Remote MONITORing of Patients With Chronic Obstructive Pulmonary Disease Using a Tablet System. A Randomized Cross Over Pilot Study of Feasibility Evaluation and Quality of Life Measurements
Phase: NA
Conditions: COPD
Sponsor: Vastra Gotaland Region

 
 
CLINICAL INVESTIGATION PLAN 
 
 
 
 
 
Remote MONITORing of patients with chronic 
obstructive pulmonary disease using a tablet system. A 
randomized cross over pilot study of feasibility evaluation 
and quality of life measurements  
 
 
 
Study Code: 
Monitor 
 
 
Version Number: 
1.0 
Date: 
20180319 
 
 
Sponsor 
 
Principal  
investigator: 
Sahlgrenska University Hospital 
 
 
Anders Ullman, MD PhD 
Head of COPD center 
Sahlgrenska University Hospital 
Vita Stråket 12 
413 45 Göteborg 
 
 
 
 
 
 
Revision summary sheet 
 
Regarding  
Revision description 
Revision 
date 
Version 
no. 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
2 (25) 
 
 
SIGNATURE PAGE 
I confirm that I have read and understood this protocol and that I will work according to the 
protocol. By my signature, I agree to personally supervise the conduct of this study in my affiliation 
and to ensure its conduct in compliance with the protocol, informed consent, IRB/EC procedures, 
the Declaration of Helsinki, ISO 14155, and local regulations governing the conduct of clinical 
studies. 
 
I will accept the monitors overseeing of the study. 
I will promptly submit the protocol to applicable ethical committee. 
 
 
 
 
 
Signature Principal Investigator 
 
Date (yyyy-mm-dd)  
 
 
Anders Ullman 
 
 
 
 
 
Signature Sponsor 
 
Date (yyyy-mm-dd)  
 
 
Anders Ullman 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
3 (25) 
 
Sponsor: 
Sahlgrenska University Hospital 
 
Investigational site: 
COPD center 
Sahlgrenska University Hospital 
Vita Stråket 12 
413 45 Göteborg 
 
Principal investigator 
Anders Ullman, MD, PhD 
Head of COPD center 
Sahlgrenska University Hospital 
Vita Stråket 12 
413 45 Göteborg 
 
Coordinating investigator(s) 
 
Claes-Göran Löfdahl, MD, PhD 
COPD center 
Sahlgrenska University Hospital 
Vita Stråket 12 
413 45 Göteborg 
 
Malte Frerichs, authorized nurse 
COPD center 
Sahlgrenska University Hospital 
Vita Stråket 12 
413 45 Göteborg 
 
Monitor 
Gothia Forum 
Gröna stråket 12 
413 45 Göteborg 
+46 31 342 96 70 
Gothia.forum@vgregion.se 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
4 (25) 
 
 
Synopsis 
 
Title of Protocol 
Remote MONITORing of patients with chronic obstructive pulmonary 
disease using a tablet system. A randomized cross over pilot study of 
feasibility evaluation and quality of life measurements 
Study purpose 
This clinical investigation will evaluate the patient-equipment interface and 
patient preference in the use of modern possibilities for remote monitoring 
of patients with COPD in a personalized care approach. 
Study Design 
Summary 
This clinical trial is an open, randomized, controlled cross-over study.  
Eligible subjects to include will be given the possibility to participate in the 
study. They will at their first visit be randomized to start either 
telemonitoring, using the tablet system arm or to normal standard of care 
period for 26 weeks. After 26 weeks the subject will have a second visit 
and after that, four weeks (wash out) of standard of care or telemonitoring 
treatment. After that there will be a third visit and the subject will start the 
second treatment period with the alternative management. At the end of 
this period (56 weeks) there will be a fourth (last) visit at the center for the 
subject. 
Study duration 
56 weeks 
Study site 
1 investigative site 
Subject population 
The target population are patient diagnosed with COPD according to 
international guidelines.  
 
Inclusion criteria 
For inclusion in the study, subjects must fulfil the following criteria: 
• 
Willingness to participate and provision of informed consent 
• 
Diagnosis of COPD 
• 
FEV1/FVC (post bronchodilator) <0.7 
• 
GOLD severity grade D 
• 
FEV, < 80% predicted 
• 
Cognitive ability relevant for the studies as judged by the 
investigator 
• 
Living in their own home and able to manage their activities of daily 
living 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
5 (25) 
 
Exclusion criteria 
 
Rapidly progressing severe disease other than COPD and COPD-
related diseases, influencing the Health-Related Quality of Life 
(HRQOL) during the study time as judged by the investigator 
 
Long-term stay ( >2 weeks) away from home during the study 
period, where there are no possibility to get internet connection 
 
COPD exacerbation during 1 month before start of study 
 
Primary 
Investigation 
Objectives 
The primary objective is to evaluate the impact and feasibility of tele 
monitoring and video contact in personalized care of moderate and severe 
COPD patients.  This should be compared to normal standards of care. 
The cross-over design evaluates the influence on general HRQOL of this 
tablet and monitoring system.  
 
Secondary 
Investigation 
Objectives 
The secondary objective(s) is to observationally evaluate various 
measurements used in this tablet system to give knowledge and 
background for an extensive, future cohort study of patients with moderate 
and severe COPD managed in this investigation center. The following 
measurements will then be used: 
 
1. CAT (COPD assessment test): well established symptom related 
questionnaire for COPD to evaluate change in COPD-related Health 
status. 
2. EQ5D: Generalised health related quality of life, to compare with SF-12 
and to use in preliminary cost-utility analysis and to evaluate in comparison 
to other measurements of HRQoL 
3. HADS Anxiety, depression: Established measurement of depression 
and anxiety, to evaluate any change in the patient’s mental status. 
4. mMRC: Established earlier dyspnea measurement scale for COPD, to 
compare this measurement with other newly developed measurements of 
symptoms in patients with COPD. 
5. Observational cost-utility evaluation 
6. Incidence of device related and procedure related serious adverse 
events will be performed 
Primary Outcome 
Measure 
Change of SF-12 over each treatment period 
 
Secondary 
Outcome Measure 
Cost-utility evaluation- the difference in costs between the two treatments 
divided by the difference in quality adjusted life years (QALYs) 
 
For other secondary measures: Descriptive statistics will be used.  
 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
6 (25) 
 
 
 
 
 
Table of Contents 
1. 
Introduction ........................................................................................................................ 9 
2. 
Identification and description of the investigational device ............................................... 10 
2.1. 
Summary description of the investigational device and its intended purpose ................... 10 
2.2. 
The manufacturer of the investigational device ................................................................ 10 
2.3. 
Device specifications ....................................................................................................... 10 
2.4. 
Traceability ...................................................................................................................... 10 
2.5. 
Necessary training in device use ..................................................................................... 11 
3. 
Justification for the design of the clinical investigation ..................................................... 11 
4. 
Risks and benefits of the investigational device and clinical investigation ........................ 11 
4.1. 
Anticipated clinical benefits .............................................................................................. 11 
4.2. 
Anticipated Adverse Device Effects (ADE) ....................................................................... 11 
4.3. 
Risks associated with participation in the clinical investigation ......................................... 11 
4.4. 
Risk/benefit assessment .................................................................................................. 12 
5. 
Objectives and hypotheses of the clinical investigation .................................................... 12 
6. 
Design of the clinical investigation ................................................................................... 12 
6.1. 
General ............................................................................................................................ 12 
6.2. 
Investigational device(s) and comparator(s)..................................................................... 14 
6.2.1. 
Auxiliary devices .............................................................................................................. 14 
6.3. 
Subjects ........................................................................................................................... 14 
6.3.1. 
Inclusion criteria ............................................................................................................... 14 
6.3.2. 
Exclusion criteria ............................................................................................................. 14 
6.3.3. 
Restrictions ...................................................................................................................... 15 
6.3.4. 
Subject withdrawal or discontinuation .............................................................................. 15 
6.3.5. 
Subject enrolment and randomization .............................................................................. 15 
6.4. 
Procedures ...................................................................................................................... 15 
6.4.1. 
Concomitant medication .................................................................................................. 18 
6.5. 
Monitoring plan ................................................................................................................ 18 
7. 
Statistical considerations ................................................................................................. 19 
8. 
Data management ........................................................................................................... 19 
9. 
Amendments to the CIP ................................................................................................... 20 
10. 
Deviations from clinical investigation plan ........................................................................ 20 
11. 
Device accountability ....................................................................................................... 21 
12. 
Statements of compliance ................................................................................................ 21 
13. 
Informed consent process ................................................................................................ 22 
14. 
Adverse events, adverse device effects and device deficiencies ..................................... 22 
14.1. 
Recording of AE and DD.................................................................................................. 24 
14.2. 
Adverse events and incidents with medical devices ......................................................... 24 
15. 
Suspension or premature termination of the clinical investigation .................................... 24 
16. 
Publication policy ............................................................................................................. 24 
17. 
Bibliography ..................................................................................................................... 25 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
7 (25) 
 
 
 
LIST OF APPENDICES 
NA 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
8 (25) 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
CAT 
COPD Assessment Test 
COPD 
Chronic Obstructive Pulmonary Disease 
EQ-5D 
EuroQol 5-dimensions 
HADS 
Hospital Anxiety and Depression Scale 
HRQOL 
Health-Related Quality of Life 
FEV 
Forced Expiratory Volume 
FVC 
Forced Vital Capacity 
GOLD 
Global Initiative for Chronic Obstructive Disease 
MRC 
Medical Research Council Dyspnea 
PRO 
Patient Reported Outcome 
SF 
Site File 
SF-12 
Short Form-12 
SpO2 
Peripheral capillary oxygen saturation 
TMF 
Trial Master File 
QALYs 
Quality adjusted life years 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
9 (25) 
 
 
 
1. 
INTRODUCTION 
Chronic Obstructive Pulmonary Disease (COPD) is a group of progressive lung diseases including 
emphysema, chronic bronchitis, refractory (non-reversible) asthma, and some forms of 
bronchiectasis. The disease is characterized by increasing breathlessness. COPD is one of the 
most important chronic diseases with regard to disability and mortality. In the western world it is the 
third most common cause of mortality (1). In Sweden it is estimated about 700 000 patients suffer 
from COPD of various degrees. Current treatment recommendations focus on smoking cessation, 
improvement of physical activity, physiotherapy, preventive measures to decrease the risk for 
exacerbations, mainly due to infections. Symptomatic pharmacological treatment to decrease 
symptoms and also decrease the risk for exacerbations is recommended (2, 3). In addition it is well 
established that a majority of COPD patients also suffer from other chronic diseases, as e g 
cardiovascular diseases, osteoporosis and metabolic diseases.  
A careful and close contact with the health care system, often with a specialized nurse in the open 
care department, has been shown to be beneficiary in several studies showing subsequent 
decreasing exacerbation rates (4). To further improve the contact with open care departments and 
the patients various approaches using telemedicine and remote monitoring have been evaluated 
(5). In a Cochrane review from 2012 it was concluded that “tele healthcare interventions can 
significantly reduce the risk of emergency department attendance and hospitalization, but has little 
effect on the risk of death”(6). Later studies and reviews have given varying results, with a positive 
effect also on Health-Related Quality of Life (HRQOL) measurements in one systematic review (7), 
but with a questionable effect in another review (8). The most recent single studies show different 
results. One big Danish study, however not well randomized and with a high withdrawal rate, could 
not find any effect on HRQOL (9), whereas a recent randomized study of patients with COPD and 
concomitant cardiac failure showed improvement of walking distance, decreasing hospitalization 
and death rate (10). Also specific HRQOL measurements, physical activity profile and evaluation of 
dyspnea was better in the telemedicine group. 
 
A probable reason for the varying results is due to variations in design, varying choices of 
outcomes and variations in patient adherence to the equipment (11, 12). E g the above mentioned 
Danish study made an intention to treat evaluation without any relation to patient preference for the 
handling and they also had a withdrawal rate of about 50% (9). 
 
Thus, there is still a need to evaluate the patient-equipment interface and patient preference in the 
use of modern possibilities for remote monitoring of patients with COPD in a personalized care 
approach. 
 
 
 
 
 
 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
10 (25) 
 
2. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE 
 
2.1. 
Summary description of the investigational device and its intended purpose 
 
The device for this trial is the application cVitals provided by FocusCura. The device has obtained 
CE marking to monitor patients with chronic conditions. Health care professionals and patients 
monitor the course of their disease by tracking vital signs and outcomes of questionnaires for 
transferring and evaluation of data from external devices or patient reported outcomes (PRO) in 
questionnaire forms used for healthcare monitoring. The study device will be used according to this 
CE marking intentions.   
 
FocusCura is certified for information security under ISO 27001 and quality management under 
ISO 9001. The servers that FocusCura uses to store personal information are located in EU data 
centers, they have ISO 27001 certification. Transmitting of data always use HTTPS (SSL) 
connections. 
 
The subjects monitor the measurements at home and healthcare professionals are given the 
permission by the patient to be able to see all the values. Within the application there are 2 
questionnaires integrated where the subject describes symptoms, COPD Assessment Test (CAT) 
and Medical Research Council Dyspnea Scale “MRC”. Furthermore measurements of objective 
health related parameters will be monitored according to specification 6.2.1.  
 
2.2. 
The manufacturer of the investigational device 
 
The device is manufactured by: 
 
FocusCura 
Odijkerweg 1 
3972 NE Driebergen-Rijsenburg 
The Netherland 
 
2.3. 
Device specifications 
 
The device used for this trial is the application cVitals with medical CE marking CE-TMA-20140401 
class 1.  
 
2.4. 
Traceability 
 
Version number of the Investigational Medical Devices (cVitals application) will be documented for 
each patient in the eCRF.  
 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
11 (25) 
 
2.5. 
Necessary training in device use 
 
Prior to study initiation, Investigator and staff will receive demonstration and training in device 
operating procedures and study protocol. Training will be documented in Site File (SF) and Trial 
Master File (TMF).  
Study participants will receive appropriate training to enable them to use the study device 
accurately according to the study protocol. The training will be recorded in the eCRF.  
 
3. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
 
There is a need to improve the open care of patients with COPD, to improve quality of life, in this 
great contingent of the total current health care need in the society. A possible way to improve this 
would be to establish a home monitoring of important measurements of these COPD patients with 
the aim to improve symptom control, prevent and detect as well as treat exacerbations at an early 
stage. This study will evaluate that possibility by using a tablet system, and in a personalized care 
manner take possible advantages of this system. The current knowledge in this area is ambiguous 
and further studies are needed, to evaluate the equipment as well as the patient handling of it. 
 
4. 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND 
CLINICAL INVESTIGATION 
4.1. 
Anticipated clinical benefits 
 
Compared to usual care the subjects will get an increased level of control of their disease under 
the phase of extended monitoring. For the patient the use of the tablet system will incur a better 
overview of the health status, and possibly an earlier detection of any deterioration. The earlier 
contact with the health care center, will also give better and more detailed information to the center 
staff. 
4.2. 
Anticipated Adverse Device Effects (ADE) 
The tablet system and external measurement devices do not per se incur any risk for the patients.  
4.3. 
Risks associated with participation in the clinical investigation 
 
A special concern is the questions of patient integrity when using an internet-based handling of 
data. These concerns are carefully handled with personal login to the equipment, and data 
handling in a secure database. In case of technical problems with the equipment, the patients will 
always have the possibility to contact the study center. 
 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
12 (25) 
 
4.4. 
Risk/benefit assessment 
 
According to the above described risks versus benefits we judge the risk for the patient to be 
minimal and the potential benefit for the individual patient as well as for future healthcare 
organization to be of greater importance.  
 
5. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL 
INVESTIGATION 
The primary objective is to evaluate the impact and feasibility of tele monitoring and video contact 
in personalized care of moderate and severe COPD patients.  This should be compared to normal 
standards of care. The cross-over design evaluates the influence on general HRQOL of this tablet 
and monitoring system.  
The hypothesis is that telemonitoring gives a better general HRQOL in moderate and severe 
COPD patients during the use of this telemonitoring system. 
 
 
The secondary objective(s) is to observationally evaluate various measurements used in this tablet 
system to give knowledge and background for an extensive, future cohort study of patients with 
moderate and severe COPD managed in this investigation center. The following measurements 
will then be used: 
 
1. CAT (COPD assessment test): well established symptom related questionnaire for COPD to 
evaluate change in COPD-related Health status. 
2. EQ-5D: Generalised health related quality of life, to compare with SF-12 and to use in 
preliminary cost-utility analysis and to evaluate in comparison to other measurements of HRQoL 
3. HADS (Hospital Anxiety and Depression Scale): Established measurement of depression and 
anxiety, to evaluate any change in the patient’s mental status. 
4. mMRC: Established earlier dyspnea measurement scale for COPD, to compare this 
measurement with other newly developed measurements of symptoms in patients with COPD. 
5. Observational cost-utility evaluation 
6. Incidence of device related and procedure related serious adverse events will be performed 
 
6. 
DESIGN OF THE CLINICAL INVESTIGATION 
 
6.1. 
General 
 
This clinical trial is an open, randomized, controlled cross-over study.  
This study will evaluate the possibility to use a tablet system with measurements of disease related 
parameters in patients with COPD, and to compare any influence of this system on general health 
related quality of life as to ordinary care without this system. 
 
The feasibility character of the study have been the reason why a cross-over design in relatively 
few patients has been chosen. It also gives a possibility to get information directly from the patients 
on positive and negative issues with the tablet system. For the length of the study, the rational 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
13 (25) 
 
have been to give patients the possibility to well adapt to the use of the assigned management. 
Furthermore this study will give possibilities for future more extensive studies of healthcare 
systems used in COPD health care to be evaluated. The inborn error of a cross over design will be 
dealt with a wash out of 4 weeks between treatments and also initial measurement of the primary 
outcome at start of both treatment periods.  
 
Eligible subjects to include will be given the possibility to participate in the study. They will at their 
first visit be randomized to start either telemonitoring, using the tablet system arm, or to normal 
standard of care period for 26 weeks. After 26 weeks the subject will have a second visit and after 
that, four weeks (wash out) of standard of care. After that there will be a third visit (week 30) and 
the subject will start the second treatment period with the alternative management. At the end of 
this period (56 weeks) there will be a fourth (last) visit at the center for the subject. 
 
 
 
 
The study will in total include 4 on clinic visits during the total study period of 56 weeks.  
 
Visit 1 Following informed consent process, screening evaluation will determine subject eligibility 
for the study. Visit includes inclusion/exclusion criteria, medical- and COPD history, demography, 
questionnaires, vital functions, training in the technical equipment,  
Visit 2 (Week 26 ± 2 weeks). Questionnaires, vital functions, Patient Reported Outcome, Adverse 
Events (AE) 
Visit 3 (Week 30 ± 2 weeks). Questionnaires, vital functions, Patient Reported Outcome, AE 
Visit 4 (Week 56 ± 2 weeks). Questionnaires, vital functions, Patient Reported Outcome, AE 
 
During the telemonitoring treatment period the subjects will register; vital functions (blood pressure, 
heart rate, weight, SpO2) twice a week, physical movement daily by using a fitness device, have 
videocalls with a nurse weekly the first 4 weeks and thereafter every fourth week the last 5 months. 
Twice a week (± 2 days) questionnaires (CAT and MRC) should be filled out at home.  
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
14 (25) 
 
6.2. 
Investigational device(s) and comparator(s) 
  
During the telemonitoring period of 26 weeks the subjects will utilize the cVitals application daily by 
log in and follow the instructions given.  
6.2.1. 
Auxiliary devices 
 
The following devices will be part of the equipment that every subject gets during the treatment 
arm with telemonitoring: 
 
 
cContact – an application to obtain a secure video connection between subject an health 
care professionals. cContacts is provided by FocusCura.  
 
 
The following study related equipment will be provided by ATEA, a Swedish company, 
leasing the devices to the centre: 
o IOS based iPad from apple for using the applications cVitals and cContact. 
o Electronic Sphygmomanometers “Track” from iHealth labs Europe: Medical class 2a 
CE0197, to measure blood pressure and pulse frequency. Will be used in 
accordance with intended use.  
o Pulse Oximeter “Air” from iHealth labs Europe: Medical class 2a CE0197, to measure 
oxygen saturation of the blood. Will be used in accordance with intended use. 
o Scale “lite” from iHealth labs Europe to weigh the subject.  
o Fitness device “Wave” from iHealth labs Europe to measure physical movement 
every day when the subject is awake.  
 
6.3. 
Subjects 
6.3.1. 
Inclusion criteria 
For inclusion in the study, subjects must fulfil the following criteria: 
• 
Willingness to participate and provision of informed consent 
• 
Diagnosis of COPD 
• 
FEV1/FVC (post bronchodilator) <0.7 
• 
GOLD severity grade D 
• 
FEV, < 80% predicted 
• 
Cognitive ability relevant for the studies as judged by the investigator 
• 
Living in their own home and able to manage their activities of daily living 
 
6.3.2. 
Exclusion criteria 
For exclusion in the study, subject must not fulfil the following criteria: 
 
Rapidly progressing severe disease other than COPD and COPD-related diseases, 
influencing the HRQOL during the study time as judged by the investigator 
 
Long-term stay ( >2 weeks) away from home during the study period, where there are no 
possibility to get internet connection 
 
COPD exacerbation during 1 month before start of study 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
15 (25) 
 
6.3.3. 
Restrictions 
Journeys for longer than 2 weeks should not be performed during the study period, where there 
are no possibility to get internet connection. 
6.3.4. 
Subject withdrawal or discontinuation  
Subjects are free to discontinue their participation in the study at any time without prejudice to 
further treatment. The subjects may be withdrawn from the study at the discretion of the 
investigator due to safety concerns or if judged non-compliant with study procedures. Other 
reasons for discontinuing a subject are incorrect enrolment and subjects lost to follow-up.  
6.3.5. 
Subject enrolment and randomization 
The study will include 70 subjects starting the study, and for each participant the total study 
participation of the study including 4 weeks wash out will be approximately 56 weeks. It is 
estimated that the total study duration, from start of the enrollment period until last subjects last 
visit will be approximately 24 months. Subject eligibility will be established before randomization. 
Subjects will be randomized strictly sequentially, as subjects are eligible for randomization. If a 
subject discontinues from the study, the subject number will not be reused, and the subject will not 
be allowed to re-enter the study. As stated in the statistical considerations below, there will be no 
need to replace withdrawn patients as the planned number of patients gives room for a drop-out 
rate of 17 %. The estimated drop-out rate is 10 %. 
 
Identified potential study subjects, listed at the COPD center at Sahlgrenska University Hospital, 
will be given thorough information regarding the study, both orally and in writing, by qualified staff 
at the COPD center. After the subject has been given the opportunity to ask any question 
regarding the study they will be asked to consent to study participation. If they do, they will sign the 
informed consent form.  
At randomization, all eligible subjects will be given a randomization number that assigns them to 
one of the treatment groups. The randomization numbers are sequentially allocated to the subjects 
in the order of randomization.  
The eCRF software creates the randomization numbers at randomization visit. 
A randomization list will be produced with random assignment of treatment groups in the specified 
ratio of 1:1.  
 
The sponsor may decide to stop the trial or part of the trial at any time. If a trial is prematurely 
terminated or suspended, the investigator should promptly inform the subjects and ensure 
appropriate therapy and follow-up. Furthermore, the investigator should promptly inform the Ethics 
Committee and provide a detailed written explanation. The regulatory authority should be informed 
according to national regulations. 
 
6.4. 
Procedures 
 
Subjects fully evaluated at the COPD-center at Sahlgrenska university hospital and who according 
to the investigator are eligible to the study with regard to inclusion and exclusion criteria, including 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
16 (25) 
 
their willingness to take part in the cross over designed study with comparison of a tablet based 
system and ordinary care, will be randomized to start with either normal care or telemonitored care. 
 
Each visit is described in detail in this section.  
 
Study activities performed at on clinic visits is specified in Table 1. 
 
Table 1 
 
Study activities 
 
 
 
 
 
 
 
 
 
Visit Number 
1 
2 
3 
4 
Study Week: 
 Day 0 
Week 26 
Week 30 
Week 56 
Visit window (weeks) 
 
±2 
±2 
±2 
Informed consent 
X 
 
 
 
Randomization 
X 
 
 
 
Demography 
X 
 
 
 
Medical history 
X 
 
 
 
COPD history 
X 
 
 
 
Patient Reported Outcome 
(CAT, MRC, HADS, EQ-5D, 
SF-12 ) 
X 
X 
X 
X 
Vital functions (blood 
pressure, heart rate, weight, 
height1, SpO2 ) 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
 
 
 
Instructing in the technical 
equipment 
(X)2 
 
 (X)2 
 
Adverse Events 
 
X 
X 
X 
1 Height is only measured on the visit 1 
2 At Visit 1 or 3 depending on when starting the telemonitoring treatment period. 
 
 
On clinic - Visit description 
Visit 1 Screening/Randomization visit (Day 0) 
Following informed consent, screening evaluation will determine subject eligibility for the study. No 
study-specific procedures may be performed prior to informed consent signature. Visit 1 is 
anticipated to last approximately 2,5 hours.  
 
The Screening/Randomization visit includes performing/collecting the following information: 
- Demographic – including age and gender. 
- Patient Reported Outcome – CAT, MRC, HADS, SF-12, EQ-5D 
- Training in technical equipment – subjects will be informed and given instructions how to use 
technical equipment (when assigned to telemonitoring arm) 
- COPD History – including grade/severity of COPD, date of diagnosis or length of COPD 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
17 (25) 
 
- Current and Past Medical History – including concomitant medications. 
- Vital functions – including blood pressure, heart rate, weight, height, SpO2 
 
The subject will then be randomized to either normal care or telemonitoring treatment period to 
start with for the first 26 weeks. 
 
Visit 2 (Week 26 ± 2 weeks), approximately 2 hours 
Patient Reported Outcome – CAT, MRC, HADS, SF-12, EQ-5D 
Vital functions – including blood pressure, heart rate, weight, SpO2 
Adverse Events 
 
Wash out period of 4 weeks. Will apply for both normal care and telemonitoring treatment 
assignments.  
 
Visit 3 (Week 30 ±2 weeks), approximately 2 hours 
Patient Reported Outcome – CAT, MRC, HADS, SF-12, EQ-5D 
Vital functions – including blood pressure, heart rate, weight, SpO2 
- Training in technical equipment – subjects will be informed and given instructions how to use 
technical equipment (when assigned to telemonitoring arm) 
Adverse Events 
 
Normal care or telemonitoring for 26 weeks depending on which arm the subject has been 
randomized to first. 
 
Visit 4 (Week 56 ±2 weeks), approximately 2 hours 
Patient Reported Outcome – CAT, MRC, HADS, SF-12, EQ-5D 
Vital functions – including blood pressure, heart rate, weight, SpO2 
Adverse Event 
 
Telemonitoring - visit description 
Study activities performed in the telemonitoring treatment period is specified in Table 2. 
 
 
Table 2 
Study activities during telemonitoring at home 
 Study month with telemonitoring 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
Visit Window (days) 
±2 
±2 
±2 
±2 
±2 
±2 
Questionnaires (CAT, MRC) 
twice a 
week 
twice a 
week 
twice a 
week 
twice a 
week 
twice a 
week 
twice a 
week 
Vital functions (blood pressure, 
heart rate, weight, SpO2) 
twice a 
week 
twice a 
week 
twice a 
week 
twice a 
week 
twice a 
week 
twice a 
week 
Vital functions (activity 
measurement) 
daily 
daily 
daily 
daily 
daily 
daily 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
18 (25) 
 
Video Call with nurse 
(conversation about health 
condition and vital parameters) 
Weekly 
4 weeks 
monthly 
monthly 
monthly 
monthly 
NA1  
1 On clinic Visit week 26 or 56 depending on treatment randomization 
 
For subjects starting the use of the tablet system they will get a thorough introduction in the use of 
the equipment. 
 
On a daily basis the subject will perform vital functions using the cVitals application and follow the 
instructions given.  
Measure physical movement by wearing the Fitness device “Wave” during the whole day when 
subject is awake. Data will automatically be transferred and no further action is needed by the 
subject. 
 
Twice a week subject will perform additional vital functions: 
Blood pressure and heart rate will be measured using the Electronic Sphygmomanometers “Track”. 
Weight will be taken using the Scale “lite” 
Oxygen saturation will be measured using Pulse Oximeter “Air” 
And 
Complete two PRO´s (integrated in the application): 
CAT 
MRC 
All this is estimated to take approximately 20-30 min each time.  
 
For the first 4 weeks there will be weekly videocalls with a COPD-center nurse discussing health 
condition and vital parameters. 
Thereafter there will be monthly videocalls with a COPD-center nurse for the remaining 5 months, 
i.e. 4 further calls. The videocalls will take approximately 15 min.  
 
Normal care 
During normal care the subjects will get the possibility to call the COPD-center via telephone on 
their own initiative e g with worsening symptoms as usual. 
6.4.1. 
Concomitant medication 
 
Medications that are considered necessary for the subject´s safety and well-being may be given at 
the discretion of the investigators unless not specified in the exclusion criteria. Concomitant 
medication will be recorded in the Case Report Form. 
 
6.5. 
Monitoring plan 
A study monitor will be appointed by the sponsor. The monitor will be appropriately trained and 
informed about the nature of the study, subject written information, GCP and applicable regulatory 
requirements. The monitor’s qualifications will be documented. 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
19 (25) 
 
The monitor will have regular contacts with the clinic to verify informed consents of participating 
subjects, to confirm that facilities remain acceptable, that the investigational team is adhering to the 
protocol, that data are being accurately recorded in the CRFs, to verify inclusion/exclusion criteria, 
study main endpoints, check safety reporting and that therapy accountability is being carried out. 
The investigator should ensure that all persons assisting with the trial are adequately informed and 
trained about the protocol, the investigational products(s) and their trial related duties and factions. 
The monitor will check that training has been performed and that this is documented. The monitor 
will also ensure source data verification (comparison of the data in the CRF with the medical 
records and other source data). The monitor must have direct access to source data. The extent of 
monitoring will be defined in a monitoring plan.  
7. 
STATISTICAL CONSIDERATIONS 
The study has a cross-over design with each a 6 month treatment period. There is a 4 weeks wash 
out between treatments. The number of included subjects is calculated to be 70. The change of 
SF-12 over each treatment period, from start to end, will be statistically evaluated. The comparison 
will primarily be done with Wilcoxson signed rank test. 
 
The power calculation with alpha 0.05 gives a power of 0.8 to detect a difference of 4,5 units on 
the physical SF-12 scale if 58 subjects are evaluable (based on a SD of 12 units). We calculate the 
maximal drop out is around 10%. Thus, starting from 70 patients there is no need to replace 
patients who withdraw, from the study. The design allows a drop-out of 17 %. There will be no 
interim analysis. The analysis of data will be done on all subjects that have followed the protocol. 
Subjects who withdraw from the protocol will be followed for the full study period for any 
unexpected adverse event. 
 
The exploratory cost-utility analysis will be a within trial analysis and it will aim at estimating the 
incremental cost-effectiveness ratio (ICER), i.e. the difference in costs between the two treatments 
divided by the difference in quality adjusted life years (QALYs). The costs will include COPD 
medication and visits, phone contacts and hospitalization related to COPD as well as loss of 
productivity (sick-leave) caused by COPD. The number of QALYs will be based on EQ5D.  
 
For other secondary measurements, descriptive statistics will be used.  
 
8. 
DATA MANAGEMENT 
 
The investigator will ensure that all data collected in the study are recorded in a timely manner 
according to any instructions provided.  
 
An electronic Case Report Form (CRF) will be used for data collection. The investigator will ensure 
that the data are recorded and that any corrections in the CRF as specified in the study protocol 
and in accordance with the instructions provided. The investigator ensures the accuracy, 
completeness and timeliness of the data recorded. The investigator will sign the completed CRF. A 
copy of the completed CRF will be archived at the study site.  
 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. All source data including informed consent, a copy of the completed 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
20 (25) 
 
CRF, original protocol with amendments and the final report will be stored for a minimum period of 
ten years after termination of the trial, in accordance with Swedish regulation/law. 
 
Staff designated by Gothia Forum and working on behalf of the Sponsor will review the data 
entered into the CRFs by investigational staff for completeness and accuracy and instruct the site 
personnel to make any required corrections or additions. Queries are issued electronically. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. 
 
At the conclusion of the study, the occurrence of any protocol deviations will be determined. After 
these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked and available for data analysis. 
 
The investigator must maintain source documents for each subject in the study. A source data 
verification log will be included in the Investigator Study File (ISF). 
 
 
9. 
AMENDMENTS TO THE CIP 
 
Modifications to the signed protocol are only possible through approved protocol amendments and 
with the agreement of all responsible persons. Details of non-substantial amendments are to be 
clearly noted in the amended protocol. 
A change that concerns; a new trial site, new principal investigator and or a new informed consent 
form should only be submitted to the concerned Ethics Committee. 
In case of a substantial protocol amendment (e.g. change of; main purpose of the trial, 
primary/secondary variable, measurement of primary variable, investigational product, or dosing), 
the concerned Ethics Committee and Competent Authority must be informed and should be asked 
for its opinion/approval prior implementation of amended protocol, as to whether a full re-evaluation 
of the ethical aspects of the study is necessary by the committee. This should be fully documented. 
 
The Investigator must not implement any deviation from, or change to the protocol, without 
discussion with, and agreement by the Sponsor and prior review and documented 
approval/favorable opinion of the amendment from the relevant ethics committee and competent 
authority, except where it is necessary to eliminate an immediate hazard to study subjects, or 
where the change(s) involves only logistical or administrative aspects of the study (e.g. change in 
monitor(s), change of telephone numbers). 
 
 
10. 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
 
Periodic monitoring of protocol compliance will be performed. The sponsor has the right 
to suspend enrollment at site deemed to have excessive protocol compliance issues. The 
investigator agrees to conduct the investigation in accordance with this protocol. An investigator 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
21 (25) 
 
must not deviate from the protocol without first receiving approval in writing from the IRB/EC. 
Under emergency circumstances, deviations from the CIP to protect the rights, safety and 
wellbeing of the subjects may proceed without prior approval of the sponsor and the EC. Such 
deviations shall be documented and explained on CRFs and reported to the sponsor and the EC 
as soon as possible. Investigators will also adhere to procedures for reporting investigation 
deviations to the IRB/EC in accordance with the specific IRB/EC reporting policies and procedures. 
 
11. 
DEVICE ACCOUNTABILITY 
 
The monitoring equipment will be stored at the COPD center and will be distributed to the subjects 
when they start the telemonitoring period of the study. At the end of this period the device will be 
returned to the center and the tablet system will be cleared from all subject data.  
 
The version number of the applications used will be documented in the eCRF for each subject.   
 
12. 
STATEMENTS OF COMPLIANCE 
Audits and inspections 
Authorized representatives of the sponsor, a Competent Authority or an Ethics Committee may 
perform audits or inspection at the center, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed and accurately reported according to the protocol, ISO 14155 and any applicable 
regulatory requirements.  
 
Ethics 
The study will be performed in compliance with the protocol, with ethical principles that have their 
origin in the Declaration of Helsinki and are consistent with ISO 14155 and applicable regulatory 
requirements.  
 
Ethics Committee 
The final study protocol, including the final version of the Informed Consent Form and other 
information given to subjects e.g. advertisements, must be approved or given a favorable opinion 
in writing by an Ethics Committee (EC) as appropriate. The Principal Investigator is responsible for 
informing the EC of any amendment to the protocol, in accordance with local requirements. 
Progress reports and notifications of any serious and unexpected adverse drug reactions will be 
provided to the EC according to local regulations and guidelines.  
 
Insurances 
The study subjects are covered by the Patient Insurance according to the Swedish Patient Injury 
Act. 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
22 (25) 
 
13. 
INFORMED CONSENT PROCESS 
 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose and possible risks and benefits of the study. Subjects must 
also be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The monitor(s), the auditor(s), and the CA(s) will be granted 
direct access to the subject’s original medical records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations and that, by signing a written informed consent form, the subject’ 
or the subject’s legally acceptable representative is authorizing such access. 
 
The original, signed Informed Consent Form (ICF) must be stored in the Investigator’s Study File. 
A copy of the signed ICF must be given to the subject.  
 
If a protocol amendment requires a change to the ICF, the EC must approve modifications that 
lead to a revised ICF before the revised form is used.  
 
Subject data protection 
The Informed Consent Form will incorporate wording that complies with relevant data protection 
and privacy legislation. Pursuant to this wording, subjects will authorize the collection, use and 
disclosure of their study data by the investigator and by those persons who need that information 
for the purposes of the study. 
The Informed Consent Form will explain that study data will be stored in a computer database, 
maintaining confidentiality in accordance with national data legislation. All data computer 
processed by the sponsor will be identified by Subject ID. 
The Informed Consent Form will also explain that for data verification purposes, authorized 
representatives of the sponsor, a regulatory authority or an Ethics Committee may require direct 
access to parts of the hospital or practice records relevant to the study, including subjects’ medical 
history.   
 
14. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES 
 
Adverse Event (AE)  
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in subjects, users or other persons whether or not 
related to the investigational medical device.  
NOTE 1: This definition includes events related to the investigational device or the comparator.  
NOTE 2: This definition includes events related to the procedures involved.  
NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices.  

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
23 (25) 
 
 
 
Serious Adverse Event (SAE)  
Adverse event that:  
a) led to a death, injury or permanent impairment to a body structure or a body function.  
b) led to a serious deterioration in health of the subject, that either resulted in:  
- a life-threatening illness or injury, or  
- a permanent impairment of a body structure or a body function, or  
- in-patient hospitalization or prolongation of existing hospitalization, or  
- in medical or surgical intervention to prevent life threatening illness  
 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.  
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered a serious 
adverse event. 
 
Device deficiency 
 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in 
the information supplied by the manufacturer.  
 
Adverse Device Effect (ADE)  
Adverse event related to the use of an investigational medical device.  
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device.  
NOTE 2- This includes any event that is a result of a use error or intentional abnormal use of 
the investigational medical device.  
 
Serious Adverse Device Effect (SADE)  
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event.  
 
Unanticipated Serious Adverse Device Effect (USADE)  
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report.  
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or 
outcome has been previously identified in the risk analysis report 
 

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
24 (25) 
 
14.1. 
Recording of AE and DD 
All AE’s and DD´s occurring during the study observed by the investigator or reported by the 
participant, whether or not attributed to the device under investigation will be recorded on the CRF 
as specified in the protocol.  All ADE’s will be recorded in the CRF.  
The following information will be recorded: description, date of onset and end date, severity, 
assessment of relatedness to device, other suspect drug or device and action taken.  Follow-up 
information should be provided as necessary.  
The relationship of AEs to the device will be assessed by a medically qualified investigator or the 
sponsor/manufacturer and will be followed up until resolution or the event is considered stable.  
All ADE that result in a participant’s withdrawal from the study or are present at the end of the 
study, should be followed up until a satisfactory resolution occurs. 
14.2. 
Adverse events and incidents with medical devices 
 
All adverse events and incidents with medical devices in the study will follow national regulations 
and routines available for regular hospital reporting of medical devices.   
15. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL 
INVESTIGATION 
 
Sponsor may choose to suspend or prematurely terminate the investigation for the following 
reasons: 
 
Device deficiency or malfunction 
 
Subject safety issue 
 
Production limitation 
 
Administrative decision 
In the case of a recurring system malfunction or subject safety issue observed across multiple 
subjects, the overall study may be suspended while the problem is diagnosed. The study may 
resume if the underlying problem can be corrected by a protocol or system modification that will not 
invalidate the results obtained prior to suspension. In the case of device-related serious adverse 
events, the Medical Monitor will consult with the sponsor and principal investigator to ensure that 
the necessary steps are taken to protect the safety and well- being of the subjects. 
In the event that that study is stopped, the investigator will promptly inform the subjects and ensure 
appropriate therapy and follow-up. Additionally the investigator will promptly inform the IRB/EC and 
provide a detailed written explanation. The pertinent regulatory authorities will be informed 
according to local regulations. 
 
16. 
PUBLICATION POLICY 
After completion of the study, the results will be analyzed and a clinical study report will be 
prepared. Within one year after the end of the study, the sponsor will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the accredited 
Ethics Committee. In addition, upon study completion and finalization of the study report the results 
of this trial will be submitted for publication and/or posted in a publicly accessible database of 
clinical trial results.   

 
Clinical Investigation Plan 
Study code: 
Monitor 
Version No: 
1.0 
Date: 
20180319 
 
25 (25) 
 
17. 
BIBLIOGRAPHY 
 
 
1. 
WHO. Ten top causes of deathe http://www.who.int/mediacentre/en/2017 [ 
2. 
GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018 http://goldcopd.org [ 
3. 
Läkemedelsverket. COPD - treatment recommendations(in Swedish) 
https://lakemedelsverket.se/upload/halso-och-
sjukvard/behandlingsrekommendationer/Kroniskt_obstruktiv_lungsjukdom_KOL_behandlingsreko
mmendation.pdf [ 
4. 
Lofdahl CG, Tilling B, Ekstrom T, Jorgensen L, Johansson G, Larsson K. COPD 
health care in Sweden - A study in primary and secondary care. Respir Med. 2010;104(3):404-11. 
5. 
Cruz J, Brooks D, Marques A. Home telemonitoring in COPD: a systematic review of 
methodologies and patients' adherence. Int J Med Inform. 2014;83(4):249-63. 
6. 
McLean S, Nurmatov U, Liu JL, Pagliari C, Car J, Sheikh A. Telehealthcare for 
chronic obstructive pulmonary disease: Cochrane Review and meta-analysis. Br J Gen Pract. 
2012;62(604):e739-49. 
7. 
Cruz J, Brooks D, Marques A. Home telemonitoring effectiveness in COPD: a 
systematic review. Int J Clin Pract. 2014;68(3):369-78. 
8. 
Gregersen TL, Green A, Frausing E, Ringbaek T, Brondum E, Suppli Ulrik C. Do 
telemedical interventions improve quality of life in patients with COPD? A systematic review. Int J 
Chron Obstruct Pulmon Dis. 2016;11:809-22. 
9. 
Lilholt PH, Witt Udsen F, Ehlers L, Hejlesen OK. Telehealthcare for patients suffering 
from chronic obstructive pulmonary disease: effects on health-related quality of life: results from 
the Danish 'TeleCare North' cluster-randomised trial. BMJ Open. 2017;7(5):e014587. 
10. 
Bernocchi P, Vitacca M, La Rovere MT, Volterrani M, Galli T, Baratti D, et al. Home-
based telerehabilitation in older patients with chronic obstructive pulmonary disease and heart 
failure: a randomised controlled trial. Age Ageing. 2017:1-7. 
11. 
Broendum E, Ulrik CS, Gregersen T, Hansen EF, Green A, Ringbaek T. Barriers for 
recruitment of patients with chronic obstructive pulmonary disease to a controlled telemedicine 
trial. Health Informatics J. 2016. 
12. 
Stausholm MN, Egmose A, Dahl SC, Lilholt PH, Cichosz SL, Hejlesen OK. 
Stratification of telehealthcare for patients with chronic obstructive pulmonary disease using a 
predictive algorithm as decision support: A pilot study. J Telemed Telecare. 2017;23(3):410-5.