Pill-in-Pocket Oral Anticoagulation Responding to Atrial Fibrillation Episodes Guided by Continuous Rhythm Monitoring and Automated Smartphone Alerts
Phase: NA
Conditions: Atrial Fibrillation (AF), Atrial Fibrillation (Prevention of Stroke)
Sponsor: Oxford University Hospitals NHS Trust

 
1 
 
Pill-in-Pocket Oral Anticoagulation Responding to Atrial Fibrillation Episodes Guided by 
Continuous Rhythm Monitoring and Automated Smartphone Alerts 
 
Internal Reference Number / Short title:  RESPOND-AF 
Date and Version No: 10th January 2025 version 3.0 
 
Chief Investigator: 
Prof Tim R. Betts MD MBChB FRCP 
Consultant Cardiologist & Electrophysiologist 
Oxford University Hospitals NHS Foundation Trust 
Associate Professor, Department of Cardiovascular Medicine, Oxford 
University 
Tel: +44 1865 220256 
Email: tim.betts@ouh.nhs.uk 
 
Investigators:  
Dr Richard Varini MBChB MRCPI 
Clinical Research Fellow,  
Oxford University Hospitals NHS Foundation Trust 
Tel: +441865220255 
Email: richard.varini@ouh.nhs.uk 
 
Dr Abhirup Banerjee PhD 
Royal Society University Research Fellow 
Institute of Biomedical Engineering 
Department of Engineering Science 
University of Oxford, UK 
Tel: +44 1865 617667 
Email: abhirup.banerjee@eng.ox.ac.uk 
 
 
Sponsor:  
Oxford University Hospitals NHS Foundation Trust 
Headley Way, Headington, Oxford (OX3 9DU) 
 
 
 
 
 
 

 
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Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee 
and Regulatory Authorities unless authorised to do so. 

 
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1. KEY TRIAL CONTACTS 
 
Chief Investigator 
Prof Tim R. Betts MD MBChB FRCP. 
Consultant Cardiologist & Electrophysiologist, Oxford University 
Hospitals NHS Foundation Trust 
Associate Professor, Department of Cardiovascular Medicine, Oxford 
University 
Tel: +44 1865 220256 
Email: tim.betts@ouh.nhs.uk 
Sponsor 
Oxford University Hospitals NHS Foundation Trust 
Headley Way, Headington, Oxford OX3 9NU 
Email: ouh.sponsorship@ouh.nhs.uk 
Funder(s) 
 Medtronic Limited 
Clinical Trials Unit 
N/A 
Committees 
 N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4 
 
 
 

 
5 
 
TABLE OF CONTENTS 
1. 
SYNOPSIS ................................................................................................................................... 7 
2. 
ABBREVIATIONS ....................................................................................................................... 10 
3. 
BACKGROUND AND RATIONALE ................................................................................................ 11 
3.1 SMART-ALERT study ......................................................................................................................... 13 
3.2 Software Bot platform ...................................................................................................................... 13 
3.3 Public and patient involvement ....................................................................................................... 14 
4. 
OBJECTIVES AND OUTCOME MEASURES .................................................................................... 15 
5. 
STUDY DESIGN .......................................................................................................................... 16 
5.1 
Study Timeline ............................................................................................................................ 18 
5.2 
Study Risks .................................................................................................................................. 18 
5.3 
Study Benefits ............................................................................................................................. 19 
6. 
PARTICIPANT IDENTIFICATION .................................................................................................. 19 
6.1 
Inclusion Criteria ......................................................................................................................... 19 
6.2 
Exclusion Criteria ........................................................................................................................ 19 
6.3 
Recruitment ................................................................................................................................ 20 
6.4 
Informed Consent ....................................................................................................................... 20 
6.5 
Screening and Eligibility Assessment ......................................................................................... 21 
6.6 
Randomisation ............................................................................................................................ 21 
6.7 
Blinding ....................................................................................................................................... 21 
6.8 
Baseline Assessments ................................................................................................................. 21 
6.9 
Intervention – LINQ II ICM implant ............................................................................................ 21 
 ................................................................................................................................................................. 23 
6.10 Subsequent Visits ............................................................................................................................ 23 
6.11 Early Discontinuation/Withdrawal of Participants ....................................................................... 23 
9 
TRIAL INTERVENTIONS .............................................................................................................. 25 
9.1 
Other Interventions .................................................................................................................... 25 
10 
SAFETY REPORTING ............................................................................................................... 25 
10.1 Definition of Serious Adverse Events ............................................................................................. 25 
10.2 Reporting Procedures for Serious Adverse Events ........................................................................ 25 
10.3 Adverse Events ................................................................................................................................ 25 
11 
STATISTICS AND ANALYSIS ..................................................................................................... 26 
12 
DATA MANAGEMENT ............................................................................................................ 27 
12.1 
Source Data ................................................................................................................................. 27 
12.2 
Access to Data ............................................................................................................................. 27 

 
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12.3 
Data Recording and Record Keeping .......................................................................................... 27 
13 
QUALITY ASSURANCE PROCEDURES ....................................................................................... 28 
13.1 
Risk assessment .......................................................................................................................... 28 
13.2 
Study monitoring ........................................................................................................................ 28 
13.3 
Study Committees....................................................................................................................... 28 
14 
PROTOCOL DEVIATIONS ........................................................................................................ 28 
15 
SERIOUS BREACHES ............................................................................................................... 28 
16 
ETHICAL AND REGULATORY CONSIDERATIONS ....................................................................... 28 
16.1 
Declaration of Helsinki ............................................................................................................... 29 
16.2 
Guidelines for Good Clinical Practice ......................................................................................... 29 
16.3 
Approvals .................................................................................................................................... 29 
16.4 
Reporting ..................................................................................................................................... 29 
16.6 
Participant Confidentiality ......................................................................................................... 29 
16.7 
Expenses and Benefits ................................................................................................................ 29 
17 
FINANCE AND INSURANCE ..................................................................................................... 30 
17.1 
Funding ........................................................................................................................................ 30 
17.3 
Contractual arrangements .......................................................................................................... 30 
18 
PUBLICATION POLICY ............................................................................................................ 30 
19 
DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY ........................................................................................................................................ 30 
20 
ARCHIVING ........................................................................................................................... 30 
21. REFERENCES ............................................................................................................................... 31 
 

 
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1. SYNOPSIS 
 
Trial Title 
Pill-in-Pocket Oral Anticoagulation: Responding to Atrial Fibrillation 
Episodes Guided by Continuous Rhythm Monitoring and Smartphone 
Alerts 
Internal ref. no. (or 
short title) 
 RESPOND-AF 
Trial registration 
Clinicaltrials.gov  
Sponsor  
Oxford University Hospitals NHS Foundation Trust 
 
Funder  
Medtronic Limited 
Clinical Phase  
Feasibility study 
Study Design 
Investigator-initiated single centre feasibility study 
Study Participants 
Participants will be recruited from Cardiology outpatient clinics and outpatient 
lists for DC Cardioversion, as well as those presenting for the first time with 
recent onset AF to Emergency Department or Acute Medical Unit. 
Those recruited will be aged 18 years or above with non-valvular paroxysmal 
atrial fibrillation or persistent AF with a rhythm control strategy. They will have 
to own a smartphone with operating system compatible with the My Carelink 
Heart application by Medtronic and be willing and able to use the application. 
They must fulfill the inclusion criteria listed later in this protocol and on the 
consent form. 
Sample Size 
50 subjects 
Planned Study Period  
24 months 
 
Objectives 
Outcome Measures 
Timepoint(s)  
Primary 
 
Primary Objective 
 
To investigate the 
reduction in oral 
anticoagulation (OAC) 
utilization during follow-
up. 
 
Primary Outcome 
Measures 
Calculate the proportion of 
time off anticoagulation  
 
 
 During follow-up 
(minimum 13 
months) 
Secondary 
 
Secondary Objectives 
 
1. Thromboembolic 
events (ischaemic stroke, 
transient ischaemic 
Secondary Outcome 
Measures 
1. Calculate the rate of 
ischaemic stroke, TIA and 
systemic embolism in 
 
 
1. During follow-up 
(minimum 13 
months) 
 

 
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attacks (TIA) and systemic 
embolism) 
 
2. Major bleeding 
 
 
 
3. Minor bleeding 
 
 
 
4. Any stroke 
(ischaemic, 
haemorrhagic or 
undermined) 
 
5. All-cause mortality 
 
 
 
 
6. Protocol adherence 
 
 
 
 
 
 
 
 
 
7. To assess response 
time from AF episode 
onset to patient starting 
as-required OAC 
 
patients on as-required 
OAC 
 
2. Calculate the rate of 
major bleeding in patients 
on as-required OAC 
 
3. Calculate the rate of 
minor bleeding in patients 
on as-required OAC 
 
4. Calculate the stroke 
rate (ischaemic, 
haemorrhagic or 
undetermined) 
 
5. Calculate the rate of all-
cause mortality in patients 
on as-required OAC 
 
 
6. Calculate the percentage 
of daily automatic 
transmissions and 
percentage of patients that 
restart OAC within 24 
hours of the smartphone-
alert. 
 
 
 
7. Time from AF episode 
onset to detection, time to 
alerts being sent and 
acknowledged and OAC 
being taken by the 
participant. Proportion of 
missed AF episodes, 
transmissions or alerts. 
 
 
 
2. During follow-up 
(minimum 13 
months) 
 
3. During follow-up 
(minimum 13 
months) 
 
4. During follow-up 
(minimum 13 
months) 
 
 
5. During follow-up 
(minimum 13 
months) 
 
 
6. During follow-up 
(minimum 13 
months) 
 
 
 
 
 
 
 
7. During follow-up 
(minimum 13 
months) 
Intervention(s) 
  
As-required oral anticoagulation (OAC): 
• 
Initiate OAC if continuous AF episodes longer than 1 hour or total AF 
burden of more than 60 minutes (>4.2%) over a 24-hour period. 
o Dabigatran 
o Rivaroxaban 
o Apixaban 

 
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o Edoxaban 
• 
Discontinue OAC if freedom over a consecutive 30-day period from: (1) AF 
episodes longer than 1 hour, and (2) AF burden more than 60 minutes in 
any 24-hour period. 

 
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2. ABBREVIATIONS 
 
AE 
Adverse event 
AF 
Atrial fibrillation 
AR  
Adverse Reaction 
AE 
Adverse event 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRT 
Cardiac Resynchronisation therapy 
CT 
Clinical Trials 
CTA 
Clinical Trials Authorisation 
DOAC 
Direct oral anticoagulant 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
ICD 
Implanted Cardioverter-Defibrillator 
ICM 
Implanted Cardiac Monitor 
ICF 
Informed Consent Form 
IRB 
Independent Review Board 
NHS 
National Health Service 
OAC 
Oral anticoagulation 
RES 
 Research Ethics Service  
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
PPG 
Photoplethysmography 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
RSI 
Reference Safety Information  
TIA 
Transient ischaemic attack 
SAE 
Serious Adverse Event 
TMF 
Trial Master File 

 
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3. BACKGROUND AND RATIONALE 
Disease burden: Atrial fibrillation (AF) is the most common sustained arrhythmia affecting millions of 
people worldwide, leading to significant morbidity and mortality.(1) It is associated with a 5-fold 
increased risk of ischaemic stroke(2), accounting for 20-25% of all strokes which are generally more 
severe and disabling than non-AF related strokes.(3)  OAC remains the cornerstone of AF management: 
it reduces by two-thirds the risk of stroke, but at the expense of major bleeding (1 in 25 patients per 
year).(1, 4) 
Clinical Challenge: Risk scores that inform anticoagulation decisions, such as the CHA2DS2-VASc score,  
do not incorporate AF temporal patterns or burden and are based solely on co-morbidities.(1) If the 
predicted yearly stroke rate is above 1%, there is a net clinical benefit of OAC.(5) Once OAC is initiated, 
patients are committed to lifelong anticoagulation regardless of the number or duration of AF 
episodes.  
Current risk scores may overestimate the stroke risk in patients with paroxysmal atrial fibrillation 
(PAF), low AF burden and short episodes.  A meta-analysis of almost 100,000 patients with AF suggests 
that both the adjusted and unadjusted stroke and mortality risks  are higher in non-Paroxysmal AF 
than in Paroxysmal AF.(6) Moreover, in a study of 21,768 non-anticoagulated patients with AF detected 
by cardiac implantable electronic devices, longer AF episode duration was associated with increased 
thromboembolic risk. Patients with intermediate CHA2DS2-VASc score (1-3) and AF episodes lasting 
less than 23.5 hours had a yearly stroke rate below 1%.(7) Therefore, indefinite OAC may expose 
patients with shorter, infrequent AF episodes to a high bleeding risk with limited benefit in stroke risk 
reduction, in particular those with low-to-moderate risk. 
Biological plausibility: Interrogation of more than 9,000 patients with cardiac implantable electronic 
devices (CIEDs) showed a seventeen-fold increase in the odds of having a stroke in the first 5 days 
after an AF episode which returns to baseline at 30 days.(8) This may be explained by both atrial 
stunning ―transient disruption of atrial and atrial appendage contractility ― following restoration of 
sinus rhythm, and an increase in thrombogenesis, from platelet activation and thrombin generation 
during AF episodes.. Atrial stunning occurs irrespective of mode of cardioversion (spontaneous, 
pharmacological or electric),(9-12) and gradually improves over time if sinus rhythm is restored.(13, 14) In 
patients undergoing direct current cardioversion, recovery of atrial mechanical function is strongly 
influenced by the duration of AF episodes.(14) Recovery within 24 hours was observed in patients with 
AF episode duration of less than two weeks; recovery increased to one month in those with 
documented AF lasting for more than 6 weeks.(15)  
Evidence gap: “As-required” OAC, guided by continuous rhythm monitoring, may be an alternative 
management strategy in patients with paroxysmal AF and persistent AF on a rhythm-control strategy 
who have short, infrequent episodes.  OAC is started at the onset of an AF episode and continued for 
the duration of the episode and for a period afterwards. This may offer the same thromboembolic 
protection as continuous OAC, whilst at the same time reducing cost and bleeding complications. 
As-required OAC: Four small feasibility studies have used an implantable cardiac monitor (ICM, e.g.  
Medtronic LINQ and Reveal XT) to guide “as required” OAC in low-to-moderate risk patients.(16-19) 
Although the authors concluded that this strategy appears safe, reducing both OAC utilisation and 

 
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bleeding, none of these studies were adequately powered to assess for rate of thromboembolic 
events. Our research group therefore conducted a systematic review and meta-analysis32 of studies 
using rhythm monitoring (intermittent and continuous) to guide OAC. Across 8 studies and a total of 
711 patients on an intermittent anticoagulation regime, the annualised mortality and ischaemic stroke 
rates per patient-year of follow-up were very low, 0.024 (95% CI [0.018–0.051]) and 0.005 (95% CI 
[0.002–0.012]), respectively. 
A significant limitation seen in studies using continuous rhythm monitoring (ICMs or cardiac 
implantable electronic devices) was the large volume of data that required adjudication and potential 
delays between episode detection and restarting OAC ― patients had to be contacted by 
telephone.(16-19) In REACT.COM, during a mean follow-up of  1.2 years, 59 patients generated 24,000 
manual transmissions. These limitations in technology and methodology hindered any attempts at a 
large RCT or incorporation into routine clinical practice.  
Innovations in digital health technology may lead to a paradigm shift: personalised treatment for 
patients with AF. The LINQ II ICM™ (Medtronic, MN, USA) with True-rhythm  now incorporates P-wave 
evidence which significantly reduces the number of false positives whilst still maintaining a very high 
positive predictive value for AF episodes.(20, 21) It is also now equipped with low-energy Bluetooth 
wireless technology that connects directly with users’ smartphones, allowing transmission of data to 
the physicians’ web portal (CareLink™) without needing a home monitor. This opens the possibility of 
real-time, automated notifications to patients informing them of the onset of an AF episode. 
Our research group at Oxford University Hospitals, UK have developed a patient messaging software 
to facilitate sending alerts to patients, which patients can respond to. We confirmed the feasibility of 
this closed-loop alert system in the recent SMART-ALERT study (discussed below). 
In the RESPOND-AF study, patients will have a LINQ II ICM implant. If the ICM picks up an episode of 
AF, this transmission will trigger our software to send an SMS alert to the patient. This alert will inform 
them of the AF episode, therefore prompting them to restart their oral anticoagulation. This closed-
loop alert system will allow for reduced time from AF episode detection to initiation of OAC and 
facilitates remote monitoring workflow.  
 
 
 
Figure 1. LINQ II implantable cardiac monitor (ICM) connectivity 
 

 
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The duration of AF episodes that start to increase thromboembolic risk (and thus merit OAC) 
remains unclear. The arbitrary diagnostic cut-off of 30 seconds of AF on an electrocardiogram was 
introduced as an inclusion criterion in clinical trials and it is still used to diagnose AF. Continuous 
rhythm monitoring with cardiac implantable electronic devices allows detection of atrial high-rate 
episodes (AHRE)/subclinical AF and assessment of episode duration and stroke risk.  In published trials, 
stroke risk began to increase after subclinical AF episodes longer than 5 minutes in the MOST trial, 
after 1 hour in SOS, 5.5 hours in TRENDS, and 24 hours in the Veteran Affairs study and ASSERT (post-
hoc analysis).(22-26) The data therefore suggest that longer episodes (hours) rather than shorter 
episodes (minutes) increase the risk of thromboembolism. 
The 2020 ESC AF guideline acknowledges the uncertainty between the duration of subclinical AF 
episode  and the thromboembolic risk but highlights that longer episodes (>24hours) have a higher 
risk of thromboembolic complications and progression to clinical AF.(27) Furthermore, it states that 
OAC may be considered in patients with high stroke risk and  subclinical AF episodes longer than 
24h, pending data from ongoing RCTs.(28, 29) 
These RCTs (ARTESIA28 study and NOAH-AFNET 629) have since reported. They were designed to 
assess the treatment of AHRE/subclinical AF episodes of >6 minutes (and <24 hours in ARTESIA) with 
a direct-acting oral anticoagulant. In ARTESIA, apixaban resulted in a lower risk of stroke or systemic 
embolism than aspirin, but a higher risk of major bleeding. In NOAH-AFNET 6, edoxaban did not lead 
to a significant reduction in the composite endpoint of stroke, systemic embolism, or cardiovascular 
death compared with placebo, and led to a higher incidence of a composite of death or major 
bleeding. A meta-analysis of these two studies(33) has demonstrated an overall significant reduction 
in ischaemic stroke in anticoagulated patients, with no reduction in cardiovascular death or all-cause 
mortality, and a significant increase in major bleeding. These results would appear to support the 
ESC guideline to consider OAC in this subclinical AF patient group. 
In the RESPOND-AF study, we have chosen a pragmatic cut-off of a continuous AF episode longer than 
one hour and/or a daily AF burden of more than 1 hour during a 24-hour period (>4.2%) to initiate 
OAC. Built into our protocol is a target for participants to commence OAC within 24 hours of AF onset, 
and no later than 48 hours.  
Preliminary data: Our research group conducted a review of patients with AF and complex cardiac 
devices treated at Oxford University Hospitals, to assess potential reduction in OAC usage if they were 
treated with an “as-required” OAC approach. Retrospective analysis of 331 patients identified 106 
with AF, corresponding to a total follow-up period of 393 patient-years. An “as-required” strategy of 
OAC for 1 month following an AF episode longer than 1 hour (as per RESPOND-AF protocol) would 
lead to a significant reduction of time on OAC: 86.5% reduction for paroxysmal AF patients, and 46.3% 
reduction in recurrent persistent AF patients.(30) 
 
 
3.1 SMART-ALERT study 
SMART-ALERT study: (study complete, analysis and preparation of manuscript ongoing) In this study 
our research group aimed to assess the feasibility and robustness of: (1) the closed-loop system 

 
14 
 
using LINQ II™ ICM remote monitoring to detect AF, (2) our custom software platform (discussed in 
section below) to alert patients of the AF episode, (3) of patients acknowledging receipt of the alert. 
We also assessed the accuracy of wearable devices during the follow-up period: the Apple Watch 
and the SkyLabs CART-I Smart Ring. We used the LINQ II as the gold standard comparator of their 
accuracy. 
Preliminary results: We recruited 50 patients with known frequent episodes of AF. Early results 
indicate this approach is reliable and accurate. On interim analysis, the median time from AF episode 
detection to SMS alert was 183 minutes (3.1 hours). The median time from SMS alert to patient 
reply was 5.1 minutes. Only 1 episode took longer than 24 hours for the patient to reply. On 3 
occasions there was no patient reply. The median total time from AF episode detection to patient 
reply was 296.5 minutes (4.9 hours) and 94% of replies occurred within 24 hours. 
In the context of the RESPOND-AF study, a median time of 4.9 hours from AF episode detection to 
commencing oral anticoagulation would be deemed safe and appropriate. In fact, most of the 
patient responses in SMART-ALERT occurred within 1 - 3 hours. 
These timings represent the combined results from versions 1.0, 2.0 and 3.0 of our custom software 
programme. The earlier versions had intermittent technical issues, with periods of the software 
programme crashing and not automatically restarting. On these occasions manual restart of the 
software programme was required. This resulted in occasions with delays to SMS alerts being sent to 
patients while versions 1.0 and 2.0 of the software programme were running. Version 3.0 did not 
require any manual restart while operational, correcting the previous technical issues. 
We are undertaking further analysis of the performance of each version of the software programme. 
We expect that the detection and response times will be much improved for version 3.0 of the 
software programme. 
 
Figure 2. Preliminary results of interim analysis A) Time to AF episodes to SMS alert, B) time from 
SMS alert to acknowledgment, total time 
 
 
Wearable device performance: Our preliminary analysis has also shown episodes of AF detected by 
the LINQ II™ that were missed by the wearable devices. As an example, in one patient, over the 
course of a 6-month period with 11 AF episodes detected by the LINQ II ICM, a total of 6/11 episodes 
were missed by the wearable device (on 3 of these occasions because the device was not being 
worn).  

 
15 
 
This raises the issues of accuracy of and patient compliance with wearable devices and gives us 
confidence in our approach for RESPOND-AF in using remote-monitoring with the LINQ II™ ICM. 
 
3.2 Custom patient notification programme 
Custom Software: Our patient messaging software was developed in-house at Oxford University 
Hospitals in collaboration with BrainLogic Ltd software development company. The programme is 
designed to monitor the Medtronic Carelink™ records of our patient cohort every 5 minutes 
continuously, and alert them via SMS message when AF episodes are detected by the LINQ II™ ICM. 
The patient is prompted to acknowledge the alert with a reply SMS, and this response is logged by 
our software programme. 
During the SMART-ALERT study the custom software had two major updates to its code. These were 
in response to issues with delays to SMS alerts being sent to patients and minor ad-hoc updates due 
to CareLink™ and Google Chrome™ browser updates and/or changes. Version 3.0 ran seamlessly 
from January 2023 until study closure in June 2023 without any human intervention or manual 
restarting required. We continue to observe and analyse participant transmissions in a post-study 
clinic for patients who have completed follow-up and agreed to ongoing remote monitoring with the 
implanted cardiac monitor. 
BrainLogic will continue to host and manage the running of the software. We also maintain 
communication with the Medtronic engineering team regarding how our software interacts with the 
Carelink™ system. 
 
The overall objective of the RESPOND-AF study is to assess the feasibility of an automated approach 
to “as-required” anticoagulation. We are not assessing the performance of the LINQ II device or of 
our messaging software, which was assessed extensively during the previous SMART-ALERT study. 
RESPOND-AF is not being carried out for the purposes of seeking CE-marking for our patient 
messaging software, and we do not intend to commercialise it. The software was developed in-
house to be used solely as a research tool for patients recruited at our single-site research institution 
and will not be used outside of the remit of this study. 
 
3.3 Public and patient involvement 
Patient-public involvement:  We conducted a survey in 320 patients with a diagnosis of AF in 
collaboration with the AF association. In this survey, a quarter of patients forget to take their OAC at 
least once a week, one third has experienced side effects from taking OAC and 70% worry about 
bleeding complications. Importantly, it highlights that patients would welcome alternative stroke 
prevention strategies, and more than half (55%) would choose an as-required OAC guided by an ICM 
if this strategy was deemed safe.  
An ICM implant does not appear to be a barrier to recruitment in trials using as-required OAC. In a 
short survey of patients with a Reveal LINQ at the John Radcliffe Hospital, 92% were very satisfied 
and would have a Reveal LINQ purely as a research device.

 
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4. OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measures 
Timepoint(s) of 
evaluation of this 
outcome measure (if 
applicable) 
Primary Objective 
To investigate the reduction in 
oral anticoagulation (OAC) 
utilisation during follow-up. 
 
Primary Outcome Measures 
Calculate the proportion of time off 
anticoagulation OAC  
 
 During follow-up 
(minimum 13 months) 
Secondary Objectives 
1. Thromboembolic events 
(Ischaemic stroke, transient 
ischaemic attack (TIA) and 
systemic embolism) 
 
2. Major bleeding 
 
 
 
3. Minor bleeding 
 
 
 
4. Any stroke (ischaemic, 
haemorrhagic or undetermined). 
 
 
5. All-cause mortality 
 
 
 
6. Protocol adherence 
 
 
 
 
 
7. To assess response time from 
AF episode onset to patient 
starting as-required OAC 
Secondary Outcome Measures 
1. Calculate the rate of ischaemic 
stroke, TIA and systemic embolism in 
patients on as-required OAC 
 
 
2. Calculate the rate of major 
bleeding in patients on as-required 
OAC 
 
3. Calculate the rate of minor 
bleeding in patients on as-required 
OAC 
 
4. Calculate the stroke rate 
(ischaemic, haemorrhagic or 
undetermined) 
 
5. Calculate the rate of all-cause 
mortality in patients on as-required 
OAC 
 
6. Calculate the number of daily 
transmissions and percentage of 
patients that restarts OAC within 
24 hours of the smartphone-alert. 
 
 
7. Time from AF episode onset to 
detection, time to alerts being 
sent and acknowledged and OAC 
 
1. During follow-up 
(minimum 13 months) 
 
2. During follow-up 
(minimum 13 months) 
 
3. During follow-up 
(minimum 13 months) 
 
4. During follow-up 
(minimum 13 months) 
 
5. During follow-up 
(minimum 13 months) 
 
6. During follow-up 
(minimum 13 months) 
 
 
 
7. During follow-up 
(minimum 13 months) 

 
17 
 
being taken by the participant. 
Proportion of missed AF episodes, 
transmissions or alerts. 
 
5. STUDY DESIGN 
The objective of the RESPOND-AF study is to evaluate the feasibility  of delivering “as-required” oral 
anticoagulation (OAC) guided by continuous rhythm monitoring with an implantable cardiac monitor 
(LINQ II™ ICM) and automated patient smartphone alerts, and to assess if this approach reduces 
OAC utilisation. 
This study will recruit 50 participants with current paroxysmal or persistent AF being treated with a 
rhythm control strategy and infrequent AF episodes. The study consists of two main phases: (1) the 
active run-in period, which lasts one month, and (2) the treatment period which will last a minimum 
of 12 months.  
All potentially eligible participants will undergo an enrolment visit (Visit 1) and, if they fulfil all the 
eligibility requirements, they will enter the active run-in period and will have a LINQ II™ ICM implant 
as a Day Case Procedure. A 3-month supply of their previously prescribed oral anticoagulant will be 
issued.   
During the run-in period, participants will continue to take OAC for 30 days. Day 30 will be the start 
of the treatment period and the participant will be contacted by the research team. If participants 
meet the discontinuation criteria, they will be asked to stop OAC, otherwise they will remain on OAC 
until discontinuation criteria (freedom from AF episodes longer than 1 hour and/or daily burden of 
more than 1 hour for 30 consecutive days) are met. The purpose of the run-in period is to ensure 
that patients do not discontinue their pre-study OAC prematurely, i.e., less than 30 days after their 
last significant AF episode. 
Figure 3. Study flow chart 
 
In the treatment period patients will only be taking daily OAC if there has been an AF episode in the 
previous 30 days. If the LINQ II™ ICM detects an episode of AF meeting the initiation of OAC criteria, 

 
18 
 
it will send an alert to the CareLink™ Network. Our software programme actively screens Carelink 
every 5 minutes and will generate a patient SMS text message in response to an AF episode. The 
SMS is sent to the participant advising of the episode, prompting them to restart OAC.  They must 
respond to the notification to acknowledge receipt and confirm they have commenced their OAC.  
The software will also send an email notification to the research team that the threshold for OAC 
initiation has been met.  If there is no response from the patient within 24 hours, they will receive a 
second notification. If they do not respond to this second notification, a member of the research 
team will make direct contact with the patient (within 48 hours of AF episode onset) to ensure they 
have commenced their OAC and troubleshoot any issues they may be having.  
A member of the research team will adjudicate all alerts and contact participants within 48 hours. If 
the alert was appropriate, participants will be advised to continue OAC for at least 30 days. If, after 
reviewing the episode, the alert is deemed inappropriate (false positive alert i.e., did not meet 
criteria for OAC initiation) participants will be instructed to stop OAC and this false positive alert will 
be logged.  
Once OAC is initiated, participants may discontinue OAC if they have 30-day freedom from: 1) any 
continuous AF episode longer than 60 minutes, and 2) any AF burden of more than 1 hour in a 24-
hour period. A member of the research team will contact them by telephone to do so. 
 
Figure 4. Study algorithm for the initiation and discontinuation of oral anticoagulation (OAC) 
 

 
19 
 
As a safety measure, the LINQ II™ ICMs perform automatic transmissions every 24 hours to 
CareLink™. The research team will conduct a daily review of all transmissions. If an AF episode/AF 
burden is identified that meets initiation criteria but failed to trigger an appropriate smartphone 
alert, participants will be contacted within 24 hours and instructed to restart OAC. Any failure of the 
system to generate an alert will be reviewed and logged. 
During the study (run-in and treatment period), participants will keep a diary of any new drugs 
started, stopped or dose changes. 
At the end of the study, participants will be invited to attend the Device Clinic for a final manual 
device interrogation and full clinical review of their medical care over the previous 12 months (Visit 
2). They may choose to have the LINQ II™ ICM explanted during the final visit or leave it in-situ. It can 
be deactivated or else continue to monitor the patient’s heart rhythm. The primary endpoint is total 
OAC utilisation which will be calculated by dividing the number of days on OAC by the total number 
of days during the treatment period.  
5.1 Study Timeline 
This 24-month prospective single centre feasibility study is to be conducted in 2 phases: 
1. Patient recruitment, ICM implant and data entry (20 months): during this period recruitment 
will take place and the LINQ II™ ICM will be implanted at the start of the active run-in period 
for 1 month. They will then enter the treatment period for a minimum of 12 months. Data 
entry to be completed within 6 weeks of enrolment and will be monitored every 2 months. 
2.  
3. Completion of data entry and analysis (4 months): to finalise the data entry, adjudicate all AF 
episodes and perform the statistical analysis. A final wrap up meeting will be convened at the 
end of the study with all key investigative staff contributing to the final report and manuscript. 
 
Figure 5.  Study timeline.  

 
20 
 
 
 
5.2 Study Risks 
 
The LINQ II™ ICM has CE marking and is used in routine clinical practice; the implant procedure is 
safe and minimally invasive.  The procedure will be performed under sterile conditions and local 
anaesthetic using the insertion tools supplied by the manufacturer to inject the ICM under the skin 
in the anterior chest wall. 
There are no known contraindications. Potential adverse events include: 
• 
bruising,  
• 
haematoma (<1%),  
• 
superficial infection (<1%),  
• 
keloid scar formation,  
• 
device migration, 
• 
device extrusion.  
By taking part in this study, participants understand that the stroke prevention strategy proposed is 
not the standard of care in current guidelines. Although the thromboembolic and bleeding events 
were low in the small studies that tested the hypothesis of as-required OAC with DOACs, they were 
not designed to provide a definitive answer regarding safety or efficacy of this novel management 
strategy. The initial data is nonetheless encouraging, and we believe that in a carefully selected 
population with low-risk of stroke and with low AF burden an as-required approach is safe and 
effective at preventing AF-related strokes.  
5.3 Study Benefits 
 
The main benefit from this study will before for future patients. It is important to understand if this 
novel approach to OAC in AF patients is a feasible, effective, and safe. It is important to develop a 
robust platform that can accurately monitor and notify patients during AF episodes, paving the way 
for a randomised trial testing the hypothesis of “as required” oral anticoagulation.   
A reliable as-required OAC strategy will offer the same thromboembolic protection as continuous 
OAC, whilst at the same time reducing bleeding complications, reduce oral anticoagulation 
requirement, and may reduce overall healthcare associated costs. Participants may experience these 
benefits directly while taking part in the study, as well as future patients experiencing these benefits. 
Patients may benefit directly from continuous heart rhythm monitoring during the study, which may 
help guide better clinical management decisions of their Atrial Fibrillation (ie. it may help their 
clinical team make decisions on medications, cardioversion, need for permanent pacemaker implant, 
need for AF ablation procedure). This would not be available if they were not part of this trial. The 
LINQ II™ ICM may also pick up other clinically relevant arrhythmia, which would not otherwise have 
been known about. 
 

 
21 
 
6. PARTICIPANT IDENTIFICATION 
6.1 Inclusion Criteria 
Study participants must satisfy the following conditions: 
• 
Participant is willing and able to give informed consent for participation in the trial. 
• 
Understand the risk and willing to discontinue oral anticoagulation (OAC). 
• 
Any gender aged 18 years or above. 
• 
Non-valvular paroxysmal atrial or persistent atrial fibrillation (AF) with a current rhythm 
control strategy. Paroxysmal patients must have < 3 documented or symptomatic episodes of 
>1 hour duration in the previous 3 months. Persistent patients must have been in continuous 
sinus rhythm for at least 4 weeks prior to enrolment. 
• 
CHA2DS2-VASc score between 1 and 3 in men and between 2 and 4 in women. 
• 
Able to take DOAC in guideline recommended doses.  
• 
Left atrial diameter on echocardiogram less than 5 cm (AP dimensions) or LA volume less than 
48 ml/m2. 
 
6.2 Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
• 
Any contraindication to OAC therapy with a DOAC in guideline recommended doses. 
• 
Mechanical heart valve prosthesis or moderate-to-severe mitral valve stenosis. 
• 
Permanent atrial fibrillation. 
• 
Hypertrophic cardiomyopathy. 
• 
Documented previous thromboembolic event (stroke, TIA or systemic embolism). 
• 
Spontaneous echo contrast observed in any imaging modality. 
• 
History of intracardiac thrombi. 
• 
History of congenital heart disease. 
• 
Severe chronic renal disease (eGFR <15 ml/m) or on renal replacement therapy. 
• 
Pregnant or planning pregnancy. 
• 
Indication for OAC other than atrial fibrillation. 
• 
Inability to comply with protocol. 
• 
Smartphone with OS not compatible with MyCareLink HeartTM app. 
• 
Contraindication for implantable cardiac monitor. 
• 
Visual or physical impairment that prevents ability to read and acknowledge 
smartphone/watch notifications. 
• 
As far as is practicable, language barriers between the investigators and study participants will 
be circumvented using NHS interpreters. If necessary, we will arrange for smartphone alerts 
to be sent to participants in their native language. 
 

 
22 
 
6.3 Recruitment 
The research team will screen the Arrhythmia Outpatient Clinics, Remote Device Clinics, AF Ablation 
lists and Cardioversion Lists at Oxford University Hospitals for potential participants. All members of 
the research team are part of the Cardiac Rhythm Management Care Team, and as such, all screened 
participants will be under their direct care. 
A letter of invitation, a patient information sheet (PIS) and a consent form will be given to potential 
participants at the time of the Outpatient Clinic or posted to them later.  
Patients will have the opportunity to contact the Research team if they wish to take part. A member 
of the Research team will also make a follow-up contact with potential participants after they have 
received their PIS. 
Once the potential participants have considered the information and had the opportunity to have 
their questions addressed and speak with their family members and /or GP, if they agree to take part 
in the study, they will be invited for Visit 1. 
During Visit 1, if participants are found to be eligible and wish to participate, they will have a 
Baseline Assessment performed and Informed Consent taken to enter the study. The aim is to recruit 
50 patients in total. 
Members of the clinical team (who are not members of the Research team) may also identify 
patients through their clinical practice and provide information (including a patient information 
leaflet) regarding the trial and put them in contact with the research team.  If the participants meet 
the inclusion criteria, they will be invited to participate in this study and, if they agree to participate, 
they will undergo screening and eligibility assessment. 
 
6.4 Informed Consent 
The participant must personally sign and date the latest approved version of the Informed Consent 
form before any trial specific procedures are performed. 
Written versions of the Participant Information Sheet and Informed Consent will be presented to the 
participants detailing no less than: the exact nature of the trial; 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 trial 
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/Cardiologist or other independent parties to 
decide whether they will participate in the trial. 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 

 
23 
 
the trial site, kept in a marked lever arch folder, in the Cardiology Clinical Research Fellows’ office, 
Level 2, John Radcliffe Hospital. This office is on a staff-only corridor, and the door is combination 
locked. Only members of the Cardiology Research team have access to this office. 
6.5 Screening and Eligibility Assessment 
If a participant meets the inclusion criteria they will be invited to participate in the study. After 
agreeing to participate and signing the consent form the following data will be collected: 
1. Demographics (age, gender, ethnicity) 
2. Detailed collection of medical history which should include atrial fibrillation history, previous 
cardiac procedure (cardiac surgery, atrial fibrillation ablation, direct current cardioversion), 
significant co-morbidities (including previous thromboembolic events) 
3. Imaging data recorded previously as part of standard clinical practice left ventricular systolic 
function, diastolic function, evidence of valvular heart disease, cardiac chamber size.  
4. Current medications 
5. Height, weight, and BMI 
 
6.6 Randomisation 
Not applicable. Single-arm feasibility study. 
6.7 Blinding  
Not applicable. Single-arm feasibility study.   
6.8 Baseline Assessments 
Baseline assessment will include:  
1. Detailed collection of medical history which should include atrial fibrillation history, previous 
cardiac procedure (cardiac surgery, atrial fibrillation ablation, direct current cardioversion), 
significant co-morbidities. 
2. Imaging data recorded previously as part of standard clinical practice: left ventricular systolic 
function, diastolic function, evidence of valvular heart disease, cardiac chamber size.  
3. Current medications 
4. Height, weight, and BMI 
 
6.9 Intervention – LINQ II ICM implant  
The LINQ II™ ICM will be implanted as a Day Case. The procedure will be performed under sterile 
conditions, will require local anaesthetic (lidocaine 1%), and insertion tools supplied by the 
manufacturer will be used. If there is suboptimal R-wave amplitude the operator can reposition the 
device. The operator may choose to close the wound with steri-strips, surgical glue or a suture. LINQ 
II™ ICM implant procedure is safe and minimally invasive and takes <15 minutes to do. There are no 

 
24 
 
known contraindications. Potential adverse events occur in less than 1% of procedures and include 
bruising, haematoma, superficial infection, keloid scar formation, migration or extrusion.  
The LINQ II™ ICM is in constant communication with the smartphone app through low-energy 
Bluetooth and transmits stored episodes to Medtronic servers via its smartphone app. Participants 
will be instructed to always keep the Bluetooth “on” and to permit a pop-up notification to appear 
on their smartphone if the LINQ II™ ICM loses connection with the smartphone app.  ICM recordings 
can only be accessed on Medtronic servers through the clinician web portal (Medtronic CareLink™ 
Network). The assigned study ID number will be used to register the device in the CareLink™ 
Network; thus, no identifiable patient information will be in the servers. Access to these servers is 
via the clinician web portal and it is password-protected.  Transmission reports will be downloaded 
from the Medtronic™ servers and stored in a password protected folder that will only be used in 
OUH trust computers for adjudication at the end of study. This system is part of routine clinical 
practice around the UK in according with GDPR guidelines. 
For this trial, if the LINQ II™ ICM detects an AF episode or AF burden that meet criteria for OAC 
initiation it will transmit in real-time to CareLink™. Our messaging software will then generate an 
email to the research team and a text message to the participant’s smartphone. The sender info of 
the text message will include the RESPOND-AF research team telephone number and prompts 
patients to initiate OAC. Participants will be instructed to acknowledge receipt of the notification by 
replying to the text message once they have taken their OAC, and thus record a time stamp (figure 
4). Adjudication of all alerts as either appropriate or inappropriate by members of the research team 
and participants contact will take place within 48 hours. 
 
 
Figure 6. Summary of study procedures during treatment period. 
 
 

 
25 
 
 
Figure 7.  Algorithm to improve compliance with LINQ II ICM and ensure daily transmission of monitoring data. 
 
        6.10 Subsequent Visits 
Visit 1 (Eligibility assessment, LINQII ICM Implant and Run-in period): If a participant agrees to take 
part, he/she will be evaluated against the entry criteria and exclusion criteria. Other tests, such as 
echocardiography, may be organised. If eligible, the participant will be asked to sign an informed 
consent. 
Participants will have a LINQ II ICM implant. They will be taught how to pair the LINQ II ICM to their 
smartphone and how to use the smartphone app (MyCareLink) to record and send manual 
transmissions. Participants will be given a 3-month supply of a DOAC and instructed to continue OAC 
for 30 days (run-in period). At the end of the run-in period, they will enter the treatment period and 
will be contacted by the research team to either continue on OAC (if they have not met the 
discontinuation criteria) or to discontinue their OAC and commence the "as-required” regimen 
guided by smartphone alerts. 
The investigator may consider the initiation or optimisation of anti-arrhythmic drugs at this time. 
Visit 2 (End of study): At the end of study, patients will attend Device Clinic for a final clinical review. 
At this time, they may choose to have the ICM removed. An updated medical and drug history will 
be recorded. At this point, patients will be instructed to revert to standard clinical care. 
Unscheduled visits: In addition to the protocol-specified visits, patients may be seen at any time 
throughout the study at the discretion of the investigator. This may include and it is not limited to 
visits to review medication, LINQII ICM troubleshooting, review adverse events, perform direct 
current cardioversion or other procedures such as catheter ablations. Periprocedural OAC will follow 
current ESC guidelines recommendation. 

 
26 
 
6.11 Early Discontinuation/Withdrawal of Participants  
During the trial a participant may choose to withdraw early from the trial treatment at any time.  
This may happen for several reasons, including but not limited to:   
• 
The occurrence of what the participant perceives as an intolerable AE.   
• 
Inability to comply with trial procedures.  
• 
Participant decision.  
• 
Loss to follow-up. 
 
Participants may choose to withdraw from study assessments but remain on study follow-up.  
Participants may also withdraw their consent, meaning that they wish to withdraw from the study 
completely. 
In addition, the Investigator may discontinue a participant from the trial treatment at any time if the 
Investigator considers it necessary for any reason including, but not limited to: 
• 
Pregnancy. 
• 
Ineligibility (either arising during the trial or retrospectively having been overlooked at 
screening). 
• 
Significant protocol deviation. 
• 
Significant non-compliance with treatment regimen or trial requirements. 
• 
Disease progression which requires discontinuation of the trial medication or results in 
inability to continue to comply with trial procedures.                                                                                                      
The type of withdrawal and reason for withdrawal will be recorded in the CRF.  
In case of withdrawal from the study in an early stage (before intervention), the patient data will be 
excluded from the analysis and a new participant will be enrolled.  
If the participant is withdrawn due to an adverse event, the Investigator will arrange for follow-up 
visits follow-up visits or telephone calls until the adverse event has resolved or stabilised. 
If the participant withdraws, he/she may choose to: 
• 
Continue to have the routine LINQ II ICM downloads as per clinical need. 
• 
To have the LINQ II ICM turned off. 
• 
To have the LINQ II ICM removed. The investigators will organise an outpatient procedure.   
 
6.12 Definition of end of study 
The end of the follow-up period will be when all participants have had a minimum of 12 months in 
the treatment period. The end of the study period will be 4 months after the end of follow-up. 
During this time investigator will conduct the analysis and draft a report of the findings.  

 
27 
 
9 TRIAL INTERVENTIONS  
9.1 Other Interventions 
The decision to organise a direct current cardioversion and/or optimisation of any antiarrhythmic 
medications is common in the management of AF and will be left to the Investigators discretion. 
Investigator may also decide to offer participants a catheter ablation if deemed appropriate. 
Periprocedural OAC will follow current ESC guidelines recommendation. 
 
10 SAFETY REPORTING  
10.1 Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death. 
• 
is life-threatening. 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation. 
• 
results in persistent or significant disability/incapacity. 
• 
consists of a congenital anomaly or birth defect. 
Other ‘important medical events’ may also be considered a serious adverse event when, based upon 
appropriate medical judgement, the event may jeopardise the participant and may require medical 
or surgical intervention to prevent one of the outcomes listed above. 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
10.2 Reporting Procedures for Serious Adverse Events 
A serious adverse event (SAE) occurring to a participant should be reported to the REC that gave a 
favourable opinion of the study where in the opinion of the Chief Investigator the event was 
‘related’ (resulted from administration of any of the research procedures) and ‘unexpected’ in 
relation to those procedures. Reports of related and unexpected SAEs should be submitted within 15 
working days of the Chief Investigator becoming aware of the event, using the HRA report of serious 
adverse event. 
 
10.3 Adverse Events 
Adverse events (AE) will be collected upon enrolment to the study until and including the final visit. 
All adverse events will be recorded in the CRF and should include the following: 
• 
AE. 
• 
Date of AE. 

 
28 
 
• 
Date when investigator become aware of AE. 
• 
Date of hospitalisation. 
• 
Date of discharge. 
• 
Outcome. 
• 
Whether this event constitutes a serious adverse event (SAE).  
• 
Whether this event is a clinical endpoint. 
• 
Action taken. 
All potential neurological symptoms or events will be formally assessed by stroke physicians or 
neurologists.  
Clinical endpoint definitions are according to the outcome measures in AF endorsed by the Heart 
Rhythm Society.(31) 
• 
Stroke: defined as acute episode of focal or global neurological dysfunction caused by brain, 
spinal cord, or retinal vascular injury as a result of haemorrhage or infarction. Symptoms or 
signs must persist for more than 24 hours, or if documented by CT, MRI or autopsy, the 
duration of symptoms/signs may be less than 24 hours. Stroke may be classified as ischemic 
(including haemorrhagic transformation of ischemic stroke), haemorrhagic, or 
undetermined. 
• 
Systemic embolism: defined as an acute arterial insufficiency or occlusion of the extremities 
or any non-central nervous system (CNS) organ associated with clinical, imaging, 
surgical/autopsy evidence of arterial occlusion in the absence of other likely mechanism. 
• 
Major bleeding: Fatal bleeding AND/OR symptomatic bleeding in a critical area or organ, 
such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or 
intramuscular with compartment syndrome AND/OR bleeding causing a fall in haemoglobin 
level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion of two or more units of 
blood. 
• 
Minor bleeding: All nonmajor bleeds. Minor bleeds are further divided into clinically relevant 
and not. 
11 STATISTICS AND ANALYSIS 
       11.1 Analysis of Outcome measures 
Descriptive statistics will be reported as count (percentage) for the categorical variables and mean (± 
standard deviation) for the continuous variables. The primary endpoint will be total OAC utilisation, 
which will be calculated by dividing the total number of days on OAC with the total follow-up 
duration. Adjudication of all LINQ II™ ICM electrograms will be performed by the research team to 
determine if notification was appropriate or inappropriate. The percentage of appropriate 
notifications and the mean time (± standard deviation) from notification to taking OAC will be 
measured. The associations of the measurements with the patient demography, medical history, 
imaging biomarkers, medications, etc. will be investigated. 
 

 
29 
 
12 DATA MANAGEMENT 
12.1 
Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, ICM and CIED reports and 
correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is 
no other written or electronic record of data).  All documents will be stored safely in confidential 
conditions. On all study-specific documents, other than the signed consent, the participant will be 
referred to by the study ID number, not by name. 
12.2 
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. 
12.3 
Data Recording and Record Keeping 
The participants will be identified by a unique study ID number which will be assigned following 
consent. The study ID number will be used in both hard-copies and electronic documents (Excel 
spreadsheets for analysis, PDF of device downloads). The hard copies (paper Consent forms and 
external hard-drive data backup) of data will be securely kept in the Research Fellows’ Office located 
in the John Radcliffe Hospital, Level 2 Blue Outpatients.  
The key to the study ID number will be maintained on a single document and will be kept on a 
separate folder in the PI’s office (Prof Tim Betts).  This office can only be accessed by authorised 
personnel via a door-code and it is also located in the John Radcliffe Hospital, Level 2 Blue 
Outpatients.  
For electronic records, all records will be stored securely on OUH servers (CTS01 drive >> CRM >> 
Research folder) in a separate, password-protected folder for the RESPOND-AF study. Only Research 
staff directly working on RESPOND-AF study will have access to this folder. This folder will have sub-
folders for each individual participant, named using their study ID. 
Our study will use Microsoft Excel as an electronic Case Report Form. At every new time-point of 
patient contact (patients visits or electronic transmissions) a blank eCRF template will be opened on 
Microsoft Excel and used for data input. Once data has been entered for that time-point, the file will 
be saved in the format “mm.dd.yyyy.hh.mm.studyID”. For example, for participant AF001 
transmission data entered on the 24th December 2024 at 13:45, the file would be saved as 
“12.24.2024.13.45.AF001”. The file will be saved in that participant’s individual folder on the 
RESPOND-AF research folder on OUH drive (as detailed above). 
All files will also be saved on an external password protected hard-drive for data backup, which will 
be kept securely in the Research Fellows’ Office (see above) with other physical study documents. 

 
30 
 
The participants’ names and any other identifying detail will NOT be included in any trial data 
electronic file. 
Individual Excel files for each timepoint data entry for each patient will eventually be merged to 
create a master database. This master database will be used for subsequent statistical analysis. 
The LINQ II™ ICM only transmits recordings to their company’s servers which can be accessed 
through the clinician’s web portal (CareLink™). This is the routine clinical practice in OUH for devices 
which are on remote monitoring (patients don’t have to physically attend hospital for a device 
interrogation). The assigned study ID number will be used to register the device in CareLink™; thus, 
no identifiable patient information will be held on Carelink servers. Moreover, all participants will be 
assigned to the RESPOND-AF research clinic in CareLink™ and all transmissions will be routinely 
monitored by the research team. AF alerts generated by CareLink™ will be sent to the research team 
email (respond-af@ouh.nhs.uk) and to participants’ smartphones.  Participants will acknowledge AF 
alerts by replying to a text message generated by CareLink which will include the research team 
telephone number in the sender details. Participants will be identified by their trial ID and the date 
and time will be recorded in the participant’s CRF. 
Our patient messaging software will be hosted and run 24 hours per day on Brain Logic servers. The 
only participant data held on the Medtronic Carelink system will be the anonymous study ID and 
mobile number. Therefore, the software programme and BrainLogic will only be able to "see" the 
study ID and mobile numbers for our participants. If there is a new AF transmission, our software 
programme will use the mobile number stored on Carelink to send an SMS alert to the participant. 
BrainLogic will not at any point have access to other participant details such as name, gender, DOB, 
address, hospital ID, etc. 
Access to CareLink™ is password protected. Transmission reports will be downloaded from 
CareLink™ and stored in a password-protected file that will only be used in OUH trust computers.  
13 QUALITY ASSURANCE PROCEDURES 
The study may be monitored, or audited in accordance with the current approved protocol, GCP, 
relevant regulations and standard operating procedures.  
13.1 
Risk assessment  
Not applicable 
13.2 
Study monitoring  
Not applicable 
13.3 
Study Committees  
Not applicable.  

 
31 
 
14 PROTOCOL DEVIATIONS  
A study related deviation is a departure from the ethically approved study protocol or other study 
document or process (e.g., consent process or administration of study intervention) or from Good 
Clinical Practice (GCP) or any applicable regulatory requirements. Any deviations from the protocol 
will be documented in a protocol deviation form and filed in the study master file. 
15 SERIOUS BREACHES 
A “serious breach” is a breach of the protocol or of the conditions or principles of Good Clinical 
Practice which is likely to affect to a significant degree – 
 (a) the safety or physical or mental integrity of the trial subjects; or 
(b) the scientific value of the research. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. 
In collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, 
the Sponsor will report it to the approving REC committee and the relevant NHS host organisation 
within seven calendar days.  
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki. 
16.2 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and 
with Good Clinical Practice. 
16.3 
Approvals 
Following Sponsor approval, the protocol, informed consent form, participant information sheet will 
be submitted to an appropriate Research Ethics Committee (REC), and HRA (where required) and 
host institutions 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. 
16.4 
Reporting 

 
32 
 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to 
the REC Committee, HRA (where required) host organisation, Sponsor and funder (where required). 
In addition, an End of Study notification and final report will be submitted to the same parties. 
 
16.5 
Other ethical issues 
In the event of a clinically relevant arrhythmia being detected by the ICM but not by their 
pacemaker, the research team will take steps to quickly inform the subject’s clinical team so that if 
required, it can be promptly acted upon. 
16.6 
Participant Confidentiality 
The study will comply with the General Data Protection Regulation (GDPR) and Data Protection Act 
2018, which require data to be de-identified as soon as it is practical to do so. The processing of the 
personal data of participants will be minimised by making use of a unique participant study number 
only 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 staff will safeguard the privacy of participants’ personal 
data. 
No identifiable details will be published. 
16.7 
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. 
17 FINANCE AND INSURANCE 
17.1 
Funding 
 Funding provided by Medtronic Limited. Medtronic will provide the 50 LINQ II implantable cardiac 
monitors at no cost. They have also supplied financial funding for the setup and running of the study. 
 
         17.2             Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If  a patient is 
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. 
Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University Hospitals 
NHS Foundation Trust, therefore, cannot agree in advance to pay compensation in these 
circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 

 
33 
 
17.3 
Contractual arrangements  
Appropriate contractual arrangements will be put in place with all third parties.  
18 PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases 
and any other publications arising from the study.   
Authorship will be determined in accordance with the ICMJE guidelines and other contributors will 
be acknowledged. 
19 DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY  
Ownership of IP generated by employees of the OUH rests in OUH.  The protection and exploitation 
of any new IP is managed by the IP and Research Contracts Team at OUH unless it is generated in 
collaboration with Oxford University in which case this is led by the University’s technology transfer 
office, Oxford University Innovations. 
20 ARCHIVING 
All documents will be stored securely in Clinical Fellows Research Office, Level 2 Blue Outpatients, in 
the John Radcliffe Hospitals   which requires a code to gain entrance to the office.  The documents 
will only be accessible by study staff and authorised personnel.  
The study staff will safeguard the privacy of participants’ personal data. 
 
 
21. REFERENCES 
1. 
Kirchhof P, Benussi S, et al. 2016 ESC Guidelines for the management of atrial fibrillation 
developed in collaboration with EACTS. European heart journal. 2016;37(38):2893-962. 
2. 
Kannel WB, Wolf PA, et al. Prevalence, incidence, prognosis, and predisposing conditions for 
atrial fibrillation: population-based estimates 11Reprints are not available. The American Journal of 
Cardiology. 1998;82(7, Supplement 1):2N-9N. 
3. 
Lin H-J, Wolf PA, et al. Stroke severity in atrial fibrillation: the Framingham Study. Stroke. 
1996;27(10):1760-4. 
4. 
Lamberts M, Staerk L, et al. Major Bleeding Complications and Persistence With Oral 
Anticoagulation in Non-Valvular Atrial Fibrillation: Contemporary Findings in Real-Life Danish 
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