Proof of Concept (Proof of Intervention Principles) Study Assessing Effects of Technology-Assisted Respiratory Adherence Prototype Version 3 (a Digital Behaviour Change Intervention, DBCI) on Proximal Clinical Outcomes and Mediators (Psychological Mediators, Self-management Behaviours) in Individuals With COPD (IwCOPD)
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim


 
 
001-MCS-40-106_RD-03 
Clinical Study Protocol  
TITLE PAGE 
Document Number: 
Not applicable 
EudraCT No.: 
EU Trial No: 
NA 
BI Study No. 
352.2154 
BI Investigational 
Product:  
NA 
Title 
Proof of concept (proof of intervention principles) study assessing 
effects of Technology-Assisted Respiratory Adherence prototype 
version 3 (a Digital Behaviour Change Intervention, DBCI) on 
proximal clinical outcomes and mediators (psychological 
mediators, self-management behaviours) in individuals with 
COPD (IwCOPD) 
Lay Title 
Proof of concept study assessing Technology-Assisted 
Respiratory Adherence prototype version 3 in individuals with 
COPD  
Clinical Phase 
ORBIT model for behavioural treatment development: Phase IIa 
(R19-2270)  
Study Team Leader 
Phone: +
 
Coordinating 
Investigator  
 
NA 
Current Version and 
Date 
Protocol Version 2.0  
Date: 16 Sep 2021 
Original Protocol 
Date 
Version 1.0, 24 Feb 2021 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Company name 
Boehringer Ingelheim  
Protocol date 
24 Feb 2021 
Revision date 
16 Sep 2021 
BI study number 
352.2154 
Title of study 
Proof of concept (proof of intervention principles) study assessing 
effects of Technology-Assisted Respiratory Adherence prototype 
version 3 (a Digital Behaviour Change Intervention, DBCI) on 
proximal clinical outcomes and mediators (psychological mediators, 
self-management behaviours) in individuals with COPD (IwCOPD) 
Principal Investigator 
NA 
Study site 
NA 
Clinical phase 
ORBIT: Phase IIa 
Study rationale 
On the basis of accumulated knowledge during Phase I development, 
the TARA development team concluded that the TARA prototype 
version 3 may be defined as a putative Minimum Functional Product 
(MFP) for the target clinical use case. As such, the development 
team determined that it was appropriate to move into Phase IIa of 
development and conduct a proof-of-concept study to determine if 
TARA prototype version 3 can achieve benefit on a clinically 
relevant target in a small, select sample. In this way, an important 
goal of this proof-of-concept study is to determine whether or not 
TARA version 3 demonstrates enough of a clinical signal to merit 
moving forward to conducting more rigorous testing using a 
randomized design in larger, more representative study population. 
Study objectives 
Primary Research Questions  
Is there a clinically significant reduction in breathlessness in 
symptomatic IwCOPD following engagement with TARA after 12 
weeks? 
 
Secondary Research Questions 
 
Activity Levels: 
Is there an associated maintenance or increase in activities of daily 
living to support a positive benefit of TARA on breathlessness?  
 
Physical Activity Experience: 
Is there an improvement in the physical activity experience of the 
patient?  
Study assessments 
Primary Assessments  
• 
Percentage of participants who experience a clinically significant 
decrease in breathlessness as measured by the Chronic 
Respiratory Questionnaire – Self Administered Individualized 
(CRQ-SAI) dyspnea domain at week 12. 
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• 
Mean change in CRQ-SAI dyspnea domain from baseline to 12 
weeks.  The CRQ-SAI dyspnea score ranges from 1 to 7 with 
higher values indicating an improvement of breathlessness.   
Secondary assessments 
Activity Levels: 
• 
Change from baseline in average number of steps measured by 
the activity tracker at week 12.   
• 
Change from baseline in average cadence (steps/min) measured 
by the activity tracker at week 12.   
 
Physical Activity Experience: 
• 
Change from baseline in the difficulty domain of the Clinical 
Visits PROactive Physical Activity in COPD instrument (C-
PPAC) at week 12. The domain score ranges from 0 to 40 with a 
higher value representing a lesser degree of difficulty. 
 
Study design 
Within-subject pre-post study design  
Total number of 
participants entered  
50 IwCOPD 
• 
Cohort 1: 25 IwCOPD (non-pharmacological self-management 
support) 
• 
Cohort 2: 25 IwCOPD (non-pharmacological + pharmacological 
self-management support) 
Number of participants 
on each treatment 
NA 
Diagnosis 
COPD (chronic bronchitis or emphysema) 
Main in- and exclusion 
criteria 
 
Key inclusion criteria 
• 
Individuals with COPD (IwCOPD)Male or females 
• 
Age ≥ 40 years 
• 
Current or ex-smokers 
• 
mMRC Score ≥ 2 (i.e. evidence of activity-related 
breathlessness) 
• 
Patients must have a prescription for either Spiriva Respimat or 
Stiolto Respimat as per one of the below scenarios: 
a. Participants must have a new prescription for either 
Spiriva Respimat or Stiolto Respimat (this could 
include a patient who has never received a 
maintenance bronchodilator for treatment before, or a 
patient who was previously on an alternative 
maintenance bronchodilator who is being switched to 
Spiriva Respimat or Stiolto Respimat to help with 
their COPD management). 
OR 
b. Participants currently on Spiriva Respimat or Stiolto 
Respimat who could benefit from engagement with 
TARA (after discussion with their physician). 
• 
Participants must be on a short-acting bronchodilator (“rescue 
medication”) 
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• 
Participants must be willing to use the study specific activity 
tracker (
 device) and be willing to complete all data 
collection requirements (within TARA plus on-line 
questionnaires plus possible phone interview) 
• 
Fluency in written English 
• 
Access to a Smartphone and at least one other device (desktop, 
laptop or tablet) with updated browsers installed (or willing to 
download up-to-date version for the study), and daily home 
access to internet  
• 
Need to have personal e-mail account that is used daily 
 
Key exclusion criteria 
• 
Patients with asthma as concurrent baseline condition at the time 
of screening 
• 
Patients with confirmed, suspected or recovered SARS-CoV-2 
infection or if the patient had household or other contact with an 
individual with confirmed SARS-CoV-2 infection within 14 
days prior to the completion of the eligibility questionnaire. 
• 
Patient with a worsening COPD episode requiring medical 
intervention within 4 weeks of enrolment 
• 
Patients who have completed a pulmonary rehabilitation (PR) or 
self-management program in the 3 months prior to enrolment or 
patients who are currently in a PR program  
• 
Patients prescribed inhaled COPD medications other than 
Spiriva Respimat plus albuterol or Stiolto Respimat plus 
albuterol 
• 
Patients with any contraindications for participating in the study 
(after discussion with their physician). 
• 
Currently enrolled in another investigational device or drug trial, 
or less than 30 days since ending another investigational device 
or drug trial(s), or receiving other investigational treatment(s) 
• 
Women who are pregnant, nursing, or who plan to become 
pregnant while in the study 
• 
Any self-reported medical or neuro-cognitive condition that 
would limit the ability of the participant to consent 
Test product(s)  
TARA1 DBCI2 prototype (version 3) 
dose 
NA 
mode of 
administration 
NA 
Comparator product(s) NA 
dose 
NA 
mode of 
administration 
NA 
Duration of observation 16 weeks maximum observation period (from informed consent to 
post-TARA in-depth interview)  
Statistical methods 
Primary Assessment Analyses 
For the primary assessment, the CRQ-SAI dyspnea domain will be 
used to calculate breathlessness measures at baseline and week 12. 
Analyses to be conducted include the following: 
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• 
The percentage of the study population who experience a 
clinically significant decrease in breathlessness (minimal 
clinically important difference (MCID) of 0.5) will be 
calculated. 
• 
The difference between week 12 and baseline will be 
calculated and compared against the criterion of minimal 
clinically important difference (MCID) of 0.5. 
 
Secondary Assessment Analyses 
Descriptive statistics of additional secondary endpoint variables will 
be explored for selection of best-fit analysis techniques. Pre-post 
differences in the physical activity experience will also be explored 
to see if TARA v3 has had a positive effect on perceived difficulty 
during activities.   
 
Interim Analyses 
NA  
 
 
 
1  TARA: Technology-Assisted Respiratory Adherence  
2 DBCI: Digital Behaviour Change Intervention 
 
 
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FLOW CHART  
Study Measures and Timepoints (beginning post-consent): 
 
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Individual Participant Flow: 
 
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SYNOPSIS..................................................................... 2 
FLOW CHART ........................................................................................................................ 6 
1. 
INTRODUCTION ............................................................................................... 14 
1.1 
MEDICAL BACKGROUND ............................................................................. 14 
1.2 
DESCRIPTION OF INTERVENTION ............................................................ 16 
1.3 
RATIONALE FOR PERFORMING THE STUDY ........................................ 18 
1.4 
BENEFIT-RISK ASSESSMENT....................................................................... 19 
1.4.1 
Benefits ................................................................................................................. 19 
1.4.2 
Risks ..................................................................................................................... 19 
1.4.2.1 
Covid-19 related risks ........................................................................................... 20 
1.4.3 
Discussion ............................................................................................................. 20 
2. 
STUDY OBJECTIVES AND ASSESSMENTS ............................................... 21 
2.1 
MAIN OBJECTIVE (RESEARCH QUESTIONS), PRIMARY 
ASSESSMENTS .................................................................................................. 21 
2.1.1 
Main objective (research question) ................................................................... 21 
2.1.2 
Primary assessments ........................................................................................... 21 
2.2 
SECONDARY RESEARCH QUESTIONS, SECONDARY 
ASSESSMENTS .................................................................................................. 21 
2.2.1 
Secondary research questions ............................................................................ 21 
2.2.2 
Secondary assessments ....................................................................................... 22 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ........................ 27 
3.1 
OVERALL STUDY DESIGN ............................................................................ 27 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ........................................................................................... 28 
3.3 
SELECTION OF STUDY POPULATION....................................................... 28 
3.3.1 
Main diagnosis for study entry .......................................................................... 29 
3.3.2 
Inclusion criteria ................................................................................................. 29 
3.3.3 
Exclusion criteria ................................................................................................ 29 
3.3.4 
Withdrawal of participants from study participation ..................................... 30 
3.3.4.1 
Withdrawal of consent to study participation ....................................................... 30 
3.3.4.2 
Discontinuation of participants ............................................................................. 30 
3.3.4.3 
Discontinuation of the study by the sponsor ......................................................... 30 
4. 
TREATMENTS ................................................................................................... 31 
4.1 
INVESTIGATIONAL INTERVENTION ........................................................ 31 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................ 31 
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4.2.1 
Other treatments and emergency procedures .................................................. 31 
4.2.2 
Restrictions .......................................................................................................... 31 
4.2.2.1 
Restrictions regarding concomitant treatment ...................................................... 31 
4.2.2.2 
Restrictions on diet and lifestyle ........................................................................... 31 
5. 
FURTHER DETAILS REGARDING ASSESSMENTS ................................. 32 
5.1 
ASSESSMENT OF EFFICACY ........................................................................ 32 
5.1.1 
Primary Assessment ............................................................................................ 32 
5.1.2 
Secondary Assessments....................................................................................... 32 
5.2 
ASSESSMENT OF ENGAGEMENT AND PERCEPTIONS OF VALUE ... 37 
5.3 
ASSESSMENT OF SAFETY ............................................................................. 37 
5.3.1 
Physical examination .......................................................................................... 37 
5.3.2 
Vital signs ............................................................................................................. 37 
5.3.3 
Safety laboratory parameters ............................................................................ 37 
5.3.4 
Electrocardiogram .............................................................................................. 37 
5.3.5 
Other safety parameters ..................................................................................... 37 
5.3.6 
Assessment of adverse events ............................................................................. 37 
5.3.6.1 
Definitions of AEs ................................................................................................ 37 
5.3.7 
Adverse Event Collection and Reporting.......................................................... 38 
5.3.7.1 
Collection of AEs .................................................................................................. 38 
5.3.7.2 
Expedited Reporting of AEs and Drug Exposure during Pregnancy to BI 
Pharmacovigilance ................................................................................................ 40 
5.4 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ................................................................................... 41 
5.5 
ASSESSMENT OF BIOMARKER(S) .............................................................. 41 
5.6 
BIOBANKING .................................................................................................... 41 
5.7 
OTHER ASSESSMENTS................................................................................... 41 
5.8 
APPROPRIATENESS OF MEASUREMENTS .............................................. 41 
6. 
INVESTIGATIONAL PLAN............................................................................. 43 
6.1 
VISIT SCHEDULE ............................................................................................. 43 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ................ 43 
6.2.1 
Screening period .................................................................................................. 43 
6.2.2 
Study and TARA Intervention period .............................................................. 44 
6.2.3 
Follow-up period (study completion) ................................................................ 45 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
 ............................................................................................................................... 46 
7.1 
NULL AND ALTERNATIVE HYPOTHESES ............................................... 46 
7.2 
PLANNED ANALYSES ..................................................................................... 46 
7.2.1 
General considerations ....................................................................................... 46 
7.2.2 
Primary assessment analyses ............................................................................. 47 
7.2.3 
Secondary endpoint analyses ............................................................................. 47 
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7.2.5 
Safety analyses ..................................................................................................... 48 
7.2.6 
Other Analyses .................................................................................................... 48 
7.2.7 
Interim Analyses ................................................................................................. 48 
7.3 
HANDLING OF MISSING DATA ................................................................... 48 
7.4 
RANDOMISATION ........................................................................................... 48 
7.5 
DETERMINATION OF SAMPLE SIZE ......................................................... 48 
8. 
INFORMED CONSENT, STUDY RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........ 50 
8.1 
STUDY APPROVAL, PARTICIPANT INFORMATION, INFORMED 
CONSENT ........................................................................................................... 50 
8.2 
DATA QUALITY ASSURANCE ...................................................................... 51 
8.3 
RECORDS ........................................................................................................... 51 
8.3.1 
Source documents ............................................................................................... 51 
8.3.2 
Direct access to source data and documents ..................................................... 51 
8.3.3 
Storage period of records ................................................................................... 51 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS .................................. 52 
8.5 
STATEMENT OF CONFIDENTIALITY AND PARTICIPANT 
PRIVACY ............................................................................................................ 52 
8.6 
STUDY MILESTONES ...................................................................................... 52 
8.7 
ADMINISTRATIVE STRUCTURE OF THE STUDY .................................. 52 
9. 
REFERENCES .................................................................................................... 54 
9.1 
PUBLISHED REFERENCES ............................................................................ 54 
9.2 
UNPUBLISHED REFERENCES ...................................................................... 59 
10. 
APPENDICES ..................................................................................................... 60 
10.1 
DETAILS OF EX-TARA ASSESSMENT TOOLS ......................................... 60 
10.1.1 
Baseline, Interim and Follow-up Survey Assessments .................................... 60 
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10.3 
QUALITATIVE INTERVIEW SAFETY PROTOCOL ................................. 90 
11. 
DESCRIPTION OF GLOBAL AMENDMENT(S) ......................................... 91 
APPROVAL / SIGNATURE PAGE .................................................................................... 93 
 
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ABBREVIATIONS  
 
ADR 
Adverse Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA 
Attributable, Legible, Contemporaneous, Original, Accurate  
BE 
Behavioural Experiment 
BI 
Boehringer Ingelheim 
CAT 
COPD Assessment Test 
COPD 
Chronic Obstructive Pulmonary Disease 
C-PPAC 
Clinical Visit PROactive Physical Activity in COPD 
CRA 
Clinical Research Associate 
CRQ-SAI 
Chronic Respiratory Questionnaire – Self-Administered 
Individualized 
CRO 
Contract Research Organisation 
CRT 
Clinical Research Testing 
DBCI 
Digital Behaviour Change Intervention 
EFL 
Expiratory Flow Limitation 
ER 
Emergency Room 
EudraCT 
European Clinical Trials Database 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Obstructive Lung Disease 
HA 
Health Authority 
HADS 
Hospital Anxiety and Depression Scale 
HCCQ 
Health Care Climate Questionnaire 
HCP 
Health Care Professional 
ICH 
International Council on Harmonisation 
IDI 
In-Depth Interview 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IwCOPD 
Individual with COPD 
LABA 
Long Acting β-Agonist 
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LAMA 
Long Acting Muscarinic Antagonist 
MC 
Motivational Communication 
MCID 
Minimal Clinically Important Difference 
MCP 
Motivational Communication Practitioner 
mMRC 
(Modified) Medical Research Council 
MFP 
Minimum Functional Product 
NPS 
Net Promoter Survey 
OCS 
Oral Corticosteriods 
 
 
PCS 
Perceived Competence Scale 
PR 
Pulmonary Rehabilitation 
PRO 
Patient Reported Outcome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
SUS 
System Usability Scale 
TARA 
Technology-Assisted Respiratory Adherence 
TSRQ 
Treatment Self-Regulation Questionnaire 
VCCQ 
Virtual Care Climate Questionnaire 
WHO 
World Health Organisation 
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1. 
INTRODUCTION  
1.1 
MEDICAL BACKGROUND 
Chronic Obstructive Pulmonary Disease (COPD): medical/scientific and patient 
perspectives  
 
COPD is a common, preventable and treatable disease that is characterized by expiratory 
flow limitation (EFL) due to airway and / or alveolar abnormalities usually caused by 
significant exposure to noxious particles or gases (P19-00675). The chronic EFL 
characteristic of COPD is caused by a mixture of small airways disease (e.g., obstructive 
bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which 
vary from person to person. These changes do not always occur together but evolve at 
different rates over time. Chronic inflammation causes structural changes, narrowing of the 
small airways, and destruction of the lung parenchyma that leads to a loss of alveolar 
attachments to the small airways and decreases lung elastic recoil. In turn, these changes 
diminish the ability of the airways to remain open during expiration. A loss of small airways 
may also contribute to EFL, and mucociliary dysfunction is a characteristic feature of the 
disease. EFL is usually measured by post-bronchodilator spirometry because this is the most 
widely available and reproducible test of lung function (P19-00675). 
 
The lung function impairment that characterizes COPD has significant impact on how the 
patient feels and functions during performance of tasks during everyday life. Patients with 
COPD have a variety of symptoms, including shortness of breath (breathlessness), chest 
tightness, wheezing, and cough with or without sputum as well as systemic symptoms such as 
fatigue and weakness (R19-2157). Breathlessness is a ubiquitous symptom in COPD and a 
key indicator used in the diagnosis of COPD according to the Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) guidelines (P19-00675); it is persistent and progressive 
over time and identified as a major concern by patients due to its impact on daily life and 
emotional well-being (R19-2157).  
 
COPD guidelines recommend that the management of stable COPD should be based on an 
individualised assessment, with the main treatment goals being reduction of symptoms 
(relieve symptoms, improve exercise tolerance, improve health status) and future risk 
(prevent disease progression, prevent and treat exacerbations, reduce mortality). Management 
strategies include pharmacological treatments complemented by appropriate non-
pharmacological interventions (P19-00675).   
 
Self-management in COPD: recent focus on adoption of healthy behaviours 
 
Self-management is now considered a major component of the “chronic care model” for 
COPD.  In general, self-management training aims to help patients acquire and practise the 
skills they need to carry out disease-specific medical regimens, to guide changes in health 
behaviour and to provide emotional support to enable patients to adjust their roles for optimal 
function and control of their disease (R19-2163, R19-2168). In addition to addressing 
behavioural risk factors (i.e. smoking, diet, exercise), self-management should involve 
patients in monitoring and managing the signs and symptoms of their disease, being adherent 
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to treatment (including to medications and other medical advice), maintaining regular contact 
with healthcare providers, and managing the psychosocial consequences of their condition 
(P19-00675). 
 
Implicit in the description of self-management is the “provision of self-management 
support/coaching”, which refers to the strategies, techniques and skills required to self-
manage their disease effectively. Patients are not always motivated to adopt healthier 
behaviours or engage in recommended disease management strategies, even when there are 
clear benefits; this is often referred to as the “knowledge–behaviour” gap, and is a major 
challenge for chronic disease management. Patient support needs to go beyond pure 
education/advice-giving (didactic) approaches to help patients learn and adopt sustainable 
self-management skills; a motivational communication (MC) style is recommended as a 
means to empower patients to take greater responsibility for their health and well-being (P19-
00675) and to support patients towards increased confidence (self-efficacy) that they can 
effectively manage their health (R19-2162; R19-2153; R19-2185).  
 
Use of digital technology to enhance accessibility and effectiveness of self-management 
 
Recent research has focused on development of enabling and assistive technologies that are 
accessible at all times to provide patients with relevant, individualised, motivational, and 
educational material that encourages, supports, and facilitates self-management; these 
interventions provide information and instruction, and facilitate goal setting and self-
monitoring, relying on one or more approaches, such as video, audio, digital images, and hard 
or digital copies, to deliver educational and motivational content related to issues such as 
smoking cessation, exercise, diet, and symptom management (R19-2223; R19-2224; R19-
2219; R19-2221; R19-2179; R19-2181). While a recent systematic review (R19-2220) was 
not able to come to a definitive conclusion about the effectiveness of smart technology as a 
means of supporting, encouraging, and sustaining self-management in COPD, preliminary 
evidence of benefits in terms of outcomes such as quality of life and physical activity up to 
six months warranted a recommendation for further high-quality research in this area. Key 
focus areas for future research include exploration of strategies that will promote long-term 
engagement with smart technology and inclusion of qualitative data collection to inform 
issues relevant to the digital divide and to reveal what influences uptake and sustained use of 
technology among people with COPD.  
 
Given the central position of behaviour change support in COPD self-management training 
and the opportunities afforded by advances in digital technology, recommendations for 
designing, evaluating, and implementing digital behaviour change interventions (DBCIs) in 
health care may support future efforts in self-management research by identifying the 
scientific principles relevant to developing effective DBCIs, and supporting multidisciplinary 
teams of digital technologists, user experience researchers, behaviour scientists, health care 
professionals and patients to work together more effectively to advance research methods and 
advance the understanding and techniques of behaviour change through digital technology 
(R19-2150).  
 
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1.2 
DESCRIPTION OF INTERVENTION 
Background 
 
Engaging in appropriate self-management involves a complex series of behavioural changes:  
addressing behavioural risk factors including smoking cessation, maintaining or increasing 
physical activity, and ensuring adequate sleep and a healthy diet; learning to self-manage 
breathlessness, energy conservation techniques, and stress/anxiety management strategies; 
avoiding aggravating factors, monitoring and managing worsening symptoms, having a 
written action plan and maintaining regular contact/communication with a healthcare 
professional. The patient’s needs, preferences, and personal goals should inform the 
personalized design of the self-management training plan (P19-00675).  
 
Within a holistic vision of a technology-enabled self-management program in COPD that 
supports all relevant treatment goals (P19-00675) and associated behaviours, our initial 
discussions prior to development of a working protype for a self-management DBCI focussed 
on (i) identifying one specific, relevant, patient-centric treatment goal (“clinical target”), and 
(ii) selecting one relevant treatment recommendation (and associated behaviour) known to be 
efficacious with respect to the achievement of this treatment goal (P19-00675). Activity 
limitation due to breathlessness is a ubiquitous burden for patients with COPD; as such, the 
initial DBCI development has focussed attention on treatment recommendations for 
breathlessness management in COPD: 
- 
adhering to prescribed symptomatic medicines 
- 
learning to self-manage breathlessness 
- 
maintaining or increasing physical activity 
- 
energy conservation techniques 
- 
avoiding aggravating factors 
- 
stress/anxiety management strategies 
 
Treatment guidelines (P19-00675) place bronchodilators as the foundation of pharmacologic 
management of COPD and are considered central to symptom management and commonly 
given on a regular basis to prevent or reduce symptoms. In patients with moderate to very 
severe pulmonary impairment (i.e., GOLD Stage II to IV) whose symptoms are not 
adequately controlled with as-needed short-acting bronchodilators, adding regular treatment 
with one or more long-acting inhaled bronchodilators is recommended (long-acting β-
agonists, LABAs; long-acting muscarinic antagonists, LAMAs). LABAs and LAMAs 
significantly improve lung function, dyspnea, health status and reduce exacerbation rates; 
combination treatment with a LABA and a LAMA increases lung function and reduces 
symptoms compared to monotherapy. 
 
Therefore, based on a review of GOLD guidelines, we decided to focus our attention on the 
following treatment goal and associated pharmacological and non-pharmacological 
recommendations for management of stable COPD:  
 
Treatment goal: Reduction of symptoms in patients with COPD 
[with initial focus on breathlessness] 
 
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Pharmacological treatment recommendation (GOLD 2020) (P20-00875): regular 
(daily, as-prescribed) treatment with long-acting bronchodilators in patients whose 
symptoms are not adequately controlled with as-needed short-acting bronchodilators  
 
Non-pharmacological management recommendation (GOLD 2020) (P20-00875): 
“…patients should be offered guidance on self-management of breathlessness, energy 
conservation and stress management, (and they should be given a written action 
plan).” 
 
With this GOLD-specified treatment goal / recommendation as a focus, we then identified the 
following target behaviours to be addressed with the initial TARA1 DBCI solution 
development: 
 
Target behaviour: (sustained) adherence to: 
- 
prescribed maintenance long-acting bronchodilator medication 
(“pharmacological self-management support”) 
- 
pursed lip breathing (“non-pharmacological self-management support”) 
- 
pacing / energy conservation (“non-pharmacological self-management 
support”) 
 
With regards to adherence to prescribed maintenance long-acting bronchodilator medication, 
for the purposes of the initial solution development and research evaluation, it was necessary 
to restrict our focus to a limited number of once daily inhaled medications in order to reduce 
the content requirements within the educational component of the DBCI working prototype 
(e.g. education on appropriate inhaler technique); our operational focus was on patients 
prescribed either Spiriva Respimat (once daily) or Stiolto Respimat (once daily) as inhaled 
maintenance pharmacological treatment as well as short-acting β-agonist for as-needed 
symptom relief. 
 
To provide additional development guidance, we focused on the following target clinical use 
case for TARA version 3 (“intended use”): 
 
TARA offers patients remote breathlessness self-management support during daily 
life. TARA is a digital behavior change intervention intended to support patients with 
COPD in adopting and sustaining clinically recommended (evidence-based) self-
management behaviours. TARA is intended to be used independently at home by 
patients using an internet-enabled device.  
 
Access to TARA will be achieved via a recommendation from a prescribing physician 
at the same time as provision of a prescription for a once daily maintenance 
bronchodilator (Spiriva/Stiolto Respimat)  
 
Appropriate patients as per GOLD recommendations (vis a vis maintenance 
bronchodilator treatment in combination with self-management). 
 
                                                 
1 Technology-Assisted Respiratory Adherence 
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The initial duration of patient engagement with TARA will be between an initial 
contact with an HCP and a follow-up contact with an HCP.  
 
Summary reports from TARA can be delivered by the patient to the HCP at the follow-
up clinical visit by print-out or screen-share to update the HCP on the patient’s 
progress in symptom self-management, which may be an enabler for a robust 
discussion with the HCP during the follow-up visit. 
 
Further details regarding the science behind the TARA development and a more detailed 
description of the TARA solution is provided in the Investigator’s Brochure. 
1.3 
RATIONALE FOR PERFORMING THE STUDY 
The early development phase of TARA has been informed by the ORBIT model for 
developing behavioural treatments to prevent and/or manage chronic disease (R19-2270). 
The ORBIT model was considered to be appropriate for a number of reasons: (i) it focuses on 
the early, pre-efficacy phases of behavioural treatment development; (ii) it was developed for 
use with a broad array of chronic diseases, (iii) it intentionally uses terminology from the 
drug development model. 
 
In accordance with the ORBIT model, the goal of Phase I was to develop an intervention or  
‘treatment package’ that is considered to contain essential components offered in an efficient 
way, is acceptable to the population of interest, and is likely to have  a clinically significant 
benefit on the behavioural risk factor.  
 
In the early stages of Phase I, the scientific foundation and the basic elements of the 
behavioural treatment were defined: (i) development of a hypothesized pathway by which a 
behavioural treatment could solve the clinical problem, (ii) specification of clinically 
significant milestones on the behavioural risk factor(s) being targeted, (iii) identification of 
appropriate target population, (iv) definition of potential treatment components, and (v) 
elucidation of basic behavioural and social sciences support for potential treatment 
components and their respective treatment targets. 
 
Phase I focussed on the design of the essential features of the (digital) behavioural treatment: 
taxonomies and “mapping” strategies that characterize behavioural interventions and their 
components were used to select treatment elements; experimental and observational studies 
in the laboratory and field enabled the identification of potential treatment components and 
the respective biological, psychophysiological, social, environmental, and behavioural targets 
needed to accomplish change in them and, in turn, in the behavioural risk factor; qualitative 
research was conducted to develop a rich understanding of the problem from the perspective 
of IwCOPD; several UXR activities were conducted to inform development of components of 
the solution; an initial clinical research study was conducted to evaluate engagement with an 
early working prototype.  
 
On the basis of accumulated knowledge during Phase I development, the TARA development 
team concluded that the TARA prototype version 3 may be defined as a putative Minimum 
Functional Product (MFP) for the target clinical use case. As such, the development team 
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determined that it was appropriate to move into Phase IIa of development and conduct a 
proof-of-concept study to determine if TARA prototype version 3 can achieve benefit on a 
relevant clinical target in a small, select sample. In this way, an important goal of this proof-
of-concept study is to determine whether or not TARA version 3 merits more rigorous testing 
using a randomized design in larger, more representative study population. 
 
TARA may be described as a complex intervention (R20-4211). An important task in 
describing a complex intervention is to identify the individual components that are being 
integrated into the holistic solution. TARA is being developed within the overarching 
framework of the GOLD clinical management guidelines, with specific attention paid to the 
GOLD classification schema of pharmacological and non-pharmacological disease 
management. Within this development framework, there is value in evaluating the extent to 
which the components contribute to the effectiveness of the holistic solution, similar to the 
evaluation of the contribution of the individual components of a combination drug product 
(P15-03349, P19-01878) drugs. As a preliminary evaluation of the effectiveness of the 
individual components of TARA [within the spirit of “proof of intervention principles”(R20-
4212)], the present study will adopt a cohort approach within the study design: the first cohort 
will engage with TARA version 3.1, which includes non-pharmacological self-management 
support (i.e. self-monitoring, pursed lip breathing, pacing and energy conservation); the 
second cohort will engage with TARA version 3.2, which includes both non-pharmacological 
and pharmacological self-management support (i.e. additional inclusion of the medication 
support component). 
 
1.4 
BENEFIT-RISK ASSESSMENT 
 
While benefit-risk assessment is standard practice within the clinical drug development 
paradigm, it is also increasingly recognised as an important consideration for non-
pharmacological interventions in healthcare (P14-02978; R19-2769).  
1.4.1 
Benefits 
Potential benefits of the fully developed TARA DBCI include improving knowledge of 
COPD and its treatments and how treatment can improve symptoms and outcomes, verifying 
inhaler technique, and learning new skills that may improve self-management of COPD; 
these same potential benefits are applicable to study participants engaging with the TARA 
DBCI working prototype (version 3).  
1.4.2 
Risks 
No adverse effects have been identified during the user experience testing rounds of 
components of the intervention or in the first clinical study (CRT1; 352.2133).  
 
Study 352.2154 will be the second study that IwCOPD will engage with TARA in a real-
world setting. There is a potential for (disease-related) behaviour change and consequent 
risks associated with changes in behaviour; in light of the fact that (i) study participants will 
only be allowed to log-on to TARA after recommendation by their primary physician, (ii) the 
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medical oversight of the participant is by their primary physician and (iii) no therapeutic 
recommendations are being provided by the software, risks associated with engagement with 
TARA in this study are considered low. The time required to engage with TARA is a 
potential inconvenience and is mitigated by the option for study participants to disengage 
from TARA / study at any time.  
 
1.4.2.1 
Covid-19 related risks 
Potential risks for participants due to the COVID-19 pandemic have been evaluated and the 
following measures have been put in place in this study to mitigate any risk: 
x Participants will be under the medical oversight of their primary physician 
x Participants with active or recovered SARS CoV-2 infection will be excluded from 
the study (Section 3.3.3.).   
x The majority of study activities will be conducted remotely and the number of on-site 
visits has been limited in this study.  However, in case of an increased risk of SARS-
CoV-2 infection due to physical visits to the sites, the visits should be conducted 
remotely (by phone or video call) if the Investigator judges that this is the safest 
course of action.  
1.4.3 
Discussion 
Study 352.2154 is designed to learn about how IwCOPD engage with TARA to allow for 
refinements during further solution development. If some of the underlying assumptions for 
the TARA development hold true, there is a potential for study participants to develop a 
stronger capacity to adhere to clinically recommended COPD self-management behaviours. 
 
As such, it is acceptable to conduct this proof-of-concept study. 
 
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2. 
STUDY OBJECTIVES AND ASSESSMENTS  
2.1 
MAIN OBJECTIVE (RESEARCH QUESTIONS), PRIMARY 
ASSESSMENTS 
2.1.1 
Main objective (research question) 
The main research question focusses on the following, relevant proximal clinical outcome in 
the context of the primary, patient-centric clinical problem addressed by TARA working 
prototype version 3 in consideration of the defined clinical use case (as described in Section 
1.2):  
 
Is there a clinically significant reduction in breathlessness in symptomatic IwCOPD 
following engagement with TARA after 12 weeks? 
 
2.1.2 
Primary assessments 
The primary measurement instrument (Clinical Outcome Assessment) that will be used to 
measure breathlessness is the dyspnea domain of the CRQ-SAI, a patient-reported outcome 
(PRO) with a two-week recall. The intention of TARA version 3 is to support the patient in 
developing skills to self-manage the breathlessness that is experienced during activities of 
daily life.  
 
Primary Assessments:  
x Percentage of participants who experience a clinically significant decrease in 
breathlessness as measured by the Chronic Respiratory Questionnaire – Self 
Administered Individualized (CRQ-SAI) dyspnea domain at week 12. 
x Mean change in CRQ-SAI dyspnea domain from baseline to 12 weeks.  The CRQ-SAI 
dyspnea score ranges from 1 to 7 with higher values indicating an improvement of 
breathlessness.   
 
2.2 
SECONDARY RESEARCH QUESTIONS, SECONDARY ASSESSMENTS 
2.2.1 
Secondary research questions 
The secondary research question focusses on activities of daily living (amount and intensity) 
as well as the perceived difficulties associated with performing physical activity in daily life.   
 
Activity Levels: 
Is there an associated maintenance or increase in activities of daily living to support a 
positive benefit of TARA on breathlessness?  
 
Physical Activity Experience: 
Is there an improvement in the physical activity experience of the patient?  
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2.2.2 
Secondary assessments 
Activity Levels: Daily activity levels will be measured using the activity tracker (
 for 
a 2-week period and an average will be taken at both timepoints to match the CRQ-SAI time 
frame for measurement. 
 
x Change from baseline in average number of steps measured by the activity tracker at 
week 12.   
x Change from baseline in average cadence (steps/min) measured by the activity tracker at 
week 12.   
 
Physical Activity Experience: 
x Change from baseline in the difficulty domain of the Clinical Visits PROactive Physical 
Activity in COPD instrument (C-PPAC) at week 12. The domain score ranges from 0 to 
40 with a higher value representing a lesser degree of difficulty. 
 
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3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION  
3.1 
OVERALL STUDY DESIGN  
The study will follow a within-subject pre-post study design and will be conducted as a 
hybrid (clinic visit/remote) study.  Participants will have clinic / telemedicine (phone or video 
calls) visit(s) with the clinical site and the completion of survey activities and engagement 
with the digital intervention TARA will take place remotely / on-line. The survey activities 
will be completed online via the study website at the time points outlined in the flow chart.  
As the TARA intervention is fully online and digital, participants in the study are free to use 
the intervention as much as they like for the 12-week study duration from their enrolment 
date. 
 
Potentially eligible IwCOPD will be recruited from clinical sites.  For participants who are 
receiving a new prescription for a once daily maintenance bronchodilator (Spiriva/Stiolto 
Respimat), the prescribing physician will recommend use of TARA to the participants at the 
same time as provision of the prescription. For participants who are currently on a once daily 
maintenance bronchodilator (Spiriva/Stiolto Respimat) but who could benefit from additional 
support, the physician will recommend the use of TARA for self-management alongside their 
existing prescription.   
 
The study will have 2 cohorts of participants in order to support the evaluation of the extent 
that pharmacological support adds value on top of non-pharmacological support: 
x The first cohort will engage with a version of TARA that includes the non-
pharmacological self-management support (self-monitoring, pursed lip breathing, 
pacing) 
x The second cohort will engage with a version of TARA that includes both non-
pharmacological and pharmacological self-management support (i.e. additional 
inclusion of medication support component). 
 
Recruitment into the cohorts will be conducted sequentially. The study will begin recruiting 
into the first cohort and once the first cohort is closed for recruitment, the second cohort will 
open for recruitment. This cohort strategy will support an iterative approach in the 
development of the digital intervention.     
 
The study consists of three broad phases:  
(1) Pre-TARA: study recruitment by clinic site, consent, screening, receipt of 
activity tracker, run-in period, and pre-TARA survey;  
(2) Intervention period (TARA delivery): up to 12-weeks of intervention 
depending on the length of time of each participant’s individual journey;  
i. Interim survey measures will be collected during this period via the 
study website at 2 weeks, 4 weeks and 8 weeks. 
ii. End of study survey measures will be collected at 12 weeks. 
(3) Post-TARA: follow-up visit with the clinic site (in-person or telemedicine), 
post-TARA survey, post-TARA interview conducted in a sub-set of 
participants and HCP interviews. 
 
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3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP 
Study design  
 
According to the ORBIT model, quasi-experimental, within-subjects designs where subjects 
act as their own controls in a pre-post treatment comparison are appropriate in Phase IIa. The 
sample size can be small since clinical, not statistical, benefit is sought, and sample size 
calculations are unnecessary. The sample can be selected from accessible subjects, rather than 
be representative, because this initial test will determine only whether the treatment merits 
more rigorous testing. The focus of Phase IIa studies is deliberately placed on the treatment 
and its ability to produce clinically significant change on a behavioural risk factor to indicate 
that the intervention is likely to be efficacious. This is in contrast to Phase IIb studies which 
focus on determining the source of a treatment effect (e.g., separation of treatment effects 
from effects due to the passage of time) and with choosing the appropriate control group, in 
itself a complex undertaking. 
 
A cohort approach has been included in the study based on the CEEBIT (Continuous 
Evaluation of Evolving Behavioural Intervention Technologies) methodologic framework 
(R20-4210) which was developed to support the evaluation of evolving versions of 
Behavioural Intervention Technologies (BITs).  
 
3.3 
SELECTION OF STUDY POPULATION 
A sufficient number of individuals will be enrolled (sign informed consent) to ensure that 
approximately 50 participants with a diagnosis of COPD are entered into the intervention 
(TARA log-in).  
 
Participants will be administered the Readiness to Change questionnaire at screening with the 
aim to enroll a higher number of participants who are not currently taking action to manage 
their COPD (patients who score a 1, 2 or 3 on the scale) vs. those participants who are 
currently taking actions to manage their COPD (participants who score a 4 or 5 on the scale).  
It is anticipated that these participants may need more support with managing their condition 
and therefore we could see a greater impact of using TARA in these participants with respect 
to their intention to self-manage their COPD. 
 
An IwCOPD can only log-in to TARA (intervention entry) if they meet all eligibility criteria. 
A log of all participants enrolled into the study (i.e. who have signed informed consent) will 
be maintained irrespective of whether or not they engage with TARA (TARA log-in). 
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3.3.1 
Main diagnosis for study entry 
Outpatients with a diagnosis of COPD (chronic bronchitis or emphysema) and prescribed 
either Spiriva Respimat or Stiolto Respimat are eligible for inclusion if they fulfil all the 
inclusion criteria (Section 3.3.2) and do not present with any of the exclusion criteria (Section 
3.3.3).   
 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria. 
3.3.2 
Inclusion criteria 
1. Signed and dated written informed consent in accordance with GCP (ISO 14155) and 
local legislation prior to admission to the study 
2. Male or female patients 
3. All patients must have a self-reported confirmation of a physician diagnosis of COPD (or 
chronic bronchitis or emphysema) 
4. Age ≥ 40 years 
5. Patients must be current or ex-smokers  
6. Modified Medical Research Council (mMRC) Score ≥ 2 (i.e. evidence of activity-related 
breathlessness) 
7. Patients must have a prescription for either Spiriva Respimat or Stiolto Respimat and as 
per one of the below scenarios: 
a. Participants must have a new prescription for either Spiriva Respimat or Stiolto 
Respimat (this could include a patient who has never received a maintenance 
bronchodilator for treatment before, or a patient who was previously on an 
alternative maintenance bronchodilator who is being switched to Spiriva Respimat 
or Stiolto Respimat to help with their COPD management). 
OR 
b. Participants currently on Spiriva Respimat or Stiolto Respimat, who could benefit 
from engagement with TARA (after discussion with their physician).  
8. Participants must be on a short-acting bronchodilator (“rescue medication”) 
9. Participants must be willing to use the study specific activity tracker (
 device) and 
be willing to complete all data collection requirements (within TARA plus on-line 
questionnaires plus possible phone interview) 
10. Fluency in written English 
11. Access to a Smartphone and at least one other device (desktop, laptop or tablet) with 
updated browsers installed (or willing to download up-to-date version for the study), and 
daily home access to internet  
12. Need to have personal e-mail account that is used daily 
 
3.3.3 
Exclusion criteria 
• 
Patients with asthma as concurrent baseline condition at the time of screening 
• 
Patients with confirmed, suspected or recovered SARS-CoV-2 infection or if the patient 
had household or other contact with an individual with confirmed SARS-CoV-2 infection 
within 14 days prior to the completion of the eligibility questionnaire. 
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• 
Patients with a worsening COPD episode requiring medical intervention within 4 weeks 
of enrolment 
• 
Patients who have completed a pulmonary rehabilitation (PR) or COPD self-management 
program in the 3 months prior to enrolment or patients who are currently in a PR program 
(rationale: PR programs typically include a self-management component which may 
interfere with study objectives) 
• 
Planned vacation or other travel during the study period that requires overnight stays 
away from home  
• 
Major surgery performed within 6 weeks prior to enrolment or planned during the course 
of the study, e.g. hip replacement 
• 
Patients prescribed inhaled COPD medications other than Spiriva Respimat plus albuterol 
or Stiolto Respimat plus albuterol 
• 
Patients with any contraindications for participating in the study (after discussion with 
their physician). 
• 
Previous enrolment in a TARA study 
• 
Previous enrolment in this study 
• 
Currently enrolled in another investigational device or drug study/trial, or less than 30 
days since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s) 
• 
Women who are pregnant, nursing, or who plan to become pregnant while in the study 
• 
Any self-reported medical or neuro-cognitive condition that would limit the ability of the 
participant to consent 
• 
Residence in State of California (rationale: new data management and privacy laws in this 
state present complications to an effective data analysis plan by allowing users to 
potentially withdraw their data from the study) 
 
3.3.4 
Withdrawal of participants from study participation 
3.3.4.1 
Withdrawal of consent to study participation  
Participants may withdraw consent to study participation at any time without the need to 
justify the decision. 
3.3.4.2 
Discontinuation of participants 
Participants will be discontinued from the study if they experience an infection with SARS-
CoV-2. 
3.3.4.3 
Discontinuation of the study by the sponsor 
Boehringer Ingelheim reserves the right to discontinue the study at any time for the following 
reasons: 
1. Failure to meet expected enrolment goals. 
2. Emergence of any new information invalidating the positive benefit-risk assessment that 
could significantly affect the continuation of the study. 
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4. 
TREATMENTS 
4.1 
INVESTIGATIONAL INTERVENTION 
No IMP treatments will be administered in this study. 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS 
4.2.1 
Other treatments and emergency procedures 
There are no special emergency procedures to be followed. 
 
There are no restrictions regarding medications for other (non-COPD) diseases. 
4.2.2 
Restrictions 
4.2.2.1 
Restrictions regarding concomitant treatment 
For a participant to be eligible for the study, they must be prescribed Spiriva plus albuterol or 
Stiolto plus albuterol according to the approved prescribing information. Participants that are 
additionally prescribed other inhaled COPD medications are not eligible. 
4.2.2.2 
Restrictions on diet and lifestyle 
There are no restrictions regarding diet and lifestyle.  
 
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5. 
FURTHER DETAILS REGARDING ASSESSMENTS  
5.1 
ASSESSMENT OF EFFICACY  
5.1.1 
Primary Assessment 
Chronic Respiratory Questionnaire – Self Administered Individualized (CRQ-SAI) 
The CRQ-SAI, a derivate of the original CRQ tool, is used to assess the patients’ perception 
of their COPD and measures the impact of COPD on their life. The CRQ-SAI has 20 items 
over 4 domains: dyspnea, fatigue, emotional function and mastery. For dyspnea, participants 
are asked to select 5 activities associated with breathlessness (from a list of 26 or custom 
response), that they have performed in the past two weeks and that are most important to 
them and indicate how much breathlessness they have experienced while performing each. 
 
The CRQ-SAI should be completed by the participants at the time points outlined in the flow 
chart.  Details of the CRQ-SAI are provided in Appendix 10.2.1. 
 
5.1.2 
Secondary Assessments 
Activity Tracker (
 device)  
A physical activity tracker is an accelerometer that is used to measure the overall movement 
of a patient. Activity trackers provide valuable information on physical activity directly from 
the patient’s body.   
 
The 
 device will be the activity tracker used in the study to measure the                                                  
amount (steps) and intensity (cadence) of daily ambulatory activities in support of the main 
research objective.  Participants will wear the activity tracker throughout the study and the 
data obtained from the activity tracker will be transferred to the study database. 
 
Instructions will be given to the participants on how to use the activity tracker. 
 
Clinical Visit PROactive Physical Activity in COPD instrument (C-PPAC) 
A secondary measure of efficacy is the C-PPAC, a hybrid measurement tool incorporating a 
patient-reported outcome (PRO) and an activity tracker.  The tool couples the difficulties 
associated with performing physical activity and the amount and intensity of the activities 
and the final instrument incorporates both a difficulty domain consisting of 10 questions and 
an amount domain consisting of 4 questions and 2 of these questions are based on data from 
the activity tracker.  
 
The difficulty domain includes questions related to breathlessness, but also includes questions 
related to other aspects of the difficulty associated with performing daily activities in 
IwCOPD.  
 
The C-PPAC should be completed by the participants at the time points outlined in the flow 
chart. Details of the C-PPAC are provided in Appendix 10.2.2. 
 
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5.2 
ASSESSMENT OF ENGAGEMENT AND PERCEPTIONS OF VALUE 
Relevant information regarding assessment of engagement and perceptions of value is 
provided in Section 2.3 (Further research questions and further assessments) and in the 352-
2154 Interview Guide. 
 
5.3 
ASSESSMENT OF SAFETY 
5.3.1 
Physical examination 
NA 
5.3.2 
Vital signs 
NA 
5.3.3 
Safety laboratory parameters 
No safety laboratory parameters will be determined.  
5.3.4 
Electrocardiogram 
NA 
5.3.5 
Other safety parameters 
NA 
5.3.6 
Assessment of adverse events 
5.3.6.1 
Definitions of AEs  
5.3.6.1.1 
Adverse event 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  
 
Adverse drug reaction 
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An adverse drug reaction (ADR) is defined as a response to a medicinal product which is 
noxious and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions 
may arise from use of the product within or outside the terms of the marketing authorisation 
or from occupational exposure. Conditions of use outside the marketing authorization include 
off-label use, overdose, misuse, abuse and medication errors. 
 
Serious adverse event 
A serious adverse event is defined as any AE which 
- results in death,  
- is life-threatening,  
- requires in-patient hospitalization, or 
- prolongation of existing hospitalization,  
- results in persistent or significant disability or incapacity, or  
- is a congenital anomaly/birth defect  
 
Life-threatening in this context refers to a reaction in which the patient 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 more severe. 
 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient 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. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction. 
 
Adverse Event of Special Interest (AESI) 
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class.  
 
No AESIs have been defined for this study. 
 
5.3.7 
Adverse Event Collection and Reporting 
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
 
5.3.7.1 
Collection of AEs 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.  
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Causal relationship of adverse event 
 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.  
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.  
 
Arguments that may suggest a reasonable causal relationship could be: 
• 
The event is consistent with the known pharmacology of the drug  
• 
The event is known to be caused by or attributed to the drug class 
• 
A plausible time to onset of the event relative to the time of drug exposure 
• 
Evidence that the event is reproducible when the drug is re-introduced 
• 
No medically sound alternative etiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications). 
• 
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
• 
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished). 
 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
 
• 
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
• 
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• 
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
 
Intensity of adverse event 
 
The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
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Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a patient has been enrolled in the study 
and has taken study Spiriva Respimat or Stiolto Respimat, the investigator must report any 
drug exposure during pregnancy in a study participant within 7 days by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point. See table below. 
 
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner. 
The ISF will contain the trial specific information and consent for the pregnant partner. 
 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form (Part B).  
 
The ISF will contain the Pregnancy Monitoring Form (Part A and B). As pregnancy itself is 
not to be reported as an AE, in the absence of an accompanying serious ADR, only the 
Pregnancy Monitoring Form and not the AE form is to be completed. If there is a serious 
ADR associated with the pregnancy a AE form must be completed in addition.  
 
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug.  
 
The following AE collection and reporting requirements have been defined:  
 
All AEs and other safety relevant information identified via all sources used in the study have 
to be reported [via the study website (i.e. questionnaires), interviews, TARA platform] to the 
investigator for causality assessment (Section 5.3.7) and reporting to sponsor regardless of 
causal relationship.   
 
 
5.3.7.2 
Expedited Reporting of AEs and Drug Exposure during Pregnancy to BI 
Pharmacovigilance 
 
Any AE or SAE must be reported to the sponsor within the timelines listed regardless of 
causality.  The following must be reported by the investigator on the NIS AE form and/or 
Pregnancy Monitoring Form from signing the informed consent onwards until the end of the 
study and provided to BI unique entry point:  
 
Type of Report 
Timeline 
All serious AEs 
immediately within 24 hours 
 
 
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All non-serious AEs 
7 calendar days 
Drug exposure during pregnancy 
7 calendar days 
 
All SAEs / AEs including those persisting after study completion must be followed up until 
they are resolved, have been sufficiently characterized, or no further information can be 
obtained.  
 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the AE form. 
 
Information required 
For each reportable adverse event, the investigator should provide the information requested 
on the AE form.  
5.4 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS 
NA 
5.5 
ASSESSMENT OF BIOMARKER(S) 
NA 
5.6 
BIOBANKING 
NA  
5.7 
OTHER ASSESSMENTS 
Modified Medication Research Council Dyspnea Scale 
The mMRC Dyspnea Scale uses a simple grading system to assess a patient’s level of 
dyspnea.  All questions relate to everyday activities and are generally easily understood by 
patients.  Score range from 0 (none) to 4 (very severe) and are usually obtained in a few 
seconds.  Participants will be asked to score their dyspnea as part of the screener. 
Details of the mMRC are provided in Appendix 10.2.11. 
 
5.8 
APPROPRIATENESS OF MEASUREMENTS  
Questionnaires  
The CRQ-SAI, D-PPAC, CAT, HADS are well established and validated questionnaires 
(R17-2573, R16-5353). 
 
The Readiness to Change, TSRQ, PCS, HCCQ questionnaires are widely used in the study of 
behaviour change in a health care setting (R20-4003). 
 
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The VCCQ is a recently validated questionnaire specific for virtual care settings (R20-3985). 
 
The SUS is a robust and valid tool (R19-2266). 
 
Activity Tracker 
The 
 device will be used as an activity tracker in this study.  This is an electronic 
device used to measure physical activity levels of the participant.  The device will be used 
according to manufacturer’s guidance.   
 
Medication Adherence 
Self-reports of daily medication adherence are commonly thought to have issues with 
reliability, but Stirrat et al (R19-2202) reports that “evidence indicates that self-report 
adherence measures show moderate correspondence to other adherence measures and can 
significantly predict clinical outcomes” and conclude that “self-report medication adherence 
measures can provide actionable information despite their limitations”.  
 
Stirrat et al suggest that the quality of self-report adherence measures “may be enhanced 
through efforts to use validated scales, assess the proper construct, improve estimation, 
facilitate recall, reduce social desirability bias, and employ technologic delivery”. In keeping 
with this recommendation, in the current study: 
- Comparisons are conducted within-subject to reduce the effect of social desirability 
bias  
- A technological delivery of the self-report is employed to provide an always-available 
way to record medication taking via a smartphone device, thus helping avoid issues 
with recall. 
- All measures are administered remotely and can be completed in privacy and without 
research staff being present to reduce social desirability bias 
 
 
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6. 
INVESTIGATIONAL PLAN  
6.1 
VISIT SCHEDULE 
This study is a hybrid study where participants will interact with the site via clinic /  
telemedicine visits as indicated in the flow chart.  It is preferable that any telemedicine visits 
are conducted via a video call, however if this is not possible then they can be done via a 
phone call. 
 
The survey activities and engagement with the digital intervention TARA will take place 
remotely / on-line.  The survey activities will be completed online via the study website at the 
time points outlined in the flow chart.  As the TARA intervention is fully online and digital, 
participants in the study are free to use the intervention as much as they like during the 12-
week study duration from their enrolment date.  
 
The majority of study activities will be conducted remotely, and the number of on-site visits 
has been limited in this study.  However, in case of an increased risk of SARS-CoV-2 
infection due to physical visits to the sites, the visits should be conducted remotely (by video 
or phone call) if the Investigator judges that this is the safest course of action.  
 
Study-specific reminder algorithms will be developed for situations where the study 
participant has not completed tasks within a certain timeframe. Additional details regarding 
this follow-up are outlined in the 352-2154 Study Operational Document. 
 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening period 
Screening Period 
The clinical site will identify potential participants for the study. Participants will be 
approached by the clinical site for participation in the study at one of their regular clinical 
visits as per the clinical sites’ normal practice (e.g. in-person or via telemedicine).  The 
prescribing physician will recommend use of TARA to patients who could benefit from self-
management strategies at the same time as provision of a prescription for a once daily 
maintenance bronchodilator (Spiriva/Stiolto Respimat). 
 
The clinical site will inform the participant about the trial and obtain informed consent in 
accordance with GCP (ISO 14155) and the local legislation.  Once consented, participants 
will be given a unique ID and a link to the study website where they will log-in to complete a 
screening survey to ensure all inclusion and exclusion criteria are met.  
 
Once the participant completes the screening survey, they will get a message describing 
whether or not they are eligible for the study.  
 
Rescreening will be allowed on a case by case basis after discussion between the site and the 
sponsor. 
 
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Activity tracker shipment 
Once the participant has signed consent and is determined to be eligible for the study, the 
activity tracker will be shipped to the study participant. Participants will be requested to wear 
the activity tracker during the run-in period, for the duration of the study and until the 12-
week survey is completed.  
 
Run-in Period 
Once participants receive and activate the activity tracker, they will enter a 2-week run-in 
period.  During this time, participants will wear the activity tracker and should take their 
medication as prescribed.  
 
Pre-TARA Survey 1  
Following the run-in period, participants will receive an email asking them to complete the 
pre-TARA survey. The email will have a link to the survey which will be completed on the 
study website. Refer to the flow chart for details of which questionnaires will be administered 
as part of this survey.   
 
Login Instructions  
After completion of pre-TARA survey 1, participants will receive their TARA login 
instructions via email along with expectations around use. The participant will then be able to 
login to the TARA web application.   
 
 
6.2.2 
Study and TARA Intervention period  
TARA DBCI 
Once the login is provided, participants will be able to engage with the TARA DBCI as much 
as they like during the 12-week intervention period. When they click on the “get help” 
buttons in the COPD program, they will receive an outreach by e-mail to explore what sort of 
help they are looking for and to resolve any issues, if possible. If the participant is interested 
in speaking with an MCP coach, they will receive an email to follow-up, and they will be 
asked to participate in the post-study IDI to give feedback on what they might want from a 
coach. 
 
Activity Tracking 
During the program use, participants will be asked to wear the activity tracker for the 
duration of the study.  
 
Surveys 
Also, during this period, participants will be requested to complete surveys at interim 
timepoints throughout the 12-week duration.  Specifically, at 2 weeks, 4 weeks and 8 weeks 
after the start of the intervention period, participants will receive an email asking them to 
complete surveys 2, 3 and 4 respectively. The email will have a link to the survey which will 
be completed on the study website and consist of the CRQ-SAI, Readiness to Change and 
PCS questionnaires via the study website. 
 
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Survey 5 
Participants will receive an email at the end of their intervention period at 12 weeks asking 
them to complete the 12-week survey 5. The email will have a link to the survey which will 
be completed on the study website. Refer to the flow chart for details of which questionnaires 
will be administered as part of this survey.   
6.2.3 
Follow-up period (study completion) 
Follow-up visit (Clinic visit or Telemedicine) 
After completion of the post-TARA survey 5, participants will have a follow-up with the 
clinical site.  This visit should be performed within 7 days of the clinical site receiving the 
email notification to schedule the visit.  The visit can be performed in clinic, however if there 
are issues with scheduling, the visit can be accommodated as a telemedicine visit preferably 
via video call.  At this visit, a summary report from TARA will be shared by the participant 
with the HCP to update the HCP on their progress in symptom self-management.  The site 
should ask the participant about any AEs at this visit. 
 
Once the participant has completed the follow-up visit, they will be requested to return the 
activity tracker. 
 
Post-Study Survey 6 
After the follow-up visit, participants will receive an email asking them to complete the post-
TARA survey 6. The email will have a link to the survey which will be completed on the 
study website. This survey will assess participants’ impression of TARA, their willingness to 
recommend it in future and the interactions with their HCPs regarding TARA.    
 
For participants not selected for the interview, this will mark the end their participation in the 
study. 
 
Post-TARA In-depth Interview (IDI) 
When participants receive their end-of-study emails, a sub-set of 8 to 15 participants will be 
asked to schedule an in-depth interview lasting approximately 60 minutes to be conducted 
remotely with a member of the digital technology research team (see Appendix 10.1.2 and the 
interview guide for more details). The final number of participants will be decided based on 
the sample set at which saturation of qualitative insight is achieved (no further new 
information is obtainable through interviews). Priority for invitations to the IDI will be given 
to participants who requested an MCP coach during the course of the study in order to allow 
them to give feedback on what they might want from a coach. At the end of the interview, 
participants will be asked to return the activity tracker if they have not done so. 
 
All HCPs will be asked to participate in an interview lasting approximately 45 minutes to be 
conducted remotely with a member of the digital technology research team (see Appendix 
10.1.3 and the interview guide for more details). 
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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE  
7.1 
NULL AND ALTERNATIVE HYPOTHESES 
According to established standards for evaluating behavioural treatments for chronic disease 
(R19-2270), in Phase IIa proof-of-concept studies: (i) a quasi-experimental pre-post study is 
considered an appropriate study design, and (ii) since clinical, not statistical benefit is sought, 
identification of formal null and alternative hypotheses, as well as power calculations and 
sample size estimates are considered unnecessary. 
 
The hypothesis for this study states that compared to baseline, IwCOPD will experience a 
clinically significant reduction in breathlessness after 12 weeks of receiving a digital 
behaviour change intervention for COPD self-management (TARA version 3).  
 
7.2 
PLANNED ANALYSES 
7.2.1 
General considerations 
In order to conclude that engagement with TARA leads to a patient benefit with regards to 
changes in breathlessness, it is important to confirm that any reduction in breathlessness at 
follow-up compared to baseline is not a consequence of a reduction in physical activity. 
Therefore, a preliminary analysis will be conducted to evaluate if changes in breathlessness 
vary with changes in physical activity from baseline to follow-up. 
 
Analysis will be performed separately for each cohort (Cohort 1: non-pharmacological self-
management support; Cohort 2: non-pharmacological + pharmacological self-management 
support).  Pooled analysis between the cohorts will not be performed. 
 
All patients enrolled will be included in analysis.  Additional explorative analysis will be 
described in statistical analysis plan.  
 
Preliminary Analysis: 
 
Study participants will be divided into three categories based on the level of change in their 
physical activity from baseline to 12-week follow-up using steps as a standard measure of 
activity. Each participant’s activity (steps) data will be descriptively analysed and 
standardized. Based on the distribution of observed data, participants will then be categorized 
into groups using an appropriate criterion of change such as: 
x Decreased activity: Activity level has decreased 1 SD or more at follow-up 
x Increased activity: Activity level has increased 1 SD or more at follow-up 
x No change: All other participants  
 
Following this categorization, differences in breathlessness scores (using the CRQ-SAI 
dyspnea domain) will be computed for each group between baseline and 12-week follow up 
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and comparisons conducted between groups. This analysis will evaluate if changes in 
breathlessness continue to be seen regardless of changes in physical activity.  
 
7.2.2 
 Primary assessment analyses 
For the primary assessment, the CRQ-SAI dyspnea domain will be used to calculate 
breathlessness measures at baseline and week 12. Analyses to be conducted include the 
following: 
x The percentage of the study population who experience a clinically significant 
decrease in breathlessness (minimal clinically important difference (MCID) of 0.5) 
will be calculated. 
x The difference between week 12 and baseline will be calculated and compared against 
the criterion of minimal clinically important difference (MCID) of 0.5. 
 
7.2.3 
Secondary endpoint analyses 
Descriptive statistics of additional secondary endpoint variables will be explored for selection 
of best-fit analysis techniques. Pre-post differences in the physical activity experience will 
also be explored to see if TARA v3 has had a positive effect on the perceived difficulty 
during activities.   
 
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7.2.5 
Safety analyses 
Standard BI summary tables and listings will be produced. All adverse events with an onset 
between informed consent signature and end of the post-TARA IDI will be assigned to the 
study period for evaluation. 
 
All study participants will be included in the safety analysis. In general, safety analyses will 
be descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock. 
 
7.2.6 
Other Analyses 
NA 
7.2.7 
Interim Analyses 
NA 
7.3 
HANDLING OF MISSING DATA 
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.   
For the primary endpoint analysis, imputation of missing values will not be 
performed.  Patterns of missing data will be analyzed descriptively and summarized.  Further 
sensitivity analyses to assess the robustness of the results on the primary endpoint may be 
performed and will be described in the TSAP.  For further endpoints, rules for handling of 
missing data will be specified in the TSAP if necessary. With respect to safety evaluations, it 
is not planned to impute missing values. 
 
7.4 
RANDOMISATION 
NA 
7.5 
DETERMINATION OF SAMPLE SIZE 
As per section 7.1, sample size power calculations are not required for ORBIT Phase IIa 
studies. Based on a literature review of similar ORBIT Phase IIa proof of concept studies, as 
well as consultation with behavioural science experts, a sample size of 25 subjects per cohort 
(50 subjects overall) was deemed appropriate for an initial evaluation of whether engagement 
with TARA results in a clinically significant change in breathlessness at 12-week follow-up 
compared with baseline. This study will be further used to generate the data needed to 
perform sample size power calculations in future studies.  
 
The following number of participants will be recruited into each cohort: 
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x Cohort 1: up to a maximum of 25 IwCOPD (non-pharmacological self-management 
support) 
x 
Cohort 2: up to a maximum of 25 IwCOPD (non-pharmacological + pharmacological 
self-management support) 
 
 
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8. 
INFORMED CONSENT, STUDY RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE 
The study will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki and relevant BI Standard Operating Procedures (SOPs).   
 
In addition, the study will be carried out in accordance with principles of the Medical Devices 
Directive (93/42/EEC), as far as possible in this early stage of development, and the 
following relevant aspects of the ISO document “Clinical Investigation of Medical Devices 
for Human Subjects – good clinical practice” (ISO 14155, current version):  
- Protection of the rights, safety and well-being of human subjects 
- Assurance of the scientific conduct of the clinical investigator  
- Definition of the responsibilities of the sponsor and principal investigator.    
 
Investigators and site staff must adhere to these principles. Deviation from the protocol, 
applicable principles or applicable regulations will be treated as “protocol deviation”.  
 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the participant. 
 
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the study participants against any immediate hazard, as well as of any serious 
breaches of the protocol or of GCP (ISO 14155) (see Appendix 10.5). 
 
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor with regard 
to publication of the results of this study are described in the investigator contract. As a rule, 
no study results should be published prior to finalisation of the study report. 
8.1 
STUDY APPROVAL, PARTICIPANT INFORMATION, INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments. 
 
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient according to GCP (ISO 14155) and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient 
information must be given to each patient. 
 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
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informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs and dates 
the informed consent. 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. 
 
The consent and re-consenting process should be properly documented in the source 
documentation. 
8.2 
DATA QUALITY ASSURANCE 
A quality assurance audit/inspection of this study may be conducted by the sponsor. The 
quality assurance auditor will have access to the investigator’s study-related files and 
correspondence, and the informed consent documentation of this study. 
8.3 
RECORDS 
8.3.1 
Source documents 
- electronic record is the source document)electronic record is the source document)In 
accordance with regulatory requirements, the investigator and digital technology 
research team should prepare and maintain adequate and accurate source documents 
and study records that include all observations and other data pertinent to the 
investigation on each study participant. Source data as well as reported data should 
follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). 
8.3.2 
Direct access to source data and documents 
The investigator will allow site study-related monitoring, audits, IRB/IEC review and 
regulatory inspections. Direct access must be provided to all source documents/data, 
including progress notes, which must be available at all times for review by the CRA, auditor 
and regulatory inspector. They may review all informed consents. Where appropriate, the 
accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will monitor compliance with the protocol and GCP 
(ISO 14155). 
8.3.3 
Storage period of records 
Study site: 
The study site must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the study (whatever is 
longer). 
 
Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
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8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS 
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.  
 
8.5 
STATEMENT OF CONFIDENTIALITY AND PARTICIPANT PRIVACY 
Data protection and data security measures are implemented for the collection, storage and 
processing of participant data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.  
 
Individual participant data obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
 
Personalised treatment data may be given to the participant’s personal physician or to other 
appropriate medical personnel responsible for the participant’s welfare. Data generated at the 
site as a result of the study need to be available for inspection on request by the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities. 
8.6 
STUDY MILESTONES 
The start of the study is defined as the date when the first participant in the whole study 
signs e-informed consent. 
 
The end of the study is defined as the date of the last visit of the last participant in the whole 
study (“Last Participant Completed”). Early termination of the study is defined as the 
premature termination of the study due to any reason before the end of the study as specified 
in this protocol. 
 
Temporary halt of the study is defined as any unplanned interruption of the study by the 
sponsor with the intention to resume it. 
 
Suspension of the study is defined as an interruption of the study based on a Health 
Authority (HA) request. 
8.7 
ADMINISTRATIVE STRUCTURE OF THE STUDY 
The study is sponsored by Boehringer Ingelheim (BI).  
 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.  
 
BI has appointed a Study Team Lead, responsible for coordinating all required activities, in 
order to  
- 
manage the study in accordance with applicable regulations and internal SOPs, 
- 
direct the study team in the preparation, conduct, and reporting of the study  
- 
ensure appropriate training and information of the investigator. 
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The organization of the study in the participating countries will be performed by a Contract 
Research Organization (CRO) with which the responsibilities and tasks will have been agreed 
and a written contract filed before initiation of the clinical study. 
  
The web-based platforms used to capture data collected in the study and for TARA will be 
developed by a digital technology provider with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical study. 
 
Data Management and Statistical Evaluation will be done in collaboration with an external 
consultant 
 
Tasks and functions assigned in order to organise, manage, and evaluate the study are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF. 
 
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9. 
REFERENCES 
9.1 
PUBLISHED REFERENCES 
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the Diagnosis, Management, and Prevention of Chronic Obstructive 
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Cooper CB. Exercise in chronic pulmonary disease: limitations and 
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Finley PJ, et. al.  Validating the theoretical structure of the treatment self-
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RA, et al, PROactive Consortium. The PROactive instruments to measure 
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Lorig KR, Holman HR. Self-management education: history, definition, 
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Jones P, Harding G, Wiklund I, Berry P, Leidy N. Improving the process 
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Kawagoshi A, Kiyokawa N, Sugawara K, Takahashi H, Sakata S, Satake 
M, et. al. Effects of low-intensity exercise and home-based pulmonary 
rehabilitation with pedometer feedback on physical activity in elderly 
patients with chronic obstructive pulmonary disease. Respiratory Medicine. 
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Miller WR, Moyers TB, Ernst D, Amrhein P, et. al. Manual for the 
Motivational Interviewing Skill Code (MISC) (Center on Alcoholism, 
Substance Abose and Additions.) 2008; 2.1. 
 
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Bandura A. Self-efficacy: toward a unifying theory of behavioral change. 
Psychological Review. 1977. 84(2):191–215. 
 
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Bourbeau J, van der Palen J. Promoting effective self-management 
programmes to improve COPD. European Respiratory Journal. 2009; 
33(3):461–3. 
 
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Dobbels F, de Jong C, Drost E, Elberse J, Feridou C, Jacobs L, et. al. The 
PROactive innovative conceptual framework on physical activity. 
EurRespir J. 2014; 44:1223–1233. 
 
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Chang SJ, Choi S, Kim S-A, Song M. Intervention strategies based on 
information-motivation-behavioral skills model for health behavior change: 
A systematic review. Asian Nursing Research. 2014; 8:172-181. 
 
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Effing TW, Bourbeau J, Vercoulen J, Apter AJ, Coultas D, Meek P, et. al. 
Self-management programmes for COPD: moving forward. Chron Respir 
Dis. 2012; 9:27–35. 
 
R19-2169 
Effing T, Vercoulen JH, Bourbeau J, Trappenburg J, Lenferink A, Cafarella 
P, et. al. Definition of a COPD self-management intervention: International 
Expert Group consensus. Eur Respir J. 2016. 48(1):46-54. 
 
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Fisher JD, Fisher WA, Mishovich SJ, Kimble DL, Malloy TE, et. al. 
Changing AIDS risk behavior: effects of an intervention emphasizing AIDS 
risk reduction information, motivation, and behavioral skills in a college 
student population; Health Psychology. 1996; 15:114 – 123. 
 
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Fisher JD, Fisher WA. Changing AIDS-risk behavior. Psychological 
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R19-2172 
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JM, et. al. The dyspnoea-inactivity vicious circle in COPD: Development 
and external validation of a conceptual model. Eur Respir J. 2018; 
52:1800079. 
 
R19-2176 
Plaza V, Fernández-Rodríguez C, Melero C, Cosio BG, Entrenas LM, Perez 
de Llano L, et. al. Validation of the 'Test of the Adherence to Inhalers' 
(TAI) for Asthma and COPD patients. J Aerosol Med Pulm Drug Deliv. 
2016; 29(2):142–152. 
 
R19-2179 
Tabak M, Vollenbroek-Hutten MR, van der Valk P, van der Palen, Hermens 
HJ, et. al. A telerehabilitation intervention for patients with Chronic 
Obstructive Pulmonary Disease: a randomized controlled pilot trial. Clinical 
Rehabilitation. 2014; 28(6):582–91. 
 
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Turner C, Lewis JR, Neilsen J. Determining usability test sample size. 
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Second Edition, Volume 3. 
 
R19-2181 
Voncken-Brewster V, Tange H, de Vries H, Naggyakaldi Z, Winkens B, 
van der Weijden T. A randomized controlled trial evaluating the 
effectiveness of a web-based, computer-tailored self-management 
intervention for people with or at risk for COPD. International Journal of 
COPD. 2015; 10:101–107. 
 
R19-2185 
Zwerink M, Brusse-Keizer M, van der Valk PDLPM, Zielhuis GA, 
Monninkhof EM, van der Palen J, et.al. Self management for patients with 
Chronic Obstructive Pulmonary Disease. Cochrane Database of Systematic 
Reviews. 2014. Issue 3.  
 
R19-2202 
Stirratt MJ, Dunbar-Jacob J, Crane HM, Simoni JM, Czajkowski S, Hillard 
ME, et. al. Self-report measures of medication adherence behavior: 
recommendations on optimal use. Transl Behav Med. 2015; 5(4):470–482. 
 
R19-2203 
van Gemert-Pijnen JE, Nijland N, van Limburg M, Ossebaard HC, Kelders 
SM, Eysenbach G, et. al. A holistic framework to improve the uptake and 
impact of eHealth technologies. J Med Internet Res. 2011; 13(4):e111. 
 
R19-2219 
McCabe C, Dinsmore J, Brady AM, Mckee G, O’Donnell, Prendergast D. 
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facilitates behavioral change and self-management in COPD. 2014;  
Volume 2014, Article ID 380919.  
 
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McCabe C, McCann M, Brady AM. Computer and mobile technology 
interventions for self-management in Chronic Obstructive Pulmonary 
Disease. Cochrane Database of Systematic Reviews. 2017. Issue 5. 
 
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R19-2221 
Moy ML, Collins RJ, Martinez CH, et al. An internet-mediated pedometer-
based program improves health-related quality-of-life domains and daily 
step counts in COPD: a randomized controlled trial. Chest 2015; 
148(1):128–37. 
 
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Moyers TB, Martin T, Manuel JK, Manuel JK, Hendrickson SML, Miller 
WR. Assessing competence in the use of motivational interviewing. J Subst 
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Nguyen HQ, Donesky D, Reinke LF, Wolpin S, Chyall L, Benditt JO. 
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Obstructive Pulmonary Disease. 2013; 46(1):43–55. 
 
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Noar SM, Benac CN, Harris MS. Does tailoring matter? Meta-analytic 
review of tailored print health behavior change interventions. 2007; 
133(4):673-93. 
 
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Shingleton R, Palfai T. Technology-delivered adaptations of motivational 
interviewing for health-related behaviors: a systematic review of the current 
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Neilsen Norman Group. Thinking Aloud: The #1 Usability Tool. 2012. 
Website: https://www.nngroup.com/articles/thinking-aloud-the-1-usability-
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West R, Michie S. A guide to development and evaluation of digital 
behaviour change interventions in healthcare. London: Silverback 
Publishing. 2016. 
 
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Michie S, van Stralen M, West R. The Behaviour Change Wheel: A new 
method for characterising and designing behaviour change interventions. 
Implementation Science. 2011; 6:42. 
 
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Bangor A, Kortum PT, Miller JT. An empirical evaluation of the System 
Usability Scale. International Journal of Human–Computer Interaction 
2008; 24(6):574-594 
 
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Bowen DJ, Kreuter M, Spring B, et al. How we design feasibility studies. 
Am J Prev Med. 2009; 36(5):452–457. 
 
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Czajkowski S, Powell L, Adler N, Naar-King S, Reynolds KD, Huneter 
CM, et. al. From Idea to Efficacy: the ORBIT Model for developing 
behavioural treatments for chronic diseases. Health Psychology. 2015; 
34(10):971-982 
 
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R19-2271 
Reiss E. The Lean Startup: How Today's Entrepreneurs Use Continuous 
Innovation to Create Radically Successful Businesses. 2011. Penguin 
Books Ltd.  
 
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Yardley L, Morrison L, Bradbury K, et al. The person-based approach to 
intervention development: application todigital health-related behavior 
change interventions. J Med Internet Res 2015; 17(1):e30 
 
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Eysenbach G. The law of attrition. J Med Internet Res. 2005; 7(1):e11. 
 
R19-2769            Boutron I, Altman DG, Moher D, Schulz KF, Ravaud P, DJ C, et al. 
CONSORT Statement for Randomized Trials of Nonpharmacologic 
Treatments: A 2017 Update and a CONSORT Extension for 
Nonpharmacologic Trial Abstracts. Annals of Internal Medicine. American 
College of Physicians; 2017 Jul 4;167(1):40.      
 
09The virtual care climate questionnaire: development and validation of a questionnaire 
measuring perceived support for autonomy in a virtual care setting. J Med 
Internet Res 2017 ; 19(5) ; e155. 
 
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Williams GC, Ryan RM, Deci EL. Health-care, self-determination theory 
questionnaire packet. https://selfdeterminationtheory.org/health-care-self-
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evaluation of evolving behavioral intervention technologies. Am J Prev 
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Mohr DC, Schueller SM, Riley WT, Brown CH, Cuijpers P, Duan N, et al. 
Trials of intervention principles: evaluation methods for evolving 
behavioral intervention technologies. J Med Internet Res 2015 ; 17(7) ; 
e166. 
      
9.2 
UNPUBLISHED REFERENCES 
Not applicable 
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10. 
APPENDICES 
10.1 
DETAILS OF EX-TARA ASSESSMENT TOOLS  
10.1.1 
Baseline, Interim and Follow-up Survey Assessments 
The baseline survey will be provided to participants before they have access to the TARA 
program. See flow chart for a complete list of survey timepoints. 
 
Survey 1 will be administered at the end of the run-in period and will contain the following 
elements: 
x Chronic Respiratory Questionnaire – Self Administered Individualized (CRQ-SAI) 
x Clinical Visit PROactive Physical Activity in COPD Instrument (C-PPAC) 
x A Knowledge assessment for COPD self-management 
x Treatment Self-Regulation Questionnaire (TSRQ) 
x Perceived Competence Scale (PCS) 
x Health Care Climate Questionnaire (HCCQ) 
x Medication adherence questions  
x COPD Assessment Test (CAT) 
x Hospital Anxiety and Depression Scale (HADS) 
x Questions assessing barriers to medication adherence  
 
Interim surveys during the TARA usage period include the following. 
 
Surveys 2, 3 and 4 will be administered at 2, 4 and 8 weeks from start of study respectively 
and will contain the following elements: 
x Chronic Respiratory Questionnaire – Self Administered Individualized (CRQ-SAI) 
x Readiness to change  
x Perceived Competence Scale (PCS) 
 
Survey 5 will be the 12-week survey and will contain the following elements: 
x Chronic Respiratory Questionnaire – Self Administered Individualized (CRQ-SAI) 
x Clinical Visit PROactive Physical Activity in COPD Instrument (C-PPAC) 
x Readiness to change 
x A Knowledge assessment for COPD self-management 
x Treatment Self-Regulation Questionnaire (TSRQ) 
x Perceived Competence Scale (PCS) 
x Virtual Care Climate Questionnaire (VCCQ) 
x Questions measuring medication adherence, PLB and pacing 
x COPD Assessment Test (CAT) 
x Hospital Anxiety and Depression Scale (HADS) 
x Questions assessing barriers to medication adherence  
x Healthcare resource utilization 
Survey 6 will be the final survey administered after the follow-up clinic visit and will contain 
the following elements: 
x System Usability Scale (SUS) https://measuringu.com/sus/  
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x ‘Perceived value and satisfaction of TARA’ Questions  
o These questions will explore participants satisfaction and willingness to 
recommend TARA (from Net Promoter Score (NPS) Survey) 
 
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10.3 
QUALITATIVE INTERVIEW SAFETY PROTOCOL 
In all contacts between interviewers and study participants, the content of the discussion will 
be monitored for Adverse Events as detailed in Section 5.3.6.  
 
During a qualitative interview, the participant may disclose information about unmet needs, 
personal risks, changes they have made (or intend to make) to medication taking behaviours 
or health concerns, and the interviewer has a responsibility to recommend the participant 
consults their personal physician or other relevant agencies.  
 
If the participant discloses the following kind of information during the interview, the 
interviewer has a responsibility to refer the participant to an appropriate healthcare provider 
or agency or support group as follows: 
1. Participant discloses information about possible medical condition, side-effect, 
change to medication taking that is not in line with their physician’s instructions, 
or symptom: interviewer to recommend participant to consult their personal 
physician or emergency service 
2. Participant discloses information about physical or mental harm or abuse, or the 
risk of harm or abuse, to themselves or others: interviewer to recommend 
participant to contact social services or police. 
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11. 
DESCRIPTION OF GLOBAL AMENDMENT(S) 
11.1 
AMENDMENT 1 
Date of amendment 
 
16 Sep 2021 
EudraCT number 
EU number 
 
NA 
BI Trial number 
 
352-2154 
BI Investigational Medicinal 
Product(s) 
 
TARA DBCI prototype (version 3)  
Title of protocol 
 
Proof of concept (proof of intervention 
principles) study assessing effects of Technology-
Assisted Respiratory Adherence prototype 
version 3 (a Digital Behaviour Change 
Intervention, DBCI) on proximal clinical 
outcomes and mediators (psychological 
mediators, self-management behaviours) in 
individuals with COPD (IwCOPD) 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
x 
 
Section to be changed 
 
Title page 
Description of change 
 
Allocation of new CTL 
Rationale for change 
 
Change in CTL 
 
Section to be changed 
 
Sections 2.3, 5.1.3.1, 10.1.1, 10.2.5. 
Description of change 
 
 
Section to be changed 
 
Synopsis, Section 3.3.3 
Description of change 
 
Exclusion criterion 1 – updated from “patients 
with asthma” to “Patients with asthma as 
concurrent baseline condition at the time of 
screening” 
Rationale for change 
 
Clarification to all enrolment of patients with a 
historical diagnosis of asthma 
 
Section to be changed 
 
Synopsis, Section 3.3.3 
Description of change 
 
Exclusion criterion 2 - updated to include a 
timeframe for contacts with an infected person 
prior to the completion of the eligibility 
questionnaire. 
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Clinical Study Protocol Outline 
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Rationale for change 
 
Updated to allow the enrolment of patients who 
have been in contact with persons infected with 
SARS COV-19, but are not infected themselves 
 
Section to be changed 
 
Section 5.3.7 
Description of change 
 
All AEs and SAEs are to be reported to BI GPV 
regardless of causal relationship to Spiriva 
Respimat or Stiolto Respimat 
Rationale for change 
 
Clarification of AE reporting requirements to 
ensure all identified events will be evaluated and 
reported accordingly. 
 
Section to be changed 
 
Synopsis, Sections 3.1, 7.2.7 
Description of change 
 
Removal of interim analysis 
Rationale for change 
 
Based on the observed TARA use by the first 
enrolled patients of cohort 1, an interim analysis 
between cohort 1 and cohort 2 is no longer 
expected to provide meaningful results. 
 
Section to be changed 
 
Section 7.2.1 
Description of change 
 
Clarification that cohorts 1 and 2 will be analysed 
separately and definition of analysis data set 
Rationale for change 
 
Further clarification on planned data analysis 
 
Section to be changed 
 
Section 7.2.5. 
Description of change 
 
Confirmation that all patients will be included in 
the safety analysis and that frequency, severity 
and causal relationship of adverse events will be 
reported. 
Rationale for change 
 
Additional clarification on planned safety 
analysis 
 
Section to be changed 
 
Section 7.3 
Description of change 
 
Confirmation that no impution of missing data 
will occur. 
Rationale for change 
 
Clarification on the handling of missing data 
 
 
 
 
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