Clinical trial NCT02459574
Conditions: Heart Failure Recurrent Atrial Fibrillation
Keywords: Heart Failure
Sponsor: Imperial College London
Start date: 2015-05-01; Completion date: 2018-11-27
Enrollment: 321 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A streamlined AF ablation procedure done without PV mapping as a daycase is more effective than anti-arrhythmic drugs at reducing all hospital episodes for recurrent atrial fibrillation.

Detailed description:
AVATAR-AF is a multicentre, randomised controlled study comparing a streamlined AVATAR-protocol ablation procedure to anti-arrhythmic therapy in patients with documented paroxysmal AF who are considered to be failing current strategy for AF. A secondary control arm will also compare the AVATAR-protocol to conventional AF ablation. 300 patients who are on no prior anti-arrhythmic, 'pill-in-pocket' or taking regular anti-arrhythmics will be randomised in a 1:1:1 manner to a treatment strategy of either AVATAR-protocol ablation, anti-arrhythmic therapy or conventional AF ablation and followed-up for 1 year.

Arms: arm 1: This will involve an ablation procedure carried out in the usual manner. The patient will have three sheaths placed in the leg veins. Catheters will be passed up to the patient's heart from these veins. Two crossing are required into the left atrium. The ablation will involve freeze technology using the Advance Cryoballoon. It will include measuring the electrical signals and may also involve radiofrequency or 'burning' technology in addition. arm 2: Anti-arrhythmic drugs: On the treatment start date the patient will have a new tablet prescribed or a change in the dosage of the medication. The patient will be reviewed at 8wks (visit 1) later to see if the medication is working. If the tablets are working, the patients medication will be left unchanged. If not, an alternative tablet or a higher dose will be used. arm 3: AF ablation with pulmonary vein isolation. The patient will have two sheaths in their leg veins instead of the usual three sheaths. Catheters will be passed up to the heart from these leg veins. The single crossing into the left atrium will be by the usual method. Veins will be ablated using freeze technology known as the Advance Cryoballoon. After the ablation is completed the patient will have scans on their heart and checks of the leg veins. If all the checks are satisfactory at six hours after the procedure the patient will be allowed to go home on the same day. The patient will be reviewed in clinic in 8 weeks (visit 1) after the procedure and if it has been successful, will be reviewed again a month later (visit 2) and if all is well, the patient will be discharged from clinic.
Interventions: intervention 1: AVATAR-AF ablation intervention 2: Anti-Arrhythmic therapy intervention 3: Conventional AF ablation
Intervention descriptions: intervention 1: Experimental ablation protocol intervention 2: Group 2 will be prescribed medication listed below:

Amiodarone; Dronaderone; Sotalol Beta blockers; Calcium channel blockers; Flecainide; or Propafenone.

You will then be discharged from clinic. A research nurse will contact you by phone to make sure there are no problems and can make hospital appointments if needed. intervention 3: Conventional ablation procedure

Protocol documents:
Prot_000.pdf: 
AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
1 
     
 
 
 
 
 
 
 
Ablation Verses Anti-arrhythmic Therapy for Reducing All 
Hospital Episodes from Recurrent Atrial Fibrillation 
 
AVATAR-AF 
 
 
Version 6.1 (9th February 2018) 
 
Study Sponsor: Imperial College Academic Health Science Centre 
 
 
Protocol Number: 13SM1798 
 
ClinicalTrials.gov identifier: NCT02459574 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
2 
 
 
Chief Investigator: Dr Prapa Kanagaratnam 
 
Study Management: Imperial Clinical Trials Unit (ICTU)  
 
 
For general queries, supply of study documentation and collection of data please contact: 
 
AVATAR-AF Project Manager: Dr Thiagarajah Sasikaran 
 
Address:  
Imperial Clinical Trials Unit 
School of Public Health 
Imperial College London 
Stadium House, 68 Wood Lane, London, W12 7RH. 
Email: avatar@imperial.ac.uk 
 
 
Clinical Queries 
 
Clinical queries should be directed to the AVATAR-AF Project Manager who will direct the 
query to the appropriate person. 
 
 
Sponsor 
 
Imperial College Academic Health Sciences Centre is the main research Sponsor for this 
study. For further information regarding the sponsorship conditions, please contact the Head 
of Regulatory Compliance at: 
 
Imperial College Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS Trust  
Room 221, Level 2, Medical School Building  
St Mary's Hospital ,Norfolk Place, London, W2 1PG 
United Kingdom 
 
Email: jrco@ic.ac.uk 
Tel: +44 (0)20 7594 1862 
 
 
This protocol describes the AVATAR-AF study and provides information about procedures for 
entering participants. Every care was taken in its drafting, but corrections and amendments 
may be necessary. These will be circulated to the investigators in the study. Problems relating 
to this study should be referred, in the first instance to the Chief Investigator. 
 
This study will adhere to the principles outlined in the NHS Research Governance Framework 
for Health and Social Care (2nd Edition). It will be conducted in compliance with the protocol, 
the Data Protection Act and other regulatory requirements as appropriate. 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
3 
 
Table of Contents 
1 
INTRODUCTION ................................................................................................................ 8 
1.1 
Background ................................................................................................................ 8 
1.2 
Research Hypothesis ............................................................................................... 10 
2 
STUDY OBJECTIVES ...................................................................................................... 10 
2.1 
Primary Objective .................................................................................................... 10 
2.2 
Secondary Objectives .............................................................................................. 10 
3 
STUDY DESIGN............................................................................................................... 10 
4 
Endpoints .......................................................................................................................... 11 
4.1 
Primary Endpoint ..................................................................................................... 11 
4.2 
Secondary Endpoints: .............................................................................................. 11 
5 
PATIENT RECRUITMENT ............................................................................................... 12 
5.1 
Patient Selection Procedures .................................................................................. 12 
5.2 
Inclusion Criteria ...................................................................................................... 12 
5.3 
Exclusion Criteria ..................................................................................................... 12 
5.4 
Randomisation Procedures ..................................................................................... 14 
6 
TREATMENT ARMS ........................................................................................................ 14 
6.1 
AVATAR-AF Ablation Protocol ................................................................................ 14 
6.1.1 
Review 1 (8 weeks ± 7 days post-ablation) ......................................................... 15 
6.2 
Anti-arrhythmic therapy ............................................................................................ 15 
6.3 
Conventional AF Ablation ........................................................................................ 15 
6.3.1 
Review 1 (8 weeks ± 7 days post-ablation) ......................................................... 16 
6.4 
Redo Ablation (10 weeks± 7 days ) ......................................................................... 16 
6.5 
Discharge Review (Week 12± 14 days) .................................................................. 16 
7 
ASSESSMENT AND FOLLOW-UP .................................................................................. 17 
7.1 
Discharge Protocol .................................................................................................. 17 
7.1.1 
Patients unable to enter the Discharge Protocol ................................................. 17 
7.2 
Telephone Follow-up (All patients) .......................................................................... 17 
7.2.1 
Telephone questions; .......................................................................................... 17 
7.3 
1-Year Follow-up (All patients) ................................................................................ 17 
8 
Endpoints .......................................................................................................................... 18 
8.1 
Primary Endpoint: .................................................................................................... 18 
8.2 
Secondary Endpoints: .............................................................................................. 18 
8.3 
Crossover between therapies .................................................................................. 18 
8.4 
Endpoint Adjudication .............................................................................................. 19 
9 
Patient visit schedule ........................................................................................................ 20 
10 
Safety Reporting .......................................................................................................... 21 
10.1 
Adverse Event Definitions........................................................................................ 21 
10.2 
Expected Serious Adverse Events .......................................................................... 21 
10.3 
Adverse Event Intensity or Severity ......................................................................... 21 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
4 
10.4 
Adverse Event Causality.......................................................................................... 22 
10.5 
Reporting Procedures .............................................................................................. 23 
11 
STATISTICAL ANALYSIS ........................................................................................... 23 
11.1 
Sample Size Calculation .......................................................................................... 23 
11.2 
Data Analysis ........................................................................................................... 24 
12 
DATA MANAGEMENT AND QUALITY CONTROL .................................................... 24 
12.1 
Electronic Recording of data ................................................................................... 24 
12.2 
Risk Assessment ..................................................................................................... 24 
12.3 
Monitoring ................................................................................................................ 24 
12.4 
Quality Control and Quality Assurance .................................................................... 25 
12.5 
Archiving .................................................................................................................. 25 
13 
ETHICAL and LEGAL ISSUES .................................................................................... 25 
13.1 
Ethics Approval ........................................................................................................ 25 
13.2 
Consent.................................................................................................................... 25 
13.3 
Confidentiality .......................................................................................................... 25 
13.4 
Indemnity ................................................................................................................. 25 
13.5 
Sponsor.................................................................................................................... 26 
13.6 
Funding .................................................................................................................... 26 
14 
STUDY MANAGEMENT STRUCTURE ...................................................................... 26 
14.1 
Trial Steering Committee (TSC) .............................................................................. 26 
14.2 
Data & Safety Monitoring Board .............................................................................. 26 
14.3 
Early Discontinuation of the Study or Individual Subjects ....................................... 26 
14.3.1 
Early Discontinuation of the Study by  Data Safety Monitoring Board (DSMB)
 
26 
14.3.2 
Early Discontinuation of Individual Subjects .................................................... 26 
14.4 
Trial Management Group (TMG) ............................................................................. 27 
14.5 
End of trial ................................................................................................................ 27 
15 
PUBLICATION POLICY............................................................................................... 27 
16 
SIGNATURE PAGE 2 (SPONSOR) ............................................................................ 29 
17 
SIGNATURE PAGE 3 (STATISTICIAN) ...................................................................... 30 
18 
SIGNATURE PAGE 4 (principal INVESTIGATOR) ..................................................... 31 
19 
REFERENCES ............................................................................................................ 32 
20 
Appendix 1: Telephone Questions .............................................................................. 34 
21 
Appendix 2: AVATAR-AF Endpoint definitions ............................................................ 35 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
5 
Glossary of Abbreviations 
 
   
AE 
: 
Adverse Event 
AF 
: 
Atrial fibrillation 
BRC 
: 
Biomedical Research Centre 
DSMB 
: 
Data & Safety Monitoring Board 
ECAS 
 
European Cardiac Arrhythmia Society 
eCRF 
: 
Electronic Case Report Form 
ECG 
: 
Electrocardiogram 
EHRA 
: 
European Heart Rhythm Association 
EP 
:  
Electrophysiology 
GI 
: 
Gastro-Intestinal 
GCP 
: 
Good Clinical Practice 
GP 
: 
General Practitioner 
HRS 
:  
Heart Rhythm Society 
ICTU 
: 
Imperial College Trials Unit 
L 
: 
Litre 
LV 
: 
Left Ventricle 
mg 
: 
Milligram 
min 
: 
Minute 
mmol 
: 
Millimole 
NHS 
: 
National Health Service 
NYHA 
: 
New York Heart Association 
OPD 
: 
Outpatients Department 
PV  
: 
Pulmonary Vein 
PVI 
: 
Pulmonary Vein Isolation 
R&D   
: 
Research and Development 
SAE 
: 
Serious Adverse Event 
s 
: 
Seconds 
SSA 
: 
Site Specific Assessment 
TOE 
TSE 
:  
Trans-Oesophageal Echocardiogram 
Trial Steering Committee 
μmol 
: 
Micromole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
6 
 
AVATAR-AF Protocol Summary 
 
SPONSOR 
Imperial College London Academic Health Science Centre 
 
 
PROTOCOL TITLE                     Ablation Verses Anti-arrhythmic Therapy for Reducing All 
Hospital Episodes from Recurrent Atrial Fibrillation (AVATAR-
AF) 
 
 
 
STUDY HYPOTHESIS                A streamlined AF ablation procedure done without PV mapping 
as a daycase is more effective than anti-arrhythmic drugs at 
reducing all hospital episodes for recurrent atrial fibrillation.   
 
 
STUDY DESIGN                         Multicentre, randomised clinical trial 
 
 
TREATMENT REGIMEN             Arm 1-AVATAR-AF Ablation Protocol 
Arm 2-Anti-arrhythmic therapy 
Arm 3-Conventional AF Ablation 
 
 
 
MAIN INCLUSION CRITERIA     1. Documented paroxysmal atrial fibrillation 
 
2. Modification or initiation of anti-arrhythmic agent required for    
    symptom control 
 
3. Males or females eighteen (18) to eighty (80) years of age. 
 
4. Suitable candidate for catheter ablation 
 
5. Signed informed consent 
 
 
MAIN EXCLUSION CRITERIA    1. Contraindication to catheter ablation 
 
2. No carer to enable daycase discharge 
 
3. Arrhythmias other than AF documented unless they have had 
curative ablation (eg. for atrial flutter)§ – Please see page 13 for 
more details. 
 
4. No documentation of sinus rhythm within 3 months 
 
5. Valvular or other heart disease needing regular follow up 
 
6. EF <45% or moderate/severe LV dysfunction (determined by 
Echocardiogram in the last 6mths) 
 
7. Active gastrointestinal disease precluding anticoagulation or 
trans-oesophageal echocardiogram 
 
8. Renal failure with creatinine >200 μmol/L or on dialysis 
 
9. Active fever or infection 
 
10. Life expectancy shorter than the trial 
 
11. Allergy to contrast 
 
12. Severe cerebrovascular disease precluding daycase 
discharge 
 
13. Bleeding or clotting disorders or inability to receive heparin 
 
14. Uncontrolled diabetes (HbA1c ≥73 mmol/mol or HbA1c     
      ≤64 mmol/mol and Fasting Blood Glucose ≥9.2 mmol/L) 
(shown in the last six months without evidence of being brought 
under control) 
 
15. Serum Potassium [K+] <3.5 mmol/L or >5.0 mmol/L (shown in 
the last six months without evidence of being brought under 
control) 
 
16. Malignancy needing surgery, chemotherapy or radiotherapy 
 
17. Pregnancy or women of child-bearing potential not using a  
     highly effective method of contraception 
 
18. Must not have previous (4 weeks prior to screening) or  
      current participation in another clinical trial with an   
      investigational drug or investigational device 
 
19. Unable to give informed consent 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
7 
20. Uncontrolled thyroid disease defined as abnormal thyroid  
function tests causing cardiac manifestations within the last 
6mths 
   
21. Unable to attend follow-up visits  
 
 
NUMBER OF PATIENTS            321 patients, 1:1:1 randomisation  
 
 
DURATION OF STUDY              1 year recruitment period/1 year follow-up for each patient 
 
 
NUMBER OF SITES                   13 United Kingdom sites  
 
 
PRIMARY ENDPOINT                Time to any hospital episodes (Emergency Room or outpatient) 
related to treatment for atrial arrhythmia 
 
 
SECONDARY ENDPOINTS        1. Time to  Death or Stroke from any cause 
 
2. Any complications caused by the procedure (pericardial 
effusion, bleeding >2 units, phrenic nerve palsy and other) or the 
anti-arrhythmic drug (GI disturbance, skin irritation and other)  
 
3. All hospital episodes which result in a change in therapy for 
atrial arrhythmia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
8 
1 
INTRODUCTION 
1.1 
Background 
 
Atrial fibrillation (AF) is the most common clinical cardiac arrhythmias and pulmonary vein 
isolation (PVI) has been shown to be more effective than anti-arrhythmic agents for maintaining 
sinus rhythm.1-4 These comparative studies have used stringent methods for judging success. 
The current 2012 HRS/EHRA/ECAS guidelines recommend assessing outcome by ‘any 
detectable AF’ which is defined as 30seconds of sustained AF on a 24hour holter monitor or 
event recorder.5 The previous 2007 guidelines, on which most current practice is based also 
indicated that Holter monitoring should be performed every 6months for 2years. These outcome 
measures are effective for determining the efficacy of a technology but have limited use for 
decision making in patients. A one minute episode on a 24hr tape at 12 months after an ablation 
in an asymptomatic patient may be deemed a ‘failure’ on scientific grounds but would not result 
in a repeat ablation or change in medication. There is a risk that trying to achieve ‘perfect’ 
outcomes may lead to procedures that are more complicated than is necessary to meet the 
patient’s needs. Furthermore, patients with effective symptom control are expected to attend 
for hospital review and investigation, with the associated inconvenience and resource 
consumption without any prospect of a change in management strategy. There is some 
evidence that pursuing such a strategy may improve the stroke risk in an asymptomatic patient, 
but this has not been incorporated into any guidelines.6,7 Multiple Holter recordings 
demonstrating sinus rhythm are reassuring but in patients with a high CHADSVASC score, the 
absolute reduction in risk and long term recurrence is not known.  We would suggest that the 
main value of Holter recording is to diagnose the cause of ongoing palpitations following 
ablation as these may not be AF. 
Therefore, we would propose that the definition of success in AF ablation and its implication 
needs re-evaluation. One level of success would be to eliminate stroke risk.  This may need 
frequent monitoring and prevention of all episodes of AF both symptomatic and asymptomatic. 
Such an approach may need aggressive ablation endpoints with increased procedural and long 
term follow-up costs.8 This may be justified by the number of strokes prevented. Studies 
addressing such endpoints would need several thousand patients, similar to RELY, ROCKET-
AF and ARISTOTLE, which is probably beyond the scope of interventional studies at present.9  
Another level of defining success would be according to symptom control, but due to the lack 
of objectivity in symptom status, it has not been a popular endpoint for studies. Quality of life 
questionnaires have been used but most clinicians find these cumbersome to use and the data 
analysis difficult to understand.10 As an alternative we would propose that attending hospital 
appointments and investigations both electively or as an emergency are objective and 
measurable events. Hospitalisation for inpatient treatment is a well-established endpoint and 
adding routine outpatient appointments is a minimal change but is more relevant to this type of 
symptom monitoring. Following post-operative checks after an AF ablation, symptom control 
that is good enough to not need regular review could be used a ‘success’ measure. ‘If 
successful, you will not need to attend hospital’ is also a tangible outcome measure for the 
patient unlike the current outcome target of ‘any detectable AF which requires the physician to 
clarify and then add the caveat of the limitations of the detection method and that stroke risk 
remains unknown despite this seemingly conclusive outcome. Furthermore, using hospital 
episodes aligns the results of the procedure with those used by healthcare commissioners. 
 
This re-evaluation of the objectives of AF ablation, also raises the question of which 
components of an AF ablation procedure are needed to deliver the effective symptom control 
rather than prevent any detectable AF. Originally, pulmonary vein (PV) ectopic foci were shown 
to trigger AF and a technique for identifying and ablating these ectopic foci was proposed as a 
potential treatment for AF. The unpredictability of ectopy and the high incidence of PV stenosis, 
led to this approach being abandoned in favour of ostial segmental pulmonary vein isolation 
(PVI) guided by circular PV mapping catheter on the basis that >90% of ectopy originated from 
the PV. Subsequently it was shown that circumferential antral ablation (CPVA) with acute 
isolation proven by PV mapping and entrance block was superior to segmental ostial ablation 
or ablation without PV mapping. Most current approaches are based on this data and produces 
a consistent and reproducible success rate of around 50-70% for paroxysmal AF.5 However, 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
9 
the mechanism for success is uncertain as a significant proportion of ablated veins will 
electrically reconnect even in patients without AF recurrence.11  It has been assumed that 
improving the durability of PV isolation by altering energy type and reducing the need for 
operator skill would be the path to better results and has included balloon ablation catheters 
such as the cryoballoon and laser balloon, robotic technologies and multipolar circumferential 
catheters that can map and ablate. However, there has been no discernible improvement with 
any of these approaches (though the cost per procedure has increased). We believe that this 
is because all these technologies use PV isolation as an endpoint and this is the outcome that 
can be expected using this endpoint.12-14 The attempts to demonstrate the benefits of these 
new technologies revealed some intriguing data, particularly the finding that ablation ‘quality’ in 
the antral region (by using steerable sheaths or simply additional lesions) has a better 
association with clinical outcomes than pulmonary vein isolation in multivariate analysis.15,16 
This may be related to effect on the local autonomic innervation, but raises the question of the 
necessity of demonstrating pulmonary vein isolation during ablations using current ablation 
modalities.17 The need for an aggressive approach with electrical isolation of all veins has not 
been tested against symptom-based outcome measures such as the requirement for further 
hospital intervention. 
 
Such a proposal may be controversial but its justification rests on whether symptom control or 
stroke prevention is the goal of AF ablation. Currently all guidelines indicate that symptoms are 
the only indication and yet ‘any detectable AF’ is used to assess procedures and it has become 
a ‘sacred cow’ that is rarely challenged. 3,4,12-14  Cost-effectiveness studies on paroxysmal AF 
ablation, which have excluded any putative stroke or mortality benefits suggest incremental 
cost-effectiveness ratio of ablation versus medical therapy was $51 431 per quality-adjusted 
life-year.18 This is still a considerable increase particularly as population studies suggest that 
the burden of AF is increasing with the aging population. Changing the definition of a successful 
ablation to the prospect of avoiding hospital episodes may enable the reduction of absolute 
costs of the procedure which would have a significantly beneficial effect on the cost 
effectiveness calculations. Review of our internal data suggests using the Advance™ 
Cryoballoon (Medtronic,Minneapolis) produces PV isolation >80% of veins without the need for 
additional ablation which requires PV mapping catheters. If the procedure is done without PV 
mapping, there are multiple cost savings PV mapping catheter, EP recording equipment and 
specialist staff. This would also shorten the procedure and may enable most patients to be 
completed as a day case which would be a cost saving through reduced bed occupancy. One 
series has suggested that nearly 90% of patient can already be discharged safely as a 
daycase.19 Our annual audits would support this view in that most complications (pericardial 
effusion, femoral bleeding, urinary retention, phrenic nerve injury) occur within three hours of 
the end of the procedure. The rest do not present during the overnight stay (atrio-oesophageal 
fistula, pulmonary vein stenosis, delayed tamponade). Simply changing the definition of 
success may enable all of these cost-savings to be made without compromising outcome to the 
patient.  
 
In summary, developments in paroxsymal AF ablation have been monitored against the 
definition of any detected 30seconds of AF, which is not necessarily measure of symptom 
control. Hospital episodes are an objective and well established endpoint throughout the 
healthcare system and are more reflective of the patient’s expectations. The increasing 
population burden of AF will need more cost effective approaches to treatment of symptoms. It 
is not known whether current approaches to antral pulmonary vein ablation still necessitates 
pulmonary vein mapping, which is a major source of to cost and complexity. 
The proposed study is based on the following observations: 
i) AF ablation is well established as the most effective method for preventing recurrence. 
ii) Current methods for AF ablation are costly and complex with only a small minority of the AF 
population having access to such procedure. 
iii) The Advance Cryoballoon is effective at producing antral PV ablation mapping. 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
10 
iv) AF ablation has not been compared against anti-arrhythmic agents with the primary goal of 
controlling symptoms. 
 
1.2 
Research Hypothesis 
 
A streamlined AF ablation procedure done without PV mapping as a daycase is more effective 
than anti-arrhythmic drugs at reducing all hospital episodes for recurrent AF. 
 
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine if antral AF ablation without electrophysiological confirmation of PV isolation is 
more effective than anti-arrhythmic agents at achieving freedom from hospital based treatment.  
 
2.2 
Secondary Objectives 
 
To determine if antral AF ablation without electrophysiological confirmation of PV isolation 
performed as a daycase is less effective than  the conventional approach.  
 
3 
STUDY DESIGN 
 
AVATAR-AF is a multicentre, randomised controlled study comparing a streamlined AVATAR-
protocol ablation procedure to anti-arrhythmic therapy in patients with documented paroxysmal 
AF who are considered to be failing current strategy for AF. A secondary control arm will also 
compare the AVATAR-protocol to conventional AF ablation.  321 patients who are on no prior 
anti-arrhythmic, ‘pill-in-pocket’ or taking regular anti-arrhythmics will be  randomised in a 1:1:1 
manner to a treatment strategy of either AVATAR-protocol ablation, anti-arrhythmic therapy or 
conventional AF ablation and followed-up for 1 year.  
 
The study will be conducted in accordance with the protocol, Good Clinical Practice (GCP) and 
all applicable regulatory requirements. 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
11 
 
4 
Endpoints 
 
4.1 
Primary Endpoint 
 
Time to all hospital episodes (Emergency Room or patient request for OPD) related to 
treatment for atrial arrhythmia. 
4.2 
Secondary Endpoints: 
 
      1. Time to death or stroke from any cause. 
 
      2. Any complications caused by the procedure (pericardial  effusion, bleeding >2 units,  
          phrenic nerve palsy and other) or the anti-arrhythmic drug (GI disturbance, skin    
          irritation and other). 
 
      3. All hospital episodes which result in a change in therapy for atrial arrhythmia. 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
12 
 
5 
PATIENT RECRUITMENT 
 
5.1 
Patient Selection Procedures 
 
Research staff will identify potential study patients against inclusion and exclusion criteria, 
before the Investigator determines their eligibility for participation. The Investigator will discuss 
the rationale for the study, study procedures, risks and benefits and all other issues mandated 
by the consent process. The potential participant will be offered an opportunity to participate in 
the study and written informed consent will be obtained if they agree. Study procedures and 
assessments will only be performed after written informed consent has been obtained. 
 
At the screening visit, the patients general health will be assessed in a physical examination 
and recording of vital signs. The patient’s medical and medication history will also be recorded.  
 
A fasting blood sample will also be taken to exclude patients with uncontrolled diabetes or [K+] 
and serum creatinine outside acceptable safety ranges and the patient will be asked to 
complete a Quality of Life questionnaire (EQ5D) and an Atrial Fibrillation Effect on QualiTy of 
life (AFEQT) questionnaire. . A blood test result within 6 months is acceptable. Any blood test 
result taken more than 6 months prior to randomisation will need to be repeated. A copy of the 
blood results must be filed in the patient notes. Any other routine clinical tests should be 
performed as per local practice. 
 
Both the AVATAR protocol and conventional ablation procedures will be discussed with the 
patient and the anti-arrhythmic agent or the change in dose that would be selected as the next 
line of treatment would be agreed at this stage in preparation for potential anti-arrhythmic arm. 
 
The informed consent process and all study assessments will be documented in the patient’s 
medical notes and study case report forms.  
 
5.2 
Inclusion Criteria 
 
To be eligible for the trial, subjects must meet all of the following criteria: 
 
1. 
Documented paroxysmal atrial fibrillation 
2. 
Modification or initiation of anti-arrhythmic agent required for symptom control 
3. 
Males or females eighteen (18) to eighty (80) years of age 
4. 
Suitable candidate for catheter ablation 
5. 
Signed informed consent 
 
 
5.3 
Exclusion Criteria 
 
Subjects with any of the following will be excluded from the study: 
 
1. 
Contraindication to catheter ablation 
2. 
No carer to enable daycase discharge 
3. 
Documented Arrhythmias other than AF unless they have had curative ablation (eg. for atrial 
flutter)§ . 
4. 
No documentation of sinus rhythm within 3 months 
5. 
Valvular or coronary heart disease needing regular follow up 
6. 
EF <45% or moderate/severe LV dysfunction(determined by Echocardiogram in the last 6 
months) 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
13 
7. 
Active 
gastrointestinal 
disease 
precluding 
anticoagulation 
or 
trans-oesophageal 
echocardiogram 
8. 
Renal failure with creatinine >200 μmol/L or on dialysis 
9. 
Active fever or infection 
10 
Life expectancy shorter than the trial 
11. 
Allergy to contrast 
12 
Severe cerebrovascular disease  
13. 
Bleeding or clotting disorders or inability to receive heparin 
14. 
Uncontrolled diabetes (HbA1c ≥73 mmol/mol or HbA1c ≤64 mmol/mol and Fasting Blood 
Glucose ≥9.2 mmol/L) (shown in the last six months without evidence of being brought under 
control)* 
15.  Serum Potassium [K+] <3.5 mmol/L or >5.0 mmol/L (shown in the last six months without 
evidence of being brought under control) 
16. 
Malignancy needing surgery, chemotherapy or radiotherapy 
17. 
Pregnancy or women of child-bearing potential not using a highly effective method of 
contraception ** 
18. 
Must not have previous (4 weeks prior to screening) or current participation in another clinical 
trial with an investigational drug or investigational device 
19. 
Unable to give informed consent 
20. 
Uncontrolled thyroid disease defined as abnormal thyroid function tests causing cardiac 
manifestations within the last 6mths21. Unable to attend follow up visits 
 
§ AVATAR-AF Guidance on Atrial Flutter 
(I) 
12 lead ECG documentation of typical atrial flutter during screening 
 
Patient should not be recruited to the AVATAR study and should undergo 
Cavo-Tricuspid Isthmus line(CTI )ablation. 
 
 If symptomatic atrial fibrillation is still present then the patient can be 
considered for AVATAR recruitment. 
(II) 
 12 lead ECG documentation of typical atrial flutter after randomisation.  
 
Patient should be suspended from the AVATAR study intervention and 
should undergo CTI ablation. 
 
 If symptomatic atrial fibrillation still present then the patient can be 
considered for AVATAR intervention. 
(III) 
Holter monitor – Atrial fibrillation + organised atrial activity suggestive of 
paroxsysmal atrial flutter.  
 
Can be recruited to AVATAR study, but cannot have CTI at first ablation. 
(IV) 
CTI dependent flutter (or any other arrhythmia) occurs during AF ablation 
procedure. 
 
These patients should not be ablated during the first ablation procedure 
(V) 
Symptomatic atrial flutter picked up as an endpoint.  
Can progress to ablation as per physician discretion 
 
 
* A fasting blood glucose must have been done within the last 6mths confirming that blood 
glucose under control. If no blood test result available,a new fasting blood glucose sample will 
be taken from all consented potential participants at screening to exclude uncontrolled diabetes, 
defined as: 
 
 
HbA1c ≥73 mmol/mol or 
                     
 
HbA1c ≤64 mmol/mol and Fasting Blood Glucose ≥9.2 mmol/L 
 
. 
 
** Women of child-bearing potential not using a highly effective method of contraception must 
undergo a pregnancy test.  Acceptable methods of contraception include the following: 
 
 


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14 
• Barrier type devices (e.g. female condom, diaphragm and contraceptive sponge)   
  used ONLY in combination with a spermicide. 
• Intra-uterine devices. 
• Oral contraceptive agents started at least 90 days before start of study. 
• Depo-Provera (medroxyprogesterone acetate). 
• Levonorgestrel implants. 
• Naturally or surgically sterile (amenorrheic for at least 1 year and no record of child 
               birth for naturally sterile persons). 
• Male partner is sterile and is the only sexual partner 
 
Women not of child-bearing potential and eligible for the trial will have been hysterectomised, 
sterilised or be post-menopausal (ie. at least one year since their last period). 
 
5.4 
Randomisation Procedures 
 
Eligible patients who have given written, informed consent and who meet all the inclusion 
criteria and no exclusion criteria will undergo 1:1:1 randomisation to an un-blinded treatment of 
either AVATAR-protocol AF Ablation, medical anti-arrhythmic therapy or conventional AF 
ablation. Randomisation will be performed electronically using the InForm electronic data 
capture system and will be stratified by site. 
 
From the date of randomisation, the 1st Intervention date (ablation or anti-arrhythmic medication 
change) must occur 28 days ± 7days after this, therefore an ablation procedure date will be 
identified according to local EP catheter lab availability for each consenting, eligible patient and 
randomisation of the patient will then be scheduled for 28 days ± 7days from this available date.  
  
The patient may be withdrawn from any AF ablation treatment by the Investigator if any safety 
concerns arise during the period between randomisation and the ablation which make the 
patient an unsuitable candidate for the procedure. The patient will then be withdrawn from the 
study.  
 
 
 
6 
TREATMENT ARMS 
 
In the 4 week period (28 days ± 7days) between Randomisation and 1st Intervention, there will 
be no change to the patient’s arrhythmia treatment: the treatment which the patient has been 
randomised to will only occur on the date of 1st Intervention. All three treatment arms will follow 
the same scheduling protocol regardless of intervention.  
 
 
 
6.1 
AVATAR-AF Ablation Protocol 
 
Anticoagulation regime will be at physician’s discretion according to established HRS/ESC 
guidelines guided by CHADSVASC scoring system. Patients on anticoagulation may follow a 
continuous, bridging or without anticoagulation as per local protocol. 
The procedure is performed under sedation or general anaesthetic according to local 
preference. TOE is performed according to local protocols. Femoral sheaths placed in the right 
femoral vein (ultrasound guidance allowed). A single transeptal puncture is performed under 
TOE, ICE, CS catheter or aortic pigtail guidance. If coronary sinus catheter is used, this should 
be performed without electrograms if possible. 
Pulmonary venography taken. The sheath is exchanged for a Cryosheath or other suitable large 
sheath and an Arctic Front Advance balloon is used to occlude the PV to Grade 3/4 and deliver 


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15 
2 x 3min cryoablations to each vein. Phrenic nerve monitoring will be done with a temporary 
transvenous pacing wire and box. No specialist EP catheters are deployed and no formal 
assessment of PVI is done.  ACT kept above 300s. Reversal of heparin with Protamine is 
allowed. 
Transthoracic Echo (hand-held echo with documentation sufficient), Hb check and groin survey 
at 6 hours post-procedure. If all are stable, the patient is discharged as a daycase procedure 
and given appropriate instructions and advice on potential concerns and process for seeking 
advice 
Patient is given a date for possible ‘redo’ procedure at 10wks ± 7 days post ablation. 
All medication is continued for 4 weeks post-ablation and then all agents being used for anti-
arrhythmic effect are stopped. 
 
6.1.1 
Review 1 (8 weeks ± 7 days post-ablation) 
The patient is first reviewed 8 weeks ± 7 days post ablation. If asymptomatic for palpitations, 
weekly improvement or not possible to assess in time scale then the patient is entered into 
discharge protocol at 12 weeks ± 14days.  
If there are ongoing symptoms then the redo procedure (as scheduled post 1st Intervention 
ablation) will be performed which will be a conventional PVI using radiofrequency thermocool 
catheter and PV mapping catheter or according to local practice. A daycase approach is taken 
again as per first procedure and the patient is reviewed at 12 weeks ± 7days and if stable enters 
Discharge protocol at 12 weeks ± 14days. 
 
6.2 
 Anti-arrhythmic therapy 
 
The anti-arrhythmic agent or the change in dose that was discussed with the patient selected 
as the next line of treatment at the initial screening visit is initiated at the 1st Intervention date. 
The anti-arrhythmic treatment is chosen should be done in accordance with local practice and 
guidelines.  
 
The patient will undergo 2 reviews prior to entering the Discharge protocol. 
 
 
Review 1 (4 weeks post-1st Intervention) 
 
 
Review 2 (8 weeks post-1st Intervention) 
 
At each review, the patient can be left unchanged, have an increase in drug dose or change of 
agent as required. Review 1 at 4 weeks post 1st intervention can take place as a telephone 
follow up followed by a clinic visit if required. Following the 2 reviews, the patient enters the 
Discharge protocol at 12 weeks ± 14days. 
 
 
6.3 
Conventional AF Ablation 
 
Patients randomised to the conventional AF Ablation arm will undergo the conventional 
Cryoablation procedure. This arm will be used as a second control arm to compare the 
differences in impact on healthcare resources, complication rates and clinical outcomes 
between conventional ablation and AVATAR-protocol ablation. 
 
Anticoagulation regime will be physician discretion according to established HRS/ESC 
guidelines guided by CHADSVASC scoring system. Patients on anticoagulation may follow a 
continuous, bridging or without anticoagulation as per local protocol. 
The procedure is performed under sedation or general anaesthetic according to local 
preference. TOE is performed according to local protocols. Femoral sheaths placed in the right 


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16 
femoral vein (ultrasound guidance allowed). A single or double transeptal puncture may be 
done guided by TOE, aortic pigtail, ICE or CS catheter guidance. Pulmonary venography taken. 
The sheath is exchanged for a Cryosheath or other suitable large sheath and an Arctic Front 
Advance balloon is used to occlude the PV to Grade 3/4 and deliver 2 x 3min cryoablations to 
each vein. Phrenic nerve monitoring can be according to local protocol. 
 
The PV will be mapped using a circular mapping catheter of the operators choice and the 
number of veins isolated with this approach documented. PV isolation is completed with either 
repeat cryoballoon, deflectable cryotherapy catheter or radiofrequency catheter. The catheters 
used and outcomes documented. 
 
The patient is monitored overnight and should have an Hb, groin and echo (handheld with 
documentation sufficient) check prior to discharge. 
 
All medication is continued for 4 weeks post-ablation and then all agents being used for anti-
arrhythmic effect are stopped. 
 
 
6.3.1 
Review 1 (8 weeks ± 7 days post-ablation) 
The patient undergoing conventional AF ablation is also first reviewed 8 weeks ± 7 days post 
ablation. If asymptomatic for palpitations, weekly improvement or not possible to assess in time 
scale then the patient is entered into discharge protocol at 12 weeks ± 14days.  
If there are ongoing symptoms then the redo procedure (as scheduled post 1st Intervention 
ablation) will be performed at 10wks  
 
 
 
6.4 
Redo Ablation (10 weeks± 7 days) 
Anticoagulation regime will be physician discretion according to established HRS/ESC 
guidelines guided by CHADSVASC scoring system. Patients on anticoagulation may follow a 
continuous, bridging or without anticoagulation as per local protocol. 
The procedure is performed under sedation or general anaesthetic according to local 
preference. TOE is performed according to local protocols. Femoral sheaths placed in the right 
femoral vein (ultrasound guidance allowed). A single or double transeptal puncture is performed 
under TOE, ICE, aortic pigtail or CS catheter guidance.  
Pulmonary venography taken and PV mapping performed. Further ablation can be performed 
according to operator preference by radiofrequency ablation, Cryoballoon or cryocatheter. 
Transthoracic Echo (hand-held echo with documentation sufficient), Hb check and groin survey 
at 6 hours post-procedure.  
Patients in AVATAR-AF protocol arm are discharged as a daycase procedure and given 
appropriate instructions and advice on potential concerns and process for seeking advice. 
Patients in conventional ablation arm are kept overnight. 
All medication being used for anti-arrhythmic effect are stopped. 
 
6.5 
Discharge Review (Week 12± 14 days) 
Patient will be assessed at week 12 for evidence of Primary and secondary endpoints. Patients 
will also be reviewed for suitability for entering discharge protocol. 
 


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7 
ASSESSMENT AND FOLLOW-UP 
 
7.1 
Discharge Protocol 
 
Patients from the all therapy arms will enter the Discharge protocol 12 weeks ± 14days post-1st 
Intervention providing no ongoing symptoms are presented before this.  
 
Patients will be given the centre’s Research Nurse contact details and are able to request an 
unscheduled visit if they experience recurrent symptoms and need hospital review. A blinded 
research Nurse or designee will contact the patient by telephone every 3 months to ensure that 
no endpoints have occurred.  
 
The patient will be advised that the blinded research Nurse or designee making the phone call 
will not know which treatment they have received and the patient will be given a copy of the 
questions that they will be asked. 
 
 
7.1.1 
Patients unable to enter the Discharge Protocol 
 
Patients not able to enter the discharge protocol at 12 weeks will have necessary advice (further 
OPD, procedure) which will be a primary endpoint. The date of the endpoint will be the date of 
the subsequent event. These patients will be followed up at their usual study visits at M6, M9 
and Final visit. 
 
 
 
 
7.2 
Telephone Follow-up (All patients) 
 
All patients who have been randomised to the trial will be followed up by telephone every three 
months (6/9/12mths) after week 12 visit. Questions asked during this follow-up will cover 
hospital attendance (reason/outcome/medication changes/investigations), any symptoms 
experienced and whether the patient needs to see the research team for an unscheduled visit. 
The Month 12 questions can be done by either telephone or face to face as a part of the End 
of Study Visit. 
 
7.2.1 
Telephone questions; 
 
The staff making the telephone query will be blinded to the treatment arm and may be from a 
different site. At the beginning of the conversation the caller will explain that they do not know 
which treatment arm they are in and that they should try to avoid any references to the 
treatment and just try and answer the question directly. Please see the Appendix 1 for the 
details of the telephone questions. 
 
 
 
7.3 
1-Year Follow-up (All patients) 
 
1st Intervention will be considered baseline, all patient returning for follow-up 1 year ± 14days 
after this date. At this visit, all patients will undergo the following assessments: 
  


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18 
- 
Physical Examination 
- 
Vital signs 
- 
Concomitant medications 
- 
ECG 
- 
24 hour holter monitor tape 
- 
EQ5D quality of life questionnaire 
- 
Adverse Events  
- 
Study Endpoints 
- 
Atrial Fibrillation Effect on QualiTy of life (AFEQT) patient questionnaire 
 
All data will be recorded on the InForm eCRF. 
 
8 
Endpoints 
 
8.1 
Primary Endpoint: 
 
1. Time to any hospital episode (Emergency Room or patient request for OPD) related to  
    treatment for atrial arrhythmia. 
 
 
 
8.2 
Secondary Endpoints: 
 
1. Time to death or stroke from any cause. 
 
2. Any complications caused by the procedure (pericardial effusion, bleeding >2 units,  
    phrenic nerve palsy and other) or the anti-arrhythmic drug (GI disturbance, skin irritation  
    and other). 
 
3. All hospital episodes which result in a change in therapy for atrial arrhythmia 
 
 
All study endpoints will be reported from the date of 1st intervention.  
 
 
8.3 
Crossover between therapies 
 
Following the week 12 visit, a patient from any group, the Investigator may initiate further drug 
therapy or schedule a standard ablation procedure for the patient. However, the following are 
required; 
 
 
i) Ablation Arms (Conventional and AVATAR-AF): Can start anti-arrhythmic drugs or further 
redo-ablation if there is ECG/Holter documentation of recurrent AF/AT 
 
ii) Drug Therapy Arm: May receive ablation therapy if failed one anti-arrhythmic at maximum 
standard dose or two anti-arrhythmic agents at sub-maximal dose or due to side effects. 
 
 
iii) New tachycardia documented that needs treatment (VT/AVNRT/AVRT). The patient is 
withdrawn from the study 
 


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19 
8.4 
Endpoint Adjudication 
 
 
The endpoint adjudication will be done by an independent Endpoint Adjudication Committee 
(EAC). The EAC will centrally review and classify suspected outcome events, verifying 
whether they meet protocol definitions.  Any hospital episodes (Emergency Room or 
outpatient) related to treatment for atrial arrhythmia, Stroke or Death from any cause,  Any 
complications caused by the procedure (pericardial effusion, bleeding >2 units, phrenic nerve 
palsy and other) or the anti-arrhythmic drug (GI disturbance, skin irritation and other),  All 
hospital episodes which result in a change in therapy for atrial arrhythmia. 
 
Any attendance to hospital or specialist cardiac clinic will require the documentation of a 
discharge letter or clinic letter for primary endpoint adjudication.  
 
Definitions of study endpoints: see Appendix 2 
 
 


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9 
Patient visit schedule 
 
 
 
 


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21 
10 Safety Reporting 
Information about trial adverse events will be collected from randomisation until the end of the 
trial 
 
 
10.1 Adverse Event Definitions 
 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject. 
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect that: 
- Results in death 
- Is life-threatening – refers to an event in which the subject was at risk of death at the     
  time of the even; it does not refer to an event which hypothetically might have   
  caused death if more severe. 
Requires hospitalisation (>24 hrs), or prolongation of existing inpatient hospitalisation 
- Results in persistent or significant disability or incapacity 
- Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other situations. 
Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of the 
other outcomes listed in the definitions above, should also be considered serious.  
 
Any Adverse Events that are related to atrial arrhythmia will be reported as endpoints rather 
than Adverse Events. Serious Adverse Events that are related to atrial arrhythmia must be 
reported as SAEs.   
 
Any planned hospitalisations such a for a redo ablation procedure prior to entry into the 
Discharge protocol or planned surgery will not be reported as Serious Adverse Events as 
these are expected. 
 
10.2 Expected Serious Adverse Events  
 
Symptoms of atrial fibrillation/tachycardia 
 
Pericardial Effusion 
 
Vascular Bleeding 
 
Phrenic Nerve Palsy 
 
PV stenosis 
 
Shortness of Breath more than 1 week from the procedure 
 
Chest pain more than 1 week from the procedure 
 
 
10.3 Adverse Event Intensity or Severity 
 
The intensity or severity of each adverse event should be classified by the investigator 
according to the following guidelines: 
 
Intensity 
Description 
Mild 
Any event that results in minimal transient 
impairment of a body function and does not 
threaten damage to a body structure, and/or 
does not require intervention other than 
monitoring.  
 


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22 
Moderate 
Any event which results in moderate 
transient impairment of a body function or 
damage to a body structure, or which 
requires intervention.  
 
Severe 
Any event which is life threatening, results or 
could 
result 
in 
significant 
permanent 
impairment of a body function or damage to 
a body structure, requires significant and 
timely intervention to prevent permanent 
impairment of a body function or damage to 
a body structure, or which is intolerable or 
places the subject at immediate risk of harm.  
 
 
 
 
10.4 Adverse Event Causality 
 
The assignment of the causality should be made by the investigator responsible for the care of 
the participant using the definitions in the table below.  
 
 
Relationship 
Description 
Unrelated 
There is no evidence of a causal relationship with the anti-
arrhythmic therapy or ablative therapy. 
 
Unlikely 
There is little evidence to suggest a causal relationship with the 
anti-arrhythmic or ablative therapy (e.g the event did not occur 
within a reasonable time after study treatment). There is another 
reasonable explanation for the event (e.g the participants clinical 
condition, other concomitant treatments). 
 
Possible 
There is some evidence to suggest a causal relationship with the 
anti-arrhythmic or ablative therapy (because the event occurs 
within a reasonable time after the study therapy). However, the 
influence of other factors may have contributed to the event (e.g 
the participant’s clinical condition, other concomitant treatments). 
 
Probable 
There is evidence to suggest a causal relationship with the anti-
arrhythmic or ablative therapy and the influence of other factors 
is unlikely. 
 
Definitely 
There is clear evidence to suggest a causal relationship with the 
anti-arrhythmic or ablative therapy and other contributing factors 
can be ruled out. 
 
Not Assessable 
There is insufficient or incomplete evidence to make a clinical 
judgement of the causal relationship.  
 
 
 
 
 
 


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23 
10.5 Reporting Procedures 
 
All adverse events should be reported via the eCRF within 24 hours of awareness of the event. 
All adverse events occurring between randomisation and the patient’s last study follow-up visit 
will be reported. All adverse events will be followed up until resolution or until the end of trial..  
 
Adverse events for any patients who withdraw from the study prematurely should be collected 
and followed up through at least the time of discontinuation.  
Depending on the nature of the event, the reporting procedures should be followed. All 
questions concerning adverse event reporting should be directed to the Chief Investigator in 
the first instance. 
 
Non-Serious AEs 
All such events, whether expected or not, should be recorded on the eCRF. 
 
 
Serious AEs  
An SAE form should be completed via the eCRF within 24 hours of awareness of the event. 
The Chief Investigator or designee will review each SAE via the eCRF,  
 
Please refer to section 7.1 Adverse Event Definitions for further clarification on definitions of 
AEs and SAEs and how to report in relation to study endpoints. 
 
Related and Unexpected SAEs 
All SAEs should be reported to the NRES Committee London - Brent (United Kingdom) where 
in the opinion of the Chief Investigator, the event was: 
- ‘related’, ie resulted from the administration of any of the research procedures; and 
- ‘unexpected’, ie an event that is not listed in the protocol as an expected occurrence 
 
Local Investigators should report any SAEs as required by the Sponsor, Research & 
Development office and other appropriate authorities/committees. 
 
 
11 STATISTICAL ANALYSIS 
 
11.1 Sample Size Calculation 
 
In this time-to-event study of hospital episodes, required sample numbers have been estimated 
using the log-rank test under the Freedman method based on the occurrence of first event 
during the 12-month follow-up period. The null hypothesis is that there is no difference in the 
distributions. Adopting a conservative approach, an initial two-sided alpha of 0.05 is chosen, 
given the need to allow for the inherent multiple testing between the three arms of the study, 
the conservative Bonferroni correction is applied and the alpha value used in the power 
calculations is reduced to 0.025.  
Estimating the proportion experiencing a hospital episode in the follow-up period in the anti-
arrhythmic arm as 0.63 and the corresponding proportion in the AVATAR ablation arm as 0.40, 
assuming the occurrence of 103 events, with 100 evaluable patients in each of the two 
treatment arms yields a power of 0.8. A similar power is obtained for the comparison of the 
AVATAR ablation arm (0.40) and the conventional AF ablation arm (0.20). 
A sensitivity analysis indicates that these sample size estimates are reasonable. It is anticipated 
that the loss to follow-up will be small, approximately 7%. Consequently, 321 patients will be 
randomised in a 1:1:1 manner to a treatment strategy of either AVATAR-protocol ablation, anti-
arrhythmic therapy or conventional AF ablation and followed-up for 1 year. 
 


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24 
 
 
11.2 Data Analysis  
 
Primary outcome: Failure is counted when a patient experiences any hospital episode related 
to treatment for atrial arrhythmia. Patients are censored from their treatment group when they 
switch to a treatment other than that to which they were originally assigned or when they leave 
their treatment group without having experienced a hospital episode. 
 
Data will be analyzed using the intention-to-treat principle and a p value of 0.05 or less will be 
considered significant. Primary outcome will be analysed using Kaplan-Meier statistics and 
differences will be tested using log-rank test and proportional hazards models. Other outcomes 
will be compared using t-test for continuous and Chi-square test or Fisher exact test for 
categorical variables and the appropriate generalized linear model will be used. 
 
12 DATA MANAGEMENT AND QUALITY CONTROL 
 
The complete dataset will be collected for all patients who are randomised into the trial. If 
consent to participate is withdrawn then any data collected will be retained and used in the 
study, with no further data collected or study procedures carried out on the patient. The 
electronic data capture system, InForm will be used to document clinical data.  
 
The signed, original informed consent forms and the documentation of all study procedures and 
assessments will be kept in the patients’ study notes. All data to be transferred to the study co-
ordination centre with all appropriate supporting documentation will be done as required such 
as hospital reports or imaging reports with all patient identifiers removed. Patients study 
documents will be identified by their study-specific patient number allocated at randomisation.  
 
12.1 Electronic Recording of data 
(Electronic CRF): The principal means of data collection from patient visits will be Electronic 
Data Capture (EDC) via the internet (InForm ).  Data is entered into the EDC system via site 
personnel.  All data recorded in the CRF will be signed by the Investigator or his/her 
appropriate designee.  All changes made following the electronic signing will have an 
electronic audit trail with a signature and date.  Specific instructions and further details will be 
outlined in SOPs and/or manuals. 
 
12.2 Risk Assessment 
A study-specific risk assessment will be performed prior to the start of the study to assign a 
risk category of ‘low’, ‘medium’ or ‘high’ to the trial. Risk assessment will be carried out by the 
ICTU QA Manager in collaboration with the Study Manager and the result will be used to 
guide the monitoring plan. The risk assessment will consider all aspects of the study and will 
be updated as required during the course of the study. 
  
 
12.3  Monitoring 
 
The trial conduct will be monitored and by Imperial Clinical Trials Unit (ICTU), in accordance 
with the trial risk assessment and monitoring plan. Further details of level of monitoring to be 
performed will be provided to study sites in the Investigator Site File. The monitor will assess 
compliance with the protocol, GCP and regulatory requirements. They will also review the 
patient consenting process, essential study documents, AE and SAE reporting as well as 
verifying source data to ensure the quality, accuracy and validity of the data at each 
investigational site. 


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25 
 
12.4 Quality Control and Quality Assurance 
Quality Control will be performed according to ICTU internal procedures. The study may be 
audited by a Quality Assurance representative of the Sponsor. All necessary data and 
documents will be made available for inspection.  
 
 
12.5 Archiving 
 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, defined as the last patient’s last visit. Local investigator sites will be 
responsible for making arrangements for the secure archiving of study documents locally.  
 
13 ETHICAL and LEGAL ISSUES 
13.1 Ethics Approval 
 
Ethics approval has been granted by the NRES Committee London - Brent to conduct the study 
in the United Kingdom. The study must be submitted for Site Specific Assessment (SSA) at 
each participating NHS Trust. ICTU will require a copy of the Trust R&D approval letter before 
participants can be entered into the study.  
The study will be conducted in accordance with the recommendations for physicians involved 
in research on human subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and 
later versions.  
 
13.2 Consent 
 
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information sheet offered and time allowed for consideration. Signed 
participant consent must be obtained. The right of the participant to refuse to participate without 
giving reasons must be respected. After the participant has entered the study the clinician 
remains free to give alternative treatment to that specified in the protocol at any stage if he/she 
feels it is in the participant’s best interest, but the reasons for doing so must be recorded. In 
these cases, the participants remain in the study for the purposes of follow-up and data 
analysis. All participants are free to withdraw at any time from the protocol treatment without 
giving reasons and without prejudicing further treatment.  
 
13.3 Confidentiality 
  The investigator must ensure that the subject’s confidentiality is maintained. On the CRF or 
other documents submitted to the Sponsors, subjects will be identified by a subject ID number 
only. Documents that are not submitted to the Sponsor (e.g., signed informed consent form) 
should be kept in a strictly confidential file by the investigator.The investigator shall permit direct 
access to subjects’ records and source document for the purposes of monitoring, auditing, or 
inspection by the Sponsor, authorised representatives of the Sponsor and RECs 
 
13.4 Indemnity 
 
Imperial College London holds negligent harm and non-negligent harm insurance policies which 
apply to this study. 
 


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26 
 
13.5 Sponsor 
 
Imperial College Academic Health Science Centre will act as the main Sponsor for this study. 
Delegated responsibilities will be assigned to the Investigational Centres taking part in the 
study. 
13.6 Funding 
 
Medtronic and British Heart Foundation (BHF) are providing the funding for this study in the 
form of a grant. 
 
 
14 STUDY MANAGEMENT STRUCTURE 
14.1 Trial Steering Committee (TSC)   
 
A Trial Steering Committee consisting of an Independent Chair (i.e. an individual with 
experience in clinical research who is not part of the trial team), Chief Investigator, Independent 
Experts, Operations Manager, Trial Manager and representatives of the funders is convened.  
The TSC will be responsible for the scientific and ethical conduct of the study and will supervise 
progress of the trial.  The trial protocol and subsequent amendments will be approved by the 
TSC.  The TSC members will be required to attend TSC meetings which will be held prior to 
the start of the trial and as required throughout the trial. 
 
14.2 Data & Safety Monitoring Board (DSMB) 
 
An independent Data & Safety Monitoring Board (DSMB) will be convened and meet to 
provide independent advice on study conduct and safety issues.  The DSMB will meet at the 
start of the trial and as required thereafter based on planned interim analyses. Meetings will 
be held approximately annually or as required throughout the duration of the trial. Safety data 
will be studied after 75 and 150 patients have received treatment, or one year after the first 
patient is randomised, whichever occurs sooner. Meetings will also be held as necessary 
should any urgent issues occur.  The DSMB will develop a charter which describes the 
framework within which it will operate.  
 
14.3 Early Discontinuation of the Study or Individual Subjects 
14.3.1 Early Discontinuation of the Study by Data Safety Monitoring Board (DSMB)   
If, in the opinion of the DSMB the clinical observations in the study suggest that it might not 
be justifiable to continue, the study may be terminated following consultation with the Sponsor 
and the TSC. Alternatively, the Sponsor may give written notification to the investigator, 
Ethics Committee of the early discontinuation of the study, including reasons. 
In case of early discontinuation of the study, the next Follow-up Visit assessment should be 
performed for each subject, as far as possible. The patient will then be returned to the treating 
secondary care team. 
14.3.2 Early Discontinuation of Individual Subjects 
The reason for a patient discontinuing study will be recorded in the case record form.  A 
discontinuation occurs when an enrolled patient permanently and totally withdrew the study 
consent regardless of the circumstances, prior to completion of the protocol.  A 
discontinuation must be reported immediately to the co-ordinating centre.  It may not be 
necessary for a patient to stop follow-up after an endpoint. The investigator will provide or 
arrange for appropriate follow-up for such patients, and document the course of the patient's 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
27 
condition.  The patients should, if at all possible, be followed to the end of the study despite 
reaching the study endpoint as the intention-to-treat analysis includes all patients. 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. In case of early discontinuation of a subject, the Follow-up assessments should be 
performed, as far as possible. 
 
 
14.4 Trial Management Group (TMG) 
The Trial Management Group (TMG) consisting of the Chief Investigator, Operations Manager, 
Trial Manager, Trial Monitor and additional members as appropriate, will meet fortnightly to 
ensure that the study runs smoothly and according to the pre-agreed timetable 
 
14.5 End of trial 
The trial will end when all patients have completed month 12 follow-up visit. 
 
15 PUBLICATION POLICY 
Trial results will be released in several manuscripts providing outcomes of the trial as a whole. 
All publications and presentations relating to the trial will be authorised by the Trial Steering 
Committee. Named authors will include the Investigators from all participating investigational 
centres.








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31 
18 SIGNATURE PAGE 4 (Principal INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the 
signatory and provides the necessary assurance that this study will be 
conducted at his/her investigational site according to all stipulations of the 
protocol including all statements regarding confidentiality. 
 
 
STUDY TITLE: AVATAR-AF 
 
 
PROTOCOL NUMBER: PROTOCOL VERSION 6.1 
 
 
ADDRESS OF INSTITUTION: 
 
____________________________________________ 
 
 
 
 
 
_______________________________________ 
 
 
 
 
 
____________________________________________ 
 
 
 
SIGNED: 
 
____________________________________________ 
 
 
PRINT NAME AND TITLE:
 
____________________________________________ 
 
 
DATE: 
 
 
_____________________ 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
32 
 
19 REFERENCES 
1. Rienstra M, Lyass A, Murabito JM, Magnani JW, Lubitz SA, Massaro 
JM, Ellinor PT, Benjamin EJ. Reciprocal relations between physical disability, 
subjective health, and atrial fibrillation: The Framingham HeartStudy. Am Heart 
J. 2013 Jul;166(1):171-178. 
2. Jaïs P, Cauchemez B, Macle L, Daoud E, Khairy P, Subbiah R, Hocini 
M, Extramiana F, Sacher F, Bordachar P, Klein G, Weerasooriya R, Clémenty 
J,Haïssaguerre M. Catheter ablation versus antiarrhythmic drugs for atrial 
fibrillation: the A4 study. Circulation. 2008 Dec 9;118(24):2498-505. 
3. Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG, Dubuc 
M, Reddy V, Nelson L, Holcomb RG, Lehmann JW, Ruskin 
JN; STOP AFCryoablation Investigators. Cryoballoon ablation of pulmonary veins 
for paroxysmal atrial fibrillation: first results of the North American Arctic Front 
(STOP AF) pivotal trial. J Am Coll Cardiol. 2013 Apr 23;61(16):1713-23. 
4. Wilber DJ, Pappone C, Neuzil P et al. Comparison of antiarrhythmic 
drug therapy andradiofrequency catheter 
ablation in patients with paroxysmal atrial fibrillation: a randomized controlled 
trial. JAMA, 2010; 303: 333-340 
5. H. Calkins, J. Brugada, D. L. Packer et al., “HRS/EHRA/ECAS expert 
consensus statement on catheter and surgical ablation of atrial fibrillation: 
recommendations for personnel, policy, procedures and follow-up. A report of 
the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical 
Ablation of Atrial Fibrillation. Developed in partnership with the European. 
6. Prystowsky EN, Camm J, Lip GY, Allessie M, Bergmann JF, Breithardt 
G, Brugada J, Crijns H, Ellinor PT, Mark D, Naccarelli G, Packer D, Tamargo 
J. The impact of new and emerging clinical data on treatment strategies for 
atrial fibrillation. J Cardiovasc Electrophysiol. 2010 Aug 1;21(8):946-58. 
7. Jared Bunch T, May HT, Bair TL, Peter Weiss J, Crandall BG, Osborn JS, 
Mallender C, Anderson JL, Brent Muhlestein J, Lappe DL, Day JD.  Atrial 
Fibrillation Ablation Patients have Long term Stroke Rates Similar to Patients 
without Atrial Fibrillation regardless of CHADS2 Score. Heart Rhythm. 2013 
(epub ahead of print) 
8. Lickfett L, Remerie S, Mittmann-Braun E, Nickenig G. Outcome of atrial 
fibrillation ablation: assessment of success. Minerva Cardioangiol. 2008 
Dec;56(6):635-41. 
9. Berman JP, Halperin JL. Novel oral anticoagulants for stroke prevention in 
patient with atrial fibrillation. Hosp Pract . 2013;41(1):37-48 
10. Wokhlu A, Monahan KH, Hodge DO, Asirvatham SJ, Friedman PA, Munger 
TM, Bradley DJ,  Bluhm CM, Haroldson JM, Packer DL. Long term quality of 
life after ablation of atrial fibrillation the impact of recurrence, symptom relief 
and placebo effect. J Am Coll Cardiol. 2010:55;2308-16 
11. Willems S, Steven D, Servatius H, Hoffmann BA, Drewitz I, Müllerleile K, Aydin 
MA, Wegscheider K, Salukhe TV, Meinertz T, Rostock T.  Persistence of 
pulmonary vein isolation after robotic remote-navigated ablation for atrial 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
33 
fibrillation and its relation to clinical outcome.  J Cardiovasc Electrophysiol. 
2010 Oct;21(10):1079-84 
12. Kojodjojo P, O'Neill MD, Lim PB, Malcolm-Lawes L, Whinnett ZI, Salukhe TV, 
Linton NW, Lefroy D, Mason A, Wright I, Peters NS, Kanagaratnam P, Davies 
DW. Pulmonary venous isolation by antral ablation with a large cryoballoon for 
treatment of paroxysmal and persistent atrial fibrillation: medium-term 
outcomes and non-randomised comparison with pulmonary venous isolation 
by radiofrequency ablation. Heart. 2010 Sep;96(17):1379-84. 
13. Neumann T, Vogt J, Schumacher B, Dorszewski A, Kuniss M, Neuser 
H, Kurzidim K, Berkowitsch A, Koller M, Heintze J, Scholz U, Wetzel 
U, Schneider MA,Horstkotte D, Hamm CW, Pitschner HF. Circumferential 
pulmonary vein isolation with the cryoballoon technique results from a 
prospective 3-center study. J Am Coll Cardiol. 2008 Jul 22;52(4):273-8. 
14. Malcolme-Lawes LC, Lim PB, Koa-Wing M, Whinnett ZI, Jamil-Copley S, 
Hayat S, Francis DP, Kojodjojo P, Davies DW, Peters NS, Kanagaratnam P. 
Robotic assistance and general anaesthesia improve catheter stability and 
increase signal attenuation during atrial fibrillation ablation. Europace. 2013 
Jan;15(1):41-7. 
15. Malcolme-Lawes LC, Juli C, Karim R, Bai W, Quest R, Lim PB, Jamil-Copley 
S, Kojodjojo P, Ariff B, Davies DW, Rueckert D, Francis DP, Hunter R, Jones 
D, Boubertakh R, Petersen SE,Schilling R, Kanagaratnam P, Peters NS. 
Automated analysis of atrial late gadolinium enhancement imaging that 
correlates with endocardial voltage and clinical outcomes: A 2-center study. 
Heart Rhythm. 2013 Aug;10(8):1184-91 
16. Piorkowski C, Eitel C, Rolf S, Bode K, Sommer P, Gaspar T, Kircher S, Wetzel 
U, Parwani AS, Boldt LH, Mende M, Bollmann A, Husser D, Dagres N, Esato 
M, Arya A, Haverkamp W,Hindricks G  Steerable versus nonsteerable sheath 
technology in atrial fibrillation ablation: a prospective, randomized study. Circ 
Arrhythm Electrophysiol. 2011 Apr;4(2):157-65. 
17. Malcolme-Lawes LC, Lim PB, Wright I, Kojodjojo P, Koa-Wing M, Jamil-Copley 
S, Dehbi HM, Francis DP, Davies DW, Peters NS, Kanagaratnam P. 
Characterization of the left atrial neural network and its impact on autonomic 
modification procedures. Circ  Arrhythm Electrophysiol. 2013 Jun;6(3):632-40. 
18. Reynolds MR, Gunnarsson CL, Hunter TD, Ladapo JA, March JL, Zhang 
M, Hao SC. Health outcomes with catheter ablation or antiarrhythmic drug 
therapy in atrial fibrillation: results of a propensity-matched analysis. 
Circ  Cardiovasc  Qual Outcomes. 2012 Mar 1;5(2):171-81. 
19. Laurent M Haegeli, Firat Duru, Evan E Lockwood, Thomas F 
Lu¨scher,Laurence D Sterns, Paul G Novak, Richard A Leather.  Feasibility 
and safety of outpatient radiofrequency catheter ablation procedures for atrial 
fibrillation Postgrad Med J 2010 86: 395-398. 
 
 
 
 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
34 
20 Appendix 1: Telephone Questions 
 
 
i) Have you attended hospital for any reason other than for routine blood tests (yes/no) 
If yes –  
a) Was the problem related to your atrial fibrillation? (yes/no) 
b) What were you suffering from? (palpitations/breathlessness/fainting/ bleeding/weakness/ 
confusion) 
c) What was the outcome? (Reassured (no further appointments or tests needed)/Asked to 
see your Cardiologist/Asked to see another hospital specialist/Asked to see GP) 
 
d)) Did you had any of the following investigations done in hospital? (ECG,Non-invasive 
ambulatory cardiac monitoring (including holter/memo etc)/Echo/Exercise test/Coronary 
angiogram/MRI/CT/Ultrasound/endoscopy/CXR) 
e) Were you given any drugs for you heart? 
If yes – which ones 
f) Were you advised to change any of your medications? 
If yes – which one 
g) Did you have any procedures whilst you were in hospital 
If yes- what was it 
 
ii) Have you had any of the following symptoms; 
a) racing heart beat lasting more than half an hour 
if yes – <1/week or >1/week 
b) racing heart beat more than 5mins but less than half an hour 
 if yes – <1/week or >1/week 
c) Have you had any unexplained breathlessness, dizzy spells, chest pain, fainting 
attacks/weakness/confusion 
if yes which- 
 
iii) Do you think you the situation is bad enough that you need to change medication or 
have another procedure to help make you better? (yes/no) 
 
iv) Do you think you are having side effects or complications from your treatment? 
(yes/no) 
 
v) If you have answered yes to any of the questions we recommend that you see your 
GP and discuss whether you need another appointment with you heart specialist. We 
will pass on the information from the phone call to you heart specialist and they may 
contact you directly if they are concerned about any of the answers you have given. 
 
 


AVATAR-AF 13SM1798       Protocol – Version 6.1 (9th February 2018) 
 
35 
21 Appendix 2: AVATAR-AF Endpoint definitions 
 
 
Symptoms of atrial 
fibrillation/tachycardia: 
 
 
 
 
ECG documentation: 
 
palpitations lasting >5min, transient dizziness or 
fainting, lethargy, shortness of breath on exertion, 
chest discomfort 
 
 
irregularly narrow QRS without p-waves 
lasting >30secs narrow QRS with A>V 
evident or 1:1 at >100bpm with sudden 
onset lasting >30sec or incessant at 
constant rate 
 
Pericardial Effusion: 
 
global echo-lucent space around myocardium 
>0.5cm maximally in diastole 
 
SEVERE: pericardial drain inserted, 
sternotomy, 
 
MODERATE: delayed discharge 
 
Vascular Bleeding: 
 
Bleeding visualised by haematoma or imaging 
associated with Hb drop of >2g/dl 
 
SEVERE: Surgical intervention, 
transfusion required 
 
Phrenic Nerve Palsy: 
 
Reduced excursion of hemi-diaphragm on chest 
x-ray in inspiration and expiration more than 1day 
after procedure 
 
SEVERE: exertional symptoms with CXR 
changes at >3mth 
 
MODERATE: asymptomatic with CXR 
changes at >3mth 
 
PV stenosis: 
 
Evidence of >50 reduction in ostial PV diameter 
by any form of imaging. 
 
SEVERE: exertional symptoms at >3mth 
 
MODERATE: asymptomatic at >3mth 
 
Drug Side Effect: 
 
Symptoms that are well recognised with drug or 
stop after ceasing drug 
 
Stroke: 
 
logical symptoms/signs associated with MRI or CT 
evidence of neurological bleeding/ischaemia 
 
 

SAP_001.pdf: 


 
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page 2 of 32 
Ablation Verses Anti-arrhythmic Therapy for Reducing All Hospital Episodes from 
Recurrent Atrial Fibrillation 
13SM1798 
Table of Contents 
2. 
Updates to SAP 
3 
3. 
Study Objectives 
4 
3.1. 
Primary Objectives 
4 
3.2. 
Secondary Objectives 
4 
4. Study Endpoints 
4 
4.1. 
Primary Endpoint 
4 
4.2. 
Secondary Endpoints 
4 
5. Background/Introduction 
4 
5.1. 
Introduction 
4 
5.2. 
Study Design 
5 
5.3. 
Treatment Groups 
5 
5.4. 
Study Population 
5 
5.5. 
Sample Size 
7 
5.6. 
Schedule of Time and Events 
7 
5.7. 
Randomisation 
9 
6. Analysis Set 
10 
7. Variables of Analysis 
10 
7.1. 
Primary Endpoint Variable 
10 
7.2. 
Secondary Endpoint Variables 
10 
7.3. 
Safety and Efficacy Variables 
11 
7.4. 
Baseline and Demographic Variables 
11 
8. Statistical Methodology 
12 
8.1. 
Baseline Demographics 
12 
8.2. 
Primary Endpoint Analysis 
12 
8.3. 
Secondary Endpoint Analysis 
12 
8.4. 
Safety Variable Analysis 
13 
8.5. 
Health Economic Analysis 
14 
8.6. 
Interim Analysis 
14 
8.7. 
Exploratory Analysis 
Error! Bookmark not defined. 
8.8. 
Tables to Present 
15 
8.9. 
Figures to Present 
32 
 


 
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page 3 of 32 
2. 
Updates to SAP 
Version 
Date 
Summary of Updates 
v1.1 
24MAR2018 
Section 3.2 – Secondary Objective: Text changed from “…performed as a daycase has a 
comparable safety and efficacy profile to the conventional approach.” to “…performed as 
a daycase is less effective than the conventional approach.” to reflect update to Protocol 
v6.1  
Section 5.5 – Sample Size: The alpha value assigned due to the Bonferroni Correction has 
been updated from 0.017 to 0.025 to as the trial is only analysing two pairs of treatments. 
Section 5.5 – Sample Size: Number of events corrected from 97 to 103 (calculation not 
affected).Section 5.6 – Time and Events: Updated to reflect protocol update (±3 days 
changed to ±7) 
Section 5.7 - Randomisation: Updated to reflect protocol update (±3 days changed to ±7) 
Section 6 – Analysis Set: Additional text added to include for proposed per-protocol 
analyses. 
Section 8.2 – Primary Analysis: The alpha has been updated to 0.025 due to the Bonferroni 
Correction alteration as above. 
Section 8.2 – Primary Analysis: Additional text added to clarify analysis is to be carried 
out as per primary (AVATAR vs Anti-Arrhythmics) and secondary (AVATAR vs 
Conventional) objectives. 
Section 8.2 – Primary Analysis: Additional text added to allow for per protocol analyses. 
Section 8.3 – Secondary Analyses: see above edits for Primary Analysis 
Section 8.4 – Safety Analyses: see above edits for Primary Analysis 
 
 
 
 
 


 
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3. 
Study Objectives  
 
 
 
3.1. Primary Objectives 
To determine if antral AF ablation without electrophysiological confirmation of PV isolation is 
more effective than anti-arrhythmic agents at achieving freedom from hospital based treatment. 
3.2. Secondary Objectives 
To determine if antral AF ablation without electrophysiological confirmation of PV isolation 
performed as a daycase is less effective than the conventional approach. 
 
4. 
Study Endpoints 
4.1. Primary Endpoint 
Time to all hospital episodes (Emergency Room or patient request for OPD) related to treatment 
for atrial arrhythmia. 
4.2. Secondary Endpoints 
1. Time to death or stroke from any cause. 
2. Any complications caused by the procedure (pericardial effusion, bleeding >2 units, phrenic 
nerve palsy and other) or the anti-arrhythmic drug (GI disturbance, skin irritation and other). 
3. All hospital episodes which result in a change in therapy for atrial arrhythmia. 
 
5. 
Background/Introduction  
5.1. Introduction 
Developments in paroxysmal AF ablation have been monitored against the definition of any 
detected 30seconds of AF, which is not necessarily measure of symptom control. Hospital 
episodes are an objective and well established endpoint throughout the healthcare system and 
are more reflective of the patient’s expectations. The increasing population burden of AF will 
need more cost effective approaches to treatment of symptoms. It is not known whether current 
approaches to antral pulmonary vein ablation still necessitates pulmonary vein mapping, which 
is a major source of to cost and complexity. 
The proposed study is based on the following observations: 
i) AF ablation is well established as the most effective method for preventing recurrence. 
ii) Current methods for AF ablation are costly and complex with only a minority of the AF 
population having access to such procedure. 


 
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iii) The Advance Cryoballoon is effective at producing antral PV ablation. 
iv) AF ablation has not been compared against anti-arrhythmic agents with the primary goal of 
reducing hospital episodes. 
5.2. Study Design 
AVATAR-AF is a multicentre, randomised controlled study comparing a streamlined 
AVATAR-protocol ablation procedure to anti-arrhythmic therapy in patients with documented 
paroxysmal AF who are considered to need an escalation of therapy. A secondary control arm 
will also compare the AVATAR-protocol to conventional AF ablation. 321 patients who are on 
no prior anti-arrhythmic, ‘pill-in-pocket’ or taking regular anti-arrhythmics will be randomised 
in a 1:1:1 manner to a treatment strategy of either AVATAR-protocol ablation, anti-arrhythmic 
therapy or conventional AF ablation and followed-up for 1 year. 
5.3. Treatment Groups 
Arm 1: AVATAR-AF Ablation Protocol 
Arm 2: Conventional AF Ablation  
Arm 3: Anti-arrhythmic therapy 
5.4. Study Population 
The AVATAR-AF study is recruiting patients between the ages of 18 and 80 with documented 
paroxysmal atrial fibrillation including modification or initiation of anti-arrhythmic agent 
required for symptom control. 
In order to be eligible for the study the patient must not have any of the following: 
 Contraindication to catheter ablation 
 No carer to enable daycase discharge 
 Documented Arrhythmias other than AF unless they have had curative ablation (e.g. for 
atrial flutter) 
 No documentation of sinus rhythm within 3 months 
 Valvular or coronary heart disease needing regular follow up 
 EF <45% or moderate/severe LV dysfunction(determined by Echocardiogram in the last 
6 months) 
 Active gastrointestinal disease precluding anticoagulation or trans-oesophageal 
echocardiogram 


 
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 Renal failure with creatinine >200 μmol/L or on dialysis 
 Active fever or infection 
 Life expectancy shorter than the trial 
 Allergy to contrast 
 Severe cerebrovascular disease 
 Bleeding or clotting disorders or inability to receive heparin 
 Uncontrolled diabetes (HbA1c ≥73 mmol/mol or HbA1c ≤64 mmol/mol and Fasting 
Blood Glucose ≥9.2 mmol/L) (shown in the last six months without evidence of being 
brought under control)* 
 Serum Potassium [K+] <3.5 mmol/L or >5.0 mmol/L (shown in the last six months 
without evidence of being brought under control) 
 Malignancy needing surgery, chemotherapy or radiotherapy 
 Pregnancy or women of child-bearing potential not using a highly effective method of 
contraception ** 
 Must not have previous (4 weeks prior to screening) or current participation in another 
clinical trial with an investigational drug or investigational device 
 Unable to give informed consent 
 Uncontrolled thyroid disease defined as abnormal thyroid function tests causing cardiac 
manifestations within the last 6mths 
 Unable to attend follow up visits 
* A fasting blood glucose must have been done within the last 6mths confirming that blood glucose under 
control. If no blood test result available, a new fasting blood glucose sample will be taken from all consented 
potential participants at screening to exclude uncontrolled diabetes, defined as:  
o 
HbA1c ≥73 mmol/mol or  
o 
HbA1c ≤64 mmol/mol and Fasting Blood Glucose ≥9.2 mmol/L  
 
** Women of child-bearing potential not using a highly effective method of contraception must undergo a 
pregnancy test. Acceptable methods of contraception include the following:  
o 
Barrier type devices (e.g. female condom, diaphragm and contraceptive sponge) used ONLY in 
combination with a spermicide.  
o 
Intra-uterine devices.  
o 
Oral contraceptive agents started at least 90 days before start of study.  
o 
Depo-Provera (medroxyprogesterone acetate).  
o 
Levonorgestrel implants. 
o 
Naturally or surgically sterile (amenorrheic for at least 1 year and no record of child birth for naturally 
sterile persons).  
o Male partner is sterile and is the only sexual partner 
 


 
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At the screening visit, the patient will be examined to ensure that none of the exclusion criteria 
are met. Their general health will be assessed in a physical examination and recording of vital 
signs. The patient’s medical and medication history will also be recorded. A fasting blood 
sample will also be taken to exclude patients with uncontrolled diabetes or [K+] and serum 
creatinine outside acceptable safety. A blood test result within 6 months is acceptable. Any 
blood test result taken more than 6 months prior to randomisation will need to be repeated. A 
copy of the blood results must be filed in the patient notes. Any other routine clinical tests 
should be performed as per local practice. 
If the patient does not meet any of the exclusion criteria and no additional complications are 
encountered during the screening process then once written, informed consent has been 
received the patient is eligible for randomisation. 
 
5.5. Sample Size 
In this time-to-event study of hospital episodes, required sample numbers have been estimated 
using the log-rank test under the Freedman method based on the occurrence of first event during 
the 12-month follow-up period. The null hypothesis is that there is no difference in the 
distributions. Adopting a conservative approach, an initial two-sided alpha of 0.05 is chosen, 
given the need to allow for the inherent multiple testing between the three arms of the study, 
the conservative Bonferroni correction is applied and the alpha value used in the power 
calculations is reduced to 0.025. 
Estimating the proportion experiencing a hospital episode in the follow-up period in the anti-
arrhythmic arm as 0.63 and the corresponding proportion in the AVATAR ablation arm as 0.40, 
assuming the occurrence of 103 events, with 100 evaluable patients in each of the two treatment 
arms yields a power of 0.80. A similar power is obtained for the comparison of the AVATAR 
ablation arm (0.40) and the conventional AF ablation arm (0.20). 
A sensitivity analysis indicates that these sample size estimates are reasonable. It is anticipated 
that the loss to follow-up will be small, approximately 7%. Consequently, 321 patients will be 
randomised in a 1:1:1 manner to a treatment strategy of either AVATAR protocol ablation, anti-
arrhythmic therapy or conventional AF ablation and followed-up for 1 year. 
5.6. Schedule of Time and Events 
In the 4 week period (28 days ± 7days) between Randomisation and 1st Intervention, there will 
be no change to the patient’s arrhythmia treatment: the treatment which the patient has been 


 
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randomised to will only occur on the date of 1st Intervention. All three treatment arms will 
follow the same scheduling protocol regardless of intervention. 
1st Intervention will be considered baseline, all patient returning for follow-up 1 year ± 14 days 
after this date. At this visit, all patients will undergo the following assessments:  
- Physical Examination  
- Vital signs  
- Concomitant medications  
- ECG  
- 24 hour holter monitor tape  
- EQ5D quality of life questionnaire  
- Adverse Events  
- Study Endpoints  
- Atrial Fibrillation Effect on QualiTy of life (AFEQT) patient questionnaire 
 
 


 
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5.7. Randomisation 
Eligible patients who have given written, informed consent and who meet all the inclusion 
criteria and no exclusion criteria will undergo 1:1:1 randomisation to an un-blinded treatment 
of either AVATAR-protocol AF Ablation, medical anti-arrhythmic therapy or conventional AF 
ablation. Randomisation will be performed electronically using the InForm electronic data 
capture system and will be stratified by site. 
From the date of randomisation, the 1st Intervention date (ablation or anti-arrhythmic 
medication change) must occur 28 days ± 7days after this, therefore an ablation procedure date 
will be identified according to local EP catheter lab availability for each consenting, eligible 


 
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patient and randomisation of the patient will then be scheduled for 28 days ± 7days from this 
available date. 
The patient may be withdrawn from any AF ablation treatment by the Investigator if any safety 
concerns arise during the period between randomisation and the ablation which make the patient 
an unsuitable candidate for the procedure. The patient will then be withdrawn from the study. 
 
6. 
Analysis Set 
All treatment evaluation will be performed on the principle of intention to treat (ITT) with 
additional per-protocol analyses ran alongside if defined (see Section 8). The per-protocol 
analysis set will consist of patients who received treatment originally allocated. 
A sensitivity analysis will also be performed excluding patients who are withdrawn from the 
study between randomisation and start of treatment / 1st intervention. Any subjects that have 
withdrawn during this period will still be required to attend the end-of-study follow-up visit. 
 
 
7. 
Variables of Analysis 
7.1. Primary Endpoint Variable 
Time from 1st intervention to any hospital episodes (Emergency Room or patient request for 
OPD) related to treatment for atrial arrhythmia that has been formally adjudicated by an 
independent committee as a primary endpoint. Failure to enter discharge protocol at the Week 
12 Review will also result in the primary endpoint being met. 
7.2. Secondary Endpoint Variables 
1. Time from 1st intervention to death or stroke from any cause.  
2. Number of and time from 1st intervention to any of the following complications caused by: 
  Pericardial Effusion 
  Vascular Bleeding (>2 units) 
  Phrenic Nerve Palsy 
  PV Stenosis 
  Drug side-effects (including GI disturbance, skin irritation and other) 
  Other  


 
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3. Number of and time from 1st intervention to any hospital episodes which result in a change 
in therapy for atrial arrhythmia. 
Information about trial adverse events will be collected from randomisation until the end of the 
trial.  
 
7.3. Safety and Efficacy Variables 
The following information will be recorded and reported to demonstrate treatment safety and 
efficacy: 
 Vital Signs (variables including; weight, blood pressure, pulse, body temp)  
 Physical Examination  
 Patient Health Questionnaires 
o Quality of Life (QoL) 
o Atrial Fibrillation Effect on QualiTy-of-life (AFEQT)  
o Telephone Follow-up  
 CHADSVASC score 
 ECG (variables including; ventricular rate, PR & QRS interval)  
 Concomitant Medications 
 Pulmonary Vein Isolation Measurements of Ablation Treatments (variables including; 
total duration of freeze, number of applications, Grade 4 occlusions, lowest 
temperature) 
 Protocol Deviations and Violations 
 Adverse and Serious Adverse Events 
 
7.4. Baseline and Demographic Variables  
The following additional information will be recorded and reported: 
 Baseline Demographics (variables including; age, gender, ethnicity, height, weight). 
 Medical History (including past cardiovascular medication) 
 Echocardiogram Results 
 


 
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8. 
Statistical Methodology 
8.1. Baseline Demographics 
Baseline demographic variables and other relevant clinical baseline characteristics (including, 
but not limited to, medical history, pulse rate, blood pressure, QoL/AFEQT questionnaire 
results, CHADSVASC score, echo-cardiology readings, ECG and 24hr holter monitor results) 
will be summarised for each treatment group. 
Summaries of continuous variables will be presented as means and standard deviations if 
normally distributed, and as medians and inter-quartile ranges for skewed data, whilst 
categorical variables will be presented as frequencies and percentages. 
8.2. Primary Endpoint Analysis 
Failure is counted when a patient experiences any hospital episode related to treatment for atrial 
arrhythmia.  Time to failure will be taken as the time from 1st Intervention to the time of event. 
Data will be analysed using the intention-to-treat principle and a p-value of 0.025 or less will 
be considered significant. Primary outcome will be analysed using Kaplan-Meier statistics and 
differences between treatment arms will be assessed using log-rank testing and proportional 
hazards models. Models containing one or more of the following covariates may also be 
assessed if deemed necessary; site, weight, hypertension, number of anti-arrhythmic taken by 
patient prior to 1st intervention. 
Primary endpoint analysis will be carried out between AVATAR-AF Ablation and the Anti-
Arrhythmic drug treatment arm in order to investigate the primary objective. The secondary 
objective will be assessed by testing AVATAR-AF Ablation against the Conventional Ablation 
arm. 
An additional per-protocol analysis will be carried out in conjunction with the above.  
 
8.3. Secondary Endpoint Analysis 
Time to death or stroke; time to procedural/drug-based complication and time to hospital 
episode resulting in change in therapy will be analysed using Kaplan-Meier statistics. 
Differences between treatment arms will be assessed using log-rank testing and proportional 
hazards models. Models containing one or more of the following co-variates may also be 
assessed if deemed necessary; site, weight, hypertension, number of anti-arrhythmic taken by 
patient prior to 1st intervention. 


 
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Secondary endpoint analysis will be carried out between AVATAR-AF Ablation and the Anti-
Arrhythmic drug treatment arm in order to investigate the primary objective. The secondary 
objective will be assessed by testing AVATAR-AF Ablation against the Conventional Ablation 
arm. 
Additional per-protocol analyses will be carried out in conjunction with the above. 
 
8.4. Safety Variable Analysis 
Adverse events will be summarised by treatment and severity. A separate table summarising 
adverse events and their relationship to study treatment will also be produced.  
Serious adverse events will be listed and summarised by site, category and treatment. A separate 
table summarising serious adverse events and their relationship to study treatment will also be 
produced. 
All safety variables will be summarized in the form of frequency tables for categorical variables 
or descriptive statistics for continuous variables. Quality-of-Life (QoL) questionnaire results 
will be summarised by Health State Score. Atrial Fibrillation Effect on QualiTy-of-life 
(AFEQT) questionnaire results will be summarised by both overall AFEQT score and subscale 
score derived using the formulae stated within the AFEQT Questionnaire Instruction and 
Scoring ManualREFERENCES 
If it is deemed appropriate, treatment effect will be assessed via t-test for continuous variables 
and Chi-square test or Fisher exact test for categorical variables (with the appropriate 
generalized linear model being used). Models containing one or more of the following co-
variates may also be assessed if deemed necessary: site, weight, hypertension, number of anti-
arrhythmics taken by patient prior to 1st intervention. A p-value of 0.025 or less will be 
considered significant. Any testing for treatment effect will be carried out between AVATAR-
AF Ablation and the Anti-Arrhythmic drug treatment arm in order to investigate the primary 
objective. The secondary objective will be assessed by testing AVATAR-AF Ablation against 
the Conventional Ablation arm. 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 14 of 32 
8.5. Health Economic Analysis 
A health economist is to analyse selected data to determine the overall economic benefits of 
antral AF ablation without electrophysiological confirmation of PV isolation. Details of this 
analysis will be covered in a separate document, external from the SAP.  
 
8.6. Interim Analysis 
Interim reports detailing baseline demographics, safety endpoints and primary endpoints (if 
requested) will be produced for assessment and discussion at DSMB meetings, the framework 
of which will be provided within the DSMB charter. 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 15 of 32 
8.7. Tables to Present 
Table 1.1: Subject Disposition  
 
Site A 
Site B 
… 
Total 
Screened 
 
 
 
 
Randomised 
 
 
 
 
Treatment A  
 
 
 
Treatment B  
 
 
 
Treatment C  
 
 
 
Withdrawn 
 
 
 
 
Reason for Withdrawal  
 
 
 
Completed 
 
 
 
 
 
 
Table 2.1: Listing of protocol deviations  
Treatment Subject 
Site 
Type 
Start Date 
End Date 
 
 
 
 
 
 
 
 
Table 2.2: Number of protocol deviations by centre and category 
Type of Deviation 
Site A 
Site B 
… 
Total 
Patient was incorrectly included in the trial (did not meet all 
the inclusion and exclusion criteria 
 
 
 
 
… 
 
 
 
 
Patient pregnancy 
 
 
 
 
Other 
 
 
 
 
Total  
 
 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 16 of 32 
Table 3.1: Baseline characteristics 
 Variable  
Statistics 
AVATAR-AF 
Ablation 
Anti-
arrhythmic 
therapy 
Conventional 
AF Ablation 
Age (y) 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
Race (n (%)) 
xxxxxx 
 
 
 
 
xxxxxx 
 
 
 
Ethnicity (n (%)) 
xxxxxx 
 
 
 
 
xxxxxx 
 
 
 
Gender (n (%)) 
Female 
 
 
 
 
Male 
 
 
 
Height (cm) 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
Weight (kg) 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
Pulse (bpm) 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
Systolic BP 
N 
 
 
 
 
Mean 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 17 of 32 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
Diastolic BP 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
QoL Score 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
QoL Score (n (%)) 
<40 
 
 
 
 
… 
 
 
 
 
90-99 
 
 
 
 
100+ 
 
 
 
Chadsvasc Score (n (%)) 
0 
 
 
 
 
1 
 
 
 
 
.. 
 
 
 
 
6 
 
 
 
AFEQT Score 
N 
 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
 
AFEQT Score (n (%)) 
0-19 
 
 
 
… 
 
 
 
80-100 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 18 of 32 
Anti-Arrhythmics Taken (n (%)) 
Amiodarone 
 
 
 
 
… 
 
 
 
 
Propafenone 
 
 
 
Beta Blockers Taken (n (%)) 
xxxxx 
 
 
 
Calc. Ch. Blocker Taken (n (%)) 
xxxxx 
 
 
 
Record of Anti-Coag Pre-
Procedure (n (%)) 
Yes – 
Bridging 
 
 
 
Yes – 
Continuous 
 
 
 
 
No 
 
 
 
Expectation of Anti-Coag Post-
Procedure (n (%)) 
Yes 
 
 
 
No 
 
 
 
Subjects displaying evidence of 
Paroxysmal Atrial Fibrillation     
(n (%)) 
Yes 
 
 
 
No 
 
 
 
ECG Rhythm (n (%)) 
Sinus 
 
 
 
 
SVT 
 
 
 
 
… 
 
 
 
 
Q-Waves 
 
 
 
Ejection Fraction (%) 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
Pericardial Effusion (n (%)) 
Yes 
 
 
 
 
No 
 
 
 
Presence of Thrombus (n (%)) 
Yes 
 
 
 
 
No 
 
 
 
*Table Note: To include the following variables - Age, race, ethnicity, gender, height, weight, pulse 
rate, Systolic BP, Diastolic BP, QoL Score, AFEQT Score, CHADSVASC Score, Heart Medications 
Taken, Record of Anti-Coagulation pre-procedure, Anti-Coagulation requirements post-procedure  
24hr Holter, ECG, Echocardiology. 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 19 of 32 
PRIMARY ENDPOINT 
Table 4.1: Listing of all hospital episodes (Emergency Room or patient request for OPD) related to 
treatment for atrial arrhythmia. 
Treatment 
Subj. 
Date of 
Visit 
Discharge 
Protocol? 
Reason for 
Adjudication 
Outcome 
Endpoint? 
Time to 
Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4.2: Log-rank test investigating occurrence of AF related hospital visits*  
Treatment Arm 
Events Observed 
Events Expected 
 
 
 
 
 
 
Total  
 
 
Chi2(1)  = 
x.xxx 
 
Pr>chi2 = 
0.xxx 
*4.2.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*4.2.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
Table 4.3: Cox proportional hazards model investigating occurrence of AF related hospital visits* 
Variable 
Obvs 
Mean 
SD 
Min 
Max 
Time to Endpoint 
xxx 
xx.x 
xx.xx 
xx 
xx 
Endpoint Occurred 
xxx 
 
 
 
 
Treatment 
xxx 
 
 
 
 
_st 
xxx 
 
 
 
 
_d 
xxx 
 
 
 
 
_t 
xxx 
 
 
 
 
_t0 
xxx 
 
 
 
 
 
_t 
Haz. Ratio 
SE 
z 
P>|z| 
95% CI 
Treatment 
x.xxx 
x.xxx 
x.xx 
0.xxx 
x.xxx x.xxx 
*4.3.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*4.3.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 20 of 32 
SECONDARY ENDPOINTS 
Table 5.1: Listing of deaths or strokes from any cause. 
Treatment 
Arm 
Subject 
Number 
Type of 
Event 
Date/Time 
of Event 
Time to 
Event 
Cause of 
Event 
Relation to 
Treatment 
Comments 
 
 
 
 
 
 
 
 
 
Table 5.2: Log-rank test investigating occurrence of deaths and strokes* 
Treatment Arm 
Events Observed 
Events Expected 
 
 
 
 
 
 
Total  
 
 
Chi2(1)  = 
x.xxx 
 
Pr>chi2 = 
0.xxx 
*5.2.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*5.2.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
Table 5.3: Cox proportional hazards model investigating occurrence of deaths and strokes* 
Variable 
Obvs 
Mean 
SD 
Min 
Max 
Time to Endpoint 
xxx 
xx.x 
xx.xx 
xx 
xx 
Endpoint Occurred 
xxx 
 
 
 
 
Treatment 
xxx 
 
 
 
 
_st 
xxx 
 
 
 
 
_d 
xxx 
 
 
 
 
_t 
xxx 
 
 
 
 
_t0 
xxx 
 
 
 
 
 
_t 
Haz. Ratio 
SE 
z 
P>|z| 
95% CI 
Treatment 
x.xxx 
x.xxx 
x.xx 
0.xxx 
x.xxx x.xxx 
*5.3.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*5.3.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 21 of 32 
Table 5.4: Listing of complications arising from therapy. 
Treatment 
Arm 
Subject 
Number 
Type of 
Event 
Date/Time 
of Event 
Time to 
Event 
Cause of 
Event 
Relation to 
Treatment 
Comments 
 
 
 
 
 
 
 
 
 
Table 5.5: Log-rank test investigating occurrence of complications* 
Treatment Arm 
Events Observed 
Events Expected 
 
 
 
 
 
 
Total  
 
 
Chi2(1)  = 
x.xxx 
 
Pr>chi2 = 
0.xxx 
*5.5.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*5.5.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
Table 5.6: Cox proportional hazards model investigating occurrence of complications* 
Variable 
Obvs 
Mean 
SD 
Min 
Max 
Time to Endpoint 
xxx 
xx.x 
xx.xx 
xx 
xx 
Endpoint Occured 
xxx 
 
 
 
 
Treatment 
xxx 
 
 
 
 
_st 
xxx 
 
 
 
 
_d 
xxx 
 
 
 
 
_t 
xxx 
 
 
 
 
_t0 
xxx 
 
 
 
 
 
_t 
Haz. Ratio 
SE 
z 
P>|z| 
95% CI 
Treatment 
x.xxx 
x.xxx 
x.xx 
0.xxx 
x.xxx x.xxx 
*5.6.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*5.6.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 22 of 32 
Table 5.7: Listing of hospital episodes resulting in a change in therapy for atrial arrhythmia 
Treatment 
Arm 
Subject 
Number 
Type of 
Event 
Date/Time 
of Event 
Time to 
Event 
Cause 
of Event 
Relation to 
Treatment 
Comments 
 
 
 
 
 
 
 
 
 
Table 5.8: Log-rank test investigating occurrence of hospital episodes resulting in a change in 
therapy for atrial arrhythmia* 
Treatment Arm 
Events Observed 
Events Expected 
 
 
 
 
 
 
Total  
 
 
Chi2(1)  = 
x.xxx 
 
Pr>chi2 = 
0.xxx 
*5.8.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*5.8.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
Table 5.9: Cox proportional hazards model investigating occurrence of hospital episodes resulting 
in a change in therapy for atrial arrhythmia* 
Variable 
Obvs 
Mean 
SD 
Min 
Max 
Time to Endpoint 
xxx 
xx.x 
xx.xx 
xx 
xx 
Endpoint Occured 
xxx 
 
 
 
 
Treatment 
xxx 
 
 
 
 
_st 
xxx 
 
 
 
 
_d 
xxx 
 
 
 
 
_t 
xxx 
 
 
 
 
_t0 
xxx 
 
 
 
 
 
_t 
Haz. Ratio 
SE 
z 
P>|z| 
95% CI 
Treatment 
x.xxx 
x.xxx 
x.xx 
0.xxx 
x.xxx x.xxx 
*5.9.1 – Comparison between AVATAR-AF and Anti- Arrthymnics 
*5.9.2 – Comparison between AVATAR-AF and Conventional Ablation 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 23 of 32 
SAFETY AND EFFICACY – TREATMENT PROCEDURE                                                            
Table 6.1: Summary of 1st Intervention (Both Ablation Arms) 
 Variable  
Statistics 
AVATAR-AF 
Ablation 
Conventional 
AF Ablation 
CHADSVASC Score 
N 
 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
No. Subjects Anti-Coagulated 
pre-procedure 
Yes – Bridging Protocol 
 
 
Yes – Cont. Protocol 
 
 
 
No  
 
 
No. Subjects Anti-Coagulated 
post-procedure 
Yes 
 
 
No 
 
 
Was TOE performed 
Yes 
 
 
 
No 
 
 
Sedation Type 
GA 
 
 
 
Sedation +/- Local 
 
 
 
Local Only 
 
 
Transseptal Puncture Method 
Transoesophageal 
Echo 
 
 
Aortic pigtail 
 
 
 
Coronary Sinus 
Catheter 
 
 
 
Intracardiac Echo 
 
 
Diaphragmatic Monitoring 
Method 
Visual Only 
 
 
Phrenic Nerve Pacing 
w/ Temp Box 
 
 
 
Phrenic Nerve Pacing 
w/ EP Stimulator 
 
 
 
Other Phrenic Nerve 
Monitoring 
 
 
RLPV Lowest Temperature 
Recorded 
N 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
RUPV Lowest Temperature 
Recorded 
N 
 
 
Mean 
 
 
 
SD 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 24 of 32 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
LUPV Lowest Temperature 
Recorded 
N 
 
 
Mean 
 
 
SD 
 
 
Min 
 
 
Median 
 
 
Max 
 
 
LLPV Lowest Temperature 
Recorded 
N 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
RLPV PV Isolation after Adv. 
Balloon Alone? 
Yes 
 
 
No 
 
 
RUPV PV Isolation after Adv. 
Balloon Alone? 
Yes 
 
 
No 
 
 
LUPV PV Isolation after Adv. 
Balloon Alone? 
Yes 
 
 
No 
 
 
LLPV PV Isolation after Adv. 
Balloon Alone? 
Yes 
 
 
No 
 
 
RLPV Complete (Grade 4) 
Occlusion Achieved? 
Yes 
 
 
No 
 
 
RUPV Complete (Grade 4) 
Occlusion Achieved? 
Yes 
 
 
No 
 
 
LUPV Complete (Grade 4) 
Occlusion Achieved? 
Yes 
 
 
No 
 
 
LLPV Complete (Grade 4) 
Occlusion Achieved? 
Yes 
 
 
No 
 
 
All Veins Isolated at end of 
procedure? 
Yes 
 
 
No 
 
 
Diaphragmatic Motion Normal 
at end of procedure? 
Yes 
 
 
No 
 
 
Patient Fully Anti-Coagulated 
on Discharge? 
Yes 
 
 
No 
 
 
Daycase Discharge? 
Yes 
 
 
No 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 25 of 32 
Table 6.2: Summary of Week 8 Review (Both Ablation Arms) 
 Variable  
Statistics 
AVATAR-AF 
Ablation 
Conventional AF 
Ablation 
Status of Patient at Review 
Asymptomatic for 
palpitations 
 
 
 
Showing weekly 
improvement 
 
 
 
Not possible to assess 
in time scale 
 
 
 
Experiencing ongoing 
symptoms 
 
 
No. Patients referred for Re-
Do Procedure 
Yes 
 
 
No 
 
 
 
Table 6.3: Summary of 2nd Intervention (Both Ablation Arms) 
 Variable  
Statistics 
AVATAR-AF 
Ablation 
Conventional AF 
Ablation 
CHADSVASC Score 
N 
 
 
 
Mean 
 
 
 
SD 
 
 
 
Min 
 
 
 
Median 
 
 
 
Max 
 
 
No. Subjects Anti-Coagulated 
pre-procedure 
Yes – Bridging Protocol 
 
 
Yes – Cont. Protocol 
 
 
 
No  
 
 
No. Subjects Anti-Coagulated 
post-procedure 
Yes 
 
 
No 
 
 
Was TOE performed 
Yes 
 
 
 
No 
 
 
… 
 
 
 
LUPV Isolation at Start? 
Yes 
 
 
 
No 
 
 
LLPV Isolation at Start? 
Yes 
 
 
 
No 
 
 
RUPV Isolation at Start? 
Yes 
 
 
 
No 
 
 
RLPV Isolation at Start? 
Yes 
 
 
 
No 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 26 of 32 
Table 6.4: Summary of 1st Intervention (Anti-Arrhythmic Arm) 
 Variable  
Statistics 
Anti-arrhythmic 
therapy 
Number of Subjects 
N 
 
Anti-Arrhythmic Assigned (%) 
Amiodarone 
 
 
Dronedarone 
 
 
Sotalol 
 
 
Digoxin 
 
 
Flecainide 
 
 
… 
 
Beta-Blocker Assigned (%) 
Atenalol 
 
 
Bisoprolol 
 
 
Metoprolol 
 
 
Propanolol 
 
 
… 
 
*Table Note: To include for all Anti-Arrhythmics and Beta-Blockers 
 
Table 6.5: Review of Intervention (Anti-Arrhythmic Arm) 
 Variable  
Statistics 
Week 4 Review 
Week 8 Review 
Number of Subjects 
N 
 
 
Was treatment changed at 
review? (%) 
No 
 
 
Increased 
 
 
 
Decreased 
 
 
 
Change of Agent 
 
 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 27 of 32 
SAFETY AND EFFICACY – ADVERSE EVENTS                                                            
Table 7.1: Summary of Adverse Events by Treatment and Severity 
 
  
Events 
Patients 
 
AVATAR-
AF 
Ablation 
Anti-
arrhythmic 
therapy 
Conventional 
AF Ablation 
Total 
AVATAR-
AF 
Ablation 
Anti-
arrhythmic 
therapy 
Conventional 
AF Ablation 
Total 
 
Number of 
Adverse 
events 
 
 
 
 
 
 
 
 
Severity 
Mild 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
Number of 
SAEs 
 
 
 
 
 
 
 
 
Reason for SAE 
Missing 
 
 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
Hospitalisation 
required 
 
 
 
 
 
 
 
 
Life 
threatening 
 
 
 
 
 
 
 
 
Other medical 
important 
events 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
Table 7.2: Number of Adverse Events by Treatment and causality relationship 
 
Subjects with AEs* 
Treatment 
No 
Relationship 
Unlikely Possible Probable Definitely 
Not Yet 
Defined 
Total 
AVATAR-AF protocol 
ablation 
 
 
 
 
 
 
 
Anti-arrhythmic 
therapy 
 
 
 
 
 
 
 
Conventional AF 
ablation 
 
 
 
 
 
 
 
All subjects 
 
 
 
 
 
 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 28 of 32 
 
All AEs 
Treatment 
No 
Relationship 
Unlikely Possible Probable Definitely 
Not Yet 
Defined 
Total 
AVATAR-AF protocol 
ablation 
 
 
 
 
 
 
 
Anti-arrhythmic 
therapy 
 
 
 
 
 
 
 
Conventional AF 
ablation 
 
 
 
 
 
 
 
All subjects 
 
 
 
 
 
 
 
*Table Note: Where subjects have more than one AE the highest relationship has been used. 
 
Table 7.3: Listing of Serious Adverse Events 
Treatment 
Subject 
AE Diagnosis 
Details 
Relation to 
Treatment 
Surgery 
Required? 
 
 
 
 
 
 
 
Table 7.3: Listing of Serious Adverse Events (Continued) 
Treatment 
Subject 
Start Date 
Recovery 
Date 
Expected- 
ness 
Event 
Frequency 
Comments 
 
 
 
  
 
 
 
 
Table 7.4: Number of Serious Adverse Events by Treatment and causality relationship 
 
Subjects with SAEs* 
Treatment 
No 
Relationship 
Unlikely Possible Probable Definitely 
Not Yet 
Defined 
Total 
AVATAR-AF protocol 
ablation 
 
 
 
 
 
 
 
Anti-arrhythmic 
therapy 
 
 
 
 
 
 
 
Conventional AF 
ablation 
 
 
 
 
 
 
 
All subjects 
 
 
 
 
 
 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 29 of 32 
 
All SAEs 
Treatment 
No 
Relationship 
Unlikely Possible Probable Definitely 
Not Yet 
Defined 
Total 
AVATAR-AF protocol 
ablation 
 
 
 
 
 
 
 
Anti-arrhythmic 
therapy 
 
 
 
 
 
 
 
Conventional AF 
ablation 
 
 
 
 
 
 
 
All subjects 
 
 
 
 
 
 
 
*Table Note: Where subjects have more than one AE the highest relationship has been used. 
 
 
SAFETY AND EFFICACY – CONCOMITANT MEDICATIONS                                                            
Table 8.1: Concomitant Medications: Anti-coagulants 
 Medication 
Statistics 
AVATAR-AF 
Ablation 
Anti-arrhythmic 
therapy 
Conventional AF 
Ablation 
xxxx 
Yes 
 
 
 
 
No 
 
 
 
 
Unavailable 
 
 
 
xxxxx 
Yes 
 
 
 
 
No 
 
 
 
Unavailable 
 
 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 30 of 32 
SAFETY AND EFFICACY – ECG & HOLTER                                                          
Table 9.1: ECG Results for Subjects with Evidence of Atrial Fibrillation 
 
 
 
Treatment 
Test 
Visit 
Statistics 
AVATAR
-AF 
Ablation 
Anti-
arrhythmic 
therapy 
Conventional 
AF Ablation 
TOTAL 
Rhythm 
BL 
Atr. Fibril. 
 
 
 
 
 
M12 
Atr. Fibril. 
 
 
 
 
Ventricular Rate 
(bpm) 
BL 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
M12 
… 
 
 
 
 
PR Interval (ms) 
… 
… 
 
 
 
 
QRS Interval (ms) 
BL 
n 
 
 
 
 
 
 
Mean 
 
 
 
 
 
M12 
… 
 
 
 
 
*Table Note: To include the following variables – Rhythm, Ventricular Rate, PR Interval, QRS 
Interval. To include the following summary statistics – n, mean, SD, median, min, max.  
 
Table 9.2: Holter Monitoring Results 
 
Treatment 
 
Visit 
AVATAR-
AF 
Ablation 
Anti-
arrhythmic 
therapy 
Convent-
ional AF 
Ablation 
TOTAL 
No. Subjects displaying evidence of 
Paroxysmal Atrial Fibrillation (n(%)) 
BL 
 
 
 
 
M12 
 
 
 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 31 of 32 
SAFETY AND EFFICACY– QUESTIONNAIRES                                                          
Table 10.1: Quality of Life Questionnaire Results 
  
 
AVATAR-AF 
Ablation 
Anti-arrhythmic 
therapy 
Conventional AF 
Ablation 
 
 
BL 
M12 
BL 
M12 
BL 
M12 
Heath State 
Score - 
Categorical 
0-20 
 
 
 
21-40 
 
 
 
41-60 
 
 
 
 
61-80 
 
 
 
 
81-100 
 
 
 
Unavailable 
 
 
 
Heath State 
Score - Summary 
N 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
Table 10.2: Atrial Fibrillation Effect on QualiTy of life (AFEQT) questionnaire Results 
  
 
AVATAR-AF 
Ablation 
Anti-arrhythmic 
therapy 
Conventional AF 
Ablation 
 
 
BL 
M12 
BL 
M12 
BL 
M12 
AFEQT Score   
N 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
Symptoms 
Subscale Score   
N 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
Daily Activities 
Subscale Score   
N 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 


 
BS001A-T Effective 04 Oct 2011 
 
page 32 of 32 
 
Max 
 
 
 
Treatment 
Concern 
Subscale Score   
N 
 
 
 
Mean 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
Treatment 
Satisfaction 
Subscale Score   
N 
 
 
 
Mean 
 
 
 
SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
 
 
8.8. Figures to Present 
 Kaplan-Meyer Plot showing incidence of Primary Outcome per treatment arm 
 Kaplan-Meyer Plot showing incidence of Secondary Outcome - Time to death or stroke 
from any cause per treatment arm 
 Kaplan-Meyer Plot showing incidence of Secondary Outcome - Complications caused 
by procedure per treatment arm 
 Kaplan-Meyer Plot showing incidence of Secondary Outcome - Hospital Episodes 
which result in a change in therapy per treatment arm 
 
 
 
 
REFERENCES 
[1] – Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) Questionnaire Instruction and 
Scoring Manual, Version 1.0 May 19 2010; 
http://www.afeqt.org/files/Instruction_Guide_for_AFEQT_Questionnaire-5-18-10.pdf