram (ECG) and adverse event reporting
Statistical methods:
Descriptive statistics, Pearson and rank-based correlation, multivariate statistical 
prediction model

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FLOWCHART
Study Periods
Screening 
Period
Observational Period
Visit
1
2
3
4

5



6
Weeks
12
26
39
52
65
78
91
104
Days
Prior to 
any study 
related 
procedure
-28 to -1
1
84
182
273
364
455
546
637
728
Time window for visits
see17 ± 7d
± 
14d
± 
14d
± 
14d
± 
14d
± 
14d
± 
14d
± 
14d
Informed consent1
X
Demographics
X
Medical history
X
Physical examination, BMI10
X
X
X
Vital signs
X
X
X
Review of in-/exclusion 
criteria
X
X12
MESI Check
X
X
X
X
X
X
X
X
X
X
Smoking Status/Cotinine 
Test18
X
X
X
X
X
X
Restrictions Check8
X
X
X
X
X
Urine pregnancy test2
X
X
X
X
X
Safety laboratory3,5
X
X
X
X
X
X
A1ATD testing14
X
12 lead-ECG
X
X
X
BODE index15
X
X
mMRC4
X
X
X
X
CAT4
X
X
X
SGRQ4
X
X
X
Pulse oximetry
X
X
X
X
X
Spirometry (PFT)19
X
X
see21
X
X
X
Lung diffusion capacity20
X
X
X
X
X
Body plethysmography20
X
X
X
X
Chest CT
X
X
X
MRI (in a substudy only)7
X
X
X
X
Induced sputum16
X
X
X
X
X
6 minute walk test (6 MWT)
X11
X
X
BM blood collection5
X
X
X
X
X
DNA banking (optional)9
X
Re-/Dispense and review
subject reminder diary13
X
X
X
X
X22
X
X22
X22
X22
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
IRT subject visit registration
X
X
X
X
X
X
X
X
X
X
Completion of subject
participation
Vital status and COPD 
exacerbation status
collection6
X
X

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FLOWCHART (continued)
Study Periods
Observational Period
Visit



7
Weeks
117
130
143
156
Days
819
910
1001 1092
Time window for visits
± 
14d
± 
14d
± 
14d
± 
14d
Informed consent1
Demographics
Medical history
Physical examination, BMI10
X
Vital signs
X
Review of in-/exclusion 
criteria
MESI Check
X
X
X
X
Smoking Status/Cotinine 
Test18
X
Restrictions Check8
X
Urine pregnancy test2
X
Safety laboratory3,5
X
A1ATD testing14
12 lead-ECG
X
BODE index15
X
mMRC4
X
CAT4
X
SGRQ4
X
Pulse oximetry
X
Spirometry (PFT)19
X
Lung diffusion capacity20
X
Body plethysmography20
X
Chest CT
X
MRI (in a substudy only)7
X
Induced sputum16
X
6 minute walk test (6 MWT)
X
BM blood collection5
X
DNA banking (optional)9
Re-/Dispense and review 
subject reminder diary13
X22
X22
X22
X
Adverse events
X
X
X
X
Concomitant therapy
X
X
X
X
IRT subject visit registration
X
X
X
X
Completion of subject
participation
X
Vital status and COPD 
exacerbation status
collection6
X

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1
All subjects must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the study, 
which includes the application of medication short-term restrictions prior to lung function testing. Re-consenting may 
become necessary when new relevant information becomes available and should be conducted according to the 
sponsor’s instructions
2
Urine pregnancy testing in women of childbearing potential only (to be assessed prior to blood collection and imaging 
assessments)
3
A full panel of hematology, blood chemistry, and coagulation parameters will be done at visits 1, 2, 5, 6 and 7. The 
reduced panel comprises hematology, 
, and creatinine at 
visits 3 and 4. Refer to Section 5.9.3
4
mMRC, followed by CAT and SGRQ in patients with COPD/COPD and A1AT deficiency only will be self-
administered at the beginning of the visit and should precede any discussion with a health professional
5
Fasted safety and biomarker blood sampling. Dedicated serum and plasma samples for biobanking will be collected in 
additional tubes
6
Phone Call: for all subjects who prematurely discontinue during observational phase. Please refer to Section 6.2.2
7
Prior to each MRI assessment, subject must meet criteria described in Section 5.3
8
Restrictions must be checked at first at the clinic visit. Please refer to Section 4.2.2 and 6.1.1.1
9
Blood draw can be done at Visit 2 or any later visit. Refer to Section 5.8.4
10
BMI will be calculated automatically on the eCRF. Refer to Appendix 10.4.3
11
The 6 MWT at Visit 1 will be performed to train the subjects for the procedure
12
Criteria, which apply at visit 2 only, not subsequent visits
13
Refer to Section 3.1.1
14
Genetic test on A1AT deficiency performed on all subjects
15
Done in patient with COPD/COPD and A1ATD only
16
Induced Sputum will be collected in all subjects at selected sites only
17
Refer to Section 6.1
18
A positive cotinine test is not exclusionary during screening and observational phase but should be explained and 
documented by the investigator
19
Spirometry will be done pre and post Salbutamol (Albuterol) administration at visits indicated in the flowchart
20
Lung diffusion capacity and bodyplethysmography will be done post Salbutamol (Albuterol) administration only at 
visits indicated in the flowchart
21
FEV1 measurement to assess safety criteria for the sputum induction procedure can be done on the centrally provided 
spirometer or on a local device
22
At the phone call visits subject reminder diary is reviewed

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL STUDY PROTOCOL SYNOPSIS.....................................................................2
FLOWCHART.........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
MEDICAL BACKGROUND.............................................................................14
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....16
RATIONALE FOR PERFORMING THE STUDY ........................................16
BENEFIT - RISK ASSESSMENT.....................................................................17
3.
DESCRIPTION OF DESIGN AND STUDY POPULATION........................20
OVERALL STUDY DESIGN AND PLAN ......................................................20
3.1.1
Administrative structure of the study...............................................................21
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................22
SELECTION OF STUDY POPULATION.......................................................23
3.3.1
Main diagnosis for study entry ..........................................................................23
3.3.2
Healthy subjects ..................................................................................................23
Inclusion criteria ...................................................................................................23
Exclusion criteria ..................................................................................................24
3.3.3
Patients with COPD............................................................................................25
Inclusion criteria ...................................................................................................25
Exclusion criteria ..................................................................................................26
3.3.4
Patients with COPD and A1AT deficiency.......................................................27
Inclusion criteria ...................................................................................................27
Exclusion criteria ..................................................................................................28
3.3.5
Removal of subjects from the study ..................................................................29
Removal of individual subjects.............................................................................29
Discontinuation of the study by the sponsor.........................................................30
4.
TREATMENTS...................................................................................................31
TREATMENTS TO BE ADMINISTERED.....................................................31
CONCOMITANT MEDICATION, RESTRICTIONS, AND RESCUE  
MEDICATION....................................................................................................31
4.2.1
Rescue medication, emergency procedures, and additional medication(s) ...31
4.2.2
Restrictions ..........................................................................................................31

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Restrictions regarding concomitant medication....................................................32
Restrictions on diet and life style..........................................................................33
5.
VARIABLES AND THEIR ASSESSMENT ....................................................34
SUMMARY OF STUDY OUTCOMES AND ASSESSMENTS ....................34
5.1.1
Main outcome measures.....................................................................................34
5.1.2
Assessments..........................................................................................................34
COMPUTED TOMOGRAPHY (CT)...............................................................34
MAGNETIC RESONANCE IMAGING (MRI) ..............................................35
SPIROMETRY (PFT) ........................................................................................35
DIFFUSING CAPACITY OF THE LUNGS FOR CARBON MONOXIDE 
(DLCO) ...................................................................................................................36
BODY PLETHYSMOGRAPHY .......................................................................37
MEDICAL EVENTS OF SPECIAL INTEREST (MESI) ..............................37
5.7.1
Respiratory Disorders.........................................................................................38
Definition and assessment of COPD exacerbations..............................................38
5.7.2
Cardiovascular disorders ...................................................................................39
5.7.3
Metabolic/ Digestive disorders...........................................................................39
5.7.4
Neurological/psychiatric disorders....................................................................39
5.7.5
Other disorders ...................................................................................................40
BIOMARKER ASSESSMENTS .......................................................................40
5.8.1
Biomarker sample collection..............................................................................41
Blood collection....................................................................................................41
Collection of sputum (in a subset of subjects only)..............................................42
5.8.2
Methods and timing of sample collection..........................................................42
5.8.3
Analytical determinations ..................................................................................43
5.8.4
Biobanking...........................................................................................................43
ASSESSMENT OF SAFETY.............................................................................43
5.9.1
Physical examination ..........................................................................................43
5.9.2
Vital Signs............................................................................................................44
5.9.3
Safety laboratory parameters ............................................................................44
5.9.4
Electrocardiogram ..............................................................................................46
5.9.5
Pregnancy tests....................................................................................................46
5.9.6
Assessment of adverse events.............................................................................46
Definitions of AEs ................................................................................................46
Adverse event collection and reporting ................................................................47
PULSE OXIMETRY ..........................................................................................48
SYMPTOM QUESTIONNAIRES.....................................................................48
5.11.1
mMRC..................................................................................................................48
5.11.2
COPD Assessment Test (CAT) ..........................................................................48
5.11.3
Saint George’s Respiratory Questionnaire (SGRQ)........................................49
6 MINUTE WALK TEST (6 MWT) .................................................................49
APPROPRIATENESS OF MEASUREMENTS..............................................50
6.
INVESTIGATIONAL PLAN.............................................................................51
VISIT SCHEDULE.............................................................................................51
6.1.1
Rescheduling clinic visits and study procedures..............................................51

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Diet and life style restrictions ...............................................................................51
Sputum induction (at selected sites only) .............................................................51
Imaging assessments (chest CT and MRI)............................................................52
COPD exacerbation and respiratory tract infection..............................................52
Rescheduling clinic visits during the screening period.........................................52
Rescheduling clinic visits during the observational period ..................................52
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ................52
6.2.1
Screening period..................................................................................................52
6.2.2
Observational period and Study Completion...................................................53
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
STATISTICAL DESIGN - MODEL.................................................................56
NULL AND ALTERNATIVE HYPOTHESES ...............................................56
PLANNED ANALYSES.....................................................................................56
7.3.1
Primary analyses.................................................................................................57
Descriptive and Summary Statistics .....................................................................57
Correlations...........................................................................................................57
ANOVA Models and Logistic regression for Baseline Biomarker Values ..........57
Predictive models..................................................................................................57
Repeated Measurement Models for Changes in Biomarkers Over Time .............58
7.3.2
Secondary analyses .............................................................................................58
7.3.4
Safety analyses.....................................................................................................58
7.3.5
Pharmacokinetic analyses ..................................................................................59
7.3.6
Pharmacogenomic analyses................................................................................59
INTERIM ANALYSES ......................................................................................59
HANDLING OF MISSING DATA ...................................................................60
RANDOMISATION ...........................................................................................60
DETERMINATION OF SAMPLE SIZE .........................................................60
7.7.1
Power computation based on FEV1 annual decline.........................................60
7.7.2
Power computation based on PD15 decline......................................................61
7.7.3
Power Computation based on Partial Pearson Correlation Coefficients ......62
8.
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS.......63
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................63
DATA QUALITY ASSURANCE ......................................................................64
RECORDS...........................................................................................................64
8.3.1
Source documents ...............................................................................................64
8.3.2
Direct access to source data and documents.....................................................64
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................64
8.4.1
Expedited reporting to health authorities and IEC / IRB...............................64
STATEMENT OF CONFIDENTIALITY........................................................65
END OF STUDY.................................................................................................65

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9.
REFERENCES....................................................................................................66
PUBLISHED REFERENCES............................................................................66
10.
APPENDICES.....................................................................................................71
COPD ASSESSMENT TEST™ (CAT).............................................................71
SAINT GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) ............72
MODIFIED MEDICAL RESEARCH COUNCIL DYSPNOEA SCALE 
(MMRC)...............................................................................................................79
ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA...........80
10.4.1
Calculation of number of pack years ................................................................80
10.4.2
Laboratory data ..................................................................................................80
10.4.3
Body Mass Index.................................................................................................80
10.4.4
Alpha1-antitrypsin deficiency............................................................................80
10.4.5
Definition of ex-smokers.....................................................................................80
INSTRUCTIONS FOR ASSESSMENTS.........................................................80
COMPUTATION OF BODE INDEX...............................................................80
GLOMERULAR FILTRATION RATE (GFR)...............................................81
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................82

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ABBREVIATIONS
A1AT
Alpha-1 Antitrypsin 
A1PI
Alpha-1 Proteinase Inhibitor
AE
Adverse Event
ANOVA
Analysis of Variance
AP/ALP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
ATS
American Thoracic Society
AUC
Area under the curve
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BM
Biomarker
BMI
Body Mass Index
BP
Blood Pressure
CAT
COPD Assessment Test Questionnaire
CART
Classification and Regression Tree
CI
Confidence Interval
CK
Creatine Kinase
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CT
Computed Tomography
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DNA
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
ECG
Electrocardiography/Electrocardiogram
ERS
European Respiratory Society
ERV
Expiratory Reserve Volume
EudraCT
European Clinical Trials Database
FEV1
Forced Expiratory Volume in 1st second
FRC
Functional Residual Capacity
GCP
Good Clinical Practice
GGT/γ-GT
Gamma-Glutamyl Transferase
GLI
Global Lung Function Initiative
GOLD
Global Initiative for Chronic Obstructive Lung Disease
Hb
Hemoglobin
Hct
Hematocrit
IC
Inspiratory Capacity
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee

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i.m.
intramuscular
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IVC
Inspiratory Vital Capacity
JRS
LDH
Japanese Respiratory Society
Lactic Dehydrogenase
MCV
Mean Corpuscular Volume
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Cellular Hemoglobin Concentration
MedDRA
Medical Dictionary for Drug Regulatory Activities
MESI
Medical Events of Special Interest
mL
Milliliter
MMPs
Matrixmetalloproteinases
mMRC
Modified Medical research Council Dyspnea Scale
MRI
Magnet Resonance Imaging
mSv
milliSievert
µM
Micrometer
NE
Neutrophil Elastase
NSP
Neutrophil-derived Serine Protease
OPU
Operative Unit
PDE-4
Phosphodiesterase 4
PFT
Pulmonary Function Test
p.o.
per os (oral)
PR
Pulse Rate
PRO
Patient Reported Outcome
q.d.
quaque die (once a day)
RNA
Ribonucleic acid
ROC
Receiver Operating Characteristics
RV
Residual Volume
SAE
Serious Adverse Event
SC
Steering Committee
s.c.
subcutaneous
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamate-pyruvate transaminase
SGRQ
St George’s Respiratory Questionnaire
SOP
Standard Operating Procedure
Sv
Sievert
TCM
Trial Clinical Monitor
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TLC
Total Lung Capacity

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TSAP
Trial Statistical Analysis Plan
6 MWT
6 Minute Walk Test

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1.
INTRODUCTION
MEDICAL BACKGROUND
The chronic airflow limitation characteristic of COPD is caused by a mixture of small 
airways disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the 
relative contributions of which vary from patient to patient [P15-01740]. Estimates for 
emphysema in patients with COPD vary up to 60%.
There is no treatment for disease progression in COPD, and current treatment options, apart 
from smoking cessation do not prevent decline of FEV1 (forced expiratory volume in 1 
second) over time, nor inhibit the lung structural damages. COPD is a heterogeneous disease 
with at least 2 clinical well recognized phenotypes (bronchitic and emphysematous). Both 
can be present alone or in combination, with varying degrees of severity.
The bronchitis phenotype is defined according to historic clinical criteria, i.e. the presence of 
cough and sputum on most days over 3 months in 2 consecutive years. Emphysema definition 
is based on pathological changes identified by radiological/functional outcomes, or ultimately 
on pathology. Clinical data suggests that the rate of decline of FEV1 varies across individual 
patients with COPD regardless of their initial GOLD (Global Initiative for Chronic 
Obstructive Lung Disease) FEV1 grade category, with a faster rate of decline observed in the 
emphysematous phenotype, but also in current smokers, and following COPD exacerbations.
The only COPD genotype identified so far is alpha1-antitrypsin deficiency. Severe deficiency 
of alpha1-antitrypsin is associated with a strong tendency for development of emphysema, 
often, but not always, panlobular in character and basal in distribution. This emphysema is 
thought to be the result of inadequate neutralisation of naturally occurring proteases, such as 
neutrophil elastase, by alpha1 proteinase inhibitor (A1PI), which normally serves as a 
protease inhibitor [R15-4639]. It is synthesized predominantly in the liver and functions as a 
serine proteinase inhibitor or serpin and provides essential protection to lung tissue against 
the actions of proteolytic enzymes such as neutrophil elastase (NE) and proteinase 3 (PR3). 
The most common deficient phenotype is PiZ, which encompasses both PiZZ and PiZ null 
genotypes. The majority of individuals with ‘severe pathophysiological deficiency’, classified 
by a serum A1AT level below the putative protective threshold (11 μM), have the PiZZ 
genotype [R15-4638].

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE STUDY
Pharmacological treatment of COPD is currently based on bronchodilators and anti-
inflammatory drugs. Approved medicines may relieve symptoms, reduce exacerbations 
and/or improve health status and exercise tolerance, but there is no treatment for disease 
progression in COPD, and systematic treatment options, apart from smoking cessation, do not 
prevent rate of decline of FEV1 over time, nor inhibit the lung structural damages. 
More in depth understanding of COPD patient phenotypes and the course and drivers of 
COPD disease progression is required to address this unmet medical need and enable drug 
development aiming at a reduction of COPD disease progression.  
Biomarkers may assist, beside clinical parameters, in characterizing patients and potentially 
in predicting and monitoring their disease course.
 
 
 
 
 
 
 
 
 
 
 
 
 increase the understanding of the 
underlying pathophysiology of emphysema progression.
BI plans to conduct this longitudinal emphysema progression biomarker study to identify 
biomarkers (soluble, functional imaging and physiological) that may be useful in 
differentiating a patient population with ongoing emphysematous destruction of lung 
parenchyma, which may enable development of drugs aiming at the reduction of COPD
progression.

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Rationale for the study extension to 3 years
It has become known from consortia data (
) that lung density decline, as 
assessed by CT and lung function decline, do not correlate across GOLD stages [R18-1744]. 
Therefore, besides characterizing emphysema progression in patients it will be important to 
also assess lung function decline by spirometry since this describes an additional high risk 
COPD patient subgroup with a large unmet medical need. Since detection of lung function 
decline is expected to take longer (3 years) than detection of lung density decline, the study is 
being extended to a 3 year observation time.
 
 
This study will include 60 healthy subjects (ex-smokers without airflow limitation), 125
COPD GOLD 1, 125 COPD GOLD 2, 125 COPD GOLD 3, and up to 20 patients with COPD
and A1AT deficiency (ZZ genotype). Soluble and imaging biomarkers will be investigated
addressing different aspects of disease pathways postulated to be relevant for COPD 
 
 
 
 
 
 
 
BENEFIT - RISK ASSESSMENT
This study is an observational study with no alteration in patient’s usual medication 
treatment. There will be no direct benefit for the participating subjects except the benefit 
which derives from the periodic monitoring of their health or disease status by the 
investigator and site staff. All subjects are allowed to continue their usual care.
The subject`s participation in the study requires standard medical procedures known to 
patients with respiratory diseases. The examinations include common procedures like 

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physical examination, cotinine test to determine smoking status, 12-lead ECG, spirometry, 
body plethysmography, and DLCO. Induction of sputum could result in bronchoconstriction 
and is performed after bronchodilation, but is usually quickly reversible with short acting ß-2-
agonist treatment [R12-5301].
Other procedures include common medical practices such as disease-specific questionnaires, 
routine blood sampling for safety assessment, and biomarker collection. All these procedures 
are known to have an acceptable safety risk and may also be performed in healthy volunteers.
A total blood volume of approximately 500 mL will be drawn over a period of about 3 years. 
Approximately 12 ml will be drawn at the screening visit and approximately 80 to 90 mL per 
biomarker sampling time point (Visit 2 – 7). This is much less than the volume of a normal 
blood donation (400 mL). No safety-related risk to the patients is expected from this blood 
withdrawal.
Monitoring for pregnancy will occur at the screening visit and prior to imaging procedures 
(CT and MRI) at Visits 2, 4, 5, 6, and 7 in order to avoid further risk. Pregnant women will 
be discontinued from further study participation, but should be followed up for vital status 
and COPD exacerbation status collection.
Imaging examinations are important components of this study. Chest CT plays a pivotal role 
to analyze pathologies of pulmonary emphysema not only in its morphological aspect but 
also in the assessment of severity. CT will also contribute to the phenotyping of COPD, such 
as primarily parenchymal disease or primarily airway disease [R15-4823].
 
 The annual exposure from natural background radiation is 2 – 3 mSv. 
The radiation dose applied per chest CT scan is approximately 5 times lower than the 
maximum effective annual dose limit of 20 mSv for people occupationally exposed (radiation 
workers) in Germany and about 12 times lower than the annual dose limit of 50 mSv for 
radiation workers in the US. The level of exposure of the chest CT scans is associated with a 
low additional lifetime risk of cancer (0.02 %), based on the assumption of the International 
Commission on Radiological Protection (ICRP) of 2007 [R15-3219] estimating an excess 
life-time cancer mortality risk of about 5% per Sv. Subjects with an increased risk of lung 
cancer (e.g. ex-smokers and smokers) may benefit from the CT assessment [R12-3778], 
considering the sensitivity of chest CT for lung cancer, critical for treatment success.
Chest CT scans will be performed in 40 to 70 years old subjects (30 to 70 years in patients 
with COPD and A1ATD) to accurately assess lung disease including emphysema, air 
trapping, small airway disease, and airway wall thickness. 
Magnet Resonance Imaging (MRI) will be conducted in a subset of subjects (substudy). MRI 
uses strong magnetic fields and radio waves to generate cross-sectional images of the body. 
In this study, MRI will be used to acquire morphological and functional information of the 
lungs and the heart. In contrast to CT, MRI does not use ionizing radiation (X-rays) and there 
are no known harmful effects associated with temporary exposure to the strong magnetic 
field of MRI scanners in patients without foreign bodies. Potential safety concerns are related 
to implanted medical devices, which can malfunction or heat up during the exams. Dyes from 
tattoos and tattooed eyeliners can cause skin or eye irritation, and medication patches can 
cause skin burn due to heating effects. Some subjects might suffer from claustrophobia

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during the examination. Subjects in the MRI scanner will be exposed to some noise, which 
will be minimized by ear protection but can still cause some discomfort. The use of contrast 
agent during the examinations is accompanied with a slight risk of an allergic reaction. 
However, the risk of a significant allergic reaction is 1:150,000 examinations. Additionally, 
MRI contrast agents can cause problems in patients with significant kidney disease. To 
minimize the risk, kidney function will be measured before the MRI scans. Only male and 
non-pregnant female subjects (without implanted devices susceptible to magnetic influence)
who present with stable clinical conditions and tolerate repeated MRI scanning will be 
considered for inclusion into the study.

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3.
DESCRIPTION OF DESIGN AND STUDY POPULATION
OVERALL STUDY DESIGN AND PLAN
This is a prospective longitudinal biomarker study in healthy subjects, patients with COPD 
and patients with COPD and A1ATD to phenotype COPD patients; the study investigates 
biomarkers potentially associated with emphysema. The study does not include 
administration of any investigational medicinal product.
This is a multi-national, multi-center study and involves approximately 12 participating 
countries with approximately 50 sites. It consists of 2 consecutive periods including a
screening and an observational period.
Figure 3.1: 1 Overview of Study Design
After informed consent all subjects will enter the screening period (Visit 1) to confirm
eligibility. All subjects who meet all inclusion criteria and do not present any of the exclusion 
criteria will enter the observational period of the study at Visit 2. Based on inclusion and 
exclusion criteria, subjects will be assigned to the following groups:

Healthy subjects

Patients with COPD grade 1

Patients with COPD grade 2

Patients with COPD grade 3

Patients with COPD and A1AT deficiency
The observational period lasts 3 years and includes 7 site visits and additional phone contacts 
to assess subjects’ status, ask for potential Medical Events of Special Interest (MESI) 
(including COPD exacerbations) and Adverse Events, and for changes in concomitant 
medication.
The observational period will be completed at Visit 7 or at the discontinuation visit, which is 
regarded as study completion.
Screening
Observational Period
Visit
Week
1
2
3
12
4
26
39
5
52

65

78

91
6
104
7
156

117

130

143


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All subjects who prematurely discontinue during the observational phase will be followed for 
vital status and COPD exacerbation status (the second for patients with COPD and patients 
with COPD and A1AT deficiency only) via phone calls until their hypothetical Visit 7 date 
(i.e. 156 weeks after Visit 2). Please refer to Section 3.3.5.1 and Section 6.2.2.
MRI will be performed in a subset of healthy subjects and patients with COPD (excluding 
patients with COPD and A1AT deficiency) only (substudy).
Sputum induction and processing will be performed in all subjects at selected sites only.
For a description of reporting of adverse events, see Section 5.9.6.2.
All study relevant documentation will be stored by Boehringer Ingelheim in the trial master 
file (TMF). Study relevant documentation for the study site(s) will be filed in the Investigator 
Site File (ISF) at the investigational site(s).
3.1.1
Administrative structure of the study
The sponsor of this study is Boehringer Ingelheim. The study will be conducted at clinical 
research center(s) specialized for pulmonary diseases, and experienced in the management of 
patients with COPD, A1ATD as well as in the recruitment of healthy volunteers.
A central laboratory facility will handle all standard safety blood laboratory analyses of the 
study.
Spirometric lung function assessment will be performed by an external vendor’s equipment in 
order to allow centralized reading.
ECG, imaging assessments, body plethysmography, pulse oximetry, 6 MWT, DLCO and 
induction of sputum (at selected sites only) will be performed with the site´s own equipment 
according to international accepted guidelines (where applicable). Please refer to Section 5.2
et seqq. and the ISF.
All samples collected for pre-specified biomarker assessments and biobanking will be 
prepared by the site according to instructions given in the ISF and frozen until shipment to 
the central CRO as indicated in the ISF. The biomarkers will be analyzed by the sponsor or 
contractors of the sponsor. Details are given in Section 5.8.
Recruitment: screening of subjects for this study is competitive, i.e. screening for the study 
will stop at all sites, when it is anticipated that a sufficient number of subjects have been 
screened to meet the planned number of study participants of up to 455 subjects. Investigators 
will be notified when the appropriate number of subjects has been screened and screening is 
complete, and will not be allowed to recruit additional subjects for this study.
Regarding the planned number of subjects per group (health volunteers, COPD grade 1, 2, 3,
patients with COPD and A1ATD) the same strategy will be applied to ensure a balanced and 
sufficient number of subjects per stratum. In other words, once a group of subjects is 
complete, the investigators will be notified in a timely manner to stop recruiting new subjects 

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to this specific cohort. Overall recruitment might be terminated independently of the number 
of enrolled A1ATD patients.
IRT: an Interactive Response Technology (IRT) system will be used in this study to keep 
track of subject enrollment. Sites are requested to register subject visits (clinic visits and 
phone calls) via IRT.
Subject reminder diary: all subjects will be provided with a paper diary to serve as a reminder 
to support the collection of Medical Events of Special Interest (MESI), adverse events and 
concomitant therapy at clinic and telephone visits. The subject reminder diary will be used to 
note new medical events, changes in symptoms, and medication usage between visits and 
serves as a reminder for the subjects. The subject reminder diaries will not be collected by the
site and remains the exclusive property of the subject.
In case of discontinuation from the observational phase, subjects are encouraged to continue 
utilization of their reminder diaries in order to be able to answer questions on their COPD
exacerbation status (only patients with COPD and patients with COPD and A1AT 
deficiency).
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 
-
manage the study in accordance with applicable regulations and internal SOPs
-
direct the clinical study team in the preparation, conduct, and reporting of the study
-
order the materials as needed for the study
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries
Data Management and Statistical Evaluation will be conducted by BI or contractors of the 
sponsor.
A joint Steering Committee (SC) consisting of experts independent of the Sponsor and 
internal BI experts will be established. The composition of the SC will be documented in the 
Trial Master File (TMF). The tasks and responsibilities will be agreed in contracts between 
the SC members and the Sponsor and also summarized in an SC-charter filed in the TMF.
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This biomarker study is planned to longitudinally assess biomarkers in different biofluids 
(whole blood, serum, plasma, induced sputum) and clinical parameters over a 3 year time
period in 60 healthy subjects, 375 patients with COPD and up to 20 patients with A1ATD 
associated COPD in order to establish surrogate markers for emphysema progression. 
 
The observational period of 156 weeks has been chosen to allow longitudinal assessment of 
emphysema progression by CT density over time. Inclusion of healthy subjects is needed to 

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provide a comparison for these biomarkers with subjects without airflow limitation. Patients 
with COPD and A1AT deficiency have been chosen, since they present with an earlier onset 
of emphysema and a faster decline in lung function as well as a faster change in lung density 
as assessed by CT. In addition the pathogenic role of antiprotease deficiency in the 
development of emphysema has been well established in those patients. 
 
 
 
 
 
 
 
 
 
SELECTION OF STUDY POPULATION
It is planned to enroll 60 healthy subjects, 125 patients with COPD of mild, 125 patients of
moderate, 125 patients of severe disease stage and up to 20 patients with COPD and A1AT
deficiency in approximately 50 sites.
A log of all subjects enrolled into the study (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have entered the 
observational period or not.
3.3.1
Main diagnosis for study entry
Population of healthy subjects, patients with COPD (GOLD grade 1 to 3) and patients with 
A1ATD according to the respective inclusion and exclusion criteria will be included into the 
study.
3.3.2
Healthy subjects
Inclusion criteria
1.
All subjects must sign an informed consent consistent with ICH-GCP guidelines prior 
to participation in the study, which also includes the application of study restrictions.
2.
Males and females must be healthy at the discretion of the investigator according to 
the following criteria: Based upon a complete medical history, including the physical 
examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests.
3.
Subjects must be ex-smokers for at least 9 months with a smoking history of ≥ 20 
pack years (see appendix 10.4, calculation of number of pack years).
4.
Subjects must be between the ages of ≥ 40 and ≤ 70 years.
5.
Subject must have a body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2 (≤30 kg/m2 in 
the MRI subset).

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6.
Subjects must have normal lung function values at Visit 1 with a documented post-
bronchodilator FEV1 ≥ 80% of predicted normal (GLI 2012 [R15-0845] and JRS 2014 
[R15-2073]; and a post-bronchodilator FEV1/FVC ≥ lower limit of normal (GLI 2012
[R15-0845] and JRS 2014 [R15-2073] documentation).
7.
Subjects must have a mean post DLCO over all acceptable measurements at Visit 1 of ≥ 
70 % of predicted normal (see Section 5.6).
8.
Subjects must be able to perform all study related procedures including technically 
acceptable pulmonary function tests, body plethysmography, DLCO, sputum induction
(if applicable), chest CT, and MRI (if applicable).
9.
Subjects must be on stable therapy (not limited to respiratory medication) for the last 
4 weeks prior to Visit 1.
Exclusion criteria
1.
Previous participation in this study or participation in another trial with an 
investigational drug within 6 weeks prior to Visit 1 or during the study.
2.
Respiratory tract infection in the 4 weeks prior to Visit 1 or during the screening 
period prior to Visit 2, if rescheduling rules of Section 6.1.1.4 cannot be met.
3.
Significant pulmonary disease or other significant medical conditions* (as determined 
by medical history, examination and clinical investigations at screening) that may, in 
the opinion of the investigator result in any of the following:
a. Put the subject at risk because of participation in the study
b. Cause concern regarding the subject’s ability to participate in the study
* e. g. rheumatoid arthritis, inflammatory bowel disease, severe liver disease, 
psoriasis, hematological, infectious and psychiatric diseases.
4.
Documented history of asthma. For subjects with allergic rhinitis or atopy, source 
documentation is required to verify that the subject does not have asthma.
5.
Planned surgery during the study expected to interfere with study procedures and 
outcome.
6.
Blood withdrawal of more than 100 mL within the past six weeks prior to Visit 1 and 
between Visit 1 and 2.
7.
Significant alcohol or drug abuse in the opinion of the investigator within past 2 years
prior to Visit 1.
8.
Women who are pregnant, nursing, or who plan to become pregnant while in the 
study.
9.
Place of permanent residence of less than 3 month prior to Visit 1.
10.
For the MRI subset: subjects who do not meet the following criteria for the MRI 
assessment at Visit 2: systolic blood pressure between 90 and 180 mmHg (SBP), 
diastolic blood pressure between 50 and 110 mmHg (DBP), pulse rate between 40 and 

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110 bpm, ear temperature between 35 - 37.5°C, and a glomerular filtration rate (GFR)
≥30 mL/min (GFR must not be older than 14 days from the MRI assessment).
11.
Subjects who are heterozygous or homozygous for the A1AT Z or S allele.
12.
Subjects presenting with an immunocompromising condition (e. g. patient is positive 
for Human Immunodeficiency Virus (HIV) or has a history of Hepatitis B or C).
3.3.3
Patients with COPD
Inclusion criteria
1.
All patients must sign an informed consent consistent with ICH-GCP guidelines prior 
to participation in the study, which also includes the application of study restrictions.
2.
Patients must be male or female outpatient.
3.
Patients must be between the ages of ≥ 40 and ≤ 70 years.
4.
Patients must have a body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2 (≤30 kg/m2 in 
the MRI subset).
5.
Patients must have a current diagnosis of COPD made by a physician prior to or 
during Visit 1 and an mMRC [R00-0206] score of 1 or more. The diagnosis of COPD 
must be in accordance with the GOLD Guidelines [P15-01740] and must be 
documented by the following criteria:
Known relatively stable airway obstruction with a post-bronchodilator FEV1/FVC < 
70 %.
6.
The current COPD must be mild, moderate or severe based on lung function and 
symptoms and the clinical situation must have been stabilized for at least 4 weeks
prior to Visit 1. The following definitions adapted from the GOLD Guidelines [P15-
01740] apply:
a.
Mild: post-bronchodilator FEV1 ≥ 80% of predicted normal (GLI 2012 [R15-
0845] and JRS 2014 [R15-2073] at Visit 1.
b. Moderate: 50% ≤ post-bronchodilator FEV1 < 80% of predicted normal (GLI 
2012 [R15-0845] and JRS 2014 [R15-2073] without chronic respiratory failure at 
Visit 1.
c.
Severe: 30% ≤ post-bronchodilator FEV1 < 50% of predicted normal (GLI 2012
[R15-0845] and JRS 2014 [R15-2073] without chronic respiratory failure at Visit 
1.
7.
Patients must be ex-smokers for at least 9 months with a smoking history of ≥ 20 pack 
years (see appendix 10.4, calculation of number of pack years).
8.
Patients must be able to perform all study related procedures including technically 
acceptable pulmonary function tests, body plethysmography, DLCO, sputum induction
(if applicable), chest CT, and MRI (if applicable).
9.
Patients must be on stable therapy (not limited to respiratory medication) for the last 4
weeks prior to Visit 1.

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Exclusion criteria
1.
Significant pulmonary disease other than COPD or other significant medical 
conditions* (as determined by medical history, examination and clinical investigations 
at screening) that may, in the opinion of the investigator result in any of the following:
a.
Put the patient at risk because of participation in the study
b. Cause concern regarding the patient’s ability to participate in the study
* e. g. rheumatoid arthritis, inflammatory bowel disease, severe liver disease, 
psoriasis, hematological, infectious and psychiatric diseases.
2.
Any respiratory tract infection or COPD exacerbation in the 4 weeks prior to Visit 1 
or during the screening period prior to Visit 2, if rescheduling rules of Section 6.1.1.4
cannot be met.
3.
A malignancy for which the patient has undergone resection, radiation or 
chemotherapy within past 5 years. Patients with treated basal cell carcinoma or fully 
cured squamous cell carcinoma are allowed.
4.
Documented history of asthma. For patients with allergic rhinitis or atopy, source 
documentation is required to verify that the subject does not have asthma.
5.
Hospitalization for respiratory failure during the year prior to Visit 1.
6.
A history of cystic fibrosis.
7.
Clinical diagnosis of bronchiectasis requiring specific treatment.
8.
A clinically relevant abnormal baseline hematology, blood chemistry in the opinion of 
the investigator.
9.
Planned surgery during the study expected to interfere with study procedures and 
outcome.
10.
Blood withdrawal of more than 100 mL within the past six weeks prior to Visit 1 and 
between Visit 1 and 2.
11.
Known active tuberculosis.
12.
Previous participation in this study or participation in another trial with an 
investigational drug within 6 weeks prior to Visit 1 or during the study.
13.
Significant alcohol or drug abuse in the opinion of the investigator within past 2 years
prior to Visit 1.
14.
Inability to comply with restrictions regarding medication, diet and life style (see 
Section 4.2.2).
15.
Newly added anti-inflammatory treatment within 4 weeks prior to Visit 1.
16.
Patients with change in any therapy within 4 weeks prior to Visit 1.
17.
Patients on treatment with PDE-4 inhibitors (e.g. Roflumilast) and maintenance 
treatment with Methylxanthines (e.g. Theophylline). Refer to Table 4.2.2: 1

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18.
Women who are pregnant, nursing, or who plan to become pregnant while in the 
study.
19.
Place of permanent residence of less than 3 month prior to Visit 1.
20.
For the MRI subset: patients who do not meet the following criteria for the MRI 
assessment at Visit 2: systolic blood pressure between 90 and 180 mmHg (SBP), 
diastolic blood pressure between 50 and 110 mmHg (DBP), pulse rate between 40 and 
110 bpm, ear temperature between 35 - 37.5°C, and a glomerular filtration rate (GFR)
≥30 mL/min (GFR must not be older than 14 days from the MRI assessment).
21.
Patients who are heterozygous or homozygous for the A1AT Z or S allele
22.
Patients presenting with an immunocompromising condition (e. g. patient is positive 
for Human Immunodeficiency Virus (HIV) or has a history of Hepatitis B or C).
3.3.4
Patients with COPD and A1AT deficiency
Inclusion criteria
1.
All patients must sign an informed consent consistent with ICH-GCP guidelines prior 
to participation in the study, which also includes the application of study restrictions.
2.
Patients must have a documented (prior to Visit 2) A1AT deficiency of ZZ genotype
(see appendix 10.4.4).
3.
Patients must be male or female outpatient.
4.
Patients must be ex-smokers for at least 9 months with a smoking history of ≥ 10 pack 
years (see appendix 10.4, calculation of number of pack years).
5.
Patients must have a current diagnosis of mild, moderate or severe COPD made by a 
physician prior to or during Visit 1 and an mMRC score of 1 or more. The diagnosis 
of COPD must be in accordance with the GOLD Guidelines [P15-01740] and must be 
documented by the following criteria:
Known relatively stable airway obstruction with a post-bronchodilator FEV1 of ≥30%
of predicted normal and a post-bronchodilator FEV1/FVC < 70 %.
6.
Patients must be between the ages of ≥ 30 and ≤ 70 years.
7.
Patients must have a body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2.
8.
Patients must be able to perform all study related procedures including technically 
acceptable pulmonary function tests, body plethysmography, DLCO, sputum induction
(if applicable), and chest CT.
9.
Patients must be on stable therapy (not limited to respiratory medication) for the last 4
weeks prior to Visit 1.

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Exclusion criteria
1.
Significant pulmonary disease other than COPD or other significant medical 
conditions* (as determined by medical history, examination and clinical investigations 
at screening) that may, in the opinion of the investigator result in any of the following:
a. Put the patient at risk because of participation in the study
b. Cause concern regarding the patient’s ability to participate in the study.
* e. g. rheumatoid arthritis, inflammatory bowel disease, severe liver disease, 
psoriasis, hematological, infectious and psychiatric diseases.
2.
Any respiratory tract infection or COPD exacerbation in the 4 weeks prior to Visit 1 
or during the screening period prior to Visit 2, if rescheduling rules of Section 6.1.1.4
cannot be met.
3.
Documented history of asthma. For subjects with allergic rhinitis or atopy, source 
documentation is required to verify that the subject does not have asthma.
4.
Current and planned A1AT augmentation therapy.
5.
Newly added anti-inflammatory treatment within 4 weeks prior to Visit 1.
6.
Patients on treatment with PDE-4 inhibitors (e.g. Roflumilast) and maintenance 
treatment with Methylxanthines (e.g. Theophylline). Refer to Table 4.2.2: 1
7.
A malignancy for which the patient has undergone resection, radiation or 
chemotherapy within past 5 years. Patients with treated basal cell carcinoma or fully 
cured squamous cell carcinoma are allowed.
8.
Hospitalization for respiratory failure during the year prior to Visit 1.
9.
A history of cystic fibrosis.
10.
Clinical diagnosis of bronchiectasis requiring specific treatment.
11.
Clinically relevant abnormal baseline hematology, blood chemistry in the opinion of 
the investigator.
12.
Planned surgery during the study expected to interfere with study procedures and 
outcome.
13.
Blood withdrawal of more than 100 mL within the past six weeks prior to Visit 1 and 
between Visit 1 and 2.
14.
Known active tuberculosis.
15.
Previous participation in this study or participation in another trial with an 
investigational drug within 6 weeks prior to Visit 1 or during the study.
16.
Significant alcohol or drug abuse in the opinion of the investigator within past 2 years
prior to Visit 1.
17.
Inability to comply with restrictions regarding medication, diet and life style (see 
Section 4.2.2).
18.
Patients with change in any therapy within 4 weeks prior to Visit 1.

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19.
Women who are pregnant, nursing, or who plan to become pregnant while in the 
study.
20.
Place of permanent residence of less than 3 month prior to Visit 1.
21.
Patients presenting with an immunocompromising condition (e. g. patient is positive 
for Human Immunodeficiency Virus (HIV) or has a history of Hepatitis B or C).
3.3.5
Removal of subjects from the study
Removal of individual subjects
In general, no subject should be removed from the study for a protocol violation before 
discussion with the clinical monitor.
An individual subject is to be withdrawn from study if any of the following criteria apply:

The subject withdraws consent for study participation, without the need to justify the 
decision.

The subject is no longer able to participate for medical reasons (such as surgery, 
adverse events, and other diseases).

The subject re-starts smoking at any time during the study (based on the investigators 
discretion). Refer to Section 4.2.2.2

The subject becomes pregnant. Refer to Section 5.9.5

A confirmed malignancy for which the patient is likely to undergo resection, radiation 
or chemotherapy.
Removal from the screening phase:
As long as a subject has not finished Visit 2, the subject is not considered to belong to the 
observational phase. Prior to Visit 2, reasons for withdrawal can be related to the criteria 
described above or to eligibility criteria (please refer to Section 3.3.2, 3.3.3, and 3.3.4). The 
data of subjects who withdraw prior to Visit 2 will be entered into the eCRF.
Removal from the observational phase:
Given the subject’s agreement, the subject should come to the site for a discontinuation visit 
at the time of the next scheduled visit. The subject will undergo the procedures of this 
particular visit as outlined in the flowchart and Section 6.2.2. If not possible, the subject 
should be encouraged to at least undergo the procedures for safety assessments. Women who 
become pregnant should undergo the procedures for safety assessments only (safety 
assessments comprise procedures outlined in Section 5.9).
The withdrawn subject should be followed-up for vital status and COPD exacerbation status. 
Please refer to Section 6.2.2.
For all subjects the reason for withdrawal (e.g. adverse events) must be recorded in the eCRF. 
These data will be included in the study database and reported.

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Discontinuation of the study by the sponsor
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the study
3. Violation of GCP, the CSP, or the contract disturbing the appropriate conduct of the 
study
The Investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).

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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
No study medication is administered in the study. All subjects are allowed to continue and 
change (e.g. in case disease progression occurs) their standard of care medications during the 
observational phase of the study. In case a patient is placed on alpha1-antitrypsin 
augmentation therapy during the observational period of the study, the patient can continue
the study.
CONCOMITANT MEDICATION, RESTRICTIONS, AND RESCUE 
MEDICATION
4.2.1
Rescue medication, emergency procedures, and additional medication(s)
Rescue medication
Administration of rescue medication can occur at any point during the study as deemed 
necessary by the subject or the investigator. If the subject requires rescue medication during 
the pulmonary function tests (PFT) and/or sputum induction (if applicable), visits will be 
continued if possible. The visit should not be re-scheduled.
All test-day rescue medication administered before the conclusion of all study-related 
procedures of this visit will be recorded in the source data and captured in the eCRF.
Rescue medication will not be provided by BI and should be made available by the
investigational site.
Emergency procedure
In the case of adverse events on a visit day, the subjects will be treated and kept under 
supervision at the study site as necessary or transferred to hospital until such time that all the 
results of the evaluations have returned to a medically acceptable level.
There are no special emergency procedures to be followed.
Additional medications
Subjects will be requested to inhale salbutamol (albuterol) as part of their spirometry, sputum 
induction (if applicable) and imaging assessments at visits indicated in the flowchart.
If subjects participate in the MRI substudy, they will be requested to receive an injection of a 
Gadolinium-based contrast agent at visits indicated in the flowchart.
4.2.2
Restrictions
There is no medication restricted from being used during the observational phase of the 
study, except for those listed in table 4.2.2: 1. Patients who are on alpha1-antitrypsin 
augmentation therapy must not be enrolled into the study.
There are short-term restrictions prior to Visit 1 and 2 (see table 4.2.2: 1), which are needed 
for the stability of lung function values and other assessments. It is recommended to avoid, if 
possible, short acting bronchodilators in the 8 hours prior to the clinic visits. Administration 
of marketed salbutamol (albuterol) which is needed for study procedures (e.g. PFTs, sputum
induction) should not exceed the total daily dose.
Treatment of adverse events is not restricted and within the responsibility of the investigator. 

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Table 4.2.2: 1
Overview of permitted, restricted, medications and therapies
Footnotes:
1.
For patients taking stable maintenance OCS with a total daily dose of ≤ 20 mg prednisone or equivalent
2.
Includes fixed dose combination therapy
3.
Allowed as stable dose for at least 4 weeks before Visit 1
4.
Allowed before Visit 1 with a washout period of 3 months or 6 half-lives whichever is greater
5.
If unstable (e.g. in case of exacerbations), extend screening period (see Section 6.1.1.4)
Restrictions regarding concomitant medication
Medications allowed to control acute COPD exacerbations or respiratory tract infection (RTI)
as medically necessary during the study:
•
Increases in the dose or addition of oral steroids are allowed. Pulmonary function 
testing visits should not occur within 14 days of the last administered dose of an 
increase or addition of oral steroids. Regular pulmonary function testing visits 
Drug Class
Prior to Visit 1
Between 
Visits 1 and 2
Observational period
Corticosteroid - nasal/ocular
Permitted
Permitted
Permitted
Corticosteroid – oral, inhaled1
Permitted3
Permitted 
(stable dose)5
Permitted 
Corticosteroid – i.v., i.m.
Permitted3
Not permitted5
Permitted
Short-acting β2-adrenergic agonist 
– Inhaled2 (SABA)
Permitted3
Permitted 
(stable dose)5
Permitted 
Long-acting β2-adrenergic
agonist – Inhaled2 (LABA)
Permitted3
Permitted 
(stable dose)5
Permitted
Short-acting anticholinergic –
Inhaled (SAMA)
Permitted3
Permitted 
(stable dose)5
Permitted
Long-acting anticholinergic –
Inhaled2 (LAMA)
Permitted3
Permitted 
(stable dose)5
Permitted
Leukotriene modifier
Permitted3
Permitted 
(stable dose)5
Permitted
Cromolyn sodium / nedocromil 
sodium
Permitted3
Permitted 
(stable dose)5
Permitted
Methylxanthines
Not Permitted4
Not Permitted
Permitted
PDE-4 inhibitors
Not Permitted4
Not Permitted
Permitted
Immunomodulators (e.g. 
methotrexate)
Not Permitted4
Not permitted
Permitted
Immunotherapy (e.g. sub 
cutaneous or sublingual)
Permitted3
Permitted
Permitted
Biologic antagonists (e.g. 
Omalizumab)
Not permitted4
Not permitted
Not permitted
A1AT augmentation therapy
Not permitted
Not permitted
Permitted
Other investigational drugs
Not permitted
Not permitted
Not permitted

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may be postponed to meet this restriction. Subsequent visits will not be adjusted, 
but will be scheduled as originally planned.
•
Additions of theophylline preparations are allowed during the observational 
portion of the study. Pulmonary function testing visits should not occur within 14
days of the last dose. Regular pulmonary function testing visits may be postponed 
to accommodate this restriction. Subsequent visits will not be adjusted, but will 
be scheduled as originally planned.
•
The use of antibiotics is not restricted and may be prescribed as medically 
necessary for COPD exacerbations and / or infections. If antibiotics are 
prescribed for a respiratory infection prior to pulmonary function testing visits, 
the visit will be postponed for 14 days after intake of the last dose. Regular 
pulmonary function testing visits may be postponed to accommodate this 
restriction. Subsequent visits will not be adjusted, but will be scheduled as 
originally planned.
Restrictions on diet and life style
•
Blood donations after Visit 2 until the end of study should be discouraged.
•
Restart of smoking until the end of study should be discouraged. Refer to Section 
3.3.5.1.
Restrictions prior to and during PFT visits:
•
Prior to pulmonary function testing and throughout the testing period, the subject 
must remain in the building where the pulmonary function testing is performed.
•
On pulmonary function test days (including the screening visit), subjects must 
refrain from strenuous activity for at least 12 hours prior to pulmonary function 
testing and throughout the testing period. Subjects should also avoid cold 
temperatures, environmental smoke, dust or areas with strong odors (e.g. 
perfumes).

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5.
VARIABLES AND THEIR ASSESSMENT 
SUMMARY OF STUDY OUTCOMES AND ASSESSMENTS
5.1.1
Main outcome measures
•
Change of lung density assessed by CT over the course of the study
•
Lung function decline over the course of the study
•
Number, duration and severity of exacerbations during the course of the study
5.1.2
Assessments
•
CT scanning
•
MRI
•
Spirometry: FEV1 and FVC
•
Diffusing capacity of the lungs for carbon monoxide: DLCO, DLCO/VA
•
Body plethysmography: TLC, IC, RV, ERV, IVC
•
Medical Events of Special Interest (including COPD exacerbations)
•
Biomarker
-
Blood (plasma, serum, whole blood)
-
Induced sputum (cells, supernatant) (at selected sites only)
•
Safety Assessments (including Adverse Events, refer to Section 5.9)
•
Pulse oximetry: SpO2
•
BODE index
•
Symptom Questionnaires:
-
Modified British Medical Research Council questionnaire (mMRC)
-
COPD Assessment test questionnaire (CAT)
-
St George's Respiratory Questionnaire (SGRQ)
•
6 minute walk test (6 MWT)
COMPUTED TOMOGRAPHY (CT)
A chest CT scan will be performed as indicated in the flowchart according to specifications 
detailed in the Central Imaging Vendor manual. A low dose inspiratory chest CT scan 
 to assess airway wall thickness and emphysema and an expiratory 
scan 
 to assess air trapping will be performed. To achieve optimal 
image quality, the chest CT will be done with subjects being in a state of bronchodilation, e.g. 
after administration of salbutamol (albuterol). Before beginning the chest CT scan, the 
inspiration/expiration maneuvers should be explained carefully to the subject. All scans on 
each subject will be completed on the same scanner used for the baseline CT and accredited 
for use by the Central Imaging Vendor. Chest CT scan will be performed at timepoints given 
in the flowchart. If a chest CT scan cannot be scheduled during the regular study visit, it has 
to be performed within 14 days after the visit. In this case, administration of salbutamol 
(albuterol) should be performed prior to the imaging assessment in patients with COPD as 
well as in healthy subjects (see Section 6.1.1.3).
All scans will be digitally transferred for central review within a pre-specified time period.
Phantom scans using the COPDGene Phantom have to be carried out regularly for quality 

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assurance purposes according to the Central Imaging Vendor manual. Further information on 
chest CT is provided in a separate manual filed in the ISF.
MAGNETIC RESONANCE IMAGING (MRI)
Magnetic resonance imaging (MRI) at 1.5 Tesla will be performed in a subset of healthy 
subjects and patients with COPD (not in patients with COPD and A1ATD) at selected sites to 
assess functional parameters using a cardio-pulmonary acquisition protocol according to 
specifications detailed in the Central Imaging Vendor manual. Overall 110 subjects, 
approximately 20 healthy subjects and 30 in each stratum of patients with COPD (GOLD 
grade 1, 2, 3) will be enrolled.
Morphological imaging of the lungs will be performed using an ultra-short-TE pulse 
sequence as well as fast T1- and T2-weighted pulse sequences. Cardiac cine images will be 
acquired in two and four chamber view as well as in short-axis view. Flow measurements 
using phase-contrast acquisitions will be performed in the pulmonary artery and the aorta. 
Contrast-enhanced time-resolved 3D MRA of the whole lung will be used to assess perfusion 
after the intravenous bolus injection of a marketed standard MRI gadolinium contrast agent.
To achieve optimal image quality, MRI will be done with subjects being in a state of 
bronchodilation, e.g. after administration of salbutamol (albuterol). Before beginning the 
MRI acquisitions, the breath hold maneuvers should be explained carefully to the subject. All 
subjects undergoing MRI must be checked for the following criteria: 90-180 mmHg (SBP), 
50-110 mmHg (DBP), 40-110 bpm (pulse rate), an ear temperature within 35-37.5°C, and a 
GFR ≥30 mL/min at each visit involving the MRI procedure (see flowchart). Subjects who 
do not meet all of these criteria are not eligible for the MRI procedure. GFR values must not 
be older than 14 days from the MRI assessment and can be assessed locally, if necessary. 
Please refer to Appendix 10.7.
All scans on each subject will be completed on the same MR scanner used for the baseline 
MRI and accredited for use by the Central Imaging Vendor. MRI scan will be performed at 
visits given in the flowchart. If an MRI examination cannot be scheduled during the regular 
study visit, it has to be performed within 14 days after the visit. In this case, administration of 
salbutamol (albuterol) should be performed prior to the imaging assessment in patients with 
COPD as well as in healthy subjects (see Section 6.1.1.3).
All scans will be digitally transferred for central review within a pre-specified time period.
Further information is provided in a separate manual filed in the ISF.
With implementation of CSP Version 6.0, the MRI sub-study will be stopped for all subjects 
who agreed to participate in this part of the study. No future MRI assessments should be 
conducted on these subjects (please also see section 7.4).
SPIROMETRY (PFT)
The spirometer and its use, including calibration (refer to procedural manual for timepoints), 
must meet ATS/ERS criteria [P05-12782]. The spirometry equipment will be provided by BI 
via a CRO for all participating sites. Spirometry will be conducted with the subject in a 
seated position. It is preferable that the same trained individual performs the PFTs for a given 
subject. The best of three efforts will be defined as the highest FEV1 and the highest FVC 
each obtained on any of three blows meeting the ATS criteria (with a maximum of eight 

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attempts). The highest FEV1 and FVC will be selected regardless of whether they come from 
different spirometric maneuvers or from the same maneuver. The 24-hour clock time of the 
first maneuver will be recorded.
At Visit 1, the PFT should be started between 7:00 a.m. and 10:00 a.m. At each following site 
visit, PFT will always start at approximately the same time of the day, i.e. with ± 60 minutes 
maximum difference between start of the tests at Visit 1 and the tests conducted on 
subsequent visits up to Visit 7.
At Visit 3, sites can use the spirometer provided by BI or a local device to assess the safety 
criteria (FEV1) for the sputum induction procedure.
Post-bronchodilator (salbutamol (albuterol)) testing:
Following the completion of three acceptable pre-bronchodilator forced expiratory 
manoeuvers, salbutamol (albuterol) will be administered to each subject. After a gentle and 
incomplete expiration, a dose of approximately 100 µg of salbutamol (albuterol) is inhaled in 
one breath to total lung capacity. The breath is inhaled for 5 – 10 sec before the subject 
exhales. Four separate doses (total dose approximately 400 µg) are delivered at 
approximately 30 sec intervals (this dose ensures that the response is high on the salbutamol
(albuterol) dose - response curve). Three additional, acceptable post-bronchodilator force 
expiratory manoeuver tests are recorded 15 – 30 minutes after the last dose of salbutamol
(albuterol) is inhaled ([P05-12782], modified in regard to timing of post-bronchodilator 
maneuvers).
During the study, a central quality control center will receive the data of spirometry 
measurements electronically to ensure that the sites maintain the same standard throughout 
the study. The central quality center will review the spirometry measurement data and report 
to the sponsor on data quality and, if required, actions to be taken.
DIFFUSING CAPACITY OF THE LUNGS FOR CARBON MONOXIDE 
(DLCO)
Diffusing capacity of the lung for carbon monoxide (DLCO) measurement will be performed 
according to American Thoracic Society (ATS)/European Respiratory Society (ERS) 
guidelines [R06-2002], after salbutamol (albuterol). The site will use its own DLCO equipment 
and conduct all measurements with the same DLCO equipment (e.g. if several devices would 
be available at the site). Before beginning the test, the maneuvers should be demonstrated and 
the subject carefully instructed. The subject should have rested 10 minutes before the test 
starts. DLCO will be measured by single breath, breath-holding technique: The subjects inhale 
a volume of defined gas during an inspiration to total lung capacity, hold their breath for 10 
seconds, and then perform an expiration smooth, unforced, without hesitation or interruption, 
and total exhalation time should not exceed 4 seconds. All measurements are to be made with 
the subjects seated upright and their nose clipped. Between the DLCO maneuvers a minimum 
waiting time of 4 minutes is required.
DLCO will be measured at timepoints given in the flowchart.
The following parameters will be reported:

DLCO: Diffusing capacity for the lungs measured using carbon monoxide

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
DLCO/VA: Diffusing capacity for carbon monoxide per unit of alveolar volume
For predicted normal values, different sites may use different prediction formulas, based on 
the method used to measure DLCO. In any case, the calculation method used must be in 
compliance with the ATS/ERS guideline on DLCO measurements [R06-2002], and the 
prediction formula appropriate for that method. Raw data (gas mixture, equation used for 
prediction of normal, further adjustments made if so) must be traced.
DLCO corrected for hemoglobin [R06-2002]:
•
Males:
DLCO corrected for Hb = DLCO measured [(10.22 + Hb)/1.7Hb]
•
Females:
DLCO corrected for Hb = DLCO measured [(9.38 + Hb)/1.7Hb]
Whereas Hb is expressed in g•dL-1.
The following rules will apply for the selection of DLCO data: For DLCO the mean value from 
three (if feasible; at least two are required) technically acceptable attempts will be used.
Repeatability criteria for DLCO according to American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines [R06-2002] have to be met.
BODY PLETHYSMOGRAPHY
Body plethysmography will be done in line with ATS/ERS standards [R08-1121], after 
salbutamol (albuterol), using the device of the investigational site for assessment of lung 
volumes and capacities. 
The measurement of functional residual capacity (FRC) will be repeated at least 3 times, until 
3 obtained FRC values show 5% variability.
Expiratory reserve volume (ERV) will be measured immediately after the FRC, followed by 
slow inspiratory vital capacity (IVC) manoeuver, all performed as ‘‘linked’’ manoeuvers (i.e. 
without the subject coming off the mouthpiece prior to the completion of the maneuvers).
COPD patients who cannot perform linked manoeuvers will be instructed to have few cycles 
of quiet breathing before initiation of the ERV/IVC manoeuvers.
Mean FRC value of at least 3 technically satisfactory FRC measurements, linked to the 
technically satisfactory ERV and IVC manoeuvers used for calculating the RV and TLC will 
be reported. Residual volume (RV) will be calculated as a difference between the reported 
FRC value and the mean of the technically acceptable ERV measurements, linked to 
technically acceptable FRC determinations. Total lung capacity (TLC) will be calculated by 
adding the reported value for RV and the largest of the technically acceptable IVCs. 
Inspiratory capacity (IC) will be derived from IVC and ERV, and IC/TLC will be calculated. 
RV % predicted will also be reported.
MEDICAL EVENTS OF SPECIAL INTEREST (MESI)
The term MESI relates to any specific event, including an exacerbation of a pre-existing 
condition that has been identified at the study level as being of particular interest for 
prospective monitoring and assessment within this study, e.g. the potential for being related 
to the underlying COPD disease based on current scientific knowledge. Additional (other) 
events might be reported at the discretion of the investigator and are then also considered 

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MESI. Occurrence of a MESI will be captured and assessed during screening (after subject 
signs inform consent) and observational period until the subject individual study completion/
discontinuation. These events can be detected during study procedures (e.g. physical 
examination, laboratory results) at clinic visits or might be reported by the subject and will be 
recorded on a specific eCRF.
If such abnormalities already pre-exist prior to study inclusion they will be considered as 
baseline conditions and recorded on a separate eCRF.
The following disorders are considered MESIs:
5.7.1
Respiratory Disorders
•
Pneumonia
•
Pulmonary fibrosis
•
Chronic respiratory failure
•
Asthma-chronic pulmonary disease overlap syndrome
•
Obstructive sleep apnoea
•
Bronchiectasis
•
Pleural effusion
•
Lung Cancer
•
COPD exacerbation
•
Other (at the discretion of the investigator)
Definition and assessment of COPD exacerbations
For the purpose of this study, a COPD exacerbation is defined as a complex of lower
respiratory events / symptoms (increase or new onset) related to the underlying COPD, with
duration of three days or more.
A complex of lower respiratory events / symptoms is defined as at least two of the following:
•
Shortness of breath
•
Sputum production (volume)
•
Change in sputum colour
•
Cough
•
Wheezing
•
Chest tightness
“Onset of exacerbation” will be defined as the onset of first recorded symptom. The “end of
exacerbation” will be decided by the investigator based on clinical judgment.
Exacerbations will be classified as follows:
Mild:
a new prescription or increased usage of maintenance bronchodilator only
Moderate:
patient receiving an exacerbation-related prescription of oral corticosteroids
and/ or antibiotic not requiring hospitalisation
Severe:
COPD-related hospitalisation including emergency room visit

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In the situation of hospitalisation associated with COPD exacerbation, the information 
collected should include the start date of all COPD-related hospitalisations as well as the 
discharge date from the hospital or equivalent.
Information regarding exacerbations will be collected by the investigators during the visits 
and telephone calls, and recorded in the eCRF. During all telephone calls and clinic visits, the 
same questions regarding exacerbation will be addressed for collecting exacerbation-related 
details and then recorded in the eCRF.
For all patients (completed/discontinued) the COPD exacerbation collection period of interest
will be the screening and observational phase ending at Visit 7/ discontinuation visit.
If subjects are hospitalized, the study site will be responsible for collecting and reviewing 
pertinent medical records so that an informed judgment can be made as to the primary cause 
for admission.
5.7.2
Cardiovascular disorders
•
Angina pectoris
•
Ischaemic heart disease (including myocardial infarction)
•
(Arterial) Hypertension (including pulmonary (arterial) hypertension)
•
Hypotension
•
Aneurysm
•
Syncope
•
Cardiac arrhythmia
•
Heart failure (including congestive heart failure)
•
Cerebrovascular disease 
•
Other (at the discretion of the investigator)
5.7.3
Metabolic/ Digestive disorders
•
Diabetes mellitus
•
Obesity
•
Hyper-/Dyslipidaemia
•
Cholecystitis
•
Cholecystolithiasis
•
Colitis (including Ulcerative colitis)
•
Gastro-oesophageal reflux disease (GERD)
•
Other (at the discretion of the investigator)
5.7.4
Neurological/psychiatric disorders
•
Dementia 
•
Cognitive impairment
•
Depression
•
Anxiety
•
Other (at the discretion of the investigator)

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5.7.5
Other disorders
•
Osteo-articular disorders (osteoporosis, rheumatoid arthritis, osteoarthritis)
•
Other (at the discretion of the investigator)
BIOMARKER ASSESSMENTS 
Pre-specified biomarkers will be analyzed in several biofluids at Visits 2 to 7. 
 
 
 
 
 
 
 
 
Whole blood
Total and differential cell counts in blood, which are assessed within the safety lab 
assessments, will also be assessed as biomarkers. 
Blood will be collected to enable DNA analyses. The DNA sample will be used to determine 
the A1AT genotype.
 
 
Sputum Subset
At those sites selected to collect induced sputum samples, sputum will be processed 
according to the manual filed in the ISF to generate different sputum samples 
 
 
 
 
 

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5.8.1
Biomarker sample collection 
Blood collection
Blood samples will be taken at time points indicated in the flowchart.
Detailed instructions for biomarker blood sampling, processing, storage and shipment of the 
different biofluids are provided in the site’s ISF.

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Collection of sputum (in a subset of subjects only)
Induction and collection of sputum will be done in all subjects at selected sites only and 
samples will be taken at time points indicated in the flowchart.
In addition, subjects who have signed informed consent might be asked to provide an induced 
test sputum sample at the screening visit in order to assess the sputum processing capabilities 
at the investigational site. In this case the test sputum induction should take place at least 20
days prior to the first subject performing Visit 2 at the site.
The provided sputum samples will be obtained and processed according to the manual for 
sputum induction and processing provided in the ISF. The processing of sputum samples 
should start immediately, but no later than 1 hour after the sample has been taken.
Sputum induction will be started following all other visit assessments and should be done 
with the subjects being in a state of bronchodilation.
Patients are allowed to take their usual COPD medication before sputum induction. In 
addition, pre-treatment with salbutamol (albuterol) should be repeated if time between 
morning administration of salbutamol (albuterol) for post-bronchodilator PFT measurement
and start of sputum induction is exceeding 4 hours.
Subjects who are not able to produce an acceptable sputum sample at Visit 2 and Visit 2 
Retest as determined by the central overread will continue in the study, however, no sputum 
induction should be performed for the remainder of the study (from Visit 3 to Visit 
7/discontinuation).
Detailed instructions for sputum induction and processing, storage and shipment are provided 
in the site’s ISF.
5.8.2
Methods and timing of sample collection
All biomarker samples will be collected according to the flowchart.
Detailed instructions for biomarker sampling, sample processing, storage and shipment are 
provided in the ISF.

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5.8.3
Analytical determinations
The analytical methods for the analysis of biomarkers will be given in detail in an analytical 
report.
5.8.4
Biobanking
All biomarker samples (
 will be used for 
further unspecified analysis to establish a better understanding of COPD and other respiratory 
diseases. The study samples will be discarded after completion of the additional 
investigations,
. 
These further scientific evaluations will be described in the subject information sheet and will 
be part of the informed consent.
 
 
 
 
 
 
 
 
 
ASSESSMENT OF SAFETY
5.9.1
Physical examination
A physical examination will be carried out at visits 1, 5, 6, and 7. In addition further physical 
examination should be performed if clarification of AEs is necessary.
All clinically significant findings at screening will be documented on the source documents 
and recorded in the eCRF as baseline conditions.

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After Visit 1, new findings or worsening of screening conditions will be reported as adverse 
event if they are, in the opinion of the investigator, associated with a study procedure as 
described in Section 5.9.6.
Body height will be determined on screening visit only (Visit 1). Body weight will be 
measured at Visit 1, 5, 6, and 7.
Body weight and height will be documented on the source documents and recorded in the 
eCRF. BMI will be calculated automatically on the eCRF (refer to Appendix 10.4.3)
5.9.2
Vital Signs
Vital signs (blood pressure, pulse rate) will be taken at Visit 1, 5, 6, and 7. Systolic and 
diastolic blood pressure (BP) and pulse rate (PR) will be measured after the subject has rested 
for at least 5 minutes in a supine position. All measurements of an individual subject shall be 
made using the same blood pressure recording instrument on the same arm. The method, the 
identifier of the blood pressure recording instrument and the arm must be recorded in the 
source documents.
The measured vital signs will be documented on the source documents and recorded in the 
eCRF.
5.9.3
Safety laboratory parameters
Safety laboratory parameters will be obtained from blood. A full panel of clinical laboratory 
tests (hematology, chemistry, and coagulation) will be done at Visit 1, 2, 5, 6, and 7. A 
reduced laboratory panel will be conducted at Visit 3 and 4 (see flowchart).
Detailed instructions for laboratory safety blood sampling, handling and shipment of samples 
will be provided in the ISF / laboratory manual.
A total amount of approximately 70 mL blood will be taken per subject (approximately 10
mL per visit) during the whole course of the study for laboratory parameters listed in Table 
5.9.3: 1. The respective reference ranges will be provided in the Investigator Site File (ISF). 
Refer to the flowchart for time points. The date and exact blood collection times must be 
documented on the source documents.
The laboratory tests listed in Table 5.9.3: 1 will be performed by a central laboratory. 
The central laboratory will send reports to the investigational site. It is the responsibility of 
the investigator/ sub-investigator to evaluate the laboratory reports. Abnormal findings as 
judged by the investigator will be reported as adverse events if they are associated with a 
study procedure (please refer to Section 5.9.6.2).
The central laboratory will transfer the results of the safety analysis to the sponsor.

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Table 5.9.3: 1 
Safety laboratory parameters and exploratory biomarkers obtained 
from blood and measured by the central laboratory
Category
Test name 
Hematology
Hematocrit (Hct) *
Hemoglobin (Hb) *
Red Blood Cell Count / Erythrocytes (inclusive MCV 
(mean corpuscular volume), MCH (mean corpuscular 
hemoglobin) and MCHC (Mean Cellular Hemoglobin 
Concentration))*
Reticulocyte Count *
Platelet Count / Thrombocytes *
Coagulation
Activated Partial Thromboplastin Time (= aPTT)
Prothrombin Time (Quick and INR)
Enzymes
SGOT
SGPT
Alkaline Phosphatase (AP/ALP)
Creatine Kinase (CK)
CK-MB if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Amylase
Substrates
Glucose (fasted)
Creatinine *
Bilirubin Total 
Bilirubin Direct
Protein, Total
Uric Acid 
Electrolytes
Calcium
Sodium
Potassium
Magnesium
* Parameters to be analyzed on the reduced safety panel.

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5.9.4
Electrocardiogram
A 12-lead ECG will be performed at Visit 1 (only for screening purposes, no data collected 
apart findings to be reported as baseline condition), visit 5, 6, and visit 7.
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using the ECG machine 
of the investigator site. ECG-records will be stored at the investigational site.
The ECGs will be recorded for about 10-second duration after the subject has rested for at 
least 5 minutes in a supine position. Electrode placement will be performed according to the 
Wilson method (precordial leads) and Goldberger and Einthoven (limb leads).
The ECG records will be evaluated for pathological results by the investigator or a designee. 
Abnormal findings as judged by the Investigator/Sub-Investigator will be reported as adverse 
events if they are associated with a study procedure (please refer to Section 5.9.6.2).
Any ECG abnormalities will be carefully monitored by the investigator and, if necessary, the 
subject will be removed from the study and medically treated.
5.9.5
Pregnancy tests
Urine pregnancy tests will be done at visits 1, 2, 4, 5, 6, and 7 in the clinic in women of 
childbearing potential only. Women not of childbearing potential are defined as women who 
are postmenopausal (12 months with no menses without an alternative medical cause) or who 
are permanently sterilized (e.g. hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy). Tubal ligation is NOT a method of permanent sterilisation. If the urine 
pregnancy test is positive, subjects will be discontinued from the study (refer to Section 
3.3.5.1), and should be asked if they agree to receive phone calls for Vital Status and COPD 
exacerbation status collection (for timepoints refer to Section 6.2.2: Vital Status and COPD 
exacerbation status collection (Phone Call)). The decision must be documented in the 
subjects’ charts.
5.9.6
Assessment of adverse events
Adverse events will be collected and assessed as outlined below.
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient or clinical investigation subject 
undergoing a study procedure (e.g. MRI with a contrast agent) according to the study 
protocol.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with a study procedure, 
whether or not considered related to the study procedure.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death

is life-threatening

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
requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability or incapacity

is a congenital anomaly/birth defect
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions
Life-threatening in this context refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
For Japan only: the following events will be handled as “deemed serious for any other 
reason”:
AEs which possibly lead to disability will be reported as SAEs.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, confounding factors such as 
concomitant medication, concomitant diseases and relevant history.
Yes:
There is a reasonable causal relationship between a study procedure and the AE.
No:
There is no reasonable causal relationship between a study procedure and the AE.
Adverse event collection and reporting
AE Collection and Reporting
The following must be collected and documented on the appropriate eCRF by the 
Investigator:

From signing the informed consent onwards until individual subject’s Visit 7/ 
discontinuation visit:
All AEs (serious and non-serious), which are associated with any study procedure.
The Investigator should enter SAEs, and non-serious AEs which are relevant for the SAE
immediately (within 24 hours) into the eCRF. The same timeline applies if SAE follow-up 
information becomes available.

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Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages.
The Investigator should determine the causal relationship to the study procedures outlined 
under Section 6.2.
All (S)AEs, including those persisting after individual subject’s study completion of study
must be followed up until they have resolved, have been sufficiently characterized, or no 
further information can be obtained.
Reporting of related Adverse Events associated with any BI drug
The investigator is encouraged to report all adverse events related to any BI drug according to 
the local regulatory requirements for spontaneous AE reporting at the investigator’s 
discretion by using the locally established routes and AE report forms. The term AE includes 
drug exposure during pregnancy, and, regardless of whether an AE occurred or not, any 
abuse, off-label use, misuse, medication error, occupational exposure, lack of effect, and 
unexpected benefit.
PULSE OXIMETRY
Oxygen saturation (SpO2) will be measured by non-invasive pulse oximetry using the pulse 
oximetry measurement device of the investigational site. All recordings shall be made using 
the same pulse oximetry measurement device per site on the same finger of the subject. The 
identifier of the pulse oximetry measurement device must be recorded in the source 
documents as well as the finger used. Refer to flowchart for time points.
Subjects will be asked not to use nail polish or acrylic nails to optimize the pulse oximeter 
measurement.
The measured SpO2 values will be documented on the source documents and recorded in the 
eCRF.
SYMPTOM QUESTIONNAIRES
5.11.1
mMRC
The Modified Medical Research Council Dyspnoea Scale (mMRC) [R00-0206] should be 
completed by COPD patients as the first questionnaire during a study visit, prior to the CAT 
and SGRQ, pulmonary function testing and all other procedures. The mMRC will be 
completed at Visit 1, 2, 5, 6, and 7.
The mMRC uses a simple grading system to assess a patient´s level of dyspnoea. All 
questions relate to everyday activities and are generally easily understood by patients. Scores 
range from 0 (none) to 4 (very severe) and are usually obtained in a few seconds.
5.11.2
COPD Assessment Test (CAT)
The CAT [R12-1915] should be completed by COPD patients after the mMRC and prior to 
the SGRQ, pulmonary function testing and all other procedures. The CAT will be completed 
at Visit 2, 5, 6, and 7.

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The CAT is designed to measure health status impairment in COPD and consists of 8 uni-
dimensional items with scores ranging from 0 to 5 (0 = no impairment). An overall score is 
calculated by adding the score from each item. The CAT is provided on paper (appendix 
10.1). Patients should be by themselves in a quiet place when they complete the 
questionnaire. The investigator (or designated site personnel) should check that all items have 
been completed by the patient, but the response to each item should not be questioned. 
Challenges to inconsistent responses (e.g. a really pronounced outlier) should only be done 
very infrequently and with very careful consideration. The scores will then be transcribed into 
the eCRF by the Investigator (or designated site personnel). The original will be retained at 
the site.
5.11.3
Saint George’s Respiratory Questionnaire (SGRQ)
The SGRQ [R96-0686] should be completed by COPD patients after the CAT test during a 
study visit, prior to pulmonary function testing and all other procedures. The SGRQ will be 
completed at Visit 2, 5, 6, and 7.
The SGRQ is designed to measure health impairment in patients with COPD. It is divided 
into two parts. Part I produce the Symptoms score, and Part 2 the Activity and Impacts 
scores. A Total score is also produced.
Part 1 (Questions 1 to 8) covers the patient’s recollection of their symptoms over a preceding 
period that may range from 1 month to 1 year. It is not designed to be an accurate 
epidemiological tool; its purpose is to assess the patient’s perception of their recent 
respiratory problems. The original version was validated using a 12-month recall period. A 
3-month recall period has been used very satisfactorily. In summary, the 3-month and 1-year 
versions provide the best properties, with no specific advantages to either. 
Part 2 (questions 9 to 16) addresses the patients’ current state (i.e. how they are these days). 
The activity score just measures disturbances to patient’s daily physical activity. The Impacts 
score covers a wide range of disturbances of psycho-social function. Validation studies 
showed that this component relates in part to respiratory symptoms, but it also correlates 
quite strongly with exercise performance (6-minute walk test), breathlessness in daily life 
(MRC breathlessness score) and disturbances of mood (anxiety and depression). The Impacts 
score is, therefore, the broadest component of the questionnaires, covering the whole range of 
disturbances that respiratory patients experience in their lives.
Details of the SGRQ are provided in appendix 10.2.
6 MINUTE WALK TEST (6 MWT)
The 6 MWT should be done according to ATS guideline [R03-0725]. Testing should be 
performed at Visits 1, 2, 6, and 7 in a location where a rapid, appropriate response in the 
event of an emergency is possible (see ATS guideline for other technical aspects, e.g. choice 
of location, required equipment, etc.).
Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
salbutamol (albuterol) in metered dose inhaler or nebulizer. A telephone or other means 
should be in place to enable a call for help.

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If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or as 
directed by a physician.
A physician is required to be present for the first test (at Visit 1) and for subsequent tests, as 
needed.
Reasons for immediately stopping a 6 MWT include the following:
•
Chest pain
•
Intolerable dyspnea
•
Leg cramps
•
Staggering
•
Diaphoresis
•
Pale or ashen appearance.
The distance walked will be measured in meters (m) and will be recorded. If the test is 
stopped prematurely, the distance (m), the duration (min), and the reason for stopping will be 
recorded.
APPROPRIATENESS OF MEASUREMENTS
The majority of measurements performed during this study are standard measurements and 
will be performed in order to monitor safety aspects or assess study objectives in an 
appropriate way.
 
 The frequency and intensity of the 
procedures was determined to guarantee a successful assessment of study parameters and to 
put study subjects at low risk.
Chest CT is the current gold standard to assess lung density or loss of lung density, i.e. 
emphysema, and airway disease, which cannot be done by other techniques including other 
imaging modalities such as MRI.
 
.

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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
The study consists of a screening period and an observational period. Following the screening 
period (up to 28 days long), subjects will enter the observational period at Visit 2. Clinic
visits and phone calls will be scheduled as per flowchart.
Subjects should make all efforts to complete the study. Investigators should encourage 
adherence to the protocol procedures. All subjects should adhere to the visit schedule as 
specified in the flowchart. Any deviations from the planned visit schedule should be 
documented.
6.1.1
Rescheduling clinic visits and study procedures
Diet and life style restrictions
Diet and life style restrictions are necessary for subjects’ safety and study assessments. Clinic 
visits involving a PFT may be rescheduled twice within the permitted time windows due to 
lack of dietary and life style restrictions. If possible, subjects should be contacted by 
telephone within 3 days before the clinic visit to remind them about the visit schedule and the 
restrictions.
Sputum induction (at selected sites only)
Sputum induction at Visit 2 can be rescheduled up to 3 days. If the subject is unable to 
produce an adequate sample of the sputum or a sputum sample of acceptable quality at visit 2
(after feedback from the vendor), repeat sputum induction should be performed. An interval 
of at least 3 full days and up to 21 days should be observed between repeat sputum induction 
procedures. All other Visit 2 procedures should have been completed on the originally 
scheduled Visit 2 date.
If sputum induction procedure at Visit 2 needs to be repeated, subject will complete only the 
sputum induction procedure at the repeat visit. In this case, sputum induction should be 
started within 15 min to 4 hours after salbutamol (albuterol) inhalation. Salbutamol 
(albuterol) can be self-administered by the subject under the supervision of the staff 
performing the sputum induction according to the inhalation procedure described for the post-
bronchodilator testing (four separate doses at approximately 30 sec interval, see Section 5.4).
Sputum induction procedures at Visits 3 - 7 will not be repeated if the subject is unable to 
produce sputum or if the sputum sample quality is not acceptable. If the sputum induction and 
processing procedure cannot be scheduled during the regular study Visits 3 to 7, it should be 
rescheduled within 21 days after the visit. In this case, administration of salbutamol 
(albuterol) should be performed prior to the procedure.

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Imaging assessments (chest CT and MRI)
If chest CT and (if applicable) MRI cannot be performed at the day of the scheduled visit the 
imaging assessment can be rescheduled up to 14 days after the visit. In this case imaging 
assessments should be performed 15 min to 4 hours after salbutamol (albuterol) inhalation. 
Salbutamol (albuterol) can be self-administered by the subject under the supervision of the 
staff performing the imaging assessments according to the inhalation procedure described for 
the post-bronchodilator testing (four separate doses at approximately 30 sec interval, see 
Section 5.4).
COPD exacerbation and respiratory tract infection
If a patient experiences a COPD exacerbation or respiratory tract infection during the 
screening period, Visit 2 will be postponed until 4 weeks following recovery from the 
exacerbation or infection. Screening period may be extended up to eight weeks if the patient 
experiences a COPD exacerbation or respiratory tract infection during the screening period
(refer to Section 4.2.2.1).
If patient has a COPD exacerbation or respiratory tract infection during the observational 
period, study visits will be rescheduled. Please discuss with the Local Clinical Monitor.
Rescheduling clinic visits during the screening period
In general, the screening period can be extended for administrative reason, e.g. (extended 
travel, life events or if lab results are not yet available). The delay should be kept as short as 
possible and if longer than additional 4 weeks, please contact the Local Clinical Monitor. A 
re-screening visit can be considered.
Rescheduling clinic visits during the observational period
All clinic visits should be completed at the time window allowed in the flowchart. 
If a clinic visit after Visit 2 is out of the time window allowed by the protocol, subsequent 
visits should occur at the originally scheduled date. Any clinic visits outside the time window 
allowed by the protocol should be discussed with the Local Clinical Monitor. All subjects are 
expected to complete the observational period.
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
An informed consent will be obtained prior to subject’s participation in the study. 
Considering the number and complexity of study procedures and the duration of the study, 
the subjects should be given sufficient time to discuss concerns, potential benefits and risks,
and obligations. Restrictions according to Section 4.2.2 are allowed only after the subject
signs the informed consent. If the subject is willing to provide a sample for unspecified 
pharmacogenomic testing, a separate consent must be obtained. If the subject is willing to 
participate in the MRI subset (only at selected study sites) a separate consent must be 

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obtained. Each subject will be assigned a unique subject number and once the subject signed 
informed consent, enrollment will be recorded in eCRF.
At Visit 1, demographics, medical history (including baseline conditions), physical 
examination, BMI, vital signs (including pulse oximetry) and eligibility criteria will be
assessed. Concomitant therapy, smoking status, MESI and AE (if study procedure related)
will be recorded. Subjects will be provided with a reminder diary (see Section 3.1.1).
Visit 1 should be scheduled to start in the morning between 6:00 am and 9:00 am. Restriction 
check, pregnancy test (if applicable) and IRT subject visit registration should be done first. 
The sequence of procedures will be mMRC, followed by ECG and pre PFT. Post PFTs 
should be done prior to post DLCO. 6 MWT should be performed after post PFTs/DLCO. Blood 
samples for safety laboratory and PGx testing should be collected after the ECG procedure is 
completed.
Instructions for shipping of laboratory samples will be provided in the manual.
If the subject has met all the eligibility criteria, Visit 2 will be scheduled.
Discontinuation during the screening period
If subjects discontinue from the study during the screening period, no additional clinic visits 
are required, and they will be marked as screen failures.
Subjects who were discontinued during screening period under the criteria of the former 
protocol version can re-enter the study if they meet the amended inclusion/exclusion criteria.
In this case, the subject will receive a new subject number and be treated like a new subject
(e.g. new informed consent).
Re-screening
Subjects may be re-screened once with approval from the Local Clinical Monitor (subjects 
keep the original subject number). Subjects who met all inclusion criteria but failed first 
screening due to acute medical conditions that have since been resolved or those who failed 
to comply with diet and life style restrictions will be good candidates for re-screening. If 
other reasons apply, please contact your local CML. The re-screening visit should be entered 
as a separate visit in in the eCRF.
6.2.2
Observational period and Study Completion
Eligibility criteria that apply at Visit 2 must be re-checked before proceeding with Visit 2.
The observational period begins after the subject completes Visit 2 and ends after completion 
of Visit 7 at Week 156 or after the discontinuation visit. Procedures listed under each visit in 
the flowchart should be completed. Visit windows should be adhered as specified in the 
flowchart.
All visits during the observational period should be scheduled to start in the mornings
according to Visit 1. Restriction check, smoking status, pregnancy test (if applicable) and IRT 
subject visit registration should be done first. Other checks include review of concomitant 
medication, MESI and AE. Physical examination and vital sign assessment (including pulse 
oximetry) will be performed additionally at Visits 5, 6, and 7.

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The sequence of procedures will be the completion of the questionnaires mMRC, CAT and 
SGRQ, followed by ECG and pre PFT. Post PFTs should be done prior to post 
DLCO/bodyplethysmography. Chest CT (and MRI, if applicable) should be performed 
between 1h and 4h after the end of the salbutamol (albuterol) administration (post-
bronchodilator testing) at timepoints indicated in the flowchart. 6 MWT should be performed 
after post PFT/DLCO/bodyplethysmography. Blood samples for safety and biomarker 
assessment should be collected after the ECG procedure is completed. Collection of induced 
sputum (if applicable) should be the last procedure. A spirometric device will be used to 
perform the PFTs and monitor subject’s lung function during sputum induction. The BODE 
index will be calculated at visit 2, 6, and 7 in patients with COPD/COPD and A1ATD only.
If the scheduled visit does not occur within the protocol allowed time window, follow 
instructions provided in Section 6.1.1 for rescheduling. Unscheduled visits may be arranged 
if necessary and the procedures completed during the unscheduled visit will depend on the 
circumstances under which the visit was scheduled.
Telephone contacts between clinic visits
Study sites will follow up subjects and collect information by telephone interviews at the 
dates indicated in the flowchart and will perform an IRT subject visit registration call. A 
subjects’ reminder card will be provided to assist their memory recall in terms of respiratory 
symptoms, COPD exacerbations, hospitalization or interim health care visits, and 
concomitant therapy.
At each telephone contact, the investigator or delegate will review with the subject new 
occurrences of MESI (including COPD exacerbation: new occurrence of exacerbation, 
respiratory symptoms, COPD exacerbation-related hospitalization and other pertaining 
information) and will record it in the eCRF. If subjects are hospitalized, the study site might
consider collecting and reviewing pertinent medical records (hospital records, telephone or 
written correspondence with primary physicians, discharge summaries, and death certificates)
so that an informed judgment can be made as to the primary cause for admission.
In case of hospitalizations, subjects will be encouraged to promptly inform the study site 
prior to their regularly scheduled telephone interviews.
Details of all COPD exacerbations will be captured in the source notes.
Study Completion
Visit 7/ discontinuation visit will mark the end of the study period, and the subject has 
completed the study.
Discontinuation during the observational period
If a subject discontinues from the study during the observational period, the subject should be 
asked to come to the site for a discontinuation visit at the time of the next scheduled visit. 
The subject will undergo the procedures of this particular visit as outlined in the flowchart. If 
not possible, the subject should be encouraged to at least undergo the procedures for safety 
assessments. Women who become pregnant should undergo the procedures for safety 
assessments only.

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Vital Status and COPD exacerbation status collection (Phone Call):
The objective of the phone call is to collect information on vital status (dead or alive) and 
COPD exacerbation status (COPD exacerbation status only in patients with COPD and 
patients with COPD and A1AT deficiency) in the time interval between the subjects’ 
discontinuation date from the observational period and their hypothetical Visit 7 date. No 
other MESI will be collected during the phone call.
Depending on the point in time when the subject discontinues, the vital status and COPD 
exacerbation status collection phone call will be scheduled as follows:
Discontinuation date between Visit 2 and 5 will result in 3 telephone calls:
1.
First collection: predicted 52 weeks (D364 ± 14) from Visit 2
2.
Second collection: predicted 104 weeks (D728 ± 14) from Visit 2
3.
Third collection: predicted 156 weeks (D1092 ± 14) from Visit 2
Discontinuation date between Visit 5 and 6 will result in 2 telephone calls:
1.
First collection: predicted 104 weeks (D728 ± 14) from Visit 2
2.
Second collection: predicted 156 weeks (D1092 ± 14) from Visit 2
Discontinuation date between Visit 6 and 7 will result in 1 telephone call:
1.
First collection: predicted 156 weeks (D1092 ± 14) from Visit 2
If death occurs, the investigator will review the circumstances, including the relevant medical
records to ascertain the most likely primary cause, if possible. Vital status and COPD 
exacerbation status information will be collected in accordance with national ethical and 
regulatory guidelines.
The purpose of the Vital Status and COPD exacerbation status collection will be explained to 
subjects prior to their participation in the study and will be part of the written informed
consent.
Informed consent procedure and Vital Status and COPD exacerbation status information 
collection:
All subjects should be asked again at the timepoint of discontinuation, if they still agree to 
participate in the Vital Status and COPD exacerbation status collection part of the study. The 
decision must be documented in the subjects’ charts.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
 
 
 
 
 
 
 
 
All subjects entering the study will be included in the analyses. Protocol violations will be 
defined in TSAP. Per-protocol set will be defined accordingly thereafter.
NULL AND ALTERNATIVE HYPOTHESES
No statistical hypotheses in a confirmatory sense are planned. All statistical tests are 
exploratory. 
PLANNED ANALYSES
Variables to be analyzed are:

Soluble biomarkers: assessments are made from blood sample (whole blood, serum, 
and plasma), and induced sputum. 
. See 
Section 5.8 for details.

Imaging biomarkers: assessments are made from CT and MRI. 
 
 See Sections 5.2 and 5.3 for details.

Clinical and disease progression biomarkers: assessments are standard clinical 
measurements for patients with COPD. Examples are FEV1, mMRC, or 6 MWT. See 
Sections 5.4, 5.5, 5.6, 5.10, 5.11 and 5.12 for details.

Medical events of special interest: they include pre-defined disorders and their 
intensities (additional other events might be reported at the discretion of the 
investigators). Examples are COPD exacerbations, heart failure or obesity. See 
Section 5.7 for details.

Safety assessments: They include, for example, laboratory parameters, adverse events 
and their intensities. See Section 5.9 for details.
Subjects’ demographics and medical history are summarized. They may be included in 
regression models to adjust for potential confounding.

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7.3.1
Primary analyses
Descriptive and Summary Statistics
Continuous variables are characterized by their distributional summary statistics. Ordinal, 
counts, and categorical variables are summarized by counts and frequencies. Statistics are 
computed for each subject group (healthy subjects, GOLD 1, GOLD 2, GOLD 3, and COPD 
with A1ATD), and for all subjects combined when appropriate. 
For variables measured for more than once during the course of the study, descriptive 
statistics are provided at each time point. In addition, if they are continuous, changes from 
baseline are calculated by subtracting baseline values from post-baseline values. Summary 
statistics are presented for each change by each subject group and by all subjects combined. 
Their 95% confidence intervals are also presented.
Summary plots such as histograms, barplots, or boxplots are produced as visual aids for 
understanding the distributions of these variables.
Correlations
Correlations between different biomarkers and between biomarkers and clinical assessments 
are estimated using Pearson or Spearman correlations for each subject group and for all 
subjects combined. Correlations between changes from baseline of the biomarker values are 
similarly estimated. Scatterplots are produced in addition.
ANOVA Models and Logistic regression for Baseline Biomarker Values
Baseline values are defined as the last measurement taken by the end of Visit 2. 
To compare baseline biomarkers and clinical assessments across subject groups, analysis of 
covariance (ANOVA) models for continuous variables and logistic regressions for ordinal 
and categorical variables will be conducted. Demographic variables and baseline disease 
status are adjusted to account for potential imbalance in baseline values. A detailed list of 
covariates will be discussed in TSAP.
Predictive models
To examine the predictive potential of the biomarkers—soluble, imaging and physiological—
in clinical outcomes, e.g. FEV1 decline at week 56, separate regression models are fitted for 
the clinical assessments using changes from baseline at each post-baseline time-point while 
adjusting for baseline covariates.
 
 
 
 

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Repeated Measurement Models for Changes in Biomarkers Over Time
Repeated measurement models are fitted for selected biomarkers and clinical assessments. 
This method provides a time profile and an overall trend for changes in these assessments.
7.3.2
Secondary analyses
Exploratory statistical regression and prediction models will be developed for clinical 
assessments based on biomarker values alone, and based on biomarker values in conjunction 
with established baseline covariates. Their performances will be evaluated. Different 
approaches such as penalized regression models, recursive partitioning, or classification and 
regression tree (CART) methods will be investigated.
7.3.4
Safety analyses
All subjects enrolled will be included in the safety analysis. In general, safety analyses are 
descriptive in nature and are based on BI standards. No hypothesis testing is planned.
Adverse events (AEs) will be coded using the latest version (at the time of database lock) of 
Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. Standard BI 
summary tables and listings will be produced by subject groups.
Statistical analysis and reporting of AEs will focus on AEs that are study procedure related as
judged by the investigators and medical events of special interest (MESI) as defined in 
Section 5.7.

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Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the latest version of MedDRA. Frequency of 
MESIs will be tabulated by disorder.
Laboratory data will be analyzed both quantitatively as well as qualitatively. The latter are 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Subject groups will be compared descriptively with regard to distribution parameters as well 
as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the study and at the end-of-study evaluation will be assessed 
with regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic analyses
Not applicable
7.3.6
Pharmacogenomic analyses
Genomic parameters are assessed at baseline only. They may be adjusted in the 
aforementioned statistical models as baseline covariates.
INTERIM ANALYSES
An interim analysis will be conducted after data from the 52-week and 104-week assessment 
are available for at least 70% of subjects entered in the study. An interim database lock will 
occur. The interim analysis will be conducted by the trial team. Detail of the planned 
statistical analyses will be defined in the TSAP. No separate CTR will be provided. Results 
of this analysis will be stored.

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HANDLING OF MISSING DATA
Missing data may be imputed if deemed necessary. Details will be discussed in the Trial 
Statistical Analysis Plan (TSAP).
RANDOMISATION
Not applicable.
DETERMINATION OF SAMPLE SIZE
Due to the exploratory nature of the study, power computations are focused on attaining 
desired precisions for biomarker estimates and relevant clinical assessments in all COPD 
patient groups except for the A1ATD group. 
Calculations are performed in SAS 9.3 using PROC POWER procedure. By assuming up to a 
20% dropout rate, at least 100 subjects are expected to contribute to the analysis at the end of 
3-year study period. The computations are thus based on 100 subjects in each COPD patient 
group.
7.7.1
Power computation based on FEV1 annual decline
Available information reports standard deviations (SD) of annual FEV1 decline ranging from 
about 20 mL/year [P12-04707] to over 60 mL/year [R15-3625]. 
Using this information, with a planned 100 subjects in each group, the following table 
provides the coverage probability for the half-width of a 95% confidence interval (CI) for the 
decline of FEV1 for a given SD. For example, if the observed SD is 50 mL/year, and the true 
half-width of the CI is 11 mL/year, with 100 subjects, the probability that the observed CI 
will cover the true CI is 93.8% (see highlighted cells in Table 7.7.1: 1).
Table 7.7.1: 1
Coverage probability of 95% confidence intervals 
(alpha = 0.05, n = 100)
Half-width of a 95% CI
SD
6
7
8
9
10
11
12
13
14
15
25
0.998
>.999
>.999
>.999
>.999
>.999
>.999
>.999
>.999
>.999
30
0.557
0.993
>.999
>.999
>.999
>.999
>.999
>.999
>.999
>.999
35
0.026
0.557
0.983
>.999
>.999
>.999
>.999
>.999
>.999
>.999
40
<.001
0.048
0.557
0.97
>.999
>.999
>.999
>.999
>.999
>.999
45
<.001
<.001
0.072
0.557
0.954
>.999
>.999
>.999
>.999
>.999
50
<.001
<.001
0.003
0.097
0.557
0.938
0.998
>.999
>.999
>.999
55
<.001
<.001
<.001
0.006
0.122
0.557
0.921
0.996
>.999
>.999

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Table 7.7.1: 1 (cont.)
Coverage probability of 95% confidence intervals 
(alpha = 0.05, n = 100)
Half-width of a 95% CI
SD
6
7
8
9
10
11
12
13
14
15
60
<.001
<.001
<.001
<.001
0.011
0.146
0.557
0.905
0.993
>.999
65
<.001
<.001
<.001
<.001
<.001
0.018
0.168
0.557
0.889
0.988
70
<.001
<.001
<.001
<.001
<.001
0.001
0.026
0.189
0.557
0.873
Figure 7.7.1: 1Visual presentation of Table 7.7.1: 1
7.7.2
Power computation based on PD15 decline
Reported SD on annual PD15 decline, a CT parameter, ranges from 3.4 to 5.5 unit [P15-
06332] [R15-3199]. Using the same assumptions as before, Table 7.7.2: 1 contains 
probability coverage of a true CI for a given SD for 100 subjects.
Table 7.7.2: 1
Coverage probability of 95% confidence intervals (alpha = 0.05, n = 
100)
Half-width of a 95% CI
SD
0.55
0.6
0.65
0.7
0.75
0.8
0.85
0.9
0.95
1
1.05
2.5
0.938
0.998
>.999
>.999
>.999
>.999
>.999
>.999
>.999
>.999
>.999
3
0.146
0.557
0.905
0.993
>.999
>.999
>.999
>.999
>.999
>.999
>.999
3.5
0.001
0.026
0.189
0.557
0.873
0.983
0.999
>.999
>.999
>.999
>.999
4
<.001
<.001
0.005
0.048
0.226
0.557
0.846
0.97
0.997
>.999
>.999
4.5
<.001
<.001
<.001
<.001
0.011
0.072
0.257
0.557
0.822
0.954
0.993
5
<.001
<.001
<.001
<.001
<.001
0.003
0.021
0.097
0.284
0.557
0.801
5.5
<.001
<.001
<.001
<.001
<.001
<.001
<.001
0.006
0.033
0.122
0.306
6
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
0.002
0.011
0.048

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Figure 7.7.2: 1Visual presentation of Table 7.7.2: 1
7.7.3
Power Computation based on Partial Pearson Correlation Coefficients
In addition, with 100 subjects in each group by allowing for up to 15 covariates, a partial 
Pearson correlation coefficient of 0.30 can be declared significant with 80% power between 
any two continuous variables (e.g. FEV1 and a new biomarker) within the group. 
Table 7.7.3: 1 below provides additional details.
Table 7.7.3: 1
Power for a given Pearson correlation coefficient (alpha = 0.05, two-
sided tests, n = 100)
Partial Pearson 
correlation
# of partial variables
0
5
10
15
0.25
0.715
0.692
0.668
0.643
0.30
0.865
0.847
0.827
0.805
0.35
0.951
0.941
0.929
0.914
0.40
0.987
0.983
0.978
0.971
The results from these calculations indicate the study has adequate power to estimate the 
biomarker values from the assessments described in previous sections.

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8.
INFORMED CONSENT, DATA PROTECTION, STUDY
RECORDS
The study will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997), relevant BI Standard Operating Procedures 
(SOPs), and relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the subject.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the study subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a rule, no study results should be 
published prior to finalization of the Clinical Study Report.
The certificate of insurance cover is made available to the Investigator and the subject, and is
stored in the ISF (Investigator Site File).
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed 
and/or approved/confirmed by the respective Institutional Review Board (IRB) / Independent 
Ethics Committee (IEC) and/or competent authority (CA) as applicable according to national 
and international regulations. The same applies for the implementation of changes introduced 
by amendments.
Prior to subject participation in the study, written informed consent must be obtained from 
each subject (or the subjects’ legally accepted representative) according to ICH / GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form retained by the Investigator as part of the study records. A signed copy of 
the informed consent and any additional subject information must be given to each subject or 
the patient’s legally accepted representative.
The Investigator (or delegate, if locally applicable) must give a full explanation to study
subjects including the items listed below in association with the use of the subject
information form, which is prepared avoiding the use of technical terms and expressions. 
The subject must be given sufficient time to consider participation in the study. The 
Investigator (or delegate, if locally applicable) obtains written consent of the subject’s own 
free will with the informed consent form after confirming that the subject understands the 
contents. The Investigator (or delegate, if locally applicable) must sign (or place a seal on) 

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and date the informed consent form. If a study collaborator has given a supplementary 
explanation, the study collaborator also signs (or places a seal on) and dates the informed 
consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this study may be conducted by the Sponsor,
Sponsor’s designees, or by IRB / IEC or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the Investigator’s study-related files and 
correspondence, and the informed consent documentation of this clinical study.
RECORDS
Electronic Case Report Forms (eCRF) for individual subjects will be provided by the Sponsor.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study; current medical records must also be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical study
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Expedited reporting to health authorities and IEC / IRB
There will be no global expedited reporting of adverse events in this study. If applicable, 
expedited reporting of serious adverse events to health authorities and IEC / IRB will be done 
according to local regulatory requirements.

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STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using Subject identification code numbers.
Treatment data may be given to the subjects’ personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
Sponsor’s representatives, by the IRB / IEC and the regulatory authorities if applicable.
END OF STUDY
The end of the study is defined as the last subject completing Visit 7, the last visit of the 
observational phase.
The IEC / competent authority in each participating EU member state will be notified about 
the end or early termination of the study as applicable according to national regulations.

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9.
REFERENCES
PUBLISHED REFERENCES
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi 
G, Wanger J
Standardisation of spirometry.
Eur Respir J 26 (2), 319 - 338 (2005)
P12-04707
Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, 
Shimizu K, Betsuyaku T, Ito YM, Fuke S, Igarashi T, Akiyama Y, Ogura S, 
Hokkaido COPD Cohort Study Investigators
Annual change in pulmonary function and clinical phenotype in chronic 
obstructive pulmonary disease.
Am J Respir Crit Care Med 185 (1), 44 - 52 (2012)
P15-01740
Global Initiative for Chronic Obstructive Lung Disease (GOLD)
Global strategy for the diagnosis, management. and prevention of chronic 
obstructive pulmonary disease (updated 2015).
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015.pdf 
(access date: 16 February 2015) (2015)
P15-06332
Coxson HO
The presence and progression of emphysema in COPD as determined by 
CT scanning and biomarker expression: a prospective analysis from the 
ECLIPSE study.
Lancet Respir Med 1, 129 (2013)
R96-0686
Jones PW, Quirk FH
A self-complete measure of health status for chronic airflow limitation. 
Am Rev Respir Dis 145, 1321 - 1327 (1992)
R00-0206
Mahler DA, Wells CK
Evaluation of clinical methods for rating dyspnea.
Chest 93 (3), 580 - 586 (1988)
R03-0725
Crapo RO, Enright PL, Zeballos RJ
ATSstatement: guidelines for the six-minute walk test. This official 
statement of the American Thoracic Society was approved by the ATS 
Board of Directors March 2002.
Am J Respir Crit Care Med 166, 111 - 117 (2002)

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R04-0879
Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez 
RA, Pinto Plata V, Cabral HJ
The body-mass index, airflow obstruction, dyspnea, and exercise capacity 
index in chronic obstructive pulmonary disease.
N Engl J Med 350 (10), 1005 - 1012 (2004)
R06-2002
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, 
Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, 
Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, 
Pellegrino R, Wanger J
Standardisation of the single-breath determination of carbon monoxide 
uptake in the lung.
Eur Respir J 26 (4), 720 - 735 (2005)
R08-1121
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, 
Casaburi R, Crapo R, Enright P, Grinten CPM van der, Gustafsson P, 
Hankinson J, Jensen R, Johnson D, MacIntyre N, McKay R, Miller MR, 
Navajas D, Pellegrino R, Viegi G
Standardisation of the measurement of lung volumes.
Eur Respir J 26 (3), 511 - 522 (2005)
R12-1915
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK
Development and first validation of the COPD Assessment Test.
Eur Respir J 34 (3), 648 - 654 (2009)
R12-3778
Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, 
Byers DA, Colditz GA, Gould MK, Jett JR, Sabichi AL, Smith-Bindman R, 
Wood DE, Qaseem A, Detterbeck FC
Benefits and harms of CT screening for lung cancer: a systematic review.
JAMA 307 (22), 2418 - 2429 (2012)
R12-5301
Pizzichini E, Pizzichini MMM, Leigh R, Djukanovic R, Sterk PJ
Safety of sputum induction.
Eur Respir J 20 (Suppl 37), 9S - 18S (2002)
R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright 
PL, Hankinson JL, Ip MSM, Zheng J, Janet Stocks on behalf of the ERS 
Global Lung Function Initiative
Multi-ethnic reference values for spirometry for the 3 - 95 year age range: 
the global lung function 2012 equations: report of the Global Lung Function 
Initiative (GLI), ERS task force to establish improved lung function 
reference values.
Eur Respir J 40 (6), 1324 - 1343 (2012)

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R15-1513
Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, 
Vestbo J, Lomas DA, Calverley PMA, Wouters E, Crim C, Yates JC, 
Silverman EK, Coxson HO, Bakke P, Mayer RJ, Celli B, Evaluation of 
COPD Longitudinally to Identify Predictive Surrogate Endpoints 
(ECLIPSE) Investigators
Persistentsystemic inflammation is associated with poor clinical outcomes 
in COPD: a novel phenotype.
Plos One 7 (5), e37483 (2012)
R15-2073
Kubota M, Kobayashi H, Quanjer PH, Omori H, Tatsumi K, Kanazawa M, 
Clinical Pulmonary Functions Committee of the Japanese Respiratory 
Society
Reference values for spirometry, including vital capacity, in Japanese adults 
calculated with the LMS method and compared with previous values. 
Respir Invest 52 (4), 242 - 250 (2014)
R15-3199
Dirksen A, Piitulainen E, Parr DG, Deng C, Wencker M, Shaker SB, 
Stockley RA
Exploring the role of CT densitometry: a randomised study of augmentation 
therapy in alpha1-antitrypsin deficiency.
Eur Respir J 33 (6), 1345 - 1353 (2009)
R15-3211
Fujita J, Nelson NL, Daughton DM, Dobry CA, Spurzem JR, Irino S, 
Rennard SI
Evaluation of elastase and antielastase balance in patients with chronic 
bronchitis and pulmonary emphysema.
Am Rev Respir Dis 142 (1), 57 - 62 (1990)
R15-3212
Paone G, Conti V, Vestri A, Leone A, Puglisi G, Benassi F, Brunetti G, 
Schmid G, Cammarella I, Terzano C
Analysis of sputum markers in the evaluation of lung inflammation and 
functional impairment in symptomatic smokers and COPD patients.
Dis Markers 31, 91 - 100 (2011)
R15-3219
International Commission on Radiological Protection (ICRP)
2007 Recommendations of the International Commission on Radiological 
Protection (users edition): abstract.
http://www.icrp.org/publication.asp?id=ICRP%20Publication%20103%20(
Users%20Editi on) (access date: 24 June 2015) ; (ICRP Publication; 103 
(Users Edition)) International Commission on Radiological Protection 
(ICRP) (2007)
R15-3605
Kelly MG, Brown V, Martin SL, Ennis M, Elborn JS
Comparison of sputum induction using high-output and low-output 
ultrasonic nebulizers in normal subjects and patients with COPD.
Chest 122 (3), 955 - 959 (2002)

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R15-3606
Sinden NJ, Stockley RA
Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin 
deficiency and COPD.
Eur Respir J 41 (5), 1042 - 1050 (2013)
R15-3607
Chapman KR, Burdon JGW, Piitulainen E, Sandhaus RA, Seersholm N, 
Stocks JM, Stoel BC, Huang L, Yao Z, Edelman JM, McElvaney NG, 
RAPID Trial Study Group
Intravenous augmentation treatment and lung density in severe alpha1 
antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-
controlled trial.
Lancet, (2015)
R15-3608
Leeming DJ, Sand JM, Nielsen MJ, Genovese F, Martinez FJ, Hogaboam 
CM, Han MLK, Klickstein LB, Karsdal MA
Serological investigation of the collagen degradation profile of patients with 
chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis.
Biomarker Insights 7, 119 - 126 (2012)
R15-3609
Cheng DT, et al, TESRA and ECLIPSE Investigators
Systemic soluble receptor for advanced glycation endproducts is a 
biomarker of emphysema and associated with AGER genetic variants in 
patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 188 (8), 948 - 957 (2013)
R15-3610
Bowler RP
Surfactant protein D as a biomarker for chronic obstructive pulmonary
disease.
COPD J Chronic Obstruct Pulm Dis 9 (6), 651 - 653 (2012)
R15-3625
COPD genetics.
http://www.copdgene.org/copd-genetics (access date: 9 July 2015) ; 
COPDGene (2015)
R15-3746
Ma S, Turino GM, Lin YY, He J, Chapman KR, Sandhaus RA, McElvaney 
NG, Yan X, Edelman JM
Effect of A1-Pi augmentation therapy on biomarkers of elastin degradation: 
analysis of samples from the RAPID trial.
ATS 2015, 111th Int Conf of the American Thoracic Society (ATS), 
Denver, 15 - 20 May 2015
Am J Respir Crit Care Med 191, A3638, Abstr (2015)
R15-4638
Guidelines for the approach to the patient with severe hereditary alpha-1-
antitrypsin deficiency.
Am Rev Respir Dis 140 (5), 1494 - 1497 (1969)

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R15-4639
Laurell CB, Eriksson S
The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin 
deficiency.
Scand J Clin Lab Invest 15 (2), 132 - 140 (1963)
R15-4823
Takahashi M, Fukuoka J, Nitta N, Takazakura R, Nagatani Y, Murakami Y, 
Otani H, Murata K
Imaging of pulmonary emphysema: a pictorial review.
Int J Chronic Obstruct Pulm Dis 3 (2), 193 - 204 (2008)
R18-1744
Diaz AA, Strand M, Coxson HO, Ross JC, Estepar RSJ, Lynch D, et al
Disease severity dependence of the longitudinal association between CT 
lung density and lung function in smokers
Chest 153 (3), 638-645 (2018)

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10.
APPENDICES
COPD ASSESSMENT TEST™ (CAT)

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SAINT GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ)
What is the St George’s Respiratory Questionnaire?
The SGRQ is designed to measure health impairment in patients with asthma and COPD. It is 
also valid for use in bronchiectasis and has been used successfully in patients with 
kyphoscoliosis and sarcoidosis. It is not suitable for cystic fibrosis. It is in two parts. Part I 
produces the Symptoms score, and Part 2 the Activity and Impacts scores. A Total score is 
also produced.
Part 1 (Questions 1 to 8) covers the patients’ recollection of their symptoms over a preceding 
period that may range 1 month to 1 year. It is not designed to be an accurate epidemiological 
tool; its purpose is to assess the patient’s perception of their recent respiratory problems. The 
original version was validated using a 12-month recall period. More recently a 1 month recall 
version (appropriately worded) has been validated. This has slightly weaker psychometric 
properties than the 12-month version and produces a marginally lower Symptom score and 
Total score.
Part 2 (Questions 9 to 16) addresses the patients’ current state (i.e. how they are these days). 
The Activity score just measures disturbances to patients’ daily physical activity. The 
Impacts score covers a wide range of disturbances of psycho-social function. Validation 
studies showed that this component relates in part to respiratory symptoms, but it also 
correlates quite strongly with exercise performance (6-minute walking test), breathlessness in 
daily life (MRC breathlessness score) and disturbances of mood (anxiety and depression). 
The Impacts score is, therefore, the broadest component of the questionnaires, covering the 
whole range of disturbances that respiratory patients experience in their lives.
How should it be administered?
The questionnaire should be completed in a quiet area free from distraction and the patient 
should ideally be sitting at a desk or table. Explain to the patient why they are completing the 
questionnaire, and how important it is for us to understand how they feel about their illness 
and the effect it has on their daily life. Ask the patient to complete the questionnaire as 
honestly as possible and stress that there are no right or wrong answers; simply the answer 
that the patient feels applies to them. Explain that they must answer every question and that 
someone will be close at hand to answer any queries.
The SGRQ is designed as a supervised self-administered questionnaire. This means that the 
patients should complete the questionnaire themselves but someone should be available to 
give advice if it is required. The patient’s responses should not be influenced by the opinions 
of family, friends or members of staff. The questionnaire is designed to elicit the patient’s 
opinion of his/her health, not someone else’s opinion of it. If the spouse or partner has 
accompanied the patient they should be asked to wait in a separate area. Similarly, do not 
allow patients to take the SGRQ home to be completed since you cannot be sure that it will 
be completed without the help of family or friends.
It is very important, once the patient has finished, that you check the questionnaire to make 
sure a response has been given to every question and return it the patient for completion of 
missed items, before the patient leaves.

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What should I do about queries regarding completion of the questionnaire?
If a patient asks for help with a question, do not provide an answer for them. The point of the 
questionnaire is to get an understanding of how the patient views his or her illness. It is 
appropriate to clarify a question but not to provide an answer. Questions may be read aloud if 
patients have difficulty with reading, but the responses must be theirs alone. If a patient gives 
an answer you disagree with it is not appropriate to challenge their response or to query it. It 
is their view of their condition we are interested in – no matter how strange the response!
The following are notes which may help you explain to patients what is required:
1.
In Part 1 of the questionnaire, emphasize to patients that you are interested in how much 
chest trouble they have had over the last month.
2.
Asthma and COPD can vary day-to day. In Part 2, we want to know about the patient’s 
current state (these days). 
3.
A severe or very unpleasant attack of chest trouble (Part 1, Question 5) is any attack that 
could be described that way in the patient’s own judgment. Not ‘severe’ as defined by 
medical staff.
4.
For Question 7 emphasize that you are interested in the number of good days that they 
have had.
5.
Question 10 regarding employment can cause patients some problems. We are interested 
in how a patient’s chest trouble affects their current working life or how it affected life 
when they were working. For example, if a patient took early retirement because of their 
chest condition, the response would be 10a – ‘My chest trouble made me stop work’, if a 
patient’s retirement was unrelated to their chest trouble, their response would be 10c ‘My 
chest trouble does not affect my work’.
6.
Questions 11 to 16 require a response to every question. It may be worth emphasizing 
this to the patient.
7.
Many patients do not engage in physical activity. It is important to determine whether
this is because they do not wish to (in which case the answer would be ‘False’) or cannot 
engage in these activities because of their chest trouble (in which case the answer would 
be ‘True’).
8.
Medication questions refer to medications and treatments given for a patient chest 
disease and may interfere with their life if, for example, they are on oxygen support and 
have to carry it around with them.
9.
It should be emphasized that responses to Question 15 are in terms of breathing 
difficulties and not any other problems. If patients do not engage in activities described 
in certain items, they should tick ‘False’. Patients, who do not engage in these activities 
because they are limited by their breathlessness, should tick ‘True’.

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EXAMPLE OF QUESTIONNAIRE
PART 1
QUESTIONS ABOUT HOW MUCH CHEST TROUBLE YOU HAVE HAD OVER THE 
LAST MONTH.   PLEASE TICK ONE BOX FOR EACH QUESTION.
Most days 
a week
Several days 
a week
A few days a 
month
Only with 
chest 
infections
Not at all
Over the last month,
I have coughed





Over the last month, I 
have brought up phlegm 
(sputum)





Over the last month, I 
have had shortness of 
breath





Over the last month, I 
have had attacks of 
wheezing





During the last month, how many severe or very unpleasant attacks 
of chest trouble have you had:
More than 3 attacks …… □
3 attacks ………………. □
2 attacks ………………. □
1 attack ……………….. □
No attacks ……………... □
How long did the worst attack of chest trouble last: (Go to 
Question 7 if you had no severe attacks)
1 week or more ……….. □
3 or more days ………... □
1 or 2 days ……………. □
Less than 1 day ……….. □
Over the last month, in an average week, how many good days 
(with little chest trouble) have you had:
No good days ………….. □
1 or 2 good days ……… □
3 or 4 good days ……… □
Nearly every day is good .□
Every day is good ……... □
If you have a wheeze, is it worse in the morning:
No …………………….
□
Yes ……………………
□

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PART 2
SECTION 1:
HOW WOULD YOU DESCRIBE YOUR CHEST CONDITION? (PLEASE TICK IN ONE 
BOX ONLY)
The most important problem I have....................................................................................................... □
Causes me quite a lot of problems......................................................................................................... □
Causes me a few problems .................................................................................................................... □
Causes me no problems ......................................................................................................................... □
IF YOU HAVE EVER HAD PAID EMPLOYMENT, PLEASE TICK ONE OF THESE
My chest trouble made me stop work altogether................................................................................... □
My chest trouble interferes with my work or made me change my job................................................. □
My chest trouble does not affect my work ............................................................................................ □
SECTION 2:
QUESTIONS ABOUT WHAT ACTIVITIES USUALLY MAKE YOU FEEL 
BREATHLESS THESE DAYS. PLEASE TICK IN THE BOX EITHER TRUE OR FALSE, 
AS IT APPLIES TO YOU
Sitting or lying still.........................................................................................□ True □ False
Getting washed or dressed..............................................................................□ True □ False
Walking around the home...............................................................................□ True □ False
Walking outside on the level ..........................................................................□ True □ False
Walking up a flight of stairs ...........................................................................□ True □ False
Walking up hills .............................................................................................□ True □ False
Playing sports or games..................................................................................□ True □ False
SECTION 3:
SOME MORE QUESTIONS ABOUT YOUR COUGH AND BREATHLESSNESS THESE 
DAYS.
PLEASE TICK IN THE BOX EITHER TRUE OR FALSE AS IT APPLIES TO YOU.
My cough hurts...............................................................................................□ True □ False
My cough makes me feel tired........................................................................□ True □ False
I am breathless when I talk.............................................................................□ True □ False
I am breathless when I bend over ...................................................................□ True □ False
My cough or breathing disturbs my sleep.......................................................□ True □ False

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I get exhausted easily
............................................□ True □ False
SECTION 4:
QUESTIONS ABOUT OTHER EFFECTS THAT YOUR CHEST TROUBLE MAY HAVE
ON YOU THESE DAYS. PLEASE TICK IN THE BOX EITHER TRUE OR FALSE AS IT 
APPLIES TO YOU.
My cough or breathing is embarrassing in public...........................................□ True □ False
My chest trouble is a nuisance to my family, friends or neighbours ..............□ True □ False
I get afraid or panic when I cannot get my breath ..........................................□ True □ False
I feel that I am not in control of my chest problem ........................................□ True □ False
I do not expect my chest to get any better ......................................................□ True □ False
I have become frail or an invalid because of my chest...................................□ True □ False
Exercise is not safe for me..............................................................................□ True □ False
Everything seems too much of an effort.........................................................□True □ False
SECTION 5
QUESTIONS ABOUT YOUR MEDICATION. IF YOU ARE RECEIVING NO 
MEDICATION GO STRAIGHT TO SECTION 6.
My medication does not help me very much
□ True □ False
I get embarrassed using my medication in public
□ True □ False
I have unpleasant side effects from my medication
□ True □ False
My medication interferes with my life a lot
□ True □ False
SECTION 6
THESE ARE QUESTIONS ABOUT HOW MUCH YOUR ACTIVITIES MIGHT BE 
AFFECTED BY YOUR BREATHING. FOR EACH QUESTION PLEASE TICK IF TRUE 
IF ONE OR MORE OF THE PARTS OF THE QUESTION APPLIES TO YOU BECAUSE 
OF YOUR BREATHING. OTHERWISE ANSWER FALSE.
It takes a long time to get washed or dressed .................................................□ True □ False
I cannot take a bath or shower, or I take a long time......................................□ True □ False
I walk much slower than other people, or I stop for rests...............................□ True □ False
Jobs such as housework take a long time, or I have to stop for rests..............□ True □ False
If I walk up one flight of stairs, I have to go slowly or stop...........................□ True □ False
If I hurry or walk fast, I have to stop or slow down........................................□ True □ False
My breathing makes it difficult to do things such as walk up hills
carrying things up stairs, light gardening such as weeding, dance, 

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play bowls, or golf..........................................................................................□ True □ False
My breathing makes it difficult to do things such as carry heavy loads, 
dig the garden or shovel snow, jog or walk at 5 miles per hour, play 
tennis or swim ................................................................................................□ True □ False
My breathing makes it difficult to do things such as very heavy manual 
work run, cycle, swim fast or play competitive sports .................................... □ True □ False
SECTION 7
WE WOULD LIKE TO KNOW HOW YOUR CHEST TROUBLE USUALLY AFFECTS 
YOUR DAILY LIFE
I cannot play sports or games .........................................................................□ True □ False
I cannot go out for entertainment or recreation ..............................................□ True □ False
I cannot go out of the house to do the shopping .............................................□ True □ False
I cannot do housework....................................................................................□ True □ False
I cannot move far from my bed or chair.........................................................□ True □ False
HERE IS A LIST OF OTHER ACTIVITIES THAT YOUR CHEST TROUBLE MAY 
PREVENT YOU FROM DOING.  (YOU DO NOT HAVE TO TICK THESE, THEY ARE 
JUST TO REMIND YOU OF WAYS IN WHICH YOUR BREATHLESSNESS MAY 
AFFECT YOU)
Going for walks, or walking the dog
Doing things at home or in the garden
Sexual intercourse
Going out to church, or place of entertainment
Going out in bad weather, or into smoky rooms
Visiting family or friends, or playing with children
PLEASE WRITE IN ANY OTHER IMPORTANT ACTIVITIES THAT YOUR CHEST 
TROUBLE MAY STOP YOU DOING
NOW, WOULD YOU TICK IN THE BOX (ONE ONLY) WHICH YOU THINK BEST 

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DESCRIBE HOW YOUR CHEST AFFECTS YOU:
It does not stop me doing anything I would like to do......................................................................□
It stops me doing one or two things I would like to do.....................................................................□
It stops me doing most of the things I would like to do....................................................................□
It stops me doing everything I would like to do

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MODIFIED MEDICAL RESEARCH COUNCIL DYSPNOEA SCALE 
(mMRC)

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ADDITIONAL INFORMATION REGARDING IN/EX CRITERIA
10.4.1
Calculation of number of pack years
ൌ
ǤǤǤǤǤǤ
ǤǤ ǤǤǤǤǤǤǤǤǤǤ
୮ୣ୰ୢୟ୷
ଶ଴
ൈ
10.4.2
Laboratory data
Subjects may not enter the observational part of the study without the availability of 
laboratory results at the actual study site (including pregnancy test).
10.4.3
Body Mass Index
BMI = body weight [kg] / body height2 [m]
10.4.4
Alpha1-antitrypsin deficiency
Genomic testing of A1ATD will be part of the centralized PGx testing at Visit 1. Inclusion/ 
stratification of subjects can be based on available test results or on PGx testing at Visit 1.
10.4.5
Definition of ex-smokers
For the purpose of this study, an ex-smoker is defined as an individual (healthy subject or 
patient with COPD) who has quit smoking for at least 9 months.
INSTRUCTIONS FOR ASSESSMENTS
Spirometers, DLCO device, body plethysmograph and their use, including daily calibration, 
must meet American Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria.
COMPUTATION OF BODE INDEX
Table 10.6.:1
Variables and Point Values Used for the Computation of the Body 
Mass Index, Degree of Airflow Obstruction and Dyspnea, and 
Exercise Capacity (BODE) Index [R04-0879]
Variable
Points on BODE Index
0
1
2
3
FEV1 (% of predicted)
≥65
50–64
36–49
≤35
Distance walked in 6 min (m)
≥350
250–349
150–249
≤149
MMRC dyspnea scale
0–1
2
3
4
Body-mass index
>21
≤21

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GLOMERULAR FILTRATION RATE (GFR)
Subjects, who are part of the MRI subset, must meet the MRI specific criteria outlined in 
Section 3.3.2.2 and 3.3.3.2. GFR must not be older than 14 days from the MRI assessment. 
Creatinine values are provided by the Central Lab, but not on the day of the blood draw. 
Note: If the MRI assessment at a visit is earlier than the availability of the creatinine value
provided by the central lab, the creatinine value must be assessed locally. GFR can be 
calculated according to the local procedure.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CSP revision
07 OCTOBER 2015
EudraCT number
n/a
BI Study number
352.2069
BI Investigational Product(s)
n/a
Title of protocol
Observational study in healthy subjects and 
patients with COPD to assess the relationship 
between clinical, imaging and biomarker 
measurements, and progression of emphysema 
over two years.
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities

To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of
change with request for 
approval
n/a
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
n/a
Section to be changed
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
Cover Page, Synopsis and section 3.1.1
Flowchart and footnotes
2.3, 5.9.1.1
3.1
3.2, 5.9
5.1.2
5.4, 5.6, 6.2.2
5.5, 5.6, 6.2.1, 6.2.2
6.1.1.2
10.6
Description of change
I)
II)
III)
IV)
V)
VI)
VII)
Deletion of Coordinating Investigator function
A1ATD testing and DNA banking added
Correction of blood volumes
Clarification of procedures during phone calls
Clarification of laboratory sampling
Clarification of DLCO assessments
Specification of timing of PFT procedure

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VIII)
IX)
X)
Rearrangement of procedures DLCO and 
bodyplethysmography
Clarification of induced sputum procedure
Addition of BODE index computation
Rationale for change
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
Role change of Coordinating Investigator
Clarification of laboratory samples (no addition 
of new procedures)
Correction
Inconsistent description
Ambiguous description
Correction
Clarification
Correction
Inconsistency, omission
Clarification
Number of global amendment
2
Date of CSP revision
15 DECEMBER 2015
EudraCT number
n/a
BI Study number
352.2069
BI Investigational Product(s)
n/a
Title of protocol
Observational study in healthy subjects and 
patients with COPD to assess the relationship 
between clinical, imaging and biomarker 
measurements, and progression of emphysema 
over two years.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities

To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
n/a
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
n/a
Section to be changed
I)
II)
III)
IV)
Cover Page
Flowchart footnotes, protocol text (various 
sections)
3.3.3.1, 3.3.4.1
4.2.1

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V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
XIII)
5.2, 5.3
5.4
5.6
5.8
5.8.1.2
6.1.1.2
6.1.1.3
7.3.1.3, 7.3.1.5, 7.4
10.4.5
Description of change
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
XIII)
Correction of number of participating sites
Text/word additions and corrections
INCL 5: change of threshold value for 
FEV1/FVC from LLN to 70%
Separate mention of additional medication
Detailed description of bronchodilation for 
imaging assessments and rescheduling
Name change of reversibility testing and 
precision of salbutamol (albuterol) dosing
Removal of shutter manoeuver
 
Addition of a description for quality check of 
sputum samples, precision of timing of sputum 
sample processing
Precision of sputum assessment rescheduling
Addition of rescheduling rules for imaging 
assessments
Rewording of statistical method, addition of 
soluble biomarkers to the interim analysis
Addition of ex-smoker definition
Rationale for change
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
XIII)
Update
Clarifications and specifications
Reconciliation
Clarification
Clarification
Clarification
Simplification
Simplification
Precision
Precision
Clarification
Clarification, precision
Clarification
Number of global amendment
3

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Date of CSP revision
18 APRIL 2017
EudraCT number
n/a
BI Study number
352.2069
BI Investigational Product(s)
n/a
Title of protocol
Observational study in healthy subjects and 
patients with COPD to assess the relationship 
between clinical, imaging and biomarker 
measurements, and progression of emphysema 
over two years.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
yes
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
n/a
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
n/a
Section to be changed
I)
II)
III)
VI)
V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
XIII)
XIV)
XV)
XVI)
XVII)
Cover Page
Synopsis
Flowchart and footnotes
Abbreviations
2.1, 2.2, 2.3
3.1, 3.2
3.3
4
5.3
5.4 – 5.7
5.8
5.9
6
7
8
9
10
Description of change
I)
II)
III)
IV)
Addition of study name, other formal changes
Formal changes related to changes in other 
sections
Changes to the study design
Addition of new abbreviations

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V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
XIII)
XIV)
XV)
XVI)
XVII)
Formal changes
Change related to sputum procedure, addition of 
recruitment strategy
Update of subject numbers, changes to 
INCL/EXCL
Minor additions and corrections
 
Minor changes
 
Addition of creatinine to safety panel, 
clarification regarding pregnancy testing, 
adaptation for Japan, minor changes and 
corrections
Update of rescheduling rules for sputum 
assessment, extension of screening period in 
case of COPD exacerbations or RTI, new 
rescheduling rule for administrative reason, 
removal of pre DLCO and pre 
bodyplethysmography, new re-screening rule 
regarding previously screen-failed subjects, 
clarification regarding re-screening, minor 
changes and clarifications
Clarification regarding analysis, update of 
interim analysis, minor text changes
Addition of text for Japan, minor changes
New R number for JRS
Addition of Section 10.7 GFR
Rationale for change
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
XIII)
XIV)
XV)
Amendment
Amendment
Simplification of study design and clarifications
Amendment
Alignment with other protocol sections
Amendment
Clarification, Facilitation of recruitment
Clarification
Amendment, Clarification
Amendment, Clarification
Amendment, Clarification
Amendment, Clarification
Amendment, Clarification
Amendment, Clarification
Amendment, Clarification

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XVI)
XVII)
Amendment
Clarification
As there was a mistake in the header (wrong 
document date) which was corrected, there are 
two versions 4.0 in the system. No content 
changed.
Number of global amendment
4
Date of CSP revision
29 MAY 2018
EudraCT number
n/a
BI Study number
352.2069
BI Investigational Product(s)
n/a
Title of protocol
Observational study in healthy subjects and 
patients with COPD to assess the relationship 
between clinical, imaging and biomarker 
measurements, and progression of emphysema 
over three years.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
yes
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
n/a
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
n/a
Section to be changed
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
XI)
XII)
Cover Page
Synopsis
Flowchart and footnotes
Abbreviations
2.1, 2.2, 2.3
3.1, 3.2
5
6
7
8
9
2.3, 5.8
Description of change
I)-
Adaptations for new 3 year observational 

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IX), 
XI)
X)
XII)
timepoint
Specification of Investigator responsibilities 
during informed consent procedure
Revision of blood sample volumes
Rationale for change
I)-
IX), 
XI)
X)
XII)
Amendment
Clarification to meet country requirements
Correction
Number of global amendment
5
Date of CSP revision
24 FEB 2020
EudraCT number
n/a
BI Study number
352.2069
BI Investigational Product(s)
n/a
Title of protocol
Observational study in healthy subjects and 
patients with COPD to assess the relationship 
between clinical, imaging and biomarker 
measurements, and progression of emphysema 
over three years [FOOTPRINTS®].
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
I)
II)
III)
IV)
Cover Page
Synopsis
Section 5.3 and 7.4
Section 5.8
Description of change
I)
II)
III)
IV)
Formal Changes
Formal Changes
 
Changed wording regarding collection and 
analysis of biomarkers
Rationale for change
I)
II)
III)
IV)
Amendment
Amendment
Clarification