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Trial registered on ANZCTR


Registration number
ACTRN12619001172190p
Ethics application status
Not yet submitted
Date submitted
15/07/2019
Date registered
20/08/2019
Date last updated
20/08/2019
Date data sharing statement initially provided
20/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Protocol for a prospective cross-sectional, study using Poisson renewal theory to study rotor formation and destruction rates in atrial fibrillation: the RENEWAL-AF study
Scientific title
Protocol for a prospective cross-sectional, study using Poisson renewal theory to study rotor formation and destruction rates in atrial fibrillation: the RENEWAL-AF study
Secondary ID [1] 298737 0
Nil Known
Universal Trial Number (UTN)
U1111-1237-0657
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 313667 0
Condition category
Condition code
Cardiovascular 312082 312082 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
RENEWAL AF is a prospective cross-sectional study at a tertiary hospital recruiting adult patients with paroxysmal or persistent atrial fibrillation (AF) undergoing clinically indicated catheter ablation. Patients will undergo intraprocedural electrophysiologic AF mapping, with lambda-f and lambda-d to be determined from 2-minute unipolar electrogram recordings acquired prior to ablation. The total duration of observation will be in a single AF EEP study procedure (usual duration 120 minutes). The primary objective will be to determine the association of lambda-f and lambda-d with clinical, electrical and structural markers of atrial fibrillation progression, measured by pre-ablation echocardiogram and cardiac magnetic resonance imaging (MRI). The secondary objective will be the association between lambda-f/lambda-d with sympathetic and cholinergic modulation using isoproterenol and edrophonium during AF ablation.
Intervention code [1] 315005 0
Not applicable
Comparator / control treatment
As an observational study, there is no comparator/control.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320727 0
Primary endpoint
The primary endpoints will be lambda-f/lambda-d (rate constants of phase singularity (PS) formation and destruction).

Phase singularity detection will be performed with an extended topological charge based approach. A look up table indexing onset and offset times and electrode location for each new PS detection will be created to determine PS lifetime and PS inter-formation event times. Using the look up table, computation of the histograms for PS lifetimes and inter-formation event times will be performed. For each epoch, observed PS lifetime data will be fitted with an exponential distribution using maximum likelihood and the PS formation rate, lambda-f and destruction rate, lambda-d determined.
Timepoint [1] 320727 0
lambda-f/lambda-d (rate constants of PS formation and destruction) will be determined from intra-procedurally acquired HD grid data.
Secondary outcome [1] 372621 0
Secondary endpoint 1 will be cholinergic modulation of lambda-d/lambda-f as assessed by edrophonium challenge;

The association of cholinergic and sympathetic modulation with lambda-f/lambda-d, will be assessed using a linear mixed effects model with repeated measures.
Timepoint [1] 372621 0
The secondary endpoint will be assessed in post-hoc analysis after the ablation procedure.
Secondary outcome [2] 373897 0
Secondary endpoint 2 will be sympathetic modulation of lambda-d/lambda-f as after isoproterenol administration.
Timepoint [2] 373897 0
Will be performed in post-hoc analysis after the ablation procedure

Eligibility
Key inclusion criteria
The inclusion criteria will be patients referred for clinically indicated AF ablation at Flinders Medical Centre and any other participating sites. Clinical indication for AF ablation includes 1) symptomatic AF refractory or intolerant to at least one class 1 or class 3 antiarrhythmic medication 2) selected symptomatic patients with heart failure and/or reduced ejection fraction.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria includes 1) patients unwilling to provide consent 2) patients unable to undergo pre-procedural cardiac magnetic resonance imaging (CMRI) 3) presence of LA thrombus 4) LA diameter>5.5 cm 5) >2 previous ablations for AF 6) contraindications to anticoagulation therapy 7) uncontrolled hypertension 8) uncontrolled thyroid disease and 9) severe cardiac valvular disease.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
The primary endpoints will be the association of each of the clinical, electrical and structural characteristics with lambda-d/lambda-f which will be determined using multivariate linear regression. Clinical, imaging and electrophysiological characteristics will be entered into the model using a stepwise block entry method. Multicollinearity will be determined using variable inflation factor analysis. The new knowledge generated will be the clinical, electrophysiological and echocardiographic parameters associated with lambda-f/lambda-d.
Secondary endpoints
Secondary endpoint will be the association between lambda-f/lambda-d with sympathetic and cholinergic modulation assessed using a linear mixed effects model with repeated measures. The association between surface ECG characteristics with lambda-f/lambda-d will then be explored with a feature engineering set/ regression algorithm such as from Google TensorFlow. For example, neural network architectures such as long short-term memory (LSTM) have been shown to effectively reveal patterns from high-dimensional time series, and have been applied in regression contexts for ECG data. We will explore the use of LSTMs for supervised prediction of lambda-f/lambda-d from surface ECG data. Furthermore, modern unsupervised clustering techniques such as dynamic time warping and non-negative matrix factorization will be used to explore if there is a relationship between quantifiable ECG features and the contemporary classification of AF. This will allow non-invasive assessment of lambda-f and lambda-d from available surface ECG data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 14312 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 27310 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 303295 0
University
Name [1] 303295 0
Flinders University
Address [1] 303295 0
1 Flinders Drive
Bedford Park
SA 5042
Country [1] 303295 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
1 Flinders Drive
Bedford Park
SA 5042
Country
Australia
Secondary sponsor category [1] 303316 0
None
Name [1] 303316 0
Not applicable
Address [1] 303316 0
Not applicable
Country [1] 303316 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 303826 0
Southern Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 303826 0
SALHN Human Research Ethics Committee
1 Flinders Drive
Bedford Park SA 5042
Ethics committee country [1] 303826 0
Australia
Date submitted for ethics approval [1] 303826 0
30/09/2019
Approval date [1] 303826 0
Ethics approval number [1] 303826 0

Summary
Brief summary
Introduction
Unstable functional re-entrant circuits known as rotors have been consistently observed in atrial fibrillation, and are mechanistically believed critical to the maintenance of the arrhythmia. Recently, using a Poisson renewal theory-based quantitative framework, we have demonstrated that rotor formation (lambda-f) and destruction rates (lambda-d) can be accurately measured using in vivo electrophysiologic data. RENEWAL-AF measures the
electrical, structural heart changes associated with differences in lambda-d and lambda-f.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94946 0
A/Prof Anand Narayan Ganesan
Address 94946 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
Bedford Park SA 5042
Country 94946 0
Australia
Phone 94946 0
+61 8 82045619
Fax 94946 0
Email 94946 0
anand.ganesan@flinders.edu.au
Contact person for public queries
Name 94947 0
A/Prof Anand Ganesan
Address 94947 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
Bedford Park SA 5042
Country 94947 0
Australia
Phone 94947 0
+61 8 82045619
Fax 94947 0
Email 94947 0
anand.ganesan@flinders.edu.au
Contact person for scientific queries
Name 94948 0
A/Prof Anand Narayan Ganesan
Address 94948 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
Bedford Park SA 5042
Country 94948 0
Australia
Phone 94948 0
+61 8 82045619
Fax 94948 0
Email 94948 0
anand.ganesan@flinders.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The study will be an exploratory study. Individual participant data will not be available unless considered supported by the SALHN Human Research Ethics Committee.
What supporting documents are/will be available?
No other documents available
Summary results
No Results