Conditions: Permanent Atrial Fibrillation
Keywords: Atrial fibrillation Quality of life Left ventricular ejection fraction Diastolic function Echocardiography Beta-blockers Digoxin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 161
Healthy volunteers: no

Brief summary:
Atrial fibrillation is a common heart rhythm disturbance, causing important discomfort for patients, a high risk of stroke, frequent hospital admissions and a two-fold increase in death. The number of patients with this condition are expected to double in the next 20 years. Medications to control heart-rate are used in the majority of patients, although the choice of agent is often guided by local preference rather than evidence from controlled trials. Despite the fact that patients with atrial fibrillation have high rates of other cardiac conditions such as heart failure, clinicians have insufficient evidence to personalise the use of different therapies. This feasibility study will allow us to develop a range of methods that can characterise patients according to the pumping and relaxing function of the heart, the burden of symptoms and to identify new blood markers. In this way, the investigators hope to improve clinical practice guidelines, allowing doctors to prescribe appropriate treatments for the right patients.

The research will be focused around a randomised trial of two medication strategies, providing much-needed data on the comparison of digoxin and beta-blockers (two commonly-used drugs in patients with atrial fibrillation). It will also allow us to identify the best way to record patient-reported quality of life and develop robust techniques to determine heart function using non-invasive imaging, facilitating the conduct of a large-scale clinical trial. The key objectives of the research programme are to define the optimal medications for patients with atrial fibrillation and identify the most valid, reproducible and cost-effective methods to examine patients. The ultimate aim of the project is to improve clinical outcomes in atrial fibrillation, benefiting patients, the National Health Service and the global community.

Detailed description:
Atrial fibrillation (AF) is an increasingly common cardiac condition that leads to a substantial burden on quality-of-life (QoL), an increased risk of cardiovascular events, hospitalisation and death, and significant healthcare costs for the NHS. In addition to anti-coagulation and considerations for rhythm control therapy, most patients with AF are in need of pharmacological control of heart rate. This aspect of care has not received stringent investigation, with treatment guidelines based on small crossover studies and observational data rather than robust controlled trials. Beta-blocker monotherapy remains the first-line option in the current NICE AF guidelines consultation document, with digoxin only for sedentary patients, although this recommendation is based on 'very low-quality evidence'. The benefit of different rate-control therapies on symptoms and other intermediate outcomes (such as left-ventricular ejection fraction \[LVEF\] and diastolic function) are unknown, as are their effects on clinical events such as hospitalisation. This situation is unacceptable in light of the potential benefits and risk of different rate-control options in AF. It also limits our ability to personalise treatment according to patient characteristics.

The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial is informed by a number of in-depth systematic reviews of management and clinical outcomes in AF patients. Taken together, this information provides a sound basis to plan a major randomised controlled trial (RCT). However as trials of rate-control in AF have typically been small or uncontrolled, further information is needed before designing a trial that can assess clinical outcomes. The RATE-AF trial will allow us to define appropriate primary and secondary outcome measures and their standard deviation in a contemporary population of patients with permanent AF. This information will allow us to estimate sample size, determination of recruitment, retention and adherence policies, and to ascertain the best methods of obtaining adverse event data and reliable economic costs for a larger trial assessing cardiovascular outcomes and hospitalization. The RATE-AF trial will also be the largest RCT of its kind, allowing us to compare the effect of beta-blockers and digoxin on QoL as initial rate-control therapy in patients with permanent AF. The long-term aim of the research is to answer key questions about how to initiate therapy, stratified by relevant patient characteristics such as systolic and diastolic cardiac function, baseline symptoms and concurrent medication. The research will also define the patho-physiological mechanisms underlying AF-related symptoms, left-ventricular function and their association with adverse clinical outcomes, and to identify clinical markers for the response to different rate control therapy.

Arms:
arm 1: In Group B, oral bisoprolol will be commenced at either 1.25mg, 2.5mg or 5mg according to the treatment schedule and uptitrated, as required, to 15mg daily. Recommended additional therapy in this arm includes diltiazem. Use of digoxin is explicitly discouraged but will not terminate participation in the study. If intolerance to bisoprolol occurs, investigators will be advised to try an alternate beta-blocker of their choosing (typically carvedilol, nebivolol, or metoprolol) at equivalent dosage. arm 2: In Group A, the maintenance dose of oral digoxin will be either 62.5mcg or 125mcg according to the pre-defined treatment schedule and uptitrated, as required, to 250mcg daily. A single loading dose of four tablets (250 or 500mcg according to target maintenance dose) will be prescribed in digoxin-naïve participants, where necessary. Recommended additional therapy in this arm includes the calcium-channel blocker diltiazem. Use of beta-blockers is explicitly discouraged but will not terminate participation in the study.

Interventions: intervention 1: Bisoprolol intervention 2: Digoxin
Intervention descriptions: intervention 1: Drug intervention intervention 2: Drug intervention

Protocol document:
Prot_000.pdf: 
 
 
 
Official Title 
Evaluating different rate control therapies in permanent atrial fibrillation:  
A prospective, randomised, open-label, blinded endpoint trial comparing 
digoxin and beta-blockers as initial rate control therapy 
 
RAte control Therapy Evaluation in Atrial Fibrillation: RATE-AF 
Acronym 
RATE-AF 
Document date 
25th July 2019 
 NCT number 
NCT02391337 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 2 of 71 
 
 
Evaluating different rate control therapies in permanent atrial 
fibrillation: A prospective, randomised, open-label, blinded 
endpoint trial comparing digoxin and beta-blockers as initial 
rate control therapy 
RAte control Therapy Evaluation in Atrial Fibrillation:  
RATE-AF 
 
RATE-AF TRIAL PROTOCOL 
Version 3.0, 25th July 2019 
 
Sponsor: 
 
 
University of Birmingham 
Chief Investigator:  
Dr Dipak Kotecha 
Coordinating Unit:  
Birmingham Clinical Trials Unit 
Funder: 
National Institute for Health Research (NIHR) 
Career Development Fellowship 
 
ISRCTN: 
 
 
95259705 
  
EudraCT No.:  
 
2015-005043-13 
REC Ref. No.: 
 
16/EM/0178 
 
 
 
 
 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 3 of 71 
 
 
TRIAL COMMITTEES AND CONTACT DETAILS 
Trial Management Group 
Chief Investigator  
Dr Dipak Kotecha  
NIHR Career Development Fellow & Clinician Scientist 
 
Institute of Cardiovascular Sciences, University of Birmingham, The Medical School, 
Vincent Drive, Birmingham, B15 2TT, UK 
Email: d.kotecha@bham.ac.uk 
Telephone: 07974 115676 
 
Prof Paulus Kirchhof 
 
Professor of Cardiovascular Medicine 
 
Institute of Cardiovascular Sciences, University of Birmingham, Institute of Biomedical 
Research, Vincent Drive, Birmingham B15 2TT, UK 
Email: p.kirchhof@bham.ac.uk 
Telephone: 0121 414 7042 
 
Dr Michael Griffith 
 
Consultant Electrophysiologist 
 
University Hospitals Birmingham NHS Trust, Nuffield House, Queen Elizabeth Hospital, 
Birmingham, B15 2TH, UK 
Email: michael.griffith@uhb.nhs.uk  
Telephone: 0121 371 4038 
 
Prof Gregory Y H Lip 
 
Professor of Cardiovascular Medicine & Director, Haemostasis Thrombosis & 
Vascular Biology Unit 
 
Institute of Cardiovascular Sciences, University of Birmingham, City Hospital, Birmingham, 
B18 7QH, UK 
Email: g.y.h.lip@bham.ac.uk 
Telephone: 0121 5075080 
 
Prof Jonathan Townend 
 
Professor of Cardiology 
 
University Hospitals Birmingham NHS Trust, Nuffield House, Queen Elizabeth Hospital, 
Birmingham, B15 2TH, UK 
Email: john.townend@uhb.nhs.uk 
Telephone: 0121 371 4623 
 
Dr Rick Steeds 
 
Consultant Cardiologist and Head of Cardiac Imaging 
 
University Hospitals Birmingham NHS Trust, Nuffield House, Queen Elizabeth Hospital, 
Birmingham, B15 2TH, UK 
Email: rick.steeds@uhb.nhs.uk 
Telephone: 0121 371 6130 
 
Prof Melanie Calvert  
 
Professor of Outcomes Methodology 
 
Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK 
Email: m.calvert@bham.ac.uk 
Telephone: 0121 414 8595 
 
Dr Susan Jowett 
 
Senior Lecturer, Health Economics 
 
Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK  
Email: s.jowett@bham.ac.uk 
Telephone: 0121 414 7898 
 
Dr Jonathan Mathers 
 
Senior Lecturer, Qualitative and Mixed Methods Applied Health Research 
 
Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK  
Email: j.m.mathers@bham.ac.uk 
Telephone: 0121 414 6024 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 4 of 71 
 
Birmingham Clinical Trials Unit 
Prof Jon Deeks 
Professor of Biostatistics and Director, BCTU 
 
Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2TT, UK 
Email: j.deeks@bham.ac.uk 
Telephone: 0121 414 5328 
 
Gemma Slinn 
 
Team Leader – Trials Management 
 
Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2TT, UK 
Email: g.slinn@bham.ac.uk 
Telephone: 0121 415 8445 
 
Sukhi Sehmi 
 
Trial Manager 
 
Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2TT, UK 
Email: rate-af@trials.bham.ac.uk   
Telephone: 0121 415 8445 
 
Samir Mehta 
 
Statistician 
 
Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2TT, UK 
Email: s.mehta.1@bham.ac.uk  
Telephone: 0121 415 9117 
Trial Oversight Committee 
Co-Chairs 
 
Dr Kazem Rahimi 
 
 
 
 
 
 
 
Prof. John Camm 
 
 
 
Associate Professor of Cardiovascular Medicine, University of Oxford 
Deputy Director, The George Institute for Global Health 
 
The George Institute for Global Health, University of Oxford, 34 Broad Street, Oxford OX1 
3BD, UK 
Email: kazem.rahimi@georgeinstitute.ox.ac.uk  
Telephone: 01865 617 201 
 
BHF Professor of Clinical Cardiology 
 
St George’s University of London,  Cranmer Terrace, London SW17 0RE, UK 
Email: jcamm@sgul.ac.uk 
Telephone: 0208 725 3414 
 
Patient Representatives 
 
Mary Stanbury 
 
Sandra Haynes, MBE 
 
Jacqueline Jones 
 
Email: dms27@btinternet.com  
 
Email: sandrahaynes64@googlemail.com 
 
Email: jones33@btopenworld.com 
 
On behalf of the Trial Management Group 
 
Dr Dipak Kotecha  
 
Prof. Jon Deeks 
 
Prof. Paulus Kirchhof 
 
 
 
For contact details, see Trial Management Group 
 
 
 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 5 of 71 
 
 
RATE-AF Trial Office 
For general protocol related queries and supply of trial materials: 
 
Birmingham Clinical Trials Unit (BCTU), Institute of Applied Health Research, College of 
Medical & Dental Sciences, Public Health Building, University of Birmingham, Edgbaston, 
Birmingham B15 2TT 
 
 
Telephone: 0121 415 8445 
Fax: 0121 415 8871 
Email: RATE-AF@trials.bham.ac.uk 
Website: www.birmingham.ac.uk/RATE-AF 
 
 
 
Randomisation 
Telephone: 0800 953 0274 
Website: https://www.birmingham.ac.uk/RATEAF  
 
Safety Reporting 
Fax SAE Forms to: 0121 415 9135 or 0121 415 8871 
 
 
 
 
 
 
Compliance statement 
 
This protocol describes the RATE-AF study only. The protocol should not be used as a guide for the treatment 
of patients not taking part in the RATE-AF study.  
 
The study will be conducted in compliance with the approved protocol, UK Policy Framework for Health and 
Social Care Research 2017, the latest Data Protection legislation , the principals of Good Clinical Practice 
as defined by the European Good Clinical Practice (GCP) Directive and the Medicines for Human Use 
(Clinical Trials) Regulations 2004 (SI 2004 No. 1031) and subsequent amendments. Every care has been 
taken in the drafting of this protocol, but future amendments may be necessary, which will receive the 
required approvals prior to implementation. 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 6 of 71 
 
 
Protocol Development and Sign Off 
Protocol Amendments 
The following amendments and/ or administrative changes have been made to this protocol since the 
implementation of the first approved version 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of amendment 
Summary of amendment 
1 
19 July 2017 
1.0 
Substantial 
Addition of PIC 
2 
23 January 
2018 
2.0 
 
Substantial 
Amendment to protocol  
 Inclusion of 2 sub-
studies (Section 9.9) 
 Option to consent 
patients already 
recruited to RATE-AF 
to sub-studies 
 Amendment to 
optional consent form 
 Addition of patient 
information leaflet for 
optional sub-studies 
 Administrative 
changes  
 Update of references 
3 
25th July 
2019 
3.0 
Substantial 
Amendment to the 
protocol:  
 Trial Manager section 
has been updated 
 Section 10.1- safety 
information has been 
edited with revised 
with new text 
 Data Protection text 
has been edited 
throughout  the 
protocol 
 Section 9.9- additional 
information has been 
added  
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 7 of 71 
 
Chief Investigator Signature Page 
 
 
Trial Name:  
 
 
RATE-AF 
Protocol Version Number: 
Version: __ __ 
Protocol Version Date: 
__ __ / __ __ __ / __ __ __ __ 
 
 
This protocol has been approved by: 
 
CI Name:  
 
Dr Dipak Kotecha 
Trial Role: 
 
Chief Investigator 
 
Signature and date: 
 
_________________________          __ __ / __ __ __ / __ __ __ __ 
 
 
 
 
 
Sponsor Statement  
Where the University of Birmingham takes on the sponsor role for protocol development oversight, 
the signing of the IRAS form by the Sponsor will serve as confirmation of the approval of this protocol. 
 
 
 
 
 
 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 8 of 71 
 
Principal Investigator Signature Page 
Principal Investigator: 
I have read and agree to the protocol, as detailed in this document. I agree to adhere to the protocol 
as outlined and agree that any suggested changes to the protocol must be approved by the Trial 
Oversight Committee prior to seeking approval from the Research Ethics Committee and Regulatory 
Authority. 
I am aware of my responsibilities as an Investigator under the guidelines of Good Clinical Practice 
(GCP), the Declaration of Helsinki, local regulations (as applicable) and the trial protocol and I agree 
to conduct the trial according to these guidelines and to appropriately direct and assist the staff under 
my control, who will be involved in the trial. 
 
 
Trial Name:  
 
 
RATE-AF 
Protocol Version Number: 
Version: __ __ 
Protocol Version Date: 
__ __ / __ __ __ / __ __ __ __ 
 
 
PI Name:  
 
<Enter> 
Trial Role: 
 
Principal Investigator 
 
Signature and date: 
 
_________________________          __ __ / __ __ __ / __ __ __ __ 
 
 
 
 
 
 
 
 
 
 
 
The Principal Investigator should sign this page and return a copy to the RATE-AF Trial Office 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 9 of 71 
 
Table of Contents 
1 
Trial Summary ........................................................................................................... 15 
1.1 Trial Schema ............................................................................................................... 17 
2 
Introduction ............................................................................................................... 18 
2.1 Background ................................................................................................................. 18 
2.2 Epidemiology and Consequences of AF ...................................................................... 18 
2.3 Rhythm-Control in AF .................................................................................................. 19 
2.4 Lack of Evidence to Guide Rate-Control Therapy ........................................................ 19 
2.5 Patient Wellbeing ........................................................................................................ 21 
2.6 Rationale for the RATE-AF Trial .................................................................................. 21 
3 
Trial Design and Objectives ..................................................................................... 22 
3.1 Hypothesis .................................................................................................................. 22 
3.2 Primary objective ......................................................................................................... 23 
3.3 Secondary objectives .................................................................................................. 23 
3.4 Feasibility objectives .................................................................................................... 23 
3.5 Exploratory objectives ................................................................................................. 23 
4 
Selection of Participants .......................................................................................... 24 
4.1 Inclusion Criteria .......................................................................................................... 24 
4.2 Exclusion Criteria ........................................................................................................ 24 
5 
Informed Consent Process....................................................................................... 25 
6 
Enrolment and Randomisation ................................................................................ 26 
6.1 Randomisation Procedures ......................................................................................... 27 
7 
Trial Treatment .......................................................................................................... 28 
7.1 Treatment .................................................................................................................... 28 
7.2 Treatment Supply and Storage .................................................................................... 28 
7.3 Dosing Schedule ......................................................................................................... 29 
7.4 Drug Interactions and Contraindications ...................................................................... 29 
7.5 Accountability Procedures and Labelling ..................................................................... 31 
7.6 Treatment Modification ................................................................................................ 31 
7.7 Assessment of Compliance ......................................................................................... 32 
8 
Trial Procedures and Schedule of Assessments .................................................... 32 
8.1 Baseline Visit ............................................................................................................... 32 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 10 of 71 
 
8.2 Up-Titration Visits ........................................................................................................ 33 
8.3 Visit 2, Month 6 ............................................................................................................ 33 
8.4 Visit 3, Month 12 (Final Trial Assessment) ................................................................... 34 
8.5 Investigator-blinded Endpoints .................................................................................... 34 
8.6 Long Term Follow-Up .................................................................................................. 34 
8.7 Withdrawal  ................................................................................................................. 35 
8.8 Trial Duration ............................................................................................................... 35 
9 
Trial Procedures ........................................................................................................ 37 
9.1 Procedures Defined as Standard Clinical Care ............................................................ 37 
9.2 Medical History ............................................................................................................ 37 
9.3 Medication History ....................................................................................................... 37 
9.4 Physical Examination .................................................................................................. 38 
9.5 Patient Reported Outcomes ........................................................................................ 38 
9.5.1 Choice of Outcomes and Qualitative Research .................................................... 38 
9.5.2 
Data Collection for PROMs ............................................................................. 39 
9.5.3 
Outcome Appraisal ......................................................................................... 40 
9.6 Transthoracic Echocardiography ................................................................................. 40 
9.6.1 
Reproducibility and Validity of Measurements ................................................ 40 
9.6.2 
Systolic LV Function ....................................................................................... 40 
9.6.3 
Diastolic LV Function ...................................................................................... 41 
9.6.4 
Left Atrial Size and Function ........................................................................... 42 
9.6.5 
Additional Echocardiography Parameters ....................................................... 42 
9.7 Laboratory Evaluations ................................................................................................ 42 
9.7.1 
Laboratory Assays .......................................................................................... 42 
9.7.2 
Cellular Response to Rate Control ................................................................. 43 
9.7.3 
Stored Blood Samples .................................................................................... 43 
9.7.4 
Specimen Preparation, Handling, Storage and Shipment ............................... 43 
9.8 Economic Evaluation ................................................................................................... 43 
9.9 Heart rate and physical activity monitoring  ................................................................. 44 
9.10 Heart rate and sympathetic nerve function................................................................. 46 
10 
Pharmacovigilance ................................................................................................... 48 
10.1 Recording and Assessment of Adverse Events ......................................................... 48 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 11 of 71 
 
10.2 Non-Serious Adverse Events/ Adverse Reactions ..................................................... 50 
10.3 Serious Adverse Events ............................................................................................ 50 
10.3.1 
Expected SAEs NOT to be Reported on a SAE Form ..................................... 50 
10.4 SUSARs .................................................................................................................... 51 
10.5 Development Safety Update Reports......................................................................... 51 
10.6 Annual Progress Reports ........................................................................................... 51 
10.7 Pregnancy ................................................................................................................. 51 
10.8 Reporting Urgent Safety Measures ............................................................................ 51 
11 
Quality Control and Quality Assurance ................................................................... 52 
11.1 Site Set-Up and Initiation ........................................................................................... 52 
11.2 Central Monitoring ..................................................................................................... 52 
11.3 Audit and Inspection .................................................................................................. 52 
11.4 Notification of Serious Breaches ................................................................................ 53 
11.5 Data Handling and Analysis ....................................................................................... 53 
11.6 End of Trial ................................................................................................................ 54 
11.7 Archiving ................................................................................................................... 55 
12 
Statistical Considerations ........................................................................................ 55 
12.1 Outcome measures ................................................................................................... 55 
12.1.1 
Primary Outcome ........................................................................................... 55 
12.1.2 
Secondary Outcomes ..................................................................................... 55 
12.1.3 
Feasibility Outcomes ...................................................................................... 55 
12.2 Power Calculations .................................................................................................... 56 
12.3 Statistical analysis ..................................................................................................... 56 
12.3.1 
Primary outcome analysis............................................................................... 57 
12.3.2 
Feasibility and Secondary outcomes analysis ................................................. 57 
12.3.3 
Missing data and sensitivity analyses ............................................................. 57 
12.3.4 
Interim analyses and Stopping rules ............................................................... 57 
12.4 Final analysis ............................................................................................................. 58 
13 
Ethics and Regulatory Requirements ...................................................................... 58 
14 
Oversight Committees .............................................................................................. 59 
14.1 Trial Management Group ........................................................................................... 59 
14.2 Trial Oversight Committee ......................................................................................... 59 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 12 of 71 
 
14.3 Protocol amendments ................................................................................................ 59 
15 
Finance ...................................................................................................................... 59 
16 
Confidentiality and Data Protection ......................................................................... 59 
17 
Insurance and Indemnity .......................................................................................... 60 
18 
Dissemination and Publication ................................................................................ 60 
19 
References ................................................................................................................ 62 
Appendix A: Randomised treatment arm - Digoxin 
Appendix B: Randomised treatment arm - Bisoprolol 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 13 of 71 
 
List of Abbreviations  
 
ABPI  
Association of the British Pharmaceutical Industry 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
BCTU 
Birmingham Clinical Trials Unit 
BNP 
B-type Natriuretic Peptide 
BPM 
Beats per Minute 
CCB 
Calcium Channel Blocker 
CI 
Chief Investigator 
CMR 
Cardiac Magnetic Resonance 
CRF 
Case Report Form 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Medicinal Product 
DIBD 
Developmental International Birth Date 
DMC 
Data Monitoring Committee 
DSUR 
Developmental Safety Update Report 
DT 
Deceleration Time 
ECG 
Electrocardiogram 
EHRA 
European Heart Rhythm Association 
EU  
European Union   
EudraCT No. 
European Union Drug Regulating Authorities Clinical Trials Number 
GCP  
Good Clinical Practice  
GFR 
Glomerular Filtration Rate 
GP 
General Practitioner  
HF 
Heart Failure 
HR 
Hazard Ratio 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
ISRCTN 
International Standard Randomised Controlled Trial Number 
IVRT 
Isovolumic Relaxation Time 
LA 
Left-Atrial 
LV 
Left-Ventricular 
LVEDD 
Left-Ventricle End-Diastolic Dimension 
LVEDV 
Left-Ventricle End-Diastolic Volume 
LVEF 
Left-Ventricular Ejection Fraction 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 14 of 71 
 
LVESD 
Left-Ventricle End-Systolic Dimension 
LVESV 
Left-Ventricle End-Systolic Volume 
LVSD 
Left-Ventricular Systolic Dysfunction 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MREC 
Main Research Ethics Committee 
NHS 
National Health Service 
NICE 
NOAC 
National Institute of Clinical Excellence 
Novel Oral Anticoagulants  
NYHA 
New York Health Association 
PEF 
Preserved Ejection Fraction 
PI 
Principal Investigator  
PIC 
Patient Identification Centre 
PIL 
Participant Information Leaflet 
PROBE  
Prospective Randomised Open Blinded End-point 
QALY 
Quality-Adjusted Life Year 
QoL 
Quality of Life 
R&D 
Research and Development 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
TDI 
Tissue Doppler Imaging 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UHB 
University Hospitals Birmingham 
WTCRF 
NIHR Wellcome Trust Clinical Research Facility at Queen Elizabeth 
Hospital, Birmingham 
 
 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 15 of 71 
 
1 
Trial Summary 
Title 
Evaluating different rate control therapies in permanent atrial 
fibrillation: A prospective, randomised, open-label, blinded endpoint 
trial comparing digoxin and beta-blockers as initial rate control 
therapy 
 
RAte control Therapy Evaluation in Atrial Fibrillation: RATE-AF 
Acronym 
RATE-AF  
Trial Design and Methods 
 
 
 
A prospective, randomised, open-label, blinded-endpoint (PROBE) trial 
design. The RATE-AF trial combines hypothesis testing (quality of life, 
cardiac function, exercise capacity and biomarkers), evaluation of 
measures (validity, reproducibility and correlation of outcomes) and a 
feasibility study for a future clinical event trial (assessing recruitment, 
retention and sample size). 
Trial Medications 
Digoxin 62.5 – 250 μg od 
Bisoprolol 1.25 – 15 mg od 
Trial Outcomes 
Primary Outcome: 
Patient-reported quality of life (QoL): SF-36 physical component summary 
score at six months 
Secondary Outcomes: 
Patient-reported QoL: 
 
SF-36 global and domain-specific scores at 6 and 12 months 
 
EQ-5D-5L summary index and visual analogue scale at six and 
twelve months  
 
AFEQT overall score at six and twelve months 
Cardiac function: 
 
Echocardiographic LVEF at 12 months 
 
Diastolic function (E/e’ and composite of diastolic indices) at 12 
months 
Functional assessment: 
 
Six-minute walking distance at 6 and 12 months 
 
Change in European Heart Rhythm Association (EHRA) class at 6 
and 12 months 
Biomarkers: 
 
Change in B-type natriuretic peptide (BNP) levels at 6 months 
Change in heart rate using 24-hour ambulatory ECG 
Feasibility Outcomes:  
Recruitment target of 3 patients per week across all participating centres.  
Compliance and reasons for non-compliance  
Number of withdrawals and losses to follow-up (with reasons) 
Drug discontinuation rate and adverse reactions requiring drug 
discontinuation. 
Number of patients needing therapy-induced requirement for additional 
treatment 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 16 of 71 
 
Population-specific standard deviations (SD) and proportions: 
 
SD of SF36 physical functioning score at 6 and 12 months  
 
SD of SF36 overall score at 6 and 12 months 
 
SD of AFEQT overall score at 6 and 12 months 
 
SD of LVEF and E/e’ scores at 6 and 12 months  
 
Unplanned hospitalisation admissions rates 
Cardiovascular Events (particularly mortality, thromboembolic events, 
myocardial infarction and cardiovascular interventions)  
Trial Duration per Participant 
12 months of trial therapy 
Planned Trial Sites 
Multiple screening sites with single site recruitment 
Total Number of Participants  160 
Main Inclusion/ Exclusion 
Criteria 
Inclusion Criteria 
Adult patients, aged 60 years or older 
Permanent AF, characterised (at time of randomisation) as a physician 
decision for rate-control with no plans for cardioversion, anti-arrhythmic 
medication, or ablation therapy 
Symptoms of breathlessness (New York Heart Association Class II or more) 
Able to provide written, informed consent 
Exclusion Criteria 
Established indication for beta-blocker therapy, e.g. myocardial infarction in 
the last 6 months 
Known contraindications for therapy with beta-blockers or digoxin, e.g. a 
history of severe bronchospasm that would preclude use of beta-blockers, 
or known intolerance to these medications 
Baseline heart rate <60 bpm  
History of second or third-degree heart block 
Supraventricular arrhythmias associated with accessory conducting 
pathways (e.g. Wolff-Parkinson-White syndrome) or a history of ventricular 
tachycardia or fibrillation 
Planned pacemaker implantation (including cardiac resynchronisation 
therapy), pacemaker-dependent rhythm or history of atrioventricular node 
ablation 
Decompensated heart failure (evidenced by need for intravenous inotropes, 
vasodilators or diuretics) within 14 days prior to randomisation 
A current 
diagnosis of 
obstructive 
hypertrophic cardiomyopathy, 
myocarditis or constrictive pericarditis 
Received or on waiting list for heart transplantation  
Receiving renal replacement therapy 
Major surgery, including thoracic or cardiac surgery, within 3 months of 
randomisation 
Severe, concomitant non-cardiovascular disease (including malignancy) 
that is expected to reduce life expectancy 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 17 of 71 
 
1.1 Trial Schema   
 
 
 
 
 
 
 
Figure 1 
 
This protocol describes the RATE-AF trial only. The trial will be conducted in accordance with the protocol, Good Clinical Practice 
(GCP) and applicable regulatory requirements. Every care has been taken in the drafting of this protocol, but future amendments may 
be necessary, which will receive the required approvals prior to implementation. 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 18 of 71 
 
2 
Introduction  
2.1 Background 
Atrial fibrillation (AF) is an increasingly common cardiac condition that leads to a substantial burden 
on quality-of-life (QoL), an increased risk of cardiovascular events, hospitalisation and death, and 
significant healthcare costs for the NHS.  In addition to anticoagulation and considerations for 
rhythm control therapy, most patients with AF are in need of pharmacological control of heart rate.  
This aspect of care has not received stringent investigation, with treatment guidelines based on 
small crossover studies and observational data rather than robust controlled trials.1-3  Beta-blocker 
monotherapy remains the first-line option in the current NICE AF guidelines consultation document, 
with digoxin only for sedentary patients, although this recommendation is based on ‘very low-quality 
evidence’.4  The benefit of different rate-control therapies on symptoms and other intermediate 
outcomes (such as left-ventricular ejection fraction [LVEF] and diastolic function) are unknown, as 
are their effects on clinical events such as hospitalisation.  This situation is unacceptable in light of 
the potential benefits and risk of different rate-control options in AF.  It also limits our ability to 
personalise treatment according to patient characteristics. 
 
The RAte control Therapy Evaluation in Atrial Fibrillation (RATE-AF) trial is informed by a number 
of in-depth systematic reviews of management and clinical outcomes in AF patients.5-11  Taken 
together, this information provides a sound basis to plan a major randomised controlled trial 
(RCT).12, 13  However as trials of rate-control in AF have typically been small or uncontrolled, further 
information is needed before designing a trial that can assess clinical outcomes.  The RATE-AF 
trial will allow us to define appropriate primary and secondary outcome measures and their 
standard deviation in a contemporary population of patients with permanent AF.  This information 
will allow us to estimate sample size, determination of recruitment, retention and adherence 
policies, and to ascertain the best methods of obtaining adverse event data and reliable economic 
costs for a larger trial assessing cardiovascular outcomes and hospitalisation.  The RATE-AF trial 
will also be the largest RCT of its kind, allowing us to compare the effect of beta-blockers and 
digoxin on QoL as initial rate-control therapy in patients with permanent AF.  The long-term aim of 
the research is to answer key questions about how to initiate therapy, stratified by relevant patient 
characteristics such as systolic and diastolic cardiac function, baseline symptoms and concurrent 
medication.  The research will also define the patho-physiological mechanisms underlying AF-
related symptoms, left-ventricular function and their association with adverse clinical outcomes, 
and to identify clinical markers for the response to different rate control therapy.   
 
2.2 Epidemiology and Consequences of AF 
AF is a common condition that is associated with increased rates of mortality and serious morbidity, 
including stroke, worsening of heart failure, sudden death, and reduced QoL.1  The prevalence of 
AF increases with age, ranging from 0.7% in those aged 55–59 years to 17.8% in those aged above 
85.14  A doubling of both incidence and prevalence of AF is predicted in the next 20 years.15    
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 19 of 71 
 
Patients with AF are twice as likely to be hospitalised as propensity score-matched controls, with 
direct medical costs estimated to be 73% higher.16  Further, AF is an independent predictor of all-
cause mortality, with a two-fold adjusted increase in death.17, 18  While most strokes in AF can be 
prevented by oral anticoagulation, AF patients still have high cardiovascular death rates due to 
sudden death or progressive heart failure.19, 20  Patients with AF also have significantly poorer 
QoL21, experiencing a variety of symptoms including lethargy, palpitations, dyspnoea, sleeping 
difficulties and psychosocial distress.22, 23  In the context of patients diagnosed with heart failure, 
the presence of AF leads to higher rates of death and hospitalisation, independent of other risk 
variables or which condition comes first.24, 25  From observational data, 40% of AF patients will be 
diagnosed with heart failure and vice-versa16, representing a large and growing unmet clinical need 
for healthcare improvement. 
 
2.3 Rhythm-Control in AF 
Numerous large RCTs comparing rhythm-control (using arrhythmic drugs and/or cardioversion) 
versus rate-control have identified no significant difference in clinical outcomes in patients with 
persistent AF.26-30  In a number of studies, hospitalisation rates were actually higher in those 
randomised to rhythm-control.26, 29, 30  Similar findings have been shown in AF patients with heart 
failure31, 32, both in those with impaired and preserved ejection fraction.33-35  Although AF ablation 
is becoming increasingly popular to restore sinus rhythm, it remains a highly invasive method to 
improve AF-related symptoms.36, 37  At present, European and NICE treatment guidelines 
recommend ablation only in symptomatic paroxysmal AF, or as a treatment option in symptomatic 
persistent AF that is refractory to other therapy.3  Further trials are currently underway to determine 
the clinical value of prompt rhythm-control, including the Early treatment of Atrial fibrillation for 
Stroke prevention Trial (EAST).38  In light of the high recurrence rate of AF (even in patients 
receiving intensive rhythm-control therapy), rate-control is an important part of AF management in 
almost all patients.  Unfortunately, rate-control therapy has much less evidence underpinning its 
use.   
 
2.4 Lack of Evidence to Guide Rate-Control Therapy 
Rate-control in AF can be achieved with beta-blockers, non-dihydropyridine calcium-channel 
blockers (CCB), digoxin and their combinations.  Unfortunately, little data exists to assist clinicians 
in choosing appropriate first-line and subsequent therapy.  Current patterns of medication usage 
vary considerably (between and within countries).  For example, in a worldwide registry, digoxin 
was prescribed in 2877 of 10,523 patients (27.3%), compared to 1599 of 3141 (50.9%) of patients 
in the German Competence NETwork on Atrial Fibrillation (AFNET).39, 40 
Current European guidelines suggest “the choice of medication should be individualised and the 
dose modulated to avoid bradycardia”.  This recommendation (Class 1, Level B) is based on a 
systematic review of trials addressing rate-control between 1983 and 1997.41  Most of the studies 
included less than 50 participants (with several less than 10).  The majority were low quality studies, 
as assessed by the risk of bias or confounding, and follow-up was typically in the order of hours, 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 20 of 71 
 
days or weeks.  Whilst this may be sufficient to assess an acute effect on heart-rate, it provides 
limited data on the longer-term effects of different treatments or the frequency of adverse reactions.   
 
Beta-blockers are often preferred over other agents due to the prognostic benefit seen in patients 
with heart failure who are in sinus rhythm.  However, in patients with heart failure, reduced LVEF 
and concomitant AF, we have shown that beta-blockers do not reduce mortality (hazard ratio 0·97, 
95% CI 0.83-1.14; p=0.73) or cardiovascular hospital admissions (hazard ratio 0·91; 95% CI 0.79-
1.04; p=0.15).5  This distinctly contrasts with the significant benefit seen in patients with sinus 
rhythm and highlights the need for further comparative RCTs specifically in patients with AF.   
 
The most highly cited trial comparing beta-blockers and digoxin for rate-control in chronic AF was 
an open-label two-week crossover study of 5 drug regimes in 12 patients.42  Peak heart-rate after 
exercise was significantly higher in those taking digoxin compared to beta-blockers but there were 
no differences in exercise duration.  In a trial of 42 patients, rate-control was improved with 
combination beta-blocker/digoxin therapy compared to digoxin alone, however there were similarly 
no differences in exercise capacity.43  Systematic review of other small randomised studies identify 
no difference in exercise tolerance with beta-blockers, despite a lowering of heart-rate.44  From 
observational data, such as the Atrial Fibrillation Follow-up Investigation of Rhythm Management 
(AFFIRM) study, more cardiac and non-cardiac adverse effects have been noted with beta-blockers 
than digoxin (n=67 vs. n=38).28   In a 3-week crossover study of 60 participants, 10% withdrew 
during beta-blocker therapy due to adverse events.45  Those in the beta-blocker group had a 
reduction in exercise capacity on cardio-pulmonary testing and a significant increase in B-type 
natriuretic peptide (BNP, a marker of ventricular strain) compared to patients treated with calcium-
channel blockers.46   
 
Only a single RCT has been published comparing digoxin and beta-blockers in patients with AF 
and heart failure (mean LVEF 24%, n=47).47  Although there was a marginally-significant 
improvement in LVEF with carvedilol/digoxin versus placebo/digoxin, blinded withdrawal of digoxin 
then led to a deterioration in LVEF, accompanied by an increase in BNP.  There was no difference 
in the number of heart-rate pauses >3 seconds or in daytime/exercise heart-rate comparing the 
two therapies alone. 
 
Digoxin itself has been associated with an increased mortality in observational cohorts of AF 
patients48, however careful adjustment of baseline differences reject a true excess in adverse 
outcomes.49-51  In a detailed systematic review of all studies published on digoxin, we identified that 
confounding was the main reason that digoxin was associated with increased mortality in 
observational studies, and confirmed a neutral association in RCTs (risk ratio 0.99, 95% CI 0.93 to 
1.05).6  Lower rates of hospitalisation have been noted with digoxin therapy, independent of the 
type of heart failure52, however the lack of randomised data versus placebo (despite widespread 
clinical use) makes true comparison difficult.  Small RCTs comparing CCB with digoxin have been 
inconsistent; two have identified lower heart-rates with CCB but no significant difference in exercise 
capacity42, 43, one demonstrated higher post-exercise cardiac output after digoxin53 and another 
showed improved exercise duration and QoL with CCB.54  These results highlight the need for 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 21 of 71 
 
randomised data with appropriately-defined outcomes to accurately identify the benefits and risks 
of common therapies in patients with AF. 
 
An example where RCT data have impacted on clinical practice is the Rate Control Efficacy in 
Permanent Atrial Fibrillation (RACE II) trial.  This study challenged conventional wisdom that stricter 
control of heart-rate would allow time for diastolic filling and improve haemodynamics.  In summary, 
614 patients with permanent AF were randomised to strict or lenient rate-control and followed for 
2-3 years.55  There was no significant difference in the cumulative incidence of the composite 
primary outcome; 14.9% in the strict-control arm and 12.9% in the lenient-control group.  There 
were also no differences in symptoms, New York Heart Association (NYHA) class or 
hospitalisations55, 56, no interaction with baseline heart failure57, and those participants achieving 
strict rate-control required more clinic visits and higher doses of medical therapy.58  Current 
guidelines therefore suggest that lenient rate-control is acceptable, except for patients with adverse 
symptoms or clinical deterioration.1  Whilst this study provides important data on the intensity of 
rate-control in AF, the more clinically-relevant questions of how to initiate therapy and the choice 
of optimal agents for individual patients remain unanswered. 
 
2.5 Patient Wellbeing 
Patient-reported outcomes are any report of a patient’s health status (for example QoL) that is 
derived directly from the patient, without interpretation by a clinician.59  There is limited data on the 
effect of pharmacological rate-control therapy on QoL and no comparative data assessing the 
benefit of different strategies.22, 60  Rate-control has been associated with improved QoL scores in 
trials assessing rate versus rhythm-control.61, 62  In the PIAF study, over 50% of participants 
randomised to calcium-channel blockers reported an improvement in health with significant benefits 
in the physical aspects of the SF-36.63  A number of smaller studies have shown inconsistent effects 
on QoL in AF, although the data is limited by inclusion of patients with paroxysmal AF, a focus on 
heart rate and the use of a variety of QoL tools.   
 
Current QoL questionnaires can be divided into disease-specific evaluations or generic health 
assessments (such as the Short Form Health Survey SF-3664 or the EuroQol EQ-5D65, 66). However 
there is a distinct lack of knowledge regarding the mechanisms that underpin AF-related symptoms, 
the responsiveness of QoL questionnaires and their validity.60  The Atrial Fibrillation Effect on 
QualiTy-of-life (AFEQT) questionnaire was designed to address these disparities by using more 
robust methods.67  Although there is limited clinical application to-date, AFEQT has demonstrated 
sensitivity to clinical change.68  An important objective of the research is to ascertain appropriate 
and responsive QoL tools for this population, as well as determine the acceptability and delivery of 
the questionnaires to patients.   
 
2.6 Rationale for the RATE-AF Trial 
Rate-control is an integral part of management in all AF patients but hardly any controlled trial 
evidence exists to guide the choice of agents.  We have shown that neither beta-blockers nor 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 22 of 71 
 
digoxin has an impact on mortality in AF patients, even with concomitant heart failure, which 
highlights the need to determine treatment effects on quality of life and cardiac function.   
 
3 
Trial Design and Objectives 
RATE-AF is Prospective, Randomised Open-label Blinded Endpoint (PROBE) clinical trial 
comparing the use of digoxin and beta-blockers as initial rate control therapy. 
 
In this section, we discuss the trial design and study objectives.  Detailed outcome measures are 
listed in Section 12. 
 
Justification for a PROBE rather than a Double Blind Trial Design 
Although a double blind design would be the most robust trial design with respect to bias, it would 
not be ethical to do so in this scenario as clinicians would feel the need to add therapy according 
to heart rate.  In addition, the RATE-AF Trial aims to test a strategy of initial care.  PROBE trial 
design maintains the benefits associated with a strict randomisation procedure, while the blinded 
end points help to eliminate bias.   
 
The trial design aims for a pragmatic ‘all-comers’ approach, applicable to those seen in clinical 
practice to allow transfer of the findings to routine clinical management of patients with permanent 
AF. 
 
Assessment and Management of Risk 
This trial is categorised by the Medicines and Healthcare products Regulatory Agency (MHRA) as:  
Type A = No higher than the risk of standard medical care 
The assessment and management of risk is detailed in the separate RATE-AF Risk Assessment 
document.  An on-going evaluation of risk will continue throughout the recruitment period. 
 
3.1 Hypothesis 
Null Hypothesis for primary outcome: 
No difference in patient-reported quality of life (measured using the physical functioning domain of 
the SF36 questionnaire) when comparing a strategy of digoxin versus beta-blocker therapy for 
initial rate control in patients with permanent AF. 
 
Alternative Hypothesis: 
Use of digoxin or beta-blocker therapy as initial rate control in patients with permanent AF is 
superior based on patient reported quality of life (measured using the physical functioning domain 
of the SF36 questionnaire). 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 23 of 71 
 
3.2 Primary objective 
 
Patient-reported quality of life (QoL), with a predefined focus on physical well-being using 
the SF-36 physical component summary at six months. 
3.3 Secondary objectives 
 
Generic and AF-specific patient-reported QoL using the SF-36 global and domain-specific 
scores, the AFEQT overall score and the EQ-5D-5L summary index and visual analogue 
scale at six and twelve months. 
 
Echocardiographic left-ventricular ejection fraction (LVEF) and diastolic function (E/e’ and 
composite of diastolic indices) at twelve months. 
 
Functional assessment, including 6-minute walking distance achieved, change in European 
Heart Rhythm Association (EHRA) class and cognitive function at six and twelve months. 
 
Change in B-type natriuretic peptide (BNP) levels as a surrogate for total cardiac strain at 
six months. 
 
Change in heart rate from baseline and group comparison using 24-hour ambulatory ECG. 
 
3.4 Feasibility objectives 
 
Successful methods for recruitment   
 
Key issues that affect retention of participants, such as convenience, compliance and cross-
over (target of 85% study completion rate). 
 
Drug discontinuation rate and adverse reactions leading to drug discontinuation. 
 
Therapy-induced requirement for additional treatment (e.g. pacemaker implantation). 
 
Population-specific standard deviations and proportions to enable sample size calculation 
for a future trial. 
 
Assessment of cardiovascular outcomes including a composite of adverse clinical events 
(mortality, thromboembolic events, myocardial infarction and cardiovascular interventions). 
 
3.5 Exploratory objectives 
 
Correlation of baseline measures, including QoL questionnaires and unblinded baseline 
investigations such as QoL, BNP, LVEF, E/e’, EHRA, intracellular methods and heart rate. 
 
Impact of therapy on intracellular sodium and calcium concentration and cardiotonic steroid 
levels as biomarkers of cellular response at six and twelve months. 
 
Impact of combination therapy on outcomes, including comparison of bisoprolol/non-
dihydropyridine calcium channel blocker (CCB) vs. bisoprolol/digoxin vs. digoxin/CCB vs. 
single therapies. 
 
Change in cognitive function at twelve months  


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 24 of 71 
 
 
Qualitative research of patient-reported QoL using focus groups to explore patient 
acceptability, optimal delivery methods and responsiveness. 
 
Assessment of the validity and reproducibility of echocardiographic measures in patients 
with AF. 
 
Correlation of serum digoxin concentration with change in QoL and intracellular methods. 
 
Cost-consequence economic analysis from an NHS perspective. 
 
4 
Selection of Participants 
Participants who potentially fulfil the inclusion criteria for this trial must have their eligibility 
confirmed by medically qualified personnel with access to and a full understanding of the potential 
participant’s medical history.  If eligibility has been assessed and documented by medically 
qualified personnel, then the process of obtaining informed consent may be delegated as 
appropriate and as documented on the RATE-AF Delegation and Signature Log.  
 
4.1 Inclusion Criteria 
 
Adult patients aged 60 years or older 
 
Permanent AF, characterised (at time of randomisation) as a physician decision for rate-
control with no plans for cardioversion, anti-arrhythmic medication, or ablation therapy 
 
Symptoms of breathlessness (New York Heart Association Class II or more) 
 
Able to provide written informed consent 
 
4.2 Exclusion Criteria 
 
Established clinical indication for beta-blocker therapy, e.g. myocardial infarction in the 
last 6 months 
 
Known contraindications for therapy with beta-blockers or digoxin, e.g. a history of 
severe bronchospasm that would preclude use of beta-blockers, or known intolerance 
to these medications 
 
Baseline heart rate <60 bpm  
 
History of second or third-degree heart block 
 
Supraventricular arrhythmias associated with accessory conducting pathways (e.g. 
Wolff-Parkinson-White syndrome) or a history of ventricular tachycardia or fibrillation 
 
Planned pacemaker implantation (including cardiac resynchronisation therapy), 
pacemaker-dependent rhythm or history of atrioventricular node ablation 
 
Decompensated heart failure (evidenced by need for intravenous inotropes, 
vasodilators or diuretics) within 14 days prior to randomisation 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 25 of 71 
 
 
A current diagnosis of obstructive hypertrophic cardiomyopathy, myocarditis or 
constrictive pericarditis 
 
Received or on waiting list for heart transplantation  
 
Receiving renal replacement therapy 
 
Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation 
 
Severe, concomitant non-cardiovascular disease (including malignancy) that is 
expected to reduce life expectancy 
 
5 
Informed Consent Process  
It will be the responsibility of the Investigator to obtain written informed consent for each participant 
prior to performing any trial related procedure. If local practice allows, this responsibility may be 
delegated by the Principal Investigator, to a Research Nurse as captured on the Site Signature and 
Delegation Log.  A Participant Information Leaflet (PIL) will be provided to facilitate this process. 
Investigators or delegate(s) will ensure that they adequately explain the aim, trial treatment, 
anticipated benefits and potential hazards of taking part in the trial to the participant. They will also 
stress that participation is voluntary and that the participant is free to refuse to take part and may 
withdraw from the trial at any time.  The participant will be given adequate time to read the PIL and 
to discuss their participation with others outside of the site research team. The participant will be 
given the opportunity to ask questions.  
 
If the participant expresses an interest in participating in the trial they will be asked to sign and date 
the latest version of the Informed Consent Form (ICF).  The participant must give explicit consent 
for the regulatory authorities, members of the research team and representatives of the sponsor to 
be given direct access to the participant’s medical records.  
 
The Investigator or delegate(s) will then sign and date the form. A copy of the ICF will be given to 
the participant, a copy will be filed in the medical notes, and the original placed in the Investigator 
Site File (ISF).  Once the participant is entered into the trial, the participant’s unique trial 
identification number will be entered on the ICF maintained in the ISF.  As part of the consent 
process, the participant will be asked to give explicit consent to their trial-related information being 
sent to the Trials Office at the University of Birmingham.   
 
This trial will include optional consent to allow linkage to patient data available in NHS routine 
clinical datasets, including primary care data (e.g. Clinical Practice Research Datalink; CPRD, The 
Health Improvement Network; THIN, QResearch), secondary care data (Hospital Episode 
Statistics; HES) and mortality data from the Office of National Statistics (ONS) through NHS Digital 
and other central UK bodies.  The consent will also allow access to other new central UK NHS 
databases that will appear in the future.  This will allow us to double check the main outcomes 
against routine data sources, and extend the follow-up of patients in the trial and collect long-term 
outcome and health resource usage data without needing further contact with the trial 
participants.  This is important as it will link a trial of treatments that may become a clinical standard 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 26 of 71 
 
of care to long-term outcomes that are routinely collected in clinical data but which may be collected 
during the follow-up period of the trial. 
 
This trial will also have optional consent for two sub-studies, further details can be found in Section 
9.9 and 9.10. Participants already recruited to RATE-AF trial will have the opportunity to consent 
to these additional sub-studies if they wish.  
 
Details of the informed consent discussions will be recorded in the participant’s medical notes.  This 
will include date of discussion, the name of the trial, summary of discussion, version number of the 
PIL given to participant and version number of ICF signed and date consent received. Where 
consent is obtained on the same day that the trial related assessments are due to start, a note will 
be made in the medical notes as to what time the consent was obtained and what time the 
procedures started.  
 
At each visit the participant’s willingness to continue in the trial will be ascertained and documented 
in the medical notes. Throughout the trial the participant will have the opportunity to ask questions 
about the trial.  Any new information that may be relevant to the participant’s continued participation 
will be provided.  Where new information becomes available which may affect the participants’ 
decision to continue, participants will be given time to consider and if happy to continue will be re-
consented.  Re-consent will be documented in the medical notes. The participant’s right to withdraw 
from the trial will remain.   
 
Electronic copies of the PIL and ICF will be available from the Trials Office and will be presented 
on the headed paper of the local institution.  Details of all participants approached about the trial 
will be recorded on the Participant Screening/Enrolment Log and with the participant’s prior 
consent, their General Practitioner (GP) will also be informed that they are taking part in the trial. 
 
6 
Enrolment and Randomisation 
A flowchart of the recruitment process is shown in the Trial Schema (Figure 1) together with the 
schedule of investigation.  Section 9 gives more detailed information of trial procedures and 
assessments. 
 
In the majority, potentially eligible participants will be identified by their Cardiologist, usually 
following referral from their General Practitioner (GP), and provided with an ethically-approved 
patient information leaflet (PIL).  The patient will then be invited to attend a baseline visit at the 
NIHR Wellcome Trust Clinical Research Facility (WTCRF) at Queen Elizabeth Hospital, 
Birmingham.  Potentially eligible participants may also be identified from inpatient referrals; these 
patients will be provided with a PIL and invited to attend a baseline visit following the same 
procedure. 
 
GP Practices in the Birmingham area may be asked to refer patients that present with AF, but are 
not on medication, to the RATE-AF Research Team at University Hospitals Birmingham (UHB).  
These patients will be given a one-page, ethics committee-approved trial summary and asked to 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 27 of 71 
 
sign a contact details form to confirm that they are happy to be contacted by a member of the 
Research Team to arrange an appointment.   
 
Prior to patients undertaking any trial-related procedures, informed consent will be obtained.  
 
Details of all patients approached about the trial should be recorded on the RATE-AF Screening & 
Enrolment Log. This Log should be maintained within the Investigator Site File. 
 
6.1 Randomisation Procedures 
After all eligibility criteria have been confirmed and informed consent has been received, the 
participants can be randomised into the RATE-AF trial. 
 
Participants will be randomised in a 1:1 ratio to either Digoxin 62.5 – 250 μg od or Bisoprolol 
1.25 – 15 mg od.  The time between randomisation and commencement of trial therapy should be 
minimised (ideally <24 hours).  Randomisation will be provided by a computer generated 
programme at the Birmingham Clinical Trials Unit (BCTU), using a minimisation algorithm to ensure 
balance between the arms with regard to important clinical variables, stratifying for baseline EHRA 
(class 1/2a and 2b/3/4) and gender.   
 
Telephone and Online Randomisation 
Participants can be randomised into the trial via a secure 24 hour internet based randomisation 
service (https://www.trials.bham.ac.uk/RATEAF) or by a telephone call to the BCTU (telephone 
number 0800 953 0274).  Telephone randomisations are available Monday-Friday, 09:00-17:00.  
For the secure internet randomisation, each site and each randomiser will be provided with a unique 
log-in username and password in order to access the online system.  Online randomisation is 
available 24 hours a day, 7 days a week, apart from short periods of scheduled maintenance and 
occasional network problems. 
 
Randomisation Forms will be provided to investigators and should be completed and used to collate 
the necessary information prior to randomisation.  Once all eligibility criteria have been provided 
and confirmed, a Trial Number and treatment allocation be given and relevant parties notified, 
including the participant’s GP. 
 
Back-up Randomisation 
If the internet based randomisation service is unavailable for an extended period of time, a back-
up paper randomisation will also be available at the BCTU.  The randomisation list will be produced 
using a random length block design.  In this instance, investigators should ring the BCTU 
randomisation service (telephone number 0800 953 0274). 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 28 of 71 
 
7 
Trial Treatment 
7.1 Treatment 
The Investigational Medicinal Products (IMPs) for this trial are Digoxin and Bisoprolol. 
 
At randomisation, participants will be allocated to open-label treatment with either Digoxin 62.5 – 
250 μg od or Bisoprolol 1.25 – 15 mg od.   
 
Digoxin 
Digoxin is a cardiac glycoside derived from the foxglove plant.  The cardiac effects of digoxin 
therapy are summarised by:  
 
Positive inotropic effects:  increased intracellular calcium due to direct inhibition of sodium-
potassium adenosine triphosphatase (Na/K-ATPase) 
 
Negative chronotropic effects:  decreased conduction velocity through the atrioventricular 
node, an increase in the effective refractory period and an increase in vagal activity leading 
to sinus node depression.     
Clinically, digoxin is commonly prescribed in two conditions, heart failure and AF. 
 
Bisoprolol 
Bisoprolol fumarate is a highly beta-1 selective adrenoreceptor blocker first approved by the U.S. 
Food and Drug Administration in 1992.  The cardiac effects of bisoprolol therapy are summarised 
by:  
 
Negative chronotropic effects:  a reduction in resting and exercise heart rate due to 
prevention of norepinephrine and epinephrine from binding to the beta-receptor in cardiac 
conduction tissue. 
 
Negative (mild) inotropic effects:  an initial fall in resting and exercise cardiac output with 
little observed change in stroke volume and only a small increase in right atrial pressure or 
pulmonary capillary wedge pressure. 
 
Clinically, bisoprolol is commonly prescribed in a range of cardiology conditions, including post-
myocardial infarction, heart failure and in patients with atrial tachyarrhythmia, including AF. 
 
7.2 Treatment Supply and Storage 
Due to the participant population and the fact that the trial closely aligns with standard care, trial 
medication may be dispensed from routine standard stock by both the pharmacy at the research 
site and community pharmacies local to the participant. Both treatments are used as per normal 
clinical practice therefore there is no additional requirement, above that of local policy, to monitor 
temperature during storage.    
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 29 of 71 
 
Digoxin 
Digoxin is available as an oral tablet in doses of 62.5, 125 and 250 μg or as an elixir (50 μg/mL).  
It is packaged in 28 or 500 tablet packs under the generic title digoxin and trade label Lanoxin.69  
Digoxin should be stored according to local policy. 
 
Bisoprolol 
Bisoprolol is available as an oral tablet in doses of 1.25, 2.5, 3.75, 5.0, 7.5 and 10 mg.  It is 
packaged as 28 tablets under the generic title bisoprolol fumarate and trade labels Cardicor and 
Emcor.69  Bisoprolol should be stored according to local policy. 
 
7.3 Dosing Schedule 
Digoxin 
An advice sheet for the investigator is presented in Appendix A. 
 
Trial maintenance doses will initially be 62.5 or 125 μg orally (at the clinician’s discretion, taking 
into account age and renal function), with planned up-titration to 125/250 μg.  The maximum trial 
dose will be 250 μg daily.   
 
A single loading dose of four tablets (250 or 500 μg according to target maintenance dose) will be 
prescribed in digoxin-naïve participants.  The clinician is permitted to omit the loading dose or 
prescribe a second, where necessary. 
 
Unblinded serum digoxin concentrations will be assessed at visits 2 and 3, with results reported 
back to the relevant clinician(s).  This process will assist in monitoring compliance, adjusting 
dosage in cases of low serum levels and avoiding toxicity.  
 
Bisoprolol 
An advice sheet for the investigator is presented in Appendix B 
 
Trial starting doses will be 1.25 or 2.5 or 5 mg (at the clinician’s discretion), with planned up-titration 
to 10 mg in increments of 1.25 or 2.5 mg.  The maximum trial dose will be 15 mg daily. No loading 
dose is required. 
 
Plasma concentrations have not shown to be associated with toxicity and are not part of standard 
clinical practice. 
 
7.4 Drug Interactions and Contraindications 
Digoxin 
Following oral administration of digoxin, approximately 60–85% of the dose is usually absorbed, 
mainly from the small intestine.  The onset of action is 0.5-2 hours and maximal effects occur in 2-


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 30 of 71 
 
6 hours.  Digoxin has a large volume of distribution and approximately 20-30% of digoxin in blood 
is bound to plasma proteins.  Metabolism is minimal but variable, with the majority of drug excreted 
unchanged in the urine by glomerular filtration and tubular secretion.  With normal renal function, 
the elimination half-life is 34-44 hours which is prolonged in patients with renal failure by two to 
threefold.  Dose adjustment is unnecessary in patients with hepatic impairment.  Therapeutic 
plasma concentrations of digoxin have been described as 0.5-2.0 ng/mL.70  In digoxin-naïve 
patients with normal renal function, approximately seven days are required to reach steady-state 
therapeutic concentrations if a loading dose is omitted.  As such, the majority of clinicians prescribe 
one or two loading doses, totalling 500 to 1000 μg over 24 hours. 
 
Caution is recommended in patients with electrolyte disturbance (due to increased risk of toxicity) 
and reduced doses are recommended in patients with renal impairment.  There are no concerns in 
pregnancy or with breast-feeding, although dose adjustment may be required.   
 
Contraindications for digoxin therapy include heart block, accessory pathway supraventricular 
tachycardia and a current diagnosis of obstructive hypertrophic cardiomyopathy, myocarditis or 
constrictive pericarditis. 
 
Digoxin has been associated with a number of adverse effects, although data from randomised 
trials show little difference in comparison to placebo, apart from cases of toxicity (2% versus 0.9% 
respectively in the DIG trial of patients with HF)71.  The most common side effects are 
gastrointestinal upset, dizziness, blurred vision, headache and rash.  In toxic states (serum levels 
>2 ng/mL), digoxin is pro-arrhythmic and can aggravate heart failure, particularly with co-existent 
hypokalaemia.  In cases of overdose, repeated early doses of activated charcoal may be given to 
reduce absorption and in severe toxicity, digoxin-specific antibody fragments are available as an 
intravenous infusion.   
 
In rigorous assessment, drug interactions with digoxin have proved inconsistent.72  Serum digoxin 
concentrations are increased by amiodarone, dronedarone, propafenone and quinidine but 
increased bioavailability with CCB and certain antibiotics (such as erythromycin and tetracycline) 
only occur in selected patients.  The risk of toxicity increases with drugs that cause electrolyte 
disturbances, such as thiazide and loop diuretics.  
 
Bisoprolol 
Following oral administration of Bisoprolol, the absolute bioavailability is approximately 80%, first 
pass metabolism of 20% and 30% protein binding.  Peak plasma concentrations occur within 2-4 
hours, the elimination half-life is 9-12 hours and steady state is attained within 5 days.  Elimination 
occurs equally by renal and non-renal pathways with about 50% of the dose remaining unchanged 
in the urine. 
 
Caution is recommended in patients with first-degree heart block, portal hypertension, diabetes, a 
history of obstructive airways disease, myasthenia gravis, a history of hypersensitivity and 
psoriasis, although many cardiologists use beta-blockers frequently in these groups with 
appropriate supervision.  In pregnancy, beta-blockers may cause intra-uterine growth restriction, 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 31 of 71 
 
neonatal hypoglycaemia, and bradycardia (although as above, these agents are frequently used in 
pregnancy).  There is a theoretical risk of toxicity in breast feeding, although the amount present in 
milk is likely too small to affect infants.  Abrupt withdrawal should be avoided, especially in cases 
of ischaemic heart disease.  Up-titration should be more cautious in patients with renal or hepatic 
impairment. 
 
Contraindications for bisoprolol therapy include cardiogenic shock, overt cardiac failure, second or 
third degree heart block, marked sinus bradycardia and severe peripheral arterial disease. 
 
Bisoprolol has been associated with a wide variety of adverse effects although data from RCTs 
suggest similar discontinuation rates compare to placebo.5, 73  The most common adverse 
symptoms are lethargy, headache, peripheral oedema, upper respiratory tract symptoms, 
gastrointestinal upset and dizziness.  In cases of overdose, bradycardia, hypotension, congestive 
heart failure, bronchospasm and hypoglycaemia may be expected, with treatment directed to 
supportive methods and atropine, fluids, glucagon or diuretics as required.   
 
Pharmacokinetic interactions with beta-blockers have not shown to be clinically significant.  Drugs 
that reduce absorption include aluminium salts and cholestyramine, whilst metabolism can be 
increased by barbiturates and rifampicin and decreased with cimetidine, erythromycin, 
fluvoxamine, and hydralazine.  
 
7.5 Accountability Procedures and Labelling 
Through the risk-adapted approach, a full risk assessment of the RATE-AF trial has been 
conducted including the drug accountability requirements.  The IMPs will be used within their 
authorisations, prescribed on an NHS prescription and dispensed by pharmacy from standard 
stock.  The risk assessment has determined that a normal dispensing label is appropriate and an 
additional clinical trial label is not necessary (as covered by Regulation 46 (2) of SI 2004/1031).   
Drug accountability will be according to standard practice for NHS prescriptions.  Details of how 
compliance will be assessed can be found in Section 7.7. 
 
7.6 Treatment Modification 
Patients that withdraw from medication for any reason will do so under strict clinical supervision. 
 
The trial is designed to assess the impact of initial impact of rate control therapy; it is expected 
that treatments will modify during the trial period (in particular, the addition of therapy to attain heart 
rate targets).  Patients will not be withdrawn from the trial if they commence therapy from the other 
arm of the trial due to any absolute or relative clinical indications (for example, patients in the 
digoxin arm starting beta-blockers due to incident myocardial infarction, or heart failure with 
reduced LVEF). 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 32 of 71 
 
7.7 Assessment of Compliance 
We will ask participants about compliance with their trial medication at each follow-up visit and this 
will be documented in the CRFs.  It may also be clinically evident from the heart rate check, 
performed as part of all visits, whether or not the patient has been compliant with their trial 
mediation. 
 
In addition, patients that are randomised to the digoxin arm will have a serum digoxin sample taken 
as part of Visit 2 (month 6) and Visit 3 (month 12) follow-ups.  The results will indicate whether the 
patient has been compliant with their trial medication. 
 
8 
Trial Procedures and Schedule of Assessments 
8.1 Baseline Visit  
The baseline visit will occur as soon as possible after screening and will involve the following 
procedures (see Section 9 for procedure details): 
 
Verify inclusion/exclusion criteria. 
 
Obtain written informed consent from the potential participant. 
 
Randomise the patient via telephone or the secure web-based system as outlined in 
Section 6 
 
Administer QoL and functional capacity questionnaires. 
 
Review recent blood results (within 6 months of Baseline Visit) 
o Assessing renal function to aid in dose assignment and serum potassium level 
as part of standard clinical care.   
 
Document the use of oral anticoagulation and arrange appropriate prescription for 
patients not on therapy according to clinical guidelines.  If the participant is already 
receiving vitamin-K antagonists (VKA), recent INR results will be documented. 
 
Record results of physical examinations. 
 
Collect blood samples for baseline blood tests and biomarker analysis. 
 
Complete case report form (CRF) 
 
Perform a 12-lead electrocardiogram. 
 
Supervise a 6-minute walk test, recording distance walked and peak heart rate. 
 
Arrange 
the 
baseline 
echocardiogram; 
images 
will 
be 
delivered 
to 
the 
echocardiographic core laboratory for blinded reporting. 
 
Discuss the randomised allocation with the participant including schedule for drug 
therapy and up-titration. 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 33 of 71 
 
Participants will be followed up by telephone call two weeks after the Baseline Visit to ensure they 
have commenced trial medication. 
 
8.2 Up-Titration Visits 
For the majority of participants, two up-titration visits will be planned to supervise the appropriate 
use of medications as per the up-titration schedule (see Appendices A and B).  Additional up-
titration visits, as required, are acceptable in order to attain a heart rate at rest of ≤100bpm. 
 
Up-titration visits will involve the following procedures: 
 
Record adverse events as reported by the participant or observed by the investigator. 
 
Review of medications and plan for trial drug up-titration 
 
Assessment of compliance 
 
Symptom-directed clinical examination 
 
Vital signs, including heart rate and blood pressure 
 
Administer QoL and functional capacity questionnaires (last uptitration visit only). 
 
Organise a 24-hour ambulatory ECG once up-titration completed (results to be forwarded to 
the clinician). 
 
8.3 Visit 2, Month 6  
Visit 2 will occur at an interval of six months (± four weeks) after the Baseline Visit and involve the 
following procedures: 
 
Administer QoL and functional capacity questionnaires. 
 
Record adverse events as reported by the participant or observed by the investigator. 
 
Confirm current rate control therapy (including dosage) and check concomitant medications. 
 
Assessment of compliance. 
 
Collect blood samples for biomarker analysis. 
 
Collect blood sample for serum digoxin concentration, potassium and creatinine as part of 
standard clinical care. 
 
Record time in therapeutic range for patients on anticoagulation with vitamin-K antagonists and 
compliance in patients receiving non-VKA oral anticoagulants. 
 
Obtain a twelve lead ECG. 
 
Record the results of physical examinations and vital signs. 
 
Supervise a 6-minute walk test, recording distance walked and peak heart rate. 
 
Complete other CRF requirements. 
 
If an echocardiogram has been performed for clinical reasons since the previous visit, images 
will be retrieved and sent to the core echocardiographic laboratory. 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 34 of 71 
 
 
Confirm appointment date for Visit 3. 
 
8.4 Visit 3, Month 12 (Final Trial Assessment) 
Visit 3 will occur at an interval of 12 months (± four weeks) after the Baseline Visit and involve the 
following procedures: 
 
Administer QoL and functional capacity questionnaires. 
 
Record adverse events as reported by the participant or observed by the investigator. 
 
Confirm current rate control therapy (including dosage) and check concomitant medications. 
 
Assessment of compliance. 
 
Transthoracic echocardiography (as per Section 9.6), with images delivered to the 
echocardiographic core laboratory for blinded reporting. 
 
Collect blood sample for serum digoxin concentration, potassium and creatinine as part of 
standard clinical care. 
 
Record time in therapeutic range for patients on anticoagulation with vitamin-K antagonists and 
compliance in patients receiving non-VKA oral anticoagulants. 
 
Obtain a twelve lead ECG. 
 
Record the results of physical examinations and vital signs. 
 
Supervise a 6-minute walk test, recording distance walked and peak heart rate. 
 
Complete other CRF requirements. 
 
If an echocardiogram has been performed for clinical reasons since the previous visit, images 
will be retrieved and sent to the core echocardiographic laboratory. 
 
Complete the end of trial standardised letter to the GP and clinician explaining that the 
participant has reached the end of the trial protocol and is no longer bound by their allocated 
medication strategy. Advise that all participants are invited for continued follow up and long 
term clinical outcome assessment. 
 
Provide final instructions to participant (e.g. follow-up of ongoing adverse events). 
 
8.5 Investigator-blinded Endpoints  
Investigator-blinded endpoints (PROMs, echocardiography and biomarkers) will be assessed by 
the core laboratory, identified only by the trial number.  Ambulatory ECG and serum digoxin level 
will remain unblinded and results delivered to the responsible clinician.   
 
8.6 Long Term Follow-Up  
In patients who have agreed to NHS data linkage, a follow-up CRF will be completed.  The CRF 
will capture items that include, but are not limited to death, hospital admissions and cardiovascular 
events.  The planned interval for outcome assessment is 2 and 5 years post-enrolment.  


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 35 of 71 
 
 
8.7 Withdrawal  
Participants may withdraw at any time during the main RATE-AF trial if they choose not to continue 
or if their clinical team feel that continued participation in the trial is inappropriate.  
An investigator may deem it necessary to withdraw a participant from the trial if: 
1) Any clinical adverse event, laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the trial would not be in the best interest of the 
participant. 
2) The participant meets an exclusion criterion (either newly developed or not previously 
recognised) that precludes further trial participation. 
Full details of the reason(s) for withdrawal should be recorded on the Case Report Forms (CRFs) 
if healthcare professional-initiated, otherwise a simple statement reflecting patient preference will 
suffice. 
Clear distinction will be made between withdrawals from trial treatments whilst allowing further 
follow-up, and any participants who refuse any follow-up.  If a participant explicitly withdraws 
consent to any further data recording, then this decision will be respected.  All communications 
surrounding the withdrawal will be noted in the participant’s records and no further data will be 
collected for the participant.  
 
In the case of missing echocardiographic outcome data due to withdrawal (but with consent for 
ongoing follow-up) or death, results of recent clinical echocardiography will be retrieved.  The 
participant’s permission to obtain such data will be obtained and documented during the consent 
process.  As with all trial echocardiograms, the scan will be reported by the core echocardiographic 
laboratory.  With respect to patient-reported outcomes, QoL questionnaires will be mailed to 
participants who withdraw from trial treatment but consent to ongoing follow up.  Those patients 
where adverse symptoms were related to withdrawal will be invited to a focus group for further 
discussion.   
 
8.8 Trial Duration 
Patients will be on trial medication for 12 months and will be followed-up, during this period 
according to the protocol.  At the end of the 12 months, the participants may, as determined by 
their clinician, continue on medication but it will not be considered part of the trial intervention. The 
trial will cease when the 12-month follow-up has been completed for the last participant recruited. 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 36 of 71 
 
 
 
Table 1: Schedule of Assessments  
Procedures 
Baseline Visit 
Up-titration Visits 
(Day 14 to 60) 
Visit 2, Month 6 
(± 4 weeks) 
Visit 3, Month 12 
(± 4 weeks) 
Assessment of eligibility criteria  
X 
 
 
 
Informed consent taken  
X 
 
 
 
Review of medical history 
X 
 
 
 
Review of medications 
X 
X 
X 
X 
Physical exam 
Complete 
X 
 
 
 
Symptom-directed 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Quality of life assessment 
X 
(X) 
X 
X 
Functional and cognitive 
assessment 
X 
 
X 
X 
Transthoracic echocardiogram 
X 
 
 
X 
12-lead electrocardiogram 
X 
 
X 
X 
6-minute walk test 
X 
 
X 
X 
24-hour ambulatory ECG 
 
X 
(X) 
 
Clinical labs 
Chemistry 
X 
 
X 
X 
Haematology 
X 
 
X 
X 
Serum digoxin 
 
 
(X) 
(X) 
Trial labs 
BNP 
X 
 
X 
X 
Stored sample 
X 
 
X 
 
Assessment of compliance 
 
X 
X 
X 
Assessment of adverse events 
 
X 
X 
X 
 
Parentheses denote where a procedure is dependent on the stage of participants within the trial. 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 37 of 71 
 
9 
Trial Procedures 
9.1 Procedures Defined as Standard Clinical Care 
The following assessments are considered part of the standard clinical care of AF patients receiving 
heart rate control therapy and will occur at all trial visits: 
 
Blood tests for haemoglobin, serum creatinine, potassium and serum digoxin concentration; 
these will be obtained by the research nurse and submitted to the site-specific hospital 
laboratory as per local guidelines and SOPs, ensuring that all specimens are accurately 
labelled and handled appropriately.  In the case of results requiring urgent action, local 
policies will be followed which may include the participant visiting their GP, local hospital or 
investigator.  In all cases, appropriate trial documentation will be completed.   
 
A 12-lead ECG; these will be completed by appropriately trained local staff. 
 
9.2 Medical History 
Medical history will be obtained by interview and from medical records (physical and electronic) at 
the Baseline Visit comprising: 
 
Cardiovascular history, including prior ischaemic coronary disease, interventions and 
surgery, history of hypertension, heart failure or hyperlipidaemia, stroke or transient 
ischaemic attack, pulmonary embolus/deep vein thrombosis and peripheral vascular 
disease. 
 
AF history, including year of diagnosis, previous cardioversions, previous ablation therapy 
and anti-arrhythmic drug history. 
 
Pacemaker history, including date and reason for implantation, type of device (single-
chamber, dual-chamber, biventricular, implanted defibrillator) and dependency. 
 
Non-cardiac history, including diabetes mellitus, airways disease (asthma/COPD), renal 
impairment, bleeding history and other major co-morbidities. 
 
Social and demographic history, including smoking status (current/ex/never), race 
(Caucasian/Indian subcontinent/Asian/African/other) and physical activity using the 
International Physical Activity Questionnaire (short form). 
 
9.3 Medication History 
Medications history will be assessed according to the categories below and include current dosage.  
Except for anticoagulation, antiarrhythmic and rate control therapies, only current medications will 
be included. 
 
Anticoagulation therapy (vitamin-K antagonists and novel agents), including past use, INR 
results and time in therapeutic range. 
 
Antiarrhythmic therapy, including past use. 
 
Rate control therapy (beta-blockers, digoxin, CCB), including past use. 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 38 of 71 
 
 
Antiplatelet therapy. 
 
Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. 
 
Aldosterone antagonists. 
 
Diuretics (loop, thiazide, potassium-sparing, others). 
 
Nitrates. 
 
Other anti-hypertensive/anti-anginal therapy. 
 
Statins. 
 
Other lipid-lowering medication. 
 
Diabetic medication and insulin. 
 
Asthma/COPD medication (including inhalers). 
 
Non-steroidal anti-inflammatory agents. 
 
9.4 Physical Examination 
Physical and vital signs will be assessed at all up-titration and trial visits.  In most cases, a targeted 
physical examination will be performed, comprising of cardiovascular elements as summarised 
below: 
 
Heart rate (manual palpation at radial artery and apex). 
 
Heart sounds. 
 
Lung auscultation. 
 
Assessment of jugular venous pressure and/or peripheral oedema. 
 
Other focused examinations according to symptoms and complaints. 
 
Blood pressure (two measurements at the right brachial in a seated position preferred, using 
a validated oscillometric device). 
 
Height (Baseline Visit only), weight (all listed visits) and waist circumference (Baseline Visit; 
defined as the narrowest point between ribs and hips when viewed from the front after 
exhaling to the nearest centimetre). 
 
9.5 Patient Reported Outcomes 
9.5.1 Choice of Outcomes and Qualitative Research 
A systematic review (according to and in collaboration with the COnsensus-based Standards for 
the selection of health Measurement Instruments, COSMIN74) is underway to evaluate PROMs in 
AF, with a focus on psychometric properties including internal consistency, reliability, and 
measurement error.  Additional assessment and practical evaluation of PROMs will follow 
published guidance75, 76, complementing qualitative research using patient focus groups, surveys 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 39 of 71 
 
and directed interviews guided by the PROMs and qualitative research centres at the University of 
Birmingham.77 
 
Instruments for assessment will be selected on the basis of overall validity, preferably in this patient 
population but including other groups where data are limited.  Patient focus groups will allow 
exploration of patient perspectives on appropriate instruments that adequately reflect the 
experience of living with AF.78  They will also allow comparison of QoL questionnaires that 
adequately summarise patient-prioritised components of their health and well-being.  Additional 
focus groups and individual interviews will occur at interim and final follow-up during the trial.  These 
aim to understand the patient experience of trial participation and processes, including the ease of 
completion of QoL questionnaires, relevance, reasons for non-completion and other feasibility 
issues that emerge during the trial e.g. non-compliance and recruitment, with reference to core 
outcome sets for this population.79  A patient and public involvement (PPI) panel will contribute to 
all stages in the focus group process.80 
 
This protocol was developed in accordance with the Standard Protocol Items for Randomized Trials 
[SPIRIT] statement81, and the latest PROM-specific guidance from the International Society for 
Quality of Life Research (ISOQOL) Best Practice taskforce.77, 82, 83  
 
9.5.2 Data Collection for PROMs 
PROMs will be assessed at all main visits (Baseline, 2 and 3) and at the participants final up-
titration visit (if applicable).  The QoL tools used will be EQ-5D-5L, SF-36 and AFEQT.  To avoid 
introducing co-intervention bias, all QoL data will be kept confidential and will not be used to inform 
clinical care.84  Patients will be advised of this in the patient information sheet.  PROMs will be 
collected at the start of each visit, before other trial procedures.  In cases where the visit coincides 
with a clinician review, questionnaires should be completed in advance.  The feasibility of using an 
online data collection tool will be explored, administered by trained research nurses and according 
to good-practice guidelines.85  We will use this trial to perform an initial small-group assessment of 
electronic PROMs-equivalence to inform a future clinical event trial.   
 
Qualitative research will be performed using a focus group of 10 volunteer patients enrolled at the 
start of the trial (5 in each randomised group).  The focus group will meet after up-titration and then 
at 6 and 12 months.  Detailed methods will be established before the first meeting, in collaboration 
with the University of Birmingham Qualitative Research Group. 
 
All staff will receive training in QoL collection, with specific guidance on reducing introduced bias, 
minimising missing data and coaching participants to use the QoL software.  Levels of missing 
PROMs data will be monitored.  The site personnel responsible for collection of patient reported 
outcomes will be the Research Nurse under the supervision of the Principal Investigator. 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 40 of 71 
 
9.5.3 Outcome Appraisal 
Each QoL tool will be scored according to their published requirements (www.euroqol.org; www.sf-
36.org; www.afeqt.org), using total and sub-category scores where appropriate. 
 
To avoid dilution of effect over time, the primary analysis will be at six months (adjusting for baseline 
QOL and stratification variables).  We have predefined a focus on physical well-being, which we 
hypothesize are where the greatest treatment effects will be observed, but will explore all aspects 
of QoL.  Exploratory analysis of medication effects over the 12-month period will also be analysed 
and remain clinically important, as little data currently exists on the longer-term profile of QoL in 
AF.   
 
Qualitative research outcomes will focus on the clinical responsiveness of the QoL instruments.  
The findings of the COSMIN systematic report will determine these outcomes and their relevant 
appraisal. 
 
The RATE-AF trial will allow us to gain an initial understanding and framework of the patient 
experience of AF.  We aim to begin the process of determining appropriate and responsive PROMs 
for AF patients and the optimum methods for delivery into a subsequent large-scale clinical trial.  
 
9.6 Transthoracic Echocardiography  
Echocardiography will be performed at Visits 1 and 3 and focus on systolic left-ventricular (LV) 
function, diastolic function and left-atrial assessment.  Images will be obtained by an accredited 
echocardiographer.  All trial echocardiograms will be labelled with the Trial Number and 
pseudoanonymised patient data, with specific instruction that the echocardiographer will remain 
blinded to the treatment assignment.  All images will be archived to the core echocardiographic 
laboratory, with a copy retained in the site file. 
 
9.6.1 Reproducibility and Validity of Measurements 
Inter-observer and intra-observer variability in measurement will be assessed by comparing results 
of the stated methods discussed below across the cardiac cycle.  To evaluate the minimum number 
of repeat measurements required that maintains clinical utility, reproducibility of single 
measurements will be compared to averages of 3/5/10 beats.  This will also include the reliability 
of using an ‘index beat’ with a cycle length equivalent to a heart rate of 70-80 beats per minute, or 
with similar preceding and pre-preceding RR intervals.   
 
9.6.2 
Systolic LV Function 
Systolic LV function will be determined by the following methods: 
 
Two-dimensional biplane Simpson’s method utilising the simultaneous multi-planar 
approach to obtain LVEF in a single heartbeat (four and two-chamber views).  In each view, 
LV end-diastolic and end-systolic volumes (LVEDV, LVESV) are computed, with LVEF 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 41 of 71 
 
calculated as (LVEDV – LVESV) / LVEDV.  Two-dimensional echocardiography has 
excellent spatial resolution but is limited by potential foreshortening of the ventricular apex 
and drop-out of the endocardial border. 
 
Standard Simpson’s biplane method with four and two-chamber volumes obtained from 
separate heartbeats.  This is the conventional method in current clinical use but is limited 
by varying RR intervals in AF. 
 
Fractional shortening on M-mode along the minor-axis of the left-ventricle (parasternal long-
axis), calculated by the formula: (LV internal dimension in diastole - LV internal dimension 
in systole) / LV internal dimension in diastole.  M-mode measurements are reproducible and 
easy to perform with excellent temporal resolution, but are limited in cases of regional wall 
motion abnormalities and in patients where the true minor-axis is difficult to visualise.   
 
Both automated endocardial tracking and speckle-tracking analysis will be utilised (where 
available) by the echocardiographic core laboratory.  Multiple planes will be obtained (four-
chamber, two-chamber and short-axis mid-ventricle views).  These methods have the 
advantage of reducing operator time and are angle-independent, but rely on good 
ultrasound windowing.  Global longitudinal systolic strain using 2D speckle-tracking has 
recently been proposed as an important marker for adverse cardiovascular outcomes in 
AF.86 
 
Three-dimensional full-volume analyses of LV function, with single-beat analysis where 
feasible.  This method has the advantage of not relying on geometric assumptions and 
allows the acquisition of full volume data within a single heartbeat.  It correlates well with 
gold standard methods such as cardiac magnetic resonance imaging, but relies on 
adequate ultrasound windowing. 
 
Peak S-wave on tissue Doppler imaging (TDI) of the mitral valve annular sub-endocardium.  
This method has good correlation with LVEF across a wide range of function and is 
obtainable in patients with poor acoustic windows, but is limited in cases of regional wall 
motion abnormality. 
 
Where poor quality acoustic windows limit accurate assessment of LV function, use of an 
intravenous contrast agent is recommended in participants without known allergy. 
 
9.6.3 
Diastolic LV Function  
Diastolic LV function will be determined using the following methods (in all cases repeated over 3-
5 cardiac cycles): 
 
 
Mitral inflow pulse-wave Doppler peak E velocity and deceleration time (DT). 
 
Mitral annular TDI to calculate septal E’, lateral E’ and the individual and averaged E/E’ ratios. 
 
LV outflow tract pulse-wave Doppler to calculate isovolumic relaxation time (IVRT). 
 
Pulmonary vein pulse-wave Doppler to calculate peak systolic (where present) and diastolic 
velocities, ratio of peak velocities and DT of diastolic PV flow. 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 42 of 71 
 
 
Colour M-mode Doppler assessment of mitral flow propagation velocity (Vp) and ratio of E/Vp. 
 
Overall diastolic function will be categorised according to the British Society of Echocardiography 
guidelines into normal function or mild/moderate/severe dysfunction based on a combination of the 
above variables.  Individual parameters will also be categorised using cut-points identified from 
published studies.87  
 
9.6.4 
Left Atrial Size and Function 
Left atrial (LA) size will be measured in the anteroposterior (parasternal long-axis), transverse and 
longitudinal dimensions (apical 4-chamber).  LA volumes will be calculated using the biplane area-
length method: (0.85 x 4-chamber LA area x 2-chamber LA area) / LA length.  The length is 
measured from the middle of the plane of the mitral annulus to the superior aspect of the LA 
(shortest of 4- and 2-chamber measurements).  LA volumes will be indexed for body surface area.   
 
Where suitable datasets are obtained, 3D LA volumetric analysis and assessment of LA function 
and strain will also be performed. 
 
9.6.5 
Additional Echocardiography Parameters 
The following parameters will be obtained in all participants: 
 
Tricuspid annular plane systolic excursion (TAPSE) for estimation of right ventricular 
function using pulse-wave Doppler. 
 
Where applicable, mitral regurgitation dP/dt. 
 
9.7 Laboratory Evaluations 
The use of biomarkers than can affect treatment decisions in AF is at an early stage of 
development.88  The RATE-AF trial will allow us to collect and store blood samples on patients at 
baseline and follow-up, providing a unique biobank of AF patients receiving rate-control.  In 
collaboration with the Human Biomaterials Resource Centre (HBRC) at the University of 
Birmingham, we will also isolate DNA for future work on predictors of response, including known 
polymorphisms of rate-responsiveness.89 
 
Laboratories at each clinical site will process the standard laboratory investigations required as part 
of standard clinical care (see Section 9.1).  Trial laboratory evaluations will be performed at the 
core laboratory and processed according to the guidelines in Sections 9.7.1, 9.7.2 and 9.7.3. 
 
9.7.1 Laboratory Assays 
NT-pro B-type natriuretic peptide will be analysed using a Sandwich immunoassay using 
monoclonal ruthenium labelled antibody and Roche Cobas 8000 e602.  The total coefficient of 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 43 of 71 
 
variation for repeatability with this assay is <2% with an estimated volume of 250 microlitres 
required for each test and measurement range of 5‑35000 pg/mL (0.6‑4130 pmol/L). 
 
9.7.2 Cellular Response to Rate Control 
The effect of baseline and follow-up serum on intracellular sodium/calcium, force of contraction and 
activation of ERK1/2-dependent cascades will be examined in human induced pluripotent stem 
cell-derived 
cardiomyocytes, 
using 
well-established 
integrated 
fluorescence/contractility 
photometry and western blotting techniques.90, 91  DigiFAB92, will be used to determine whether 
changes are dependent on endogenous cardiotonic steroids, which can modulate intracellular ion 
concentration in cardiomyocytes93, 94, and potentially contribute to treatment discontinuation (or the 
development of toxicity).95  The concentration of serum cardiotonic steroids will be determined 
using liquid chromatography–tandem mass spectrometry.  Individual change in cardiotonic steroids 
and intracellular sodium/calcium will be correlated with the change in heart rate, LVEF, B-type 
natriuretic peptide and quality of life.  In addition, we will identify patterns in patients withdrawing 
from treatment or experiencing adverse reactions. 
 
9.7.3 Stored Blood Samples 
Blood samples will be stored at HBRC for future biomarker and genetic analysis, with participants 
providing explicit consent for this process.  Any future use of these samples will be undertaken with 
ethical approval. 
 
9.7.4 
Specimen Preparation, Handling, Storage and Shipment 
Specimens will be handled according to local standard operating procedures consisting of the time 
requirements for processing, required temperatures, aliquots of specimens, where they will be 
stored, how they will be labelled, the process for remnant samples/disposal and appropriate 
instructions for transportation. 
 
9.8 Economic Evaluation  
The RATE-AF trial will allow determination of the most appropriate data collection methods and 
ease of acquiring resource use and cost data for a subsequent outcomes trial.  Specifically, how 
data is obtained from secondary care records, patient-reported resource use and the feasibility of 
obtaining primary care records.  A preliminary economic evaluation from an NHS perspective will 
be performed to estimate costs over the 12-month period.  The patient-level cost-analysis will 
determine all AF-related costs, with respect to trial interventions and secondary-care resource use 
(including adverse events) in the two arms of the trial.  We will collect both cost and outcome data 
and present them in a cost-consequence analysis.  Costing for this trial suggests that simplifying 
medication alone could result in a saving of £5900 over each 12-month period.  Considering the 
high and increasing prevalence of AF, this could result in a substantial NHS cost savings, 
particularly if adverse reactions are also reduced.  The aim of this objective within the trial is to 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 44 of 71 
 
prepare the groundwork for a future cost-per-quality adjusted life year (QALY) analysis of rate-
control in AF. 
 
Costs of care will be derived from patient level resource-use data, focusing on secondary care 
costs, and including adverse effects, such as pacemaker implantation.  Other major drivers of cost 
are hospitalisation (including visits to Accident & Emergency), unplanned outpatient visits and 
outpatient tests such as echocardiography or ambulatory ECG.  The cost analysis will also consider 
therapy costs, both trial drug and additional treatments.  Unit costs will be obtained from standard 
sources including NHS Reference Costs, Unit Costs of Health and Social Care96 and health care 
providers.  Total per-patient health care costs will initially be calculated thus allowing the estimation 
of mean costs per trial arm over 12 months follow-up.  Responses to the EQ-5D-5L questionnaire 
at baseline, visit 2 (6 months) and visit 3 (12 months) will be used to plan a future QALY analysis. 
 
Key feasibility elements are: 
 
Determining the best methods for obtaining hospitalisation data, including where 
participants have been hospitalised outside of research site  
 
Whether robust primary care costs can be estimated and the method(s) for acquiring this 
type of data   
 
How key cost drivers can be incorporated into data collection for any future trial 
 
9.9 Heart rate and physical activity monitoring  
Secondary objectives of the RATE-AF trial include assessment of heart rate and physical 
functioning.  Conventional measures of obtaining this information include periodic measurement of 
pulse rate; apex beat rate and ECG data, and 6-minute walk tests and activity questionnaires 
respectively.  These type of measures are limited to specific time points, and are unable to explore 
the interaction of heart rate with physical activity in the patients’ normal environment.  To obtain 
more detailed information, RATE-AF trial participants will be asked to join an optional sub-study 
which uses a wearable device connected to a smartphone for a period of 6-12 months.  Potential 
participants will be given a specific Patient Information Leaflet written by the RATE-AF Patient and 
Public Involvement Team, and asked to sign the RATE-AF optional consent form.  Our intention is 
to enrol 75-100 participants to this sub-study, either at baseline or follow-up visits.  The technology 
for this research is supported by funding from an Innovative Medicines Initiative European Union 
Horizon 2020 grant (BigData@Heart; https://www.bigdata-heart.eu/).97 The work will be a 
collaboration between the University of Birmingham, University College London and Utrecht 
Medical Centre (the Netherlands), in addition to the Hyve (an IT support company based in the 
Netherlands), who are all major partners in this initiative.   
 
Wearable device: 
 
A commercially-available wrist-worn device will be used that measures physical activity 
(movement, activity, physical exercise and step count) and sleep (sleep efficiency, latency, wake 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 45 of 71 
 
episodes and fragmentation) using heart rate and accelerometer sensors.  The device is non-
invasive, painless, and extremely low risk.  They are similar in size and dimension to a watch, 
manufactured primarily in rubber, and are marked as lifestyle devices, therefore not denoting 
participation in a research study, reducing stigmatisation and eliminating the possibility of 
identifying an individual as a research participant. 
 
Smartphone and software: 
Participants will be provided with a suitable Android platform smartphone, which functions as a 
regular mobile phone and allows users to make calls to all UK landlines and mobiles, or access the 
internet.  Software on the phone will connect with the wearable device and also passively collect 
information about the environment and phone usage, using sensors which are built into all modern 
smartphones. This includes the amount of noise and light in surroundings, Bluetooth interactions, 
local weather conditions, location, length and duration of texts and phone calls, keystrokes, and 
battery life.  GPS location will be anonymised in a way that does not reveal actual geographic 
location.  Similarly, we will not be able to see the content of text messages, or phone numbers that 
have been contacted.  Applications will be installed to record the pulse, AF symptoms and quality 
of life, and provide an educational resource for patients.98 
 
Data handling: 
All of the information collected will be pseudo-anonymised and kept confidential.  Data collected 
via the wrist-worn wearable device and smartphone will be encrypted, uploaded to a secure server 
and will not be identifiable by patient name. Data will be temporarily cached on the smartphone 
until an appropriate Wi-Fi or mobile data connection is available, and will then be automatically 
deleted from the phone memory. A contract between the University of Birmingham and The Hyve 
who will assist with the hosting of the RADAR platform has been made. Data are securely stored 
in the established RADAR platform (Remote Assessment of Disease and Relapse; 
https://www.radar-cns.org/) . Data collected from the devices will then be processed at the 
University of Birmingham.  The pseudo-anonymised data acquired may be shared with members 
of the BigData@Heart consortium in the UK and other countries of the European Union, after 
agreement from the RATE-AF Trial Steering Committee. 
 
Participant support: 
Contact will be made with participants by the BigData@Heart team throughout the course of follow-
up if there is a loss of data stream from a device.  The participant will be contacted by telephone to 
ensure compliance and correct use.  In addition to a telephone call provided after an introductory 
training session, participants will receive further call as needed to address any concerns or 
questions, and brief follow-up phone-calls will then be offered as needed to maintain engagement 
with participants and address any technical concerns. 
 
Objectives and analysis: 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 46 of 71 
 
The objectives of this sub-study are exploratory – our hypothesis is that periodic ambulatory heart 
rate and physical activity monitoring will demonstrate a higher correlation with changes in SF36 
physical functioning, cardiac function and NTpro-BNP than conventional ECG-derived heart rate, 
IPAQ score or 6-minute walk distance.99  An analysis plan for this sub-study will be agreed before 
access to data.  
Pseudo-anonymised data will also contribute to the BigData@Heart Consortium, which in 
combination with other studies and registries across the European Union aims to redefine clinical 
phenotypes of common cardiovascular diseases.  Collaboration with the RATE-AF trial will allow 
development of the remote monitoring platform for capturing patient-related outcomes in this 
patient group.  We will demonstrate the feasibility of the platform for running further studies in the 
BigData@Heart Consortium, designed to have future impact on improving treatment outcomes in 
patients with AF. 
 
 
9.10 Heart rate and sympathetic nerve function  
A secondary objective of the RATE-AF trial is to compare heart rate control in patients randomised 
to beta-blockers and digoxin using 24-hour ambulatory ECG.  However, heart rate is not only 
affected by therapy, but also intrinsic variability in control by the autonomic nervous system.  
Sympathetic activity is elevated in cardiovascular conditions and could have a profound effect on 
heart rate response in individual patients, potentially masking the effects of therapy.100  The 
proposed assessment uses a fine Tungsten needle (human hair width) that records nerve activity 
from a sympathetic nerve, performed at the baseline visit and then at the final uptitration visit.  
MSNA is an established research investigation which is virtually painless, safe and allows direct 
measurement of sympathetic tone.  Our team have successfully used this technique in a range of 
conditions.101, 102   
10-15 patients from each treatment group will be asked to participate in a sub-study of muscle 
sympathetic nerve activity (MSNA).  Patients will be selected that lack existing impairment (or 
potential impairment) of the nervous system, excluding those with diabetes, other medical 
conditions affecting autonomic function (for example, Sjogren's syndrome, systemic lupus 
erythematosus and rheumatoid arthritis), prior stroke and previous neurological conditions 
(Parkinson's disease, dementia, multiple sclerosis or Guillain-Barre syndrome).  Potential 
participants will be given a specific Patient Information Leaflet written by the RATE-AF Patient and 
Public Involvement Team, and asked to sign the RATE-AF optional consent form.   
 
Protocol: 
Patients will be studied supine, in uniform conditions in a clinical environment.  They will be 
monitored with continuous heart rate and beat-to-beat blood pressure in response to handgrip 
exercises and other simple sympathetic stimulation exercises (Portapres, Finapres Medical 
Systems).  Recordings of postganglionic, multiunit MSNA will be obtained using a sterile 200μm 
tungsten microelectrode placed into the peroneal nerve at the fibular head and a reference 
electrode inserted subcutaneously at a site 2–3 cm distal.  Prior to digitization, raw signals are 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 47 of 71 
 
amplified (×100,000), filtered (bandwidth 700–2000Hz), rectified and integrated (time constant 
100ms), in order to obtain a mean voltage sympathetic neurogram.     
 
Recovery: 
No recovery period is required; patients can immediately mobilise after the assessment is 
complete.  Rarely, some patients may exhibit temporary leg/foot paraesthesia which settles 
spontaneously.    
 
Objectives and analysis: 
The objectives of this sub-study are exploratory – our hypothesis is that MSNA will identify a subset 
of patients with autonomic dysfunction that have an altered or distinct response to rate control 
therapy.     
Change in sympathetic activity from baseline to after treatment with rate control will be analysed in 
comparison to change in heart rate to understand if sympathetic activity broadly interacts with 
treatment effects.  The results will be used as pilot data to formulate a new research study 
investigating the role of autonomic dysfunction and outcomes in patients with AF.  An analysis plan 
for this sub-study will be agreed before access to data. 
  
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 48 of 71 
 
10 
Pharmacovigilance 
Definitions of different types of AE are listed in Table 2. The Investigator should assess the 
seriousness and causality (relatedness) of AEs experienced by the participant (this should be 
documented in the source data).  For further information please refer to Section 10.1.   
 
Table 2: Standard AE Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
participant administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment 
Adverse Reaction (AR) 
Any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant  
Serious adverse event 
(SAE), serious adverse 
reaction (SAR) or 
unexpected serious 
adverse reaction  
Any adverse event, adverse reaction or unexpected adverse 
reaction, respectively, that: 
 
results in death; 
 
is life-threatening; 
 
requires hospitalisation or prolongation of existing 
hospitalisation; 
 
results in persistent or significant disability or 
incapacity; or 
 
consists of a congenital anomaly or birth defect 
Unexpected Adverse 
Reaction 
An adverse reaction the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
(a) in the case of a product with a marketing authorisation, in the 
summary of product characteristics for that product;  
(b) in the case of any other investigational medicinal product, in the 
investigator's brochure relating to the trial in question. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
10.1 Recording and Assessment of Adverse Events 
Targeted adverse events as they appear on the CRF will be reportable to the RATE-AF Trial Office 
up to 30 days post last IMP administration.  Any SUSAR related to the IMP should to be reported 
irrespective of how long after IMP administration the reaction has occurred. 
Adverse events will be recorded in the medical records and CRFs.  Most AE/ARs that occur in this 
trial, whether they are serious or not, will be ‘expected’ treatment-related toxicities due to the drugs 
used in this trial.   
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 49 of 71 
 
Refer to Table 3 for definition of expectedness.   
 
Table 3: Expectedness 
Category 
Definition 
Expected 
An adverse event that is classed in nature as serious and which is 
consistent with the information about the IMP listed in the Investigator 
Brochure (or section 4.8 of the relevant SmPC if Licensed IMP) or clearly 
defined in this protocol 
Unexpected 
An adverse event that is classed in nature as serious and which is not 
consistent with the information about the IMP listed in the Investigator 
Brochure (or SmPC if Licensed IMP)  
 
Adverse events will be recorded with clinical symptoms and accompanied with a simple, brief 
description of the event, including dates as appropriate.  
 
The assessment of relationship of adverse events to the administration of IMP is a clinical decision 
based on all available information at the time. The following categories as outlined in Table 4 will 
be used to define the causality of the adverse event.        
 
Table 4: Categorisation of Causality 
 
Category 
Definition 
Relatedness 
Definitely 
There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out 
Related 
 
Probably 
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the 
event occurred within a reasonable time after administration of 
the trial medication).  However, the influence of other factors may 
have contributed to the event (e.g. the patient’s clinical condition, 
other concomitant events) 
Unlikely 
There is little evidence to suggest there is a causal relationship 
(e.g. the event did not occur within a reasonable time after 
administration of the trial medication).  There is another 
reasonable explanation for the event (e.g. the patient’s clinical 
condition, other concomitant treatments) 
 
 
Not related 
Not related 
There is no evidence of any causal relationship 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 50 of 71 
 
The collection and reporting of Adverse Events (AEs) will be in accordance with the Medicines for 
Human Use (Clinical Trials) Regulations 2004 and subsequent amendments. The Investigator will 
assess the seriousness and causality (relatedness) of all applicable AEs experienced by the 
participant with reference to the reference safety information. This should be documented in the 
source data with reference to the approved reference safety information (Section 4.8, Undesirable 
Effects) of the SmPC for Digoxin (dated: 20th March 2014) and the reference safety information 
(Section 4.8, Undesirable Effects) of the SmPC for Bisoprolol (dated: 19th June 2015). 
 
10.2 Non-Serious Adverse Events/ Adverse Reactions 
Refer to Table 2 for definitions 
 
Common adverse reactions (see Section 7.4) will be recorded on the relevant CRF and sent to the 
RATE-AF Trial Office. 
 
10.3 Serious Adverse Events 
Refer to Table 2 for definitions 
 
All Serious Adverse Events (SAEs), that are not excluded from expedited reporting will be recorded 
in the hospital notes and should be reported to the RATE-AF Trial Office on a SAE Form. The 
completed form should be faxed to the RATE-AF Trial Office on 0121 415 9135 or 0121 415 
9136, as soon as possible and ideally within one working day of becoming aware of the event.  The 
site Investigator should be able to respond to any related queries raised by the RATE-AF Trial 
Office as soon as possible.  
 
10.3.1 Expected SAEs NOT to be Reported on a SAE Form 
Expected SAEs are those listed in the current SmPC for the trial IMPs and can be excluded from 
the expedited reporting outlined in Section 10.1, for example if they are expected to occur on a 
regular basis, are no more severe and offer no further new information to the safety profile. These 
events should continue to be recorded in the source data and relevant CRFs.  
 
In addition, events NOT considered to be SAEs are hospitalisations for: 
 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 
Treatment, which was elective or pre-planned, for a pre-existing condition that is unrelated 
to the indication under trial, and has not worsened 
Note: Death from any cause should be reported on an SAE Form and returned to the RATE-AF 
Trial Office. 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 51 of 71 
 
 
10.4 SUSARs 
Refer to Table 2 for definitions 
SAEs classed by as both suspected to be related to the trial IMP and unexpected are categorised 
as SUSARs, and are always subject to expedited reporting.  An SAE Form should be completed, 
and faxed to the RATE-AF Trial Office within 24 hours of the research staff at site becoming aware 
of the event. The local investigator will provide the causality assessment. 
 
The Chief Investigator (or nominated individual) will undertake urgent review of all such SAEs and 
may request further information immediately from the clinical team at site.  Causality will be 
assessed by a medically qualified doctor who has been delegated the task and then reviewed by 
the local PI.  The Chief Investigator will not overrule the causality or seriousness assessment given 
by the local investigator but may add additional comment on these. The Chief Investigator will 
provide the determination of expectedness according to the reference safety information. 
 
SUSARs will be notified to the MHRA and REC by the RATE-AF Trial Office.  SUSARs that are 
fatal or life-threatening will be notified to the MHRA and REC within 7 days after the RATE-AF Trial 
Office has been notified.  Other SUSARs will be reported to the REC and MHRA within 15 days 
after the Trial Office has been notified.  
 
10.5 Development Safety Update Reports  
The RATE-AF Trial Office will provide the MHRA with Development Safety Update Reports 
(DSURs).  The reports will be submitted within 60 days of the Developmental International Birth 
Date (DIBD) of the trial each year until the trial is declared ended. 
 
10.6 Annual Progress Reports 
An annual progress report will be submitted to the REC within 30 days of the anniversary date on 
which the favourable opinion was given, and annually until the trial is declared ended.  
 
10.7 Pregnancy  
Due to the age of participants that will be randomised into the RATE-AF Trial (≥ 60 years), it is 
highly improbable that female participants will be pregnant at the time of randomisation, or become 
pregnant during the trial.  Any pregnancies will be followed up for outcome; any outcome meeting 
the definition of an SAE will be reported to the RATE-AF Trial Office on the relevant CRF.  
 
10.8 Reporting Urgent Safety Measures  
If any urgent safety measures are taken the Principal Investigator/BCTU/Sponsor shall immediately 
and in any event no later than 3 days from the date the measures are taken, give written notice to 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 52 of 71 
 
the MHRA and the REC of the measures taken and the circumstances giving rise to those 
measures. 
 
11 
Quality Control and Quality Assurance 
11.1 Site Set-Up and Initiation 
All participating Principal Investigators will be asked to sign the necessary agreements and supply 
a current CV to the Trials Office.  All members of the site research team will also be required to 
sign a site signature and delegation log. Prior to commencing recruitment all sites will undergo a 
process of initiation and will have completed GCP training. Key members of the site research team 
will be required to attend either a meeting or a teleconference covering aspects of the trial design, 
protocol procedures, Adverse Event reporting, collection and reporting of data and record keeping.  
Sites will be provided with an Investigator Site File containing essential documentation, instructions, 
and other documentation required for the conduct of the trial.  The Trials Office must be informed 
immediately of any change in the site research team. 
 
11.2 Central Monitoring 
Monitoring of this trial will be to ensure compliance with Good Clinical Practice.  A risk proportionate 
approach to the initiation, management and monitoring of the trial will be adopted (as per the 
MRC/DH/MHRA Joint Project: Risk-adapted Approaches to the Management of Clinical Trials of 
Investigational Medicinal Products) and outlined in the trial-specific risk assessment.  
 
The Trials Office will be in regular contact with the site research team to check on progress and 
address any queries that they may have.  The Trials Office will check incoming CRFs for 
compliance with the protocol, data consistency, missing data and timing. Sites will be asked for 
missing data or clarification of inconsistencies or discrepancies. Sites will be requested to send in 
copies of signed Informed Consent Forms and other documentation for in-house review for all 
participants providing explicit consent.   
 
Additional on-site monitoring visits may be triggered, for example by poor CRF return, poor data 
quality, low SAE reporting rates, excessive number of participant withdrawals or deviations. This 
will be detailed in the monitoring plan. If a monitoring visit is required the Trials Office will contact 
the site to arrange a date for the proposed visit and will provide the site with written confirmation. 
Investigators will allow the RATE-AF trial staff access to source documents as requested.   
  
11.3 Audit and Inspection 
The Principal Investigator will permit trial-related monitoring, quality checks, audits, ethical reviews, 
and regulatory inspection(s) at their site, providing direct access to source data/documents. The 
Principal Investigator will comply with these visits and any required follow up. Sites are also 
requested to notify the Trials Office of any MHRA inspections.  


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 53 of 71 
 
  
11.4 Notification of Serious Breaches 
In accordance with Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 
2004 and its amendments the Sponsor of the trial is responsible for notifying the licensing authority 
in writing of any serious breach of the conditions and principles of GCP in connection with that trial 
or the protocol relating to that trial, within 7 days of becoming aware of that breach. 
 
For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a 
significant degree the safety or physical or mental integrity of the participants of the trial; or the 
scientific value of the trial. Sites are therefore requested to notify the Trials office of any suspected 
trial-related serious breach of GCP and/or the trial protocol. Where the Trials Office is investigating 
whether or not a serious breach has occurred sites are also requested to cooperate with the Trials 
Office in providing sufficient information to report the breach to the MHRA where required and in 
undertaking any corrective and/or preventive action.  Sites may be suspended from further 
recruitment in the event of serious and persistent non-compliance with the protocol and/or GCP, 
and/or poor recruitment.  Any major problems identified during monitoring may be reported to Trial 
Management Group and Trial Oversight Committee, the REC and the relevant regulatory bodies.  
This includes reporting serious breaches of GCP and/or the trial protocol to the REC and MHRA. 
A copy is sent to the University of Birmingham Clinical Research Compliance Team at the time of 
reporting to the REC and/or relevant regulatory bodies. 
 
11.5 Data Handling and Analysis 
Paper CRFs must be completed from source, signed and dated by members of the site research 
team. CRFs will then be entered directly on to the RATE-AF database by members of the RATE-
AF Trial Office. Randomisation of the trial must be completed by an authorised member of the site 
research team (as delegated on the RATE-AF Trial Signature and Delegation Log) within the 
timeframe listed in Table 5.  Copies of all completed CRFs should be filed in the site file.  Entries 
on paper CRFs should be made in ballpoint pen, in black ink, and must be legible.  Any errors 
should be crossed out with a single stroke, the correction inserted and the change initialled and 
dated.  If it is not obvious why a change has been made, an explanation should be written next to 
the change.  
 
CRFs 
can 
be 
entered 
by 
CTU 
staff 
or 
viewed 
online 
by 
site 
staff 
at 
http://www.bctu.bham.ac.uk/RATEAF.  Authorised staff at sites will require an individual secure 
login username and password to access this online data system. 
 
Data reported on each CRF should be consistent with the source data or the discrepancies should 
be explained.  If information is not known, this must be clearly indicated on the CRF.  All missing 
and ambiguous data will be queried as detailed in the Trial Data Management Plan.  All sections 
are to be completed. 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 54 of 71 
 
CRF versions may be updated by the RATE-AF Trial Office, as appropriate, throughout the duration 
of the trial.  Whilst this will not constitute a protocol amendment, new versions of the CRFs must 
be implemented by participating sites immediately on receipt. 
 
It will be the responsibility of the Principal Investigator to ensure the accuracy of all data entered in 
the CRFs.  The RATE-AF Trial Signature & Delegation Log will identify all those personnel with 
responsibilities for data collection.  
 
Access to data, including the final trial dataset, will be limited to members of the Research Team. 
 
The investigator(s)/institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents.  Trial participants are 
informed of this during the informed consent discussion and will consent to provide access to their 
medical notes. 
 
Table 5: Data Collection Forms 
 
Form Name 
Schedule for submission 
Randomisation Form 
Collected at randomisation 
Baseline and Follow-
Up CRFs 
As soon as possible after each follow-up 
assessment time point 
Serious Adverse Event 
Form 
Faxed within 24hrs of research staff at 
site becoming aware of event 
 
 
11.6 End of Trial 
The end of trial will be 30 days after the last data capture. This will allow sufficient time for the 
completion of protocol procedures, data collection and data input.  The Trials Office will notify the 
MHRA and REC that the trial has ended within 90 days of the end of trial. Where the trial has 
terminated early, the Trials Office will inform the MHRA and REC within 15 days of the end of trial. 
The Trials Office will provide them with a summary of the clinical trial report within 12 months of the 
end of trial.  
 
A copy of the end of trial notification as well as the summary report is also sent to the University of 
Birmingham Research Governance Team at the time of sending these are sent to the MHRA and 
REC.  
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 55 of 71 
 
11.7 Archiving 
Archiving will be authorised by the BCTU on behalf of the Sponsor following submission of the end 
of trial report.  
 
Principal Investigators are responsible for the secure archiving of essential trial documents (for 
their site) as per their NHS Trust policy.  All essential documents will be archived for a minimum of 
25 years after completion of trial.  
Destruction of essential documents will require authorisation from the BCTU on behalf of the 
Sponsor.   
 
12 Statistical Considerations 
12.1 Outcome measures 
12.1.1 
Primary Outcome 
Patient-reported quality of life (QoL) - SF-36 physical component summary score at six months 
 
12.1.2 
Secondary Outcomes 
Patient-reported QoL: 
 
SF-36 global and domain-specific scores at 6 and 12 months 
 
EQ-5D-5L summary index and visual analogue scale at six and twelve months  
 
AFEQT overall score at six and twelve months 
Cardiac function: 
 
Echocardiographic LVEF at 12 months 
 
Diastolic function (E/e’ and composite of diastolic indices) at 12 months  
 
Functional assessment 
 
Six-minute walking distance at 6 and 12 months 
 
Change in European Heart Rhythm Association (EHRA) class at 6 and 12 months 
Biomarkers: 
 
Change in B-type natriuretic peptide (BNP) levels at 6 months 
 
Change in heart rate using 24-hour ambulatory ECG 
 
12.1.3 
Feasibility Outcomes 
 
Recruitment target of 3 patients per week across all participating centres.  
 
Compliance and reasons for non-compliance  


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 56 of 71 
 
 
Number of withdrawals and losses to follow-up (with reasons) 
 
Drug discontinuation rate and adverse reactions requiring drug discontinuation. 
 
Number of patients needing therapy-induced requirement for additional treatment 
 
Population-specific standard deviations (SD) and proportions 
o SD of SF36 physical functioning score at 6 and 12 months 
o SD of SF36 overall score at 6 and 12 months 
o SD of AFEQT overall score at 6 and 12 months  
o SD of LVEF and E/e’ score at 6 and 12 months  
o Unplanned hospitalisation admissions rates 
 
Cardiovascular Events (particularly mortality, thromboembolic events, myocardial 
infarction and cardiovascular interventions) 
 
The final analyses will follow a pre-specified analysis plan, drafted in conjunction with the 
Birmingham Clinical Trials Unit and submitted to the steering committee at the penultimate meeting.  
We intend to perform a primary intention-to-treat analysis, in addition to a per-protocol analysis. 
 
Any additional (exploratory) analyses will be explicitly labelled as such in any subsequent 
manuscript.  
 
12.2 Power Calculations 
Randomising 144 patients we can assume an 85% power to detect an effect size of half a standard 
deviation in a continuous outcome measure of QoL (two-sided alpha of 0.05).  A sample size of 
160 patients would account for an estimated 10% loss to follow-up (including withdrawal and death 
prior to 12-month assessment).  There is some evidence from existing research to support the 
notion that the treatment effect could be this large.  The mean SF-36 role-physical score from the 
rate-control arm of the RACE study was 47, with a 17% improvement with rate-control over time.62  
In another study, CCB resulted in 22% improvement in a proprietary symptom-checklist, compared 
to a non-significant 8% change in those assigned to beta-blockers (SD 10-points in both groups).  
These values are also consistent with a 17% improvement in SF-36 scores in a third trial, PIAF.63  
Thus whilst it is possible that this trial may provide a clear indication of effect,  it is accepted that 
the trial will be underpowered to detect smaller differences, reinforcing the requirement for a larger 
definitive trial which would also be powered to assess impact on clinical event rates.  
 
12.3 Statistical analysis 
A separate Statistical Analysis Plan for the RATE-AF trial provides a detailed description of the 
planned statistical analyses. A brief outline of these analyses is given below. 
 
The primary comparison groups will be composed of those who are randomised to digoxin group 
and those randomised to the beta-blockers group. All analyses will be based on the intention to 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 57 of 71 
 
treat principle, with all patients analysed in the arms to which they were allocated irrespective of 
compliance with the randomised allocated treatment, and all patients will be included in the 
analyses. We will, as a sensitivity analysis, conduct per-protocol analyses, where appropriate. 
For all analyses, a p-value <0.05 will be considered statistically significant.  
 
12.3.1 Primary outcome analysis 
The primary outcome for this trial is the continuous SF36 physical functioning domain score at 6 
months. This outcome will be analysed using an ANCOVA model adjusting for treatment arm, 
baseline score and all minimisation variables. Results will be presented as difference in means and 
95% confidence intervals.  
 
12.3.2 Feasibility and Secondary outcomes analysis 
The feasibility and secondary outcomes for the trial comprise of a combination of both continuous 
and categorical (dichotomous) data items.  
 
Categorical endpoints: 
For outcomes which are categorical (dichotomous) in nature, the proportion of participants and 
percentages will be analysed between arms.  
 
Logistic/Log-binomial regression models will be fitted (where appropriate) to adjust for treatment 
arm, baseline scores and all minimisation variables.  
 
Results will be presented as odds ratios/relative risks and 95% confidence intervals.    
 
Continuous endpoints: 
Any outcomes that are continuous in nature will be analysed in the same way as the primary 
outcome.  
 
12.3.3 Missing data and sensitivity analyses 
Primary analysis will concentrate on available data only, with no attempt made to impute missing 
data.  Where appropriate, sensitivity analyses will be carried out to examine the possible impact of 
missing data on the results (full details will be discussed within the Statistical Analysis Plan).  
 
12.3.4 
Interim analyses and Stopping rules 
Analysis of the data with respect to efficacy and safety will be performed at 12 months and sent to 
Data Monitoring Committee (DMC); see Section 16.  The DMC will outline and agree the stopping 
rules for the trial which will be documented in the DMC charter.  It is likely that the Haybittle-Peto 
boundary will be used. This states that if an interim analysis shows a probability of less than 0.001 
that the treatments are different, then the trial should be stopped early.  This will be used alongside 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 58 of 71 
 
data on important secondary endpoints and all other relevant evidence.  A DMC report and charter 
outlining the terms of reference (including information on stopping rules) will be agreed with the 
DMEC.  
 
12.4 Final analysis 
The final analysis for the RATE-AF trial will occur once the last randomised participant completes 
their 12-month follow-up.  
 
13 
Ethics and Regulatory Requirements 
The trial will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human participants, adopted by the 18th World Medical Association 
General Assembly, Helsinki, Finland, June 1964, amended at the 48th World Medical Association 
General Assembly, Somerset West, Republic of South Africa, October 1996 (website: 
http://www.wma.net/en/30publications/10policies/b3/index.html).  
 
The trial will be conducted in accordance with the Research Governance Framework for Health 
and Social Care, the applicable UK Statutory Instruments, (which include the Medicines for Human 
Use Clinical Trials 2004 and subsequent amendments,the latest Data Protection legislation, the 
Human Tissue Act 2008, EU Clinical Trials Directive and amendment Regulations as appropriate) 
and Guidelines for Good Clinical Practice (GCP).  This trial will be carried out under a Clinical Trial 
Authorisation in accordance with the Medicines for Human Use Clinical Trials regulations. The 
protocol will be submitted to and approved by the REC prior to circulation.  
 
Before any participants are enrolled into the trial, the Principal Investigator at each site is required 
to obtain local R&D approval. Sites will not be permitted to enrol participants until written 
confirmation of R&D approval is received by the Principal Investigator.  
 
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments gain 
the necessary local approval.  This does not affect the individual clinicians’ responsibility to take 
immediate action if thought necessary to protect the health and interest of individual participants. 
 
Within 90 days after the end of the trial, the Chief Investigator/Sponsor will ensure that the REC 
and the MHRA are notified that the trial has finished.  If the trial is terminated prematurely, those 
reports will be made within 15 days after the end of the trial.  The Chief Investigator will provide the 
Sponsor with a summary report of the clinical trial, which will then be submitted to the MHRA and 
REC within one year after the end of the trial.  
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 59 of 71 
 
14 
Oversight Committees 
14.1 Trial Management Group 
The Trial Management Group (TMG) will comprise the CI, other lead investigators (clinical and non-
clinical) and members of the BCTU.  The TMG will be responsible for the day-to-day running and 
management of RATE-AF.  The TMG will convene at regular intervals. 
 
14.2 Trial Oversight Committee  
A joint oversight committee comprising a Trial Steering Committee (TSC) and Data Monitoring 
Committee (DMC) will be engaged for this trial.  
 
The role of the TSC is to provide the overall supervision of the trial.  The TSC will monitor trial 
progress and conduct and advice on scientific credibility.  The TSC will consider and act, as 
appropriate, upon the recommendations of the Data Monitoring Committee.  Further details of the 
remit and role of the TSC are available in the TSC Charter. 
 
An independent DMC will be established to oversee the safety of participants in the trial.  The DMC 
will meet prior to the trial opening to enrolment, and then meet at least annually, or as per a 
timetable agreed by the DMC prior to trial commencement.  Data analyses will be supplied in 
confidence to the DMC, which will be asked to give advice on whether the accumulated data from 
the trial, together with the results from other relevant research, justifies the continuing recruitment 
of further participants.  The DMC will operate in accordance with the trial specific charter. 
 
14.3 Protocol amendments 
Where important protocol modifications are required as a result of oversight (for example, changes 
to eligibility criteria, outcomes or analyses), this information will be communicated to relevant 
parties, such as investigators, the REC, trial registries and regulators.   
 
15 
Finance 
The RATE-AF Trial is funded through a Career Development Fellowship awarded to the Chief 
Investigator by the National Institute for Health Research (NIHR). 
 
16 
Confidentiality and Data Protection 
Personal data recorded on all documents will be regarded as strictly confidential and will be handled 
and stored in accordance with the latest Data Protection legislation. 
 
Participants will be identified using their unique trial identification number, date of birth and hospital 
number on the CRFs. and correspondence between the Trials Office and the participating site. 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 60 of 71 
 
Participants will give their explicit consent for the movement of their consent form, giving permission 
for the Trials Office to be sent a copy.  This will be used to perform in-house monitoring of the 
consent process. 
 
The Investigator must maintain documents not for submission to the Trials Office (e.g. Participant 
Identification Logs) in strict confidence. In the case of specific issues and/or queries from the 
regulatory authorities, it will be necessary to have access to the complete trial records, provided 
that participant confidentiality is protected.  
 
The Trials Office will maintain the confidentiality of all participants’ data and will not disclose 
information by which participants may be identified to any third party other than those directly 
involved in the treatment of the participant and organisations for which the participant has given 
explicit consent for data transfer (e.g. competent authority, sponsor).  Representatives of the 
RATE-AF Trials Office and sponsor may be required to have access to participant’s notes for 
quality assurance purposes but participants should be reassured that their confidentiality will be 
respected at all times. 
 
17 
Insurance and Indemnity 
The University of Birmingham has in place Clinical Trials indemnity coverage for this trial which 
provides cover to the University for harm which comes about through the University’s, or its staff’s, 
negligence in relation to the design or management of the trial and may alternatively, and at the 
University’s 
discretion 
provide 
cover 
for 
non-negligent 
harm 
to 
participants. 
 
With respect to the conduct of the trial at the Clinical Site and other clinical care of the patient, 
responsibility for the care of the patients remains with the NHS organisation responsible for the 
Clinical Site and is therefore indemnified through the NHS Litigation Authority.  
 
The University of Birmingham is independent of any pharmaceutical company, and as such it is not 
covered by the Association of the British Pharmaceutical Industry (ABPI) guidelines for participant 
compensation. 
 
18 
Dissemination and Publication  
Regular newsletters will keep collaborators informed of trial progress and regular meetings will be 
held to report the progress of the trial and to address any problems encountered in the conduct of 
the trial.  The CI will coordinate dissemination of data from this trial.  All publications and 
presentations, including abstracts, relating to the main trial will be authorised by the RATE-AF 
TMG.  The results of the analysis will be published in the name of the RATE-AF Collaborative 
Group in a peer reviewed journal (provided that this does not conflict with the journal’s policy). 
 
Named authors must satisfy the International Committee of Medical Journal Editors (ICMJE) criteria 
for authorship (contribute to drafting of the article or revision for important intellectual content), 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 61 of 71 
 
provide timely approval of the final version to be published and supply detailed statements on any 
potential conflict of interest or financial relationship (http://www.icmje.org/).  Members of the group 
who do not fulfil ICMJE criteria for authorship will be listed in the article appendix.  Trial participants 
will be sent a lay summary of the final results of the trial, which will contain a reference to the full 
paper. 
 
 
 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 62 of 71 
 
19 
References 
1. 
Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, 
Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van 
Putte B, Vardas P. 2016 ESC Guidelines for the management of atrial fibrillation developed in 
collaboration with EACTS. Eur Heart J. 2016;37:2893-2962 
2. 
Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Guyton RA, 
Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen W-K. Management of patients 
with atrial fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS 
recommendations). Circulation. 2013;127:1916-1926 
3. 
Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P, E. 
S. C. Committee for Practice Guidelines. 2012 focused update of the ESC Guidelines for the 
management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of 
atrial fibrillation. Developed with the special contribution of the European Heart Rhythm 
Association. Eur Heart J. 2012;33:2719-2747 
4. 
National Institute for Health and Care Excellence. Atrial fibrillation: the management of atrial 
fibrillation. NICE clinical guideline 180. 2014; Accessed 15/09/2016; 
http://www.nice.org.uk/guidance/cg180/ 
5. 
Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson 
B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD, Beta-
Blockers in Heart Failure Collaborative Group. Efficacy of beta blockers in patients with heart 
failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet. 2014;384:2235-2243 
6. 
Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, Steeds RP, Townend J, Kotecha D. 
Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled 
trial data. BMJ. 2015;351:h4451 
7. 
Kotecha D, Banerjee A, Lip GY. Increased stroke risk in atrial fibrillation patients with heart failure: 
does ejection fraction matter? Stroke. 2015;46:608-609 
8. 
Kotecha D, Kirchhof P. Rate and rhythm control have comparable effects on mortality and stroke in 
atrial fibrillation but better data are needed. Evid Based Med. 2014;19:222-223 
9. 
Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J. 
2015;36:3250-3257 
10. 
Senoo K, Lip GY, Lane DA, Buller HR, Kotecha D. Residual risk of stroke and death in 
anticoagulated patients according to the type of atrial fibrillation: AMADEUS Trial. Stroke. 
2015;46:2523-2528 
11. 
Kotecha D, Chudasama R, Lane DA, Kirchhof P, Lip GY. Atrial fibrillation and heart failure due to 
reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and 
adverse outcomes. Int J Cardiol. 2016;203:660-666 
12. 
Arain M, Campbell MJ, Cooper CL, Lancaster GA. What is a pilot or feasibility study? A review of 
current practice and editorial policy. BMC Med Res Methodol. 2010;10:67 
13. 
Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, 
Goldsmith CH. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 
2010;10:1 
14. 
Heeringa J, van der Kuip DAM, Hofman A, Kors JA, van Herpen G, Stricker BHC, Stijnen T, Lip 
GYH, Witteman JCM. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam 
study. Eur Heart J. 2006;27:949-953 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 63 of 71 
 
15. 
Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of Current and Future 
Incidence and Prevalence of Atrial Fibrillation in the U.S. Adult Population. Am J Cardiol. 
2013;112:1142-1147 
16. 
Kim MH, Johnston SS, Chu BC, Dalal MR, Schulman KL. Estimation of total incremental health 
care costs in patients with atrial fibrillation in the United States. Circ Cardiovasc Qual Outcomes. 
2011;4:313-320 
17. 
Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of Atrial 
Fibrillation on the Risk of Death: The Framingham Heart Study. Circulation. 1998;98:946-952 
18. 
Stewart S, Hart CL, Hole DJ, McMurray JJV. A population-based study of the long-term risks 
associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med. 
2002;113:359-364 
19. 
Marijon E, Le Heuzey JY, Connolly S, Yang S, Pogue J, Brueckmann M, Eikelboom J, Themeles 
E, Ezekowitz M, Wallentin L, Yusuf S. Causes of death and influencing factors in patients with atrial 
fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant 
therapy study. Circulation. 2013;128:2192-2201 
20. 
Chen LY, Sotoodehnia N, Buzkova P, Lopez FL, Yee LM, Heckbert SR, Prineas R, Soliman EZ, 
Adabag S, Konety S, Folsom AR, Siscovick D, Alonso A. Atrial fibrillation and the risk of sudden 
cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. 
JAMA Intern Med. 2013;173:29-35 
21. 
Dorian P, Jung W, Newman D, Paquette M, Wood K, Ayers GM, Camm J, Akhtar M, Luderitz B. 
The impairment of health-related quality of life in patients with intermittent atrial fibrillation: 
implications for the assessment of investigational therapy. J Am Coll Cardiol. 2000;36:1303-1309 
22. 
Thrall G, Lane D, Carroll D, Lip GYH. Quality of Life in Patients with Atrial Fibrillation: A Systematic 
Review. Am J Med. 2006;119:448.e441-419 
23. 
Sears SF, Serber ER, Alvarez LG, Schwartzman DS, Hoyt RH, Ujhelyi MR. Understanding Atrial 
Symptom Reports: Objective versus Subjective Predictors. Pacing Clin Electrophysiol. 
2005;28:801-807 
24. 
Dries D, Exner D, Gersh B, Domanski M, Waclawiw M, Stevenson L. Atrial fibrillation is associated 
with an increased risk for mortality and heart failure progression in patients with asymptomatic and 
symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. J Am 
Coll Cardiol. 1998;32:695-703 
25. 
Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D’Agostino RB, Murabito JM, Kannel 
WB, Benjamin EJ. Temporal Relations of Atrial Fibrillation and Congestive Heart Failure and Their 
Joint Influence on Mortality: The Framingham Heart Study. Circulation. 2003;107:2920-2925 
26. 
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A 
Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation. N Engl J Med. 
2002;347:1825-1833 
27. 
Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, 
Timmermans AJM, Tijssen JGP, Crijns HJGM. A Comparison of Rate Control and Rhythm Control 
in Patients with Recurrent Persistent Atrial Fibrillation. N Engl J Med. 2002;347:1834-1840 
28. 
Olshansky B, Rosenfeld LE, Warner AL, Solomon AJ, O'Neill G, Sharma A, Platia E, Feld GK, 
Akiyama T, Brodsky MA, Greene HL. The Atrial Fibrillation Follow-up Investigation of Rhythm 
Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. 
2004;43:1201-1208 
29. 
Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--Pharmacological 
Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356:1789-1794 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 64 of 71 
 
30. 
Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U, Investigators S. 
Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies 
of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol. 2003;41:1690-1696 
31. 
de Denus S, Sanoski CA, Carlsson J, Opolski G, Spinler SA. Rate vs rhythm control in patients 
with atrial fibrillation: a meta-analysis. Arch Intern Med. 2005;165:258-262 
32. 
Chatterjee S, Sardar P, Lichstein E, Mukherjee D, Aikat S. Pharmacologic rate versus rhythm-
control strategies in atrial fibrillation: an updated comprehensive review and meta-analysis. PACE. 
2013;36:122-133 
33. 
Shelton RJ, Clark AL, Goode K, Rigby AS, Houghton T, Kaye GC, Cleland JG. A randomised, 
controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart 
failure: (CAFE-II Study). Heart. 2009;95:924-930 
34. 
Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JMO, Buxton AE, 
Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey 
J-Y, O'Hara G, Pedersen OD, Rouleau J-L, Singh BN, Stevenson LW, Stevenson WG, Thibault B, 
Waldo AL. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure. N Engl J 
Med. 2008;358:2667-2677 
35. 
Kong MH, Shaw LK, O'Connor C, Califf RM, Blazing MA, Al-Khatib SM. Is rhythm-control superior 
to rate-control in patients with atrial fibrillation and diastolic heart failure? Ann Noninvasive 
Electrocardiol. 2010;15:209-217 
36. 
Wazni O, Wilkoff B, Saliba W. Catheter Ablation for Atrial Fibrillation. N Engl J Med. 
2011;365:2296-2304 
37. 
Jones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley SL, McDonagh TA, 
Underwood SR, Markides V, Wong T. A randomized trial to assess catheter ablation versus rate 
control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol. 
2013;61:1894-1903 
38. 
Kirchhof P, Breithardt G, Camm AJ, Crijns HJ, Kuck KH, Vardas P, Wegscheider K. Improving 
outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial 
fibrillation for Stroke prevention Trial. Am Heart J. 2013;166:442-448 
39. 
Steg PG, Alam S, Chiang C-E, Gamra H, Goethals M, Inoue H, Krapf L, Lewalter T, Merioua I, 
Murin J, Naditch-Brûlé L, Ponikowski P, Rosenqvist M, Silva-Cardoso J, Zharinov O, Brette S, Neill 
JO. Symptoms, functional status and quality of life in patients with controlled and uncontrolled atrial 
fibrillation: data from the RealiseAF cross-sectional international registry. Heart. 2012;98:195-201 
40. 
Nabauer M, Gerth A, Limbourg T, Schneider S, Oeff M, Kirchhof P, Goette A, Lewalter T, Ravens 
U, Meinertz T, Breithardt G, Steinbeck G. The Registry of the German Competence NETwork on 
Atrial Fibrillation: patient characteristics and initial management. Europace. 2009;11:423-434 
41. 
Segal JB, McNamara RL, Miller MR, Kim N, Goodman SN, Powe NR, Robinson K, Yu D, Bass EB. 
The evidence regarding the drugs used for ventricular rate control. J Fam Practice. 2000;49:47-59 
42. 
Farshi R, Kistner D, Sarma JSM, Longmate JA, Singh BN. Ventricular rate control in chronic atrial 
fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug 
regimens. J Am Coll Cardiol. 1999;33:304-310 
43. 
Koh KK, Kwon KS, Park HB, Baik SH, Park SJ, Lee KH, Kim EJ, Kim SH, Cho SK, Kim SS. 
Efficacy and safety of digoxin alone and in combination with low-dose diltiazem or betaxolol to 
control ventricular rate in chronic atrial fibrillation. Am J Cardiol. 1995;75:88-90 
44. 
Nikolaidou T, Channer KS. Chronic atrial fibrillation: a systematic review of medical heart rate 
control management. Postgrad Med J. 2009;85:303-312 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 65 of 71 
 
45. 
Ulimoen SR, Enger S, Carlson J, Platonov PG, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, 
Tveit A. Comparison of four single-drug regimens on ventricular rate and arrhythmia-related 
symptoms in patients with permanent atrial fibrillation. Am J Cardiol. 2013;111:225-230 
46. 
Ulimoen SR, Enger S, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Calcium channel 
blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels 
compared with beta-blockers in patients with permanent atrial fibrillation. Eur Heart J. 2014;35:517-
524 
47. 
Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedilol alone or in 
combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am 
Coll Cardiol. 2003;42:1944-1951 
48. 
Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-
analysis of the literature. Eur Heart J. 2015; In press: 10.1093/eurheartj/ehv143 
49. 
Gheorghiade M, Fonarow GC, van Veldhuisen DJ, Cleland JG, Butler J, Epstein AE, Patel K, Aban 
IB, Aronow WS, Anker SD, Ahmed A. Lack of evidence of increased mortality among patients with 
atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM 
trial. Eur Heart J. 2013;34:1489-1497 
50. 
Friberg L, Hammar N, Rosenqvist M. Digoxin in atrial fibrillation: report from the Stockholm Cohort 
study of Atrial Fibrillation (SCAF). Heart. 2010;96:275-280 
51. 
Flory JH, Ky B, Haynes K, S MB, Munson J, Rowan C, Strom BL, Hennessy S. Observational 
cohort study of the safety of digoxin use in women with heart failure. BMJ Open. 2012;2:e000888 
52. 
Andrey JL, Romero S, Garcia-Egido A, Escobar MA, Corzo R, Garcia-Dominguez G, Lechuga V, 
Gomez F. Mortality and morbidity of heart failure treated with digoxin. A propensity-matched study. 
Int J Clin Pract. 2011;65:1250-1258 
53. 
Lewis RV, Irvine N, McDevitt DG. Relationships between heart rate, exercise tolerance and cardiac 
output in atrial fibrillation: the effects of treatment with digoxin, verapamil and diltiazem. Eur Heart 
J. 1988;9:777-781 
54. 
Tsuneda T, Yamashita T, Fukunami M, Kumagai K, Niwano S, Okumura K, Inoue H. Rate control 
and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial 
Fibrillation (QOLAF) Study. Circ J. 2006;70:965-970 
55. 
Van Gelder IC, Groenveld HF, Crijns HJGM, Tuininga YS, Tijssen JGP, Alings AM, Hillege HL, 
Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van Veldhuisen DJ, Van den Berg 
MP. Lenient versus Strict Rate Control in Patients with Atrial Fibrillation. N Engl J Med. 
2010;362:1363-1373 
56. 
Groenveld HF, Crijns HJGM, Van den Berg MP, Van Sonderen E, Alings AM, Tijssen JGP, Hillege 
HL, Tuininga YS, Van Veldhuisen DJ, Ranchor AV, Van Gelder IC. The Effect of Rate Control on 
Quality of Life in Patients With Permanent Atrial Fibrillation: Data From the RACE II (Rate Control 
Efficacy in Permanent Atrial Fibrillation II) Study. J Am Coll Cardiol. 2011;58:1795-1803 
57. 
Mulder BA, Van Veldhuisen DJ, Crijns HJGM, Tijssen JGP, Hillege HL, Alings M, Rienstra M, 
Groenveld HF, Van den Berg MP, Van Gelder IC. Lenient vs. strict rate control in patients with 
atrial fibrillation and heart failure: a post-hoc analysis of the RACE II study. Eur J Heart Fail. 
2013;15:1311-1318 
58. 
Groenveld HF, Tijssen JG, Crijns HJ, Van den Berg MP, Hillege HL, Alings M, Van Veldhuisen DJ, 
Van Gelder IC. Rate control efficacy in permanent atrial fibrillation: successful and failed strict rate 
control against a background of lenient rate control: data from RACE II (Rate Control Efficacy in 
Permanent Atrial Fibrillation). J Am Coll Cardiol. 2013;61:741-748 
59. 
US Department of Health and Human Services Food and Drug Administration. Guidance for 
industry: patient-reported outcome measures: use in medical product development to support 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 66 of 71 
 
labeling claims. 2009;[Accessed 01-Jan-2016]: Available from: 
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM19328
2.pdf. 2009 
60. 
Rienstra M, Lubitz SA, Mahida S, Magnani JW, Fontes JD, Sinner MF, Van Gelder IC, Ellinor PT, 
Benjamin EJ. Symptoms and Functional Status of Patients With Atrial Fibrillation: State of the Art 
and Future Research Opportunities. Circulation. 2012;125:2933-2943 
61. 
Pepine CJ. Effects of pharmacologic therapy on health-related quality of life in elderly patients with 
atrial fibrillation: a systematic review of randomized and nonrandomized trials. Clin Med Insights 
Cardiol. 2013;7:1-20 
62. 
Hagens VE, Ranchor AV, Van Sonderen E, Bosker HA, Kamp O, Tijssen JGP, Kingma JH, Crijns 
HJGM, Van Gelder IC. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation: 
Results from the Rate Control Versus Electrical Cardioversion (RACE) study. J Am Coll Cardiol. 
2004;43:241-247 
63. 
Grönefeld GC, Lilienthal J, Kuck K-H, Hohnloser SH. Impact of rate versus rhythm control on 
quality of life in patients with persistent atrial fibrillation: Results from a prospective randomized 
study. Eur Heart J. 2003;24:1430-1436 
64. 
Ware Jr JE, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life 
Assessment (IQOLA) Project. J Clin Epidemiol. 1998;51:903-912 
65. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20:1727-1736 
66. 
Devlin NJ, Krabbe PF. The development of new research methods for the valuation of EQ-5D-5L. 
Eur J Health Econ. 2013;14 Suppl 1:S1-3 
67. 
Spertus J, Dorian P, Bubien R, Lewis S, Godejohn D, Reynolds MR, Lakkireddy DR, Wimmer AP, 
Bhandari A, Burk C. Development and validation of the Atrial Fibrillation Effect on QualiTy-of-Life 
(AFEQT) Questionnaire in patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:15-
25 
68. 
Dorian P, Burk C, Mullin CM, Bubien R, Godejohn D, Reynolds MR, Lakkireddy DR, Wimmer AP, 
Bhandari A, Spertus J. Interpreting changes in quality of life in atrial fibrillation: How much change 
is meaningful? Am Heart J. 2013;166:381-387.e388 
69. 
Joint Formulary Committee. British National Formulary. London: BMJ Group and Pharmaceutical 
Press; 2013. 
70. 
American Hospital Formulary Service. Drug Information. Bethesda: American Society of Health-
System Pharmacists; 2013. 
71. 
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with 
heart failure. N Engl J Med. 1997;336:525-533 
72. 
Magnani B, Malini PL. Cardiac glycosides. Drug interactions of clinical significance. Drug Safety. 
1995;12:97-109 
73. 
Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and 
symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288:351-357 
74. 
Terwee C, Mokkink L, Knol D, Ostelo RJG, Bouter L, Vet HW. Rating the methodological quality in 
systematic reviews of studies on measurement properties: a scoring system for the COSMIN 
checklist. Qual Life Res. 2012;21:651-657 
75. 
Streiner DL, Norman GR. Health measurement scales : a practical guide to their development and 
use. Oxford ; New York: Oxford University Press; 2008. 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 67 of 71 
 
76. 
Staniszewska S, Haywood KL, Brett J, Tutton L. Patient and public involvement in patient-reported 
outcome measures: evolution not revolution. Patient. 2012;5:79-87 
77. 
Calvert M, Kyte D, Duffy H, Gheorghe A, Mercieca-Bebber R, Ives J, Draper H, Brundage M, 
Blazeby J, King M. Patient-reported outcome (PRO) assessment in clinical trials: a systematic 
review of guidance for trial protocol writers. PLoS One. 2014;9:e110216 
78. 
McCabe PJ, Schumacher K, Barnason SA. Living with atrial fibrillation: a qualitative study. J 
Cardiovasc Nurs. 2011;26:336-344 
79. 
Kirchhof P, Auricchio A, Bax J, Crijns H, Camm J, Diener H-C, Goette A, Hindricks G, Hohnloser S, 
Kappenberger L, Kuck K-H, Lip GYH, Olsson B, Meinertz T, Priori S, Ravens U, Steinbeck G, 
Svernhage E, Tijssen J, Vincent A, Breithardt G. Outcome parameters for trials in atrial fibrillation: 
Recommendations from a consensus conference organized by the German Atrial Fibrillation 
Competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eur Heart 
J. 2007;28:2803-2817 
80. 
Haywood K, Brett J, Salek S, Marlett N, Penman C, Shklarov S, Norris C, Santana MJ, 
Staniszewska S. Patient and public engagement in health-related quality of life and patient-
reported outcomes research: what is important and why should we care? Findings from the first 
ISOQOL patient engagement symposium. Qual Life Res. 2014: Epub ahead of print; PMID 
25194573 
81. 
Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hrobjartsson A, 
Schulz KF, Parulekar WR, Krleza-Jeric K, Laupacis A, Moher D. SPIRIT 2013 explanation and 
elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586 
82. 
Calvert M, Kyte D, von Hildebrand M, King M, Moher D. Putting patients at the heart of health-care 
research. Lancet. 2015;385:1073-1074 
83. 
Kyte D, Duffy H, Fletcher B, Gheorghe A, Mercieca-Bebber R, King M, Draper H, Ives J, Brundage 
M, Blazeby J, Calvert M. Systematic evaluation of the patient-reported outcome (PRO) content of 
clinical trial protocols. PLoS One. 2014;9:e110229 
84. 
Kyte D, Draper H, Calvert M. Patient-reported outcome alerts: ethical and logistical considerations 
in clinical trials. JAMA. 2013;310:1229-1230 
85. 
Zbrozek A, Hebert J, Gogates G, Thorell R, Dell C, Molsen E, Craig G, Grice K, Kern S, Hines S. 
Validation of electronic systems to collect patient-reported outcome (PRO) data-recommendations 
for clinical trial teams: report of the ISPOR ePRO systems validation good research practices task 
force. Value Health. 2013;16:480-489 
86. 
Su H-M, Lin T-H, Hsu P-C, Lee W-H, Chu C-Y, Lee C-S, Voon W-C, Lai W-T, Sheu S-H. Global left 
ventricular longitudinal systolic strain as a major predictor of cardiovascular events in patients with 
atrial fibrillation. Heart. 2013;99:1588-1596 
87. 
Al-Omari MA, Finstuen J, Appleton CP, Barnes ME, Tsang TSM. Echocardiographic assessment of 
left ventricular diastolic function and filling pressure in atrial fibrillation. Am J Cardiol. 
2008;101:1759-1765 
88. 
Hijazi Z, Oldgren J, Siegbahn A, Granger CB, Wallentin L. Biomarkers in atrial fibrillation: a clinical 
review. Eur Heart J. 2013;34:1475-1480 
89. 
Parvez B, Chopra N, Rowan S, Vaglio JC, Muhammad R, Roden DM, Darbar D. A common beta1-
adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial 
fibrillation. J Am Coll Cardiol. 2012;59:49-56 
90. 
Mahmmoud YA, Shattock M, Cornelius F, Pavlovic D. Inhibition of K+ transport through Na+, K+-
ATPase by capsazepine: role of membrane span 10 of the alpha-subunit in the modulation of ion 
gating. PLoS One. 2014;9:e96909 


RATE-AF Trial Protocol 
 
 
 
 
 
                 
Version 3.0, 25th July 2019  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 68 of 71 
 
91. 
Pavlovic D, Hall AR, Kennington EJ, Aughton K, Boguslavskyi A, Fuller W, Despa S, Bers DM, 
Shattock MJ. Nitric oxide regulates cardiac intracellular Na(+) and Ca(2)(+) by modulating Na/K 
ATPase via PKCepsilon and phospholemman-dependent mechanism. J Mol Cell Cardiol. 
2013;61:164-171 
92. 
Pullen MA, Brooks DP, Edwards RM. Characterization of the neutralizing activity of digoxin-specific 
Fab toward ouabain-like steroids. J Pharmacol Exp Ther. 2004;310:319-325 
93. 
Manunta P, Messaggio E, Casamassima N, Gatti G, Carpini SD, Zagato L, Hamlyn JM. 
Endogenous ouabain in renal Na(+) handling and related diseases. Biochim Biophys Acta. 
2010;1802:1214-1218 
94. 
Pavlovic D. The role of cardiotonic steroids in the pathogenesis of cardiomyopathy in chronic 
kidney disease. Nephron Clin Pract. 2014;128:11-21 
95. 
Song H, Karashima E, Hamlyn JM, Blaustein MP. Ouabain-digoxin antagonism in rat arteries and 
neurones. J Physiol. 2014;592:941-969 
96. 
Curtis L. Unit Costs of Health & Social Care 2012. Personal Social Services Research Unit. 
2012:http://www.pssru.ac.uk/archive/pdf/uc/uc2012/full-with-covers.pdf 
97. 
Hemingway H, Asselbergs FW, Danesh J, Dobson R, Maniadakis N, Maggioni A, van Thiel GJM, 
Cronin M, Brobert G, Vardas P, Anker SD, Grobbee DE, Denaxas S, BigData@Heart Consortium. 
Big data from electronic health records for early and late translational cardiovascular research: 
challenges and potential. Eur Heart J. 2017;10.1093/eurheartj/ehx487 
98. 
Kotecha D, Chua WWL, Fabritz L, Hendriks J, Casadei B, Schotten U, Vardas P, Heidbuchel H, 
Dean V, Kirchhof P. European Society of Cardiology smartphone and tablet applications for 
patients with atrial fibrillation and their health care providers. Europace. 
2017;10.1093/europace/eux299 
99. 
Kotecha D, Breithardt G, Camm AJ, Lip GYH, Schotten U, Ahlsson A, Arnar D, Atar D, Auricchio A, 
Bax J, Benussi S, Blomstrom-Lundqvist C, Borggrefe M, Boriani G, Brandes A, Calkins H, Casadei 
B, Castella M, Chua W, Crijns H, Dobrev D, Fabritz L, Feuring M, Freedman B, Gerth A, Goette A, 
Guasch E, Haase D, Hatem S, Haeusler KG, Heidbuchel H, Hendriks J, Hunter C, Kaab S, 
Kespohl S, Landmesser U, Lane DA, Lewalter T, Mont L, Nabauer M, Nielsen JC, Oeff M, Oldgren 
J, Oto A, Pison L, Potpara T, Ravens U, Richard-Lordereau I, Rienstra M, Savelieva I, Schnabel R, 
Sinner MF, Sommer P, Themistoclakis S, Van Gelder IC, Vardas PE, Verma A, Wakili R, Weber E, 
Werring D, Willems S, Ziegler A, Hindricks G, Kirchhof P. Integrating new approaches to atrial 
fibrillation management: the 6th AFNET/EHRA Consensus Conference. Europace. 
2018;10.1093/europace/eux318 
100. 
Kotecha D, Flather MD, Altman DG, Holmes J, Rosano G, Wikstrand J, Packer M, Coats AJS, 
Manzano L, Bohm M, van Veldhuisen DJ, Andersson B, Wedel H, von Lueder TG, Rigby AS, 
Hjalmarson A, Kjekshus J, Cleland JGF, Beta-Blockers in Heart Failure Collaborative G. Heart 
Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure. J Am Coll 
Cardiol. 2017;69:2885-2896 
101. 
Adlan AM, Paton JF, Lip GY, Kitas GD, Fisher JP. Increased sympathetic nerve activity and 
reduced cardiac baroreflex sensitivity in rheumatoid arthritis. J Physiol. 2016;10.1113/jp272944 
102. 
Deo SH, Fisher JP, Vianna LC, Kim A, Chockalingam A, Zimmerman MC, Zucker IH, Fadel PJ. 
Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart 
failure. Am J Physiol Heart Circ Physiol. 2012;303:H377-385 


APPENDIX A – Dosing Schedule (Digoxin)  
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 69 of 71 
 
 
 
 
 
 
 


APPENDIX B – Dosing Schedule (Bisoprolol)  
 
 
 
 
                 
     
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 70 of 71 
 
 


APPENDIX B – Dosing Schedule (Bisoprolol)  
 
 
 
 
                 
     
EudraCT No.: 2015-005043-13 
 
 
 
 
 
 
 
 
Page 71 of 71 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
Official Title 
Evaluating different rate control therapies in permanent atrial 
fibrillation:  
A prospective, randomised, open-label, blinded endpoint trial 
comparing digoxin and beta-blockers as initial rate control therapy 
 
RAte control Therapy Evaluation in Atrial Fibrillation: RATE-AF 
Acronym 
RATE-AF 
Document date 
17th December 2019 
 NCT number 
NCT02391337 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 2 of 46 
 
 
Evaluating different rate control therapies in 
permanent atrial fibrillation: 
A Prospective, randomised, open-label, blinded endpoint trial of comparing 
digoxin and beta-blockers as initial control therapy  
The RATE-AF Trial 
 
Trial registration number: ISCRCTN 95259705 
Statistical Analysis Plan 
SAP Version Number 
1.0 
 
Author: 
Samir Mehta 
Role: 
Trial Statistician 
Affiliation: 
BCTU 
University of 
Birmingham 
Signature: 
 
 
Date: 
 
Reviewer: 
Prof. Jon Deeks 
Role: 
Senior Statistician 
Affiliation: 
BCTU 
University of 
Birmingham 
Signature: 
 
 
Date: 
 
Chief 
Investigator: 
Dr. Dipak Kotecha 
Role: 
Chief Investigator 
Affiliation: 
Institute of 
Cardiovascular Sciences 
University of 
Birmingham 
Signature: 
 
 
Date: 
 
This Statistical Analysis Plan has been approved by: 
Approver: 
 
Role: 
Senior Statistician 
Affiliation: 
BCTU 
University of 
Birmingham 
Signature: 
 
 
Date: 
 
 


 
 
Page 3 of 46 
 
Statistical Analysis Plan Amendments 
 
† This SAP was written based on information contained in the trial protocol version as listed here. 
 
SAP 
version 
number 
Date Approved 
Protocol 
version 
number† 
Section 
number 
changed 
Description of and reason for change 
Timing of change 
with respect to 
interim/final 
analysis 
Blind Reviewer 
 
 
 
 
 
 
Name: 
 
Signature:  
 
Date: 
 
 
 
 
 
 
 
Name: 
 
Signature:  
 
Date: 
 
 
 
 
 
 
 
Name: 
 
Signature:  
 
Date: 
 


 
Page 4 of 46 
 
 
Abbreviations & Definitions 
 
Abbreviation / Acronym 
Meaning 
BCTU 
Birmingham Clinical Trials Unit 
CONSORT 
Consolidated Standards of Reporting Trials 
DMC 
Data Monitoring Committee 
ISRCTN 
International Standard Randomised Controlled Trial 
Number 
ITT 
Intention to Treat 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSC 
Trial Steering Committee 
QoL 
Quality of life 
PCS 
Physical Component Score 
MCS 
Mental Component Score 
 
 
Term 
Definition 
International Standard Randomised 
Controlled Trial Number 
A clinical trial registry 
Protocol 
Document that details the rationale, objectives, design, 
methodology and statistical considerations of the study 
Randomisation 
The process of assigning trial subjects to intervention or 
control groups using an element of chance to determine 
the assignments in order to reduce bias. 
Statistical Analysis Plan 
Pre-specified statistical methodology documented for 
the trial, either in the protocol or in a separate 
document. 
 
 
 
 


 
Page 5 of 46 
 
TABLE OF CONTENTS 
 
1. 
Introduction .................................................................................................................................... 7 
2. 
Background and rationale .............................................................................................................. 7 
3. 
Trial objectives ............................................................................................................................... 7 
4. 
Trial methods .................................................................................................................................. 8 
4.1. 
Trial design.................................................................................................................................. 8 
4.2. 
Trial interventions ...................................................................................................................... 8 
4.3. 
Primary outcome measure ......................................................................................................... 8 
4.4. 
Secondary outcome measures ................................................................................................... 8 
4.5. 
Timing of outcome assessments ................................................................................................ 9 
4.6. 
Randomisation ........................................................................................................................... 9 
4.7. 
Sample size ................................................................................................................................. 9 
4.8. 
Framework .................................................................................................................................. 9 
4.9. 
Interim analyses and stopping guidance ................................................................................... 9 
4.10. 
Pilot Progression Rules ......................................................................................................... 10 
4.11. 
Timing of final analysis ......................................................................................................... 10 
4.12. 
Timing of other analyses ...................................................................................................... 10 
4.13. 
Trial comparisons ................................................................................................................. 10 
5. 
Statistical Principles ..................................................................................................................... 10 
5.1. 
Confidence intervals and p-values ........................................................................................... 10 
5.2. 
Adjustments for multiplicity .................................................................................................... 10 
5.3. 
Analysis populations ................................................................................................................ 11 
5.4. 
Definition of adherence ........................................................................................................... 11 
5.5. 
Handing protocol deviations and violations ........................................................................... 11 
5.6. 
Unblinding ................................................................................................................................ 12 
6. 
Trial population ............................................................................................................................ 12 
6.1. 
Recruitment .............................................................................................................................. 12 
6.2. 
Baseline characteristics ............................................................................................................ 12 
7. 
Intervention(s) .............................................................................................................................. 12 
7.1. 
Description of the intervention(s) ........................................................................................... 12 
7.2. 
Adherence to allocated intervention ...................................................................................... 12 
8. 
Protocol deviations and violations .............................................................................................. 12 
9. 
Analysis methods ......................................................................................................................... 12 
9.1. 
Covariate adjustment ............................................................................................................... 12 
9.2. 
Distributional assumptions and outlying responses ............................................................... 13 
9.3. 
Handling missing data .............................................................................................................. 13 
9.4. 
Data manipulations .................................................................................................................. 13 
9.5. 
Analysis methods – primary outcome(s) ................................................................................. 19 
9.6. 
Analysis methods – secondary outcomes ............................................................................... 19 
9.7. 
Analysis methods – exploratory outcomes and analyses ....................................................... 23 
9.8. 
Safety data ................................................................................................................................ 23 
9.9. 
Planned subgroup analyses ..................................................................................................... 23 
9.10. 
Sensitivity analyses .............................................................................................................. 24 
10. 
Analysis of sub-randomisations ............................................................................................... 24 
11. 
Health economic analysis ......................................................................................................... 24 


 
Page 6 of 46 
 
12. 
Statistical software ................................................................................................................... 24 
13. 
References ................................................................................................................................ 25 
Appendix A: Deviations from SAP ....................................................................................................... 26 
Appendix B: Trial schema ..................................................................................................................... 27 
Appendix C: Schedule of assessments ................................................................................................. 28 
Appendix D1: CONSORT flow diagram ................................................................................................ 29 
Appendix D2: Baseline characteristics ................................................................................................. 30 
Appendix D3: Adherence to allocated intervention ........................................................................... 32 
Appendix D4: Protocol deviations and violations ............................................................................... 33 
Appendix D5: Primary outcome results ............................................................................................... 34 
Appendix D6: Secondary outcomes results ......................................................................................... 35 
Appendix D7: Feasibility outcomes ..................................................................................................... 42 
Appendix D8: Safety ............................................................................................................................. 44 
Appendix D9: Subgroup analysis for primary outcome ...................................................................... 46 


 
Page 7 of 46 
 
 
1. Introduction 
This document is the Statistical Analysis Plan (SAP) for the RATE-AF trial, and should be read in conjunction with 
the current trial protocol.  This SAP details the proposed analyses and presentation of the data for the main 
paper(s) reporting the results for the RATE-AF trial. 
 
The results reported in these papers will follow the strategy set out here.  Subsequent analyses of a more 
exploratory nature will not be bound by this strategy, though they are expected to follow the broad principles 
laid down here.  The principles are not intended to curtail exploratory analysis (e.g. to decide cut-points for 
categorisation of continuous variables), nor to prohibit accepted practices (e.g. transformation of data prior to 
analysis), but they are intended to establish rules that will be followed, as closely as possible, when analysing and 
reporting data. 
 
Any deviations from this SAP will be described and justified in the final report or publication of the trial (using a 
table as shown in Appendix A).  The analysis will be carried out by an appropriately qualified statistician, who 
should ensure integrity of the data during their data cleaning processes. 
 
2. Background and rationale 
The background and rationale for the trial are outlined in detail in the protocol1.  In brief, Atrial fibrillation (AF) is 
an increasingly common cardiac condition that leads to a substantial burden on quality-of-life (QoL), an increased 
risk of cardiovascular events, hospitalisation and death, and significant healthcare costs for the NHS. Beta-
blocker monotherapy remains the first-line option in the current NICE AF guidelines consultation document, with 
digoxin only for sedentary patients, although this recommendation is based on very low-quality evidence. 
 
The RAte control Therapy Evaluation in Atrial Fibrillation (RATE-AF) trial is Prospective, Randomised Open-label 
Blinded Endpoint (PROBE) clinical trial comparing the use of digoxin and beta-blockers as initial rate control 
therapy. The RATE-AF trial combines hypothesis testing (quality of life, cardiac function, exercise capacity and 
biomarkers), evaluation of measures (validity, reproducibility and correlation of outcomes) and a feasibility study 
for a future clinical event trial (assessing recruitment, retention and sample size).  
 
3. Trial objectives 
The primary objective is the patient-reported QoL, with a predefined focus on physical well-being using the SF-
36v2 physical component summary at 6 months. 
 
Secondary objectives are as follows:  
• 
Generic and AF-specific patient-reported QoL using the SF-36 global and domain-specific scores, the 
AFEQT overall score and the EQ-5D-5L summary index and visual analogue scale at 6 and 12 months. 
• 
Echocardiographic left-ventricular ejection fraction (LVEF) and diastolic function (E/e’ and composite of 
diastolic indices) at 12 months. 
• 
Functional assessment, including 6-minute walking distance achieved, change in European Heart Rhythm 
Association (EHRA) class and cognitive function at 6 and 12 months. 
• 
Change in B-type natriuretic peptide (BNP) levels as a surrogate for total cardiac strain at 6 months. 
• 
Change in heart rate from baseline and group comparison using 24-hour ambulatory ECG. 
 
Feasibility objectives: 
• 
Successful methods for recruitment 
• 
Key issues that affect retention of participants, such as convenience, compliance and cross-over (target 


 
Page 8 of 46 
 
of 85% study completion rate). 
• 
Drug discontinuation rate and adverse reactions leading to drug discontinuation. 
• 
Therapy-induced requirement for additional treatment (e.g. pacemaker implantation). 
• 
Population-specific standard deviations and proportions to enable sample size calculation for a future 
trial. 
• 
Assessment of cardiovascular outcomes including a composite of adverse clinical events (mortality, 
thromboembolic events, myocardial infarction and cardiovascular interventions). 
 
4. Trial methods 
4.1. Trial design 
RATE-AF is a Prospective, Randomised Open-label Blinded Endpoint (PROBE) clinical trial comparing the use of 
Digoxin and beta-blockers (Bisoprolol) as initial rate control therapy. This study also designed to assess the 
feasibility of conducting a future clinical event trial. See Appendix B for trial schema. 
 
4.2. Trial interventions 
Digoxin 62.5-250 µg od 
Bisoprolol 1.25-15 mg od 
 
4.3. Primary outcome measure 
The primary outcome is the Patient-reported Quality of life (QoL) SF-36v2 Physical Component Summary (PCS) 
score at 6 months.  
 
4.4. Secondary outcome measures 
Patient-reported QoL: 
• 
SF-36 global and domain-specific scores at 6 and 12 months  
• 
EQ-5D-5L summary index and visual analogue scale at 6 and 12 months  
• 
AFEQT overall score at 6 and 12 months  
 
Cardiac function: 
• 
Echocardiographic LVEF at 12 months 
• 
Diastolic function (E/e’ and composite of diastolic indices) at 12 months 
• 
Change in heart rate using 24-hour ambulatory ECG 
 
Functional assessment: 
• 
Six-minute walking distance at 6 and 12 months 
• 
Change in European Heart Rhythm Association (EHRA) class at 6 and 12 months 
 
Biomarkers: 
• 
Change in B-type natriuretic peptide (BNP) levels at 6 and 12 months 
 
Feasibility outcomes: 
• 
Recruitment target of 3 patients per week across all participating centres 
• 
Compliance and reasons for non-compliance 
• 
Number of withdrawals and losses to follow-up (with reasons) 
• 
Drug discontinuation rate and adverse reactions requiring drug discontinuation 


 
Page 9 of 46 
 
• 
Number of patients needing therapy-induced requirement for additional treatment 
• 
Cardiovascular events (mortality, thromboembolic events, myocardial infarction and cardiovascular 
intervention) 
• 
Population-specific standard deviations (SD) and proportions for all outcomes 
 
4.5. Timing of outcome assessments 
The schedule of trial procedures and outcome assessments are given in Appendix C. 
 
4.6. Randomisation 
Participants will be randomised in a 1:1 ratio to either Digoxin 62.5 – 250 μg od or Bisoprolol 1.25 – 15 mg od. 
The time between randomisation and commencement of trial therapy should be minimised (ideally <24 hours).  
 
Randomisation will be provided by a computer generated programme at the Birmingham Clinical Trials Unit 
(BCTU), using a minimisation algorithm incorporating the following factors:  
• 
Baseline EHRA (class 1/2a and class 2b/3/4)  
• 
Gender (Male and Female) 
 
4.7. Sample size 
Randomising 144 patients we can assume an 85% power to detect an effect size of half a standard deviation in a 
continuous outcome measure of QoL (two-sided alpha of 0.05).  
 
A sample size of 160 patients would account for an estimated 10% loss to follow-up (including withdrawal and 
death prior to 12-month assessment). 
 
There is some evidence from existing research to support the notion that the treatment effect could be this 
large. The mean SF-36 role-physical score from the rate-control arm of the RACE study was 47, with a 17% 
improvement with rate-control over time.2 In another study, CCB resulted in 22% improvement in a proprietary 
symptom-checklist, compared to a non-significant 8% change in those assigned to beta-blockers (SD 10-points in 
both groups). These values are also consistent with a 17% improvement in SF-36 scores in a third trial, PIAF.3  
 
4.8. Framework 
The objective of the trial is to test the superiority of one intervention to another as well as to assess the 
feasibility of running a future clinical event study. 
 
Null Hypothesis for primary outcome: 
No difference in the SF-36v2 PCS score when comparing a strategy of digoxin versus beta-blocker therapy for 
initial rate control in patients with permanent AF. 
 
Alternative Hypothesis: 
Use of digoxin or beta-blocker therapy as initial rate control in patients with permanent AF is superior based on 
the PCS score from SF-36v2. 
 
4.9.  Interim analyses and stopping guidance 
A joint oversight committee comprising a Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) 
will be engaged for this trial. The role of the TSC is to provide the overall supervision of the trial. The TSC will 


 
Page 10 of 46 
 
monitor trial progress and conduct and advice on scientific credibility. The TSC will consider and act, as 
appropriate, upon the recommendations of the Data Monitoring Committee. Further details of the remit and 
role of the TSC are available in the TSC Charter. 
 
An independent DMC will be established to oversee the safety of participants in the trial. The DMC will meet 
prior to the trial opening to enrolment, and then meet at least annually, or as per a timetable agreed by the DMC 
prior to trial commencement. Data analyses will be supplied in confidence to the DMC, which will be asked to 
give advice on whether the accumulated data from the trial, together with the results from other relevant 
research, justifies the continuing recruitment of further participants. The DMC will operate in accordance with 
the trial specific charter. It is likely that the Haybittle-Peto boundary will be used. This states that if an interim 
analysis shows a probability of less than 0.001 that the treatments are different, then the trial should be stopped 
early. This will be used alongside data on important secondary endpoints and all other relevant evidence. A DMC 
report and charter outlining the terms of reference (including information on stopping rules) will be agreed with 
the DMEC. 
 
4.10. Pilot Progression Rules 
N/A 
 
4.11.  Timing of final analysis 
The final analysis for the trial will occur after last randomised participant completes their 12-month follow-up 
and the corresponding outcome data has been entered onto the trial database and validated as being ready for 
analysis.  This is provided that the trial has not been stopped early for any reason (e.g. DMC advice or funding 
body request). 
 
4.12.  Timing of other analyses 
N/A 
 
4.13.  Trial comparisons 
All references in this document to ‘group’ refer to Digoxin or Bisoprolol.   
 
5. Statistical Principles 
5.1. Confidence intervals and p-values 
All estimates of differences between groups will be presented with two-sided 95% confidence intervals, unless 
otherwise stated.  P-values will be reported from two-sided tests.  
 
5.2. Adjustments for multiplicity 
No correction for multiple testing will be made. 
 


 
Page 11 of 46 
 
 
5.3. Analysis populations 
All primary analyses (primary and secondary outcomes including safety outcomes) will be by intention-to-treat 
(ITT).  Participants will be analysed in the intervention group to which they were randomised, and all participants 
shall be included whether or not they received the allocated intervention.   
 
As a sensitivity analysis, a per-protocol analysis may also be carried out for the primary outcome if it is deemed a 
worthwhile investigation to further understand drug efficacy. See section 5.4 for how adherence information will 
be summarised.  See section 9.10 for further details on any sensitivity analyses. 
 
5.4. Definition of adherence 
Data on adherence to medication was collected at each follow up visit and captured in two ways:  
1. By asking the patients if they have taken “All”, “Some” or “None” of their medication 
i) 
If patients have taken “Some” of their medication, then further asked if they have taken “>75%”, 
“>50-75%”, “>25-50%” or “≤25%”  
2. By assessing the data on any oral medications that patient is taking to normalise their heart rate  
 
Hence treatment adherence will be summarised in both ways described above and will be summarised 
separately for 6 and 12 months.  
 
Per-Protocol population set: 
Since the primary outcome for this study is at 6-months, the per-protocol population will therefore form of only 
those patients that have remained adherent to their treatment allocation at 6 months. Adherence to treatment 
allocation will be based on data collected on oral medication that the patients are taking at 6 months. Hence 
adherence will be computed as a binary “yes/no”. The per-protocol set will therefore consist of patients that 
remained adherent to their treatment allocation at 6 months (based on data from oral medications) as well as 
those patients that remain in atrial fibrillation, as documented on the AFEQT questionnaire at 6 months. 
 
Patients could also be taking additional rate control therapy beyond their randomised treatment allocation and 
so although not part of definition for adherence, this data will also be summarised by treatment arm. Similarly 
we also collect data on compliance by asking patients at each visit if they have been compliant with drugs used 
to control heart rate and so this data will also be summarised by treatment arm. 
 
5.5. Handing protocol deviations and violations 
A protocol deviation/violation is defined as a failure to adhere to the protocol such as errors in applying the 
inclusion/exclusion criteria, the incorrect intervention being given, incorrect data being collected or measured, 
follow-up visits outside the visit window or missed follow-up visits.  We will apply a strict definition of the ITT 
principle and will include all participants as per the ITT population described in section 5.3 in the analysis in some 
form regardless of deviation from the protocol.4 This includes participants who were randomised but later found 
to violate the inclusion or exclusion criteria. This does not include those participants who have specifically 
withdrawn consent for the use of their data in the first instance; however these outcomes will be explored as per 
other missing responses. 
 
Where appropriate, additional sensitivity analysis for any protocol deviations and violations will be conducted for 
the primary outcome only. These will be described in section 9.10.  
 


 
Page 12 of 46 
 
5.6. Unblinding 
RATE-AF is an open label trial, blinded endpoint trial and so patients are unblinded however the investigators are 
blinded to the summary QoL scores at 6 and 12 months and detailed echocardiographic variables at 12 months. 
NTpro-BNP levels at 6 and 12 months are not known during the clinical consultation. 
 
6. Trial population 
6.1.  Recruitment 
A flow diagram (as recommended by CONSORT5, 10) will be produced to describe the participant flow through 
each stage of the trial.  This will include information on the number (with reasons) of losses to follow-up (drop-
outs and withdrawals) over the course of the trial.  A template for reporting this is given in Appendix D1. 
 
6.2.  Baseline characteristics 
The trial population will be tabulated as per Appendix D2.  Categorical data will be summarised by number of 
participants, counts and percentages.  Continuous data will be summarised by the number of participants, mean 
and standard deviation if deemed to be normally distributed or number of participants, median and interquartile 
range if data appear skewed, and ranges if appropriate.  Tests of statistical significance will not be undertaken, 
nor confidence intervals presented.6 
 
7. Intervention(s) 
7.1.  Description of the intervention(s) 
N/A. 
 
7.2.  Adherence to allocated intervention 
A cross-tabulation of allocated intervention by the adherence categories stated in section 5.4 will be produced 
(proportions and percentages).  A template for reporting adherence is given in Appendix D3. 
 
8. Protocol deviations and violations 
Frequencies and percentages by group will be tabulated for the protocol deviations and violations as per 
Appendix D4.  
 
9. Analysis methods 
Intervention groups will be compared using appropriate statistical models, to adjust for all covariates as specified 
in section 9.1, where possible. See section 9.5 - 9.10 which describes in detail for each outcome the type of 
analysis method to be used.  
 
9.1. Covariate adjustment 
In the first instance, intervention effects between groups for all outcomes will be adjusted for the baseline score 
(where appropriate), minimisation parameters (Gender, baseline EHRA) as well as age at randomisation and 


 
Page 13 of 46 
 
baseline LVEF (as continuous variables). The minimisation variable EHRA is a categorical score with the following 
categories (1, 2a, 2b, 3, 4) and for minimisation, this score was categorised into (class 1, 2a) and (class 2b, 3, 4). 
However for the analysis we will be adjusting this variable in its original 5 categorical form.   
 
The Bisoprolol arm will be used as a reference category for all model based analyses.  
 
For some binary outcomes, sometimes the effect size to be estimated of interest is the relative risk rather than 
the odds ratio and so for these outcomes, a log-binomial model is often used. However there are convergence 
issues with this type of model and so if the log-binomial model fails to converge, a Poisson regression model with 
robust standard errors will be used to estimate the same parameters.7 If this also fails to converge, unadjusted 
estimates will be produced from the log-binomial model.  It will be made clear in the final report why this 
occurred (e.g. not possible due to low event rate/lack of model convergence). 
 
9.2. Distributional assumptions and outlying responses 
Distributional assumptions (e.g. normality of regression residuals for continuous outcomes) will be assessed 
visually prior to analysis; although in the first instance the proposed primary method of estimation in this 
analysis plan will be followed.  If responses are considered to be particularly skewed and/or distributional 
assumptions violated, the impact of this will be examined through sensitivity analysis; this will consist of 
transformation of responses prior to analysis (e.g. log transformation) in the first instance. 
 
9.3. Handling missing data 
In the first instance, analysis will be completed on received data only with every effort made to follow-up 
participants even after protocol violation to minimise any potential for bias.  To examine the possible impact of 
missing data on the results, and to make sure we are complying with the intention-to-treat principle, sensitivity 
analysis will be performed on the primary outcome measure only.8  See section 9.10 for further details. 
 
9.4. Data manipulations 
The Trial Statistician will derive all responses from the raw data recorded in the database: 
 
Age at randomisation 
(Randomisation date – Date of birth) / 365.25, taking the integer part of age 
 
SF-36 version 2 
The SF-36v2 questions will be coded as follows: 
SFQ1  - 
Excellent=5 
 
 
Very good=4.4 
 
Good=3.4 
 
Fair=2 
 
Poor=1 
 
SFQ2  -  
Much better now than one year ago = 5 
 
 
Somewhat better now than one year ago = 4 
 
 
About the same as one year ago = 3 
 
 
Somewhat worse now than one year ago = 2 
 
 
Much worse now than one year ago = 1 
 
SFQ3a  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 


 
Page 14 of 46 
 
 
 
No, not limited at all = 3 
 
SFQ3b  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3c  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3d  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3e  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3f  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3g  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3h  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3i  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ3j  -   
Yes, limited a lot = 1 
 
 
Yes, limited a little = 2 
 
 
No, not limited at all = 3 
 
SFQ4a - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ4b - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ4c - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 


 
Page 15 of 46 
 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ4d - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ5a - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ5b - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ5c - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ6 - 
Not at all = 5 
 
 
Slightly = 4 
 
 
Moderately = 3 
 
 
Quite a bit = 2 
 
 
Extremely = 1 
 
SFQ7 - 
None = 6 
 
 
Very mild = 5 
 
 
Mild = 4 
 
 
Moderate = 3 
 
 
Severe = 2 
 
 
Very severe = 1 
 
SFQ8 - 
Not at all = 5 
 
 
A little bit = 4 
 
 
Moderately = 3 
 
 
Quite a bit = 2 
 
 
Extremely = 1 
 
SFQ9a - 
All of the time = 5 
 
 
Most of the time = 4 
 
 
Some of the time = 3 
 
 
A little of the time = 2 
 
 
None of the time = 1 
 
SFQ9b - 
All of the time = 1 


 
Page 16 of 46 
 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ9c - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ9d - 
All of the time = 5 
 
 
Most of the time = 4 
 
 
Some of the time = 3 
 
 
A little of the time = 2 
 
 
None of the time = 1 
 
SFQ9e - 
All of the time = 5 
 
 
Most of the time = 4 
 
 
Some of the time = 3 
 
 
A little of the time = 2 
 
 
None of the time = 1 
 
SFQ9f - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ9g - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ9h - 
All of the time = 5 
 
 
Most of the time = 4 
 
 
Some of the time = 3 
 
 
A little of the time = 2 
 
 
None of the time = 1 
 
SFQ9i - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 
SFQ10 - 
All of the time = 1 
 
 
Most of the time = 2 
 
 
Some of the time = 3 
 
 
A little of the time = 4 
 
 
None of the time = 5 
 


 
Page 17 of 46 
 
SFQ11a - 
Definitely true = 1 
 
 
Mostly true = 2 
 
 
Don’t know = 3 
 
 
Mostly false = 4 
 
 
Definitely false = 5 
 
SFQ11b- 
Definitely true = 5 
 
 
Mostly true = 4 
 
 
Don’t know = 3 
 
 
Mostly false = 2 
 
 
Definitely false = 1 
 
SFQ11c - 
Definitely true = 1 
 
 
Mostly true = 2 
 
 
Don’t know = 3 
 
 
Mostly false = 4 
 
 
Definitely false = 5 
 
SFQ11d- 
Definitely true = 5 
 
 
Mostly true = 4 
 
 
Don’t know = 3 
 
 
Mostly false = 2 
 
 
Definitely false = 1 
 
The following domains will be computed from the SF-36 questionnaire: 
• 
Physical Function (PF) = SFQ3a + SFQ3b + SFQ3c + SFQ3d + SFQ3e + SFQ3f + SFQ3g + SFQ3h +  
 
 
 
      SFQ3i + SFQ3j 
• 
Physical Function Score = ((PF-10)/20)*100 
• 
Role Limitation Due to Physical Problems (RP) = SFQ4a + SFQ4b + SFQ4c + SFQ4d 
• 
Role Limitation Due to Physical Problems score = ((RP-4)/16)*100 
• 
Role Limitation Due to Emotional Problems (RE) = SFQ5a + SFQ5b + SFQ5c 
• 
Role Limitation Due to Emotional Problems Score = ((RE-3)/12)*100 
• 
Social Functioning (SF) = SFQ6 + SFQ10 
• 
Social Functioning Score = ((SF-2)/8)*100 
• 
Mental Health (MH) = SFQ9b + SFQ9c + SFQ9d + SFQ9f + SFQ9h 
• 
Mental Health Score = ((MH-5)/20)*100 
• 
Energy/Vitality (EV) = SFQ9a + SFQ9e + SFQ9g + SFQ9i 
• 
Energy/Vitality Score = ((EV-4)/16)*100 
• 
Pain (P) = SFQ7 + SFQ8 
• 
Pain Score = ((P-2)/9)*100 
• 
General Health Perception (GHP) = SFQ1 + SFQ11a + SFQ11b + SFQ11c +  SFQ11d 
• 
General Health Perception Score = ((GHP-5)/20)*100 
 
AGPHYSCO  
(PF*0.456) + (RP*0.362) + (Pa*0.367) + (GHP*0.199) + (EV*-0.050) + (SF*-0.028) + (RE*-0.110) + (MH*-0.256) 
 
AGMENTCO  
(PF*-0.227) + (RP*-0.102) + (P*-0.130) + (GHP*0.036) + (EV*0.278) + (SF*0.272) + (RE*0.329) + (MH*0.460) 
 
Physical Component Summary score (PCS)  
(((AGPHYSCO-82.261)/20.867)*10)+50 
 


 
Page 18 of 46 
 
Mental Component Summary score (MCS)  
(((AGMENTCO-63.7796)/19.582)*10)+50 
 
EQ-5D (5 level) 
The current NICE guidelines (updated October 2019) on the use of EQ-5D-5L scoring based on the most recent 
value set for England published by Devlin et al. 2018 was not to use this and instead to map the 5L data into 3L 
value set based on mapping function developed by van Hout et al. 2012.  
 
EQ-5D-5L have developed the crosswalk value sets for the 5L to 3L and so these values will be used for scoring: 
(https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-sets/crosswalk-index-value-
calculator/).   
 
For those patients that die prior to completing the EQ5D questionnaire, for the Index score a value of “0” will be 
imputed since for this questionnaire, a value of 0=death.  
 
AFEQT questionnaire overall score 
 
*Note: ignore last two questions of the AFEQT questionnaire for scoring as they will be tabulated separately 
 
IPAQ score (as continuous score) 
• Sitting = N/A for IPAQ score 
• Walking = 3.3 METs 
• Moderate Intensity = 4.0 METs  
• Vigorous Intensity = 8.0 METs  
 
Total MET-minutes/week: MET level x minutes of activity/day x days per week  
IPAQ score= Walk (3.3*min/day*days) + Moderate (4.0*min/day*days) + Vigorous (8.0*min/day*days) 
 
NT-pro-BNP 
Since this data is expected to be not normally distributed, a log transformation (natural log) for this data will 
need to be done to approximate normality prior to any analysis. 
 
Composite of diastolic indices  
This outcome will be coded as a binary yes/no, with “yes” representing patients that have a diastolic dysfunction 
present and “no” for patients that don’t.  
 
There is an algorithm to determine whether the patient has a diastolic function or not and it will be computed 
based on the following: 
 
Does the patient have any one of the following diastolic parameters? 
• 
Average E/e’ (taken from lateral and septal wall) ≥ 15  
 
If yes, then Diastolic dysfunction present  
 
If no, then  
 
Does the patient have two or more of the following diastolic parameters? 
• 
IVRT (ms) ≤ 65 ms 
• 
Mitral Valve E deceleration time  (ms) ≤ 120ms 
• 
Average E/e’(taken from lateral and septal wall) ≥ 11 
• 
Pulmonary Vein  diastolic deceleration time (ms) ≤ 220 
 
If yes, then Diastolic dysfunction present  
 
If no, then no diastolic dysfunction present 


 
Page 19 of 46 
 
 
Change in European Heart Rhythm Association (EHRA) class 
This outcome will be analysed as ordinal data initially but will also be analysed as a binary yes/no variable. The 
original classification for this score is in an ordinal scale and the categories are 1, 2a, 2b, 3, 4 where lowest 
category 1 indicates best outcome and highest category 4 indicates worst outcome. For this outcome to be 
coded as binary we will consider any one with a change in 2 categories from worse to better as “yes” for this 
outcome. Comparison will be made from baseline score to 6 months and baseline score to 12 months separately. 
EG: if a patient had a baseline EHRA class of 3a and by 6 months they had an EHRA class of 2a then this patient 
will be considered as “yes” for the classification of change in EHRA class. There may be some patients that cannot 
achieve a 2 point improvement in the score due to the score they originally had at baseline (i.e. if someone has a 
baseline score of 2a or below at baseline). These patients will be classed as not improved.    
 
9.5.  Analysis methods – primary outcome(s) 
The primary outcome is the SF-36v2 physical component summary (PCS) score at 6 months.  
 
The data for this outcome is continuous in nature and the computation for this score is described in the data 
manipulations section 9.4. The mean and standard deviation along with minimum and maximum values for the 
PCS score will be presented by treatment arm.  
 
Data will be analysed using a linear regression model with outcome being the 6 months PCS score and 
independent variables in the model being the baseline PCS score, treatment arm, all minimisation variables, age 
at randomisation and baseline LVEF. An adjusted mean difference and 95% confidence interval will be estimated 
from the linear regression model and the p-value from the associated model will be produced. The Bisoprolol 
arm will be used as a reference category in the model and so higher values will indicate better outcome for 
Digoxin arm. A template for reporting the primary outcome is given in Appendix D5. 
 
9.6.  Analysis methods – secondary outcomes 
A template for reporting all the secondary outcomes is given in Appendix D6. 
 
Patient-reported QoL 
For the RATE-AF trial, questionnaires SF-36v2, EQ-5D-5L and AFEQT are administered at baseline, 6 months and 
12 months.  
 
Up-titration visits: 
These questionnaires are also administered for each patient at their last up-titration visit.  
Note: the data for last up-titration visit is not done at any scheduled time-point due to the fact that each patient 
will have different up-titration visits (i.e. some will have 6 and some may only have 1) and so for this reason the 
data collected for last up-titration visit will only be summarised by treatment arm and no formal analysis for this 
data will be conducted.  
 
• SF-36v2 global and domain specific scores at 6 and 12 months 
The data for these outcomes are continuous in nature and the computation for the global and domain specific 
scores is described in the data manipulations section 9.4. The mean and standard deviation along with minimum 
and maximum values for global and domain specific scores will be presented by treatment arm and time-point. 
 
The global and domain-specific scores will be analysed separately at 6 and 12 months using the same analysis 
methods as described in section 9.5. for primary outcome:  
▪ 
Physical component summary (PCS) score at 12 months 
▪ 
Mental component summary (MCS) score at 6 months and 12 months  
▪ 
Physical Function score at 6 months and 12 months 


 
Page 20 of 46 
 
▪ 
Role Limitation Due to Physical Problems score at 6 months and 12 months 
▪ 
Role Limitation Due to Emotional Problems score at 6 months and 12 months 
▪ 
Social Functioning score at 6 months and 12 months 
▪ 
Mental Health score at 6 months and 12 months 
▪ 
Energy/Vitality score at 6 months and 12 months 
▪ 
Pain score at 6 months and 12 months 
▪ 
General Health Perception score at 6 months and 12 months 
 
The range for each domain of the SF-36v2 is from 0=worst score to 100=best score. The Bisoprolol arm will again 
be used as a reference category for all model based analysis for SF-36v2 and so higher values will indicate better 
outcome for Digoxin arm. 
 
For SF36v2 PCS, additional secondary analysis will also be conducted using a mixed effects repeated measures 
model. The outcome in the model will be the repeated measure for PCS score and independent variables will be 
treatment arm, all minimisation variables, age at randomisation and baseline LVEF. Time (in days) will also be 
included in the model and a constant treatment effect over time will be assumed in the first instance, however a 
treatment by time interaction term will also be included in the model to check for its significance. If interaction is 
significant (p<0.05), then estimates at each time point will be produced from the model including the interaction 
term. An unstructured covariance data structure will be used in the model. Results will be presented as adjusted 
mean difference and 95% confidence interval.  
 
• EQ-5D-5L summary index and visual analogue scale at 6 and 12 months 
The data for these outcomes are continuous in nature and the computation for the index summary score is 
described in the data manipulations section 9.4. The visual analogue score (VAS) is obtained from a scale so this 
score doesn’t need to be derived. The mean and standard deviation along with minimum and maximum values 
for index summary score and VAS score will be presented by treatment arm and time-point. 
 
The following will be analysed separately at 6 and 12 months using the same analysis methods as described in 
section 9.5. for primary outcome:  
▪ 
EQ-5D-5L summary index score at 6 months and 12 months  
▪ 
EQ-5D-5L visual analogue scale score at 6 months and 12 months 
 
The range for summary index is from -0.285=worst score to 1=best score and for visual analogue score is from 
0=worst score to 100=best score. The Bisoprolol arm will again be used as a reference category for all model 
based analysis of EQ-5D-5L and so higher values will indicate better outcome for Digoxin arm. 
 
• AFEQT overall score at 6 and 12 months 
The data for this outcome is continuous in nature and the computation for the AFEQT overall score is described 
in the data manipulations section 9.4. The mean and standard deviation along with minimum and maximum 
values for AFEQT overall score will be presented by treatment arm and time-point. 
 
The following will be analysed separately at 6 and 12 months using the same analysis methods as described in 
section 9.5. for primary outcome:  
▪ 
AFEQT overall score at 6 months and 12 months  
 
The range for AFEQT overall score is from 0=complete disability to 100=no disability. The Bisoprolol arm will 
again be used as a reference category for the model based analysis of this and so higher values will indicate 
better outcome for Digoxin arm. 
 
Cardiac function 
• Echocardiographic LVEF at 12 months 
The data for this outcome is a continuous score (presented as a percentage of volume ejected) and is also 
categorised using the following categories; “<40%”, “40-49%”, “≥50%”. This data is collected at baseline and at 


 
Page 21 of 46 
 
12 months. This data will be summarised as the mean, standard deviation, minimum and maximum values for 
the continuous score as well as number and percentage for the categories by treatment arm and time-point.  
 
The main analysis of this data will be based on the continuous data so this outcome will be analysed using the 
same analysis methods as described in section 9.5 for primary outcome. For this outcome only, additional 
covariates for history of myocardial infarction (MI) at baseline, coronary angioplasty or stents (PCI) at baseline 
and coronary artery bypass surgery (CAPG) at baseline will also be adjusted for in the model. Higher values of 
LVEF are considered better and since the Bisoprolol arm will again be used as a reference category for the model 
based analysis of this, higher values will indicate better outcome for Digoxin arm. 
 
• Diastolic function (E/e’ and composite of diastolic indices) at 12 months 
The data for E/e’ is a ratio and so continuous in nature. This data is collected at baseline and at 12 months. The 
mean and standard deviation along with minimum and maximum values will be presented by treatment arm and 
time-point.  
 
This outcome will be analysed using the same analysis methods as described in section 9.5 for primary outcome. 
Lower values of E/e’ are considered better and since the Bisoprolol arm will again be used as a reference 
category for the model based analysis of this, lower values will indicate better outcome for Digoxin arm. 
 
The data for the composite of diastolic indices is a binary (yes/no) and will be computed as described in the data 
manipulations section 9.4. This data is collected at baseline and 12 months and will be summarised as number 
and percentage by treatment arm and time-point. The analysis for this outcome will be conducted using a logistic 
regression model, where the outcome will be the binary category (yes/no) at 12 months and independent 
variables in the model being the baseline category, treatment arm, all minimisation variables, age at 
randomisation and baseline LVEF. An adjusted odds ratio and 95% confidence interval will be estimated from the 
logistic regression model.   
 
• Change in heart rate  
The data type for heart rate is continuous in nature. This data is collected at baseline, 6 months and at 12 
months. The mean and standard deviation along with minimum and maximum values will be presented by 
treatment arm and time-point for 1) Radial heart rate, 2) Apical heart rate, 3) 12-lead ECG heart rate, and 4) 24-
hour ambulatory average heart rate. The 24-hour ambulatory heart rate is only measured once and so no 
baseline score will be there to adjust for it in analysis.  
 
These outcomes will be analysed using the same analysis methods as described in section 9.5 for primary 
outcome and analysis will be done separately for 6 and 12 month time-points.  
 
A scatter plot of radial vs apical heart rate at each time point will be produced to visualise the radial-apical 
discrepancy. 
 
Functional assessment 
• Six-minute walking distance at 6 and 12 months 
The data for this outcome is continuous in nature and this test is conducted at baseline, 6 months and 12 
months. The time (measured in min/s) and distance (measured in metres) are only recorded if the patient did the 
test. Therefore this data will be summarised by treatment arm and time-point with respect to the number of 
patients conducting the test, the mean and standard deviation, median and IQR as well as minimum and 
maximum values for time and distance covered. Reasons for stopping the test prematurely were also collected 
and so this will also be summarised by treatment arm and time-point.  
 
The main endpoint for this outcome is the distance (in metres) walked and so this will be analysed using the 
same analysis methods as described in section 9.5 for primary outcome and analysis will be done separately for 6 
and 12 month time-point. 
 


 
Page 22 of 46 
 
• Change in European Heart Rhythm Association (EHRA) class at 6 and 12 months 
The data for this outcome is categorical in nature and in 5 orderly categories; 1=None, 2a=Mild, 2b=Moderate, 
3=Severe, 4=Disabling. This data is collected as baseline, 6 months and 12 months. This data will be summarised 
as number and percentage by treatment arm and time-point with respect to the EHRA class.  
 
The analysis for this outcome will be conducted using an ordinal logistic regression model, where the outcome 
will be the EHRA class at follow up (with EHRA class 1 being the reference category) and independent variables in 
the model being the baseline EHRA class, treatment arm, gender, age at randomisation and baseline LVEF. An 
adjusted odds ratio and 95% confidence interval will be estimated from the ordinal logistic regression.   
 
Higher EHRA class is considered to be a worse outcome and since the Bisoprolol arm will be used as a reference 
category in the model, higher values will indicate worse outcome for Digoxin arm. 
Note: separate analysis will be done for 6 month and 12 month time-point.  
 
We will also code this outcome as a binary “yes/no” variable where “yes” will be determined if patients had a 2 
class improvement in the EHRA class from baseline. The full details for the computation of this are described in 
the data manipulations section 9.4.   
 
The analysis for this outcome will be conducted using a logistic regression model, where the outcome will be the 
computed binary variable “yes/no” (with yes being the reference category) and independent variables in the 
model being treatment arm, gender, age at randomisation and baseline LVEF. An adjusted odds ratio and 95% 
confidence interval will be estimated from the logistic regression model.   
 
Since we are modelling whether patients had an improvement from baseline and that the Bisoprolol arm will be 
used as a reference category in the model, higher values will indicate better outcome for Digoxin arm. 
Note: again separate analysis will be done for 6 month and 12 month time-point.  
 
 
Biomarkers 
• Change in NTpro-B-type natriuretic peptide (NTpro-BNP) levels 
The data for NTpro-BNP is continuous in nature and likely to be skewed and not normally distributed. Hence this 
data will need to be log-transformed first before analysis (see section 9.4 for more details). This data is collected 
at baseline, 6 month and 12 month. The raw untransformed data will be presented as mean standard deviation, 
median and interquartile range along with minimum and maximum values by treatment arm and time-point.  
 
This outcome (log-transformed score) will be analysed using the same analysis methods as described in section 
9.5 for primary outcome. Higher values of NTproBNP are considered worse and the Bisoprolol arm will again be 
used as a reference category for the model based analysis. Since we will be modelling the log-transformed scores 
and then exponentiate the effect size, the outcome will be in terms of geometric mean ratio and so values <1 will 
indicate better outcome for Digoxin arm. 
Note: separate analysis will be done for 6 month and 12 month time-point. 
 
 
Feasibility outcomes 
• 
Recruitment target of 3 patients per week across all participating centres 
• 
Compliance and reasons for non-compliance 
• 
Number of withdrawals and losses to follow-up (with reasons) 
• 
Drug discontinuation rate and adverse reactions requiring drug discontinuation 
• 
Number of patients needing therapy-induced requirement for additional treatment 
• 
Population-specific standard deviations (SD) and proportions: 
o SD of SF36 physical functioning score at 6 and 12 months 
o SD of SF36 overall score at 6 and 12 months 


 
Page 23 of 46 
 
o SD of AFEQT overall score at 6 and 12 months 
o SD of LVEF and E/e’ scores at 6 and 12 months 
• 
Unplanned hospitalisation admissions rates 
• 
Cardiovascular Events (particularly mortality, thromboembolic events, myocardial infarction and 
cardiovascular interventions) 
 
No formal model based analysis will be conducted for the feasibility outcomes and outcomes will be summarised 
using appropriate summary statistics.  
 
A template for reporting this data is given in Appendix D7. 
 
9.7.  Analysis methods – exploratory outcomes and analyses 
Any data that does not form a pre-specified outcome will be presented using simple summary statistics by 
intervention group (i.e. numbers and percentages for binary data and means (or medians) and standard 
deviations (or inter-quartile ranges) for continuous normal (or non-normal) data. 
 
9.8.  Safety data 
The number and percentage of participants experiencing any adverse events, serious adverse events (SAEs) and 
suspected unexpected serious adverse reactions (SUSARs) will be presented by treatment arm.  A table listing all 
the SAEs will be provided.   
 
The safety data will also include summaries by treatment arm for: 
• 
Digoxin levels at 6 and 12 months  
• 
Number of patients requiring pacemaker implantation  
• 
Unplanned hospitalisation rates (from the SAE form) 
• 
Number of patients that had pauses and duration of pause (from the 24 hour tape form) 
• 
All cardiovascular events (as recorded in the cardiovascular events form)  
• 
Number of GP visits (from the GP form) 
 
A template for reporting this data is given in Appendix D8. 
 
9.9. Planned subgroup analyses 
Interpretation of subgroup analysis will be treated with caution with output treated as hypothesis generating 
rather than definitive9.   
 
Analysis will be limited to the primary outcome and the following subgroups: 
• Gender (Male, Female) 
• 
Modified EHRA (Class 1/2a, Class 2b/3/4) 
• 
Receiving beta-blocker therapy within 1 month of randomisation (No, Yes) 
• 
Age (<75 years, ≥75 years) 
• 
Left Ventricular Ejection Fraction (<50%, ≥50%) 
 
The effects of these subgroups will be examined by including a treatment group by subgroups interaction 
parameter in the linear regression model.  
 
A template for reporting is given in Appendix D9. 
 


 
Page 24 of 46 
 
9.10. Sensitivity analyses 
Sensitivity analyses will be limited to the primary outcome only and will consist of: 
 
• 
Per-protocol analysis (population described in sections 5.3 and 5.4) 
• 
Adjust the final model for additional covariate of baseline apical heart rate 
• 
SF36v2 questionnaire completed outside the pre-specified visit window of ±4 week’s 
 
We have stated in the protocol that we will allow a ±4 week’s window for the follow up visits and so any 
questionnaires for SF36v2 at 6 months completed outside this time window will be excluded in this sensitivity 
analysis.  
• 
Analysis to assess the impact of missing data (see below for method) 
 
Missing data will be imputed using multiple imputation with chained equations in Stata 16 (or above). Stata’s 
“MI” command will be used to carry out this analysis and the “regress” option will be used since the primary 
outcome is continuous data. 50 imputations will be generated for any missing data for primary outcome (i.e. 
SF36v2 PCS score at 6 months) and all minimisation variables (Gender, EHRA score), treatment arm, baseline PCS 
score and any other baseline data deemed appropriate will be used to aid the multiple imputation procedure. 
Imputed results will be combined using Stata’s “mi estimate” command.    
 
10. Analysis of sub-randomisations 
N/A 
 
11. Health economic analysis 
Health economic analysis is planned for this trial and will be described separately in the health economic analysis 
plan by the health economist for the trial. 
 
12. Statistical software 
Statistical analysis will be undertaken in the following statistical software packages:  
• 
Stata version 15 (or higher)  
• 
SAS software, version 9.4 (or higher)  
 


 
Page 25 of 46 
 
 
13. References 
 
1. Kotecha D, Calvert M, Deeks JJ, Griffith M, Kirchhof P, Lip GY, Mehta S, Slinn G, Stanbury M, Steeds RP, 
Townend JN. A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF 
trial. BMJ Open. 2017;7:e015099  
 
2. Hagens VE, Ranchor AV, Van Sonderen E, Bosker HA, Kamp O, Tijssen JGP, Kingma JH, Crijns HJGM, Van 
Gelder IC. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation: Results from the 
Rate Control Versus Electrical Cardioversion (RACE) study. J Am Coll Cardiol. 2004;43:241-247 
 
3. Grönefeld GC, Lilienthal J, Kuck K-H, Hohnloser SH. Impact of rate versus rhythm control on quality of life in 
patients with persistent atrial fibrillation: Results from a prospective randomized study. Eur Heart J. 
2003;24:1430-1436 
 
4. Gupta SK. Intention-to-treat concept: A review. Perspect Clin Res. 2011;2(3):109-112. 
 
5. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for 
reporting parallel group randomised trials. BMJ. 2010;340:c332.  
 
6. Altman DG, Dore CJ. Randomisation and baseline comparisons in clinical trials. Lancet. 1990;335:149–53. 
 
7. Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 
2004;159(7):702-6. 
 
8. White IR, Horton NJ, Carpenter J, Pocock SJ. Strategy for intention to treat analysis in randomised trials with 
missing outcome data. BMJ. 2011;342:d40. 
 
9. Wand R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Reporting of subgroups analyses in clinical trials. 
NEJM. 2007;357:2189-94. 
 
10. Melanie Calvert, PhD; Jane Blazeby, MD; Douglas G. Altman, DSc; et al; Reporting of Patient-Reported 
Outcomes in Randomized Trials: The CONSORT PRO Extension; JAMA. 2013;309(8):814-822. 
doi:10.1001/jama.2013.879 
 


 
Page 26 of 46 
 
 
Appendix A: Deviations from SAP 
This report below follows the statistical analysis plan dated <insert effective date of latest SAP> apart 
from following: 
 
Section of report not following SAP 
Reason 
 
 
 
 


 
Page 27 of 46 
 
 
Appendix B: Trial schema 
 


 
Page 28 of 46 
 
 
Appendix C: Schedule of assessments 
 
Procedures 
Baseline Visit 
Up-titration Visits 
(Day 14 to 60) 
Visit 2, Month 6 
(± 4 weeks) 
Visit 3, Month 12 (± 4 
weeks) 
Assessment of eligibility criteria  
X 
 
 
 
Informed consent taken  
X 
 
 
 
Review of medical history 
X 
 
 
 
Review of medications 
X 
X 
X 
X 
Physical exam 
Complete 
X 
 
 
 
Symptom-directed 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Quality of life assessment 
X 
(X) 
X 
X 
Functional and cognitive assessment 
X 
 
X 
X 
Transthoracic echocardiogram 
X 
 
 
X 
12-lead electrocardiogram 
X 
 
X 
X 
6-minute walk test 
X 
 
X 
X 
24-hour ambulatory ECG 
 
X 
(X) 
 
Clinical labs 
Chemistry 
X 
 
X 
X 
Haematology 
X 
 
X 
X 
Serum digoxin 
 
 
(X) 
(X) 
Trial labs 
BNP 
X 
 
X 
 
Stored sample 
X 
 
X 
 
Assessment of compliance 
 
X 
X 
X 
Assessment of adverse events 
 
X 
X 
X 
 


 
Page 29 of 46 
 
 
Appendix D1: CONSORT flow diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Randomised 
 
 
 
 
 
 
 
 
N= 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Digoxin 
 
 
Bisoprolol 
 
 
 
 
N= 
 
 
N= 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline visit 
 
 
Baseline visit 
 
 
 
 
Expected = N 
 
 
Expected = N 
 
 
 
 
Completed = N (%) 
 
 
Completed = N (%) 
 
 
 
 
Primary outcome available = N (%) 
 
 
Primary outcome available = N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uptitration visits 
 
 
Uptitration visits 
 
 
 
 
Mean [SD] 
 
 
Mean [SD] 
 
 
 
 
xx.x [xx.x] 
 
 
xx.x [xx.x] 
 
 
 
 
Min - Max 
 
 
Min - Max 
 
 
 
 
xx -xx 
 
 
xx -xx 
 
 
 
 
 
 
 
 
 
 
 
 
Dropouts 
 
 
 
 
 
 
Dropouts 
Died = xx 
 
 
 
 
 
 
Died = xx 
Withdrawn = xx 
 
 
 
 
 
 
Withdrawn = xx 
Lost to FU = xx 
 
 
 
 
 
 
Lost to FU = xx 
 
 
 
 
 
 
 
 
 
 
 
 
6 months follow up 
 
 
6 months follow up 
 
 
 
 
Expected = N 
 
 
Expected = N 
 
 
 
 
Completed = N (%) 
 
 
Completed = N (%) 
 
 
 
 
Primary outcome available = N (%) 
 
 
Primary outcome available = N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Dropouts 
 
 
 
 
 
 
Dropouts 
Died = xx 
 
 
 
 
 
 
Died = xx 
Withdrawn = xx 
 
 
 
 
 
 
Withdrawn = xx 
Lost to FU = xx 
 
 
 
 
 
 
Lost to FU = xx 
 
 
 
 
 
 
 
 
 
 
 
 
12 months follow up 
 
 
12 months follow up 
 
 
 
 
Expected = N 
 
 
Expected = N 
 
 
 
 
Completed = N (%) 
 
 
Completed = N (%) 
 
 
 
 
Primary outcome available = N (%) 
 
 
Primary outcome available = N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 30 of 46 
 
 
Appendix D2: Baseline characteristics 
 
Baseline data 
Digoxin (N=) 
Bisoprolol 
Total (N=) 
Age (Years) 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
Gender* 
 
 
 
Female 
 
 
 
Male 
 
 
 
Creatinine (micromol/L) 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
On anticoagulant before randomisation 
 
 
 
No 
 
 
 
Yes 
 
 
 
EHRA class* 
 
 
 
1 
 
 
 
2a 
 
 
 
2b 
 
 
 
3 
 
 
 
4 
 
 
 
NYHA class 
 
 
 
I£ 
 
 
 
II 
 
 
 
III 
 
 
 
IV 
 
 
 
Previous diagnosis of heart failure? 
 
 
 
No 
 
 
 
Yes 
 
 
 
Any signs of heart failure at baseline 
 
 
 
No 
 
 
 
Yes 
 
 
 
Type I diabetes 
 
 
 
No 
 
 
 
Yes 
 
 
 
missing 
 
 
 
Type II diabetes 
 
 
 
No 
 
 
 
Yes 
 
 
 
missing 
 
 
 
Unplanned admission for AF or HF in last 12 months 
 
 
 
No 
 
 
 
Yes 
 
 
 
Any previous cardioversions 
 
 
 
No 
 
 
 


 
Page 31 of 46 
 
Yes 
 
 
 
Number of cardioversions (Min – Max) 
 
 
 
Previously undergone AF ablation 
 
 
 
No 
 
 
 
Yes 
 
 
 
Number of ablations (Min – Max) 
 
 
 
Previous history of anti-arrhythmic drugs 
 
 
 
No 
 
 
 
Yes 
 
 
 
Baseline NTproBNP (pg/mL) 
 
 
 
N 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
Radial artery heart rate (bpm) 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
Apex beat heart rate (bpm) 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
12-Lead ECG Heart Rate (bpm) 
 
 
 
N 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
Systolic BP (mmHg) 
 
 
 
N 
 
 
 
Mean [SD] 
 
 
 
Med {IQR} 
 
 
 
Min - Max 
 
 
 
Self-declared ethnicity  
 
 
 
White - English / Welsh / Scottish / Northern Irish / British 
 
 
 
White - Irish 
 
 
 
Asian / Asian British – Indian 
 
 
 
Asian / Asian British – Pakistani 
 
 
 
Black / African / Caribbean / Black British – Caribbean 
 
 
 
Black / African / Caribbean / Black British – African 
 
 
 
Estimated ejection fraction 
 
 
 
Mean [SD] 
 
 
 
Median {IQR} 
 
 
 
Min-Max 
 
 
 
<40% 
 
 
 
40-49% 
 
 
 
≥50% 
 
 
 
*Minimisation variables  
(Note: categories of the EHRA class for the minimisation algorithm were combined into  EHRA class 1/2a and EHRA class 2b/3/4) 
 


 
Page 32 of 46 
 
 
Appendix D3: Adherence to allocated intervention 
 
Adherence to treatment allocation based on actual medication taken  
Adherent to treatment allocation 
Digoxin 
Bisoprolol 
Total 
At 6 months  
 
 
 
N 
 
 
 
No 
 
 
 
Yes 
 
 
 
 
If yes, taking additional rate control therapy 
 
 
 
No 
 
 
 
Yes 
 
 
 
At 12 months  
 
 
 
N 
 
 
 
No 
 
 
 
Yes 
 
 
 
 
If yes, taking additional rate control therapy  
 
 
 
No 
 
 
 
Yes 
 
 
 
 
Oral medication type by treatment arm and time point 
Medication* 
6 months 
12 months 
Digoxin 
Bisoprolol 
Total 
Digoxin 
Bisoprolol 
Total 
Digoxin 
 
 
 
 
 
 
Β-blocker 
 
 
 
 
 
 
Diltiazem 
 
 
 
 
 
 
Verapamil 
 
 
 
 
 
 
Amiodarone 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
*Medications not mutually exclusive  
 
Adherence assessed by asking the patient 
Medication 
taken 
6 months 
12 Months 
Digoxin 
(N=) 
Bisoprolol  
(N=) 
Total 
(N=) 
Digoxin 
(N=) 
Bisoprolol  
(N=) 
Total 
(N=) 
All 
 
 
 
 
 
 
Some 
 
 
 
 
 
 
>75% 
 
 
 
 
 
 
>50-75% 
 
 
 
 
 
 
>25-50% 
 
 
 
 
 
 
≤25% 
 
 
 
 
 
 
None 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 


 
Page 33 of 46 
 
 
Appendix D4: Protocol deviations and violations 
 
List of patients with follow-up visits conducted outside the specified ±4 week’s window by treatment arm 
 
Digoxin (N=xx) 
1) 
2) 
… 
 
Bisoprolol (N=xx) 
1) 
2) 
… 
 
 
 
 
 


 
Page 34 of 46 
 
 
Appendix D5: Primary outcome results 
 
SF-36v2 physical component summary (PCS) score at 6 months  
Primary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
Intention to treat analysis 
PCS 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Sensitivity Analysis – Multiple imputation for missing data  
PCS 
Baseline 
N 
 
 
- 
- 
Mean [SE] 
 
 
6 months 
N 
 
 
 
 
Mean [SE] 
 
 
Per-Protocol analysis (i.e. adherent to treatment allocation and remained in permanent AF at 6 months) 
Included in 
per-protocol 
analysis set  
6 months 
No 
 
 
- 
- 
Yes 
 
 
Total  
 
 
PCS 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
Reference group for the treatment arm in the model is Bisoprolol arm 
Higher values indicate better scores so a positive mean difference favours Digoxin arm 
 
 


 
Page 35 of 46 
 
 
Appendix D6: Secondary outcomes results 
SF-36v2 global and domain specific scores at 6 and 12 months 
Secondary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
Physical  Component Summary (PCS) 
PCS 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Mental  Component Summary (MCS) 
MCS 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Physical Function Domain score (PF) 
PF 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Role Limitation Due to Physical Problems Domain score (RP) 
RP  
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Role Limitation Due to Emotional Problems Domain score (RE) 
RE  
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 


 
Page 36 of 46 
 
Social Functioning Domain score (SF) 
SF  
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Mental Health Domain score (MH) 
MH 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Energy/Vitality Domain score (EV) 
EV  
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Pain score (Pain) 
Pain  
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
General Health Perception Domain score (GHP) 
GHP  
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
Reference group for the treatment arm in the model is Bisoprolol arm 
Higher values indicate better scores so a positive mean difference favours Digoxin arm 
 


 
Page 37 of 46 
 
 
EQ-5D-5L summary index and visual analogue scale at 6 and 12 months 
Secondary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
EQ-5D-5L summary index score£ 
EQ-5D-5L 
summary 
index score 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
EQ-5D-5L visual analogue scale (VAS) score$ 
EQ-5D-5L  
VAS  
score 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
£-The range for summary index is from -0.285=worst score to 1=best score  
$-The range for visual analogue score is from 0=worst score to 100=best score 
The Bisoprolol arm will be used as a reference category and so positive mean difference will indicate better outcome for Digoxin arm 
 
 
AFEQT overall score at 6 and 12 months 
Secondary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
AFEQT overall score£ 
AFEQT overall 
score 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
£-The range for visual analogue score is from 0=worst score to 100=best score 
The Bisoprolol arm will be used as a reference category and so positive mean difference will indicate better outcome for Digoxin arm 
 
 
 
 
 
 


 
Page 38 of 46 
 
 
Echocardiographic LVEF at 12 months 
Echocardiographic 
LVEF  
Time 
point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
LVEF 
Baseline 
<40% 
 
 
- 
- 
40-49% 
 
 
≥50% 
 
 
N 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
<40% 
 
 
- 
- 
40-49% 
 
 
≥50% 
 
 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation, baseline LVEF, history of myocardial infarction (MI) at 
baseline, coronary angioplasty or stents (PCI) at baseline and coronary artery bypass surgery (CAPG) at baseline 
Reference group for the treatment arm in the model is Bisoprolol arm 
Higher values indicate better scores so a positive mean difference favours Digoxin arm 
 
 
Diastolic function (E/e’ and composite of diastolic indices) at 12 months 
Diastolic 
function 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
E/e’ 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
Reference group for the treatment arm in the model is Bisoprolol arm 
Higher values indicate better scores so a positive mean difference favours Digoxin arm 
 
Diastolic 
function 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Logistic regression model 
Adjusted Odds Ratio1  
95% CI 
P-value1 
Composite of 
diastolic 
indices 
Baseline 
No 
 
 
- 
- 
Yes 
 
 
12 months 
No 
 
 
 
 
Yes 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
Reference group for the treatment arm in the model is Bisoprolol arm  
Higher values indicate better scores so an odds ratio >1 favours Digoxin arm 
 
 
 
 
 
 
 


 
Page 39 of 46 
 
 
Change in heart rate  
Secondary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
Radial Heart (bpm) 
Radial  
Heart rate 
(bpm) 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
Apical Heart rate (bpm) 
Apical  
Heart rate 
(bpm) 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12-lead ECG Heart rate (bpm) 
12-lead ECG 
Heart rate 
(bpm) 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
24-hour ambulatory average Heart rate (bpm) 
24-hour 
ambulatory 
Heart rate  
24-hour 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
The Bisoprolol arm will be used as a reference category  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 40 of 46 
 
 
Six-minute walking distance at 6 and 12 months 
Six-minute walking test 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
6 months follow-up 
Did the patient undergo the 6-min walk test? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes: 
 
 
 
 
Total time spent (min/s) 
 
 
 
Median {IQR}   
 
 
Min - Max  
 
 
 
Total distance covered (m) 
 
 
 
Median {IQR}   
 
 
Min - Max  
 
 
 
Was the test stopped prematurely? 
 
 
 
No   
 
 
Yes  
 
 
12 months follow-up 
Did the patient undergo the 6-min walk test? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes: 
 
 
 
 
Total time spent (min/s) 
 
 
 
Mean [SD]  
 
 
Median {IQR}   
 
 
Min - Max  
 
 
 
Total distance covered (m) 
 
 
 
Mean [SD]  
 
 
Median {IQR}   
 
 
Min - Max  
 
 
 
Was the test stopped prematurely? 
 
 
 
No   
 
 
Yes  
 
 
 
Distance covered (in metres) from the 6-minute walk test 
Secondary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Adjusted mean difference1  
95% CI 
P-value1 
Distance  
(metres) 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
The Bisoprolol arm will be used as a reference category and so positive mean difference will indicate better outcome for Digoxin arm 
 


 
Page 41 of 46 
 
Change in European Heart Rhythm Association (EHRA) class at 6 and 12 months 
 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Ordinal Logistic regression model 
Adjusted odds ratio1  
95% CI 
P-value1 
EHRA Class 
Baseline 
Class 1 
 
 
- 
- 
Class 2a 
 
 
Class 2b 
 
 
Class 3 
 
 
Class 4 
 
 
6 months 
Class 1 
 
 
 
 
Class 2a 
 
 
Class 2b 
 
 
Class 3 
 
 
Class 4 
 
 
12 months 
Class 1 
 
 
 
 
Class 2a 
 
 
Class 2b 
 
 
Class 3 
 
 
Class 4 
 
 
1-Adjusted for treatment arm, all minimisation variables, age at randomisation and baseline LVEF. 
Reference group for the treatment arm in the model is Bisoprolol arm.  
Lower odds indicate better outcome so values <1 favours Digoxin arm. 
 
2 class improvement in EHRA class at 6 and 12 months compared to baseline 
EHRA Class 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Logistic regression model 
Adjusted Odds Ratio1  
95% CI 
P-value1 
2 class 
improvement 
from baseline 
6 months 
No 
 
 
 
 
Yes 
 
 
 
 
 
12 months 
No 
 
 
 
 
Yes 
 
 
 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
Reference group for the treatment arm in the model is Bisoprolol arm  
Higher values indicate better scores so an odds ratio >1 favours Digoxin arm 
 
Change in B-type natriuretic peptide (BNP) (NTproBNP) levels at 6 months 
Secondary 
outcome 
Time point 
Statistic 
Digoxin 
Bisoprolol 
Linear regression model 
Ratio of geometric means 1  
95% CI 
P-value1 
Log-
transformed 
NTproBNP 
(ng/L) 
Baseline 
N 
 
 
- 
- 
Mean [SD] 
 
 
Min - Max 
 
 
6 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
12 months 
N 
 
 
 
 
Mean [SD] 
 
 
Min - Max 
 
 
1-Adjusted for treatment arm, baseline score, all minimisation variables, age at randomisation and baseline LVEF 
Reference group for the treatment arm in the model is Bisoprolol arm 
Lower ratio indicates better scores so values <1 favours Digoxin arm 


 
Page 42 of 46 
 
Appendix D7: Feasibility outcomes 
 
Recruitment target of 3 patients per week across all participating centres 
To be presented graphically  
 
Compliance and reasons for non-compliance  
See section Appendix D3 
 
Number of withdrawals and losses to follow-up (with reasons) 
Drop-outs 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
Lost to follow-up 
 
 
 
Withdrawn 
 
 
 
Death 
 
 
 
Total 
 
 
 
List of reason for withdrawals – Digoxin  
1)  
2)  
3) 
… 
 
List of reason for withdrawals – Bisoprolol  
1)  
2)  
3) 
… 
 
List of reason for death – Digoxin 
1)  
2)  
3) 
… 
 
List of reason for death – Bisoprolol 
1)  
2)  
3) 
… 
 
Drug discontinuation rate and adverse reactions requiring drug discontinuation 
Has patient stopped medication due to AE’s? 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
No 
 
 
 
Yes 
 
 
 
Missing 
 
 
 
If yes, was it stopped: 
 
 
 
Temporarily   
 
 
Permanently 
 
 
 
 
 
Cardiovascular Events (from the cardiovascular event form and as identified from the SAE form) 
• 
List of all cardiovascular related events 
 
 
 
 


 
Page 43 of 46 
 
 
Number of patients needing therapy-induced requirement for additional treatment 
Therapy-induced requirement 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
6 months follow-up 
Did the patient have a pacemaker fitted? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes: 
 
 
 
 
Type of pacemaker 
 
 
 
Single chamber   
 
 
Dual chamber  
 
 
12 months follow-up 
Did the patient have a pacemaker fitted? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes: 
 
 
 
 
Type of pacemaker 
 
 
 
Single chamber   
 
 
Dual chamber  
 
 
 
 
Population-specific standard deviations (SD) and proportions 
Outcome 
6 months 
12 months 
Digoxin 
Bisoprolol 
Total 
Digoxin 
Bisoprolol 
Total 
SF36 PCS 
N - [SD]  
 
 
 
 
 
 
SF36 MCS  
N - [SD] 
 
 
 
 
 
 
AFEQT  
N - [SD] 
 
 
 
 
 
 
LVEF 
N - [SD] 
 
 
 
 
 
 
E/e’ 
N - [SD] 
 
 
 
 
 
 
 
 
Unplanned hospitalisation rates (as recorded from the SAE form) 
Unplanned hospitalisation rates 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
No of patients exactly with:  
 
 
 
1 unplanned hospitalisation 
 
 
 
2 unplanned hospitalisation 
 
 
 
… unplanned hospitalisation 
 
 
 
Total number of unplanned hospitalisation 
 
 
 
 
 


 
Page 44 of 46 
 
 
Appendix D8: Safety 
 
Adverse Events  
Adverse event type 
Digoxin 
Bisoprolol 
Total 
N (%) of pts 
(N=) 
N of 
Events 
N (%) of pts 
(N=) 
N of 
Events 
N (%) of pts 
(N=) 
N of 
Events 
Gastrointestinal upset 
 
 
 
 
 
 
Blurred vision 
 
 
 
 
 
 
Rash 
 
 
 
 
 
 
Peripheral oedema 
 
 
 
 
 
 
Symptomatic bradycardia 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
Lethargy 
 
 
 
 
 
 
Upper respiratory tract symptoms 
 
 
 
 
 
 
Symptomatic hypotension 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Total 
- 
xx 
- 
xx 
- 
xx 
 
 
 
 
N of pts with at least one AE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Chi2 test for difference in number of patients with at least one AE between treatment groups 
P-value = x.xxx 
 
 
SAE’s 
SAE’s 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
Chi2 Test 
P-value 
Patients with at least one SAE:  
 
 
 
 
No 
 
 
 
 
Yes 
 
 
 
No of patients exactly with:  
 
 
 
 
1 SAE 
 
 
 
- 
2 SAE’s 
 
 
 
- 
… SAE’s 
 
 
 
- 
Total number of SAE’s 
 
 
 
- 
 
 
• 
List of all SAE’s 
 
 
 
 
 
 
 
 


 
Page 45 of 46 
 
 
GP visits by trial arm at 6 and 12 months 
GP visits 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
6 months follow-up 
Has the patient seen their GP since last trial visit? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes, how many times: 
 
 
 
N   
 
 
Mean [SD]  
 
 
Median {IQR}  
 
 
Min-Max  
 
 
Total number of visits for all patients  
 
 
12 months follow-up 
Has the patient seen their GP since last trial visit? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes, how many times: 
 
 
 
N   
 
 
Mean [SD]  
 
 
Median {IQR}  
 
 
Min-Max  
 
 
Total number of visits for all patients  
 
 
 
 
Number of patients that had pauses and duration of pause (from the 24 hour tape form) 
Pauses and duration from 24-hour tape 
Digoxin 
(N=) 
Bisoprolol 
(N=) 
Total 
(N=) 
Did the patient have any pauses? 
 
 
 
No  
 
 
Yes  
 
 
Missing  
 
 
If yes, maximal pause duration (seconds): 
 
 
 
N   
 
 
Mean [SD]  
 
 
Median {IQR}  
 
 
Min-Max  
 
 
 
 
Digoxin levels at 6 and 12 months for Digoxin arm  
Digoxin levels (ug/l)  
6 months 
12 months 
N  
 
Mean [SD]  
 
Median {IQR}  
 
Min-Max  
 


 
Page 46 of 46 
 
 
Appendix D9: Subgroup analysis for primary outcome 
 
Subgroup analysis for PCS of SF36v2 at 6 months  
Subgroup 
Adjusted Mean difference 
(95% CI) 
Interaction  
P-value 
Gender 
Male 
 
 
Female 
 
 
Modified EHRA class 
(1, 2a) 
 
 
(2b, 3, 4) 
 
 
Receiving beta-blocker therapy within  
1 month of randomisation 
No 
 
 
Yes 
 
 
Age (in years) 
<75 years 
 
 
≥75 years 
 
 
Left Ventricular Ejection Fraction (%) 
<50% 
 
 
≥50% 
 
 
 
Forest plot of subgroup analysis for primary outcome