INtra-procedural ultraSound Imaging for DEtermination of Atrial Wall Thickness and Acute Tissue Changes During Isolation of the Pulmonary Veins
Conditions: Atrial Fibrillation
Sponsor: Oxford University Hospitals NHS Trust

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 1 of 29 
 
 
Study Title: INtra-procedural ultraSound Imaging for DEtermination of atrial wall thickness and acute 
tissue changes during isolation of the Pulmonary Veins 
Internal Reference Number / Short title: INSIDE PVs study 
IRAS Ref: 156673 
Ethics Ref: 16/WM/0379 
Date and Version No: 3rdAugust2016, version 1.0 
 
Chief Investigator/Principal 
Investigator: 
Dr Tim R Betts, Consultant Cardiologist and Electrophysiologist 
Oxford University Hospitals NHS Foundation Trust 
 
Investigators:  
Dr Andrew Kelion, Consultant in Cardiac Imaging 
Oxford University Hospitals NHS Foundation Trust 
 
Dr Milena Leo, Clinical Research Fellow 
Oxford University Hospitals NHS Foundation Trust 
 
Sponsor:  
Oxford University Hospitals NHS Foundation Trust  
Funder: 
BRC Research Capacity Funding 
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. 
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
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TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................................................... 4 
2. 
ABBREVIATIONS .......................................................................................................................................... 5 
3. 
KEY CONTACTS SECTION ............................................................................................................................. 6 
4. 
BACKGROUND AND RATIONALE ................................................................................................................. 7 
4.1 Rationale for real-time imaging of the left atrial (LA) wall during atrial fibrillation ablation ...................... 7 
4.2 Techniques for LA wall thickness imaging .................................................................................................... 8 
4.3 Research questions ....................................................................................................................................... 9 
5. 
STUDY DESIGN .......................................................................................................................................... 10 
6. 
OBJECTIVES AND OUTCOME MEASURES .................................................................................................. 11 
7. 
STUDY RISKS AND BENEFITS ..................................................................................................................... 12 
7.1. 
Study risks ......................................................................................................................................... 12 
6.1.1 CT scans ................................................................................................................................................... 12 
6.2. Study benefits ............................................................................................................................................ 14 
8. 
PARTICIPANT IDENTIFICATION ................................................................................................................. 14 
8.1. 
Study Participants ............................................................................................................................. 14 
8.2. 
Inclusion Criteria ............................................................................................................................... 14 
8.3. 
Exclusion Criteria .............................................................................................................................. 14 
9. 
STUDY PROCEDURES ................................................................................................................................ 15 
9.1. 
Recruitment ...................................................................................................................................... 15 
9.2. 
Baseline visit ..................................................................................................................................... 15 
9.2.1. 
Informed Consent ......................................................................................................................... 15 
9.2.2. 
Screening and Eligibility Assessment ............................................................................................ 16 
9.2.3. 
Pre-procedural CT imaging ........................................................................................................... 16 
9.3. 
AF ablation ........................................................................................................................................ 16 
9.4. 
Pre-discharge review ........................................................................................................................ 17 
9.5. 
Post-procedural CT imaging ............................................................................................................. 17 
9.6. 
Telephone follow-up at 1 week ........................................................................................................ 17 
9.7. 
Image integration and data analysis ................................................................................................ 18 
9.8. 
Discontinuation/Withdrawal of Participants from Study ................................................................. 18 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
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9.9. 
Definition of End of Study ................................................................................................................ 18 
10. 
INTERVENTIONS .................................................................................................................................... 19 
10.1. 
CT imaging .................................................................................................................................... 19 
10.2. 
Intra-procedural ultrasound imaging (ICE/IVUS) .......................................................................... 19 
11. 
SAFETY REPORTING .............................................................................................................................. 20 
11.1. 
Definition of Serious Adverse Events ........................................................................................... 20 
11.2. 
Reporting Procedures for Serious Adverse Events ....................................................................... 20 
12. 
STATISTICS AND ANALYSIS .................................................................................................................... 20 
12.1. 
The Number of Participants ......................................................................................................... 21 
12.2. 
Description of Statistical Methods ............................................................................................... 21 
12.3. 
Analysis of Outcome Measures .................................................................................................... 21 
13. 
DATA MANAGEMENT ........................................................................................................................... 21 
13.1. 
Access to Data .............................................................................................................................. 21 
13.2. 
Data Recording and Record Keeping ............................................................................................ 21 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................................... 22 
14.1. 
Declaration of Helsinki.................................................................................................................. 22 
14.2. 
Guidelines for Good Clinical Practice ........................................................................................... 22 
14.3. 
Approvals ...................................................................................................................................... 22 
14.4. 
Reporting ...................................................................................................................................... 22 
14.5. 
Participant Confidentiality ............................................................................................................ 22 
14.6. 
Expenses and Benefits .................................................................................................................. 23 
15. 
FINANCE AND INSURANCE ................................................................................................................... 23 
15.1. 
Funding ......................................................................................................................................... 23 
15.2. 
Insurance ...................................................................................................................................... 23 
16. 
PUBLICATION POLICY ............................................................................................................................ 23 
17. 
REFERENCES ......................................................................................................................................... 24 
APPENDIX B:  SCHEDULE OF TIMING OF STUDY APPOINTMENTS AND STUDY PROCEDURES ......................... 28 
18. 
APPENDIX C:  AMENDMENT HISTORY .................................................................................................. 29 
 
 
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
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1. SYNOPSIS 
 
Study Title 
Intra-procedural ultraSound Imaging for DEtermination of atrial wall 
thickness and acute tissue changes after isolation of the Pulmonary 
Veins 
Internal ref. no. / short title 
INSIDE PVs 
Study Design 
Pilot study 
Study Participants 
Patients admitted for elective catheter ablation for paroxysmal atrial 
fibrillation (AF) 
Planned Sample Size 
12 patients (4 elected to radiofrequency, 4 to cryo-balloon and 4 to laser 
balloon ablation for atrial fibrillation) 
Planned Follow-up duration 
1 week 
Planned Study Period 
12 months 
 
Objectives 
Outcome Measures 
Primary 
Evaluation of the accuracy of intra-
procedural intracardiac 
echocardiography (ICE) and 
intravascular ultrasound (IVUS) for 
real time imaging of the LA wall 
thickness and PV ostial diameters 
during AF ablation 
 
ICE/IVUS measurements of LA wall 
thickness and PV ostial diameters 
in comparison with the 
corresponding cardiac computed 
tomography (CT) measurements  
 
Secondary  
1. Evaluation of the feasibility of 
ICE/IVUS for real time imaging of the 
LA wall thickness and PV ostial 
diameters during AF ablation 
1a. Additional procedural time 
 
1b. Image quality 
 
2. Comparison between acute tissue 
changes produced by radiofrequency 
(RF), cryo and laser energy 
2. Percentage change of LA wall 
thickness with each ablation 
modality (RF, cryo and laser 
energy) 
 
3. Standardization of CT for LA wall 
thickness imaging with identification 
of a minimum dataset of acquisitions 
and reduction of radiation exposure  
3. CT acquisitions associated to 
reproducible measurement of LA 
wall thickness with the lowest 
radiation exposure 
 
 
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
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Page 5 of 29 
 
 
2. ABBREVIATIONS 
 
ACT 
Activated Clotting Time 
AF 
Atrial fibrillation 
CF 
Contact Force 
CI 
Chief Investigator 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTRG 
Clinical Trials & Research Governance, University of Oxford 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICE 
IntraCardiac Echocardiography 
ICF 
Informed Consent Form 
IVUS 
IntraVascular UltraSound 
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 
3D 
Three-dimensional 
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
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3.  KEY CONTACTS SECTION 
 
Chief Investigator 
Dr Tim R Betts, Consultant Cardiologist and Electrophysiologist 
Department of Cardiology, Level 2, Blue Outpatient Area   
John Radcliffe Hospital  
Oxford University Hospitals NHS Foundation Trust  
Headley Way, Oxford OX3 9DU                                  
 
Tel: 01865 220256 Fax: 01865 221194 
 
E-mail: tim.betts@ouh.nhs.uk 
 
Leading fellow 
 
Dr Milena Leo, Clinical Research Fellow 
 
Clinical Research Fellows Office, Level 2, Blue Outpatient Area   
John Radcliffe Hospital 
Oxford University Hospitals NHS Foundation Trust,  
Headley Way Oxford OX3 9DU        
 
Tel 01865 220255 
 
e-mail: milena.leo@ouh.nhs.uk 
 
Sponsor 
Ms Heather House 
 
Research and Development Department, Joint Research Office 
Block 60, Churchill Hospital 
Oxford OX3 7LE 
 
Tel 01865 572230 
 
E-mail: ouh.sponsorship@nhs.net 
 
 
 
 
  
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
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Ethics Ref: 
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Page 7 of 29 
 
 
4. BACKGROUND AND RATIONALE 
4.1 Rationale for real-time imaging of the left atrial (LA) wall during atrial fibrillation ablation 
Catheter ablation is a well-recognized treatment, with a class I indication, for symptomatic, drug-refractory 
atrial fibrillation (AF) (1, 2). The current technique focuses on the elimination of mechanisms involved in the 
initiation and maintenance of AF. The pulmonary veins (PVs) play a major role as the site of origin of ectopic 
atrial activity initiating and maintaining AF (3, 4) .Radiofrequency (RF) catheter ablation is a long-standing 
method for burning heart muscle to create scars that prevent the conduction of the electrical impulse 
through heart muscle. Catheter ablation of the 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 (5) . 
Despite widespread adoption of this approach over the last decade (with over 10,000 cases per annum in 
the UK), the long-term success rate, particularly single-procedure success rate, is still suboptimal and the 
associated risk of heart perforation and collateral damage is small but not negligible. 
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 veins (6), although if seen during the operation energy can be reapplied until the vein is re-isolated. 
Late PVR, in the weeks or months following the procedure, is a common cause of recurrent arrhythmias 
leading to procedure failure and a need for repeat ablation in 30-50% of patients (7).  
The pathological basis of PVR is not completely known, but 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 
lead to permanent, transmural necrosis and permanent scar. Recent histological data have correlated 
partial thickness ablation lesions with chronic and persistent PV conduction (8). 
The acute development of tissue oedema has been advocated as one of the possible factors responsible for 
lesion failure when using RF energy delivered through an ablation catheter.  Trans-oesophageal (TOE) 
echocardiographic evidence of acute oedema, causing immediate tissue swelling and thickening of the atrial 
myocardium, narrowing the pulmonary vein ostia and increasing the thickness of the ridge between the left 
PVs and left atrial appendage in response to RF ablation, has been reported (9). Immediate expansion of the 
myocardium between the coronary sinus and the left atrium has also been demonstrated on intra-cardiac 
echocardiography (ICE) during mitral isthmus ablation (10). The hypothesis is that sudden increases in wall 
thickness may prevent subsequent lesion delivery achieving the depth required for transmural necrosis and 
permanent conduction block. 
PV reconnection may also be found following cryo-balloon ablation and laser-balloon ablation, which have 
similar long-term results to RF energy. With cryo-ablation, recovery is thought to be due to temporary 
injury at the freezing border zone, where temperatures don’t drop below -40°C, with only a transient effect 
on conduction and absence of tissue necrosis (11). Tissue oedema does occur after surgical cryo-ablation, 
but only once the tissue has thawed and become hyperaemic and it gradually progresses over the next 24 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 8 of 29 
 
 
hours (12). Cryo-ablation preserves tissue architecture and whether local oedema leading to immediate 
atrial wall thickening, inhibiting subsequent attempts at ablation, is not known (13). Even less is known 
about the acute tissue changes produced by endoscopic laser balloon ablation. Although laser energy 
causes focal myocardial tissue ablation through tissue heating (similar to RF), gross pathological 
examination performed in animals acutely after delivery of laser energy has showed homogeneous lesions, 
with well-demarcated borders, no evidence of endocardial destruction such as surface pitting or granulation 
and no evidence of oedema (14).  
At the other end of the spectrum, deep lesions can potentially result in perforation and collateral damage. 
Cadaveric anatomical studies show that the LA wall thickness is extremely variable from subject to subject, 
from less than 1 to more than 7 mm. Even within individual patient, significant differences in the mean and 
maximum LA wall thickness exist among different areas that are often targeted during catheter ablation 
(15). This inter- and intra-patient regional variability has significant implications in determining the 
appropriate duration and intensity of energy delivered during catheter-based ablation procedures.  
For these reasons, real-time information about LA wall thickness and morphological changes of the LA wall 
during energy delivery for ablation would be extremely useful to predict the achievement of permanent 
trans-mural lesions, to identify the possible causes of ablation failure and to avoid the occurrence of 
perforation and/or other collateral damage (16) .   
4.2 Techniques for LA wall thickness imaging 
Cardiac computed tomography (CT), routinely used for the characterization of LA and PV anatomy and 
coronary arteries imaging before an AF ablation, has been recently tested to measure the mean LA wall 
thickness in patients with and without AF and to evaluate regional differences in patients with persistent 
AF. Of note, serial CT scans, performed before, immediately after and 1 month after the AF ablation, have 
documented the transient LA wall thickening suggestive of oedematous changes immediately after PVI by 
using RF ablation (17).Different CT study protocols have been successfully described for LA wall imaging (17-
21) . 
Preliminary data on animal studies also support the accuracy of real-time ultrasound imaging modalities 
such as intracardiac echocardiography (ICE) or IntraVascular Ultrasound (IVUS) imaging (22, 23). Compared 
with cardiac CT, they have the advantage of not requiring ionizing radiation and allow a real-time imaging of 
the LA wall, with measurement of wall thickness and monitoring of acute tissue changes related to AF 
catheter ablation, during the ablation procedure. 
Both ultrasound techniques use miniaturized versions of traditional ultrasound transducers attached to a 
catheter tip. The catheter is introduced into a vessel via an arterial or venous puncture, advanced to the 
area of interest and pulled back through the vessel (or chamber of interest) to obtain a series of 
tomographic images. Most probes image in the axial plane, providing cross-sectional images of the vessel 
(or chamber of interest) and surrounding tissues. The close proximity of the catheter to the intervening 
tissue between the transducer and the object of interest improves the quality of the image by increasing 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
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Page 9 of 29 
 
 
spatial resolution (the ability to discriminate between adjacent small objects) and contrast resolution (the 
ability to distinguish between differences in image intensity, i.e. the spectrum of gray scale of an ultrasound 
image). Moreover, higher ultrasound frequencies can be used to increase spatial and contrast resolution, 
although at the price of reduced image penetration (24, 25). 
Ultrasound imaging with ICE has been used for years during ablation procedures to monitor the catheter 
position, to guide the trans-septal puncture and to help the electro-anatomical reconstruction of the left 
atrium. Radial ICE (e.g., Ultra ICE™ catheter, Boston Scientific) uses a mechanical, 9 Fr, 9 MHz catheter, with 
360° radial image. The ultrasound transducer rotates every 1.4° and, with full mechanical rotation of the 
transducer, a panoramic 360° image is created that is perpendicular to the catheter shaft at the tip. The 
360° scan with radial ICE allows for a comprehensive depiction of both atrial chambers and atrioventricular 
valves, and it also can be used as intravascular ultrasound for big vessels. Its placement in the LA through a 
deflectable trans-septal sheath and advancement into the PVs allows a detailed anatomic reconstruction of 
LA and PVs and close proximity of the catheter to the LA wall at the ablation sites, with higher image 
resolution(26). In a previous animal study ICE was successfully used to evaluate the changes in LA wall 
thickness and echo density at the ablation sites following RF delivery. 
Since the development of IVUS in the late 1980s, this modality has been used both to image the vascular 
system and to direct interventions in target vessels. It was initially used to image atherosclerosis and aid in 
its treatment, but it has more recently been employed within the venous system (including the PVs through 
an intracardiac trans-septal approach), allowing for both intravenous and transvenous image-guided 
interventions (25, 27). A range of IVUS catheters are currently available, mainly differing in the ultrasound 
frequency used (from 10 to 45 MHz) that impacts on the maximum imaging diameter (from 60 to 14 mm 
respectively). Of note, a 40 MHz IVUS probe coupled to an RF catheter has been recently used to measure 
the LA wall thickness and image the acute LA wall changes associated with RF ablation in a porcine model 
(23).    
Data about real-time imaging of LA wall thickness and ablation lesions in humans are lacking to date. 
Although both ICE and IVUS are routinely used in clinical practice in the cardio-vascular system (27, 28), 
their use for LA wall imaging in this setting has never been reported.  
4.3 Research questions 
• 
Intra-procedural ultrasound techniques (ICE and IVUS) have not previously been evaluated for LA 
wall imaging (thickness and acute changes in response to ablation) during PV isolation ablation. 
How feasible is it to use these technologies for this purpose and do they provide accurate and 
reliable measurements compared to the gold standard of cardiac CT? 
• 
Are there any differences in terms of acute tissue changes produced by the different energy 
modalities for AF ablation?   
• 
What is the minimum dataset of CT acquisitions for a reproducible measurement of LA wall 
thickness with the lowest radiation exposure?  

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 10 of 29 
 
 
We plan to address these questions in order to build a user-friendly, reliable and safe model to image the 
LA wall and to measure the acute tissue changes occurring during catheter ablation for AF. 
 
5. STUDY DESIGN 
Patients scheduled for their first pulmonary vein isolation ablation for symptomatic, drug-refractory 
paroxysmal AF, will be considered for inclusion in the study.  
Potential subjects will initially be approached some weeks before their ablation procedure, in order to give 
the patients enough time to consider the information, to ask questions to the Investigator, their general 
practitioner (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. Moreover, a pre-operative 
imaging assessment with a cardiac CT scan will be performed to define the LA and PV anatomy and to 
measure the baseline LA wall thickness and PVs ostial diameters.  
All AF ablation procedures will be performed in a standard fashion by using RF energy, cryo-balloon or laser 
balloon ablation under general anaesthesia (5) and with continuous oesophageal temperature monitoring. 
Ultrasound imaging by IVUS or ICE will be performed at sites corresponding with the PV/LA junction at the 
beginning and the end of the procedure in order to measure acute changes in LA wall thickness and PV 
ostial diameters.  
The cardiac CT will be repeated within 24 hours post-procedure.  
After the procedure, a pre-discharge review and a telephone follow-up at 1 week will be performed to 
identify any early and late complications related to the procedure.   
A total of 12 patients will finally be enrolled in the study, 4 for each energy modality (RF, cryo and laser).  
The end of the study for each patient will be the date of the telephone follow-up 1 week after the 
procedure.  
For each patient the pre-procedural and post-procedural CT measurements of LA wall thickness and PVs 
ostial diameters will be compared with the corresponding IVUS or ICE measurements. Moreover, the acute 
tissue changes produced by the different energy modalities will be compared. Table 1 shows the main 
differences between the standard NHS process  for AF ablation and the INSIDE PVs study appointments.  
Standard NHS process for AF ablations 
INSIDE PVs study appointments 
Referral for procedure 
Identification of participants 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
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Patient sent booking letter 
Patient sent Information Leaflet 
Opportunity for telephone questions 
Pre-assessment clinic visit 1-2 weeks pre-procedure 
 
Baseline assessment  
Recruitment and consent 
Pre-ablation cardiac CT 
Pre-ablation cardiac CT 
AF ablation with PVI  
AF ablation with PVI 
Intra-procedural ICE/IVUS imaging 
Pre-discharge review 
Pre-discharge review 
--- 
Post-ablation Cardiac CT (12-24 h after ablation) 
--- 
Telephone follow-ups at 1 week 
 
A flowchart of the study design, indicating the time points and procedures, is shown in Appendix 1.  
 
 
6. OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measures  
Timepoint(s) of 
evaluation of this 
outcome measure (if 
applicable) 
Primary Objective 
Primary Outcome Measure 
 
1.Evaluation of the accuracy of 
intra-procedural intracardiac 
echocardiography (ICE) and 
intravascular ultrasound (IVUS) 
for real time imaging of the LA 
wall thickness and PV ostial 
diameters during AF ablation 
1. ICE/IVUS measurements of LA wall 
thickness and PV ostial diameters before 
and after pulmonary vein isolation (PVI) in 
comparison with the corresponding cardiac 
CT measurements (before and the day 
following the AF procedure) 
1.Day of and day 
after AF ablation 
procedure  
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 12 of 29 
 
 
 
Secondary Objectives 
1. Feasibility of ICE/IVUS for real 
time imaging of the LA thickness 
and PV ostial diameters during AF 
ablation 
Secondary Outcome Measure 
1a. Additional procedural time 
1b. Image quality 
 
 
Day of AF ablation 
procedure 
2. Comparison between acute 
tissue changes produced by RF, 
cryo and laser energy 
2. Percentage change of LA wall thickness 
with each ablation modality (RF, cryo and 
laser energy) 
Day of AF ablation 
procedure 
3. Standardization of CT for LA 
wall thickness imaging with 
identification of a minimum 
dataset of acquisitions and 
reduction of radiation exposure  
3. 
CT 
acquisitions 
associated 
to 
reproducible measurement of LA wall 
thickness 
with 
the 
lowest 
radiation 
exposure 
Some days before 
and day after AF 
ablation procedure 
 
7. STUDY RISKS AND BENEFITS 
7.1. Study risks 
6.1.1 CT scans 
Pre-procedure cardiac CT imaging is common practice for patients undergoing pulmonary vein isolation 
ablation for atrial fibrillation. The scans provide information on the presence or absence of coronary artery 
disease (which may have a role in antiarrhythmic and anticoagulant drug prescription) and pulmonary vein 
anatomy to aid procedure planning. The CT images can also be incorporated into the ablation guidance 
system for more precise delineation of the anatomy of interest, with reduced X-ray and left atrial access 
times  (5, 29). 
The post-operative CT scan to look for acute changes is an additional scan that would not take place as part 
of standard care.  The mean radiation dose associated with the investigation has been previously estimated 
to 9-12mSv (30-32), which is approximately equivalent to 40-53 months exposure to UK background 
radiation (average UK natural background radiation dose 2.7mSv). This may be theoretically associated with 
an increased lifetime risk of developing a cancer of0.7%-0.07%, according to age and sex (32), over a latency 
period of 10-40 years. However, given this risk is age-dependent, it becomes 0.35% or less for ages above 
40. The lifetime risk of developing a cancer in the general population is around 30 to 40%, so overall the risk 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 13 of 29 
 
 
of cancer associated to an additional CT represents a very small addition to the underlying cancer risk from 
all causes.  
We expect a mean effective dose equivalent of 9mSv for each research CT scan due to the need of multiple 
acquisitions for optimal standardization of the measurements.  However, we are confident that at the end 
of this pilot study we will be able to restrict the number of CT acquisitions needed for optimal LA wall 
thickness imaging to a limited series, with a significant reduction of the radiation exposure to CT.   
Of note, sophisticated CT imaging protocols have become widely available that can reduce the effective 
dose estimated to 2-4 mSv, nearly corresponding to the average annual UK natural background radiation 
dose  (33).  
6.1.2 AF ablation procedure 
The patients taking part to the study will be undergoing a completely standard AF ablation on the basis of 
clinical reasons (symptoms and no response to medical therapy). No changes will be made to the standard 
ablation protocol in case of participation to the study; therefore no additional risks are expected (34). When 
compared with the standard AF ablation procedure, the study ablation procedure differs only with the 
additional use of ICE or IVUS for LA and PVs imaging during the procedure.  
Standard risks associated with an AF ablation procedure in our centre are:  
-bruising in the groin, mild chest discomfort, a sore throat and palpitations, which are usually self-limiting, 
occur in 1 in 10-20 people; 
- cardiac perforation requiring a drain at the time of the operation occurs in 1 in 50-100 people;  
- femoral vascular injury requiring a minor surgical repair occurs in 1 in 200 people; 
- TIA or stroke is approximately 1 in 200 people;  
- pulmonary vein stenosis requiring treatment is 1 in 500;  
- needing urgent open-heart surgery is 1 in 500 people;  
- fatal complication is estimated to be 1 in 1000 people. 
 
6.1.3 Intra-procedural ultrasound imaging  
Both rotational ICE and IVUS are approved for cardiac use. Possible complications are access site 
complications, benign and self-limiting catheter-induced atrial tachy-arrhythmias, LA perforation with 
pericardial effusion, LA thrombosis. Previous studies have documented no additional stroke events related 
to the use of ICE during AF ablation, and even a reduction of LA perforations and pericardial effusions, due 
to ICE guidance during trans-septal puncture, LA reconstruction and ablation (26).  

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 14 of 29 
 
 
We plan to introduce the ICE/IVUS catheter by exchange with the PV mapping catheter, without needing an 
additional venous puncture; therefore we do not expect additional access site complications. Similarly, we 
do not expect an increased stroke risk associated with ICE/IVUS because the catheter will be left in the LA 
only for the minimum time needed for imaging.  The risk of perforation cannot be denied but we expect it 
to be negligible due to ultrasound-guidance. 
6.2. Study benefits 
Enormous benefits could come from this study if a user-friendly, reliable and not harmful technique for 
real-time imaging of the LA is developed. The real-time delineation of LA and PVs anatomy and 
measurement of the LA wall thickness could guide the catheter ablation, avoiding the occurrence of 
perforation and/or other collateral damage and predicting the achievement of trans-mural lesions. The 
monitoring of acute tissue thickness changes due to catheter ablation could help to identify the possible 
causes of ablation failure and develop new strategies to improve the procedure success. Ultimately the aim 
is to facilitate a safer procedure with increased single procedure success rates. Finally, the study could give 
us some insights regarding possible different mechanisms of lesion formation with the different energy 
modalities, to be investigated further in a bigger research study.  
8. PARTICIPANT IDENTIFICATION 
8.1. Study Participants 
Patients scheduled for elective AF ablation in view of a history of symptomatic and drug-refractory 
paroxysmal AF.  
8.2. Inclusion Criteria 
The participant must satisfy the following conditions: 
• 
Males older than 40 years or females older than 40 and sterile or in post-menopausal age; 
• 
willing  and able to give informed consent for participation in the study; 
• 
history of symptomatic and drug-refractory paroxysmal atrial fibrillation; 
• 
planned AF ablation on a clinical basis. 
 
8.3. Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
• 
age less than 40 years and more than 80 years; 

 
 
   
 
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• 
pregnancy, trying for a baby or breast feeding; 
• 
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; 
• 
documented allergy to iodinated contrast medium; ;  
• 
renal insufficiency (eGFR<30);  
• 
weight exceeding the maximum load of the scanner (250kg). 
9. STUDY PROCEDURES 
9.1. Recruitment 
Potential participants will first be approached some 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 a few weeks in advance). 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 invited to contact a member of the study team who can 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, eligibility assessment and 
pre-procedural cardiac CT imaging. 
9.2. Baseline visit 
9.2.1. 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 
the participant is free to withdraw from the study at any time without giving a reason or any prejudice to 
future care and rights. 

 
 
   
 
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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. 
 
9.2.2. 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;  
d. list of current medications and antiarrhythmic drugs previously taken. 
9.2.3. Pre-procedural CT imaging 
As current practice, a pre-procedural cardiac CT scan will be performed to define the LA and PV anatomy 
and to measure the baseline LA wall thickness and PVs ostial diameters. The technical aspects of CT imaging 
are described in the intervention section. 
9.3. AF ablation 
The patient will be admitted to the hospital on the morning of the procedure or on the night before the 
procedure, as per local SOP’s. Apart from intra-procedural ICE/IVUS imaging, the AF ablations will be 
conducted in a completely standard fashion.  
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. Three-dimensional (3D) electro-anatomical mapping 
and/or fluoroscopy will be used by the operator, as usual, as anatomical guide during the procedure. 
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.  
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.   

 
 
   
 
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After the trans-septal puncture(s), pulmonary vein isolation (PVI) will be performed by using RF, cryo or 
laser energy as per operator’s preference.  
When using RF energy, the LA geometry will be reconstructed by using a 3-dimensional (3D) electro-
anatomical mapping (EnSite Velocity or CARTO mapping system) and a multipolar circular mapping catheter 
(St Jude Medical Optima or Biosense Webster Lasso). Then a contact force ablation catheter (St Jude 
Medical EndosenseTacticath or Biosense Webster SmartTouch) through a deflectable sheath St Jude 
Medical Agilis will be used for PVI. The ablation sites will be annotated on the 3D electro-anatomical map. 
The choice of RF power, application time and mean contact force will be also left to operator preference.  
When using cryo energy, LA and PV angiography will be performed in order to delineate their anatomy. A 
11F FlexCath sheath (Medtronic, CA, USA) will be advanced to the LA and used to deliver either a 28 mm 
cryoablation balloon (Arctic Front Advance, Medtronic, CA, USA). ). The balloon will be inflated at the 
ostium of each PV. After retrograde PV angiography, used to demonstrate PV occlusion, one or two 180-
seconds freezes will be performed in each PV until PV isolation is confirmed using PV mapping with an 
Achieve guidewire and exit block confirmed with pacing. 
When using laser energy, a laser balloon system (HeartLight, CardioFocus) will be delivered to the LA 
through a 12-F deflectable sheath and inflated at the ostium of each PV. Ablation lesions will be delivered in 
a circumferential, contiguous, and overlapping manner around the PV using 5–12 W power. Pulmonary vein 
isolation will be confirmed using PV mapping with an Achieve guidewire (Medtronic, CA, USA ) and exit 
block confirmed with pacing (5)Before and after PVs encirclement, ultrasound imaging of the PVs-LA 
junctions with ICE or IVUS will be performed as described in the intervention section.  
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. 
9.4. Pre-discharge review 
As part of standard care, each patient will be reviewed the day after the ablation procedure, before 
discharge. The occurrence of any procedural complications will be investigated. 
9.5. Post-procedural CT imaging 
A post-procedural cardiac CT will be performed within 24h of the AF ablation to look at acute changes in LA 
wall thickness and PVs ostial diameters. The technical aspects of CT imaging are described in the 
intervention section. 
9.6. Telephone follow-up at 1 week 
As part of the research study, a telephone follow-up will be performed 1 week after the procedure to assess 
late-presentation procedural complications (i.e. acute cerebrovascular events as TIA or stroke, pericardial 

 
 
   
 
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effusion, etc.). The patient’s existing clinical care team will be informed about any symptoms and the 
decision to carry any additional investigations to investigate will be left to them. 
The 1-week telephone follow-up will be the end of the study for each patient. 
9.7. Image integration and data analysis 
The pre-procedural CT images and the post-procedural CT images will be compared for each patient.  
Moreover, the pre and post-procedural CT images will be compared with the corresponding IVUS or ICE 
images. The plane of the circumferential ablation line will be identified by using PV branching as reference 
anatomical markers and it will be divided into 12 segments by using a clock-face model. The LA wall 
thickness will be measured at each segment and comparisons will be made between pre and post-ablation 
and between IVUS/ICE and CT at each timepoint.  
The percentage changes in LA wall thickness after AF ablation will be compared between the three energy 
modalities (RF, cryo and laser). 
9.8. 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: 
• 
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.  
The reason for withdrawal will be recorded in the CRF. 
In case of withdrawal from the study in an early stage (before the study interventions), 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.  
9.9. Definition of End of Study 
The end of study will be the date of last data analysis that will approximately be 3-5 days after the AF 
ablation of the last patient. 

 
 
   
 
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10. INTERVENTIONS 
10.1. 
CT imaging 
All cardiac computed tomographic (CT) studies will be performed using an Aquilion One scanner (Toshiba 
Medical Systems, Otawara, Japan), with 320 detector rows (each 0.5mm wide) and a gantry rotation time of 
350ms. This allows the entire heart to be imaged in a single heartbeat, from carina to diaphragm, with a 
maximum of 16cm cranio-caudal coverage. The electrocardiogram (ECG) will be monitored to allow 
prospective gating of image acquisition, with a phase window set to 30-80% of the R-R interval to allow 
assessment of left atrial wall thickness in both atrial diastole and systole. If necessary, metoprolol will be 
administered intravenously in a series of doses (to a maximum of 80mg) to achieve a heart rate of 60bpm. 
The lowest tube voltage (100kVp or 120kVp) will be used that delivers a small focal spot based on scout 
image attenuation, with automatic selection of tube current (200-500mA). 
A power injection of intravenous iodinated contast (Niopam 370, or equivalent) will be given via an 
intravenous cannula sited in an antecubital vein. A volume of 40-80ml will be used at an infusion rate of 4-
6ml/s, depending on patient morphology. This will be followed by 50ml of normal saline given at a similar 
rate. A region of interest will be positioned within the descending aorta on a test slice, and when the 
Hounsfield units exceed 180 a breath-hold and image acquisition after a 3s delay will be triggered. Given 
uncertainty about the optimal way to image and measure the left atrial myocardium, after a delay of 40s, a 
second (“venous phase”) acquisition will be performed using the same parameters as the first. 
Images will be reconstructed iteratively with soft and sharp kernels, with a slice thickness of 0.5mm and an 
increment of 0.25mm. Analysis will be performed on a dedicated post-processing workstation (Terarecon). 
The thickness of the left atrial wall will be measured at a number of locations and especially in 
correspondence of the circumferential ablation line, identified retrospectively by using PV branching as 
anatomical markers. Of note, measurements will be optimally standardized according to position, phase of 
the R-R interval and arterial versus venous acquisition as this is another important aim of this pilot study. 
Based on previous experience with an Aquilion One scanner (ADK), a prospectively gated scan covering 30-
80% of the R-R interval (9 patients, range of kVp) delivers a dose-length-product of 165±100 mGy.cm. 
Therefore, the total DLP for study patients having two acquisitions (arterial and venous) before ablation and 
two afterwards will be 660 mGy.cm. Using a conversion factor of 0.014 mSv/mGy.cm, this equates to a 
mean effective dose equivalent of 9mSv. 
10.2. 
Intra-procedural ultrasound imaging (ICE/IVUS) 
Ultrasound imaging via ICE or IVUS will be performed in each patient during the AF ablation procedure. 
IVUS catheters Visions PV .018 (20 MHz digital probe, maximum imaging diameter 24 mm, Volcano Corp) or 

 
 
   
 
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ICE catheters Ultra ICE (9 MHz rotational transducer, maximal radial depth 50 mm, Boston Scientific) will be 
alternatively used. Before RF/cryo/laser delivery for PVI, the imaging catheter will be introduced in the LA. It 
will be sequentially placed in each PV, 1-2 cm distal to the ostium. Images will be recorded during slow 
retraction of the probe with a motorized linear pullback system from each vein to the trans-septal 
access.The same process will be repeated after PVI. 
Reproducibility will be assessed by repeating the image acquisition via motorized linear pullback at least 
twice before and twice after PVI in two randomly chosen veins per patient.  
 
11. SAFETY REPORTING 
11.1. 
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 
 
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. 
11.2. 
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). 
12. STATISTICS AND ANALYSIS 

 
 
   
 
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12.1. 
The Number of Participants 
This investigational study aims at building a model for real-time imaging of LA wall thickness and acute 
changes produced by catheter ablation for AF. As pilot study, it will enrol 12 patients elected to AF ablation 
with radiofrequency energy (4 patients), cryo-balloon (4 patients) or laser balloon (4 patients). 
As each patient will undergo two cardiac CT scans (one before and after AF ablation), with LA wall thickness 
measurements in different locations, and repeated intra-procedural ultrasound imaging, with 1-2 
acquisitions before and 1-2 acquisitions shortly after RF delivery for PVI in each PV, we expect that at the 
end of the study we will have enough information to confirm if intra-procedural ICE and/or IVUS are 
feasible for real-time imaging of the LA wall thickness during AF ablation and to streamline the CT protocol 
to a minimum dataset of acquisitions, with reduced radiation exposure. The study could also give us some 
insights about different mechanisms of lesion formation and different acute tissue changes caused by the 
different energy modalities, to be investigated further in a bigger randomized study.  
12.2. 
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.  
12.3. 
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. For every participant who withdraws, another participant will be sought in order to have a total 
of 12 full datasets for 12 participants. 
13. DATA MANAGEMENT 
13.1. 
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. 
13.2. 
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. 

 
 
   
 
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• 
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 Kelion, Dr Leo and Dr Betts in the JR hospital. No further data 
transfer will be performed. 
• 
As per Trust Policy, after the end of the trial period, all study data will be kept for a further period of 
years before being deleted, to allow for full analysis and results publication. 
14. ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the Declaration 
of Helsinki.  
14.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
14.3. 
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. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
14.4. 
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. 
14.5. 
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 

 
 
   
 
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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. 
14.6. 
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. 
15. FINANCE AND INSURANCE 
15.1. 
Funding 
This research study was selected for the NIHR Oxford Biomedical Research Centre (BRC) Young investigator 
Award in 2014 and will be supported by the corresponding research grant awarded. The study cost centre 
A20328 Cardiac Rhythm Management Research (CRM) Hub will cover any shortfalls.  
15.2. 
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 Foundation 
Trust, therefore, cannot agree in advance to pay compensation in these circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
 
16. 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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Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 26 of 29 
 
 
33. 
Public Health England. Ionising radiation: dose comparisons. 
34. 
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 
Dec;6(6):1082-8. 
 
 
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 27 of 29 
 
 
 
 
 
 
 
 
APPENDIX A:  STUDY FLOW CHART 
 
 
 
Patients with paroxysmal/persistent AF  
elected to AF ablation (12 pts) 
STUDY POPULATION 
Cardiac CT scan 
Screening and eligibility assessment  
Informed consent 
BASELINE VISIT 
(- 1-2 WEEKS) 
ICE/IVUS imaging 
PV isolation (RF, cryo or Laser) 
ICE /IVUS imaging 
Cardiac CT scan 
Telephone follow-up 
AF ABLATION 
 + 1 WEEK 
End of the study 
Pre-discharge review 
 + 12-24 HOURS 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 28 of 29 
 
 
APPENDIX B:  SCHEDULE OF TIMING OF STUDY APPOINTMENTS AND STUDY PROCEDURES 
 
 
Recruitment 
Baseline 
visit 
AF ablation 
Pre-discharge 
review 
Telephone f-up 
Time since AF 
ablation 
≥ 6 wks 
- 1-2 wks 
0 
+ 1 d 
+ 1 wk 
 
Study procedures 
 
Eligibility 
assessment 
X 
X 
 
 
 
Patient’s 
information 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Medical history 
 
X 
 
X 
X 
Cardiac CT 
 
X 
 
X 
 
PVI 
 
 
X 
 
 
ICE/IVUS imaging 
 
 
X 
 
 
 
AF= atrial fibrillation; ICE= IntraCardiac Echoardiography; IVUS= IntraVascular UltraSound; PVI= Pulmonary 
Vein Isolation; d = day; f-up = follow-up; wks = weeks. 
 
 
 

 
 
   
 
Subject: Research protocol 
Short Title: INSIDE PVs study 
Chief Investigator: Tim Betts  
Version/Date: 1.0 /30th June 2016 
IRAS Ref:  156673 
Ethics Ref: 
16/WM/0379 
 
 
 
 
 
Page 29 of 29 
 
 
18. APPENDIX C:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of changes 
Details of Changes made