A Prospective Observational Study of Prolonged Electrocardiographic Monitoring in Patients With Heart Failure in Sinus Rhythm or Atrial Fibrillation
Conditions: Heart Failure, Atrial Fibrillation
Sponsor: Imperial College London

version 1  23.09.2015  
 
 
 
POP-ECG-HF-AF 
 
 
 
A Prospective Observational Study of  
Prolonged Electrocardiographic Monitoring  
in Patients with Heart Failure in Sinus Rhythm or 
Atrial Fibrillation 
 
 
 
 
 
<Version 1 23.09.2015> 
 
 
 
 
MAIN SPONSOR: Imperial College London  
 
 
 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

version 1  23.09.2015  
 
 
Study Management Group 
 
Chief Investigator: John Cleland 
 
Co-investigators: Alex Lyon, Nick Peters 
 
Statistician: Jufen Zhang 
 
Study Management: Professor Cleland and Peters and Dr Lyon and Mareev supported by 
Jufen Zhang (Statistician – University of Hull) will constitute the Trial Management Group 
(TMG). No Independent Data Monitoring Committee (IDMC) or Trial Steering Committee 
(TSC) is envisaged. 
 
 
Study Coordination Centre not applicable 
 
 
Clinical Queries 
 
Clinical queries should be directed to Yura Mareev who will direct the query to the 
appropriate person 
 
 
Sponsor 
 
Imperial College London/Imperial College Healthcare NHS Trust is the main research 
Sponsor for this study.  For further information regarding the sponsorship conditions, please 
contact the Head of Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London 
5th Floor, Lab Block 
Charing Cross Hospital 
Fulham Palace Road 
London 
W6 8RF 
Tel: 0203 311 0212 
Fax: 0203 311 0203 
 
 
Funder 
 
Dr Mareev is supported by a fellowship from the European Society of Cardiology. Funding 
for monitoring patches will be provided from funds held by Professor Cleland. 
 
 
This protocol describes the POP-ECG-HF-AF study and provides information about procedures for 
entering participants.  Every care was taken in its drafting, but corrections or amendments may be 
necessary. These will be circulated to investigators in the study.  Problems relating to this study should 
be referred, in the first instance, to the Chief Investigator.  

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This study will adhere to the principles outlined in the NHS Research Governance Framework for Health 
and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data Protection 
Act and other regulatory requirements as appropriate.  
Table of Contents 
1. 
INTRODUCTION 
6 
1.1 BACKGROUND 
6 
2.  STUDY OBJECTIVES 
6 
3.  STUDY DESIGN 
6 
3.1 STUDY OUTCOME MEASURES 
7 
4. 
PARTICIPANT ENTRY 
7 
4.1 PRE-REGISTRATION EVALUATIONS 
7 
4.2 INCLUSION CRITERIA 
7 
4.3 EXCLUSION CRITERIA 
7 
4.4 WITHDRAWAL CRITERIA 
7 
5. 
ADVERSE EVENTS 
7 
5.1 DEFINITIONS 
7 
5.3 REPORTING PROCEDURES 
8 
6. 
ASSESSMENT AND FOLLOW-UP 
8 
7. 
STATISTICS AND DATA ANALYSIS 
9 
8. 
REGULATORY ISSUES 
10 
8.1 ETHICS APPROVAL 
10 
8.2 CONSENT 
11 
8.3 CONFIDENTIALITY 
11 
8.4 INDEMNITY 
11 
8.5 SPONSOR 
11 
8.6 FUNDING 
11 
8.7 AUDITS AND INSPECTIONS 
11 
9. 
STUDY MANAGEMENT 
11 
10. 
PUBLICATION POLICY 
11 
 
APPENDIX 1. 
SUMMARY OF INVESTIGATIONS, TREATMENT AND ASSESSMENTS 
12 
 
 
 
 
 
 

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GLOSSARY OF ABBREVIATIONS 
AE 
ADVERSE EVENT 
AF 
ATRIAL FIBRILLATION 
AR 
ADVERSE REACTION 
ASR 
ANNUAL SAFETY REPORT 
CI 
CHIEF INVESTIGATOR 
CRF 
CASE REPORT FORM 
DMC 
DATA MONITORING COMMITTEE 
ECG 
ELECTROCARDIOGRAM 
GAFREC 
GOVERNANCE ARRANGEMENTS FOR NHS 
RESEARCH ETHICS 
GCP 
GOOD CLINICAL PRACTICE 
GMP 
GOOD MANUFACTURING PRACTICE 
ICF 
INFORMED CONSENT FORM 
ISF 
INVESTIGATOR SITE FILE 
 
 
 
MUST 
MALNUTRITION UNIVERSAL SCREENING 
TOOL 
NHS R&D 
NATIONAL HEALTH SERVICE RESEARCH & 
DEVELOPMENT   
PI 
PRINCIPAL INVESTIGATOR 
PIS 
PARTICIPANT INFORMATION SHEET 
QA 
QUALITY ASSURANCE 
QC 
QUALITY CONTROL 
 
RCT RANDOMISED CONTROL TRIAL 
REC 
RESEARCH ETHICS COMMITTEE 
SAR 
SERIOUS ADVERSE REACTION 
SAE 
SERIOUS ADVERSE EVENT 
SDV 
SOURCE DOCUMENT VERIFICATION 
SSA 
SPECIFIC ASSESSMENT SITE 
TMG 
TRIAL MANAGEMENT GROUP 
TSC 
TRIAL STEERING COMMITTEE 
 
 
 
KEYWORDS 
Observational study, Heart falure, Atrial fibrillation, heart rate, ambulance ECG monitor, 
 
 

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STUDY SUMMARY 
 
TITLE A Prospective Observational Study of  Prolonged Electrocardiographic Monitoring 
in Patients with Heart Failure in Sinus Rhythm or Atrial Fibrillation 
DESIGN prospective observational study 
AIMS Primary Objective: To quantify, in patients with heart failure who are either in 
sinus rhythm or in atrial fibrillation, the burden of brady- and tachy-
arrhythmias and provide insights into the relationship between resting 
daytime heart rate and nocturnal heart rhythms 
Secondary Objective: Identify the relationship between the burden of brady- 
and tachy-arrhythmias and clinical events  
OUTCOME MEASURES Primary: 
 Co-primary endpoints 
1. Identification of an arrhythmia for which there is a Class I or IIa 
recommendation for treatment with medication or devices 
2. Either the above or one or more of the following (expanded endpoint) even 
if it does not otherwise meet guideline-indication for treatment:- 
• Sinus bradycardia ≤30bpm for ≥one minute  
• High-degree atrioventricular (AV) block (3rd degree or Mobitz Type I or II) 
• Pauses lasting ≥3 seconds (either sinus or AV block) 
• Frequent ventricular ectopy defined as >1,000 ectopic beats per day. 
• Ventricular tachycardia with rate ≥100 bpm for ≥5 beats. 
Secondary: Relationship of the above to all-cause mortality, cardiovascular 
mortality, hospitalization for heart failure or arrhythmia, implantation of a device 
with a capacity to pace the heart. 
POPULATION Patients with Heart failure (HF) 
ELIGIBILITY 1. 
Diagnosis of heart failure 
2. 
Treated with loop diuretics for at least six weeks 
3. 
Willing and legally able to sign informed consent 
4. 
At least 18 years of age 
5. 
New York Heart Association (NYHA) class II – IV 
DURATION 5 years (clinical phase 18 months) 
 
 
 
 
 
 
 
 

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
Patients with heart failure may experience a variety of irregular heart rhythms (arrhythmia) 
that may or may not be symptomatic. Remarkably little-detailed information on arrhythmias 
in patients with heart failure has been published in the last decade, whilst methods of 
monitoring and the management of some types of heart failure has improved dramatically 
making older studies on this topic out-of-date. The emphasis in the ‘old’ literature was on fast 
heart rhythms, but there is growing awareness that slow heart rhythms might be even more 
important. Older technologies only assessed heart rhythm over 24-48 hours, but new, 
wearable, patient-friendly devices can monitor for much longer, creating a much richer 
patient arrhythmia profile. 
We intend to conduct an observational study in patients with heart failure, investigating the 
incidence of arrhythmias using a wearable device that can monitor heart rhythm for up to 14 
days. In addition to gathering routine clinical information, research assessments include a 
symptoms questionnaire and a corridor walk test. Patients will be followed for clinical events 
(interventions for arrhythmias, hospitalisation, death) for up to 5 years. 
 
 
1.2 
RATIONALE FOR CURRENT STUDY 
The purpose of this study is to quantify the total arrhythmia burden (both slow and fast 
rhythms) in patients with heart failure using a wearable patch that can monitor the heart for up 
to 14 days. We then intend to follow the patients’ progress over the next 5 years. We may find 
serious rhythm problems, in which case we will recommend treatment according to expert 
international guidelines (Guidelines on pacing 2013 and on sudden death 2015).  
This information will provide information on the incidence of severe arrhythmias that guidelines 
indicate should be treated and of the association of less severe arrhythmias (or their absence) 
with prognosis. This should improve patient care and inform the design of further research. 
 
2.STUDY OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVE 
To quantify, in patients with heart failure who are either in sinus rhythm or in atrial fibrillation, 
the burden of brady- and tachy-arrhythmias and provide insights into the relationship 
between resting daytime heart rate and nocturnal heart rhythms 
 
2.2 
SECONDARY OBJECTIVES 
Identify the relationship between the burden of brady- and tachy-arrhythmias and clinical 
events. 
 
3.  STUDY DESIGN 
 
Observational study; non-commercial. 
Duration 5 years (clinical phase 18 months).  
400 patients with heart failure  
 
We will include patients with heart failure. We are investigating the prevalence of subclinical 
arrhythmias in this population and their association with clinical outcomes The patient will 
have a 7-14 days ambulatory ECG after which we will follow them up every 6 months for up 
to 5 years. At each time point, we will contact patients by phone or post and ask them if they 
have any hospital admissions. Every effort will be made to ensure that we know the patients 

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mortality status, before each planned follow up. We will call the patient's GP prior to making 
any direct contact with the patients. 
 
 
3.1 
STUDY OUTCOME MEASURES 
Primary:  
Co-primary endpoints 
1. Identification of an arrhythmia for which there is a Class I or IIa recommendation for 
treatment with medication or devices 
2. Either the above or one or more of the following (expanded endpoint) even if it does not 
otherwise meet guideline-indication for treatment:- 
• Sinus bradycardia ≤30bpm for ≥one minute  
• High-degree atrioventricular (AV) block (3rd degree or Mobitz Type I or II) 
• Pauses lasting ≥3 seconds (either sinus or AV block) 
• Frequent ventricular ectopy defined as >1,000 ectopic beats per day. 
• Ventricular tachycardia with rate ≥100 bpm for ≥5 beats. 
Secondary:  
Relationship of the above to all-cause mortality, cardiovascular mortality, hospitalization 
for heart failure or arrhythmia, implantation of a device with a capacity to pace the heart. 
 
4. 
PARTICIPANT ENTRY  
 
4.1 
PRE-REGISTRATION EVALUATIONS  
Review of the patients medical record for inclusion/exclusion criteria 
 
4.2 
INCLUSION CRITERIA 
 
1. 
Heart Failure 
2. 
Treated with Loop Diuretics for at least six weeks 
3. 
Willing and legally able to sign informed consent 
4. 
At least 18 years of age 
5. 
New York Heart Association (NYHA) class II - IV 
 
4.3 
EXCLUSION CRITERIA 
1. Myocardial infarction in the previous six weeks,  
2. Implanted pacemaker, including cardiac resynchronisation device, or defibrillator 
3. Already participating in an interventional randomized controlled trial assessing effects on 
morbidity and mortality (this study does not preclude participation in future clinical trials). 
 
 
4.4 
WITHDRAWAL CRITERIA 
No withdrawal criteria. Patients may decide to remove the monitoring patch, may request 
that their data are not analysed or that they are not followed up for clinical events. They may 
also decline any intervention advised based on the findings of the monitoring test. Patients 
with incomplete data for any reason will be replaced. All patients will be followed up unless 
they refuse. There are no stopping rules. 
 
5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 

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Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject 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 
 
• 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
 
5.3 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded.   
 
5.3.2 Serious AEs 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  
However, relapse and death due to heart failure, and hospitalisations for elective treatment of 
a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the London - Brent Research Ethics Committee where in the 
opinion of the Chief Investigator, the event was: 
• 
‘related’, ie resulted from the administration of any of the research procedures; 
and 
• 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
email: j.cleland@imperial.ac.uk and Y.Mareev@rbht.nhs.uk 
Please send SAE forms to: John Cleland 
Tel: 01895-823737 Bleep - 6085 (Mon to Fri 09.00 – 17.00) 
 
6. 
ASSESSMENT AND FOLLOW-UP  
SCREENING ASSESSMENTS 
None other than entry criteria. 
 

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BASELINE ASSESSMENTS 
1) Prolonged ECG (up to 7 days) monitoring using a patch-electrode  
2) Symptom Questionnaire 
3) Evaluation of NYHA functional class. 
4) Physical examination including blood pressure 
4) 6-min corridor walk distance for patients who are willing and able.   
5) Most recent, clinically indicated, haematology, biochemistry, ECG and Echo results (these 
will not be repeated for research purposes).  
 
TREATMENT PROCEDURE 
Not applicable. No protocol driven treatment. Patients will be treated according to guidelines 
if electrocardiographic abnormalities are identified. 
 
10.4 
SUBSEQUENT ASSESSMENTS 
We will contact patients every 6 months by telephone or post (according to their preference) 
or opportunistically at NHS clinics to identify hospitalizations. We will ensure that the patient 
is still alive just before making remote contact by checking the hospital electronic record and 
with the GP reception staff. Hospitalizations and deaths will also be identified through 
electronic patient records.  
 
 
Definition of end of study 
The end of the study will occur when the last patient enrolled has been followed for 5 years. 
A long-term extension is considered. Dr Mareev’s fellowship is only for 2 years and other 
personnel are required for longer follow-up. 
 
 
7. 
STATISTICS AND DATA ANALYSIS 
 
The design is a prospective, observational trial with two cohorts of 200 patients; one in sinus 
rhythm and the other in atrial fibrillation. 
 
This should generate in excess of 50 deaths in the year following observation assuming a 
substantial proportion of patients are enrolled soon after an episode of worsening heart 
failure. We will investigate which measured variables predict overall mortality, sudden death 
and out-of-hospital sudden death with a particular focus on electrocardiographic findings. We 
will investigate mode of death, if necessary, by contacting medical and nursing staff 
(including the patients GP) who attended the patient around the time of death. 
 
 
SAMPLE SIZE AND RECRUITMENT 
The sample size is based on the precision of the estimated prevalence of serious 
arrhythmia. As this is, surprisingly, virtually unknown for similar contemporary populations 
we intend to study with the proposed technology, this should be considered a pilot. 
Assuming the incidence of events is low, medium or high (eg:- 5%, 25% or 50%), 200 
patients provides a precision around these estimates of approximately ±5%, ±10% and 
±12% with 90% power.  
 
We aim to recruit this population over 12 months – this will entail enrolling about two patients 
every working day. Due to the small imposition on the patient, the lack of many exclusion 
criteria and the potential for referrals from across North-West London we believe this is 
feasible. 
 
  

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ENDPOINTS 
Primary endpoint 
1. Identification of an arrhythmia for which there is a Class I or IIa recommendation for 
treatment with medication or devices 
2. Either the above or one or more of the following (expanded endpoint) even if it does not 
otherwise meet guideline-indication for treatment:- 
• Sinus bradycardia ≤30bpm for ≥one minute  
• High-degree atrioventricular (AV) block (3rd degree or Mobitz Type I or II) 
• Pauses lasting ≥3 seconds (either sinus or AV block) 
• Frequent ventricular ectopy defined as >1,000 ectopic beats per day. 
• Ventricular tachycardia with rate ≥100 bpm for ≥5 beats. 
 
Secondary endpoints 
Relationship of the above to all-cause mortality, cardiovascular mortality, hospitalization for 
heart failure or arrhythmia, implantation of a device with a capacity to pace the heart. 
 
STATISTICAL ANALYSIS PLAN 
The design is a prospective, observational trial with two cohorts of 200 patients; one in sinus 
rhythm and the other in atrial fibrillation. 
Data will be expressed as proportions for categorical data and median with quartile range for 
continuously distributed data. 
Loss to follow-up for the primary or secondary endpoints is not anticipated. It is anticipated 
that monitoring data may not be acquired in some patients. This will be recorded. Missing 
data will not be imputed. Monitored events will be expressed as a rate per day of monitoring 
data and per patient regardless of the duration of monitoring. 
 
Primary endpoint analysis 
The primary analysis is the incidence rate of the primary composite endpoint. 
 
We will investigate factors associated with the primary point. Pre-specified variables include: 
age, sex, NYHA class, body mass index, heart rate measured at examination, left ventricular 
ejection fraction, presence of calcific aortic or mitral valve disease, left atrial volume, 
conduction abnormalities on the 12-lead ECG, serum potassium and serum creatinine.  
 
Secondary endpoint analysis 
Secondary analyses include the incidence rate of each component of the primary composite 
endpoint and their association with the above variables. 
 
Multi-variable models will be developed to investigate associations between the above 
variables, the components of the primary endpoint and all-cause mortality, cardiovascular 
mortality and the composite outcome measure. 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, including the follow-up period.   
 
 
8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
The Chief Investigator has obtained approval from the London - Brent Research Ethics 
Committee. The study must be submitted for Site Specific Assessment (SSA) at each 
participating NHS Trust.  The Chief Investigator will require a copy of the Trust R&D approval 
letter before accepting participants into the study.  The study will be conducted in accordance 
with the recommendations for physicians involved in research on human subjects adopted by 
the 18th World Medical Assembly, Helsinki 1964 and later revisions. 

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8.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration.  Signed 
participant consent should be obtained.  The right of the participant to refuse to participate 
without giving reasons must be respected. All participants are free to withdraw at any time 
from the protocol treatment without giving reasons and without prejudicing further treatment. 
 
8.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
8.4 
INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study 
 
8.5 
SPONSOR 
Imperial College London will act as the main sponsor for this study. Delegated responsibilities 
will be assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
Dr Mareev is supported by an ESC fellowship. Prof Cleland has the resources to cover costs 
of patch-monitors and statistical analysis. 
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College London under their remit 
as sponsor and other regulatory bodies to ensure adherence to GCP and the NHS Research 
Governance Framework for Health and Social Care (2nd edition).  
 
 
9. 
STUDY MANAGEMENT 
 
The day-to-day management of the study will be co-ordinated through Dr Mareev   
 
10. 
PUBLICATION POLICY 
Data ownership rights will lie with the institution. The results will be presented at local, national 
and international meetings and published in a peer-reviewed journal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1. Summary of investigations, treatment and assessments 
 
 
Baseline 
Informed consent 
X 
Demographic Data 
X 
Symptom Questionnaire 
X 
NYHA Class 
X 
Physical Examination 
X 
6 min corridor walk test (if willing & able) 
X 
Prolonged ECG (up to 14 days) monitoring 
X 
Haematology 
X (nearest in time clinical result) 
Biochemistry  
X (nearest in time clinical result) 
ECG 
X (nearest in time clinical result) 
Echo  
X (nearest in time clinical result) 
   
 
 

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Patient Study Number: 
 
 
INFORMED CONSENT FORM 
 
 
Full Title of Project: A Prospective Observational Study of Prolonged Electrocardiographic 
Monitoring in Patients with Heart Failure in Sinus Rhythm or Atrial Fibrillation 
 
 
 
Name of Principal Investigator: Dr  Alex Lyon and Dr Rebecca Lane 
 
 
Please initial the boxes 
1. I confirm that I have read and understand the information sheet (Version 3, 14-12-2015) 
for the above study. I have had the opportunity to consider the information, 
       ask questions and have had these answered satisfactorily. 
 
2. I understand that my participation is voluntary and that I am free to withdraw at any time 
       without giving any reason, although data collected until that point may be used for research  
       purposes with my agreement, without my medical care or legal rights being affected. 
 
3. I understand that sections of my medical notes relating to the study, may be looked at by 
regulatory bodies conducting inspections which may include members of staff within the 
        NHS Trust who are outside of the immediate clinical and research teams. I give 
        permission for these individuals to have access to my records. 
 
                         
4. I agree to my GP being informed of my participation in the study.                
 
 
5. I agree to take part in the above study. 
 
 
 
6. I wish to receive feedback on the study results when available. 
 
 
 
Name of Patient  
 Date 
 
Signature 
 
 
Name of Person taking consent 
Date 
Signature 
(if different from researcher) 
 
 
Researcher 
Date   
Signature