A 24-week Randomized, Controlled, Multicenter, Open-label Study to Evaluate the Effect of Reminder Notifications and Motivational/Adaptive Messaging on Treatment Adherence of COPD Subjects Receiving Ultibro® Breezhaler® Treatment Using the Concept2 Inhaler for Dose Administration and Tracking
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Novartis Pharmaceuticals

Global Clinical Development - General Medicine 
IDD001D Electronic Remote Patient Monitoring
Clinical Trial Protocol CIDD001D2402 / NCT03379233
A 24-week randomized, controlled, multicenter, open-label 
study to evaluate the effect of reminder notifications and 
motivational/adaptive messaging on treatment adherence 
of COPD subjects receiving Ultibro® Breezhaler® treatment 
using the Concept2 inhaler for dose administration and 
tracking
Document type:
Clinical Trial Protocol
EUDRACT number:
2017-001593-42
Version number:
01 (Amendment 1 to original protocol released on 10Nov2017)
Clinical trial phase:
Phase III
Release date:
18-May-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.4 (May 2017)
 

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 1 ....................................................................................................................13
Amendment rationale ........................................................................................................13
Changes to the Protocol.....................................................................................................14
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.2
Purpose ..................................................................................................................25
2
Study objectives and endpoints .........................................................................................25
2.1
Primary objectives .................................................................................................25
2.1.1
On-time treatment adherence ................................................................26
2.1.2
Total treatment adherence.....................................................................26
2.2
Secondary objectives .............................................................................................26
26
2.4
Objectives and related endpoints...........................................................................27
3
Study design ......................................................................................................................31
4
Rationale............................................................................................................................36
4.1
Rationale for study design .....................................................................................36
4.2
Rationale for dose/regimen, route of administration and duration of treatment....38
4.3
Rationale for choice of comparator .......................................................................39
4.4
Purpose and timing of interim analyses/design adaptations..................................39
4.5
Risks and benefits..................................................................................................40
5
Population..........................................................................................................................41
5.1
Inclusion criteria ....................................................................................................41
5.2
Exclusion criteria...................................................................................................41
6
Intervention........................................................................................................................43
6.1
Control arm (Usual care group).............................................................................48
6.2
Study arm (Telehealth group)................................................................................48
6.3
Subject numbering, assignment of intervention and randomization .....................48
6.3.1
Subject numbering ................................................................................48
6.3.2
Assignment of intervention and randomization....................................48
 

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6.4
Blinding .................................................................................................................49
6.5
Treating and monitoring the subject......................................................................50
6.5.1
Dispensing the investigational digital(s) system and the medicinal 
product...................................................................................................50
6.5.2
Handling of devices and medication.....................................................51
6.5.3
Instructions for using the devices and taking medication.....................52
6.5.4
Permitted dose adjustments and interruptions of Ultibro®
Breezhaler® treatment ...........................................................................52
6.5.5
Treatment compliance and exposure.....................................................52
6.5.6
Rescue medication ................................................................................52
6.5.7
Concomitant medication .......................................................................53
6.5.8
Prohibited medication ...........................................................................53
6.5.9
Emergency breaking of assigned treatment code..................................53
7
Informed consent procedures ............................................................................................53
8
Visit schedule and assessments .........................................................................................54
8.1
Screening ...............................................................................................................57
8.1.1
Information to be collected on screening failures.................................57
8.2
Subject demographics/other baseline characteristics.............................................57
8.3
Efficacy..................................................................................................................58
8.3.1
On-time treatment adherence (Dose inhaled on-time)..........................58
8.3.2
Total treatment adherence (Daily inhalation) .......................................58
58
8.3.4
Appropriateness of efficacy assessments..............................................61
8.4
Safety.....................................................................................................................61
8.4.1
Physical examination ............................................................................62
8.4.2
Vital signs..............................................................................................62
8.4.3
Laboratory evaluations..........................................................................62
8.4.4
Electrocardiogram (ECG) .....................................................................62
8.4.5
Pregnancy and assessments of fertility .................................................62
8.4.6
Reporting of inhalation errors (overuse)...............................................63
8.4.7
Device Event/Device deficiencies.........................................................63
8.4.8
Appropriateness of safety measurements..............................................63
8.5
Other assessments..................................................................................................63
9
Study discontinuation and completion ..............................................................................64
9.1
Discontinuation......................................................................................................64
9.1.1
Discontinuation of intervention.............................................................64
9.1.2
Withdrawal of informed consent...........................................................64
 

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9.1.3
Lost to follow-up...................................................................................65
9.1.4
Study stopping rules..............................................................................65
9.1.5
Early study termination by the sponsor.................................................65
9.2
Study completion and post-study treatment ..........................................................66
10 Safety monitoring..............................................................................................................66
10.1
Adverse events and Adverse device effects definitions and reporting 
requirements ..........................................................................................................67
10.2
Serious adverse events and Serious adverse device effects definitions and 
reporting requirements...........................................................................................69
10.2.1
Serious adverse events ..........................................................................69
10.2.2
Serious adverse device effects ..............................................................71
10.3
Pregnancy reporting...............................................................................................73
10.4
Additional Safety monitoring ................................................................................74
10.4.1
Liver safety monitoring.........................................................................74
10.4.2
Renal safety monitoring........................................................................74
10.4.3
Prospective suicidality assessment........................................................74
11 Data Collection and Database management......................................................................74
11.1
Data collection.......................................................................................................74
11.2
Database management and quality control............................................................75
11.3
Site monitoring ......................................................................................................75
12 Data analysis and statistical methods ................................................................................76
12.1
Analysis sets ..........................................................................................................76
12.2
Subject demographics and other baseline characteristics......................................76
12.3
Intervention............................................................................................................77
12.4
Analysis of the primary variable(s) .......................................................................77
12.4.1
Variable(s).............................................................................................77
12.4.2
Statistical model, hypothesis, and method of analysis..........................78
12.4.3
Handling of missing values/censoring/discontinuations.......................79
12.4.4
Multiplicity adjustment .........................................................................79
12.4.5
Sensitivity analyses ...............................................................................80
12.5
Analysis of secondary variables ............................................................................80
12.5.1
Efficacy variables..................................................................................80
12.5.2
Safety variables .....................................................................................80
12.5.3
Resource utilization...............................................................................80
12.5.4
Pharmacokinetics ..................................................................................80
12.5.5
Pharmacogenetics/pharmacogenomics .................................................81
12.5.6
Biomarkers............................................................................................81
 

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12.5.7
PK/PD ...................................................................................................81
81
12.7
Interim analyses.....................................................................................................82
12.8
Sample size calculation..........................................................................................82
13 Ethical considerations........................................................................................................83
13.1
Regulatory and ethical compliance........................................................................83
13.2
Responsibilities of the investigator and IRB/IEC..................................................83
13.3
Publication of study protocol and results...............................................................83
13.4
Quality Control and Quality Assurance.................................................................84
14 Protocol adherence ............................................................................................................84
14.1
Protocol amendments.............................................................................................84
15 References .........................................................................................................................85
88
100
114
19 Appendix 4: Quality of life Questionnaire EuroQol EQ-5D-5L (EQ-5D-5L)................115
20 Appendix 5: St. George’s Respiratory Questionnaire for COPD patients (SGRQ-
C).....................................................................................................................................117
126
127
23 Appendix 8: Exacerbations..............................................................................................128
24 Appendix 9: Concept2 Inhaler Unique Device Identification.........................................130
25 Appendix 10: GOLD 2017 guidelines.............................................................................131
List of tables
Table 2-1
Objectives and related endpoints ..........................................................27
47
Table 6-2
Blinding and unblinding plan................................................................49
Table 8-1
Assessment schedule.............................................................................55
.59
126
Table 22-1
Reminders to inhale the medication on-time ......................................127
Table 25-1
Classification of airflow limitation severity in COPD (based on 
post-bronchodilator FEV1)..................................................................131
 

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List of figures
Figure 3-1
Study design..........................................................................................32
Figure 6-1
Overview of the components of the digital adherence system and 
data flow................................................................................................46
Figure 6-2
Dispensing of Concept2 inhalers and clinical trial formulation of 
Ultibro® Breezhaler® capsules ..............................................................51
Figure 10-1
Safety monitoring..................................................................................67
Figure 25-1
The refined ABCD assessment tool GOLD Strategy 2017.................131
 

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List of abbreviations
ADE
Adverse Device Effect
AE
Adverse Event
ANCOVA
Analysis of Covariance Model
AVRF
Audiovisual Reminder Function
BIPQ
Brief Illness Perceptions Questionnaire
BPH
Benign Prostatic Hyperplasia
BMI
Body Mass Index
BMQ
CDS
CE
Beliefs about Medicine Questionnaire
Core Data Sheet
Conformité Européenne
CFR
US Code of Federal Regulations 
COPD
Chronic Obstructive Pulmonary Disease 
CPO
Country Pharma Organization
CRO
Clinical Research Organization
CRA
Clinical Research Associate
CRF
CTFG
Case Report/Record Form
Clinical Trial Facilitation Group 
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
ER
Emergency Room
EU
European Union
FAS
Full Analysis Set
FEV1
FSH
FVC
Forced expiratory volume in 1 second
Follicle Stimulating Hormone
Forced Vital Capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GVP
Guideline on Good Pharmacovigilance Practices
hCG
human Chorionic Gonadotropin
β-hCG
Beta- human Chorionic Gonadotropin
IB
Investigator Brochure
ICH
International Council for Harmonization
ICF
Informed Consent Form
ICS
Inhaled corticosteroids
 

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ID
Identification
IFU
Instructions for use 
IEC
Independent Ethics Committee
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISM
Industrial, Scientific and Medical
IUD
Intrauterine device
IUS
Intrauterine system 
LABA
Long-Acting Beta-Adrenoceptor agonists
LAMA
Long-Acting Muscarinic Agents
MARS
Medication Adherence Rating Scale
MEDDEV
Medical devices
MedDRA
Medical Dictionary for Regulatory Activities 
nPI
National Prescribing Information
PIT
Preferred Inhalation Time
PPS
Per-Protocol Set 
prn 
pro re nata
PSW
Premature subject withdrawal
QM
Quality Management
QoL
Quality of Life
RAN
Randomized
SABA
Short-Acting β2-Adrenergic agonist
SADE
Serious Adverse Device Effect
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAR
Specific Absorption Rate
SGRQ-C
St. George's Respiratory Questionnaire
SMS
Short Message Service
SOP
Standard Operating Procedure
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
UK
United Kingdom
US
United States
USADE
Unanticipated serious adverse device effect
WIFI
Wireless Local Area Network
 

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WHO
World Health Organization 
 

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Glossary of terms
Assessment
A procedure used to generate data required by 
the study
Biologic Samples
A biological specimen including, for example, 
blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study subject 
Cohort 
A specific group of patients/subjects fulfilling 
certain criteria
Control drug
Drugs(s) used as a comparator to reduce 
assessment bias, preserve blinding of 
investigational drug, assess internal study 
validity, and/or evaluate comparative effects of 
the investigational drug
Dosage
Dose of the study treatment given to the subject
in a time unit (e.g. 100 mg once a day, 75 mg 
twice a day)
Electronic Data Capture (EDC)
Electronic data capture (EDC) is the electronic 
acquisition of clinical study data using data 
collection systems, such as Web-based 
applications, interactive voice response systems 
and clinical laboratory interfaces. EDC includes 
the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data 
transcribed from paper source forms used at the 
point of care.
End of the clinical trial
The end of the clinical trial is defined as the last 
visit of the last subject or at a later point in time 
as defined by the protocol. 
Enrollment
Point/time of subject entry into the study at 
which informed consent must be obtained (e.g. 
prior to starting any of the procedures described 
in the protocol)
Investigational drug/treatment
The drug or treatment whose properties are 
being tested in the study. 
Investigational medical device
Medical device being assessed for safety or 
performance in a clinical investigation
This includes medical devices already on the 
market that are being evaluated for new 
intended uses, new populations, new materials 
or design changes.
Medication number
A unique identifier on the label of each
medication/inhaler kit
Mis-randomized subjects
Mis-randomized subjects are those who were 
not qualified for randomization and who did not 
take study treatment, but have been 
inadvertently randomized into the study 
Part 
A sub-division of a study used to evaluate 
specific objectives or contain different 
populations. For example, one study could 
 

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contain a single dose part and a multiple dose 
part, or a part in subjects with established 
disease and in those with newly-diagnosed 
disease.
Patient/subject ID 
A unique number assigned to each subject upon 
signing the informed consent 
Period
The subdivisions of the trial design (e.g. 
Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the 
study phases and will be used in clinical trial 
database setup and eventually in analysis
Personal Data
Subject information collected by the Investigator 
that is transferred to Novartis for the purpose of 
the clinical trial. This data includes subject 
identifier information, study information and 
biological samples.
Premature subject withdrawal
Point/time when the subject exits from the study 
prior to the planned completion of the study drug 
intervention and/or assessments; at this time the 
intervention, and all study drug administration is 
discontinued and no further assessments are 
planned
Randomization number
A unique identifier assigned to each randomized 
subject.
Screen Failure
A subject who did not meet one or more criteria 
that were required for participation in the study
Source Data/Document
Source data refers to the initial record, 
document, or primary location from where data 
comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded 
data, such as paper.
Start of the clinical trial
The start of the clinical trial is defined as the 
signature of the informed consent by the first 
subject.
Per European Union (EU) Regulation 536/2014 
the start of a clinical trial’ means the first act of 
recruitment of a potential subject for a specific 
clinical trial, unless defined differently in the 
protocol.
Study drug/ treatment
Any single drug or combination of drugs 
administered to the subject as part of the 
required study procedures; includes 
investigational drug (s), placebo/comparator 
active drug run-ins or background therapy
Study Treatment Discontinuation (TD)
When the subject permanently stops taking 
study treatment prior to the defined study 
treatment completion date 
Subject
A trial participant (can be a healthy volunteer or 
a patient)
Subject number
A unique number assigned to each subject upon 
signing the informed consent. This number is the 
 

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definitive, unique identifier for the subject and 
should be used to identify the subject throughout 
the study for all data collected, sample labels, 
etc.
Variable
A measured value or assessed response that is 
determined in specific assessments and used in 
data analysis to evaluate the drug being tested 
in the study
Withdrawal of study consent (WoC)
Withdrawal of consent from the study occurs 
only when a subject does not want to participate 
in the study any longer, and does not allow any 
further collection of personal data
 

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Amendment 1
Amendment rationale
This amendment addresses comments received from the Ethics Committees and Health 
Authorities to clarify study procedures and includes editorial changes related to the new 
Novartis protocol template regarding data protection measures. 
Recruitment for the study has not initiated as of the time of this protocol amendment 
finalization.
Changes to the protocol:
- The classification of this study has been changed to ‘an open label controlled trial’ instead of
‘single blind’ to match with the study procedures already planned for the trial. 
- The trial phase has been changed from Proof of Concept to Phase III since the 
Investigational Medicinal Product is a registered/ approved product being investigated in this 
trial with unapproved Concept2 inhaler and the trial is intended to support registration of the 
Concept 2 inhaler with the DAS with potential inclusion in Summary of Prouct 
Characteristics (SmPC).
- The study design has been amended to use only a single written informed consent form (ICF) 
required to be signed by subjects at the start of the clinical trial, instead of two ICFs planned to 
be used in the earlier study design. The second ICF is therefore no longer required. 
- Inclusion Criteria 4 has been altered to include subjects who have either (spirometric) post-
bronchodilator OR pre-bronchodilator forced expiratory volume in 1 second (FEV1) in the last 
year, if the Chronic Obstructive Pulmonary Disease (COPD) diagnosis was confirmed with 
(spirometric) post-bronchodilator FEV1/forced vital capacity (FVC) <0.7 in the past. This is 
reflected in the protocol summary and Section 5.1. The reason to change this inclusion criteria 
is to also allow subjects with a historical COPD diagnosis (>1 year) to be included in the trial 
to reflect the routine medical practice in the participating countries.
- Exclusion criteria 2 has been updated to reflect the contraception requirements as defined in 
the Clinical Trial Facilitation Group (CTFG) Recommendations related to contraception and 
pregnancy testing in clinical trials (Version Final 2014-09-15). The changes are reflected in the 
protocol summary and Section 5.2.
- The glossary of terms is updated to include the definition of personal data, and clarify the 
definition of withdrawal of consent - which is also updated in Section 9.1.2. Additional terms 
which are used in the protocol have been added for more clarity.
- Section 6.5 is updated to clarify that the Ultibro® Breezhaler® capsules used in the trial for 
treatment is a clinical trial formulation of the Ultibro® Breezhaler® capsules
- The definition of end of study is added to Section 9.2.
- The timelines for Serious Adverse Device Event (SADE) safety reporting have been updated 
to reflect Medical Devices (MEDDEV) 2.7/3 revision 3, May 2015 regulations. Changes are 
reflected in Section 10.2.2.2.
- Section 6.4 has been clarified and table 6.2 inserted to document the blinding procedures in 
the study.
 

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- Sections 4, 7 and 9 have been introduced as per new Novartis protocol template. As a result 
section numbers for some of the other sections have changed.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through for deletions and underlining for insertions.
The described changes pertaining to the aforementioned amendment rationale are implemented 
throughout the protocol.
 

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Protocol summary
Protocol number
CIDD001D2402
Title
A 24-week randomized, controlled, multicenter, open-label study 
to evaluate the effect of reminder notifications and 
motivational/adaptive messaging on treatment adherence of COPD 
subjects receiving Ultibro® Breezhaler® treatment using the 
Concept2 inhaler for dose administration and tracking
Brief title
A 24-week randomized, controlled study in subjects with Chronic 
Obstructive Pulmonary Disease (COPD) to evaluate the effect of 
reminders and motivational/adaptive messages on their treatment 
adherence tracked by the Concept2 inhaler
Sponsor and Clinical 
Phase
Novartis 
Investigation type
Devices
Study type
Phase 3
Purpose and rationale
This study will evaluate the effect of dose tracking in conjunction 
with reminder notifications and motivational/adaptive messages 
over 24 weeks on treatment adherence behavior in subjects with 
COPD. The dose tracking is done by the Concept2 inhaler and the 
reminder notifications, feedback on inhaler use and 
motivational/adaptive messages are sent by the patient application.
Primary Objective(s) 
The two primary objectives of this trial are to evaluate the effect of 
dose tracking in conjunction with reminder notifications and 
motivational/adaptive messages sent by the patient application over 
24 weeks for
(1) on-time treatment adherence
(2) total treatment adherence
Secondary Objectives
The secondary objectives are to evaluate the effect of dose tracking 
in conjunction with reminder notifications and 
motivational/adaptive messages sent by the patient application over 
24 weeks for
(1) on-time adherence over the last four weeks of the 
Interventional period
(2) total adherence over the last four weeks of the Interventional 
period
Study design
This is a 24 weeks multicenter, randomized, controlled, open label 
parallel-group study.
Population
The study population will consist of approximately 146 male and 
female adults age 18 years and older, with a clinical diagnosis of 
COPD (spirometric grade 2 or 3 according to GOLD 2017 criteria), 
a smoking history of at least 10 pack years, receiving COPD 
 

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maintenance treatment with Ultibro® Breezhaler® for at least 3 
months prior to screening and with a known poor treatment 
adherence.
Key Inclusion criteria
1.a Signed informed consent must be obtained prior to participation 
in the study
2. Male and female adults aged ≥18 years.
3. Current or ex-smokers who have a smoking history of at least 10 
pack years. (Ten pack-years are defined as 20 cigarettes a day 
for 10 years, or 10 cigarettes a day for 20 years).
4.a A historical diagnosis of COPD confirmed by a post-
bronchodilator FEV1/FVC < 0.70 in the past and a pre-
bronchodilator or post bronchodilator FEV1 ≥30% and < 80% of 
the predicted normal value within the last year.
5. Have been taking Ultibro® Breezhaler® for at least 3 months
prior to Visit 1 (in accordance with the local product label).
6. Have a total adherence of more than 10% but less than or equal 
to 70% during Screening period. Total adherence is defined as 
percentage of days on which the subject inhaled a dose of 
Ultibro® Breezhaler®.
7. Have been in the Screening period ≥35 days.
Key Exclusion criteria
1. Pregnant or nursing (lactating) women, where pregnancy is 
defined as the state of a female after conception and until the 
termination of gestation, confirmed by a positive human 
Chorionic Gonadotropin(hCG) laboratory test.
2.a Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are 
using basic methods of contraception during the study. 
3. Subjects contraindicated for treatment with, or having a history 
of reactions/ hypersensitivity to any of the following inhaled 
drugs, drugs of a similar class or any component thereof:
• anticholinergic agents
• long and short acting beta-2 agonists
• sympathomimetic amines
4. Subjects contraindicated for having a history of reactions/ 
hypersensitivity to lactose or any of the other excipients of trial 
medication. 
5. Subjects with a history of malignancy of any organ system, 
treated or untreated, within the past 5 years whether or not there 
is evidence of local recurrence or metastases, with the exception 
of localized basal cell carcinoma of the skin.  
6. Subjects with narrow-angle glaucoma, symptomatic benign 
prostatic hyperplasia or bladder-neck obstruction or moderate to 
severe renal impairment or urinary retention. Benign Prostatic 
 

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Hyperplasia (BPH) subjects who are stable on treatment can be 
considered.
7. Subjects who have had a COPD exacerbation that required 
treatment with antibiotics and/or systemic corticosteroids and/or 
hospitalization in 6 weeks prior to Visit 1. 
8. Subjects who develop a COPD exacerbation between screening 
(Visit 1) and prior to intervention (Visit 110) will not be eligible 
but will be permitted to be re-screened after a minimum of 6
weeks after the resolution of the COPD exacerbation.
9. Subjects who have had a respiratory tract infection within 3
weeks prior to Visit 1.
10.a Subjects who develop a respiratory tract infection between 
screening (Visit 1) and prior to intervention (Visit 110) will not 
be eligible, but will be permitted to be re-screened after a 
minimum of 3 weeks after the resolution of the respiratory tract 
infection.
11. Subjects with a current diagnosis of asthma.
12. Subjects with concomitant pulmonary disease (e.g. lung 
fibrosis, sarcoidosis, interstitial lung disease, pulmonary 
hypertension, and pulmonary tuberculosis).
13. Use of investigational drugs or other investigational devices at 
the time of enrollment, or within 30 days or 5 half-lives of 
Visit 1, whichever is longer.
14. Subjects with a preferred inhalation time (PIT) between 10.00 
pm and 2.00 am.
15. Subjects taken off Ultibro® Breezhaler® treatment/inhaler use 
by the investigator during the Screening period for more than 
7 days.
16. Subjects not returning all Concept2 inhalers received during the 
Screening period, for the calculation of total adherence before 
randomization at Visit 110.
17. Subjects who have demonstrated inability or unwillingness to 
use the digital system or to fill in questionnaires.
Study intervention
The intervention in this study consists solely of the use of an 
investigational digital system, consisting of the patient application 
and the Concept2 inhaler. The digital system will be used in half of 
the subjects while the other group (control) will receive Usual Care 
delivered by the Concept2 inhaler, with no patient application. The 
drug treatment in this trial is not under investigation. All subjects in 
this study will receive daily Ultibro® Breezhaler® treatment as 
prescribed by their physician prior to their inclusion in the study. In 
this study the clinical trial formulation of Ultibro® Breezhaler®
(capsules 110/50 µg) medicinal product will be provided to the 
subjects.
 

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The Concept2 inhaler will track subjects’ treatment adherence with 
the once daily dosing regimen for Ultibro® Breezhaler® capsules. 
The digital adherence system, in addition, enables the real-time, 
wireless transfer of inhaler use data recorded by the Concept2 
inhaler, to the patient application. These inhaler data are then 
interpreted and specific appropriate feedback to the subject are 
provided. Such feedback may include reminders to inhale 
medication, motivational/adaptive messages to encourage 
adherence with the treatment regimen and reports on inhaler use 
(daily, weekly, monthly).
Efficacy assessments
On-time treatment adherence
Total treatment adherence
Key safety 
assessments
• COPD exacerbations regardless of suspected causality to 
concomitant treatments will be recorded into the Case Report 
Form (CRF) page(s) capturing the AE/SAE.
• Device deficiencies/Device Events
• Drug administration error, inhaler overuse, incorrect dose
administration notified by the subject 
• New findings/updates in relation to already reported events
• Adverse Events (AEs) and Adverse Device Effects (ADEs) 
• Serious adverse events (SAEs) and Serious Adverse Device 
Effects (SADEs) 
• Physical Examination
• Vital signs
• Height and weight
• Highly sensitive urine or serum pregnancy test (for females of 
childbearing potential), and in case of positive testing, serum 
pregnancy test (β-hCG)
Other assessments
None
Data analysis
The primary objectives are to determine whether the use of dose 
tracking by the Concept2 inhaler in conjunction with reminder 
notifications and motivational/adaptive messages sent by the 
patient application can improve on-time adherence or total 
adherence over 24 weeks of intervention. 
On-time adherence is defined as the percentage of days on which 
the subject inhaled at least one dose within (±) 2 hours of the 
agreed preferred daily inhalation time. The daily inhalation time 
must be defined by the subject at the start of the study and can only 
be modified at scheduled study visits by the study investigator at 
the request of the subject.
 

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Total adherence is defined as the percentage of days on which the 
subject inhaled at least one dose (daily inhalation) and will be 
calculated as the sum of on-time adherence and off-time adherence. 
Off-time adherence is defined as percentage of days on which the 
subject did not inhale the daily dose within the (±) 2 hours of the 
predefined preferred inhalation time (PIT), but outside. 
Variable(s)
The primary variables for the study are the change from baseline 
(Visit 110) in on-time adherence and change from baseline in total 
adherence during 24 weeks of Interventional period. The on-time 
adherence will be calculated as the  number of days with at least 
one dose/inhaler use recorded via the Concept2 inhaler within (±) 2 
hours of planned PIT, divided by the  number of days the subject 
had the Concept2 inhaler over 24 weeks. Total adherence will be 
calculated as the sum of on-time adherence and off-time adherence. 
Off-time adherence will be calculated as the number of days the 
subject did not inhale the daily dose within the (±) 2 hours of the 
predefined PIT, but outside, divided by the number of days the 
subject had the Concept2 inhaler over 24 weeks.
If more than one dose is inhaled within (±) 2 hours of the preferred 
inhalation time, it will be counted once for the purpose of on-time 
adherence (numerator) day calculation. The additional dose(s), if 
any, will be considered as overuse, if it meets the criteria outlined 
in Section 12.6.1.5.
If the subject is inhaling one or more doses during one day, in 
addition to the dose administration within (±) 2 hours of preferred 
inhalation time, that will not be counted towards off-time 
adherence calculation, hence not in total adherence calculation.   
The dispensing period is 4 weeks, when one inhaler will be 
dispensed. In addition one Concept2 back-up inhaler will be 
dispensed at Visit 110 and Visit 140, each. In case the back-up 
inhaler is used before Visit 140 or end of Interventional period    
(Visit 170) the subject will receive a new one. Each inhaler is 
designed and validated for a maximum of 30 days delivery.
In each 4-week dispensing period the number of days for the 
denominator will be defined as follows:
- Date of the first inhaler use data recorded into the Concept2 
inhaler or Pairing Time, whichever comes first, plus 27 days or last 
data recorded in Concept2 inhaler, whichever is later (from all used 
Concept2 inhalers, regular and back-up’s). If the inhaler is lost then 
the corresponding visit day will be used as the first inhaler use date.  
- If a subject discontinues the study, the denominator for each of 
the remaining 4-week periods will be defined as 28. The missing 
data will be imputed as outlined in Section 12.4.3.
 

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- The number of days from each of the six 4-week periods will be 
summed to be used as the overall denominator in calculations. 
Baseline on-time adherence and total adherence will be calculated 
from the 6 weeks Screening period (Visit 110 has a visit window of 
± 7 days, that is days 35-49). The number of days in the 
denominator will be defined as:
- Days between Visit 1 (exclusive) and Visit 110 (inclusive). A 
minimum of 35 days in the screening are expected for a subject to 
be eligible for having baseline adherence calculation performed.
Subjects with a COPD exacerbation during Screening are 
considered screening failure. 
The period for which subject was taken off Ultibro® Breezhaler® 
treatment/inhaler use by investigator will be excluded from 
adherence calculation (for both Screening and Interventional
period).
Statistical model, hypothesis, and method of analysis
The use of dose reminder notifications and motivational/adaptive 
messages will be evaluated by testing the following two null 
hypotheses H1 and H2 for on-time adherence and total adherence, 
respectively.
H1: There is no difference in change from baseline in on-time 
adherence for subjects who received dose reminder and 
motivational/adaptive messages compared to subjects who received 
none.
H2: There is no difference in change from baseline in total 
adherence for subjects who received dose reminder and 
motivational/adaptive messages compared to subjects who received 
none.
The alternative hypothesis for each of H1 and H2 is that- there is a 
difference, respectively.
Each of the primary variables will be analyzed using the analysis of 
covariance model (ANCOVA) for the FAS. The ANCOVA model 
will contain intervention (here defined as dose reminders and 
motivational/adaptive messages versus usual care), baseline total 
adherence group, country and baseline COPD severity as fixed 
effects with baseline on-time adherence/total adherence rate as 
covariate. 
The estimated adjusted difference of the intervention for the 
Telehealth group minus Usual Care group will be displayed along 
with the associated 95% (two-sided) confidence interval.
Also the means of on-time adherence/total adherence will be 
presented graphically over 4-week time intervals by intervention 
group.
 

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If at least one of the primary endpoints is significant the study will 
be considered positive.    
To control the overall type-1 error rate, multiplicity adjustment (for 
2 endpoints) is described in Section 12.4.4.
Handling of missing values/censoring/discontinuations
Missing data for adherence will be imputed through a multiple 
imputation approach, under the assumption of missing data are 
missing at random. Utilizing this approach all subjects in the FAS 
will contribute in the analysis. For the primary analysis- data from 
inhalers (through investigator application) will be used. The 
supplemental data from patient application will not be used, to 
ensure a consistent imputation process for both groups.   
A sensitivity analysis will be done including the supplemental data 
from the patient application. That is, the missing data (from 
inhaler/investigator application) will first be imputed/updated with 
the patient application data, if available. Then the overall 
imputation will be done using the multiple imputation approach 
mentioned above.
Further elaboration of the multiple imputations will be provided in 
the statistical analysis plan (SAP).     
Multiplicity adjustment 
To control the family-wise type-I error rate at the two-sided 5% 
significance level, the trimmed  Simes test in  Brannath et al (2009)
is used. The family for the overall type-I error rate control contains 
2 hypotheses- one for the on-time adherence primary endpoint and 
the other for the total adherence primary endpoint. Denote the two 
hypotheses for the two primary endpoints as H1 and H2, 
respectively. Below is a description of the testing procedure.
Let p1 and p2 be the corresponding p-values (2-sided) of the two 
hypotheses of H1 and H2.
Step 1: Retain both hypotheses and stop if ANY pi≤0.05 (for i=1 
or 2) AND the observed treatment difference for the 
corresponding pi is in the wrong direction (i.e. Usual Care group 
is better than intervention group); otherwise go to step 2.
Step 2: Reject both hypotheses if pi<0.05 for BOTH i=1, 2, and 
stop here; otherwise go to step 3.
Step 3: Perform the Bonferroni test and reject H1 if p1<0.025 
and reject H2 if p2<0.025. 
For H1 and H2, their corresponding testing statistics follow jointly 
bivariate normal distribution. Therefore this testing procedure 
controls the overall type–I error rate at the 2-sided 0.05 level in the 
 

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strong sense regardless if the bivariate normal distributions have 
positive or negative correlations as shown in  Brannath et al (2009).
Other than the primary analysis, all other analyses will be 
performed at the nominal 2-sided 0.05 significance level without 
multiplicity adjustments.
Sensitivity analyses
As sensitivity analyses, the same ANCOVA used in the primary 
analysis will be also performed on the PPS to assess the robustness 
of the results from the primary analysis. 
The primary analysis model will be re-run including additional 
covariates, for example age and sex, to investigate the impact of 
these on any intervention effect. Details of these analyses will be 
pre-planned and described in the SAP.
The secondary objectives on-time adherence and total adherence 
over the last four weeks of Interventional period (Week 21-24) will 
be summarized by intervention group. 
The change from baseline in on-time adherence/total adherence 
over the last 4 weeks of Interventional period will be analyzed 
using the same ANCOVA model specified for the primary analysis. 
The missing data imputation will be done using the same method 
used for the primary endpoints analysis
Key words
Concept2, Ultibro® Breezhaler®, adherence, digital system
 

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1
Introduction
1.1
Background 
Poor adherence to drug therapy is a widespread issue affecting subjects irrespective of disease 
and treatment type. Treatment adherence is impacting the clinical benefit of the therapy
influencing the results of clinical trials leading to erroneous conclusions, including 
underestimated 
efficacy, 
underestimated 
incidence 
of 
adverse 
effects, 
distorted 
pharmacoeconomic analyses and overestimated dosing requirements (Vrijens et al 2014). Poor 
adherence to medications therefore may account for many of the observed differences between 
the efficacy assessed in clinical trials and the real-world effectiveness of the drug treatment.  
Results from SUMMIT and TORCH (Vestbo et al 2009, Vestbo et al 2016) indicate that good 
adherence to inhaled medication was significantly associated with reduced risk of admission to 
hospital due to exacerbations in subjects with COPD (good adherence was associated with a 
44% lower rate of severe exacerbations in the Torch trial; in the SUMMIT trial, the rate of 
adherence to treatment was high, only 3% of patients were taking less than 80% of prescribed 
study medication doses, with a reduction in COPD exacerbations of 18% to 27%).
Although adherence rates in clinical trials may be as high as 70% to 90%, in clinical practice 
adherence to treatment can be as low as 10% to 40% (Bourbeau and Bartlett 2008, Huetsch et 
al 2012) and decline with time. In the Lung Health Study, ~70% of participants reported 
satisfactory or better adherence to inhaled medication for COPD at the first 4-month follow-up 
visit; this decreased to ~60% over the next 18 months (Rand 2005). A similar observation was 
also reported by Chan et al (2015). In this study, the overall adherence in pediatric subject with 
asthma fell in both observed groups over time. Mean percentage adherence at 2, 4, and 6 months 
were 91%, 84%, and 79%, respectively, for the intervention group, compared with 40%, 33%, 
and 27%, respectively, for the control group. In Chronic Obstructive Pulmonary Disease 
(COPD) adherence to inhaled and oral medications has been reported to be between 41% and 
57% (Bryant et al 2013, Cecere et al 2012), and up to 88% of subjects do not use their inhaler 
correctly (Thompson et al 1994, van Beerendonk et al 1998, van der Palen et al 1995, Serra-
Batlles et al 2002, Molimard et al 2017). An increase of exacerbations frequency, number of 
hospitalizations and mortality rate are the consequences of the low adherence (Bourbeau and 
Bartlett 2008, Regueiro et al 1998, Plaza et al 2015). Adherence is often influenced by subject’s 
perception of symptoms and beliefs about the necessity of medication. The most common self-
reported reasons for poor adherence to inhaler use are forgetting (30% to 48%) (Osterberg and 
Blaschke 2005, Rand et al 1995) and consciously deciding not to use it when feeling good (31%; 
Dolce et al 1991, Bourbeau and Bartlett 2008). Other causes of non-adherence include concerns 
over the efficacy and safety of the drug and disagreement with the physician’s diagnosis of the 
disease or its severity. To a lesser extent, non-adherence is also associated with the frequency 
of dosing and inhaler technique. If inhalers are used incorrectly, it remarkably reduces the 
efficacy of the drug and, consequently, the subject’s adherence (Sanduzzi et al 2014).
Adherence to treatment is difficult to monitor or evaluate without bias, as subjects tend to over-
estimate their adherence when using self-reporting questionnaires. Furthermore, most integral 
dose counters for inhaler devices and pill counters do not provide precise information about 
when the doses were taken. Rand et al (1992) showed that 14% of subjects with COPD, who 
were participating in a large multicenter clinical trial over the course of 1 year, were dumping 
 

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inhaled corticosteroid (ICS) medication (activation of canisters or removal of pills) immediately 
prior to a clinic visit presumably to make oneself appear adherent.
COPD is a progressive, debilitating and often fatal disease of the airways characterized by 
airflow limitation, which is not fully reversible and associated with an inflammatory response 
of the lung to noxious particles or gases. The aim of COPD treatment is to increase lung function, 
prevent disease progression, decrease symptoms and exacerbations, and improve Quality of life 
(QoL). Current treatment guidelines for COPD recommend the use of bronchodilators for all 
severities, either on an as-required (pro re nata: prn) basis, or on a regular basis (GOLD 
guidelines 2017) delivered by an appropriate inhaler. LABAs (Long-Acting Beta-Adrenoceptor 
agonists), such as formoterol, salmeterol and indacaterol, and LAMAs (Long-Acting 
Muscarinic Agents) achieve this goal as they provide long-term sustained bronchodilation. 
Published studies (Mak and Barnes 1990, Carstairs et al 1985, Ikeda et al 1995) have shown 
that the mechanisms of action of LABAs and LAMAs are complementary due to the differential 
density of β2-adrenoceptors and M3-receptors in central versus smaller airways. Thus, LABAs 
work by relaxing small airways and LAMAs have a bronchodilatory effect in larger airways. 
There is also clinical evidence which suggests that combining bronchodilators from these two 
pharmacological classes results in significantly greater improvements in lung function (FEV1) 
compared with individual components alone without increasing adverse effects (Cazzola and 
Molimard 2010, Wang et al 2011). Subjects in this study will be treated with clinical trial 
formulation of the Ultibro® Breezhaler® (QVA149), a fixed combination of LABA and LAMA 
(a long acting β2-agonist Indacaterol maleate (QAB149) and a long acting muscarinic 
antagonist Glycopyrronium bromide (NVA237)), which has been approved in Europe and 
Japan for once-daily maintenance treatment of COPD. Ultibro® Breezhaler® has been evaluated
as safe and efficacious in a comprehensive Phase III development program comprising more 
than 12000 COPD subjects. Data from the studies have demonstrated improvement in lung 
function and health-related quality of life, decrease in COPD symptoms and decrease in use of 
short-acting β2-adrenergic agonist (SABA) with a safety profile similar to placebo (Bateman et 
al 2013).
The intention of this study is to test whether subjects with COPD of spirometric grade 2 or 3
(according to GOLD 2017 criteria) on a regular once daily dosing regimen of Ultibro®
Breezhaler® treatment using a patient adherence application in conjunction with the Concept2 
inhaler, have improved adherence to treatment compared to subjects using the Concept2 inhaler 
alone. The Concept2 inhaler investigated in this study is a modification of the CE marked 
Ultibro® Breezhaler® inhaler (Concept1 inhaler), with the addition of electronics incorporated 
into the base of the device. The additional electronics do not alter the drug delivery 
characteristics of the inhaler itself, but produce a recording of each administered dose with a
date and time stamp whenever the subject inhales a dose using the Concept2 device. Therefore, 
the Concept2 inhaler can be used to capture subjects’ adherence with the approved once daily 
dosing regimen for Ultibro® Breezhaler® capsules. The digital adherence system enables in 
addition the real-time, wireless transfer of inhaler use data. These inhaler use data are then 
interpreted and specific appropriate feedback to the subject are provided. Such feedback may 
include reminders to inhale the medication and/or motivational/adaptive messages to encourage 
adherence with the treatment regimen. 
 

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The digital adherence system, being employed in this study, comprises the following 
components:
(a) The Concept2 inhaler (also called eConcept1 Mark 1): The Concept2 inhaler is a device 
used by the subject to deliver the medication (Ultibro® Breezhaler®) from the capsule to 
the lungs and has electronic components in the base, 
 
 The additional electronics do not alter the drug delivery 
characteristics of the inhaler itself, but produce a recording of each administered dose 
 based on the sound produced by the spinning capsule during 
inhalation. The recorded information 
 is then transmitted to the 
patient application.
(b) A subject facing application (patient application or patient adherence application) 
running on a tablet device for home use and able to receive data from the Concept2 
inhaler and transmit this data to the central data base (Concept2 portal). The intended 
use of the application is to monitor adherence to COPD maintenance therapy medication 
delivered through the Concept2 inhaler and to drive improvement in adherence by 
providing dose reminders, adaptive and motivational messages, and feedback on 
subject’s level of adherence. The feedback comprises reports 
 
 for each individual subject.
Additional supportive components used for the conduct of the study are:
(c) An investigator application (only used by the investigator) running on a tablet device
and able to upload the data from the Concept2 inhaler(s) and to transmit this data to the 
Concept2 portal. An additional functionality of the application is to calculate the total 
adherence for each subject based on the uploaded screening data.
(d) The Concept2 portal; a system made up of a central database for centrally storing inhaler 
usage data, answers/scores from questionnaires and study information.
1.2
Purpose 
This study will evaluate the effect of dose tracking in conjunction with reminder notifications 
and motivational/adaptive messages over 24 weeks on treatment adherence behavior in subjects 
with COPD. The dose tracking is done by the Concept2 inhaler and the reminder notifications, 
feedback on inhaler use and motivational/adaptive messages are sent by the patient application.
2
Study objectives and endpoints
2.1
Primary objectives
This study considers two primary endpoints:
(1) the effect of the intervention on the on-time treatment adherence of the subjects 
(2) the effect of the intervention on the total treatment adherence of the subjects
 

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2.1.1
On-time treatment adherence
This objective will evaluate the effect of dose tracking in conjunction with reminder 
notifications and motivational/adaptive messages sent by the patient application over 24 weeks 
on the subject’s on-time treatment adherence.
On-time adherence is defined as percentage of days on which the subject inhaled at least one
dose within (±) 2 hours of the agreed preferred daily inhalation time (PIT). The preferred daily 
inhalation time is defined by the subject at study start (Visit 1) and can only be modified on 
subject’s request by the study investigator.
2.1.2
Total treatment adherence
This objective will evaluate the effect of dose tracking in conjunction with reminder 
notifications and motivational/adaptive messages sent by the patient application over 24 weeks 
on the subject’s total treatment adherence. 
Total adherence is defined as percentage of days on which the subject inhaled at least one dose 
and represents the sum of on-time adherence and off-time adherence. 
Off-time adherence is defined as percentage of days on which the subject inhaled a dose of 
medication, but did not do so within the target window (±) 2 hours of the agreed PIT.
2.2
Secondary objectives
To evaluate the effect of dose tracking in conjunction with reminder notifications and 
motivational/adaptive messages sent by the patient application over 24 weeks for the subject’s 
On-time adherence over the last four weeks of the Interventional period
Total adherence over the last four weeks of the Interventional period
 

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2.4
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
OBJECTIVE(s)
Endpoint(s)
Stat Analysis Section
Primary
To evaluate the effect of dose 
tracking in conjunction with 
reminder notifications and 
motivational/adaptive messages 
sent by the patient application 
over 24 weeks on the subject’s 
on-time treatment adherence 
and therefore treatment 
behavior
Title: On-time adherence over 24 weeks
On-time treatment adherence is defined 
as percentage of days on which the
subject inhales at least one dose on-time. 
Dose inhaled on-time is a dose inhaled 
within (±) 2 hours of the agreed 
predefined preferred daily inhalation time
(PIT).  
The number of days with an on-time
treatment adherence will be calculated 
based on the recorded date and time for 
each inhaler use (inhalation) and the 
predefined PIT. The PIT is specific for 
each individual subject and defined by the 
subject. The first dose each day inhaled 
within the (±) 2 hours of the PIT will be 
considered for the on-time adherence 
calculation.
Description: At screening subjects will be 
asked to use the Concept2 in the same 
way 
they 
were 
using 
the 
Ultibro®
Breezhaler® inhaler prior to enrollment.
Only at randomization subjects in the 
study will be instructed to inhale their daily 
Ultibro® Breezhaler® medication at the 
same time every day, using the Concept2 
inhaler. During the study the Concept2 
inhaler will track/record each time a 
subject uses the inhaler. 
Dose reminders and 
motivational/adaptive messages provided 
by the patient application for subjects in 
the Telehealth group will support the 
subject to inhale the dose at the same 
time every day.
Unit of Measure: % of days  
Time Frame : 24 weeks
Section 12.4.
To determine the effect of dose 
tracking in conjunction with 
reminder notifications and 
motivational/adaptive messages 
sent by the patient application 
over 24 weeks on the subject’s 
Title: Total adherence over 24 weeks
Total adherence is defined as percentage 
of days on which the subject inhaled at 
least one dose and will be calculated for 
each subject as the sum of on-time 
adherence and off-time adherence.
Section 12.4.
 

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OBJECTIVE(s)
Endpoint(s)
Stat Analysis Section
total treatment adherence and 
therefore treatment behavior
The definition of on-time adherence is 
explained in previous objective for on-
time adherence.  Off-time adherence is 
defined as percentage of days on which 
the subject did not inhale a dose within 
the (±) 2 hours of the predefined PIT, but 
outside.
The number of days with a total 
adherence will be calculated based on the 
recorded date and time of each inhaler
use (inhalation). 
Description: At screening subjects will be 
asked to use the Concept2 in the same 
way they were using the Ultibro®
Breezhaler® inhaler prior to enrollment. 
Only at randomization subjects in the 
study will be instructed to inhale their 
daily Ultibro® Breezhaler® medication at 
the same time every day, using the 
Concept2 inhaler. During the study the 
Concept2 inhaler will track/record each 
time a subject uses the inhaler.
Unit of Measure: % of days 
Time Frame : 24 weeks
Secondary
To explore the effect of dose 
reminders and 
motivational/adaptive messages 
sent by the patient application 
on the long term on-time 
adherence by comparing on-
time adherence over the last 
four weeks of Intervention to the 
on-time adherence at baseline
Title: On-time adherence over the last 4 
weeks of Intervention
On-time adherence is defined as 
percentage of days on which the subject 
inhales at least one dose on-time. A dose 
inhaled on-time is a dose inhaled within (±) 
2 hours of the agreed predefined preferred 
daily inhalation time.  
Description: The description is the same 
as for “on-time adherence over 24 weeks”, 
only the time frame considered is changed. 
The relevant time frame for this secondary 
endpoint is the last 4 weeks of the 
Interventional period. This assessment will 
allow to explore the difference in long term 
on-time adherence between both groups 
(last 4 weeks of Intervention compared to 
baseline on-time adherence)
Unit of Measure: % of days  
Time Frame : 4 weeks
  Section 12.5.1.1 
 

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OBJECTIVE(s)
Endpoint(s)
Stat Analysis Section
To explore the effect of dose 
reminders and 
motivational/adaptive messages 
sent by the patient application 
on the long term total 
adherence by comparing total 
adherence over the last four 
weeks of Intervention to the 
total adherence at baseline
Title: Total adherence over the last 4 weeks 
of Intervention
Description: The description is the same 
as for “total adherence over 24 weeks”, only 
the time frame considered is changing. The 
relevant time frame for this secondary 
endpoint is the last 4 weeks of the 
Interventional period. The assessment will 
allow to explore the difference in long term 
total adherence between both groups (last 4 
weeks of Intervention compared to baseline 
total adherence)
Unit of Measure: % of days 
Time Frame : 4 weeks
  Section 12.6.1.1 
 

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3
Study design
This is a multicenter, 1:1 randomized, controlled, parallel-group open label study to investigate 
whether COPD subjects on Ultibro® Breezhaler® once daily dosing regimen using a patient 
application in conjunction with the Concept2 inhaler have improved treatment adherence 
compared to subjects using the Concept2 inhaler alone.
It is planned to randomize approximately 146 subjects. These estimates are based on published 
literature used for sample size estimation (Section 12.8).
The total study duration is anticipated to be 34 weeks, which consists of a 6-week Screening 
period and a 24-week randomized Interventional period. A 4-week follow-up period will ensue 
to monitor subject’s safety. 
At Visit 1 all subjects eligible for the study will receive 3 Concept2 inhalers (two regular and
one back-up inhaler), each one to be used for a maximum of 30 days, and clinical trial 
formulation of the Ultibro® Breezhaler® capsules for 6 weeks to use with the Concept2 inhaler. 
All subjects will continue to receive the Ultibro® Breezhaler® treatment they received prior to 
enrollment, as prescribed by their physician. At the end of the 6-week Screening period inhaler 
use data will be uploaded from the returned Concept2 inhalers and evaluated by the investigator 
application. 
 
Subjects, who during the Screening period have > 10% and ≤ 70% total adherence (evaluated 
by the investigator application) and fulfill all other eligibility criteria, will be randomized via 
Interactive Response Technology (IRT) to one of the two study groups for 24 weeks. Total 
adherence results > 70% and ≤70.49% will be rounded down to 70% total adherence. 
 

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Subjects will be randomized 1:1to either the Telehealth group or the Usual Care group. On the 
first day (Day 1, Visit 110) subjects randomized to the Telehealth group will receive Ultibro® 
Breezhaler® capsules (clinical trial formulation), the Concept2 inhaler and a tablet device with 
a pre-installed patient application to collect data and to receive dose reminder notifications and 
motivational/adaptive messages aimed at encouraging treatment adherence.
 
 
 
 
The other half of the randomized subjects assigned to the Usual Care group (control) will 
receive Ultibro® Breezhaler® capsules (clinical trial formulation) and the Concept2 inhaler
only. They will continue to receive the usual care they received prior to study start. 
The study design is illustrated in Figure 3-1.
Figure 3-1
Study design
The study consists of 8 planned study visits and a telephone contact. Investigators will be 
required to follow all procedures during the conduct of the study. Details of all efficacy and 
safety measurements made at each of the study visits are provided in Section 8.3 and 
Section 8.4 respectively and the timings of these measurements are detailed in Table 8-1.
The definitions of adherence in this study are as follows: 
• A day, where at least one dose is inhaled within (±) 2 hours from preferred inhalation time is 
classified as an “on-time adherent” day
Visit 110
Randomization
Screening 
Period
6 weeks
24 Weeks
Visit 1
Screening
Visit 170 
Randomization
Interventional Period
Telephone
Contact
4 weeks 
Follow-up 
Period
Telehealth
Usual Care
Visit 140 
Visit 120 Visit 130
Visit 150 Visit 160
 

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• A day, where no dose is inhaled within (±) 2 hours from preferred inhalation time, but one or 
more doses are inhaled outside of (±) 2 hours from preferred inhalation time, is classified as an 
“off-time adherent” day
• A day where no dose is inhaled is classified as a “non-adherent” day
• On-time adherence is the percentage of ‘on-time adherent’ days (with respect to time of 
consideration)
• Off-time adherence is the percentage of ‘off-time adherent’ days (with respect to time of 
consideration) 
• Total adherence is defined as percentage of days on which the subject inhaled a dose and 
represents the sum of on-time adherence and off-time adherence
• Non-adherence is the percentage of ‘non-adherent’ days
Screening period
At the Screening visit (Visit 1) informed consent will be obtained before any study related 
assessments or procedures are performed and subject eligibility to take part in the study will be 
determined. Subjects will be asked to complete
 
 a questionnaire aiming 
 
 Baseline demographic details and concomitant medications,
including rescue medication use, will be reviewed and the subject’s medical history, history of 
cardiovascular risk factors, pulmonary disease history, COPD exacerbation history/events and 
smoking history will be recorded. All subjects will receive two Concept2 inhalers (each one to 
be used for a maximum of 30 days), one Concept2 back-up inhaler, the Instructions for Use 
(IFU) for the inhaler and clinical trial formulation of the Ultibro® Breezhaler® capsules to use 
with the Concept2 inhalers. Subjects will be instructed not to use the inhalers simultaneously 
and to only use the Concept2 back-up inhaler in case the regular Concept2 inhaler is damaged
or lost. In the event, any of the Concept2 inhalers dispensed during this visit are not returned at 
Visit 110, the subject will be considered a screening failure and not permitted to be re-screened. 
 
However the subjects 
will be asked to follow the instructions for use (IFU) and to use the Concept2 in the same way 
they were using the Ultibro® Breezhaler® inhaler prior to enrollment. At this visit, participants 
should be instructed that for the inhalation of their medicinal product (Ultibro® Breezhaler®
capsules) during the trial they should only use the Concept2 inhalers provided by the 
investigator.
Subjects will be asked about their preferred time of inhalation (PIT) during the day. The subjects 
PIT and the last 5 characters of the unique identification number of the dispensed inhalers 
(MAC Address; Appendix 9) will be noted in the investigator application page(s) capturing this 
information. In addition, every subject who enters the Screening period, will get a record in the 
Concept2 portal with the trial and subject number. 
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At Visit 110, (which will occur 6 weeks ± 7 days after Visit 1) subjects will return all 3 Concept2 
inhalers received at Visit 1 and the unused medication. 
 
 
The investigator will download the data 
for the six weeks Screening period from the 3 returned inhaler(s) using the investigator 
application and subject’s total adherence will be calculated by the investigator application. The 
calculation will consider the downloaded inhaler data from all 3 inhalers and the days the 
subject was taken off Ultibro® Breezhaler® treatment/inhaler use by the investigator. The 
period, for which a subject was taken off Ultibro® Breezhaler® treatment/inhaler use by the 
investigator, will be excluded from the adherence calculation and should not exceed 7 days. 
Subjects taken off the Ultibro® Breezhaler® treatment/inhaler use for more than 7 days will 
not be eligible and not permitted to be re-screened. In the event the downloaded data from all 3 
inhalers comprises less than 35 days (lower bound of 42 days ± 7 days’ time window for Visit 
110) the subject will be considered a screening failure and not be considered for a re-screening. 
All downloaded data from the inhalers will be transferred via wireless connection and stored in 
the Concept2 portal. All Concept2 inhalers dispensed during the Screening period are returned
to Novartis at the end of the study. 
The investigator will ask the subject about the rescue medication use in the past 6 weeks and 
enter the information in the CRF page capturing information about concomitant medication. 
Exacerbations that occurred during the Screening period will be recorded in the CRF as Adverse 
event (AE). Subjects who develop a COPD exacerbation after Screening (Visit 1) and prior to 
intervention (Visit 110) will not be eligible but will be permitted to be re-screened after a 
minimum of 6 weeks after the resolution of the COPD exacerbation.
Subjects who meet all eligibility criteria and who have a total adherence during Screening 
period >10% and less than or equal to 70%, will be considered for randomization (Day 1). All 
foreseen assessments for Visit 110 will be performed as listed in Table 8-1. Subjects will also 
be asked to fill in a number of self-reported questionnaires and scales such as the “EuroQol EQ-
5D-5L” questionnaire to assess the health status and the “St. George's Respiratory 
Questionnaire for Chronic Obstructive Pulmonary Disease Patients” (SGRQ-C).
At each visit, subjects will be given an adequate supply of drug and Concept2 inhalers. Details 
on dispensing are described in Section 6.5.1.
Half of the subjects will be randomized to the Telehealth group and the other half of subjects 
will be randomized to the Usual Care group (Day1). Subjects in both groups receive clinical 
trial formulation of the Ultibro® Breezhaler® capsules, a Concept2 inhaler to be used for a 
maximum of 30 days plus a Concept2 back-up inhaler and will be trained on how to use the 
inhalers and not to use them simultaneously. 
 
 
 
The Concept2 back-up inhaler should only be used in case the regular Concept2 inhaler is 
damaged and/or not functional, lost or if the next study visit scheduled is more than 30 days 
from the previous visit. The investigator will enter the last 5 characters of the unique 
identification number (MAC Address; Appendix 9) of all dispensed inhalers in the appropriated 
investigator application page(s) capturing the MAC Address. Subjects will be instructed to 
inhale Ultibro® Breezhaler® with the Concept2 inhaler at the same time every day, or as close 
 

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as possible. Subjects PIT will be recorded in the appropriated page(s) of the investigator 
application capturing the PIT; for subjects in the Telehealth group, the PIT will be 
entered/transferred to the patient application. The same PIT should be kept during the entire
study but can, if requested by the subject, be changed by the study investigator at a scheduled 
visit. All changes to the PIT are recorded in the investigator application capturing the PIT.
Subjects who are randomized to the Telehealth group will receive, in addition, a tablet device 
with a pre-installed patient application. They will be trained on how to use the application in 
conjunction with the Concept2 inhaler and how to connect the Concept2 inhalers with the 
application.
 
 
Visits 120 and 130 will take place 4 weeks and 8 weeks respectively after Visit 110. A window 
of + 2 days will be allowed for the timing of these visits. At each of these two visits subjects 
will routinely bring all received Concept2 inhaler(s), the Concept2 back-up inhaler and unused 
medication back to the site or to any other agreed person/place. A download of data from all 
used Concept2 inhalers, using the investigator application, will be performed by the site for all 
subjects independent of the study group they have been randomized. Subjects will receive a 
new Concept2 inhaler to be used for a maximum of 30 days, medication for the next 4 weeks
and, if necessary, also a new Concept2 back-up inhaler. The investigator will ensure that the 
last 5 characters of the unique inhaler identification number of dispensed inhaler(s) (MAC 
Address) are entered in the appropriated page(s) of the investigator application capturing the 
MAC Address (Appendix 9). 
Visit 140 will take place 4 weeks after Visit 130. A window of + 2 days will be allowed for the 
timing of this visit based on the timing of Visit 130. At Visit 140 subjects will bring all received 
Concept2 inhaler(s), the Concept2 back-up inhaler and unused medication back to the site and 
download of data from used Concept2 inhalers, using the investigator application, will be 
performed for all subjects independent of the study group to which they have been randomized. 
Subjects will receive a new Concept2 inhaler to be used for a maximum of 30 days, medication 
for the next 4 weeks and a new Concept2 back-up inhaler. The subjects will be instructed not 
to use the inhalers simultaneously and will be re-trained on how to connect the Concept2 inhaler 
with the patient application, if required. The Concept2 back-up inhaler should only be used in 
case the regular Concept2 inhaler is damaged and/or nonfunctional, lost or if next study visit is 
scheduled more than 30 days from previous visit. The investigator will enter the last 5 characters 
of the unique inhaler identification number of the dispensed inhalers in the appropriated page(s) 
of the investigator application capturing the MAC Address (Appendix 9). The investigator will 
ask the subject about the rescue medication use during the past 12 weeks and enter the 
information in the CRF page capturing the concomitant medication. Exacerbations that 
occurred during the last 12 weeks will be recorded in the CRF as AEs. 
The list of examinations to perform at this visit can be found in Table 8-1.
Visits 150 and 160 will take place 4 weeks and 8 weeks respectively after Visit 140. A window 
of + 2 days will be allowed for the timing of these visits. At each of these two visits subjects 
will routinely bring all received Concept2 inhaler(s), the Concept2 back-up inhaler and unused 
 

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medication back to the site or to any other agreed person/place. A download of data from used 
Concept2 inhalers, using the investigator application, will be performed by the site. Subjects 
will receive a new Concept2 inhaler to be used for a maximum of 30 days, medication for 4 
weeks and, if necessary, also a new Concept2 back-up inhaler. The investigator will ensure that 
the last 5 characters of the unique inhaler identification number (MAC Address) of the 
dispensed inhaler(s) are entered in the appropriated page(s) of the investigator application 
capturing the MAC Address (Appendix 9). 
Visit 170 will take place 4 weeks after Visit 160. This is the final study visit of the Interventional 
period. A window of + 2 days will be allowed for the timing of this visit based on the timing of 
Visit 160.
The list of assessments to perform at this final study visit can be found in Table 8-1.
During this visit, the investigator will ask the subject about the rescue medication use during 
the past 12 weeks and enter the information in the CRF page capturing the concomitant 
medication. Exacerbations that occurred during the past 12 weeks will be recorded in the CRF 
as AE. All subjects will return the Concept2 inhaler(s) received at Visit 160, the Concept2 back-
up inhalers received and all study medication not used during the trial. Inhaler use data from 
the used Concept2 inhalers will be uploaded by the investigator using the investigator app and 
data transferred to the Concept2 portal. Subjects randomized in the “Telehealth” group will in 
addition also return the tablet device. The tablet device and the Concept2 inhalers from all 
subjects will be collected by the trial monitors at the conclusion of the study and returned to 
Novartis/vendors. 
Follow-up period
All randomized subjects, regardless of whether they completed study through Week 24 or 
discontinued prior to Week 24, will be contacted (by telephone) 4 weeks after Visit 170 or study 
discontinuation for a Safety Follow-up. A window of ± 10 days will be allowed for the timing 
of this visit based on the timing of Visit 170 or study discontinuation visit. 
The list of assessments to perform at the follow up study visit can be found in Table 8-1.
If a subject refuses to return for any assessments or is unable/ unwilling to do so, every effort 
(preferable at least three documented efforts) should be made to contact the subject or a person 
pre-designated by the subject to ensure the safety of the subject. Attempts to contact the subject 
should be documented in the source records.
4
Rationale
4.1
Rationale for study design
The subject population will be described in more detail in Section 5.
This is a randomized, controlled, parallel-group, open label study. The use of a parallel-group 
controlled study design enables a comparison between the subject groups during a 24 weeks 
Interventional period. The design of the study also intends to simulate the “real world” to the 
extent feasible within a controlled clinical trial, by minimizing the number of clinic visits and 
study interventions imposed.
 

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A baseline total adherence will be established through the 6-week Screening period. The defined 
baseline treatment adherence (total adherence) of > 10% and less or equal to 70% has been 
chosen based on the published expected treatment adherence for COPD patients between 41% 
and 57% (Bryant et al 2013, Cecere et al 2012) and the anticipated treatment adherence for 
COPD patients in well-controlled clinical studies of 70-90% (Hawthorne effect; Bryant et al
2013). To study the relevant population, this study focuses on poorly adherent subjects, i.e. 
subjects with ≤70% total adherence, in order to fully explore the adherence digital system’s 
effectiveness. Subjects with a treatment adherence >70% during Screening period are therefore 
excluded from the participation in the study.
During the Screening period all subjects will receive the Concept2 inhaler without tablet
device/application and no reminders or messages will be sent. As described earlier, the 
Concept2 inhaler looks similar to the commercially available Ultibro® Breezhaler® inhaler 
(Concept1 inhaler) and both are used in the same way. It is hence assumed, that the adherence 
behavior of the subjects during the Screening period, will not be different from the adherence
behavior the subjects had prior to study enrollment.
Half of the subject population in this study will be assigned to the Telehealth group and on the 
first day of the Interventional period they will receive clinical trial formulation of the Ultibro® 
Breezhaler® capsules, a Concept2 inhaler and a tablet device with a pre-installed patient 
application (patient app). 
 
 
 
The other half of subjects will be assigned to the Usual Care group and will receive clinical 
trial formulation of the Ultibro® Breezhaler® capsules and the Concept2 inhaler only, with the 
standard Instructions for use (IFU). After randomization both groups will receive training on 
how to use the Concept2 inhaler and will be reminded about the importance of treatment 
adherence.
Group
Telehealth

Concept2 inhaler/ Ultibro® Breezhaler® capsules, 

Patient application pre-installed on the tablet device for home use 
displaying dose-reminder notifications, feedback to the subject 
 
to 
encourage treatment adherence 
 
 

Regular Medical visits
Usual Care

Concept2 inhaler/ Ultibro® Breezhaler® capsules,

IFU for the Concept2 inhaler (Instructions for use; paper)

Regular Medical visits
A 24-week Interventional period is considered to be a reasonable time frame to observe changes 
in subjects’ treatment adherence behavior expecting that adherence will decline with time more
in the control group. In the Lung Health Study, ~70% of participants reported satisfactory or 
 

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better adherence to inhaled medication for COPD at the first 4-month follow-up visit; this 
decreased to ~60% over the next 18 months (Rand 2005). A similar observation was also 
reported by Vrijens et al (2014) and Chan et al (2015). In the study conducted by Chan et al 
(2015) the overall adherence in pediatric subject with asthma fell in both observed groups over 
time. Mean percentage adherence at 2, 4, and 6 months were 91%, 84%, and 79%, respectively, 
for the intervention group, compared with 40%, 33%, and 27%, respectively, for the control 
group.
Self-reporting of adherence has moderate reliability (25%–67%) when compared against more 
objectives measures of adherence such as canister weight of pressurized Metered Dose Inhalers 
(Rand et al 1995, Rand et al 1992) or electronic monitoring (Gong et al 1988, Nides et al 1993, 
Bosley et al 1996). 
 
 
 
 
 
Only a few studies have been carried out to improve adherence and most have concentrated on 
quantifying adherence, rather than exploring the factors which affect non-adherence, although 
need for motivational and cognitive ways to improve adherence has been pointed out (George 
et al 2005). The patient application along with the Concept2 inhaler, tracking the daily inhaler 
use, will remind the subjects randomized to Telehealth group every day to take their medication,
if not done, on time; 
 
The patient application will also provide feedback on inhaler use 
 
 
 
 
 
4.2
Rationale for dose/regimen, route of administration and duration 
of treatment
The intervention in this study consists solely of the use of an investigational digital system 
consisting of the patient application and the Concept2 inhaler. All subjects in this study will 
continue to receive Ultibro® Breezhaler® treatment daily as prescribed by their physician prior 
to their enrollment in the study. Ultibro® Breezhaler® treatment is approved for the maintenance 
bronchodilator treatment of symptoms in subjects with COPD. In accordance with the EU 
product label, Ultibro® Breezhaler® (143 μg of indacaterol maleate equivalent to 110 μg of 
indacaterol and 63 μg of glycopyrronium bromide equivalent to 50 μg of glycopyrronium) 
should be inhaled once daily on a regular basis. The treatment is delivered via the Ultibro®
Breezhaler® inhaler (Concept1 inhaler).
 

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This study will recruit subjects who have been prescribed treatment with Ultibro® Breezhaler®
(110/50 µg) for at least 3 months prior to Visit 1. The clinical trial formulation of Ultibro® 
Breezhaler® medicinal product will be used in this study. Subjects will be required to inhale 
the capsules via the Concept2 inhaler, instead of the Ultibro® Breezhaler® inhaler. Other than 
this, there will be no change to the subjects’ prescribed dose and treatment. 
The subjects are also permitted to use inhaled COPD rescue medication on ‘as needed’ basis as 
prescribed by their treating physician prior to enrollment in the trial according to the locally 
approved label. The use of rescue medication will be asked and recorded in study documents.
However, the subjects will not be supplied with inhaled COPD rescue medication. It has been 
demonstrated that the inhalation performance of the Concept2 inhaler is comparable to the 
approved Concept1 inhaler (the Breezhaler®), hence there are no additional anticipated risks 
by not providing the subjects with rescue medication. Further, a change in the type of COPD 
rescue medication supply may have the potential to bias subject’s behavior towards their COPD 
treatment.
Changes to the subject’s therapy and treatment interruptions are permitted at the discretion of 
the investigator. During the 6 weeks Screening period, treatment interruptions exceeding a total 
of 7 days will result in screening failure. Interruption of therapy or changes in treatment will be 
recorded on the appropriate CRF page. Treatment for COPD concomitant illnesses are at the 
discretion and choice of the managing physician at the study site. 
The Concept2 inhaler used to deliver Ultibro® Breezhaler® treatment in this study has the same 
user steps, materials and equivalent dose delivery characteristics as the Ultibro® Breezhaler®
inhaler (Concept1 inhaler) that the subjects were using prior to trial enrollment and therefore 
should not affect subjects’ use of the inhaler device.
4.3
Rationale for choice of comparator
Adherence tracking is normally not performed in routine clinical practice. In this study the 
comparator will be the group assigned to use the Concept2 inhaler only. This group represents
the usual care with Ultibro® Breezhaler®, using the Breezhaler® inhaler to deliver the 
medication, and will be considered the Usual Care (control) group. The drug delivery with the 
Concept2 inhaler has been shown to be not altered with the addition of the electronic
components and subjects can’t download the inhaler use information recorded by the Concept2 
inhaler. The primary reason for using the Concept2 inhaler in the Usual Care group is, that it 
will provide an actual measure of adherence similar to that provided for the Telehealth group.
Thus, the only difference of intervention between the two study groups is the system of devices 
comprising of the patient app on the tablet device and its electronic connectivity to the Concept2 
inhaler/s in the Telehealth group; which is not the case in the control group. The investigator in 
the study will be able to download the inhaler use data from all Concept2 inhalers by using the 
investigator app 
 The data is 
wirelessly transmitted from the investigator app to the Concept2 portal
 
4.4
Purpose and timing of interim analyses/design adaptations
No interim analysis is planned.
 

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4.5
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria, 
study procedures and close clinical safety monitoring.
It has been demonstrated that the inhalational performance of the Concept2 inhaler is 
comparable to the approved Concept1 inhaler (the Breezhaler®), hence there are no additional 
risks associated with its use. Risks associated with the Concept2 inhaler are described in the 
Investigator Brochure (IB) Edition 1 for the Concept inhaler. Risks associated with the use of 
Ultibro® Breezhaler®, are those described in the Summary of Product Characteristics 
(SmPC)/National Prescribing Information (nPI) and the Investigator’s Brochure for QVA149.
Women of child bearing potential and sexually active males will be informed during the first 
visit that taking Ultibro® Breezhaler® may involve unknown risks to the fetus if pregnancy 
were to occur during the study, and have to agree that in order to participate in the study they 
must adhere to the contraception requirements outlined in the exclusion criteria. If there is any 
question that the subject will not reliably comply, they should not be entered or continue in the 
study.
Improved total and on-time adherence to Ultibro® Breezhaler® prescribed for COPD is expected 
to result in subjects’ benefit, by improvement in symptoms related to COPD.
It is possible that subjects in the Telehealth group may perceive the monitoring system to be 
invasive or intrusive on the subject’s privacy. To mitigate this, the nature of the technology will 
be thoroughly explained at the randomization visit. The subject will be able to opt out of the 
study at any time and the study will be conducted in accordance with currently accepted ethical 
principles and International Conference on Harmonisation Good Clinical Practice (ICH GCP)
guidelines.
In case a subject in the Telehealth group may inhale more than one dose in a given day the 
subjects will receive a notification via the patient application that they have exceeded the 
recommended daily dosing. This information will also be noted on the subject’s daily dosing 
record, which is located on the patient’s application.
One potential benefit for the subject lies in a thorough medical evaluation of the subjects’ 
disease and close clinical monitoring for the duration of the study. In addition, the inhaler 
training provided to all subjects will represent a tangible benefit.
The tablet device and the Concept2 devices are designed to emit electro-magnetic radiation in 
the Industrial, Scientific and Medical (ISM) and cellular radio frequency bands. Government 
and regulatory agencies have established SAR (Specific Absorption Rate) limits under which 
cellular devices have been determined to be safe and the devices being used in this study meets 
these limits. The technology chosen to enable the devices to communicate with the CDR (file 
format) is subject to regulation under European Radio Equipment Directive (RED) (i.e.: 
Directive 2014/53/EU of the European Parliament and of the Council of 16 April 2014 on the 
harmonization of the laws of the Member States relating to the making available on the market 
of
radio equipment and repealing Directive 1999/5/EC) on radio equipment and 
telecommunications terminal equipment and complies with the essential requirements of both.
 

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5
Population
The study population will consist of approximately 146 male and female adults age 18 years 
and older, with a clinical diagnosis of COPD (spirometric grade 2 or 3 according to GOLD 
2017 criteria; Appendix 10), a smoking history of at least 10 pack years, receiving COPD 
maintenance treatment with Ultibro® Breezhaler® for at least 3 months prior to trial enrollment
and with a known poor treatment adherence.
146 subjects are planned to be randomized into the study with the expectation that at least 120 
subjects will complete the study. The study will be multicenter and drop-outs will not be 
replaced.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1.a Signed informed consent must be obtained prior to participation in the study.
2. Male and female adults aged ≥18 years.
3. Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten 
pack- years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 
years).
4.a A historical diagnosis of COPD confirmed by a post-bronchodilator FEV1/FVC < 0.70 
in the past and a pre-bronchodilator or post-bronchodilator FEV1 ≥30% and < 80% of the 
predicted normal value within the last year.
5. Have been taking Ultibro® Breezhaler® for at least 3 months prior to Visit 1 (in 
accordance with the local product label).
6. Have a total adherence of more than 10% but less than or equal to 70% during Screening 
period. Total adherence is defined as percentage of days on which the subject inhaled a 
dose of Ultibro® Breezhaler®.
7. Have been in the Screening period ≥35 days.
5.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG (human 
Chorionic Gonadotropin) laboratory test.
2.a Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception while taking 
Ultibro® Breezhaler® medication during the study. Basic contraception methods include:
 

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• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject.
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps). For UK: with spermicidal foam/gel/film/cream/ vaginal suppository.
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS). 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before entering the study.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
3. Subjects contraindicated for treatment with, or having a history of reactions/ hypersensitivity 
to any of the following inhaled drugs, drugs of a similar class or any component thereof:
• anticholinergic agents
• long and short acting beta-2 agonists
• sympathomimetic amines
4. Subjects contraindicated for having a history of reactions/ hypersensitivity to lactose or any 
of the other excipients of trial medication. 
5. Subjects with a history of malignancy of any organ system, treated or untreated, within the 
past 5 years whether or not there is evidence of local recurrence or metastases, with the 
exception of localized basal cell carcinoma of the skin.  
6. Subjects with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-
neck obstruction or moderate to severe renal impairment or urinary retention. Benign 
Prostatic Hyperplasia (BPH) subjects who are stable on treatment can be considered.
 

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7. Subjects who have had a COPD exacerbation that required treatment with antibiotics and/or 
systemic corticosteroids and/or hospitalization in 6 weeks prior to Visit 1.
8. Subjects who develop a COPD exacerbation between screening (Visit 1) and prior to 
intervention (Visit 110) will not be eligible but will be permitted to be re-screened after a 
minimum of 6 weeks after the resolution of the COPD exacerbation.
9. Subjects who have had a respiratory tract infection within 3 weeks prior to Visit 1.
10.a Subjects who develop a respiratory tract infection between screening (Visit 1) and prior to 
intervention (Visit 110) will not be eligible, but will be permitted to be re-screened after a 
minimum of 3 weeks after the resolution of the respiratory tract infection.
11. Subjects with a current diagnosis of asthma.
12. Subjects with concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis, interstitial 
lung disease, pulmonary hypertension, and pulmonary tuberculosis).
13. Use of investigational drugs or other investigational devices at the time of enrollment, or 
within 30 days or 5 half-lives of Visit 1, whichever is longer.
14. Subjects with a preferred inhalation time between 10.00 pm and 2.00 am.
15. Subjects taken off Ultibro® Breezhaler® treatment/inhaler use by the investigator during 
the Screening period for more than 7 days.
16. Subjects not returning all Concept2 inhalers, received during the Screening period, for the 
calculation of total adherence at Visit 110.
17. Subjects who have demonstrated inability or unwillingness to use the digital system or to 
fill in questionnaires.
6
Intervention
The intervention in this study consists solely of the use of an investigational digital system,
composed by the patient application and the Concept2 inhaler. The digital system will be used 
in half of the subjects while the other group (control) will receive Usual Care delivered by the 
Concept2 inhaler, with no patient application. The drug treatment in this trial is not under 
investigation. All subjects in this study will receive Ultibro® Breezhaler® capsules (110/50 µg) 
daily as prescribed by their physician prior to their enrollment in the study. The clinical trial 
formulation of Ultibro® Breezhaler® medicinal product will be provided to the subjects, 
required to be inhaled with the Concept2 inhaler instead of the Concept1 inhaler. (Section 4.2).
In this section, the details of the components of the digital system used in the study are described. 
The overview of the components and data flow is shown in Figure 6-1.
(a) Concept2 inhaler: The Concept2 inhaler (or also called eConcept1 Mark1) is a modification 
of the currently marketed Ultibro® Breezhaler® inhaler (Concept1 inhaler), with the addition 
of electronic components in the base of the device: 
 
 The additional electronics do not alter the drug delivery characteristics of the 
inhaler itself, but produce a recording of each administered dose
 
and a date and time stamp whenever the 
 

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subject uses the inhaler with the intention to inhale a dose of drug
 after 
pushing the buttons.
 
(b) Concept2 portal: is a central data base for centrally storing of study relevant data, subject’s 
ID numbers,
 PIT, 
Mac-address of inhalers and inhaler use data. The data base will receive data from the tablet 
device running the patient and investigator application. All relevant clinical data in this data 
base will be sent to the clinical data base at Novartis on an ongoing basis and at the end of 
the study.
(c) Applications: the users of the applications are subjects and investigators. The applications 
will require a standard tablet device running an Android operating system. 
 
 Some of the described functionalities 
require an internet connection.
Application for the patient: the intended use of the patient application is to monitor 
adherence to COPD maintenance therapy medication delivered through the Concept2 inhaler 
and to drive improvement in adherence by providing dose reminders, motivational/adaptive
messages and feedback on subject’s level of adherence. The application will run on a 
customized tablet device for home use. The patient application also transmits the inhaler use 
data to the central data base (Concept2 portal). Functionalities:
a.) Initial setup
b.) Connect with the Concept2 inhalers
c.) Receive data on inhaler use from a connected Concept2 inhaler
d.) Display dose reminders or notifications 
 
 
h.) Change of settings
i.) Transfer data to the data base (Concept2 portal)
Application for the investigator: this application runs on a customized tablet device and 
has functionalities for the investigator such as:
a.) Download of inhalers use data from the Concept2 inhalers returned by subjects’ after 
use 
b.) Transmitting of Concept2 inhaler use data to the Concept2 portal 
c.) Calculation of screening total adherence
 
 

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e) Capturing of subjects preferred inhalation time and the Mac-Addresses of the dispensed 
inhaler for the individual subjects
 

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Figure 6-1
Overview of the components of the digital adherence system and data 
flow
Inhaler
Tablet & app 
Concept2 
portal
Concept2 Inhaler
Applications
Database (Concept2 portal)
Delivers the medication 
from the capsule to the 
subject’s lungs
Records and stores 
inhaler use data (date and 
time stamp)
Transmits wireless 
recorded inhaler use data 
to the patient application 
on the tablet device
Patient application:
Receives inhaler use data from a connected 
Concept2 inhaler
Reminds subjects to use their inhaler within 
their PIT
 
Enables subjects to understand their 
adherence profile
Transfers wireless inhaler use data to the 
Concept2 portal
Stores
- downloaded inhaler use 
data
 
 
- subject ID and study 
number 
- subject’s PIT and Mac-
Addresses of the 
dispensed inhaler(s)
Transfers relevant data to 
the Novartis Clinical 
Database
Investigator application:
Downloads inhaler use data from the
Concept2 inhalers
Calculates screening total adherence data
Transfers wireless inhaler use data
 
 
The Concept2 inhaler will record the date and time at each occasion when the subject uses the 
Concept2 inhaler 
 
 In the Telehealth group this information will be transmitted to the patient’s application 
allowing subjects in this group to monitor their level of adherence. 
 
ZIGBEE
Inhaler data
Concept2
 

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 In 
the Usual Care group inhaler use information will be 
 
 uploaded by the investigator via the investigator application. 
 
 
 If subjects in the Telehealth group do not use the inhaler once daily by their PIT, 
the application running on the tablet device will be pre-programmed to deliver reminders to the 
subjects to inhale their medication. Subjects who use the inhaler twice or more times within one 
day (overuse) with the intention to inhale the medication, will also be notified to only inhale 
one dose per day. 
 
 
 
The application will in addition display regular 
motivational and adaptive messages to the subject to encourage adherence. 
 
 
 
 
 
 

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6.1
Control arm (Usual care group)
Subjects in the control arm will receive Usual Care (Ultibro® Breezhaler®) daily as prescribed 
by their physician prior to their enrollment in the study. The clinical trial formulation of Ultibro®
Breezhaler® capsules (110/50 µg) will be provided) with the Concept2 inhaler, with no patient 
application and no tablet device.
6.2
Study arm (Telehealth group)
Subjects in the study arm (Telehealth group) will receive (Ultibro® Breezhaler®) treatment
(110/50 µg) daily as prescribed by their physician prior to their enrollment in the study. The 
clinical trial formulation of Ultibro® Breezhaler® capsules (110/50 µg) will be provided to the 
subjects with the Concept2 inhaler and patient application (app) pre-installed on a tablet device.
6.3
Subject numbering, assignment of intervention and 
randomization
6.3.1
Subject numbering
Each subject is uniquely identified by a Subject Number assigned by Novartis. The subject 
number is composed of a site number and a sequential number. Once assigned to a subject, the 
Subject Number will not be reused. Upon signing the informed consent form, the subject is 
assigned the next sequential number available in electronic data capture (EDC) system. The 
investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the subject to register them into the IRT. The site must select the CRF book 
with a matching Subject Number in the EDC system to enter data.  Once assigned to a subject, 
the subject number will not be reused. If the subject fails to be randomized for any reason, the 
IRT must be notified within 2 days that the subject was not randomized.
6.3.2
Assignment of intervention and randomization
At Visit 110 all eligible subjects will be randomized via Interactive Response Technology (IRT) 
to one of the study arms. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. 
The randomization numbers will be generated using the following procedure to ensure that 
intervention assignment is unbiased and concealed from subjects and investigator staff. A 
subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different study arms, which in turn are linked to kit
numbers. 
 
 
 
 
 

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 (Bryant et al 2013, Cecere et al 2012)).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
6.4
Blinding
This is a randomized, controlled open label study in which investigators will have full 
knowledge of the allocation of the subjects.
 
 
 
Sponsor Staff
With the exception of any unblinded sponsor staff identified below, Novartis staff will stay 
blinded to group allocation of the subjects until database lock. The following unblinded sponsor 
roles are required for this study:

Unblinded clinical data review to review the safety reporting of devices

Unblinded data manager to reconcile the serious adverse device events
The monitors will be unblinded through the review of the source documentation at site (source 
documentation will detail if the training for the patient application was done by the subject).
However, none of the unblinded roles will have access to subject’s treatment adherence data 
contributing to the co-primary endpoints analyses in the study
Table 6-2
Blinding and unblinding plan 
Role
Time or Event
Randomization 
list generated
Intervention 
allocation 
Safety event 
(single 
subject 
unblinded)
Adherence 
data 
(inhaler 
use)
Subjects
B
UI
NA
UI*
Site staff
Pharmacy staff, nurse, 
investigator, site coordinator
B
UI
UI
B
Drug Supply and 
Randomization Office
UI
UI
B
B
Sponsor staff
Trial monitors
B
UI
UI
B
Clinical data reviewer (safety 
review of device events)
B
UI
UI
B
Data manager (reconciliation
of SADE)
B
UI
UI
B
Pharmacovigilance staff
B
UI
UI
B
 

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Role
Time or Event
Randomization 
list generated
Intervention 
allocation 
Safety event 
(single 
subject 
unblinded)
Adherence 
data 
(inhaler 
use)
Statistician/statistical 
programmer/ data analysts 
(e.g. biomarker, PK1)
B
B
B
B
All other sponsor staff not 
identified above (e.g. trial 
team, other clinical data 
reviewers, other data 
managers, project team, 
management & decision 
boards, support functions)
B
B
B
B
Independent committees used 
for assessing interim results, if 
required (e.g. DMC2)
NA
NA
NA
NA
UI: Allowed to be unblinded on individual subject level; B: Remains blinded; NA: Not applicable to this study
*: only for the subjects in the Telehealth group
1 :Pharmacokinetic
2 :Data Monitoring Committee
6.5
Treating and monitoring the subject
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
6.5.1
Dispensing the investigational digital(s) system and the medicinal 
product 
The subjects assigned to the Telehealth group will receive upon randomization clinical trial 
formulation of the Ultibro® Breezhaler® capsules and the following devices: Concept2 inhalers 
and a tablet device with a pre-installed patient application. They will be training on how to use 
the inhaler and the application. The subjects assigned to the Usual Care group will receive, upon 
randomization, clinical trial formulation of the Ultibro® Breezhaler® capsules and the 
Concept2 inhalers only and be trained on how to use the inhaler. Each Concept2 inhaler has a 
label adhered to the Concept2 inhaler base including the 16 characters unique identification of 
the device (MAC Address). The Concept2 inhalers for the individual subjects will be assigned 
by IRT. At each visit subjects will bring all Concept2 inhalers received at the previous visit
back to the site. Used inhalers will be replaced with new ones to use for a period of 30 days. 
The medication will be dispensed at each visit as detailed in Figure 6-2.
 

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Figure 6-2
Dispensing of Concept2 inhalers and clinical trial formulation of 
Ultibro® Breezhaler® capsules
Screening
Intervention
Follow 
up
Visit 1
Visit 110
Visit 120
Visit 130
Visit 140
Visit 150
Visit 160
Visit 
170
Visit 
1999
-
-
back-up
back-up
back-up
Ultibro®
Breezhaler®
capsules 
Ultibro®
Breezhaler®
capsules 
Ultibro®
Breezhaler®
capsules
Ultibro®
Breezhaler®
capsules
Ultibro®
Breezhaler®
capsules
Ultibro®
Breezhaler®
capsules
Ultibro®
Breezhaler®
capsules
-
-
6.5.2
Handling of devices and medication
Concept2 inhalers, tablets running the app’s and Ultibro® Breezhaler® capsules provided by 
Novartis must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designees have 
access. Upon receipt, medication and inhalers should be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Complaints are to be reported to the trial monitor and respective Novartis CPO Quality 
Assurance.
Device and medication (clinical trial formulation of the Ultibro® Breezhaler® capsules) labels 
will be in the local language and comply with the legal requirements of each country. They will 
include storage conditions. The Concept2 inhaler will in addition have a label adhered to the 
Concept2 inhaler base including a unique 16 characters MAC Address identification. The last 
5 characters of this MAC Address will be entered by the investigator in the appropriate page(s)
capturing the MAC Address when dispensing the inhaler(s) to the subject.
The investigator must maintain an accurate record of the shipment and dispensing of 
devices/tablets and medication in a device/drug accountability log. Monitoring of device 
accountability will be performed by monitors during site visits or remotely and at the 
completion of the trial. Subjects will be asked to return at each study visit the Concept2 inhalers 
received and the unused medication. 
At the conclusion of the study, and as appropriate during the course of the study, used and 
unused Concept2 inhalers will be returned to Novartis. Subjects randomized in the Telehealth 
group will in addition also return the tablet device to the site after completing the intervention. 
At the conclusion of the study all tablets will be collected by the trial monitors and returned as 
appropriate. A copy of the completed device accountability log are collected at the site close 
out visit.
 

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6.5.3
Instructions for using the devices and taking medication
All subjects will continue to receive Ultibro® Breezhaler® throughout the study as prescribed 
by their physician prior to their inclusion in the study. The clinical trial formulation of the 
Ultibro® Breezhaler® is required to be inhaled however with the Concept2 inhaler. 
All subjects entering the study will be trained on how to complete the questionnaire(s)    
(Section 8.3.3) and will be encouraged to refer to the instructions for use (IFU) of the Concept2 
inhaler. After randomization they will be trained in the use of the Concept2 inhaler (Appendix 
2). Subjects randomized to the Telehealth group, will in addition, receive training on how to 
use the patient application and how to synchronize the patient application and the Concept2 
inhaler. 
The investigator should promote adherence by instructing the subject to inhale Ultibro®
Breezhaler® exactly as prescribed and by stating that adherence is necessary for the subject’s 
safety. The subject should be instructed to contact the investigator if he/she is unable, for any 
reason, to inhale the medication or use the Concept2 inhaler or the patient adherence application.
6.5.4
Permitted dose adjustments and interruptions of Ultibro® Breezhaler®
treatment 
The COPD treatment with Ultibro® Breezhaler® is not the investigational part of the study. All 
subjects will continue to receive Ultibro® Breezhaler® treatment throughout the study as 
prescribed by their physician prior to their inclusion in the study. The clinical trial formulation 
of the Ultibro® Breezhaler® will be provided to subjects in the study. Treatment interruptions 
are permitted at the discretion of the investigator. Treatment for COPD concomitant illnesses 
are at the discretion and choice of the managing physician at the study site. Changes in therapy 
will be recorded in the appropriated CRF page(s).
If at any point during the Interventional period the subject is taken off study drug by the 
investigator, this will be noted by the investigator in the CRF page(s) capturing interruptions of 
treatment, in order that the adherence calculation is based on the number of days the subject 
was scheduled to inhale Ultibro® Breezhaler®. For example, if the subject has an exacerbation 
of COPD and enters the hospital, any days off Ultibro® Breezhaler® will need to be recorded in 
the CRF. If the subject is discontinued from the study, this date will also be noted and entered 
in the CRF.
6.5.5
Treatment compliance and exposure
In addition to the tracking of treatment adherence by the Concept2 inhaler, the Investigator or 
designee will collect at each visit the used/unused medication and packaging from the subject 
(unused capsules, blister strips).
6.5.6
Rescue medication
There are no study specific requirements regarding the use of rescue medications. COPD rescue 
medication will not be provided to the subjects. The subjects are permitted to use their inhaled 
COPD rescue medication on ‘as needed’ basis as prescribed by their treating physician prior to 
enrollment in the trial and according to the locally approved label.  Their use of rescue 
medication will be asked and recorded in study document at certain visits (Table 8-1).   In the
 

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event that a subject uses a dose of rescue medication, date of intake should be captured on the 
CRF page(s) capturing concomitant medications.
6.5.7
Concomitant medication
Treatment for COPD concomitant illnesses are at the discretion and choice of the managing
physician at the study site. Each concomitant drug must be individually assessed against all 
exclusion criteria and the investigator should consult the section “Interaction with other 
medicinal products and other forms of interaction” of the SmPC for Ultibro® Breezhaler®.
In addition, the investigator will instruct the subject to notify the study site about any new 
medications he/she takes after the subject was enrolled into the study. All medications, 
procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject was enrolled into the study must be recorded in the 
appropriate CRF.
6.5.8
Prohibited medication
There is no additional prohibited treatment in this trial. The investigator should consult the 
SmPC for Ultibro® Breezhaler®. 
6.5.9
Emergency breaking of assigned treatment code
Not applicable. 
7
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC)-approved informed consent. If applicable, in cases where the subject's 
representative(s) gives consent (if allowed according to local requirements), the subject must 
be informed about the study to the extent possible given his/her understanding. If the subject is 
capable of doing so, he/she must indicate agreement by personally signing and dating the 
written informed consent document. Informed consent must be obtained before conducting any 
study-specific procedures (e.g. all of the procedures described in the protocol). The process of 
obtaining informed consent must be documented in the subject source documents
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis/sponsor before submission to the IRB/IEC.
Information about common side effects already known about the components of the 
investigational digital adherence system (the Concept2 inhaler and the Patient app) can be found 
in the respective Investigator's Brochure (IB); for the Ultibro® Breezhaler® treatment the 
information can be found in the Core Data Sheet (CDS). This information will be included in 
the subject informed consent and should be discussed with the subject during the study as 
needed. Any new information regarding the safety profile of the investigational intervention
that is identified between IB updates will be communicated as appropriate, for example, via an 
 

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investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the Ultibro® Breezhaler®
treatment may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the contraception 
requirements.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
8
Visit schedule and assessments
Table 8-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Subjects should be seen for all visits on the designated day as close as possible within the time 
window. If this is not possible for any reason, the investigator must ensure the subject has 
received appropriate amount of Concept2 inhalers to not exceed the 30 days of use of each 
inhaler.
 
 
Missed or re-scheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for study discontinuation visit will be 
performed. At this final visit, all dispensed Concept2 inhalers, tablets and unused medication 
should be returned and the adverse events and concomitant medications reconciled on the CRF.
Subjects will be contacted for safety evaluations during the 30 days following study Visit 170
or last study visit, in case they discontinued earlier. 
 

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Table 8-1
Assessment schedule
Period
Screening
Intervention
Follow 
up
Visit Number
1
110
120
130
140
150
160
170
1999
Visit
Randomization
End of intervention 
PSW/Study 
Discontinuation 
Study completion
Week
-6
1
4/8
12
16/20
24
28
Day
-42 ± 7 days
1
28/56
+2 days
84      
+2 days
112/140
+2 days
168     
+ 2 days
196 ± 
10 days
Obtain informed consent
X
Demographics
X
Medical history including 
COPD exacerbation history
X
History of cardiovascular risk 
factors
X
Pulmonary diseases history
X
COPD exacerbation events1
X
X
X
Smoking History
X
Smoking Status
X
X
Inclusion / exclusion criteria
X
Pregnancy test (urine or 
serum)**
S
S
S
Concomitant medication 
review, including rescue 
medication use
X
X
X
X
Physical Examination
S
S
S
Height and weight
X
Vital signs
X
X
Randomization via IRT
X
Contact IRT in order to receive 
kit id # assignment
S
S
S
S
S
Contact IRT to confirm 
discontinuation or end of 
intervention
S
Dispensing of Concept2 
inhalers and CT formulation of 
Ultibro® Breezhaler®  
capsules 
S
S
S
S
S
Entering Mac Address of 
dispensed inhalers
X
X
X
X
X
 

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Period
Screening
Intervention
Follow 
up
Visit Number
1
110
120
130
140
150
160
170
1999
Visit
Randomization
End of intervention 
PSW/Study 
Discontinuation 
Study completion
Concept2 inhaler(s) return to 
site
S
S
S
S
S
Dispensing of tablets*
S
Tablets return* to site
S
Concept2 inhaler training
S
Application training*
S
Subject setup into investigator 
application/ Concept2 portal
S
Setting/re-setting of Preferred 
Inhalation Time (PIT)
X
X2
X2
Download of Concept2 inhaler 
use data by the investigator
S
S
S
S
S
Adverse Events/Serious 
Adverse event recording
X
X
X5
X
X5
X
X
Device Event/Device 
deficiency/Adverse Device 
Effects/Serious Adverse 
Device Effects recording
X
X
X5
X
X5
X
X
Medication return to site
S
S
S
S
S
Concept2 inhaler and tablets 
recovery (device(s))
S
Intervention completion status
X
Study completion status
X
PSW = Premature subject withdrawal
X = assessment to be recorded on clinical data base
S = assessment to be recorded on source documentation only
* = only subjects randomized to Telehealth group
**= only women of child-bearing potential
1. All exacerbations occurring during the study are to be recorded as AE/SAE in the CRF capturing AE/SAE, including the intervention/treatment 
and hospitalization and/ or emergency room visit 
2. Only if during the visit the subject is asking to change the Preferred Inhalation Time
 
5. When exchanging the inhalers occurrence of AE/SAE/ADE/SADE should be sought and recorded 
 

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Period
Screening
Intervention
Follow 
up
Visit Number
1
110
120
130
140
150
160
170
1999
Visit
Randomization
End of intervention 
PSW/Study 
Discontinuation 
Study completion
8.1
Screening
In this trial re-screening of subjects is allowed if they were excluded due to exclusion criteria 
number 8 or 10 (see Section 5.2). Re-screening of subjects can only occur after they have been 
entered as screening failures in the IRT system. Re-screened subjects should be re-consented 
and a new subject ID should be assigned to them.
8.1.1
Information to be collected on screening failures
All subjects who have signed informed consent but not entered into the Interventional period
will have the study completion page for the screening visit, subject ID, demographics, 
inclusion/exclusion, device event/device deficiencies, ADEs and SAEs/SADEs data collected. 
AEs that are not SAEs will be followed by the investigator and collected only in the source data. 
8.2
Subject demographics/other baseline characteristics
The following demographics/baseline characteristics will be collected and recorded in the 
appropriate CRF page(s):
•
Age
•
Sex
•
Race and ethnicity
•
Smoking history
•
Prior and concomitant medications
•
Date of diagnosis of COPD
•
Relevant medical history including COPD exacerbation history
•
Height and Weight
 

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Investigators will have the discretion to record abnormal test findings on the CRF pages 
capturing medical history whenever, in their judgment, the test abnormality occurred prior to 
the informed consent signature.
8.3
Efficacy
The Concept2 inhaler will track/record each time a subject uses the inhaler with the intention 
to inhale a dose of Ultibro® Breezhaler®
 For subjects 
that are randomized to the Telehealth group, this information will be sent to the tablet device 
and displayed on the patient application 
 
 
 For subjects in the Usual Care group
without the patient application the dosing will be tracked by the Concept2 inhaler 
 
 
 The Concept2 inhaler data, for subjects in both study groups will be downloaded at 
the study visits by the investigator using the investigator application and transmitted to the 
Concept2 portal (central database).
8.3.1
On-time treatment adherence (Dose inhaled on-time)
Subjects will be instructed at the start of the Screening period (Visit 1) to inhale their daily 
Ultibro® Breezhaler® medication at the same time every day using the Concept2 inhaler. The 
PIT will be recorded in the investigator application. 
On-time adherence is defined as percentage of days on which the subject inhales at least one
dose within (±) 2 hours of the agreed PIT. The number of doses inhaled on-time will be recorded
by the Concept2 inhaler. The dose reminders provided by the patient application will support 
the subject to inhale the dose at the same time every day.
8.3.2
Total treatment adherence (Daily inhalation)
Total adherence is defined as percentage of days on which the subject inhales at least one dose 
and will be calculated for each subject as the sum of on-time adherence and off-time adherence.
The definition of on-time adherence is explained in Section 8.3.1. Off-time adherence is defined 
as percentage of days on which the subject did not inhale the daily dose within the (±) 2 hours 
of the predefined PIT, but outside. The number of doses not inhaled on-time will be recorded
by the Concept2 inhaler. 
 
 
 

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8.3.4
Appropriateness of efficacy assessments 
The efficacy assessments planned for this study are in line with the objectives and include 
change in adherence level, 
8.4
Safety 
The intervention in this study consists solely in the use of an investigational digital adherence 
system, comprising the patient application and the Concept2 inhaler. The investigational 
investigator application is only used as a supportive component in the study to download the 
inhaler data from the Concept2 inhaler. The drug treatment in this trial is not under investigation. 
Subjects enrolled in this study continue to receive their prescribed Ultibro® Breezhaler®  
medication as part of the medical management of their COPD. The clinical trial formulation of 
Ultibro® Breezhaler® medicinal product will be provided to the subjects which is to be inhaled 
using the Concept2 inhaler, instead of the approved Ultibro® Breezhaler® inhaler. It has been 
demonstrated that the inhalation performance of the Concept2 inhaler is comparable to the 
approved Concept1 inhaler (the Breezhaler®), hence there are no additional anticipated risks to 
the subjects related to the medicinal product used in this trial.
Safety assessments will consist of monitoring and recording the following:
• COPD exacerbations regardless of suspected causality to concomitant treatments will be 
recorded into the CRF page(s) capturing AEs/SAEs (definition of a COPD exacerbation can 
be found in Appendix 8.
• Device deficiencies/Device Events
• Drug administration error, inhaler overuse, incorrect dose administration notified by the 
subject 
• New findings/updates in relation to already reported events
• Adverse Events (AEs) and Adverse Device Effects (ADEs) 
• Serious adverse events (SAEs) and Serious Adverse Device Effects (SADEs) 
• Physical Examination
 

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• Vital signs
• Height and weight
• Highly sensitive urine or serum pregnancy test (for females of childbearing potential), and 
in case of positive testing, serum pregnancy test (β-hCG) 
8.4.1
Physical examination
A complete physical examination will be performed at study visits as described in Table 8-1. It 
will include the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to providing written informed consent for 
participation in the study by the subject must be included in the CRF capturing medical history. 
Significant findings made after the start of study, which meet the definition of an Adverse Event 
or Serious Adverse Event, must be recorded on the appropriate CRF page(s) capturing AEs.
8.4.2
Vital signs 
Vital signs will include pulse rate (measured for 60 seconds) and systolic and diastolic blood 
pressure. Pulse rate and blood pressure will be assessed after the subject has rested in the 
supine/sitting position for at least 10 minutes.  
Vital signs will be obtained at study visits as described in Table 8-1. In the event of premature 
study withdrawal, vital signs will be collected at study discontinuation visit.
8.4.3
Laboratory evaluations
No laboratory evaluations are required by the study. Although formal laboratory evaluations 
are not included in the protocol per se, the study investigator should review the prescribing 
information for Ultibro® Breezhaler® and conduct any investigations as needed to provide 
appropriate care for the subject.
8.4.4
Electrocardiogram (ECG) 
ECG evaluations are not required by the study. Although formal ECG evaluations are not 
included in the protocol, the study investigator should review the prescribing information for 
Ultibro® Breezhaler® and conduct any investigations as needed to provide appropriate care for 
the subject.
8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. The 
Investigator must establish at the start of the study whether a female subject is of childbearing 
potential. Female subjects of childbearing potential must practice safe contraception (see 
exclusion criteria for a definition of safe contraception Section 5.2). In these women, a highly 
sensitive urine or serum pregnancy test will be done at Visits 1, 110 and 170, respectively. 
 

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If the subject discovers that she is pregnant during the course of the study, she must inform the 
Investigator immediately. Where the pregnancy is confirmed (either through the laboratory β-
hCG test or through the subject’s primary care physician, etc.), the subject must be withdrawn 
from the study and followed up to determine outcome.
Assessment of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:
1. surgical bilateral oophorectomy without a hysterectomy
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile.
In the absence of the above medical documentation, (Follicle Stimulating Hormone) FSH 
testing is required of any female subject, regardless of reported reproductive/menopausal status 
at screening/baseline.
8.4.6
Reporting of inhalation errors (overuse)
Inhalation errors refer to situations where the medicinal product is unintentionally/intentionally 
and inappropriately inhaled, not in accordance with the protocol.
Drug administration error, inhaler overuse, incorrect dose administration notified by the subject 
will be recorded into the CRF page(s) capturing Device Events. In addition, drug inhalation 
frequency (more than one inhalation per day; potential overuse) will be tracked and recorded 
by the Concept2 inhaler and data downloaded by the investigator using the investigator 
application. Evaluation of overuse (more than one inhalation per day) will be evaluated by study 
arm.
8.4.7
Device Event/Device deficiencies
A device event is any event suspected to be related to the device(s). Device deficiencies refer 
to the inadequacy of an investigational device related to its identity, quality, durability, 
reliability, safety or performance. This may include technical issues, device deteriorations in 
the characteristics or performance, device misuse, malfunctions, use error, device occlusion or 
inadequacy in the information supplied by the manufacturer.
Any device event or device deficiency will be recorded on the CRF page(s) capturing Device 
Event. A device event or device deficiency that might lead to an ADE or SADE will be reported 
as described in Section 10.1 or Section 10.2.
8.4.8
Appropriateness of safety measurements 
The safety measurements being captured are those expected for this subject population.
8.5
Other assessments
No additional tests will be performed on subjects entered in the study.
 

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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of intervention
Discontinuation of study intervention for a subject occurs when the intervention is stopped 
earlier than the protocol planned duration, and can be initiated by either the subject or the 
investigator. 
The investigator must discontinue study intervention for a given subject if, he/she believes that 
continuation would negatively impact the risk/benefit of trial participation.
Study intervention must be discontinued under the following circumstances:
• Subject/guardian decision
• Pregnancy
• Any situation in which study participation might result in a safety risk to the subject
• Inability of subject to use the device (Concept2 inhaler or the patient application)
If discontinuation of study intervention occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation from intervention
and record this information.
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by documenting in the 
source documents steps taken to contact the subject. The investigator must also contact the IRT 
to register the subject’s discontinuation from study intervention. After discontinuation of 
intervention, at a minimum, in abbreviated visits, the following data should be collected at clinic 
visits or via telephone/email contact:
• New / concomitant treatments
• Adverse events/Serious Adverse Events/adverse device effect/Serious Adverse Device Effects
Subjects who discontinue study should undergo an end of study visit and then be discontinued 
from the trial.
9.1.1.1
Replacement policy
Subjects who are discontinued from the study will not be replaced by an equal number of newly 
enrolled subjects. 
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:
• Does not want to participate in the study anymore
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• Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study intervention and Ultibro® Breezhaler® medication provided within the study must be 
discontinued and no further assessments conducted. The data that would have been collected at 
subsequent visits will be considered missing. 
The investigator has to ensure that all dispensed Concept2 inhalers (used and unused), the 
Ultibro® Breezhaler® medication and the tablet device (if applicable) are returned to the study 
site.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in Table 8-
1.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. All biological samples not yet analyzed at the time of withdrawal will no longer be used, 
unless permitted by applicable law. They will be stored according to applicable legal 
requirements
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Study stopping rules
Not applicable
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking treatment and use the intervention, when the subject 
should come for a final visit) and treated as a prematurely withdrawn subject. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
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depending on the local regulation will be responsible for informing IRBs/IECs of the early 
termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any assessments associated with this visit have been documented and followed-up appropriately 
by the Investigator, or in the event of an early study termination decision, the date of that 
decision 
Subjects completing 24 weeks Interventional period will not be given further access to the 
digital adherence system.
The investigator must provide follow-up medical care for all subjects completing the study or 
who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
For all subjects a safety follow-up visit (Visit 1999) is conducted (e.g. by telephone) 30 days 
after last visit (Visit 170) or after the subject has been prematurely withdrawn. The information 
to be collected at this follow up visit includes concomitant medications, adverse events, and 
survival status (Table 8-1).
10
Safety monitoring
In this trial, safety monitoring will be done for 
(1) the devices: the components of the investigational digital system (Concept2 inhaler and 
patient application) and the investigator application following the GVP Volume IX and 
MEDDEV regulations (MEDDEV 2.7/3 revision 3, May 2015) and 
(2) the medicinal product (clinical trial formulation of the Ultibro® Breezhaler®), despite 
not being an investigational treatment
by reporting:
-
Device related events: Adverse device effects and serious adverse device effects,
device deficiency that might lead to an SADE, and new findings/updates to already 
reported events for the devices
-
Not device related events: Adverse events and serious adverse events (which may or 
may not be related to the medical product (Ultibro® Breezhaler®)
Device related cases (such as device malfunction, device deficiency, procedural errors, device 
deterioration, inaccurate instructions, degradation or destruction of the device) not meeting the 
definition of an adverse event are not considered ADE and are reported as Device Events.
 

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Figure 10-1
Safety monitoring
10.1
Adverse events and Adverse device effects definitions and 
reporting requirements
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal product or device. This definition includes also events 
related to the procedures involved. All reports of intentional misuse and abuse of the medicinal 
product are also considered an adverse event irrespective if a clinical event has occurred. AEs, 
which are related to the use of the device, are reported as adverse device effects as described 
hereafter.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
 

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baseline or the previous visit, or values which are considered to be non-typical in subjects with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subjects and identifying adverse events. 
An adverse device effect (ADE) is an adverse event related to the use of a device. This includes 
any adverse event resulting from insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or any malfunction of the device(s). 
This includes also any event that is a result of a use error or intentional misuse. 
The occurrence of adverse events or adverse device effects should be sought by non-directive 
questioning of the subject at each visit during the study. Adverse events or adverse device 
effects also may be detected when they are volunteered by the subject during or between visits 
or through physical examination, laboratory test, or other assessments.
Adverse events and adverse device effects must be recorded on the appropriate CRF page(s) 
capturing AEs or ADEs under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information:
1. the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the device(s) or medicinal product (No Relationship to medicinal product 
or device(s)/Relationship to medicinal product/Relationship to device(s)
3. its duration (start and end dates or if the event is ongoing an outcome of not recovered/not 
resolved must be reported)
4. whether it constitutes a serious adverse event (SAE) or serious adverse device effect (SADE) 
and which seriousness criteria have been met
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: 

treatment dosage not changed (i.e., no action taken, further observation only) 

treatment dosage increased/reduced

treatment or inhaler use interrupted/withdrawn 

concomitant medication given 

non-drug therapy given 

subject hospitalized/subject’s hospitalization prolonged 

its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown)
Once an adverse event or adverse device effect is detected, it should be followed until its 
resolution or until it is judged to be permanent, and assessment should be made at each visit (or
 

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more frequently, if necessary) of any changes in severity, the suspected relationship to the 
medicinal product or device(s), the interventions required to treat it, and the outcome.
Information about known side effects of the device(s) can be found in the device specific 
Investigator Brochure (IB) or will be communicated between IB updates in the form of 
Investigator Notifications. This information will be included in the subject’s informed consent 
and should be discussed with the subject during the study as needed. Known side effects of the 
drug can be found in the drug IB.
The investigator should also instruct each subject to report any new adverse event/adverse 
device effect (beyond the protocol observation period) that the subject, or the subject’s personal 
physician, believes might reasonably be related to the medicinal product or device(s) used. This 
information should be recorded in the investigator’s source documents; however, if the 
AE/ADE meets the criteria of an SAE/SADE, it must be reported to Novartis.
10.2
Serious adverse events and Serious adverse device effects
definitions and reporting requirements
10.2.1
Serious adverse events 
A serious adverse event (SAE) is an adverse event, related or not to the drug, that meets the 
criteria of seriousness as defined in Section 10.2.1.1. Serious adverse events related to the use 
of a device are reported as serious adverse device effects as described in Section 10.2.2.
10.2.1.1 Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing)) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
1. routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)
2. elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
3. treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
4. social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention
All malignant neoplasms will be assessed as serious under “medically significant” if other 
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Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important device or medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the subject
or might require intervention to prevent one of the other outcomes listed above. Examples of 
such events are intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization or development of 
dependency or abuse (ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF page(s) capturing AEs, SAEs SAE 
reporting.
To ensure subjects safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 day period after the last study visit should only be reported to 
Novartis safety if the investigator suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the subject continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
 

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reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
10.2.2
Serious adverse device effects
A serious adverse device effect (SADE) is an adverse event related to the use of a device, which 
meets the seriousness criteria defined in Section 10.2.2.1.
10.2.2.1 Definition of SADE
An SADE is defined as an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event:

led to a death, injury or permanent impairment to a body structure or a body function.

led to a serious deterioration in health of the subject, that either resulted in:
1. a life-threatening illness or injury, or
2. a permanent impairment of a body structure or a body function, or
3. in-patient hospitalization or prolongation of existing hospitalization, or
4. in medical or surgical intervention to prevent life threatening illness

led to foetal distress, foetal death or a congenital abnormality or birth defect
10.2.2.2 SADE reporting
The investigator must assess the relationship to each specific component of study intervention
(Concept2 inhaler, patient application, investigator application) and complete and submit the 
SADE Report Form in English.
The investigators will distinguish between the serious adverse events related to the device(s)
and those related to the procedures (any procedure specific to the clinical investigation).
Each SADE will be classified according to five different levels of causality. The investigators 
will use the following definitions to assess the relationship of the serious adverse event to the 
investigational device or procedures.
1) Not related: relationship to the device or procedures can be excluded when:
- the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures;
- the event has no temporal relationship with the use of the investigational device or the 
procedures;
- the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible;
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious event;
 

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- the event involves a body-site or an organ not expected to be affected by the device or 
procedure;
- the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors);
- the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable;
- harms to the subject are not clearly due to use error;
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event.
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained.
3) Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases where 
relatedness cannot be assessed or no information has been obtained should also be classified as 
possible.
4) Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot be reasonably explained by another cause, but additional information may be 
obtained.
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when:
- the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures;
- the event has a temporal relationship with investigational device use/application or procedures;
- the event involves a body-site or organ that

the investigational device or procedures are applied to;

the investigational device or procedures have an effect on;
- the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known);
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible);
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out;
- harm to the subject is due to error in use;
- the event depends on a false result given by the investigational device used for diagnosis, when 
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In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event.
Events to be reported include:  
-
any SADE 
-
new finding/updates in relation to reported events
-
any investigational Device deficiencies that might lead to a SAE if 

suitable action had not been taken or

intervention had not been made or

if circumstances had been less fortunate
Once completed and signed the SADE form is sent by the investigator by fax immediately but 
not later than 3 calendar days after the site study personnel’s awareness of the event to the local 
Novartis Patient Safety Department. If the SADE indicates an imminent risk of death, serious 
injury, serious illness or requires prompt remedial action for other subjects, users or other 
persons or a new finding to it, the SADE has to be reported immediately to the local Novartis 
Patient Safety Department. The telephone and fax number of the contact persons in the local 
department of Patient Safety, specific to the site, are listed in the investigator folder provided 
to each site. The original copy of the SADE Report Form and the fax confirmation sheet must 
be kept with the case report form documentation at the study site. Follow-up information should 
be provided using a new paper SADE Report Form stating that this is a follow-up to a previously 
reported SADE.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, and whether the subject continued or withdrew from study participation. 
Each re-occurrence, complication, or progression of the original event must be reported as a 
follow-up to that event regardless of when it occurs.
If the SADE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study intervention a Patient Safety associate 
may urgently require further information from the investigator for health authority reporting. 
Novartis may need to issue an Investigator Notification (IN) to inform all investigators involved 
in any study with the same study intervention that this SADE has been reported. Serious adverse 
device effect which by its nature, incidence, severity or outcome has not been identified in the 
current version of the risk analysis report is defined as an unanticipated serious adverse device 
effect. Unanticipated serious adverse device effect (USADE) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
10.3
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
 

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Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the Ultibro® Breezhaler®
treatment. Any SAE experienced during pregnancy must be reported.
10.4
Additional Safety monitoring
10.4.1
Liver safety monitoring
No liver safety monitoring is required by the study. Although formal evaluations are not 
included in the protocol, the study investigator should review the prescribing information for 
Ultibro® Breezhaler® and conduct any investigations as needed to provide appropriate care for 
the subject.
10.4.2
Renal safety monitoring
No renal safety monitoring is required by the study. Although formal evaluations are not 
included in the protocol per se, the study investigator should review the prescribing information 
for Ultibro® Breezhaler® and conduct any investigations as needed to provide appropriate care 
for the subject.
10.4.3
Prospective suicidality assessment
Not applicable.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 (US code of Federal Regulations)
requirements. Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies in the eCRFs, allow 
modification and/or verification of the entered data by the investigator staff.
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. After database 
lock, the investigator will receive copies of the subject data for archiving at the investigational 
site.
This study will incorporate electronic technology to capture source data electronically 
(Concept2 inhaler(s) capturing subject inhaler use data over 4 weeks and electronic 
questionnaires running on a site tablet or investigator application). The data will be downloaded
and transmitted or directly transmitted to the Concept2 portal system or vendor’s data base and 
then sent electronically to Novartis. After database lock, the investigator will receive copies of 
the subject data for archiving at the investigational site.
 

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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Questionnaire data will be entered into an electronic tablet by the subject. The system will be 
supplied by a vendor(s), who will also manage the database. The database will be sent 
electronically to Novartis.
The data collected in the Concept2 portal system will be sent electronically to Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked. Any changes to the database after that time can only be made after written agreement 
by Novartis Development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or CRFs) 
with the investigators and their staff. During the study, Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The field 
monitor will visit the site to check the completeness of subjects records, the accuracy of data 
capture / data entries on the CRFs, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that medication and Concept2 inhalers are stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits.  Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis CRA (Clinical Research Associate) organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent forms signed by 
the subject (a signed copy is given to the subject).
 

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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or CRF entries. Novartis monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.
12
Data analysis and statistical methods
The analysis will be conducted on all subject data at the time the trial ends. The primary analysis 
will be performed after all randomized subjects have completed the study or have withdrawn 
early from the study.  A detailed Statistical Analysis Plan (SAP) will contain further explanation
about the analysis plans. It will include details on the methodology used in the statistical 
analyses as well as details about reporting and data derivations.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The following analysis sets are defined for data analysis:
The randomized (RAN) set will consist of all subjects who were assigned a randomization 
number. The RAN set will be used for a summary of subject disposition, demographics and 
baseline characteristics.
The Full Analysis Set (FAS) will include all randomized subjects who inhaled at least one dose 
with the Concept2 inhaler and have one time and date stamp on the chip. Following the intent-
to-treat principle, subjects will be analyzed according to the intervention group (either Concept2 
with “application” or Concept2 alone) they were assigned to at randomization. Analysis of all 
efficacy variables will be done on the FAS.
The Per-Protocol Set (PPS) will include all subjects in the FAS without any major protocol 
deviations. Major protocol deviations will be defined in the statistical analysis plan prior to 
database lock and the un-blinding of the study. Subjects will be analyzed according to the 
intervention they received (either Concept2 with “application” or Concept2 alone).  The PPS 
will be used for the supportive analysis of the primary variable. 
The Safety Set will include all subjects who inhaled at least one dose with the Concept2 inhaler 
and have one time and date record. Subjects will be analyzed according to the intervention they 
received (either Concept2 with “application” or Concept2 alone). The safety set will be used in 
the analysis of all safety variables.
12.2
Subject demographics and other baseline characteristics
Demographic and baseline characteristics including age, gender, race, ethnicity, height, weight, 
body mass index (BMI), duration of COPD (as time span between date of diagnosis of COPD 
to date of enrollment), relevant medical history, COPD exacerbation history, smoking history, 
prior and concomitant medications, vital signs (Sitting systolic and diastolic blood pressure, 
 

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pulse rate), baseline adherence, 
 
 will be summarized by intervention group. 
Continuous variables will be summarized using descriptive statistics (mean, median, standard 
deviation, minimum, and maximum) and categorical variables will be summarized in terms of 
the number and percentage of subjects in each category.
Baseline is defined as the last measurement before the first inhalation of Ultibro® Breezhaler®
medication with the Concept2 inhaler during the interventional period, if available.
12.3
Intervention
The number of subjects and the length of time (in days) in the study will be summarized by 
intervention group for the safety set.
Concomitant medications will be summarized by intervention group for the safety set. 
Concomitant medications will be summarized by route of administration and preferred term”
12.4
Analysis of the primary variable(s)
The primary objectives are to determine whether the use of dose tracking by the inhaler in 
conjunction with reminder notifications and motivational/adaptive messages sent by the patient 
application can improve on-time adherence or total adherence over 24 weeks of intervention.
On-time adherence is defined as the percentage of days on which the subject inhaled at least 
one dose within (±) 2 hours of the agreed preferred daily inhalation time. The daily preferred 
inhalation time (PIT) must be defined by the subject at the start of the study and can only be 
modified at scheduled study visits by the study investigator at the request of the subject.
Total adherence is defined as the percentage of days on which the subject inhaled at least one 
dose and will be calculated as the sum of on-time adherence and off-time adherence. Off-time 
adherence is defined as percentage of days on which the subject did not inhale the daily dose 
within the (±) 2 hours of the PIT, but outside.
12.4.1
Variable(s)
The primary variables for the study are the change from baseline (Visit 110) in on-time 
adherence and change from baseline in total adherence during 24 weeks of Interventional period. 
The on-time adherence will be calculated as the  number of days with at least one dose/inhaler 
use recorded via the Concept2 inhaler within (±) 2 hours of planned PIT, divided by the  number 
of days the subject had the Concept2 inhaler over 24 weeks. Total adherence will be calculated 
as the sum of on-time adherence and off-time adherence. Off-time adherence will be calculated 
as the number of days the subject did not inhale the daily dose within the (±) 2 hours of the 
predefined PIT, but outside, divided by the number of days the subject had the Concept2 inhaler 
over 24 weeks.
If more than one dose is inhaled within (±) 2 hours of preferred inhalation time, it will be 
counted once for the purpose of on-time adherence (numerator) day calculation. The additional 
dose(s), if any, will be considered as overuse, if it meets the criteria outlined in Section 12.6.1.5.
 

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If the subject is inhaling one or more doses during one day, in addition to the dose administration 
within (±) 2 hours of PIT, that will not be counted towards off-time adherence calculation, hence 
not in total adherence calculation.   
The dispensing period is 4 weeks, when one inhaler will be dispensed. In addition one Concept2 
back-up inhaler will be dispensed at Visit 110 and Visit 140, each. In case the back-up inhaler 
is used before Visit 140 or end of Interventional period (Visit 170) the subject will receive a 
new one. Each inhaler is designed and validated for a maximum of 30 days delivery.
In each 4-week dispensing period the number of days for the denominator will be defined as 
follows:
- Date of the first inhaler use data recorded into the Concept2 inhaler or Pairing Time, whichever 
comes first, plus 27 days or last data recorded in Concept 2 inhaler, whichever is later (from all 
used Concept2 inhalers, regular and back-up’s). If the inhaler is lost then the corresponding 
visit day will be used as the first inhaler use date.  
- If a subject discontinues the study, the denominator for each of the remaining 4-week periods
will be defined as 28. The missing data will be imputed as outlined in Section 12.4.3.
- The number of days from each of the six 4-week periods will be summed to be used as the 
overall denominator in calculations. 
Baseline on-time adherence and total adherence will be calculated from the 6 weeks Screening 
period (Visit 110 has a visit window of ± 7 days, that is days 35-49). The number of days in the 
denominator will be defined as:
- Days between Visit 1 (exclusive) and Visit 110 (inclusive). A minimum of 35 days in the 
screening are expected forr a subject to be eligible for having baseline adherence calculation 
performed. Subjects with a COPD exacerbation during Screening are considered screening 
failure. 
The period for which subject was taken off Ultibro® Breezhaler® treatment/inhaler use by 
investigator will be excluded from adherence calculation (for both Screening and Interventional
period)
12.4.2
Statistical model, hypothesis, and method of analysis
The use of dose reminder notifications and motivational/adaptive messages will be evaluated 
by testing the following two null hypotheses H1 and H2 for on-time adherence and total 
adherence, respectively.
H1: There is no difference in change from baseline in on-time adherence for subjects who 
received dose reminder and motivational/adaptive messages compared to subjects who received 
none.
H2: There is no difference in change from baseline in total adherence for subjects who received 
dose reminder and motivational/adaptive messages compared to subjects who received none.
The alternative hypothesis for each of H1 and H2 is that- there is a difference, respectively.
Each of the primary variables will be analyzed using the analysis of covariance model 
(ANCOVA) for the FAS. The ANCOVA model will contain intervention (here defined as dose 
 

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reminders and motivational/adaptive messages versus usual care), baseline total adherence
group, country and baseline COPD severity as fixed effects with baseline on-time 
adherence/total adherence rate as covariate. 
The estimated adjusted difference of the intervention for the Telehealth group minus Usual Care 
group will be displayed along with the associated 95% (two-sided) confidence interval.
Also the means of on-time adherence/total adherence will be presented graphically over 4-week 
time intervals by intervention group.
If at least one of the primary endpoints is significant the study will be considered positive.    
To control the overall type-1 error rate, multiplicity adjustment (for 2 endpoints) is described 
in Section 12.4.4.
12.4.3
Handling of missing values/censoring/discontinuations
Missing data for adherence will be imputed through a multiple imputation approach, under the 
assumption of missing data are missing at random. Utilizing this approach all subjects in the 
FAS will contribute in the analysis. For the primary analysis- data from inhalers (through 
investigator application) will be used. The supplemental data from patient application will not 
be used, to ensure a consistent imputation process for both groups.   
A sensitivity analysis will be done including the supplemental data from the patient application. 
That is, the missing data (from inhaler/investigator application) will first be imputed/updated 
with the patient application data, if available. Then the overall imputation will be done using 
the multiple imputation approach mentioned above.
Further elaboration of the multiple imputations will be provided in the statistical analysis plan 
(SAP).    
12.4.4
Multiplicity adjustment 
To control the family-wise type-I error rate at the two-sided 5% significance level, the 
trimmed Simes test in Brannath et al (2009) is used. The family for the overall type-I error 
rate control contains 2 hypotheses- one for the on-time adherence primary endpoint and the 
other for the total adherence primary endpoint. Denote the two hypotheses for the two primary 
endpoints as H1 and H2, respectively. Below is a description of the testing procedure.
Let p1 and p2 be the corresponding p-values (2-sided) of the two hypotheses of H1 and H2.
Step 1: Retain both hypotheses and stop if ANY pi ≤0.05 (for i=1 or 2) AND the observed 
treatment difference for the corresponding pi is in the wrong direction (i.e. Usual Care group is 
better than Intervention group); otherwise go to step 2.
Step 2: Reject both hypotheses if pi<0.05 for BOTH i=1, 2, and stop here; otherwise go to step 3.
Step 3: Perform the Bonferroni test and reject H1 if p1<0.025 and reject H2 if p2<0.025. 
For H1 and H2, their corresponding testing statistics follow jointly bivariate normal distribution. 
Therefore this testing procedure controls the overall type–I error rate at the 2-sided 0.05 level 
 

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in the strong sense regardless if the bivariate normal distributions have positive or negative 
correlations as shown in Brannath et al (2009).
Other than the primary analysis, all other analyses will be performed at the nominal 2-sided 
0.05 significance level without multiplicity adjustments.
12.4.5
Sensitivity analyses
As sensitivity analyses, the same ANCOVA used in the primary analysis will be also performed 
on the PPS to assess the robustness of the results from the primary analysis. 
The primary analysis model will be re-run including additional covariates, for example age and 
sex, to investigate the impact of these on any intervention effect. Details of these analyses will 
be pre-planned and described in the SAP.
12.5
Analysis of secondary variables
12.5.1
Efficacy variables
12.5.1.1 On-time adherence and total adherence over the last four weeks
The on-time adherence and total adherence over the last four weeks of Interventional period
(Week 21-24) will be summarized by intervention group.
The change from baseline in on-time adherence/total adherence over the last 4 weeks of 
Interventional period will be analyzed using the same ANCOVA model specified for the 
primary analysis. The missing data imputation will be done using the same method used for the 
primary endpoints analysis.
12.5.2
Safety variables
12.5.2.1 Adverse events
All device related ADE/SADE and non-device related AE/SAE will be summarized by 
intervention group and by screening and Interventional period separately. Also COPD 
exacerbations during the Interventional period will be summarized by intervention group. 
Subjects having a COPD exacerbation during the Screening period are considered screening
failures.  
The following adverse event summaries will be produced: overall by system organ class and 
preferred term; overall by system organ class; preferred term and maximum severity; serious 
adverse events by system organ class and preferred term; and adverse events leading to 
permanent discontinuation of study by system organ class and preferred term.
12.5.3
Resource utilization
Data relating to resource utilization may be used for the purpose of economic evaluation, which 
will be carried out and reported as a separate activity.
12.5.4
Pharmacokinetics
Not applicable.
 

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12.5.5
Pharmacogenetics/pharmacogenomics
Not Applicable. The drug treatment in this trial is not under investigation. 
12.5.6
Biomarkers
Not applicable.
12.5.7
PK/PD 
Not applicable.
 

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12.7
Interim analyses
No interim analyses is planned.
12.8
Sample size calculation
Sample size calculation takes into account the following considerations:
1.
To achieve 90% power (with multiplicity adjustment) for primary endpoint on-time 
adherence with a group difference of 15% between intervention group  vs. Usual Care 
group (i.e. change from baseline in mean on-time adherence in intervention group – (minus) 
change from baseline in mean on-time adherence in Usual Care group), assuming a 
common standard deviation of 25%, based on reference below.
 

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2.
To achieve 90% power (with multiplicity adjustment) for primary endpoint total adherence 
with a group difference of 15% between intervention group vs. Usual Care group (i.e. 
change from baseline in mean total adherence in intervention group – (minus) change from 
baseline in mean total adherence in Usual Care group), assuming a common standard 
deviation of 25%, based on reference below.
In absence of any available assessment of the correlation between the two primary endpoints, a 
relatively conservative measurement (of 0.8) has been chosen for the simulation. Considering 
a 15% dropout, the simulation (under the testing scheme in Section 12.4.4.) shows that the 
sample size of 146 (73 per arm) will provide 90% power for on-time adherence and 90% power 
for total adherence, with multiplicity adjustment. With zero (0) correlation the power for on-
time adherence will be above 90% and the power for total adherence will be above 90%.
The sample size and power calculations are performed in R 3.3.0.
(Reference: Charles et al (2007) an audiovisual reminder function (AVRF) study reported a 
difference in median adherence between the two groups (AVRF group vs. control group) as 18% 
(95% CI, 10% to 26%, P<0.0001); Strandbygaard et al (2009), a daily SMS reminder study 
reported a difference in change from baseline in mean adherence between two groups, one 
received daily SMS and one did not, as 17.8%, 95% CI (3.2 – 32.3%), p=0.019; common 
standard deviation for mean changes in adherence = 19%, (calculated)).
13
Ethical considerations
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US 21 CFR part 11 and with the 
ethical principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
 

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and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines..
Audits of investigator sites, vendors, and Novartis systems are performed by auditors,
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs or devices under the 
protocol other than the purpose of the study. If despite this interdiction prohibition, data, 
information, observation would be incidentally collected, the investigator shall immediately 
disclose it to Novartis and not use it for any purpose other than the study, except for the 
appropriate monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any subject included in this study, even if this action represents a deviation from the protocol. 
 

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In such cases, Novartis should be notified of this action and the IRB/IEC at the study site should 
be informed according to local regulations. 
15
References
References are available upon request
Bateman ED, Ferguson GT, Barnes N et al (2013) Dual bronchodilation with QVA149 versus 
single bronchodilator therapy: the SHINE study. Eur Respir J; 42:1484–94.
Bourbeau J et Bartlett SJ (2008) Patient adherence in COPD. Thorax; 63:831–838.
Bosley CM, Corden ZM, Rees PJ, Cochrane GM (1996) Psychological factors associated with 
use of home nebulized therapy for COPD. Eur Respir J.; 9(11):2346-50.
Bryant J, McDonald VM, Boyes A et al (2013) Improving medication adherence in chronic 
obstructive pulmonary disease: a systematic review. Respiratory Research; 14:109.
Brannath W, Bretz F, Maurer W and Sarkar S (2009), Trimmed Weighted Simes' Test for Two 
One-Sided Hypotheses With Arbitrarily Correlated Test Statistics. Biom. J., 51: 885–898.
Carstairs JR, Nimmo AJ and Barnes PJ (1985) Autoradiographic Visualization of Beta-
Adrenoceptor Subtypes in Human Lung. American Review of Respiratory Disease; 132(3):
541-547.
Cazzola M, Molimard M (2010) The scientific rationale for combining long-acting β2-agonists 
and muscarinic antagonists in COPD. Pulm Pharmacol Ther; 23:257-267.
Cecere LM, Slatore CG, Uman JE et al (2012) Adherence to Long-Acting Inhaled Therapies 
among Patients with Chronic Obstructive Pulmonary Disease (COPD), COPD: Journal of 
Chronic Obstructive Pulmonary Disease; 9 (3): 251-258
Chan A, Stewart AW, Harrison J et al (2015) The eﬀect of an electronic monitoring device with 
audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in 
children with asthma: a randomised controlled trial. Lancet Respir Med; 3: 210–219.
Charles T, Quinn D, Weatherall M et al (2007) An audiovisual reminder function improves 
adherence with inhaled corticosteroid therapy in asthma. J Allergy Clin Immunol; 119(4):811–
816.
Clinical Trial Facilitation Group (CTFG) (2014) Recommendations related to contraception and 
pregnancy testing in clinical trials
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf
Dolce JJ, Crisp C, Manzella B, et al (1991) Medication adherence patterns in chronic 
obstructive pulmonary disease. Chest; 99:837–41.
George J, Kong DC, Thoman R, Stewart K (2005) Factors associated with medication 
nonadherence in patients with COPD. Chest; 128 (5):3198-204.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) 2017
 

Novartis
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Gong H Jr, Simmons MS, Clark VA, Tashkin DP (1988) Metered-dose inhaler usage in 
subjects with asthma: comparison of Nebulizer Chronolog and daily diary recordings. J 
Allergy Clin Immunol; 82(1):5-10.
Huetsch JC, Uman JE, Udris E and Au DH (2012) Predictors of Adherence to Inhaled 
Medications Among Veterans with COPD. J Gen Intern Med; 27(11):1506–12.
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002807.pdf Accessed on: 02Dec2016.
Ikeda A, Nishimura K, Koyama H et al (1995) Bronchodilating Effects of Combined Therapy 
With Clinical Dosages of Ipratropium Bromide and Salbutamol for Stable COPD: Comparison 
With Ipratropium Bromide Alone. Chest; 107(2):401-405. 
Mak JC and Barnes PJ (1990) Autoradiographic Visualization of Muscarinic Receptor Subtypes 
in Human and Guinea Pig Lung. American Review of Respiratory Disease; 141(6): 1559-1568.
Molimard M, Raherison C, Lignot S et al (2017) Chronic obstructive pulmonary disease 
exacerbation and inhaler device handling: real-life assessment of 2935 patients. Eur Respir; 
49:1601794.
Nides MA, Tashkin DP, Simmons MS et al (1993) Improving inhaler adherence in a clinical 
trial through the use of the nebulizer chronolog. Chest; 104(2):501-7.
Osterberg L and Blaschke T (2005) Adherence to Medication. N Engl J Med; 353:487-97.
Plaza V, Fernandez-Rodriguez C, Melero C et al. (2015) Validation of the Test of the Adherence 
to Inhalers (TAI) for Asthma and COPD patients. JAMP; 28:1-11.
Post-approval Safety Data Management: Definitions and Standards for Expedited Reporting,
ICH Harmonised Tripartite Guideline, 2003 (ICH-E2D)
Rand CS, Wise RA, Nides M et al (1992) Metered-Dose Inhaler Adherence in a Clinical Trial. 
American Review of Respiratory Disease; 146(6):1559-1564.
Rand CS, Nides M, Cowles MK, et al (1995) Long-term metered-dose inhaler adherence in a 
clinical trial: The Lung Health Study Research Group. Am J Respir Crit Care Med; 152:580–8.
Rand CS (2005) Patient adherence with COPD therapy. Eur Respir Rev; 14(96):97-101.
Regueiro CR, Hamel MB, Davis RB, Desbiens N et al (1998) A comparison of generalist and 
pulmonologist care for patients hospitalized with severe chronic obstructive pulmonary 
disease: resource intensity, hospital costs, and survival. Am J Med; 105:366–372.
Sanduzzi A, Balbo P, Candoli P et al (2014) COPD: adherence to therapy. Multidisciplinary 
Respiratory Medicine; 9:60
 

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Serra-Batlles J, Plaza V, Badiola C et al (2002) Patient perception and acceptability of multidose 
dry powder inhalers: a randomized crossover comparison of Diskus/Accuhaler with Turbuhaler. 
J Aerosol Med; 15:59–64.
Strandbygaard U, Thomsen SF, Backer V (2009) Daily SMS reminders for asthma treatment 
adherence: A three month follow up study. Respiratory medicine; 104:166-171.
Thompson J, Irvine T, Grathwohl K et al (1994) Misuse of metered-dose inhalers in hospitalized 
patients. Chest; 105 (3):715–7.
van Beerendonk I, Mesters I, Mudde AN et al (1998) Assessment of the inhalation technique in 
outpatients with asthma or chronic obstructive pulmonary disease using a metered-dose inhaler 
or dry powder device. J Asthma; 35:273–9.
van der Palen J, Klein JJ, Kerkhoff AH, et al (1995) Evaluation of the effectiveness of four 
different inhalers in patients with chronic obstructive pulmonary disease. Thorax; 50:1183–7.
Vestbo J, Anderson JA, Calverley PMA et al (2009) Adherence to inhaled therapy, mortality 
and hospital admission in COPD. Thorax; 64:939–943.
Vestbo J, Anderson JA, Brook RD et al (2016) Fluticasone furoate and vilanterol and survival 
in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a 
double-blind randomised controlled trial. Lancet; 387: 1817–26.
Vrijens B, Urquhart J and White D (2014) Electronically monitored dosing histories can be used 
to develop a medication-taking habit and manage patient adherence. Expert Review of Clinical 
Pharmacology; 7 (5): 633-644,
Wang J, Jin D, Zuo P et al (2011) Comparison of tiotropium plus formoterol to tiotropium alone 
in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology; 16:350–358.
 

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Appendix 4: Quality of life Questionnaire EuroQol EQ-5D-5L 
(EQ-5D-5L)
Samples of questionnaires provided here are for illustrative purposes only 
  Under each heading, please tick the ONE box that best describes your health TODAY
MOBILITY
I have no problems in walking about                                                                           
I have slight problems in walking about                                                                      
I have moderate problems in walking about                                                               
I have severe problems in walking about                                                                    
I am unable to walk about                                                                                            

SELF-CARE
I have no problems washing or dressing myself                                                        
I have slight problems washing or dressing myself                                                    
I have moderate problems washing or dressing myself                                            
I have severe problems washing or dressing myself                                                 
I am unable to wash or dress myself                                                                           

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities)
I have no problems doing my usual activities                                                             
I have slight problems doing my usual activities                                                        
I have moderate problems doing my usual activities                                                 
I have severe problems doing my usual activities                                                      
I am unable to do my usual activities                                                                          

PAIN / DISCOMFORT
I have no pain or discomfort                                                                                         
I have slight pain or discomfort                                                                                    
I have moderate pain or discomfort                                                                             
I have severe pain or discomfort                                                                                 
I have extreme pain or discomfort                                                                               

ANXIETY / DEPRESSION
I am not anxious or depressed                                                                                    
I am slightly anxious or depressed                                                                              
I am moderately anxious or depressed                                                                       
I am severely anxious or depressed                                                                            
I am extremely anxious or depressed                                                                         
 

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Appendix 5: St. George’s Respiratory Questionnaire for 
COPD patients (SGRQ-C)
(A) Guidelines for Administering the SGRQ-C Questionnaire:
Before the Trial Begins
Study coordinators should familiarize themselves with the questionnaires and training 
materials in the trial, and identify any items where a patient’s response might highlight issues
of potential concern.
Before Completion
Explain to the patient why they are completing the questionnaires, 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 questionnaires 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 should answer every question and that someone will be close at hand to answer any
queries.
Patients should be provided with the correct questionnaires at the appropriate visits, and in the
appropriate language (The same language should be used by the patient for all visits). 
Patients should have adequate space and time to complete the forms. 
Patients should be provided with a firm writing surface (such as a table or a clip board) and a
pencil.
Questionnaires should be completed before the clinical assessments.
During Completion
The administrator may clarify the questions but may not influence the response. The
questionnaires are 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. Do not allow patients to take the questionnaires home to be completed.
Ensure there is only one response for each question
Also see ‘Addressing Problems and Concerns’ on the next page.
After Completion
Check for completeness but not for content
Check for multiple responses that were made in error
File completed questionnaires in the patient study file notebooks provided for the study
Any response which may directly impact on or reflect the patient’s medical condition (e.g.
noting of depression) should be communicated by the study coordinator to the investigator.
 

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Addressing Problems and Concerns
Occasionally a patient may have concerns or questions about the questionnaires administered.
Guidance related to some of the most common concerns and questions are given below.
(1) The patient does not want to complete the questionnaire(s):
Tell the patient that completion of the questionnaire(s) is voluntary. The goal is to better
understand the physical, mental, and social health problems of patients. Emphasize that this
information is as important as any of the other medical information, and that the
questionnaire(s) is simple to complete. Suggest that the questionnaire(s) may be different from 
anything the respondent has filled in the past. If the patient still declines, retrieve the
questionnaires. Record the reason for the decline, and thank the patient.
(2) The patient is too ill or weak to complete the questionnaire(s)
In these instances, the coordinator may obtain patient responses by reading out loud each
question, followed by the corresponding response categories, and entering the patient’s
response. No help should be provided to the patient by any person other than the designated
study coordinator. The coordinator should not influence patient responses. The study
coordinator cannot translate the question into simpler language and it has to be read verbatim.
(3) The patient wants someone else to complete the questionnaire(s)
In no case should the coordinator or anyone other than the patient provide responses to the
questions.
(4) The patient does not want to finish completing the questionnaire(s)
If non-completion is a result of the patient having trouble understanding particular items, ask
the patient to explain the difficulty. Re-read the question for them verbatim, but do not
rephrase the question. Guidance notes on queries of understanding for specific questions from
the SGRQ-C User Manual are provided below. If the respondent is still unable to complete 
the questionnaire, accept it as incomplete. 
(5) The patient is concerned that someone will look at his/her responses
Emphasize that all responses are to be kept confidential. Point out that their names do not
appear anywhere on the questionnaire, so that their results will be linked with an ID number
and not their name. Tell the patient that his/her answers will be pooled with other patients’
answers and that they will be analyzed as a group rather than as individuals. Tell the patient
that completed forms are not routinely shared with treating staff, and that their responses will
only be seen by you (to check for completeness), and possibly the investigator. Any response
which may directly impact on or reflect their medical condition (e.g. noting of severe
depression) will be communicated by the coordinator to the physician.
(6) The patient asks the meaning of a question / item
While completing a questionnaire, some patients might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the patient by rereading the 
question for them verbatim. If the patient asks to interpret the meaning of an item, do not try 
to explain it, but suggest that he/she use his/her own interpretation of the question. Patients 
should answer the questions based on what they think the questions mean. However there are 
some guidance notes in the SGRQ-C User Manual regarding queries relating to specific 
questions that may be of use. They are provided below.
 

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Responding to a patient’s queries regarding completion of the questionnaire
If a patient asks for help with a question, do not provide an answer for them. The questionnaire 
is designed 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 that 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 recently. The exact period is not important. We are looking for an impression 
or perception of health.
2. An attack of chest trouble (Part 1, Question 5) is any episode of worse symptoms that 
constitutes an attack in the patient’s own judgment. Not just severe attacks as judged by medical 
staff.
3. COPD can vary day-to-day. Part 2 is concerned with the patient’s current state (i.e. on average 
over ‘these days’), not necessarily just today.
4. For Part 1 Question 6, emphasize that you are interested in the number of good days that they 
have had.
5. In Part 2, Questions 8 and 14 require a single response, but Questions 9 to 13 require a 
response to every question. It may be worth emphasizing this to the patient.
6. 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’).
7. Responses to Questions 12 and 13 concern limitations due to breathing difficulties and not 
any other problems. If the patient does not engage in an activity for another reason, they should 
tick ‘False’.
 

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(B) Sample of the questionnaire (the samples provided here are for illustrative purposes only):
 

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Appendix 8: Exacerbations
COPD exacerbation is defined as:
A worsening of the following two or more major symptoms for at least 2 consecutive days:
•
dyspnea
•
sputum volume
•
sputum purulence
OR
A worsening of any 1 major symptom together with an increase in any one of the following 
minor symptoms for at least 2 consecutive days:
•
sore throat
•
colds (nasal discharge and/or nasal congestion)
•
fever without other cause
•
cough
•
wheeze
A COPD exacerbation is considered of moderate severity if treatment with systemic 
corticosteroids or antibiotics or both was required and severe, if hospitalization was required. 
An emergency room (ER) visit of longer than 24 hours will be considered a hospitalization.
A COPD exacerbation is considered of mild severity if there is a worsening of symptoms that 
either do not meet the above symptom definition but is treated by the investigator with systemic 
corticosteroids or antibiotics, or that meets the symptom definition but is not treated with 
antibiotics and/or systemic corticosteroids.
The above criteria for a COPD exacerbation are based on a worsening of symptoms occurring 
after  randomization  as  compared  to  the  baseline  threshold  established  during  the  run-in 
period. The baseline threshold is determined by subject recording of daily symptoms using an 
electronic diary device supplied at the start of the study.
An increase in ICS dose will not be counted as an exacerbation. In the event of a COPD 
exacerbation matching the above definition occurring at any time after signing of informed 
consent, subjects should be treated for the exacerbation as deemed necessary by the investigator.
Pneumonia will be defined as an event characterized by increased respiratory symptoms (e.g. 
increased cough, dyspnea, wheezing, purulent sputum and fever, i.e. body temperature greater 
than 38 °C) or pleuritic chest pain or leukocytosis or other clinical signs consistent with 
pneumonia considered relevant in the opinion of the investigator. Radiographic imaging, 
preferably a chest x-ray, will be required to facilitate the diagnosis. The diagnosis of COPD 
exacerbation will not preclude a diagnosis of pneumonia. The investigator will use clinical 
judgment to determine if the events are occurring simultaneously.
Subjects who develop a COPD exacerbation during screening will be screen failed but will be 
permitted to be re-screened after a minimum of 6 weeks and after the resolution of the COPD 
exacerbation.
 

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Following treatment for the exacerbation, the subject will be expected to continue in the study 
provided the investigator considers that the subject can safely return to his/her pre- exacerbation 
medications.
 

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Appendix 9: Concept2 Inhaler Unique Device Identification
The label adhered to the Concept2 inhaler base includes the unique 16 characters long unique 
identification of the device (MAC Address) as described hereafter. The characters are 
alphanumeric.
 

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Appendix 10: GOLD 2017 guidelines
Spirometry is required to make the diagnosis of COPD; the presence of a post-bronchodilator 
FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation.
Classification of severity of airflow obstruction according to GOLD 2017 guidelines are shown 
in Table 25-1. Spirometry should be performed after the administration of an adequate dose of 
at least one short-acting inhaled bronchodilator in order to minimize variability.
Table 25-1
Classification of airflow limitation severity in COPD (based on post-
bronchodilator FEV1)
Spirometric grade                                                                                             In patients with FEV1/FVC<0.70:
GOLD 1:
Mild
FEV1 ≥ 80% predicted
GOLD 2:
Moderate
50% ≤ FEV1 < 80% predicted
GOLD 3:
Severe
30% ≤ FEV1 < 50% predicted
GOLD 4:
Very Severe
FEV1 < 30% predicted
In the refined assessment scheme of the GOLD 2017 guidelines (Figure 25-1), patients however 
should undergo, in addition to spirometry to determine the severity of airflow limitation (i.e., 
spirometric grade), also assessment of either dyspnea using mMRC or symptoms using CATTM. 
Finally, their history of exacerbations (including prior hospitalizations) should be recorded.
Figure 25-1
The refined ABCD assessment tool GOLD Strategy 2017