Evaluation of a New 6 Minute Walk Test Smartphone App in Patients With Pulmonary Hypertension (The 6-APP Study)
Conditions: Pulmonary Hypertension
Sponsor: Oxford University Hospitals NHS Trust

Date and version No:     version 1.0, 03 August 2017 
 
 
 
 
Study Title:  Evaluation of a new 6 minute walk test smartphone app in patients with pulmonary 
hypertension (the 6-APP Study) 
Internal Reference Number / Short title: 6-APP Study 
Ethics Ref: 17/WM/0355 
  
 
Date and Version No: version 2.0, 018December 2017 
 
Chief Investigator: 
Dr. Elizabeth Orchard, 
Consultant Cardiologist  
Oxford University Hospitals NHS Foundation Trust 
Investigators:  
Dr. Dario Salvi, PostDoc Research Assistant, Department of Engineering 
Science, University of Oxford 
Dr. Carmelo Velardo, Departmental Lecturer, Department of 
Engineering Science, University of Oxford 
Professor Lionel Tarassenko, Head of the Department of Engineering 
Science, University of Oxford 
Emma Weingart, ACHD&PHT specialist Nurse, Oxford University 
Hospitals NHS Foundation Trust 
Sponsor:  
Oxford University Hospitals NHS Foundation Trust  
Funder: 
NHIR BRC 
Chief Investigator Signature:   
 
No conflicts of Interest 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
Ethics Ref: 
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TABLE OF CONTENTS 
 
1. 
SYNOPSIS ............................................................................................................................................... 4 
2. 
ABBREVIATIONS ..................................................................................................................................... 4 
3. 
BACKGROUND AND RATIONALE ............................................................................................................ 5 
4. 
OBJECTIVES AND OUTCOME MEASURES ............................................................................................... 7 
5. 
STUDY DESIGN ....................................................................................................................................... 8 
6. 
PARTICIPANT IDENTIFICATION ............................................................................................................ 10 
6.1. 
Study Participants ........................................................................................................................ 10 
7. 
STUDY PROCEDURES ........................................................................................................................... 10 
7.1. 
Recruitment ................................................................................................................................. 10 
7.2. 
Screening and Eligibility Assessment ........................................................................................... 11 
7.3. 
Informed Consent ........................................................................................................................ 11 
7.4. 
Baseline Assessments .................................................................................................................. 11 
Discontinuation/Withdrawal of Participants from Study ........................................................................ 12 
7.5. 
Definition of End of Study ........................................................................................................... 12 
7.6. 
Definition of Serious Adverse Events .......................................................................................... 13 
7.7. 
Reporting Procedures for Serious Adverse Events .......................... Error! Bookmark not defined. 
8. 
STATISTICS AND ANALYSIS ................................................................................................................... 17 
8.1. 
Description of Statistical Methods .............................................................................................. 17 
8.2. 
Number of Participants ............................................................................................................... 17 
8.3. 
Analysis of Outcome Measures ................................................................................................... 17 
9. 
DATA MANAGEMENT .......................................................................................................................... 18 
9.1. 
Access to Data ............................................................................................................................. 18 
9.2. 
Data Recording and Record Keeping ........................................................................................... 18 
10. 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 19 
11. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 19 
11.1. 
Declaration of Helsinki............................................................................................................. 19 
11.2. 
Guidelines for Good Clinical Practice ...................................................................................... 19 
11.3. 
Approvals ................................................................................................................................. 19 
11.4. 
Reporting ................................................................................................................................. 19 
11.5. 
Participant Confidentiality ....................................................................................................... 20 
11.6. 
Expenses and Benefits ............................................................................................................. 20 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
Ethics Ref: 
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11.7. 
Other Ethical Considerations ................................................................................................... 20 
12. 
FINANCE AND INSURANCE .............................................................................................................. 20 
12.1. 
Funding .................................................................................................................................... 20 
12.2. 
Insurance ................................................................................................................................. 20 
13. 
PUBLICATION POLICY ....................................................................................................................... 21 
14. 
REFERENCES .................................................................................................................................... 22 
15. 
APPENDIX A:  STUDY FLOW CHART ................................................................................................. 23 
 
 
 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
Ethics Ref: 
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1. SYNOPSIS 
Study Title 
Evaluation of a new 6 minute walk test smartphone app in patients with 
pulmonary arterial hypertension (the 6-APP Study) 
Internal ref. no. / short 
title 
6-APP Study 
Study Design 
 Comparison of standard 6 minute walk test with 6 minute walk test 
smartphone app 
Study Participants 
Patients with, or being assessed for, pulmonary hypertension 
Planned Sample Size 
30 
Planned Study Period 
Q4 2017- Q4 2019 
 
Objectives 
Outcome Measures 
Primary 
 
To demonstrate that patients are able 
and willing to use the app for the 
6MWT  
Percentage of participants who 
perform app-based home 6MWT 
Secondary 
 
To validate app 6MWT measurements 
against the hospital 6MWT 
 
 
To compare the outdoor 6MWT app 
with the hospital based 6MWT 
 
 
To assess the usability and acceptance 
of the app and the physicians’ website 
Average and standard deviation of 
the difference in distance as 
measured by physiologists and the 
app 
 
Correlation of outdoor 6MWT app 
parameters 
with 
the 
hospital 
6MWT test. 
 
Standard usability and acceptance 
questionnaires, semi structured 
interviews, analysis of technical 
logs 
 
2. ABBREVIATIONS 
 
CI 
Chief Investigator 
CRF 
Case Report Form 
 
 
GCP 
Good Clinical Practice 

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GP 
General Practitioner 
ICF 
Informed Consent Form 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
NYHA class 
New York Heart Association class  
PAH 
Pulmonary arterial hypertension 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
VO2 Max 
Maximal oxygen consumption on exercise test 
6MWT 
Six minute walk test 
 
3. BACKGROUND AND RATIONALE 
 
Pulmonary Arterial Hypertension (PAH) is a progressive illness that; if not diagnosed early or left 
untreated, can be a severe life limiting condition (1). It is a chronic disease of the pulmonary vasculature, 
with vascular proliferation and remodelling of the small pulmonary arteries leading to a progressive 
increase in pulmonary vascular resistance (PVR). This can ultimately lead to right heart failure and 
premature death (2). The predominant symptom of PAH is dyspnoea on exertion, with a decrease in 
exercise capacity, and most patients present with this symptom (2). 
PAH is an uncommon condition, affecting about 6000 patients in the United Kingdom (3), and due to its 
rarity, the NHS commissions 7 centres to care for patients with PAH (4). Oxford University Hospital works 
closely with the Royal Brompton Hospital to provide care for patients with PAH in Oxfordshire and the 
surrounding region. 
The six-minute walk test (6MWT) is a standard method for measuring exercise capacity in patients with 
cardiopulmonary disease such as PAH. The 6MWT measures how far a patient can walk in 6 minutes. 
Walking is an activity performed every day, by most patients except for those most severely limited. By 
assessing patients’ ability to exercise, the 6MWT provides a global assessment of respiratory, 
cardiovascular, neuromuscular and cognitive function. The 6MWT does not differentiate what limits the 
patient, nor does it assess maximal exercise capacity. Instead, the 6MWT allows the patient to exercise 
at a daily functional level, and is a useful tool for assessing changes after a therapeutic intervention, and 
correlates with a subjective improvement in dyspnoea (5). 
In PAH the 6MWT is used to evaluate patients’ response to treatment, with an increase in 6MWT 
distance of greater than 42 m being considered a clinically significant improvement (6). Furthermore, 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
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Short Title: 
6-APP Study 
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change in 6MWT distance correlates with VO2 max, NYHA class and mortality in PAH patients, (7) 
providing an objective assessment of disease progression, prognosis and response to treatment. It is a 
universally accepted test as it is safe and easily performed by the patient. 
The 6MWT has become the primary end-point for many trials, and as a surrogate invalidated survival 
outcome for all placebo controlled trials of PAH therapy (8). It is used by regulatory bodies to determine 
whether a treatment should be approved.  However, there is much discrepancy between whether it is 
the total distance walked at baseline prior to treatment, a decrease in total distance walked over time or 
a percentage increase in walking distance that correlates best with survival outcome. We hypothesize 
that it is all 3 of these measures, and that having a validated and more reproducible 6MWT would help 
assess patients and guide treatment strategies better.  
The test is usually performed in hospital, by walking along a hospital corridor, where many factors on the 
day of the test can affect patients’ performance, including tiredness, unfamiliarity with the environment 
or anxiety. The test typically requires 2 physiologists to monitor the distance walked by the patient, their 
oxygen saturations by pulse oximetry, and to record symptoms felt during the test.  To improve the 
assessment of a patient’s exercise capacity using a 6MWT, we hypothesized that the test would reflect 
more the patient’s functional status, if it were undertaken prior to the hospital outpatient appointment. 
We have designed a mobile-phone “app” that allows patients to perform the 6MWT within the patient’s 
home environment. This is felt to be more appealing to the patients, and would reduce the time spent in 
hospital on the day of their outpatient appointment.  
The 6MWT app is categorised as mobile-health (m-health) system, a form of telehealth whereby 
healthcare is delivered at a distance using smartphones. By utilizing biometric collection devices such as 
a pulse oximeter monitor with Bluetooth capability, m-health can be used to measure the oxygen 
saturation levels in the blood from patients, and transmit them to a secure server, allowing them to be 
reviewed by cardiologists and other healthcare professionals. 
The evidence-base for m-health as a tool for assessing physical fitness is increasingly established (9, 10). 
This new approach not only offers the opportunity for reliable collection of data, but provides the 
infrastructure to do this at scale and will allow decisions on patient’s health to be based on more 
frequent and more accurate information. 
There are no known risks to undertaking a 6MWT in the community as walking is an activity of daily 
living, and all patients are encouraged to walk daily. 
The population to be studied would be those with PAH who are currently assessed with a 6MWT. Once 
the app has been validated, patients with any type of cardiorespiratory disease who are assessed with a 
6MWT could use the app, for example patients with chronic obstructive airways disease, heart failure, 
renal failure, pre-transplantation work up.  
The 6MWT results form part of the NHS data set collected by NHS England for patients with PAH, and it 
would be beneficial to have a more reproducible assessment, whose results can be compared between 
the 7 centres providing care for these patients. At present, there is much variability in how 6MWTs are 
performed between units, and the app would reduce this variability. 
 

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The 6MWT has been undertaken at the JR for 5 years and we would like to retrospectively analyse the 
data from the 6MWT that have previously been undertaken. The data on patients will be pseudo-
anonymised, i.e. no personal information like name, surname or address, will be used, but we will keep 
date of birth, gender, diagnosis, dates and results of the 6MWT, date and causes of death. As part of the 
clinical care team reviewing the data is part of the normal standard of care for patients with PHT.   The 
data is collected on the Solus cardiac reporting system and can be extracted from this database and the 
data will be  pseudo-anonymised by the PI for analysis, and then shared with the wider research team. 
The data would be analysed  to look at  distance walked, and change in Oxygen saturation and heart rate 
during the test. We would analyse the data over time, to look for changes in these parameters and 
correlate these with outcome data, ie mortality. The data would be anonymised when reviewed. 
 
4. OBJECTIVES AND OUTCOME MEASURES 
Objectives 
Outcome Measures  
Timepoint(s) of evaluation of 
this outcome measure (if 
applicable) 
Primary Objective 
O1:  To demonstrate that patients 
are able and willing to use the app 
for the 6MWT 
 
Percentage of participants who 
perform app-based home 6MWT 
 
 
TP 1: 3 months after baseline 
visit 
TP 2: 6 months after baseline 
visit 
Secondary Objectives 
O2: To validate app 6MWT 
measurements against the 
hospital 6MWT. 
 
 
Average and variability of the 
difference 
in 
distance 
as 
measured by physiologists and 
the app. 
 
TP 1: at baseline visit 
TP 2: at 3-month visit 
TP 3: at 6-month visit 
O3: To compare the outdoor 
6MWT app with the hospital 
based 6MWT.  
Correlation of outdoor 6MWT 
app 
parameters 
with 
the 
hospital 6MWT test. 
TP 1: baseline visit 6MWT 
compared with following 
home test  
TP 2: 3-month visit 6MWT 
compared with closer home 
test before or after 
TP 3: 6-month visit 6MWT 
compared with closer home 
test before or after 
 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
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O4: To assess the usability and 
acceptance of the app and the 
physicians’ website. 
Standard 
usability 
and 
acceptance 
questionnaire 
to 
users assessing their use of the 
app 
and 
website, 
semi 
structured interviews, analysis of 
technical logs. 
TP 1: at 6 months after 
baseline visit 
Tertiary Objectives 
O5: To test whether the 6MWT 
app can detect changes in 6MWT 
distance more effectively than the 
hospital 6MWT, in patients 
starting advanced therapies. 
 
Comparison of change in 6MWT 
app measurement with hospital 
6MWT measurement, measured 
before and after initiation of 
new therapies. 
 
TP 1: at baseline visit 
TP 2: at 3-month visit 
TP 3: at 6-month visit 
 
 
 
 
 
5. STUDY DESIGN 
 
We propose to evaluate a novel approach to service delivery by monitoring PAH patients using an 
established m-health system to send 6MWT results to a central server where they can be accessed by 
the clinical team (Figure 1). The system includes a mobile phone “app” to allow participants to 
comfortably perform the 6MWT at home (indoors or outdoors). In the outdoor scenario, the app makes 
use of GPS to track the user’s position. In the indoor scenario it uses the phone’s accelerometer and 
magnetometer (compass) to count the number of laps over a fixed-length walkway. 
Figure 1. Diagram of the system 
 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
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Undertaking a 6MWT test within the participant’s home environment, using mobile technology to 
transmit the results via a software application on a mobile phone is appealing as it is likely to be more 
acceptable to the participant, may provide more consistent and functionally relevant data, and may 
reduce hospital attendances and healthcare costs. By utilizing biometric collection devices such as a 
pulse oximeter monitor with Bluetooth capability, telehealth can be used to capture the oxygen 
saturation levels in the blood from participants and transmit them to a secure server, allowing them to 
be reviewed by cardiologists and other healthcare professionals.  
This study aims to compare the indoor 6MWT, with the hospital performed 6MWT. It will assess the 
feasibility and acceptance of a mobile phone app as an instrument to measure the 6MWT. 
The 6MWT is currently undertaken at every Outpatient appointment, normally at 0- 3-, 6- and 12-month 
outpatient reviews. The participant would perform a hospital based 6MWT, whilst simultaneously using 
the indoor version of the app on their own mobile phone at baseline, 3- and 6-month follow up. This will 
demonstrate to the participant how to use the app, and we will be able to understand whether they are 
able to use it correctly. It will also allow direct comparison of the standard 6MWT distance measurement 
with the measurement provided by the app. 
The participant will be then invited to use the app in their local environment, preferably in the outdoor 
scenario, and the collected information would then be transmitted to the hospital servers where it could 
be reviewed. The app could be used many times prior to attendance in outpatients, giving the clinicians 
more detailed information as to the overall functional status of the patient. Participants will be required 
to perform a test before and after their follow up appointments so that home-based measurements can 
be compared to hospital-based ones. They will be allowed to do as many tests as they are willing to, 
preferably once per week and at least each month. 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
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In total, we aim to collect 3 indoor hospital-based measurements (baseline, 3- and 6-month) and at least 
5 outdoor home measurements, one close to each hospital visit plus one between two visits. The data 
collected will allow us to understand the usage of the app by participants, validate the indoor 
measurements and correlate the home measurements with the hospital-based ones. 
 
6. PARTICIPANT IDENTIFICATION 
6.1. Study Participants 
Participants with pulmonary arterial hypertension due to any cause who are able to perform a 6MWT. 
Patients on long term oxygen therapy will not be included as it will be difficult to perform the outside 
6MWT whilst on oxygen. Also patients with cognitive impairments, even if able to use a smartphone, will 
be excluded as they would possibly introduce noise for not being able to use the app correctly. 
6.2. Inclusion Criteria 
 
Participant is willing and able to give informed consent for participation in the study 
 
Male or Female, aged 18 years or above 
 
Diagnosed with PAH who are able to undertake 6MWT off-oxygen 
 
Being of PAH group 1 or 4 
 
Participant owns a compatible smartphone (Android or iPhone) and is able to use it. 
 
6.3. Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
 
Long term oxygen therapy 
 
Cognitive impairments 
 
Rheumatological diseases that limit the measurement of finger Oxygen saturations 
 
PAH groups 2, 3 or 5 
 
Cannot use a smartphone 
 
Pregnancy. 
7. STUDY PROCEDURES 
7.1. Recruitment 

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Patients undergoing follow up in the PAH clinic will be eligible for participation. They will be approached 
by a member of the clinical team for consideration and recruited. We will recruit 30 compliant patients 
to enrol in the study. 
7.2. Screening and Eligibility Assessment 
The patients attending the PHT outpatient clinics will be screened to assess whether they have 
pulmonary arterial hypertension and assessed as to whether they will be able to undertake a 6MWT 
using the App and then recruited 
7.3. Informed Consent 
The participant must personally sign and date the latest approved version of the Informed Consent form 
before any study specific procedures are performed. 
Written and verbal versions of the Participant Information and Informed Consent will be presented to 
the participants detailing no less than: the exact nature of the study; what it will involve for the 
participant; the implications and constraints of the protocol; the known side effects and any risks 
involved in taking part. It will be clearly stated that the participant is free to withdraw from the study at 
any time for any reason without prejudice to future care, without affecting their legal rights, and with no 
obligation to give the reason for withdrawal. 
The participant will be allowed as much time as wished to consider the information, and the opportunity 
to question the Investigator, their GP or other independent parties to decide whether they will 
participate in the study. Written Informed Consent will then be obtained by means of participant dated 
signature and dated signature of the person who presented and obtained the Informed Consent. The 
person who obtained the consent must be suitably qualified and experienced, and have been authorised 
to do so by the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the 
participant. The original signed form will be retained at the study site and a copy filed in participants 
medical notes. 
7.4. Baseline Assessments 
The baseline assessment will be a standard 6MWT which measures resting heart rate and oxygen level at 
rest, the distance walked over 6 minutes, then the oxygen saturations and heart rate at end of the 
6MWT. Prior to the initiation of the test, participants will be asked to download the app onto their 
personal mobile phones. Participants will also be asked to use the app in its indoor mode, while 
performing the test in hospital. Participants who are not able to either download the app or use it 
correctly will be unable to participate. We will be using the BORG questionnaire at the end of both the 
app test and the hospital 6MWT. The Borg Rating of Perceived Exertion (RPE) is a way of measuring 
physical activity intensity level. Perceived exertion is how hard a patient feels they are working. It is 
based on the physical sensations a person experiences during physical activity, including increased heart 
rate increased breathing rate, increased sweating, and muscle fatigue. Although this is a subjective 
measure, a person's exertion rating may provide a fairly good estimate of the actual heart rate during 
physical activity (11). During activity, the patient uses the Borg Scale to assign numbers as to how hard 
they think they are working. Participants will be provided with the questionnaire at the end of their 

Date and version No:     version 1.0, 03 August 2017 
 
Principal Investigator: 
Dr. Elizabeth Orchard 
 
 
Short Title: 
6-APP Study 
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6MWT and are encouraged to complete the questionnaire by the app or by the hospital physiologist. The 
physiologists undertaking the test will measure the distance walked using the system website to record 
the measurement. This way all measurements will be digitally available in one place. At the end of the 
assessment, participants will be asked to perform a home-based 6MWT within 3 days of the visit and 1 
home test per week, or, at least, one per month. 
 
7.5. Subsequent Visits 
The participants will be followed up as per the normal outpatient protocol at 3 and 6 months. At all the 
appointments they will perform a standard hospital based 6MWT, which will again document resting 
heart rate and oxygen saturations, the distance the participant walks in 6 minutes and their heart rate 
and oxygen saturations at the end. Participants will be asked to use the app while performing the test. 
The BORG questionnaire will be also presented at the end of the test.  
After the test, if no home 6MWT was performed within 3 days before the visit, participants will be 
reminded to perform a home test within the following 3 days. In addition, participants will be reminded 
to perform 6MWTs at home once per week, or at least once per month. At the end of the study, all 
participants will be asked to complete a usability and technology acceptance questionnaire and a group 
of randomly chosen 5 to 10 patients will be asked to attend a short interview about the use of the app. 
7.6. Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time. In addition, the Investigator may 
discontinue a participant from the study at any time if the Investigator considers it necessary for any 
reason including: 
 
Pregnancy 
 
Ineligibility (either arising during the study or retrospectively having been overlooked at 
screening) 
 
Significant protocol deviation 
 
Significant non-compliance with study requirements 
 
Withdrawal of Consent 
 
Loss to follow up 
If participants withdraw from the study, their data until that point will still be analysed, unless deletion of 
data is requested by the participant (e.g., by withdrawing consent). Any participant that withdraws from 
the study will be replaced with a new participant. The reason for withdrawal will be recorded in the CRF. 
 
7.7. Definition of End of Study 
The end of study is the date of the 6-month follow up appointment for the last participant. 

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8. IDENTIFICATION & DESCRIPTION OF THE DEVICE 
8.1. Description of the Device 
The app used in the study, called “SMWT” is a smartphone "app",  and is  a software device. Its main 
purpose is to measure the walked distance in a timed walk. In the "outdoor mode", the app makes use of 
GPS to track the user's position and compute the distance. In the "indoor mode" it uses the phone's 
compass to count the number of laps over a fixed-length walkway. The app also collects blood saturation 
and pulse samples from commercially available pulse-oximeters, connected to the phone via a wireless 
link. The app is available, free of charges, on common "app stores" (Google Play Store and Apple iTunes) 
and is currently not distributed as a medical device but as a research prototype. 
The app is able to retrieve data from two commercial pulse-oximeters: Creative Medical PC-68B and 
Nonin Onyx II, both certified as medical devices in Europe and United States. The validation of the pulse-
oximeters is not object of this research. 
8.2. Device Safety 
The app is being tested in relation to its reliability and the accuracy of distance estimation. 
In the "indoor mode", from 46 tests in lab and with actual patients, the app has an average absolute 
error of 5.58 m and a maximum of of 21.46 m, which is below the threshold that is considered clinically 
relevant. In the "outdoor" mode, from 24 tests performed in lab, the average error is 11.23 m and the 
maximum 27.19 m, both still not clinically significant. 
There are no safety risks associated to use of the app. 
Volunteers are also being involved  in  technical testing and assessing usability and long-term 
acceptance. 
8.3. Device Accountability 
The production of the software app is responsibility of the Department of Engineering Science of the 
University of Oxford. 
 
 
9. SAFETY REPORTING 
The study is low risk however, in the event of an adverse event (AE) or serious adverse event (SAE) 
occurring to a participant this would be reported to the REC and MHRA in the annual report.  
9.1. Definitions 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory findings) in 
participants, users or other persons whether or not related to the 

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investigational medical device. This includes events related to the 
investigational device or comparator, events related to the procedures 
involved (any procedure in the protocol). For users or other persons 
this is restricted to events related to the investigational medical device. 
Adverse Device effect 
(ADE) 
 
An adverse event related to the use of an investigational medical 
device. This definition includes any events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational device. This 
definition also includes any event resulting from user error or form 
intentional misuse of the investigational device. 
 
Serious 
Adverse 
Event 
(SAE) 
An adverse event that: 
 
Led to death 
 
Resulted in serious deterioration in the health of the subject 
that: 
o resulted in a life-threatening illness or injury 
o resulted in a permanent impairment of a body 
structure or a body function 
o required 
in-patient 
care 
or 
prolongation 
of 
hospitalisation 
o resulted in medical or surgical intervention to prevent 
life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
This includes device deficiencies that might have led to a serious 
adverse event if: 
a) suitable action had not been taken or 
b) intervention had not been made or 
c) circumstances had been less fortunate.  
These are handled under the SAE reporting system. 
Planned hospitalisation for a pre-existing condition, or a procedure 
required by the trial protocol, without serious deterioration in health, 
is not considered a serious adverse event. 
Serious Adverse Device 
Effect (SADE) 
Any untoward medical occurrence that can be attributed wholly or 
partly to the device, which resulted in any of the characteristics of a 
serious adverse event as described above. 
Unanticipated Serious Adverse Device Effects (USADE) 

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Any serious adverse device effect which, by its nature, incidence, 
severity or outcome, has not been identified  
Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance.  Device deficiencies 
include malfunctions, use errors and inadequate labeling. 
Device deficiencies that did not lead to an adverse event, but could 
have led to a medical occurrence if suitable action had not been taken, 
or intervention had not been made or if circumstances had been less 
fortunate 
User error 
Act or omission of an act that results in a different medical device 
response than intended by the manufacturer or expected by the user.  
Use error includes slips, lapses and mistakes.  An unexpected 
physiological response of the subject does not itself constitute a use 
error. 
 
Severity definitions 
The following definitions will be used to determine the severity rating for all adverse events: 
Mild: awareness of signs or symptoms, that does not interfere with the subject’s usual activity or is 
transient that resolved without treatment and with no sequelae. 
Moderate: a sign or symptom, which interferes with the subject’s usual activity. 
Severe: incapacity with inability to do work or perform usual activities. 
9.2. Causality 
The relationship of each adverse event to the trial device may be determined by the manufacturer 
and/or a medically qualified Investigator according to the following definitions:  
Not related: The event is clearly related to other factors such as the patients/participants clinical 
condition, therapeutic intervention, concomitant medication. 
Unlikely: The event is probably produced by other factors such as the patients/participants clinical 
condition, therapeutic intervention, concomitant medication and does not follow a known response 
pattern to the device 
Possibly: The event follows a reasonable temporal relationship form the time of 
placement/administration and/or follows a known response pattern to the device but could have been 
caused by other factors such as the patients/participants clinical condition, therapeutic intervention, 
concomitant medication. 

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Most probable: The event follows a reasonable temporal relationship form the time of 
placement/administration and/or follows a known response pattern to the device and could not have 
been caused by other factors such as the patients/participants clinical condition, therapeutic 
intervention, concomitant medication. Further the event immediately follows the 
administration/placement of the device and improves on stopping or removing the device. 
9.3. Procedures for Recording Adverse Events 
All adverse events (including ADEs) and device deficiencies occurring during the course of the study will 
be recorded on the CRF whether or not attributed to the trial device. The information recorded will 
include but not be limited to: 
 
A description of the event 
 
The dates of the onset and resolution 
 
Action taken 
 
Outcome 
 
Assessment of relatedness to the device 
 
Whether the AE is serious or not 
 
Whether the AE arises from device deficiency 
 
Whether the AE arises from user error 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe. 
AEs/ADEs considered related to the device as judged by a medically qualified investigator or the Sponsor 
will be followed either until resolution, or the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE/ADE is of sufficient 
severity to require the participant’s removal from treatment.  A participant may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE/ADE.  If either of these 
occurs, the participant must undergo an end of trial assessment and be given appropriate care under 
medical supervision until symptoms cease, or the condition becomes stable. 
9.4. Reporting Procedures for Serious Adverse Events 
Reporting of all Serious Adverse Events will be done in accordance with the European Commission 
Guidelines on Medical Devices Serious Adverse Event Reporting (MEDDEV 2.7/3; December 2010). 
SADEs/USADEs that pose an immediate risk to patient health or safety, will be reported to the OUH R&D 
team immediately or no later than 24 hours after the Investigator is aware. All information must be 
recorded on an SAE form and emailed to R&D at ouhsae.reports@ouh.nhs.uk.   
 
R&D will perform an initial check of the report, request any additional information, and ensure it is 
reviewed by the Medical Monitor on a weekly basis.  It will also be reviewed at the next Trial Safety 
Group meeting.   
This information will also be reported to the device manufacturer, competent authority and the REC 
within 2 calendar days of the Chief Investigator becoming aware of the event.   

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SAEs/SADEs will be recorded for a 24 hour period following the use of the device. All SAEs will be 
followed up to resolution.  
9.5. Safety Monitoring Committee 
The Oxford University Hospitals Trust / University of Oxford Trials Safety Group (TSG) will conduct a 
review of all SAEs/SADEs for the trial reported during the quarter and cumulatively. The aims of this 
committee include: 
 
To pick up any trends, such as increases in un/expected events, and take appropriate action 
 
To seek additional advice or information from investigators where required 
 
To evaluate the risk of the trial continuing and take appropriate action where necessary 
 
10. STATISTICS AND ANALYSIS 
 
10.1. 
Description of Statistical Methods 
Data will be analysed when the study is completed. 
Statistical methods that will be employed to analyse and validate the results of the study are:  
 
Descriptive statistics (mean, standard deviation, median, interquartile range) 
 
Pearson correlation coefficients 
 
Distribution plots 
 
Scatter plots 
 
Bland Altman charts 
 
Error bars and confidence intervals 
 
10.2. 
Number of Participants 
 This is an exploratory observational study and therefore no sample size calculation is provided, we 
propose collecting data on 30 participants. 
 
10.3. 
Analysis of Outcome Measures 
All participants’ data will be used excluding those who withdrew consent.  
Primary Objective: 

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O1: We will measure the percentage of participants who perform at least one home 6MWT between 
baseline visit and 3-month visit and the percentage of participants who perform at least one home 
6MWT between baseline visit and 6-month visit. These two percentages will be used as the main 
measure of the success of this study. 
In addition, the distribution over time of when home performed tests will be computed. 
Secondary Objectives 
O2: We will compute the mean and standard deviation of the difference in distance as measured by the 
physiologists and the app. To evaluate the agreement between the two approaches, a Bland Altman 
graph will be also prepared. 
O3: We will compute the correlation of the distance as computed by the app when used at home within 
3 days from the hospital visit with the one gathered in the hospital 6MWT test. 
O4: Ease of use, acceptance and mobile phone affinity will be measured with standard questionnaires. 
Compliance with the use of the app will be measured by counting the frequency of use of the app. 
Simple descriptive statistics will be computed and correlations among quantities will be explored. A 
selected number of participants will be chosen for semi-structured interviews in order to gain a deeper 
understanding of their usage of the app.  
 
Tertiary Objectives 
O5: Descriptive statistics about the walked distance, blood oxygen saturation and heart rate, BORG scale 
and number of steps will be used to compare changes before and after initiation of new therapies. 
 
11. DATA MANAGEMENT 
11.1. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor and host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. All authorised 
representatives will be employed by the Oxford University Hospitals Trusts (OUH), hold honorary 
contracts with OUH, or hold a valid NHS Research Passport. 
11.2. 
Data Recording and Record Keeping 
Participants’ data will be recorded on an ad-hoc system developed by the Institute of Biomedical 
Engineering of the University of Oxford. The data will be collected in two ways: by the app and through 
forms submission on a website. The app will be used by participants, the website will be used by 
physicians. 

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All the communication between the patients’ apps and / or the physicians’ browsers and the server is 
encrypted though state-of-the-art web technology. The web interface and the database are hosted on 
computers within the OUH network and protected by the NHS firewall. Access to the server from both 
patients’ apps and physicians is allowed only through the submission of personal, private user 
credentials. 
The data will be pseudo-anonymised, therefore no directly identifiable information will be stored. 
Participants will be given pseudonyms (e.g. participant1, participant2 etc.) that will be used to log into 
the app. Only study staff and authorised personnel will be given credentials for reviewing participants’ 
data. 
 A paper form will be kept by the principal investigator  
Data will be kept for up to 10 years after study completion or until ethical approval terminates, 
whichever is sooner. 
 
12. QUALITY ASSURANCE PROCEDURES 
The study may be monitored, or audited in accordance with the current approved protocol, GCP, 
relevant regulations and standard operating procedures. 
 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
13.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
13.3. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (REC), and host institution(s) for 
written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
13.4. 
Reporting 

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The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the 
REC Committee, host organisation and Sponsor.  In addition, an End of Study notification and final report 
will be submitted to the same parties. 
13.5. 
Participant Confidentiality 
 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by a participant ID number on all study documents and any electronic database, with the 
exception of the CRF, where participant initials may be added.  All documents will be stored securely and 
only accessible by study staff and authorised personnel. The study will comply with the Data Protection 
Act, which requires data to be anonymised as soon as it is practical to do so. 
13.6. 
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
13.7. 
Other Ethical Considerations 
 
6MWTs 
6MW testing is very safe and is used in many conditions including in people with heart failure. However, 
as can occur with all forms of exercise, very occasionally some people have significant changes in their 
heart rate and rhythm that requires medical attention. Although the risk of this happening is small, the 
test is carried out in hospital in with physiologists monitoring the patients. The participants undergoing 
the home or outdoor 6MWT will be provided with a checklist for them to assess themselves with, and 
would not undertake a test if they fail this. 
 
Participants will be provided with all necessary information and can access their right to make a decision 
regarding participation.  
14. FINANCE AND INSURANCE 
14.1. 
Funding 
The NIHR Oxford Biomedical Research Centre will fund involvement of a research engineer and the 
electronic equipment (pulse oximeters). 
14.2. 
Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If you are harmed 
whilst taking part in a clinical research study as a result of negligence on the part of a member of the 
study team this liability cover would apply. 

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Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
 
 
15. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study. Authors will acknowledge that the study was funded by 
NIHR Oxford Biomedical Research Centre. Authorship will be determined in accordance with the ICMJE 
guidelines and other contributors will be acknowledged. 
 
 

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16. REFERENCES 
 
1. Agarwal, Richa, and Mardi Gomberg-Maitland. "Current therapeutics and practical management 
strategies for pulmonary arterial hypertension." American heart journal 162.2 (2011): 201-213. 
2. Galiè, Nazzareno, et al. "Tadalafil therapy for pulmonary arterial hypertension." Circulation 
119.22 (2009): 2894-2903. 
3. Peacock, A. J., et al. "An epidemiological study of pulmonary arterial hypertension." European 
Respiratory Journal 30.1 (2007): 104-109. 
4. National policy for targeted therapies for the treatment of pulmonary hypertension in adults 
May 2014 Reference: NHS ENGLAND NHS ENGLAND A11/P/b Clinical Commissioning Policy 
5. Gabler, Nicole B., et al. "Validation of six-minute-walk distance as a surrogate endpoint in 
pulmonary arterial hypertension trials." Circulation (2012): CIRCULATIONAHA-112. 
6. Mathai, Stephen C., et al. "The minimal important difference in the 6-minute walk test for 
patients with pulmonary arterial hypertension." American journal of respiratory and critical care 
medicine (2012). 
7. Miyamoto, Shoichi, et al. "Clinical correlates and prognostic significance of six-minute walk test 
in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise 
testing." American journal of respiratory and critical care medicine 161.2 (2000): 487-492. 
8. Barst, Robyn J., et al. "A comparison of continuous intravenous epoprostenol (prostacyclin) with 
conventional therapy for primary pulmonary hypertension." New England Journal of Medicine 
334.5 (1996): 296-301. 
9. Higgins, John P. "Smartphone applications for patients' health and fitness." The American journal 
of medicine 129.1 (2016): 11-19. 
10. Rospo, Gianluca, et al. "Cardiorespiratory improvements achieved by American College of sports 
medicine’s exercise prescription implemented on a mobile app." JMIR mHealth and uHealth 4.2 
(2016). 
11. Borg, Gunnar A. "Psychophysical bases of perceived exertion." Med sci sports exerc 14.5 (1982): 
377-381. 
 
 
 

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17. APPENDIX A:  STUDY FLOW CHART