Radiofrequency Power, Lesion Size Index and Oesophageal Temperature Alerts During Atrial Fibrillation Ablation: A Pilot Study
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Oxford University Hospitals NHS Trust

PiLOT-AF Study Protocol  
 
  Date and version No: 10th March 2016, version 1.2  
 
 
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Study Title: Radiofrequency Power, Lesion size Index and Oesophageal Temperature alerts during Atrial 
Fibrillation ablation: a pilot study 
Internal Reference Number / Short title: PiLOT-AF study  
Ethics Ref:  
Date and Version No: 10th March 2016, version 1.2 
 
Chief Investigator: 
Dr Tim R Betts, Consultant Cardiologist and Electrophysiologist 
Department of Cardiology, John Radcliffe Hospital, Oxford University 
Hospitals NHS Trust, Headley Way Oxford OX3 9DU                                 
Tel: 01865 220256 Fax: 01865 221194 
Investigators:  
Dr Yaver Bashir, Consultant Cardiologist and Electrophysiologist 
Department of Cardiology, John Radcliffe Hospital, Oxford University 
Hospitals NHS Trust, Headley Way Oxford OX3 9DU                                 
Tel: 01865 222044 
Dr Kim Rajappan, Consultant Cardiologist and Electrophysiologist 
Department of Cardiology, John Radcliffe Hospital, Oxford University 
Hospitals NHS Trust, Headley Way Oxford OX3 9DU                                 
Tel: 01865 220454 
Dr Matthew Ginks, Consultant Cardiologist and Electrophysiologist 
Department of Cardiology, John Radcliffe Hospital, Oxford University 
Hospitals NHS Trust, Headley Way Oxford OX3 9DU                                
Tel: 01865 222044 
Dr Milena Leo, Clinical Research Fellow 
Clinical Research Fellows Office, Level 2, Blue Outpatient Area,  John 
Radcliffe Hospital, Oxford University Hospitals NHS Trust, Headley Way 
Oxford OX3 9DU                                                                                                
Tel 01865 220255 
Dr Michala Pedersen 
Locum Acting Consultant Cardiologist and Electrophysiologist  
Clinical Research Fellows Office, Level 2, Blue Outpatient Area,  John 
Radcliffe Hospital, Oxford University Hospitals NHS Trust, Headley Way 
Oxford OX3 9DU                                                                                                
Tel 01865 220255 
Sponsor:  
Oxford University Hospitals NHS Trust  
Funder: 
St Jude Medical, Dot Medical Ltd, Oxfordshire Health Services Research 
Committee (OHSRC) 

PiLOT-AF Study Protocol  
 
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Chief Investigator Signature:   
 
Potential conflicts of interest to declare: none. 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 

PiLOT-AF Study Protocol  
 
  Date and version No: 10th March 2016, version 1.2  
 
 
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TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................................................... 5 
2. 
ABBREVIATIONS .......................................................................................................................................... 6 
3. 
BACKGROUND AND RATIONALE ................................................................................................................. 6 
3.1 Pulmonary Vein Isolation (PVI): rationale and pitfalls ............................................................................ 6 
3.2 Radiofrequency (RF) ablation: principles and determinants of lesion formation ................................... 7 
3.3 Oesophageal damage and atrio-oesophageal fistula after AF ablation .................................................. 8 
3.4 Research questions ................................................................................................................................. 9 
4. 
OBJECTIVES AND OUTCOME MEASURES .................................................................................................... 9 
5. 
STUDY DESIGN .......................................................................................................................................... 10 
6. 
STUDY RISKS AND BENEFITS ..................................................................................................................... 11 
6.1. 
Study risks ......................................................................................................................................... 11 
6.2. Study benefits ....................................................................................................................................... 12 
7. 
PARTICIPANT IDENTIFICATION ................................................................................................................. 12 
7.1. 
Study Participants ............................................................................................................................. 12 
7.2. 
Inclusion Criteria ............................................................................................................................... 12 
7.3. 
Exclusion Criteria .............................................................................................................................. 12 
8. 
STUDY PROCEDURES ................................................................................................................................ 13 
8.1. 
Recruitment ...................................................................................................................................... 13 
8.2. 
Baseline visit ..................................................................................................................................... 13 
8.2.1. 
Informed Consent ......................................................................................................................... 13 
8.2.2. 
Screening and Eligibility Assessment ............................................................................................ 14 
8.2.3. 
Randomisation .............................................................................................................................. 14 
8.3. 
AF ablation ........................................................................................................................................ 14 
8.4. 
Pre-discharge review ........................................................................................................................ 15 
8.5. 
Arrhythmia Clinic visit at 3-4 months ............................................................................................... 15 
8.6. 
Telephone follow-ups 1 (at 3 months) and 2 (at 6 months) ............................................................ 15 
8.7. 
Discontinuation/Withdrawal of Participants from Study ................................................................. 15 
8.8. 
Definition of End of Study ................................................................................................................ 16 
9. 
INTERVENTION: AF ablation ..................................................................................................................... 16 
10. 
SAFETY REPORTING .............................................................................................................................. 17 
10.1. 
Definition of Serious Adverse Events ........................................................................................... 17 
10.2. 
Reporting Procedures for Serious Adverse Events ....................................................................... 18 
11. 
STATISTICS AND ANALYSIS .................................................................................................................... 18 

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11.1. 
The Number of Participants ......................................................................................................... 18 
11.2. 
Description of Statistical Methods ............................................................................................... 18 
11.3. 
Analysis of Outcome Measures .................................................................................................... 18 
12. 
DATA MANAGEMENT ........................................................................................................................... 19 
12.1. 
Access to Data .............................................................................................................................. 19 
12.2. 
Data Recording and Record Keeping ............................................................................................ 19 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................................... 19 
13.1. 
Declaration of Helsinki.................................................................................................................. 19 
13.2. 
Guidelines for Good Clinical Practice ........................................................................................... 19 
13.3. 
Approvals ...................................................................................................................................... 19 
13.4. 
Reporting ...................................................................................................................................... 20 
13.5. 
Participant Confidentiality ............................................................................................................ 20 
13.6. 
Expenses and Benefits .................................................................................................................. 20 
14. 
FINANCE AND INSURANCE ................................................................................................................... 20 
14.1. 
Funding ......................................................................................................................................... 20 
14.2. 
Insurance ...................................................................................................................................... 20 
15. 
PUBLICATION POLICY ............................................................................................................................ 21 
16. 
REFERENCES ......................................................................................................................................... 22 
APPENDIX B:  SCHEDULE OF TIMING OF STUDY APPOINTMENTS AND STUDY PROCEDURES ......................... 26 
17. 
APPENDIX C:  AMENDMENT HISTORY .................................................................................................. 27 
 
 
 

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1. SYNOPSIS 
 
Study Title 
Radiofrequency Power, Lesion Size Index and Oesophageal 
Temperature alerts during Atrial Fibrillation ablation: a pilot study  
Internal ref. no. / short title 
PiLOT-AF study 
Study Design 
Prospective, randomized, single centre observational clinical investigation  
Study Participants 
Patients admitted for elective radiofrequency (RF) ablation for paroxysmal 
or persistent atrial fibrillation (AF) 
Planned Sample Size 
80 patients (pilot study) 
Planned Follow-up duration 
6 months 
Planned Study Period 
15 months 
 
Objectives 
Outcome Measures 
Primary 
 
Assessment of the risk of 
oesophageal damage associated 
with radiofrequency (RF) ablation on 
the left atrial (LA) posterior wall 
when using different power settings   
Luminal oesophageal temperature 
rises > 39◦C during RF application 
on the LA posterior wall as 
recorded by an oesophageal 
temperature probe  
Secondary 
 
Comparison of oesophageal 
complications with the different RF 
settings on LA posterior wall  
 
Comparison of acute and short-term 
procedure success using different RF 
settings on LA posterior wall as 
marker of lesion transmurality and 
durability 
Symptoms of oesophageal injury 
during 6 months follow-up 
 
 
Rate of first-pass pulmonary vein 
isolation (PVI), rate of acute 
pulmonary vein reconnection 
(PVR), total procedure time and RF 
time of the index ablation 
procedure 
AF-free survival during 6 months 
follow-up  
 
Tertiary 
Comparison of rate of procedural 
complications using the different RF 
settings  
pericardial effusion, TIA/stroke, 
phrenic nerve injury, pulmonary 
vein stenosis, open-heart surgery, 
death 
 
 
 
 
 

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2. ABBREVIATIONS 
 
ACT 
Activated Clotting Time 
AF 
Atrial fibrillation 
CF 
Contact Force 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTRG 
Clinical Trials & Research Governance, University of Oxford 
GCP 
Good Clinical Practice 
FTI 
Force Time Integral 
GP 
General Practitioner 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
LA 
Left atrium 
LSI 
Lesion Size Index 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
OXTREC 
Oxford Tropical Research Ethics Committee 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
PVs 
Pulmonary Veins 
PVI 
Pulmonary Vein Isolation 
PVR 
Pulmonary Vein Reconnection 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
RF 
Radiofrequency 
SOP 
Standard Operating Procedure 
TOE 
Trans-Oesophageal Echocardiogram 
 
3. BACKGROUND AND RATIONALE  
3.1 Pulmonary Vein Isolation (PVI): rationale and pitfalls  
Catheter ablation is a well-recognized treatment, with a class I indication, for symptomatic and drug-
refractory atrial fibrillation (AF) (1-3). The current technique focuses on the elimination of mechanisms 
involved in the initiation and maintenance of AF. In this scenario, the pulmonary veins (PVs) are considered 

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to play a major role as the site of origin of ectopic atrial activity initiating and maintaining AF. Therefore, 
ablation of myocardium at the junction between the PVs and the left atrium (LA), leading to electrical 
isolation of the PVs, is currently the cornerstone of the treatment of both paroxysmal and persistent AF (4, 
5). Unfortunately, although pulmonary vein isolation (PVI) can be achieved acutely in up to 100% of cases, 
recovery of electrical conduction of one or more arrhythmogenic PVs is quite common, both acutely and 
chronically. Acute pulmonary vein reconnection (PVR) is observed before the end of the ablation procedure 
in up to 50% of cases (6). Even if PVI is reached and maintained until the end of the procedure, chronic PVR 
is found in up to 80% of redo procedures performed for arrhythmia recurrence (7). As a consequence of 
reconnection rate, AF or associated atypical flutter recurrences lead to repeat AF ablation procedures in 30-
50% of patients (8).   
Although the pathological basis of PV reconnection is not yet known, it is suspected to result from 
deficiencies of the index ablation procedure, specifically gaps in the initial line of ablation, and/or failure of 
initial lesions to deliver permanent, transmural necrosis and permanent scar. Of note, recent histological 
data have correlated partial thickness ablation lesions with chronic and persistent PV conduction (9).   
3.2 Radiofrequency (RF) ablation: principles and determinants of lesion formation  
For radiofrequency (RF) energy delivered through an irrigated-tip ablation catheter, the reasons for lesion 
failure are multifactorial.  
RF energy generates an ablation lesion through tissue heating. The transformation of electromagnetic 
energy into thermal energy, as electrical current passes through a resistive medium, is responsible for direct 
resistive heating in the narrow rim of tissue in close contact with the catheter electrode (2 to 3 mm). 
However, because direct resistive heating of the tissue decreases proportionally with the distance from the 
electrode to the fourth power, heating of deeper tissue layers occurs passively through heat conduction. 
While resistive heating is a fast process, taking place in a few seconds, conductive heating is a much slower 
process, requiring up to 30 sec (10, 11).  In this process, delivered power, application time and catheter tip-
tissue contact pressure all play a role (12, 13). Higher power delivery increases the source temperature and 
the radius of the heat source (although it hardly exceeds 2-3 mm regardless of the delivered power), 
thereby increasing lesion size in two ways. Time is required for thermal conduction to deeper tissue layers. 
Greater electrode-tissue contact pressure increases lesion size by improving electrical coupling with the 
tissue, increasing the electrode surface area in contact with the tissue, and reducing the shunting of current 
to the blood pool.   
It has been demonstrated that the maximum lesion size is achieved after 40 to 60 seconds of RF delivery 
and longer RF deliveries increase the risk of complications without a substantial benefit in terms of lesion 
formation (36). 
Contact force (CF)-sensing ablation catheters, able to monitor constant, real-time contact force during 
mapping and ablation, are now available for clinical use (14-16). Moreover, formulas combining contact 
force, RF power and application time such as Force Time Integral (FTI) (17) or Lesion Size Index (LSI) have 
been developed in order to predict the lesion size and depth and to guide the RF ablation.  In particular, LSI 
is a non-linear function that combines power, CF and ablation duration; it has been found to be especially 
effective in calculating gap formation and estimating lesion quality (18).  

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Based on clinical studies (19-24), the current CF recommendations to achieve transmural lesions and 
durable PVI are: minimum CF > 10 g with target CF of 20 g, target FTI > 400 gs, suggested LSI ≥ 6 on the LA 
anterior wall, ≥ 5 on the LA posterior wall and ≥ 5.5 on the LA roof and floor.  
Among the different parameters (RF power, CF, FTI, LSI), LSI seems to be the best predictor of lesion size 
and gap formation at 3 months post-PVI (23).  
3.3 Oesophageal damage and atrio-oesophageal fistula after AF ablation 
Unfortunately, deeper lesions mean a higher risk of overheating and damage of extra-cardiac structures 
close to the LA, in particular the oesophagus when ablating on the LA posterior wall. Heating of the 
connective tissue layer between the LA and oesophagus, containing oesophageal vascular structures, and of 
the oesophageal wall itself, are thought to contribute to the genesis of atrio-oesophageal fistulae, a rare but 
fatal complication of AF ablation (25).   
In view of the variable position of the oesophagus relative to LA posterior wall, its positional changes over 
time and of the variable thickness of the posterior LA wall, fat pad and connective tissue layer between the 
LA and oesophagus, the prevention of oesophageal damage during AF ablation is quite challenging (26-29).   
Lower RF powers and shorter application times are usually used on the LA posterior wall but this is a 
completely empirical approach which has not been proved to be effective in preventing oesophageal 
damage. Continuous luminal oesophageal temperature monitoring during the AF procedure is a suggested 
strategy to prevent oesophageal damage related to AF ablation. The rationale behind this strategy is that 
luminal oesophageal temperature is a surrogate marker of the mural temperature and therefore it can 
predict and avoid tissue damage. Observational studies employing real-time luminal oesophageal 
temperature measurements during LA catheter ablation have shown that lower oesophageal luminal 
temperatures are associated with lower rates of oesophageal ulcerations detected by endoscopy after 
ablation (30-33). To this aim, a temperature probe is inserted nasally or orally and advanced to the level of 
the posterior LA under fluoroscopic guidance where it permits real-time intraluminal oesophageal 
temperature monitoring during the ablation. Moreover, it marks the location of the oesophageal lumen 
that can also be visualized in the electro-anatomical map to evaluate the distance of the ablation catheter 
tip from it. Different oesophageal temperature probes are currently available: single-sensor ones, linear 
multi-sensor and 2-dimensional sinusoidal multi-sensor ones. The advantage of the multi-sensor probes, 
and especially of the sinusoidal one, is that their design allows for a greater area of temperature monitoring 
and their position does not require adjustments to be in close vicinity of the ablation catheter tip during RF 
delivery (34). 
When using an oesophageal temperature probe-guided ablation strategy, RF delivery on the LA posterior 
wall is promptly terminated in case of any oesophageal temperature rises >39°C and power is reduced in 
contiguous sites.  However, the big challenge of this approach is in not knowing how much delivered RF 
energy is both simultaneously “safe” and “effective”.  
In our experience, oesophageal temperature alerts are very common during PV encirclement on LA 
posterior wall, occurring in the majority of procedures and, regardless of the power used, they tend to 
occur before the achievement of the suggested LSI of 5. Moreover, lower RF powers are generally used on 
LA posterior wall but, in view of the strict relation between power and application time in determination of 

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lesion size, the adoption of lower RF powers usually implies longer RF applications in order to reach the 
suggested LSI and maximize the chance to achieve a durable PVI.  
Interestingly, the relationship between RF energy settings and oesophageal temperature alerts is anything 
but clearly defined (35). Of note, the oesophageal injury during LA ablation is attributed to conductive heat 
transfer from the ablation site, a time-dependant process.  
 
3.4 Research questions 
On these premises, our research questions are:  
- is it better to use higher RF powers for shorter times, than lower RF powers for longer times, to reduce the 
risk of oesophagus overheating and oesophageal temperature alerts? 
- is the suggested LSI value of 5 on the LA posterior wall feasible or thwarted by frequent occurrence of 
temperature alerts leading to premature termination of RF delivery, regardless of maximum power? 
- what is the impact of the different RF energy settings on PVI, acute pulmonary vein reconnection (PVR) 
and short-term clinical success of the AF procedure? 
- which LSI value and RF power should be used during RF ablation on the LA posterior wall in order to 
achieve the best compromise between safety from oesophageal damage and lesion transmurality and 
durability?  
To these aims, the PiLOT-AF study aims to test different combinations of RF power and LSI during PV 
encirclement on LA posterior wall.  
The rate of oesophageal alerts will be collected and compared for each procedure modality. The rate of first 
pass PVI and acute PVR (related to breakthrough signals on LA posterior wall), the procedure duration and 
RF ablation time will be also collected as clinical indicators of lesion transmurality and acute procedure 
success.  The freedom from AF at 6 months follow-up will be used as clinical indicators of lesion durability 
and short-term procedure success. The occurrence of any oesophageal symptoms at follow-up will be 
recorded as surrogate clinical indicators of oesophageal damage. All other procedural complications will be 
also recorded as safety outcomes.  
No data are currently available on this topic. Therefore, this study has been designed as pilot study for 
power analysis and sample size calculation of a further main study. 
This pilot study will hopefully give us some insights about the best combination of RF power, application 
time and target LSI to use during AF ablation on the LA posterior wall in order to achieve durable PVI with 
minimal risks of oesophageal damage.  
 
4. OBJECTIVES AND OUTCOME MEASURES 
 

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Objectives 
Outcome Measures  
Timepoint(s) of 
evaluation of this 
outcome measure (if 
applicable) 
Primary Objective 
 
 
To compare the risk of 
oesophageal damage associated 
with different RF settings during 
AF ablation on the LA posterior 
wall  
Rate of oesophageal temperature alerts 
(defined as oesophageal temperature rise 
> 39◦C) during RF ablation on the LA 
posterior wall  
Index procedure 
Secondary Objectives 
 
 
1. To compare the acute success 
of the index AF ablation using 
different RF settings on the LA 
posterior wall 
1. Rate of first-pass PVI, rate of acute PVR 
related to breakthrough signals on the LA 
posterior wall, total procedure time and RF 
ablation time  
1. Index procedure 
2. To compare the short-term 
success of the index AF ablation 
using different RF settings on the 
LA posterior wall 
 
3. To compare the rate of 
oesophageal injury related to 
different RF settings on the LA 
posterior wall during the index AF 
ablation  
2. Freedom from atrial fibrillation  
 
 
 
3. Rate of oesophageal symptoms (difficult 
or painful swallowing, heartburn, acid 
reflux, sore throat, hoarseness, cough, 
nausea, vomiting, non-cardiac chest pain) 
2. During the follow-
up period (6 months) 
 
 
3. During the follow-
up period (6 months) 
Tertiary objectives 
 
 
To evaluate the rate of 
complications associated with the 
different RF settings 
Pericardial effusion, TIA/stroke, phrenic 
nerve injury, pulmonary vein stenosis, 
open-heart surgery, death 
Index procedure 
 
 
5. STUDY DESIGN 
The PiLOT-AF study is a prospective single-centre randomized observational study aiming at comparing 
different RF settings during AF ablation on the LA posterior wall, in terms of oesophageal heating, acute and 
long-term procedure success and procedural complications. 

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Patients, age 18-80, scheduled for their first RF ablation because of a history of symptomatic and drug-
refractory paroxysmal or persistent atrial fibrillation, will be considered for inclusion in the study.  
Potential subjects will initially be approached 4-6 weeks before their ablation procedure, in order to give 
the patients enough time to consider the information, to ask questions to the Investigator, their GP or other 
independent parties to decide whether they wish to participate in the study or not.  
For those interested in participation, a baseline assessment will be arranged to coincide with their standard 
pre-admission visit, for informed consent, screening and eligibility assessment and randomization.  
All AF ablation procedures will be performed in a standard fashion, under general anaesthesia and with 
continuous oesophageal temperature monitoring using a sinusoidal multi-sensor oesophageal temperature 
probe (CIRCAtemp). After LA geometry reconstruction using 3-dimensional electroanatomical mapping 
EnSite Velocity and a multipolar circular mapping catheter St Jude Medical Optima, a CF ablation catheter 
Endosense Tacticath through a deflectable sheath St Jude Medical Agilis will be used for PVI. Standardized 
RF settings will be used during ablation on the LA anterior wall as current practice in our centre. Different 
RF settings will be used on the LA posterior wall, according to randomization group. Duration of RF delivery 
on the LA posterior wall will be dictated by achievement of target LSI or oesophageal temperature rise > 
39◦C during ablation. PVI will be achieved and confirmed after 30 minutes waiting time. In case of acute PV 
reconnection, ablation at sites of breakthrough signals will be performed in order to achieve durable PVI. 
The occurrence of acute PV reconnection with sites of breakthrough signals on the LA posterior wall will be 
recorded for each procedure. The total procedure and RF ablation times will be also collected.  
After the ablation, before discharge the symptoms status and heart rhythm will be assessed and the patient 
will be instructed to commence a symptoms diary. Telephone follow-ups will be then performed at 3 and 6 
months to assess current symptom status. Standard care follow-up Arrhythmia Clinic visits will be also 
performed 3-4 months after the ablation procedure. Ad hoc visits and/or additional investigations as 
prolonged ECG monitoring will also take place, dictated by arrhythmia symptoms and assessment for 
potential adverse events related to the procedure, in accordance with standard practice.  
The end of the study for each patient will be the date of the 6 months telephone follow-up.  
A flowchart of the study design, indicating the time points and procedures, is shown in Appendix 1.  
 
 
6. STUDY RISKS AND BENEFITS 
6.1. Study risks 
The patients taking part will be undergoing a standard AF ablation on the basis of clinical reasons 
(symptoms and no response to medical therapy). When compared with the ablation protocol currently used 
in our centre, the study ablation protocol differs only for the use of predefined RF powers and target LSI 
values during PV encirclement on LA posterior wall. All proposed values of RF power and LSI have been 
already tested and approved in preclinical and clinical studies. Therefore no additional risks are expected 
from the study procedure.  

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Standard risks associated with an AF ablation procedure in our centre:  
- bruising in the groin, mild chest discomfort, a sore throat and palpitations, which are usually self-limiting, 
occur in 1 in 10-20 people  
- femoral vascular injury requiring a minor surgical repair occurs in 1 in 200 people; 
- cardiac perforation requiring a drain at the time of the operation occurs in 1 in 50-100 people;  
- pulmonary vein stenosis requiring treatment is 1 in 500;  
- TIA or stroke is approximately 1 in 200 people;  
- needing urgent open-heart surgery is 1 in 500 people;  
- fatal complication is estimated to be 1 in 1000 people; 
- cancer secondary to fluoroscopy exposure during the AF ablation is negligible considering the average low 
radiation dose and the short fluoroscopy time used. 
6.2. Study benefits 
The patient could get direct benefit from the study participation in terms of reduction of oesophageal 
temperature alerts during the procedure and more durable PVI, translating into freedom from AF and no 
need for redo procedure.   
The main benefits will be for future patients if the best combination of RF power and LSI is found for 
ablation on LA posterior wall. 
7. PARTICIPANT IDENTIFICATION 
7.1. Study Participants 
Patients aged 18-80 years old, scheduled for elective AF ablation in view of a history of symptomatic and 
drug-refractory AF.   
7.2. Inclusion Criteria 
The participant must satisfy the following conditions: 
 
male or female, aged 18 to 80 years; 
 
willing  and able to give informed consent for participation in the study; 
 
history of symptomatic and drug-refractory atrial fibrillation; 
 
planned AF ablation on a clinical basis. 
 
7.3. Exclusion Criteria 

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The participant may not enter the study if ANY of the following apply: 
 
previous AF ablation;  
 
pregnancy, trying for a baby or breast feeding; 
 
oesophageal obstruction (mass, stricture), diverticulum or varices, tracheo-oesophageal fistula or 
any other oesophageal conditions prohibiting the use of oesophageal temperature probe for 
continuous luminal temperature monitoring;  
 
any other significant disease or disorder which, in the opinion of the investigator, may either put 
the participants at risk because of participation in the study, or may influence the result of the 
study, or the participant’s ability to participate in the study. 
 
 
8. STUDY PROCEDURES 
8.1. Recruitment 
Potential participants will first be approached 4-6 weeks before the AF procedure. Outpatient clinic letters 
of patients placed on the waiting list for catheter ablation of AF by the OUH NHS Trust Cardiac Rhythm 
Management team will be screened by a member of the research team to assess suitability for inclusion in 
the study.  A letter of invitation, a patient information leaflet and a consent form will be given to potential 
participants at their routine clinic visits or sent by post at the time their procedure date is determined 
(usually 6 weeks in advance). The letter will contain a reply slip which patients can use to express their 
interest in the study and request more information if they wish. The participant will be allowed time to 
consider the information, and the opportunity to ask questions to the Investigator, their GP or other 
independent parties to decide whether they will participate in the study.  
Once patients have had time to consider the information (and discuss with relatives, friends and their GP if 
they wish), they will be contacted by an investigator who will ask if they wish to discuss the study further. If 
they wish to take part, they will be approached at their pre-admission visit before the procedure (1-2 weeks 
before the AF ablation) for a baseline visit including informed consent, screening and eligibility assessment 
and randomization. 
8.2. Baseline visit 
8.2.1. Informed Consent 
Informed consent will be obtained by a qualified and experienced investigator who is familiar with the study 
protocol and procedures. This may be the chief investigator, a principal investigator, the research fellow or 
a research nurse. The list of eligible individuals will be specified in the delegation log.  
Written versions of the Participant Information and Informed Consent will be presented to the participants 
detailing no less than: the exact nature of the study; what it will involve for the participant; the implications 
and constraints of the study and the benefits and  risks involved in taking part. It will be clearly stated that 

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the participant is free to withdraw from the study at any time without giving a reason or any prejudice to 
future care and rights.  
Written Informed Consent will then be obtained by means of participant dated signature and dated 
signature of the person who presented and obtained the Informed Consent.  A copy of the signed consent 
form will be given to the participants. The original signed form will be retained at the study site. The 
participant must personally sign and date the latest approved version of the informed consent form before 
any study specific procedures are performed. 
 
8.2.2. Screening and Eligibility Assessment 
It will include:  
a. demographics; 
b. exclusion of pregnancy or breast feeding in case of child-bearing age female; 
c. detailed collection of any relevant medical history, but especially concerning AF, heart (including 
left atrial size and left ventricular function on most recent echocardiogram if any) or oesophageal 
diseases; 
d. list of current medications and antiarrhythmic drugs previously taken;  
e. current heart rhythm on 12-lead ECG.   
8.2.3. Randomisation       
A block randomization, with blocks of size four, type 1234, will be used to assign each patient to one of the 
following four treatment arms:  
 Group 1: 20 W RF power and target LSI = 4 on LA posterior wall; 
 Group 2: 40 W RF power and target LSI = 4 on LA posterior wall; 
 Group 3: 20 W RF power and target LSI = 5 on LA posterior wall;  
 Group 4: 40 W RF power and target LSI = 5 on LA posterior wall.  
Briefly, the study population will be divided into 4 blocks of 20 patients. Within each block, every 
patient will be randomly assigned to 1 of the 4 treatment arms by using sealed envelopes. At the end of 
each block of 20 patients, there will be 5 patients enrolled in each of the 4 treatment arms. At the 
baseline visit, following consent, the study nurse or doctor will telephone the Research Office and ask 
the administrator to open a sealed envelope from the current block of 20 and reveal the allocated 
treatment arm. The treatment will be unblinded to the investigator and blinded to the patient. 
 
8.3. AF ablation 
The patient will be admitted to hospital on the morning of the procedure or on the night before the 
procedure, as per local SOP’s.  Apart from the RF settings on the LA posterior wall that will be dictated by 
the study randomization group, the AF ablation will be conducted in a completely standard fashion. After 
the procedure, the patient will be kept in hospital overnight and monitored. 

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The procedure details are described in the intervention section.  
8.4. Pre-discharge review  
As part of standard care, each patient will be reviewed the day after the ablation procedure, before 
discharge. The current symptoms status and occurrence of any procedural complications will be 
investigated and an ECG will be performed to check the heart rhythm. As part of the research study, the 
patient will be advised to commence a symptom diary where to record occurrence of palpitations and/or 
any other cardiovascular symptoms as well as oesophageal symptoms (difficult or painful swallowing, 
heartburn, acid reflux, sore throat, hoarseness, cough, nausea, vomiting, non-cardiac chest pain). 
8.5. Arrhythmia Clinic visit at 3-4 months 
As part of standard care, each patient will be reviewed in the Arrhythmia Clinic 3-4 months after the 
ablation to assess the current symptoms status and check the heart rhythm on ECG. In the case of 
recurrence of AF, the decision to restart an antiarrhythmic drug and/or to plan a redo procedure will be left 
to the clinician involved in the care of the patient. Moreover, in accordance with usual practice, additional 
investigations as prolonged ECG monitoring will also take place dictated by arrhythmia symptoms and 
assessment for potential adverse events related to the procedure. 
 
 
8.6. Telephone follow-ups 1 (at 3 months) and 2 (at 6 months)  
As part of the research study, telephone follow-ups will be performed 3 and 6 months after the procedure 
to assess the current symptoms status and collect information about symptoms recorded in the diary. The 
patient’s existing clinical care team will be informed about occurrence of palpitations and any other 
cardiovascular or oesophageal symptoms and the decision to carry any additional investigations to 
investigate will be left to them.  
8.7. Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time.  In addition, the Investigator may 
discontinue a participant from the study at any time if the Investigator considers it necessary for any reason 
including: 
 
Pregnancy 
 
Ineligibility (either arising during the study or retrospectively having been overlooked at screening) 
 
Significant protocol deviation 
 
Significant non-compliance with study requirements 
 
Withdrawal of Consent 
 
Loss to follow up 
No specific procedures or observations will be required in case of discontinuation/withdrawal of 
participants from study rather than standard medical care.  

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The reason for withdrawal will be recorded in the CRF. 
In case of withdrawal from the study in an early stage (before the intervention), the patient data will be 
excluded from the analysis and a new participant will be enrolled.  
In case of withdrawal from the study during the follow-up period, neither exclusion of the data of that 
participant from analysis nor replacement with a new participant will be required.  
8.8. Definition of End of Study 
The end of study will be the date of the last 6-month telephone follow-up. 
 
9. INTERVENTION: AF ablation 
As current practice in our centre, all AF ablations will be performed under general anaesthesia and on 
uninterrupted therapeutic anticoagulation with warfarin (target INR 2-3 in the last 3 weeks at least) or one 
of the new non-Vitamin K anticoagulant drugs. A heparin infusion will also be administered during the 
procedure, with target Activated Clotting Time (ACT) values of 300-350 sec. Fluoroscopy and tri-dimensional 
electroanatomical mapping will be used by the operator, as usual, as anatomical guide during the 
procedure. 
The procedure critical steps can be detailed as follow: 
- General anaesthesia and TOE. After general anaesthesia and oro-tracheal intubation, a trans-oesophageal 
echocardiogram (TOE) will be performed to rule out the presence of thrombus in the LA appendage.  
- Vascular access, coronary sinus catheter placement and LA access. Venous femoral access will be achieved 
and a deflectable decapolar diagnostic catheter placed to the coronary sinus. One or two atrial trans-septal 
punctures will be performed under TOE-guidance. The choice of the trans-septal kit (needle and sheath) 
and of the number of performed trans-septal punctures will be left to the operator.   
- Luminal oesophageal temperature monitoring. After the trans-septal puncture(s), the TOE probe will be 
taken out. A two-plane sinusoidal oesophageal temperature probe, CIRCA’s S-Cath (CIRCA, Englewood, CO) 
will be placed orally to the oesophagus and advanced to the level of the LA. It will be connected to a 
dedicated CIRCA Temperature Monitor (CIRCA, Englewood, CO), displaying graphically and numerically 
temperature data from all 12 sensors, updated 20 times per second. Any luminal oesophageal temperature 
rise ≥ 39◦C will result in a temperature alert and cessation of RF delivery at that site. 
- LA geometry. The LA geometry will be reconstructed using the EnSite Velocity mapping system (SJ Medical, 
St Paul, MN, USA) and an Optima mapping catheter (SJ Medical, St Paul, MN, USA). 
- LA ablation strategy and technique. The PVs will be encircled in pairs to isolation using an irrigated-tip 
ablation catheter Tacticath Quartz (SJ Medical, St Paul, MN, USA) via an Agilis deflectable sheath. A point-
by-point ablation technique will be used, with a minimum CF of 10 g and a target CF of 20 g for each RF 
lesion. As current practice, the circumferential ablation line around the PV pairs will be predefined on the 
electroanatomical LA map, at 1-2 cm from PV ostia with individual adjustments in order to avoid RF delivery 
in close proximity of the oesophageal probe.   

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- RF settings on the LA anterior wall, roof and floor. As current practice in our centre, an RF power of 40 W 
will be used on LA anterior wall, roof and floor. The RF application time will be dictated by the achievement 
of the target FTI and LSI (FTI ≥ 400 gs; LSI ≥ 6 on LA anterior wall and LSI ≥ 5.5 on LA roof and floor).  
- RF settings on the LA posterior wall. Different RF settings will be used during RF ablation on LA posterior 
wall, according to randomization group:  
 Group 1: 20 W RF power, with target LSI = 4; 
 Group 2: 40 W RF power, with target LSI = 4; 
 Group 3: 20 W RF power, with and target LSI = 5;  
 Group 4: 40 W RF power, with target LSI = 5. 
Regardless of the LSI achieved, RF delivery on the LA posterior wall will be promptly terminated in case of 
any oesophageal temperature rise ≥ 39◦C or after 60 seconds of continuous RF delivery. The ablation 
catheter will be then moved to a contiguous lower or higher site on the predefined circumferential ablation 
line.  
- PVI confirmation. Disappearance of PV potentials or dissociated PV potentials in the vein and inability to 
capture the LA during PV pacing will confirm bidirectional block across the PV circumferential ablation line 
and PVI.  
- Waiting time. After a waiting time of 30 min, the PVs will be rechecked in order to confirm the persistence 
of PVI. 
- Acute PVR. In case of acute PVR, additional RF ablation will be performed in correspondence of 
breakthrough signals. The same RF settings of the first PV encirclement will be used.   
- Procedure completion. The procedure will be terminated after achievement of electrical isolation of all 
PVs. A trans-thoracic echocardiogram will be performed at the end of the procedure to rule out the 
presence of pericardial effusion. Protamine will be administered to reverse heparin. 
Apart from the RF settings on LA posterior wall (RF power and target LSI) that will be dictated by the study 
randomization, every other procedure step will be performed according to standard clinical practice. Of 
note, no particular equipment will be used for the research study rather standard clinical equipment. No 
additional fluoroscopy time or procedure time will be added to the standard procedure.  
10. SAFETY REPORTING  
10.1. 
Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
 
results in death 
 
is life-threatening 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
congenital anomaly/birth defect 
 
results in persistent or significant disability/incapacity 

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Other ‘important medical events’ may also be considered serious if they jeopardise the participant or 
require an intervention to prevent one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
10.2. 
Reporting Procedures for Serious Adverse Events 
A serious adverse event (SAE) occurring to a participant should be reported to the REC that gave a 
favourable opinion of the study where in the opinion of the Chief Investigator the event was ‘related’ 
(resulted from administration of any of the research procedures) and ‘unexpected’ in relation to those 
procedures. Reports of related and unexpected SAEs should be submitted within 15 working days of the 
Chief Investigator becoming aware of the event, using the HRA report of serious adverse event form (see 
HRA website). 
 
11. STATISTICS AND ANALYSIS 
11.1. 
The Number of Participants 
The PiLOT-AF study aims to give some insights about the relation among RF power, LSI and incidence of 
oesophageal temperature alerts during AF ablation on the LA posterior wall. In view of the absence of data 
on this topic, it has been designed as pilot study for power analysis and sample size calculation of a further 
main study.  
As suggested before for pilot studies (38), we aim to a final sample size of 12 patients with primary outcome 
data per each treatment group. We know from previous studies that oesophageal temperature alerts occur 
in 55-75% of AF ablations. Therefore, if taking into account also participants who do not experience 
oesophageal temperature alerts during AF ablation, we plan to recruit a total of 80 patients in order to 
achieve primary outcome data in 12 patients per group.  
11.2. 
Description of Statistical Methods 
Comparison of primary, secondary and tertiary outcome measures among different treatment groups will 
be performed at each time point using appropriate statistical testing. In particular, ANOVA tests will be used 
to compare numerical variables and chi-square tests will be used to compare categorical values.  
11.3. 
Analysis of Outcome Measures 
Summary statistics, including means, medians, and variances, will be calculated at each time point and for 
each type of data (e.g. parameters derived from index AF procedure and follow-up visits).  
If patients withdraw from the study we will analyse data already collected, unless the patients request 
otherwise. 

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12. DATA MANAGEMENT 
12.1. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor or host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. 
12.2. 
Data Recording and Record Keeping 
 
The study staff will ensure that the participants’ anonymity is maintained.  
 
NHS code of confidentiality will be followed. 
 
All electronic records will be stored on a NHS server within password-protected user accounts. 
 
Personal data will be anonymised with the use of a study participant number. The study number 
will be correlated with personal data about the patient in one electronic file, which will be 
individually password protected and secured as above. 
 
Paper records will be stored in a locked filing cabinet to which only the research team have access. 
 
The study will comply with the Data Protection Act which requires data to be anonymised as soon 
as it is practical to do so. 
 
Data analysis will be performed by Dr Leo and Dr Betts in the JR hospital. No further data transfer 
will be performed. 
 
After the end of the trial period, participant’s personal data will be stored and accessible for 5 
years.  
 
Similarly, remaining patient data, labelled only with study participant number, will be kept for a 
further period of up to 5 years to allow for full analysis and results publication, as per Trust Policy, 
before being deleted. 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the Declaration 
of Helsinki.  
13.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
13.3. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising material 
will be submitted to an appropriate Research Ethics Committee (REC), and host institution(s) for written 
approval. 

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The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
13.4. 
Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the REC 
Committee, host organisation and Sponsor.  In addition, an End of Study notification and final report will be 
submitted to the same parties. 
13.5. 
Participant Confidentiality 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by initials and a participants ID number on the CRF and any electronic database.  All 
documents will be stored securely and only accessible by study staff and authorised personnel. The study 
will comply with the Data Protection Act, which requires data to be anonymised as soon as it is practical to 
do so. 
13.6. 
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
We intend that the majority of study visits will be performed at the time of routine clinical visits to hospital 
so would not expect that patients will have to make many extra visits to hospital. 
Light refreshments will also be available. 
14. FINANCE AND INSURANCE 
14.1. 
Funding 
The study will be supported by the Cardiac Rhythm Management Unit, which research funds will be used to 
cover additional expenses apart from standard medical care. 
14.2. 
Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If you are harmed 
whilst taking part in a clinical research study as a result of negligence on the part of a member of the study 
team this liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
  

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15. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any 
other publications arising from the study.  Authorship will be determined in accordance with the ICMJE 
guidelines and other contributors will be acknowledged. 
 
 

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16. REFERENCES 
1. 
Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, et al. 2012 HRS/EHRA/ECAS expert 
consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient 
selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research 
trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of 
Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a 
registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society 
(ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association 
(AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed 
by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, 
the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic 
Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm. 2012 
Apr;9(4):632-96 e21. 
2. 
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et al. 2014 AHA/ACC/HRS 
guideline for the management of patients with atrial fibrillation: a report of the American College of 
Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. 
Circulation. 2014 Dec 2;130(23):e199-267. 
3. 
. 2014 Jun. 
4. 
Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, et al. Initiation of atrial fibrillation by ectopic 
beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological 
responses, and effects of radiofrequency ablation. Circulation. 1999 Nov 2;100(18):1879-86. 
5. 
Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of 
atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998 Sep 3;339(10):659-
66. 
6. 
Cheema A, Dong J, Dalal D, Marine JE, Henrikson CA, Spragg D, et al. Incidence and time course of 
early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation. J Cardiovasc 
Electrophysiol. 2007 Apr;18(4):387-91. 
7. 
Cappato R, Negroni S, Pecora D, Bentivegna S, Lupo PP, Carolei A, et al. Prospective assessment of 
late conduction recurrence across radiofrequency lesions producing electrical disconnection at the 
pulmonary vein ostium in patients with atrial fibrillation. Circulation. 2003 Sep 30;108(13):1599-604. 
8. 
Ouyang F, Tilz R, Chun J, Schmidt B, Wissner E, Zerm T, et al. Long-term results of catheter ablation 
in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation. 2010 Dec 7;122(23):2368-77. 
9. 
Kowalski M, Grimes MM, Perez FJ, Kenigsberg DN, Koneru J, Kasirajan V, et al. Histopathologic 
characterization of chronic radiofrequency ablation lesions for pulmonary vein isolation. J Am Coll Cardiol. 
2012 Mar 6;59(10):930-8. 
10. 
Petersen HH, Chen X, Pietersen A, Svendsen JH, Haunso S. Tissue temperatures and lesion size 
during irrigated tip catheter radiofrequency ablation: an in vitro comparison of temperature-controlled 
irrigated tip ablation, power-controlled irrigated tip ablation, and standard temperature-controlled 
ablation. Pacing Clin Electrophysiol. 2000 Jan;23(1):8-17. 
11. 
Huang SKS, Wood MA, Miller Jm. Catheter ablation of cardiac arrhythmias. Expert Consult. 
2010;2nd edition. 
12. 
Haines DE. Determinants of lesion size during radiofrequency catheter ablation: the role of 
electrode-tissue contact pressure and duration of energy delivery. Journal of Cardiovascular 
Electrophysiology. 2008;2(6):509-15. 
13. 
Wittkampf FH, Hauer RN, Robles de Medina EO. Control of radiofrequency lesion size by power 
regulation. Circulation. 1989 Oct;80(4):962-8. 
14. 
Yokoyama K, Nakagawa H, Shah DC, Lambert H, Leo G, Aeby N, et al. Novel contact force sensor 
incorporated in irrigated radiofrequency ablation catheter predicts lesion size and incidence of steam pop 
and thrombus. Circ Arrhythm Electrophysiol. 2008 Dec;1(5):354-62. 
15. 
Perna F, Heist EK, Danik SB, Barrett CD, Ruskin JN, Mansour M. Assessment of catheter tip contact 
force resulting in cardiac perforation in swine atria using force sensing technology. Circ Arrhythm 
Electrophysiol. 2011 Apr;4(2):218-24. 

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16. 
Ikeda A, Nakagawa H, Lambert H, Shah DC, Fonck E, Yulzari A, et al. Relationship between catheter 
contact force and radiofrequency lesion size and incidence of steam pop in the beating canine heart: 
electrogram amplitude, impedance, and electrode temperature are poor predictors of electrode-tissue 
contact force and lesion size. Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1174-80. 
17. 
Shah DC, Lambert H, Nakagawa H, Langenkamp A, Aeby N, Leo G. Area under the real-time contact 
force curve (force-time integral) predicts radiofrequency lesion size in an in vitro contractile model. J 
Cardiovasc Electrophysiol. 2010 Sep;21(9):1038-43. 
18. 
Mansour M. Force sensing ablation catheters: have our hopes been realized. 2014 AF Summit, HRS 
Conference 2014;San Francisco, California(May 7-10, 2014). 
19. 
Kuck KH, Reddy VY, Schmidt B, Natale A, Neuzil P, Saoudi N, et al. A novel radiofrequency ablation 
catheter using contact force sensing: Toccata study. Heart Rhythm. 2012 Jan;9(1):18-23. 
20. 
Reddy VY, Shah D, Kautzner J, Schmidt B, Saoudi N, Herrera C, et al. The relationship between 
contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the 
TOCCATA study. Heart Rhythm. 2012 Nov;9(11):1789-95. 
21. 
Neuzil P, Reddy VY, Kautzner J, Petru J, Wichterle D, Shah D, et al. Electrical reconnection after 
pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I 
study. Circ Arrhythm Electrophysiol. 2013 Apr;6(2):327-33. 
22. 
Kautzner J, Neuzil P, Peickl P. Contact force, FTI and Lesion continuity are critical to improve durable 
PV isolation: EFFICAS 2 results. Heart Rhythm. 2012;9(5S):1-564. 
23. 
Neuzil P, Kuck KH, Nakagawa H. Lesion Size Index for prediction of reconnection risk following RF 
ablation for PVI. Heart Rhythm Society. 2012;Boston(May 9-12, 2012). 
24. 
Mansour M, Shah D, S K. Application of contact force guidelines increases durable isolation after 
pulmonary vein isolation for paroxysmal atrial fibrillation. Heart Rhythm Society. 2013;Denver, 
Colorado(May 8, 2013):abstract P001-133. 
25. 
Ghia KK, Chugh A, Good E, Pelosi F, Jongnarangsin K, Bogun F, et al. A nationwide survey on the 
prevalence of atrioesophageal fistula after left atrial radiofrequency catheter ablation. J Interv Card 
Electrophysiol. 2009 Jan;24(1):33-6. 
26. 
Sanchez-Quintana D, Cabrera JA, Climent V, Farre J, Mendonca MC, Ho SY. Anatomic relations 
between the esophagus and left atrium and relevance for ablation of atrial fibrillation. Circulation. 2005 Sep 
6;112(10):1400-5. 
27. 
Good E, Oral H, Lemola K, Han J, Tamirisa K, Igic P, et al. Movement of the esophagus during left 
atrial catheter ablation for atrial fibrillation. J Am Coll Cardiol. 2005 Dec 6;46(11):2107-10. 
28. 
Ho SY, Sanchez-Quintana D, Cabrera JA, Anderson RH. Anatomy of the left atrium: implications for 
radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 1999 Nov;10(11):1525-33. 
29. 
Platonov PG, Ivanov V, Ho SY, Mitrofanova L. Left atrial posterior wall thickness in patients with and 
without atrial fibrillation: data from 298 consecutive autopsies. J Cardiovasc Electrophysiol. 2008 
Jul;19(7):689-92. 
30. 
Singh SM, d'Avila A, Doshi SK, Brugge WR, Bedford RA, Mela T, et al. Esophageal injury and 
temperature monitoring during atrial fibrillation ablation. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):162-
8. 
31. 
Halm U, Gaspar T, Zachaus M, Sack S, Arya A, Piorkowski C, et al. Thermal esophageal lesions after 
radiofrequency catheter ablation of left atrial arrhythmias. Am J Gastroenterol. 2010 Mar;105(3):551-6. 
32. 
Perzanowski C, Teplitsky L, Hranitzky PM, Bahnson TD. Real-time monitoring of luminal esophageal 
temperature during left atrial radiofrequency catheter ablation for atrial fibrillation: observations about 
esophageal heating during ablation at the pulmonary vein ostia and posterior left atrium. J Cardiovasc 
Electrophysiol. 2006 Feb;17(2):166-70. 
33. 
Sause A, Tutdibi O, Pomsel K, Dinh W, Futh R, Lankisch M, et al. Limiting esophageal temperature in 
radiofrequency ablation of left atrial tachyarrhythmias results in low incidence of thermal esophageal 
lesions. BMC Cardiovasc Disord. 2010;10:52. 
34. 
Tschabrunn CM, Silverstein J, Berzin T, Ellis E, Buxton AE, Josephson ME, et al. Comparison between 
single- and multi-sensor oesophageal temperature probes during atrial fibrillation ablation: thermodynamic 
characteristics. Europace. 2015;Mar 15. 

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35. 
Cummings JE, Schweikert RA, Saliba WI, Burkhardt JD, Brachmann J, Gunther J, et al. Assessment of 
temperature, proximity, and course of the esophagus during radiofrequency ablation within the left atrium. 
Circulation. 2005 Jul 26;112(4):459-64. 
36. Haines DE: Determinants of lesion size during radiofrequency catheter ablation: The role of electrode- 
tissue contact pressure and duration of energy delivery. J Cardiovasc Electrophysiol I991;2:5O9-515.  
37. 
Gupta A, Perera T, Ganesan A, Sullivan T, Lau DH, Roberts-Thomson KC, et al. Complications of 
catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol. 2013;6:1082-8. 
38. 
Moore, Carter, Nietert, Stewart. Recommendations for planning pilot studies in clinical and 
translational research. Clin Transl Sci. 2011;4(5):332-7. 
 
 
 
 

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APPENDIX A:  STUDY FLOW CHART 
 
 
 

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APPENDIX B:  SCHEDULE OF TIMING OF STUDY APPOINTMENTS AND STUDY PROCEDURES 
 
 
Recruit-
ment 
Baseline 
visit 
Study 
intervention 
Pre-
discharge 
review 
Telephone 
f-up 1 
Arrhythmia 
Clinic visit 
Telephone 
f-up 2 
Time since AF 
ablation 
≥ 6 wks 
- 1-2 wks 
0 
+ 1 d 
+ 3 mts 
3-4 mts 
+ 6 mts 
 
Study 
procedures 
 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
Patient’s 
information 
X 
 
 
 
 
 
 
Informed 
consent 
 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
X 
X 
X 
X 
ECG 
 
X 
X 
X 
 
X 
 
AF ablation 
 
 
X 
 
 
 
 
Symptom diary 
instruction 
 
 
 
X 
 
 
 
Symptom diary 
collection 
 
 
 
 
X 
X 
X 
 
d = day; f-up = follow-up; mts = months; wks = weeks. 
 
  
 

PiLOT-AF Study Protocol  
 
  Date and version No: 10th March 2016, version 1.2  
 
 
Clinical Research Protocol Template version 9.0     
 
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Trust 2014  
Page 27 of 27 
17. APPENDIX C:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued 
Author(s) of changes 
Details of Changes made 
1 
1.1 
11/11/2015 
Dr M Leo/ Dr T Betts 
Method of 
randomization clarified 
in detail (paragraph 
8.2.3, page 14) 
 
As requested by Ethic 
Committee, period of 
time during which the 
patients’ personal data 
will be stored and 
accessed after the study 
prolonged to 5 years 
(paragraph 12.2, page 2) 
2 
1.2 
10/03/2016 
Dr M Leo/Dr T Betts 
On the basis of 
observations during the 
first 10 research cases, 
study intervention 
protocol modified as 
follow: 
 
- FTI removed from the 
target parameters for 
termination of RF 
delivery on the LA 
posterior wall; 
 
- maximal duration cut-
off of 60 sec added for 
RF delivery on the LA 
posterior wall.