Objective Randomised Blinded Investigation of Therapeutic Ablation Versus Cardioversion for Persistent Atrial Fibrillation
Phase: NA
Conditions: Persistent Atrial Fibrillation, Cardiac Arrhythmia
Sponsor: Barts & The London NHS Trust

  
                                         
                                           
 
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JRMO Research Protocol for Interventional Studies 
 
 
 
Full Title  
Objective Randomised Blinded Investigation 
of Therapeutic Ablation versus 
cardioversion for persistent Atrial 
Fibrillation 
 
Short Title 
ORBITA-AF 
 
Version 
1.0 
 
Version date 
12 February 2019 
 
 
Sponsor 
Barts Health NHS Trust 
 
Contact person: 
 
Dr Mays Jawad 
Research & Development Governance 
Operations Manager 
Joint Research Management Office 
 
5 Walden Street 
 
London 
 
E1 2EF 
 
Phone: 020 7882 7275/6574 
 
Email: researchgovernance@qmul.ac.uk 
 
 
IRAS Number 
237038 
 
Sponsor (ReDA) Number 
N/A 
 
REC Reference 
<REC Reference number> 
 
Chief Investigator 
Professor Richard Schilling 
 
Principal Investigator 
Dr Malcolm Finlay 
 
Co-Investigator 
Dr Vivienne Monk 
 
List of sites 
Whipps Cross Hospital, Barts Heart Centre 
 
List of laboratories 
Royal London Hospital Laboratories 
 
List of technical departments 
Medical Physics? 
 
List of central facilities  
Barts Cardiovascular Clinical Trials Unit (CVCTU) 
William Harvey Research Institute -  Heart Centre  
Barts and The London School of Medicine  
Queen Mary University of London  

  
                                         
                                           
 
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Charterhouse Square  
London, EC1M 6BQ

  
                                         
                                           
 
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1. Contents 
 
1. 
Contents .............................................................................................................. 3 
2. 
Glossary .............................................................................................................. 5 
3. 
Signature page.................................................................................................... 8 
4. 
Summary and synopsis ...................................................................................... 9 
5. 
Introduction ....................................................................................................... 11 
5.1 
Background ................................................................................................... 11 
5.2 
Preclinical data .............................................................................................. 11 
5.3 
Clinical data ................................................................................................... 12 
5.4 
Rationale ....................................................................................................... 13 
5.5 
Risks / benefits .............................................................................................. 13 
5.5.1 
Hypothesis ............................................................................................. 14 
6. 
Study objectives ................................................................................................ 14 
6.1 
Primary objective........................................................................................... 14 
6.2 
Secondary objective ...................................................................................... 14 
6.3 
Primary endpoint ........................................................................................... 14 
6.4 
Secondary endpoints .................................................................................... 14 
6.5 
Long Term passive follow-up ........................................................................ 14 
7. 
Study population ............................................................................................... 15 
7.1 
Inclusion criteria ............................................................................................ 15 
7.2 
Exclusion criteria ........................................................................................... 15 
8. 
Study design ..................................................................................................... 15 
9. 
Study procedures .............................................................................................. 16 
9.1 
Recruitment ................................................................................................... 16 
9.2 
Informed Consent.......................................................................................... 16 
9.3 
Procedure protocol ........................................................................................ 17 
9.3.1 
All patients.............................................................................................. 17 
9.3.2 
DCCV + PVI group................................................................................. 17 

  
                                         
                                           
 
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9.3.3 
DCCV group ........................................................................................... 18 
9.3.4 
All patients.............................................................................................. 18 
9.4 
Schedule of Assessment............................................................................... 19 
9.5 
Study Scheme Diagram ................................................................................ 20 
9.6 
Blinding procedures ...................................................................................... 21 
9.7 
Follow up ....................................................................................................... 21 
9.8 
End of Study Definition.................................................................................. 21 
9.9 
Entry into Registry ......................................................................................... 21 
9.10 Subject Withdrawal ....................................................................................... 22 
10. 
Assessment and management of risk .............................................................. 22 
10.1.1 
DCCV risks:............................................................................................ 22 
10.1.2 
Catheter ablation of AF risks: ................................................................ 22 
10.1.3 
Changes in risks c.f. standard cardioversion procedure in placebo 
group 
22 
11. 
Statistical considerations .................................................................................. 23 
11.1 Sample size ................................................................................................... 23 
11.2 Method of analysis ........................................................................................ 23 
12. 
Ethics................................................................................................................. 24 
12.1 Risks of the procedures: ............................................................................... 24 
12.2 Informed consent:.......................................................................................... 25 
12.3 Blinding considerations ................................................................................. 25 
12.3.1 
Rationale for blinding ............................................................................. 25 
12.4 Specific procedural considerations ............................................................... 25 
12.5 Annual Safety Reporting ............................................................................... 26 
13. 
Public Involvement ............................................................................................ 26 
14. 
Data handling and record keeping.................................................................... 26 
14.1 Data management......................................................................................... 26 
14.2 Source data ................................................................................................... 27 
14.3 Confidentiality ................................................................................................ 27 
14.4 Record Retention and Archiving ................................................................... 28 
15. 
Laboratories ...................................................................................................... 28 
15.1 Central and local laboratories ....................................................................... 28 

  
                                         
                                           
 
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15.2 Sample collection and preparation ............................................................... 28 
Blood tubes will be labelled with the following information: ........................................ 28 
16. 
Interventions and tools...................................................................................... 28 
16.1 Devices .......................................................................................................... 28 
16.2 Techniques and interventions ....................................................................... 29 
16.2.1 
PVI group ............................................................................................... 29 
16.2.2 
DCCV group ........................................................................................... 30 
16.2.3 
All patients.............................................................................................. 30 
16.3 Tools .............................................................................................................. 30 
16.3.1 
Questionnaires: ...................................................................................... 30 
16.4 Medicinal product .......................................................................................... 30 
16.5 Antiarrhythmic drugs ..................................................................................... 30 
17. 
Safety reporting................................................................................................. 31 
17.1 Adverse Events (AEs) ................................................................................... 31 
17.2 Adverse Reaction (ARs)................................................................................ 31 
17.3 Notification and reporting of Adverse Events and Reactions ....................... 31 
17.4 Serious Adverse Events (SAEs) or reactions ............................................... 31 
17.5 Notification and reporting of Serious Adverse Events .................................. 32 
17.6 Urgent Safety Measures ............................................................................... 32 
17.7 Annual Safety Reporting ............................................................................... 32 
17.8 Overview of the Safety Reporting responsibilities ........................................ 32 
18. 
Monitoring and auditing .................................................................................... 33 
19. 
Trial committees................................................................................................ 33 
20. 
Finance and funding ......................................................................................... 34 
21. 
Indemnity........................................................................................................... 34 
22. 
Dissemination of research findings................................................................... 34 
23. 
References ........................................................................................................ 34 
 
 
2. Glossary 
 

  
                                         
                                           
 
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AE 
 
 
Adverse Event 
 
 
AF 
 
 
Atrial Fibrillation 
AR 
 
 
Adverse Reaction 
ASR 
 
 
Annual Safety Report 
AV 
 
 
Atrioventricular 
BMI 
 
 
Body Mass Index 
BP 
 
 
Blood Pressure 
CA 
 
 
Competent Authority 
CA 
 
 
Cryoballoon Ablation 
CHADS VAR  
Score for estimating risk of stroke 
CI 
 
 
Chief Investigator 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organisation 
CVCTU 
 
Cardiovascular Clinical Trials Unit 
DC 
 
 
Direct Current 
DCCV  
 
Direct Current Cardioversion 
DMC  
 
Data Monitoring Committee 
EC 
 
 
European Commission 
ECG 
Electrocardiogram 
eGFR 
estimated Glomerular Filtration Rate 
EOS 
End of Study 
FU 
Follow-up 
GA 
General Anaesthetic  
GAfREC 
Governance Arrangements for NHS Research Ethics 
Committees 
GCS  
 
Glasgow Coma Scale 
HRA  
 
Health Research Authority 
ICD  
 
 
Implantable cardioverter-defibrillator  
ICF 
 
 
Informed Consent Form 
ILR 
 
 
Implantable loop recorder 
ISF 
 
 
Investigator Site File 
JRMO  
 
Joint Research Management Office 
LA 
 
 
Left Atrial 
LIPV  
 
Left Inferior Pulmonary Vein 
LSPV  
 
Left Superior Pulmonary Vein 
NICE  
 
National Institute for Health and Care Excellence 
NHS REC 
 
National Health Service Research Ethics Committee 
NHS R&D 
 
National Health Service Research & Development   
pAF 
 
 
Paroxysmal Atrial Fibrillation 
Participant 
 
An individual who takes part in a clinical trial 
PI 
 
 
Principal Investigator 
PIS 
 
 
Participant Information Sheet  
PVI 
 
 
Pulmonary Vein Isolation 
QA 
 
 
Quality Assurance 
QC 
 
 
Quality Control 
QoL 
 
 
Quality of Life 
QUALY 
 
Quality Adjusted Life Year 
RCT 
 
 
Randomised Controlled Trial 
RAG  
 
Red Amber Green 
REC  
 
Research Ethics Committee 
RFV 
 
 
Right Femoral Vein 
RIPV  
 
Right Inferior Pulmonary Vein 
RSPV  
 
Right Superior Pulmonary Vein 
SAE 
 
 
Serious Adverse Event 
SDV 
 
 
Source Document Verification 

  
                                         
                                           
 
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SOP  
 
Standard Operating Procedure  
SSA 
 
 
Site Specific Assessment 
TMF 
 
 
Trial Master File 
TMG  
 
Trial Management Group 
TSC 
 
 
Trial Steering Committee 
TSP 
 
 
Transeptal Puncture 
 

  
                                         
                                           
 
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3. Signature page 
 
 
Chief Investigator Agreement 
 
The study as detailed within this research protocol will be conducted in accordance 
with the principles of Good Clinical Practice, the UK Policy Framework for Health and 
Social Care Research, and the Declaration of Helsinki and any other applicable 
regulations. I delegate responsibility for the statistical analysis and oversight to a 
qualified statistician (see declaration below). 
 
Chief Investigator name: 
Richard Schilling 
 
Signature: 
 
 
Date: 
12 February 2019 
 
 
Principal Investigator Agreement 
 
The study as detailed within this research protocol will be conducted in accordance 
with the principles of Good Clinical Practice, the UK Policy Framework for Health and 
Social Care Research, and the Declaration of Helsinki and any other applicable 
regulations. I delegate responsibility for the statistical analysis and oversight to a 
qualified statistician (see declaration below). 
 
Chief Investigator name: 
Malcolm Finlay 
 
Signature: 
 
 
 
Date: 
12 February 2019 
 
 
Statistician’s Agreement 
 
The study as detailed within this research protocol will be conducted in accordance 
with the current UK Policy Framework for Health and Social Care Research, the 
World Medical Association Declaration of Helsinki (1996), principles of ICH E6-GCP, 
ICH E9 - Statistical principles for Clinical Trials and ICH E10 - Choice of Control 
Groups. 
 
I take responsibility for ensuring the statistical work in this protocol is accurate, and I 
take responsibility for statistical analysis and oversight in this study.  
 
Statistician’s name: 
Jackie Cooper 
 
Signature: 
 
 
Date: 
12 February 2019 

  
                                         
                                           
 
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4. Summary and synopsis 
 
Short title 
ORBITA-AF 
Methodology 
Internal Pilot as part of a future study, Randomised, blinded, 
controlled trial, 2 arms. 
Research sites 
1 Barts Health NHS Trust – 2 sites: Whipps Cross and Barts 
Heart Centre for the pilot study, with the potential to 
progress recruitment within 4-5 UK centres for larger 
Objectives / aims 
The main aim of the research is to investigate whether 
patients undergoing pulmonary vein isolation with 
cryoablation for atrial fibrillation (AF) will have lower rates of 
AF recurrence than those treated by DC cardioversion 
without an ablation procedure. 
The objectives of the Pilot Study are to trial the key study 
logistics with a view to optimising methods to be used in the 
main study. 
Number of 
participants 
20 patients (10 per group) for the pilot study 
208 patients for the larger trial 
Inclusion and 
exclusion criteria 
Inclusion criteria : 
Persistent AF (atrial fibrillation lasting > 7days) of total 
continuous duration <2 years, Age 18-80, ability to give 
informed consent. 
Exclusion criteria :  
Creatinine clearance (eGFR) < 30mls/min, contraindication 
or unable to take anticoagulation, uncontrolled 
hypertension, contraindication or catheter ablation, BMI > 
35. Contraindication or unable to tolerate amiodarone. 
 
Statistical 
methodology and 
analysis (if 
applicable) 
The sample size for a pilot study is based on 10% of the 
sample size of the full trial. The sample size for the full trial 
is calculated based on the comparison of recurrence free 
survival in the two groups using the logrank test. The 
expected percentage of patients with recurrence of AF 
within one year is 47% for the ablation group1 (January et al., 2014) 
and 66% for DCCV2,3,4 (Heeringa et al., 2006; Jones, Pollit, Fitzmaurice, Cowan, 
& Guideline Development, 2014; Wilber et al., 2010)based on published data. 
This is equivalent to a hazard ratio of 1.7.To detect an effect 
of this size with 80% power at the 5% significance level 
would require N=104 patients in each group. 
For secondary endpoints the sample size of 104 patients 
will give 80% power at the 5% significance level to detect an 
effect size of 0.4 standard deviations in any continuous 
variable.  
Secondary endpoints: 
Results will be presented as the mean (SD), median (IQR) 
or percentage (number) in each group. Continuous 
variables will be compared between the two groups using 
Student's T test for normally distributed variables and 
Mann-Whitney 
U 
test 
for 
those 
with 
non-normal 
distributions. Categorical variables will be compared with 
Chi-squared tests. 
 
Study duration 
The Pilot study will take place at Barts Health NHS Trust : 4 

  
                                         
                                           
 
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months to set up, 3 months to recruit, treatment (1 day), 3 
month follow up and 2 months study closure. 
For the larger trial in 4-5 UK centres: Set-up 6 months, 6 
month recruitment, treatment (1 day), 12 month follow-up, 3 
months study closure.  
 

  
                                         
                                           
 
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5. Introduction 
 
Patients with persistent atrial fibrillation undergoing catheter ablation are reported to 
have fewer symptoms and better quality of life than those undergoing DC 
cardioversion (DCCV) or optimal medical therapy. However, as yet this has not been 
subjected to a randomised, prospective, blinded clinical trial (January et al., 2014). 
 
Atrial fibrillation (AF) is the commonest cardiac arrhythmia, with a prevalence of 5.5% 
(Heeringa et al., 2006). A major cause of the life-changing complication of stroke, AF 
is associated with severe symptoms, such as palpitations, shortness of breath, 
lethargy and a reduced quality of life. AF can be classified into paroxysmal, persistent 
or long-standing persistent. Paroxysmal AF refers to when episodes last less than 7 
days before spontaneously termination, persistent AF implies episodes lasting 
greater than 7 days or requiring either electrical or pharmacological cardioversion, 
and longstanding persistent AF describes AF episodes lasting more than one year in 
duration trial (January et al., 2014). 
 
Patients differ widely in the diversity and severity of their AF symptoms. Some 15-
30% of patients with AF are asymptomatic. Data from implantable cardioverter-
defibrillators (ICDs) and pacemakers have demonstrated that up to 70% of 
paroxysms of AF are asymptomatic. There is a need to clarify the relationship 
between patient reported symptoms and the arrhythmia itself. It is likely that both 
somatic and psychological factors contribute to this relationship. Patient perception or 
awareness of symptoms is often not a good discriminator of the severity of the 
arrhythmia. In the present study we will also collect information from patients on 
reported symptoms and effects on quality of life (both physical and mental), 
functional status and treatment satisfaction. We will be able to look at these and 
assess the correlations between reported symptoms and arrhythmia as captured by 
the LINQ device.  
 
 
 
5.1 
Background  
 
After adequate stroke prevention (e.g. anticoagulation) and rate control, the optimum 
strategy for patients who continue to be symptomatic with persistent atrial fibrillation 
has not been established for patients without heart failure (Jones et al., 2014). 
Cardioversion with antiarrhythmic medication is commonly used as a first-line rhythm 
control strategy despite very high recurrence rates of the index arrhythmia and high 
serious complications associated with this strategy. Further treatment options, such 
as catheter ablation or implantation of a pacemaker and ablation of the AV node, are 
considered once AF recurrs. The benefits of first-line ablation in patients presenting 
with persistent AF has not been tested. We seek to perform a blinded, randomised 
trial comparing an electrical cardioversion-led strategy with a pulmonary-vein 
isolation strategy for the treatment of persistent atrial fibrillation.  
 
 
 
5.2 
Preclinical data  
 
Catheter ablation of AF has emerged as a highly effective treatment for symptomatic 
atrial fibrillation (AF), particularly in those cases refractory to antiarrhythmic 
treatment, (Calkins et al., 2009; January et al., 2014; Stabile et al., 2006; Wilber et 

  
                                         
                                           
 
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al., 2010) and has become an established treatment of paroxysmal AF (pAF). 
Registry and trial data suggest that pulmonary vein isolation, involving the electrical 
isolation of the pulmonary veins by endocardial ablation, can lead to a >80% 
maintenance of sinus rhythm in patients with pAF, even up to five years (Ouyang et 
al., 2010). Recent data have indicated that patients with persistent AF and heart 
failure have improved outcomes, including in all-cause mortality, over and above best 
conservative therapy with catheter ablation (Packer et al., 2018).  Furthermore, on-
treatment analysis of the CABANA trial (Packer et al., 2018), showed patients who 
underwent catheter ablation for AF had better survival and fewer unplanned hospital 
admissions than those treated with best medical therapy. 
 
Electrical reconnection of the pulmonary veins after the initial ablation procedure has 
been held responsible for the majority of recurrences following ablation (Rajappan et 
al., 2008), and has driven technical and procedural efforts towards establishing 
durable electrical isolation of the pulmonary veins at the first procedure. Specifically, 
the cryoballoon (Artic Front, Medtronic) has emerged as a leader in enabling durable 
pulmonary vein isolation from predictable, safe and reproducible procedures (Aryana 
et al., 2016; Canpolat & Aytemir, 2016; Kojodjojo et al., 2010; Tzeis, Pastromas, 
Sikiotis, & Andrikopoulos, 2016). Point-by-point radiofrequency ablation procedures 
have also become more rapid, safe and reproducible with technology developments 
such as catheter contact force sensing, 3D mapping and better steerability of 
catheters (Finlay et al., 2012; Lee et al., 2016).  
 
 
5.3 
Clinical data  
 
Catheter ablation of AF is less established in patients with persistent AF, but 
compelling evidence exists that AF recurrence is reduced in patients with persistent 
AF who undergo catheter ablation when compared to electrical cardioversion plus 
antiarrhythmic medication. The SARA study (Mont et al., 2014)randomised 146 
patients with persistent AF to antiarrhythmic medication plus electrical cardioversion 
or to catheter ablation, with 60% vs 30% of patients having recurrence of their 
arrhythmia at one year. The recent STAR-AFII trial (Conti et al., 2017) confirmed 
pulmonary vein isolation as the cornerstone of catheter ablation in this patient group, 
with no difference in the recurrence rates of patients undergoing AF ablation with 
pulmonary vein isolation alone (41% recurrence) or those who had pulmonary vein 
isolation plus electrogram ablation (51%) or plus linear ablation (54%) (Verma et al., 
2015). Similar or greater rates of freedom from AF after a single procedure have 
been seen in registry data, with up to around 80% long-term freedom from AF with 
multiple procedures (Hunter & Schilling, 2010; January et al., 2014).   
 
These data imply that the newer one-shot technologies such as the cryoballoon 
which provide durable PVI from a single, rapid, safe procedure, and thus would be 
effective in the ablation of persistent atrial fibrillation. Registry data support this 
assumption, with between 55 and 70% of persistent AF patients maintaining long-
term sinus rhythm following cryoablation PVI (Ciconte et al., 2015; Coutino et al., 
2016). These assumptions are being tested in ongoing clinical trials, where the 
efficacy of cryoablation PVI is being tested against point-by-point radiofrequency 
ablation. 
 
However, it is well established that the effectiveness of any therapy aiming for rhythm 
control is determined in part to the duration of AF (Kirchhof & Calkins, 2017; 
Voskoboinik et al., 2017). The mantra “AF begats AF” has repeatedly been shown to 
be relevant to catheter ablation of persistent AF (Wijffels, Kirchhof, Dorland, & 
Allessie, 1995). The enthusiasm for treating AF aggressively early in the course of 

  
                                         
                                           
 
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the disease is reflected in recent NICE guidelines (Jones et al., 2014). A treatment 
strategy where patients have a definitive PVI procedure early may be far more 
effective, and prevent multiple repeated hospital attendances. Side-effects of 
antiarrhythmic medications may be also be avoided. 
 
But a major stumbling block in performing early AF ablation for such patients has 
been the length and complexity of the procedure, drawbacks which have now been 
overcome by refinement of the cryoballoon ablation technique (Kojodjojo et al., 
2010). Indeed, an effective PVI procedure can now be performed routinely in under 
one hour, with complications only occurring rarely (Ang, Domenichini, Finlay, 
Schilling, & Hunter, 2015). Certainly, when compared to the effectiveness and risk of 
an electrical cardioversion, early PVI with a cryoballoon ablation for persistent AF 
appears a very attractive treatment proposition (Buch & Shivkumar, 2017).  
 
 
5.4 
Rationale 
 
No blinded randomised controlled trial comparing early-ablation strategies to 
cardioversion-led strategies has been performed. The rationale for blinding where 
possible in clinical trials is well established (Brim & Miller, 2013; Miller & Kaptchuk, 
2004; Redberg, 2014). The recently published ORBITA trial (Al-Lamee et al., 2018) 
performed a blinded, multicentre randomised trial of PCI in stable angina compared 
to a placebo procedure. This trial demonstrated that the efficacy of invasive 
procedures can be assessed with a placebo procedure and that this type of trial 
remains necessary. Knowledge of treatment assignment influences physician 
behaviour, drug recommendations and encourages bias in outcome reporting. The 
treatment effect size and the effects of confounding factors will be exaggerated and 
thus limit the interpretation of the true patient experienced outcomes either strategy. 
In a comparison of surgical procedures, a sham-control arm represents the gold 
standard of blinding. In a systematic review of placebo-controlled surgical trials 
(Wartolowska et al., 2014) found no evidence of harm to participants assigned to the 
placebo group. For a procedure whose primary purpose is to give sustained 
symptomatic relief, definitive quantification of the true placebo-controlled effect size 
of AF ablation is necessary. There is a need to clarify the relationship between 
patient reported symptoms and the arrhythmia itself. Patient reported symptoms may 
not always be related to the severity of the arrhythmia or quality of life. No bias-
resistant blinded, randomised, trial has yet been performed seeking to measure the 
benefits of AF ablation. 
 
 
 
5.5 
Risks / benefits  
 
The potential subjects for this study would be eligible to have either a DCCV or AF 
ablation as these are standard procedures for treatment of AF, and as such these 
interventions are performed as standard in the NHS care setting and have known 
risks and benefits. The risks of the ablation procedure also need to be balanced 
against the risks associated with the patient being maintained on medications to 
reduce their risk of arrhythmia. 
 
The study procedures will be performed by an experienced clinical team, such that 
the risks associated with the interventions are low, and procedures are in place to 
minimise risks. A more detailed explanation of risks and mitigations for the study 
interventions are documented in Section 10. 
 

  
                                         
                                           
 
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5.5.1 Hypothesis  
We hypotheses that AF ablation reduces recurrences of persistent AF and improves 
quality of life compared to acute treatment of heart rhythm by cardioversion and best 
medical therapy. 
 
6. Study objectives 
 
 
6.1 
Primary objective 
 
The primary hypothesis being tested is that 20 patients undergoing pulmonary 
vein isolation with cryoablation with DCCV for atrial fibrillation will have lower 
rates of AF recurrence than those treated by DC cardioversion without an 
ablation procedure.  
 
Once funding is available and dependent on the results of the pilot, it is planned 
that the study will be extended to a larger trial following an amendment to the 
REC, to increase the recruitment target to 208 participants and involve 4-5 other 
UK centres.  
 
6.2 
Secondary objective 
 
The secondary objective of the trial will be to determine whether an early-
ablation strategy is superior in terms of patient’s quality of life than a 
cardioversion strategy, and to compare medication burden, cost efficacy and 
secondary endpoints of cardiac function (change in ejection fraction) between 
these strategies. Finally, the safety of the approaches will be compared.  
 
6.3 
Primary endpoint 
 
• 
Recurrence of Persistent AF (AF episode lasting > 7 days).  
 
6.4 
Secondary endpoints 
 
• 
Death 
• 
Hospital admission 
• 
Procedural complications 
• 
Bleeding events 
• 
Requirement for repeat procedures 
• 
Change in ejection fraction 
• 
Cumulative treatment cost at 12 months 
• 
Clinical success (as defined by 75% or greater reduction in the number of 
AF episodes – or percentage time the patient is in AF as measured by 
the LINQ device.) 
• 
Change in quality of life, as measured by SF-12 and AF-PROMS 
questionnaires.  
• 
AF symptom score 
• 
AF burden as measured on continuous monitoring  
• 
Antiarrhythmic drug use. 
 
6.5 
Long Term passive follow-up 
 

  
                                         
                                           
 
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Follow the completion of the active portion of the larger trial, patients will be 
followed up in a registry to track their long-term outcomes from routinely 
collected clinical data. During this period, patients may be contacted to ascertain 
their AF and medical status, but no investigations or interventions other than 
those in routine clinical care will be performed. 
 
 
7. Study population 
 
Patients referred for either cardioversion for persistent AF or catheter ablation of 
persistent AF will be approached. 
 
7.1 
Inclusion criteria 
 
Patients who meet the following inclusion criteria will be eligible for the study; 
 
• 
Ability to give informed consent 
• 
Age 18-80 years 
• 
Persistent AF (atrial fibrillation lasting > 7days) of total continuous duration <2 
years as documented in medical notes.  
• 
Patients being considered for cardioversion. 
 
 
 
 
7.2 
Exclusion criteria 
 
Patients who meet the following exclusion criteria will be ineligible for study 
participation; 
 
• 
Creatinine clearance (eGFR) < 30mls/min 
• 
Contraindication or unable to take anticoagulation 
• 
Contraindication or unable to tolerate amiodarone 
• 
Uncontrolled hypertension 
• 
Contraindication or catheter ablation 
• 
BMI > 35 
 
 
8. Study design 
 
Bart’s Health patients referred from other Barts Health NHS Trust Hospitals 
(Homerton, Chase Farm, Barnet) for either cardioversion for persistent AF or catheter 
ablation of persistent AF will be approached for recruitment.  
• 
All patients: 
o Patient drug treatment will follow local clinical guidelines for AF ablation 
and be recorded in the CRF. 
o Patient baseline characteristics recorded at preadmission 
▪ 
Estimated AF duration 
▪ 
LA dimensions (Echocardiogram) 
▪ 
Ejection fraction 
▪ 
Routine Bloods  

  
                                         
                                           
 
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• 
Creatinine & Electrolytes,  
• 
Full blood count,  
• 
Thyroid function 
▪ 
Quality of Life measures 
▪ 
BP 
▪ 
CHADS VASC score / assessment 
▪ 
Medical History and Comorbidities 
▪ 
Demographics (Age, sex , ethnicity) 
▪ 
Physical exam (BP, HR, Weight, Height, BMI) 
▪ 
Medications 
• 
Day of Procedure – blinded randomisation to intervention (DCCV, or Pulmonary 
Vein Isolation plus DCCV). Reveal LINQ inserted during procedure. 
• 
6 weeks: QoL measures, telephone FU 
• 
3 months: Clinical follow up, 12 lead ECG, Repeat QOL measures 
• 
12 months: Clinical follow up, Endpoints measured. Once subject participation in 
the trial is complete, the patient and physician will be unblinded. If the patient is in 
AF, management of AF proceeds as clinically indicated. 
• 
All patients who consent to have data capture continue in AF registry for 5 years. 
The pilot study patients will be analysed at 3 months and 12 months to allow 
assessment of feasibility of a larger trial, and patients who complete the 12 month 
follow-up visit and consent will continue in registry follow-up for 5 years post 
procedure. 
 
9. Study procedures 
 
9.1 
Recruitment 
 
The usual clinical care provider will identify patients suitable for the study who will 
then be approached by the study team for consent. Patients referred for DC 
cardioversion or management of persistent AF will be screened for inclusion into the 
trial. 
 
All potential participants will be given the Participant Information Sheet by a member 
of the study team, once identified as interested and eligible by their usual treating 
clinician, and be given sufficient time to consider study participation.  
 
9.2 
Informed Consent 
 
The clinicians obtaining informed consent will have current GCP training. They will be 
familiar with the study, the clinical procedures and will use the current version of the 
Patient Information Sheet (PIS) and Informed Consent Form (ICF) which has been 
approved by the HRA/REC.  
 
The clinicians obtaining consent at the pre-admission (screening) visit will ensure that 
the participant is able to understand the information given and will explain the nature, 
purpose, procedures, risks and benefits of the study to the participant. The clinician 
will answer any questions the patient may have to the patient's satisfaction. The 
patient will be given at least 24 hours to decide whether or not to take part in the 
study following being given the PIS. The date the PIS is given to the patient will be 

  
                                         
                                           
 
ORBITA-AF Protocol V1.0  12 FEBRUARY  2019    
 Page 17 of 37 
 
 
 
 
documented in the hospital notes to ensure that sufficient time is given for 
consideration. 
 
The clinician will explain the consent form and obtain the patient's initials and dated 
signature on the consent form. They will then countersign and date the consent form 
after the participant has signed it. The original signed consent and PIS will be kept in 
the Investigator Site File, a copy will be filed in the hospital notes, and a copy will be 
given to the patient.  
 
Any delegation of responsibility by the PI for consent taking, or any other trial activity, 
should be documented on the Study Delegation Log.  
 
Written informed consent from the participant must be obtained prior to his or her 
involvement in any aspect of the trial that requires consent. Any revised written ICF 
and other written information to be provided should receive favourable opinion by the 
REC in advance of use and distribution. The PIS and ICF will be identifiable by date, 
version number and be printed on local trust headed paper of the trial site at which 
the participant is to be consented.  
 
 
9.3 Procedure protocol 
9.3.1 All patients 
Patient gives informed consent in pre-admission. Patients will be blinded to their 
ECG and rhythm. Admitted to day ward. Arrival in Lab and checked in as for Cryo 
PVI. Skin electrodes placed. Conscious sedation or GA administered and sterile field 
prepared. 8F and 7F sheaths placed in RFV under ultrasound guidance.  Heparin 
given as per local AF ablation protocol. 
 
Once sheaths in place and GCS < 10, randomisation will be performed via REDCap, 
a web-based, electronic database. Patients will be randomised in a 1:1 ratio to either 
DCCV+ PVI or DCCV alone. 
9.3.2 DCCV + PVI group 
Transeptal puncture done using standard techniques. Heparin given as per local 
protocol. Change TSP sheath over-the-wire to cryosheath. Cryoballoon to LA. 
Achieve wire through cryoballoon. Cryoablation to LSPV, RIPV, RSPV, LLPV, with 
phrenic pacing via quadripolar catheter via 7F sheath during right sided lesions. As is 
standard practice, the catheter will be placed in the superior vena cava and 
manipulated to allow consistent phrenic capture with pacing stimulation. Phrenic 
stimulation will be confirmed by diaphragmatic movement and recording of 
diaphragmatic surface electrograms. Pulmonary venous isolation will be confirmed 
with electrograms in veins. Veins considered isolated if sudden loss of electrogram 
signal, or if pacing through all poles of achieve catheter is able to produce electrical 
capture of vein but not of LA. Termination of freeze if loss of phrenic capture, vein 
temperature < -60ºC, or operator decision for termination. Isolation was considered 
indeterminate if unable to confirm signal loss or electrical capture. At end of isolation, 
DCCV performed (if patient still in AF). Sheath withdrawal, Femostop haemostasis 
and protamine as per local protocol. An implantable loop recorder will be inserted in 
the prepectoral area with local anaesthetic at the end of the procedure. Confirmed 
electrical isolation of all 4 pulmonary veins will be classified as a procedural success. 
Confirmation of electrical recording by the implantable loop recorder will be 
considered implant procedural success. 

  
                                         
                                           
 
ORBITA-AF Protocol V1.0  12 FEBRUARY  2019    
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9.3.3 DCCV group 
Sedation maintained for 30 minutes. An electrophysiological catheter will be passed 
to the superior vena cava using fluoroscopic guidance and 6 minutes of phrenic 
pacing will be performed, starting at 20 minutes following first local anaesthetic. At 30 
mins, sedation optimised and DCCV performed. Sheath withdrawal, Femostop 
haemostasis and protamine as per local protocol. An implantable loop recorder will 
be inserted in the prepectoral area with local anaesthetic at the end of the procedure. 
9.3.4 All patients 
Recovered to ward. 12 lead ECG performed but not shown to patient. Patient 
mobilised and discharged after 4 hours.  
 
 
Blinding 
 
There is a study specific Standard Operating Procedure on the blinding procedure 
used in this study. No information on the procedure given will be transferred from 
cath lab staff to the recovery ward staff.  
 
Patients and other healthcare professionals will also be blinded to which treatment 
the patient received. The cath lab staff performing the procedure will have no further 
contact with the patient during the study. A ‘chaperone’ will be assigned for each 
patient, who will take over from the cath lab staff in caring for the patient post 
intervention.  
 
A standard procedure report will be used for clinical records, with a procedure report 
entered into the study database. This will be transferred to the clinical database at 
the end of the study or at a patient unblinding event, whichever is earlier. 
 
 
In the present study we will use a modification of the blinding procedure used in the 
ORBITA trial (Al-Lamee et al., 2018). A specific blinding questionnaire will be used at 
the end of the day of the intervention asking the patient and ward staff to guess the 
treatment allocation. As is typical of AF studies involving ablation, a blanking period 
will be observed.  This accounts for the frequent recurrence of arrhythmia in the days 
following ablation, where healing atrial tissue can be vulnerable to arrhythmia which 
is not predictive of longer-term outcome. At the end of the blanking period (ie. 6 
weeks) patients will be asked to complete the blinding questionnaire again. This 
blinding index will be reported on the day of the intervention and at 6 weeks and 3 
months follow up to allow the degree of blinding to be assessed.  

  
                                         
                                                                                                                                  
 
ORBITA-AF Protocol V1.0  12 FEBRUARY  2019    
 Page 19 of 37 
 
 
 
 
9.4 
Schedule of Assessment 
 
Assessment 
Screening/ 
pre-
admission 
Randomi
sation 
Treatment/ 
Procedure 
Implant 
Recovery 
6 weeks 
(telephone) 
3 month 
 
(clinic)  
12 month 
/EOS 
(clinic) 
Monthly 
downloads 
Registry 
Visit window 
 
 
 
 
 
 
+/- 7 
days 
+/- 2 
weeks 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Patient baseline 
characteristics recorded: 
estimated AF duration, LA 
dimensions (echo), LVEF, 
Bloods,  Medications, Age, 
Sex, BP, CHADS VASC 
score, co-morbidities, 
demographics, weight, 
height, BMI. 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
DCCV only 
 
 
X 
 
 
 
 
 
 
 
DCCV plus Pulmonary Vein 
Isolation 
 
 
X 
 
 
 
 
 
 
 
Telephone FU 
 
 
 
 
 
X 
 
 
 
 
Quality of life measures 
X 
 
 
 
 
X 
X 
 
 
 
Clinical FU 
 
 
 
 
 
X 
X 
X 
 
 
Loop recorder inserted 
 
 
 
X 
 
 
 
 
 
 
12 lead ECG 
 
 
 
 
X 
 
X 
X 
 
 
Interrogation of loop recorder  
 
 
X 
 
 
X 
X 
X 
 
Symptom questionnaires 
X 
 
 
 
 
X 
X 
X 
 
 
Clinical status and mortality 
data 
 
 
 
 
 
 
 
 
 
X 
 
The long term passive follow up will track patient mortality and clinical status from routinely collected clinical data. No intervention or 
investigations will be performed as part of this long term follow up. 

  
                                         
                                               
 
ORBITA-AF Protocol V1.0  12 FEBRUARY  2019    
 Page 20 of 37 
 
 
 
 
9.5 
Study Scheme Diagram  
 
 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 21 of 37 
 
 
9.6 
Blinding procedures 
The aim of blinding will be to prevent patients, their treating clinicians and their 
treatment choices being influenced by knowledge of the procedure being performed. 
The pilot study will establish the effectiveness and feasibility of blinding procedures. 
Patients will be admitted to the day ward for “Orbita AF DCCV±ablation”. They will 
undergo confirmation of study and procedural consent by a senior cardiology 
fellow/registrar or consultant. Patients will be accompanied to the cath lab by a clinical 
fellow or research nurse (Chaperone), and at this point their care will be transferred to 
the cath lab team. The patient will enter the catheter lab and standard AF preprocedural 
checks will be performed. Patients will be offered to wear headphones playing relaxing 
music of their choice during the procedure. A groin access / draping pack will be 
opened for all patients and sedation given. After GCS < 10, the patient will be 
randomised to either DCCV and ablation, or DCCV alone using REDcap (mobile app). 
The procedure will be performed according to protocol. At the end of the procedure, a 
“sign out” will be performed, where the procedure performed is confirmed to the 
operating team. Here the randomised allocation will not be specified in keeping with the 
blinding SOP. If no complications occurred, the procedure performed will not be 
specified on sign-out, hand over to the ward staff will be as follows:  
 
“A DC cardioversion plus or minus Cryoablation under the study protocol was 
performed with groin sheath access and no complications. The patient should be 
managed assuming they have undergone an ablation procedure”.  
 
Patients who are accidentally unblinded will be withdrawn from the trial. 
 
Patients will complete a questionnaire immediately prior to discharge to establish their 
perception of which procedure was performed. 
 
Randomisation will be performed in a 1:1 ratio, between 3 and 4 patients per day will 
have procedures performed as per this protocol. Individual randomisation will be 
performed after insertion of groin sheath and administration of sedation.  
 
9.7 
Follow up 
Patients will be followed up for a total of 12 months regardless of the results of any 
interim analysis. Monthly remote interrogation of the loop recorder will measure the 
burden of AF (proportion of time in AF) and the duration of AF episodes. At follow up 
patients will undergo interrogation of their loop recorder, a 12 lead ECG and a symptom 
questionnaire. For patients travelling long distances for their treatment ECGs and 
device interrogations will be requested from their local device centre and questionnaires 
will be administered by telephone, mail and or email. Patients will remain within an 
observational registry for 5 years following the end of the trial.  
 
9.8 
End of Study Definition  
The last patient attending for the 12 month clinic assessment will mark the end of the 
study. Patients who have consented to have their AF data collected will then go into the 
registry for 5 years. Once all the data has been collected from the last clinic 
assessments then final data analysis will be completed.   
 
9.9 
Entry into Registry 
Following study completion, patients will be entered into a data registry which will 
gather standard clinical data from patient notes. This will follow patients up for 5 years. 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 22 of 37 
 
9.10 
Subject Withdrawal 
 
Patients can withdraw from the trial at any time and without giving a reason. The 
Principal Investigator can also withdraw a patient from the study for any of the following 
reasons: 
1. Any adverse event or serious adverse event 
2. Any concurrent illness that prevents further treatment 
3. Any change in the patient’s condition that justifies the discontinuation of 
treatment in the clinician’s opinion 
4. Withdrawal of consent for treatment by the patient 
5. Any study device or procedural complications  
6. Any reasons the subject cannot adhere to study visits or procedures 
 
If a patient withdraws from the study, another patient will be randomised to replace 
them. Patients who are randomised but withdraw will not have their medical care 
affected and return to standard clinical care. 
 
 
10. Assessment and management of risk 
 
The risks of both DC cardioversion and of catheter ablation for AF are well established, 
as detailed below. However, the procedures will be performed by experienced clinicians 
who part of the research team for all study participants, which should minimise any 
known/expected risks. 
 
10.1.1 DCCV risks: 
• 
Sedation complications (<1%), chest discomfort, redness, irritation at site of skin 
pads (5%),  failure of DCCV. 
10.1.2 Catheter ablation of AF risks: 
• 
Groin access complications (1% historically, <0.2% with ultrasound guidance) 
• 
Minor (Total <6%) 
o Groin: Bleeding bruising at groin access site (5%) 
o Pericardial effusion not requiring drainage (1%) 
o Transient phrenic nerve palsy (3%) 
• 
Major (Total <1%) 
o Groin complication or vascular damage requiring surgical or radiological 
intervention (0.5%) 
o Cardiac tamponade requiring percutaneous drainage (0.7%) 
o Stroke (<0.2%) 
o Oesophageal damage (<0.2%) 
o Death (<0.1%) 
o Pulmonary vein stenosis causing breathlessness (<0.1%) 
 
 
 
10.1.3 Changes in risks c.f. standard cardioversion procedure in placebo 
group 
o Groin access complications (<0.2% with ultrasound guidance) 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 23 of 37 
o Electrophysiologist 
administering 
cardioversion 
in 
catheter 
lab 
environment (potentially better safety monitoring than in standard 
cardioversion environment) 
 
11. Statistical considerations 
 
11.1 
Sample size 
 
The sample size of 20 subjects for the pilot study has been chosen as an achievable 
recruitment target that would enable assessment of feasibility of the study, and to 
confirm whether a larger trial could be conducted. 
 
The sample size for the larger trial is calculated based on the comparison of recurrence 
free survival in the two groups using the logrank test. The expected percentage of 
patients with recurrence of AF within one year is 47% for the ablation group1 and 66% 
for DCCV2,3,4 based on published data. This is equivalent to a hazard ratio of 1.7. To 
detect an effect of this size with 80% power at the 5% significance level would require 
N=104 patients in each group. 
 
For secondary endpoints the sample size of 104 patients will give 80% power at the 5% 
significance level to detect an effect size of 0.4 standard deviations in any continuous 
variable.  
 
 
 
11.2 
Method of analysis  
 
The statistical analysis plan (SAP) will describe the statistical methods which will be 
used in the analysis of data, including any interim analyses and the level of significance 
that is to be used. 
 
Progression criteria 
 
This study has been designed with an internal pilot phase aimed at assessing the 
feasibility and optimizing the methods to be used in the main study, piloting key study 
logistics, improving quality and efficient use of resources. Eldridge (Eldridge et al., 
2016)have described a new framework where ‘internal pilot’ studies  which have some 
feasibility objectives but focus on the processes to be used in the main study generating 
data which can contribute to the final analyses. They describe the use of operational 
‘progression criteria’ which can be used to measure pre-identified targets at the end of 
the pilot phase which will determine whether or not to proceed to the main trial. This 
approach has been advocated by the members of the Internal Pilot Trials Workshop 
supported by the Hubs for Trials Methodology Research (Avery et al., 2017). Avery and 
colleagues describe some of the key issues to consider in development and review of 
these criteria. 
 
In the current study the following progression criteria have been identified to assess 
operational aspects of the design and progression to the main trial: 
• 
Protocol non-adherence – (a) cross-over from DCCV to AF ablation group. 
Estimate 25-30% as in CABANA trial (Packer et al., 2018). We will take this 
level of cross-over into account in our power calculations. (b) Measure the 
amount of off protocol intervention.  

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 24 of 37 
• 
Recruitment rate – we estimate being able to recruit 4 patients per month. If the 
number falls below this we will need to build this into timelines for the larger trial.  
• 
Loss to follow-up. Estimate 2%. 
• 
Key study logistics – especially around the delivery of the intervention, including 
the use of a ‘chaperone’ to maintain blinding.  
• 
Identifying barriers and facilitators to implementation. 
• 
Assessment of the success of the blinding procedure (ie. blinding index).  
• 
Assessment of the feasibility of the blinding SOP.  
• 
Assessment of the acceptability of the interventions  
• 
Data collection – completeness and quality. How much missing data are we 
willing to tolerate?  
• 
Assessment of outcome measures.  
 
 
The TSC will discuss and evaluate the progression criteria at the end of the Pilot phase 
and use a Red Amber Green (RAG) system to decide which operational aspects of the 
design need to be changed before proceeding to the main trial.  
 
 
12. Ethics 
 
The Principal Investigator will ensure that the study will be carried out in accordance 
with the ethical principles in the UK Policy Framework for Health and Social Care 
Research (Nov 2017), and applicable legal and regulatory requirements. This protocol 
and any subsequent amendments, along with any accompanying material provided to 
the patient in addition to any advertising material will be submitted by the Investigator to 
an independent NHS Research Ethics Committee (REC). Written Approval from the 
Committee must be obtained and subsequently submitted to the JRMO to obtain Final 
Sponsorship approval.  
 
 
12.1 
Risks of the procedures: 
All patients having either a DCCV or AF ablation are given conscious sedation or 
general anaesthetic. 
 
An AF ablation is performed using transeptal puncture using standard techniques. The 
risks associated with a transeptal puncture are very low. Groin access complications 
are around 1% and even less with ultrasound guidance (0.2%).  
 
The DCCV only group would require the patients to have a line put in, which is not 
normally done. However, this venous access could be used for the administration of 
anaesthetic agents, sedation and fluids.  The use of a femoral venous access will allow 
patients to be blinded to which procedure they have received and enable the specific 
effects of the AF ablation to be measured. 
 
Any risks associated with femoral access will have been minimised by using ultrasound 
guidance for the venous access. The risks of the ablation procedure also need to be 
balanced against the risks associated with the patient being maintained on medications 
to reduce their risk of arrhythmia.  
 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 25 of 37 
12.2 
Informed consent:  
The risks to the study participants will be adequately explained in the Patient 
Information Sheet and Informed Consent Form.  
 
The patients will be considered suitable to have either a cardioversion of ablation 
procedure. So, they need to be willing to have the transeptal puncture for the AF 
ablation. The risks of this procedure are low (as detailed above). As the procedure is 
performed under anaesthetic it will be performed without the patient experiencing any 
pain.   
 
There is a benefit to participants in the study in having the implantable cardiac device 
which will monitor their heart allowing immediate knowledge if their heart rhythm goes 
back into AF. Otherwise there are no further individual benefits in participating in the 
study. 
 
 
12.3 
Blinding considerations 
 
No blinded randomized controlled trial comparing early-ablation strategies to 
cardioversion-led strategies has been performed. For a procedure whose primary 
purpose is to give sustained symptomatic relief, definitive quantification of the true 
placebo-controlled effect size of AF ablation is necessary. The present study was 
designed to address the lack of clinical research / lack of evidence-based practice in 
this area. 
 
12.3.1 Rationale for blinding
 
The rationale for blinding where possible in clinical trials is well established, and 
discussed in Introduction (Section 5.4).  
 
Placebo effects and distorted participant reporting appear to be greater in surgical trials 
than in drug trials. There are many factors involved in surgical procedures such as 
hospitalization, ancillary treatments, the surgical ritual itself or the technology used that 
can all heighten the placebo effect. Correcting for placebo effects is becoming more 
important as more subjective ‘soft’ outcome measures are used eg. Quality of Life 
(which are more prone to be influenced by placebos).  
 
The magnitude of the placebo effect may be a critical factor in determining the outcome 
of a trial. A difference between two treatments such as DCCV and PVI might result from 
differences in their placebo effects so it is important to blind patients to the intervention 
they have received.  
 
Specific emphasis will be placed on this being a blinded trial. Patients will be informed 
that they may receive an electrical cardioversion with or without pulmonary vein 
isolation procedure. The procedure performed will be determined at random following 
administration of sedation and insertion of groin sheaths under ultrasound guidance. 
Patients will not be informed which procedure they have undergone until the end of the 
trial period or the study end-point whichever is sooner. Patients who undergo a 
cardioversion only who revert to persistent AF will be offered a pulmonary vein isolation 
procedure if indicated as standard medical care under current guidelines.  
  
12.4 
Specific procedural considerations 
All patients having either a DCCV or AF ablation are given conscious sedation or 
general anaesthetic. 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 26 of 37 
 
An AF ablation is performed using transeptal puncture using standard techniques. The 
risks associated with a transeptal puncture are very low. Groin access complications 
are around 1% and even less with ultrasound guidance (0.2%).  
 
The DCCV only group would require the patients to have a line put in, which is not 
normally done. However, this venous access could be used for the administration of 
anaesthetic and sedation agents, and for fluids if required. This will allow the patients to 
be effectively blinded to which procedure they have received and allow the specific 
effects of the AF ablation to be measured. 
 
The risks and harms to the patient of a transeptal puncture are very low and patients 
who are suitable for an AF ablation (i.e. all patients eligible for the trial) would require 
this access for the procedure to be performed. The risks have been minimised by using 
ultrasound guidance for the venous access.  
 
The risks of this procedure also need to be balanced against the risks associated with 
the patient being maintained on medications to reduce their risk of arrhythmia.  
 
Subjects are free to withdraw from the study at any time, without providing a reason. If 
the subject asks the investigator to destroy all identifiable samples taken from the 
subject and/or not enter into the CRF results of the follow-up examination, the 
investigator will comply with the subject’s requests. 
 
The CI will ensure that the REC is informed promptly of any serious adverse event that 
occurs during this study and that is both related and unexpected (see section 13), in 
line with NRES SOPs, and will provide the REC with annual progress reports of the 
study, if it lasts longer than a year.   
 
 
 
12.5 
Annual Safety Reporting  
 
The CI will send an Annual Progress Report to the REC and the sponsor using the HRA 
template on the anniversary of the REC “favourable opinion”. 
 
13. Public Involvement 
 
We have obtained input from our patient volunteers at the William Harvey Heart Centre 
and from the Trials Connect patient group. They have reviewed our patient facing 
literature (PIS and ICF) and had input into our trial design. This has ensured that our 
proposal, particularly the lay summary, is understandable to our patient population. We 
have also had input from our AF patients treated at our Trust. We will also include a 
patient representative on our Trial Steering Committee.  
 
 
14. Data handling and record keeping 
 
14.1 
Data management 
 
A REDCap database will be designed by CVCTU to capture the study data. The eCRFs 
will have an audit trial, will have electronic signatures, users will have specific access 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 27 of 37 
and user rights, and they will enable real-time data clarifications and cleaning, and data 
exports and analysis. All source documents will be kept securely in the participant study 
files or Investigator Site File (ISF) within locked cabinets in restricted access rooms 
within the Barts Health Centre. The CVCTU will maintain the Trial Master File (TMF), 
and provide trial management support and tracking for recruitment, data capture, 
monitoring and safety reporting. 
 
 
14.2 
Source data 
 
Source data are the original forms of data used in the study. Some source data will be 
generated directly by the study (e.g. ablation reports, questionnaire responses) while 
others may need to be collected from other ‘source documents’ (e.g. a participant’s 
medical history in their case notes for inclusion). All source data will be collected by the 
Investigator or delegated member of the research team, filed in a participant study file 
(which will include study documents such as the consent form, inclusion and exclusion 
criteria, cardioversion and ablation reports, AEs, medication records, EQ5D 
questionnaire etc), and source data will be captured in an electronic database 
(REDCap). A Source Data Agreement will be completed to determine what is 
considered as the ‘source’ data for the trial. 
 
 
14.3 
Confidentiality 
 
The Principal Investigator has a responsibility to ensure that participant anonymity is 
protected and maintained. They must also ensure that their identities are protected from 
any unauthorised parties. Information with regards to study participants will be kept 
confidential and managed in accordance with the Data Protection Act, the General Data 
Protection Regulation (GDPR), NHS Caldecott Principles, the UK Policy Framework for 
Health and Social Care Research, and the conditions of Research Ethics Committee 
favourable opinion. All research team members have undergone GCP training. The 
Chief Investigator and the study team will adhere to these parameters to ensure that the 
Participant’s identity is protected at every stage of their participation within the study.  
 
Following consent and during the study, all participant study records and samples will 
be marked by a single, unique pseudoanonymised identifier. The code for the 
pseudoanonymised will be kept on a study ID log with the ISF, which will be kept within 
a locked filing cupboard within a locked room that only the researchers involved have 
access to. A paper record of any information will be coded and any patient identifiable 
information (PID) will be removed e.g. name, date of birth and NHS number. 
 
Personal 
information 
will 
only 
be 
used 
on 
the 
consent form and the 
pseudoanonymisation code (screening log). Personal information will be used by the 
site study team to contact participants if needed and to remind participants of study 
dates. Fully anonymised data will be shared with fellow researchers via conference 
presentation and via publication of the results in scientific journals. Pseudoanonymised 
data will be shared between the research teams named in the application, and access 
will be granted to members of the Sponsor and Barts CVCTU teams for the purposes of 
data monitoring and audit. 
 
Only the clinical care team will have access to clinical case notes, which have 
identifiable personal information for the purposes of identifying potential participants.  
 
The research team will create a separate study file for each participant which will 
comprise of information given by the participant at the time of screening and during 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 28 of 37 
visits. Routine biochemistry will be measured in Barts Health NHS Trust clinical 
laboratory by the laboratory biochemists. 
 
The Investigator Site File (ISF) and subject study files will be kept in a locked cupboard 
in a locked room that only the researchers involved have access to. The Trial Master 
File (TMF) will be maintained and stored by the Barts CVCTU in the William Harvey 
Heart Centre, in a locked room with restricted access.  
 
Under no circumstances will non-encrypted named data be placed on a laptop 
computer, portable storage device (memory stick or CD-ROM) or transferred by email.  
 
 
14.4 
Record Retention and Archiving 
 
Data will be managed with reference to the Barts CTU SOP 'Data Management'. During 
the course of research, all records are the responsibility of the Chief Investigator and 
must be kept in secure conditions. The UK Policy Framework for Health and Social 
Care Research requires that research records are kept for 20 years after the project 
has completed. For studies involving Barts Health NHS Trust patients, undertaken by 
Barts Health NHS Trust staff, or sponsored by Barts Health NHS Trust or Queen Mary, 
University of London, the approved repository for long-term storage of local records is 
the Trust Corporate Records Centre. Both electronic and paper documentation will be 
retained in physical form for archiving. Sponsor approval will be requested prior to final 
destruction of the trial records. 
 
 
15. Laboratories  
 
15.1 
Central and local laboratories 
 
Biochemical and haematology assays will be performed in the pathology labs of the 
Barts Health NHS Trust. Blood samples will be taken at the screening visit, and these 
are standard blood tests to assess baseline characteristics of the participant and 
confirm eligibility. 
 
15.2 
Sample collection and preparation 
 
Blood tubes will be labelled with the following information: 
• Subject Number  
• Date of Collection 
• Sampling Time (nominal) 
• Study Name 
 
 
16.  Interventions and tools  
 
16.1 
Devices 
 
Loop recorder 
• 
Manufacturer: MEDTRONIC LTD 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 29 of 37 
• 
Indication 
: 
Long-term 
monitoring 
of 
heart rhythm. 
Determination of duration of AF episodes and confirmation of 
primary endpoint 
• 
CE Mark : Yes 
• 
Source of Device : Medtronic Ltd In-kind research grant 
contribution 
• 
How device used : The Reveal device is inserted in the pre-
pectoral position under the skin. This is performed with local 
anaesthetic in the preadmission clinic by a trained nurse or 
doctor. The device will provide a continuous recording of the 
heart rhythm and rate, and will be able to down load duration of 
AF episodes via a home monitoring system to establish the 
primary endpoint of the study. 
Cryoballoon, 
Cryocath, 
Achieve wire, 
Console and 
related items 
• 
Manufacturer: MEDTRONIC 
• 
Indication: AF ablation catheter and sheath 
• 
CE Mark: Yes 
• 
Source of Device: Clinical use for AF ablation 
• 
How device used: The cryoballoon is the key specified technique 
for performing pulmonary vein isolation in the ablation arm in 
this trial. This allows the physician electrophysiologist to 
perform a circumferential freeze around the pulmonary veins to 
electrically isolate the vein, thus preventing pulmonary vein 
ectopy from triggering arrhythmia.  
 
 
16.2 
Techniques and interventions 
 
Conscious sedation or GA administered and sterile field prepared. 8F and 7F sheaths 
placed in RGV under ultrasound guidance.  
16.2.1 PVI group 
Transeptal puncture (TSP) done using standard techniques using operator preference 
equipment. Heparin given as per local protocol. Change TSP sheath over-the-wire to 
cryosheath. Achieve wire through cryoballoon and cryoballoon placed in LA through 
cryosheath. Cryoablation to LSPV, RIPV, RSPV, LLPV, with phrenic pacing via 
quadripolar catheter via 7F sheath during right sided lesions. Isolation confirmed with 
electrograms in veins. Veins considered isolated if sudden loss of electrogram signal, or 
if pacing through all poles of achieve catheter is able to produce electrical capture of 
vein but not of LA. Termination of freeze if loss of phrenic capture, vein temperature < -
60ºC, or operator decision for termination. Isolation was considered indeterminate if 
unable to confirm signal loss or electrical capture. At end of isolation, DCCV performed 
(if patient still in AF). Sheath withdrawal, Femostop haemostasis and protamine as per 
local protocol.  
 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 30 of 37 
REVEAL-LINQ insertion will be performed at the end of the case. Prepectoral area will 
be cleaned and any overlying ECG leads removed. 10mls of local anaesthetic will be 
infiltrated to the skin and the device injected under the skin in a sterile manner. The 
incision will be closed according to local practice. 
16.2.2 DCCV group 
Sedation maintained for 30 minutes. At 30 minutes, sedation optimised and DCCV 
performed. Sheath withdrawal, Femostop haemostasis and protamine as per local 
protocol. 
 
REVEAL-LINQ insertion will be performed at the end of the case. Prepectoral area will 
be cleaned and any overlying ECG leads removed. 10mls of local anaesthetic will be 
infiltrated to the skin and the device injected under the skin in a sterile manner. The 
incision will be closed according to local practice. 
 
16.2.3 All patients 
Recovered to ward. 12 lead ECG performed but not shown to patient. Patient mobilised 
and discharged after 4 hours. The cardiac physiologist will register the patient for 
remote monitoring, a physiologist will show the patient how to use their monitoring 
station. 
 
 
16.3 
Tools 
 
16.3.1 Questionnaires:  
Short Form (SF 12) The short form health survey 
This is a shorter version of the SF-36 and consists of 12 questions. It is comparable 
with the SF-36 especially for the physical component summary (PCS) and mental 
component summary (MCS). This test gives more precision than the EQ-5D and has 
been extensively validated in general and also in cardiac populations (De Smedt, Clays, 
Annemans, & De Bacquer, 2014). 
 
Atrial Fibrillation Specific Patient Reported Outcome Measure (AF PROMS) 
This 28 item inventory measures how AF has impacted the patient’s quality of life. It 
assesses how much the patient has been concerned by specific symptoms and how AF 
has impacted their emotional state and daily activities. This inventory was developed at 
Barts and has been validated by Sarah Horan (unpublished PhD thesis).  
 
 
16.4 
Medicinal product  
 
• Heparin given as per local AF ablation protocol 
 
16.5 
Antiarrhythmic drugs 
 
Physicians will be encouraged to use anti-arrhythmic drugs in the periprocedural period, 
such as Amiodarone 200mg tds in a reducing dose commencing at least 2 weeks prior 
to index procedure. Choice of antiarrhythmic medication will be at the discretion of the 
patient’s physician and will be recorded on the CRF. Participating centres will be 
encouraged to follow local centre periprocedural guidelines for antiarrhythmic 
medication for AF ablation for all patients 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
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17. Safety reporting  
 
17.1 
Adverse Events (AEs) 
 
An AE is any untoward medical occurrence in a participant to whom an intervention has 
been administered, including occurrences which are not necessarily caused by or 
related to that intervention. An AE can therefore be any unfavourable or unintended 
sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with study activities. 
 
 
17.2 Adverse Reaction (ARs)  
 
An AR is any untoward and unintended response in a participant to an intervention.  All 
adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to the intervention qualify as adverse reactions. The 
expression ‘reasonable causal relationship’ means in general that there is evidence or 
an argument to suggest a causal relationship. 
 
 
17.3 
Notification and reporting of Adverse Events and Reactions 
 
If the AE is not defined as serious, the AE will be recorded in the study documents and 
the participant followed up by the research team. The AE will be documented in the 
participants’ source documents, the Case Report Form (CRF), and, where appropriate, 
medical records. 
 
The following events will be considered and reported as Adverse Events, and not 
serious adverse events, as they are expected as known complications of procedures: 
• 
Phrenic nerve damage 
• 
Tampanade or pericardial effusion 
• 
Haematoma 
• 
Skin Burns 
• 
Chest pain 
• 
Groin vascular complications. 
 
The period for adverse events reporting will be from the signing of consent until the end 
of study visit at 12 month follow-up. 
 
 
17.4 
Serious Adverse Events (SAEs) or reactions 
 
A serious adverse event (SAE) is defined as an untoward occurrence that: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires hospitalisation or prolongation of existing hospitalisation, 
• 
Results in persistent or significant disability or incapacity, 
• 
Consists of a congenital anomaly or birth defect, or 
• 
Is otherwise considered medically significant by the investigator. 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 32 of 37 
 
SARs will be reported to the REC where in the opinion of the Chief Investigator the 
event was serious and: 
• 
Related (it may have resulted from administration of any of the research 
interventions), and 
• 
Unexpected (the type of event is not listed in the protocol or other Reference 
Safety Information as an expected occurrence). 
 
 
17.5 
Notification and reporting of Serious Adverse Events  
 
Serious Adverse Events (SAEs) that are considered to be ‘related’ and ‘unexpected’ will 
be reported to the sponsor within 24 hours of learning of the event, and to the REC 
within 15 days in line with the required timeframe.  
 
The treatment code for the participant will be broken when reporting an ‘unexpected 
and related’ SAE. The unblinding of individual participants by the PI / CI in the course of 
a clinical study will only be performed if necessary for the safety of the study participant.  
 
 
17.6 
Urgent Safety Measures 
 
The CI will take urgent safety measures if necessary to ensure the safety and protection 
of the clinical study participant from immediate hazards to their health and safety. The 
measures will be taken immediately. The approval of the REC prior to implementing 
urgent safety measures is not required. However the CI will inform the sponsor and 
Research Ethics Committee (via telephone) of this event immediately.  
 
The CI will inform the REC in writing within 3 days, in the form of a substantial 
amendment. The sponsor (Joint Research Management Office (JRMO)) will be sent a 
copy of the correspondence with regards to this matter.  
 
 
17.7 
Annual Safety Reporting 
 
The CI will send the Annual Progress Report to the REC using the HRA template (the 
anniversary date is the date on the REC “favourable opinion” letter) and to the sponsor.  
 
 
17.8 
Overview of the Safety Reporting responsibilities 
 
The CI is the medical assessor on behalf on the sponsor and will review all events 
reported. The CI will ensure that safety monitoring and reporting is conducted in 
accordance with the sponsor’s requirements.  
 
The CVCTU team will maintain safety reporting responsibilities on behalf of the 
Sponsor, following the JRMO SOP 26b – Safety reporting for non-CTIMPs and using 
the SAE template to capture SAEs electronically via REDCap, and the Investigator 
teams will report all SAEs to the CVCTU, and the CVCTU will ensure adherence to the 
Sponsor safety reporting requirements. 
 
For the purposes of this protocol, a ‘serious breach’, is a breach which is likely to effect 
to a significant degree:  

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 33 of 37 
  The safety or physical or mental integrity of the participants of the trials; or  
  The scientific value of the trial.  
 
The CI is responsible for reporting any serious breaches to the sponsor (JRMO) within 
24 hours. The sponsor will notify and report to REC within 7 working days of becoming 
aware of the serious breach.  
 
These non-compliances may be captured from a variety of different sources including 
monitoring visits, CRFs, communications and updates. The CVCTU will maintain a log 
of the non-compliances identified and reported to them, and these will be maintained on 
a site Deviation log. The CVCTU will action a timeframe in which they need to be dealt 
with, and each action will be given a different timeframe dependent on the severity. If 
the actions are not dealt with accordingly, they will be escalated to the Sponsor, who 
will confirm an appropriate action, which may include an on-site audit.  
 
 
 
18. Monitoring and auditing 
 
The sponsor or delegate retains the right to audit any study, study site, or central 
facility. Any part of the study may be audited by the funders, where applicable. 
 
The trial will be monitored with reference to the Barts CTU SOP Monitoring. A trial 
specific monitoring plan will be developed by the CVCTU and determined by a formal 
risk assessment. The Study team will be initiated and monitored in accordance with the 
sponsor SOPs led by the Barts CVCTU, who will provide overall study management. A 
CVCTU monitor will conduct on-site monitoring visits, and be the primary contact for the 
research team in relation to study queries, including those related to source data and 
data capture, safety reporting, and participant recruitment and follow-up activities. 
 
The CVCTU Project Manager is responsible for creating the trial specific monitoring 
plan, to ensure adequate monitoring of the trial and that both on-site and central 
monitoring is conducted to verify that source data is accurate, reliable and complete. 
The CVCTU will have its own audit schedule for trials on their portfolio. A study may be 
identified for audit by any method listed below:  
1.  A project may be identified via the risk assessment process. 
2.  An individual investigator or department may request an audit. 
3.  A project may be identified via an allegation of research misconduct or fraud or a 
suspected breach of regulations. 
4.  Projects may be selected at random. The Department of Health states that Trusts 
should be auditing a minimum of 10% of all research projects. 
5.  Projects may be randomly selected for audit by an external organisation. 
 
Internal audits may be conducted by a sponsor’s or funder representative. 
 
 
19. Trial committees 
 
Trial Steering Committee  
 
A Trial Steering Committee (TSC) will be established to review and monitor all aspects 
of the conduct and progress of the trial, ensuring that the protocol is adhered to, 
appropriate action is taken to safeguard the twenty participants and the quality of the 

 
 
 
ORBITA-AF Protocol V1.0  12 DECEMBER 2018    
Page 34 of 37 
trial maintained. The TSC will be composed of two independent experts in the field of 
electrophysiology with experience in clinical trials along with the investigators and the 
trial manager. A medical statistician will join the TSC to provide expertise in clinical 
trials and one lay members of the committee will be appointed. This committee would 
meet before patient recruitment and then quarterly to assess safety, feasibility or any 
other arising problems (e.g. with recruitment) and their recommendations will be 
followed. 
 
The TSC will meet on a monthly basis, and will include the following: 
o An independent/external Chair 
o One independent/external collaborator who will participate in the larger trial 
o CI/PI 
o Statistician 
o Trial Manager  
o Patient representative 
 
Data Monitoring and Safety Committee 
 
An independent Data and Safety and Monitoring Committee (DSMC) will be formed to 
monitor patient safety as the study progresses. The DSMC has been selected by and 
communicates directly to the study's TSC. There will be an independent chair of this 
committee, an independent member with clinical cardiovascular trials expertise, and 
other members of the trial management group, including the PI, statistician, and trial 
manager will attend open sessions. The DSMC will meet prior to initiation of the clinical 
study, after the recruitment of 4 patients and then at 3 monthly intervals. The DSMB will 
have access to unblinded patient data. If a serious concern with the safety of the 
patients in the trial would arise, the DSMC may recommend early termination of the 
study.  
 
 
 
20. Finance and funding 
 
Funding for the study has been provided by the Barts Charity and with support from 
Medtronic, who are providing the REVEAL devices for the trial. 
 
 
 
21. Indemnity 
 
The NHS indemnity scheme will apply. It provides cover for the design, management, 
and conduct of the study. 
 
 
22. Dissemination of research findings 
 
All relevant data from this study will be submitted to peer review journals for publication 
following the termination of the study in line with sponsor and trust publication policy. 
 
23. References 
 
 

 
 
 
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