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Trial registered on ANZCTR


Registration number
ACTRN12620000045910
Ethics application status
Approved
Date submitted
23/05/2019
Date registered
21/01/2020
Date last updated
21/01/2020
Date data sharing statement initially provided
21/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Catheter Ablation versus Medical Therapy for Ventricular Tachycardia in Non-Ischemic Heart Disease: A Randomised Trial
Scientific title
Catheter Ablation versus Antiarrhythmic Drugs for Ventricular Tachycardia in Non-Ischemic Cardiomyopathy (CAAD-VT): A Randomised Trial
Secondary ID [1] 298268 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
CAAD-VT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Ischemic Cardiomyopathy 312913 0
Ventricular Tachycardia 312914 0
Dilated Cardiomyopathy 315640 0
Sarcoidosis 315641 0
Hypertrophic Cardiomyopathy 315642 0
Arrhythmogenic right ventricular cardiomyopathy 315643 0
Condition category
Condition code
Cardiovascular 311371 311371 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be expected to have a catheter ablation procedure within 2 weeks post randomisation and no longer than 30 days post randomisation.

Medical therapy can be used as a temporising measure before catheter ablation, as is standard of care. If there is breakthrough VT during the period before the clinical procedure, standard practice will be followed in stabilising the ventricular tachycardia (VT) including intravenous short acting anti-arrhythmic drugs (AAD), admission to hospital, internal or external cardioversion. However, preference will be given to scheduling the procedure within 24-48 hours in this situation.

Catheter ablation procedures will be performed in the standard fashion, as described in the international guidelines for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death from the American Heart Association/American College of Cardiology/ Heart Rhythm Society and the expert consensus statement on Catheter Ablation of Ventricular Arrhythmias from Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society/Latin-America Heart Rhythm Society .Procedures will be performed under conscious sedation or general anaesthesia by a cardiologist trained in electrophysiology procedures and cardiac arrhythmia ablation. Ablation will be guided by a combination of mapping techniques, as per standard practice, and described in the guidelines for catheter ablation for VT. Mapping techniques will incorporate electro-anatomic substrate mapping, pace mapping, entrainment mapping and activation mapping where haemodynamically tolerated. The expected procedure duration will be between 3-6hrs.

Post procedure, AAD is stopped if the patient was drug naïve before randomisation. The baseline type and dose of AAD pre-randomisation is continued if the patient was on an AAD pre-randomisation. Repeat ablation procedures, if necessary, are permitted during the 30 days post-randomisation.
Intervention code [1] 314513 0
Treatment: Other
Comparator / control treatment
Patients managed with medical therapy alone by their usual medical practitioners. A protocol aligned with standard clinical care/current clinical guidelines will be provided for guidance, the objective being that the control arm replicates what would constitute standard of care for patients with ventricular tachycardia managed with a non-interventional approach.

Standard clinical care would usually encompass patients who have not previously been on an antiarrhythmic, being commenced on sotalol 80mg twice daily. A lower dose may be initiated by the treating physician, as clinically indicated. If there is contraindication to sotalol, an alternative beta-blocker may be initiated using standard doses eg metoprolol, atenolol, bisoprolol, carvedilol. Clinicians may consider alternative antiarrhythmic if there is a contraindication to a beta-blocker. For example, a dihydropyridine calcium channel blocker such as verapamil or diltiazem may be initiated, using standard dosing or amiodaraone. Doses would be up titrated to the maximal tolerated amount.

For patients already on an AAD, amiodarone would usually be added. A previously published protocol from the Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) trial, similarly describes this method.
They will receive a loading dose 400 mg twice daily for 2 weeks, followed by 400 mg/day for 4 weeks and 200 mg/day thereafter. Patients who have “failed” amiodarone of dose <300 mg/day will receive a repeat loading dose of 400 mg twice a day for two weeks, followed by 400 mg/day for 1 week, and 300 mg/day thereafter.

If their treating physician during the time-course of the trial decides to do a catheter ablation for VT, the occurrence and time point of this cross-over will be recorded. Cross-over is estimated to be <2% as per the VANISH trial.
Control group
Active

Outcomes
Primary outcome [1] 320101 0
The primary outcome of this study will be a composite of recurrent ventricular tachycardia (detected by cardiac device as lasting greater than or equal to 30 seconds or shorter in duration if treated by the implanted cardioverter-defibrillator [ICD]).
Timepoint [1] 320101 0
median follow up of 18 months
Primary outcome [2] 320102 0
VT storm (three or more documented episodes of ventricular tachycardia within 24 hours or incessant VT); assessed through: home monitoring (online transmissions via implanted device), medical records, hospital admissions and other records linked into the hospital system, patient reporting of symptoms and therefore being brought in for follow-up of their device.
Timepoint [2] 320102 0
median follow up of 18 months
Primary outcome [3] 320103 0
Death (at any time) due to any cause occurring during study follow-up and after the 30-day treatment ‘blanking’ period after randomisation.
This will be assessed through: home monitoring (online transmissions via implanted device), medical records, patient family contact.

(The 30-day treatment blanking period is imposed to exclude nonfatal outcomes that might occur before adequate medical therapy is established or actual performance of catheter ablation.)
Timepoint [3] 320103 0
median follow up of 18 months
Secondary outcome [1] 370537 0
Recurrent sustained ventricular tachycardia ascertained by implanted an ICD where VT is identified as being any of the following:
a. Treated by the ICD with anti-tachycardia pacing (ATP) and/or,
b, Internal device delivered shock
c, Equal or greater than 30 seconds of VT if untreated by ICD
Timepoint [1] 370537 0
median follow up of 18 months
Secondary outcome [2] 370539 0
VT burden (number of episodes of VT in the preceding 6 months compared to the 6 months after randomisation and therapy); measured by home monitoring device recording transmissions from a patients implanted defibrillator
Timepoint [2] 370539 0
median follow up of 18 months
Secondary outcome [3] 370540 0
Cardiovascular hospitalisation (all cause, heart failure and hospitalisation for arrhythmia), monitored via hospital admissions / medical records
Timepoint [3] 370540 0
median follow up of 18 months
Secondary outcome [4] 370541 0
Mortality
a. All-cause mortality
b. Cardiac death
c. Non-cardiac death

Data collected from medical records and during patient follow up over trial period
Timepoint [4] 370541 0
median follow up of 18 months
Secondary outcome [5] 370542 0
Serious Adverse Events (SAE) and Adverse Events of Special Interest (AESI)
a. AESI related to effects of catheter ablation - any adverse event that, in the investigator’s and cardiologist opinion, is a complication of the catheter ablation procedure and occurs within 48 hours of catheter insertion while the patient is in hospital.
b. AESI related to medical anti-arrhythmic drug therapy - symptoms reported via the patient via phone or in-clinic. Drug toxicity noted via biomarkers using serum assay of liver function test and thyroid function test. Renal function will also be measured.
Timepoint [5] 370542 0
median follow up of 18 months
Secondary outcome [6] 370543 0
Effect of intervention on quality of life metrics post intervention. Measured using the SF-36 questionnaire, the implanted cardioverter defibrillator (ICD) Concerns questionnaire (ICDC), the Hospital Anxiety and Depression Scale (HADS), and the EuroQol five dimensions’ questionnaire (EQ-5D);

Timepoint [6] 370543 0
Monitored time points of 1, 6, 12, 24, 36 months
Secondary outcome [7] 378063 0
VT storm (three or more documented episodes of VT within 24 hours) or incessant VT. Measured by implanted defibrillator recordings.
Timepoint [7] 378063 0
Median follow up of 18 months
Secondary outcome [8] 378705 0
Quality of Life - Effect of intervention on exercise tolerance and capacity as measured by the 6-minute walk test and Minnesota Living with Heart Failure Questionnaire
Timepoint [8] 378705 0
Monitored time points of 1, 6, 12, 24, 36 months
Secondary outcome [9] 378706 0
Quality of Life - Effect of intervention on ventricular function as assessed by transthoracic echocardiography
Timepoint [9] 378706 0
Monitored time points of 1, 6, 12, 24, 36 months

Eligibility
Key inclusion criteria
Patients will be eligible for inclusion if they have:
1. New diagnosis or established history of non-ischemic heart disease
a. Coronary artery disease and prior myocardial infarction has been ruled out as the cause of VT as per standard evaluation with cardiac catheterisation or coronary CT scan (with or without functional testing such as nuclear sestamibi scan or a dobutamine stress echo);

2. prior episode of spontaneous sustained VT in the prior 6 months;
a. Spontaneous VT: equal to or greater than 1 episode of monomorphic VT treated by anti-tachycardia pacing (ATP) and/or internal shock by an ICD; lasting greater than 10 seconds in the absence of intra-cardiac device therapy that could either be self-terminating or require reversion by pharmacological therapy or external cardioversion;
b. Spontaneous VT: greater than or equal to 1 episode of sustained spontaneous monomorphic VT lasting greater than 10 seconds documented on Holter, ECG, Loop recorder or other cardiac monitoring device that could either be self terminating or require reversion by pharmacological therapy or external cardioversion;
c. Inducible VT: with syncope or palpitations – inducible VT defined as sustained monomorphic VT of CL greater than 200 ms lasting for greater than 10 seconds during a cardiac electrophysiology study (note with 4 extrastimuli with or without provocation with isoprenaline)

3. Already a recipient of an implanted cardiac device such as a pacemaker, defibrillator or a cardiac resynchronisation therapy device and/or is indicated to receive one given a new diagnosis of non-ischemic heart disease, based on current guideline recommendations.

5. Age equal to or greater than 18 years
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if they are:
1. Unable or unwilling to provide informed consent or patients physician feels there is not significant equipoise to justify randomisation;
2. Coronary Ischaemia: defined as a history of prior obstructive coronary artery disease, prior myocardial infarction or prior coronary artery bypass surgery, percutaneous transluminal coronary angioplasty or coronary artery stenting;
3. Cardiomyopathy related to congenital heart disease;
4. Women who are pregnant, breast feeding;
5. Medical illness with an anticipated life expectancy less than 3 months;
6. Unable to complete study procedures or attend clinical follow up;
7. Have a concomitant illness, physical impairment or mental condition which in the opinion of the study team/ primary care physician could interfere with the conduct of the study including outcome assessments;
8. Known channelopathy such as long QT, short QT, Brugada syndrome, catecholaminergic polymorphic VT.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software. Randomisation of intervention and control will be in the ratio 1:1. and occur in variable block sizes from 2-6, performed using a secure, password-protected web portal (Redcap). Randomisation will incorporate stratification into two groups:
1. LVEF less than or equal to 35 percent
2. LVEF greater than 35 percent
The randomisation allocation will be open to all participants, study team members, and the primary study statistician.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
At 12 months, published data suggests spontaneous VT recurs in an estimated 62% of patients on antiarrhythmic drugs with NICM. To detect a relative risk reduction of 35% with catheter ablation, power 80%, 2-sided significance of P<0.05 and allowing for a 2% drop out rate, 84 patients (42 in each arm) will be randomised. This relative risk seems realistic as an estimate for as few as 30% of patients recurred with VT and NICM after catheter ablation has been reported.

A detailed statistical analysis plan will be developed prior to analysis. The primary analysis approach will be by intention to treat and will compare the time to the primary outcome (composite of recurrent VT, VT storm and death) in ablation versus medical therapy groups using survival analysis techniques. The time-to-event will be summarised using Kaplan-Meier product limit estimates and the non-parametric log rank test procedure will be used for comparing the survival curves. The null hypothesis is that the time-to-event of the primary outcome is not different between the ablation and medical therapy groups. The alternative hypothesis is that the time-to-event of the primary outcome is different between these therapy groups. The intention-to-treat populations will be used.

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)
NSW
Recruitment hospital [1] 13772 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 26522 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 302810 0
Government body
Name [1] 302810 0
NSW Health Early-Mid Career Research Grant
Address [1] 302810 0
73 Miller Street
North Sydney NSW 2060
Australia
Country [1] 302810 0
Australia
Primary sponsor type
Individual
Name
A/Prof Saurabh Kumar
Address
Room 2111, Level 2, Clinical Sciences Corridor,
Westmead Public Hospital,
Cnr Darcy and Hawkesbury Roads,
Westmead, NSW, 2145
Country
Australia
Secondary sponsor category [1] 304819 0
None
Name [1] 304819 0
Address [1] 304819 0
Country [1] 304819 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303394 0
Western Sydney Local Health District (WSLHD) HREC
Ethics committee address [1] 303394 0
Cnr Darcy and Hawkesbury Road
Westmead Hospital
Westmead, NSW, 2145
Ethics committee country [1] 303394 0
Australia
Date submitted for ethics approval [1] 303394 0
22/11/2019
Approval date [1] 303394 0
13/12/2019
Ethics approval number [1] 303394 0
AU RED HREC/18/WMEAD/501

Summary
Brief summary
Sudden cardiac death (SCD) due to recurrent ventricular tachycardia (VT) is an important clinical sequela in patients with structural heart disease. VT generally occurs as a result of electrical re-entry in the presence of arrhythmogenic substrate (scar). Scar tissue forms due to an ischemic cardiomyopathy (ICM) from prior coronary obstructive disease or a non-ischemic cardiomyopathy (NICM) from an inflammatory or genetic disease. These NICM conditions encompass idiopathic dilated cardiomyopathy (DCM), genetic or familial forms of DCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), cardiac sarcoidosis, and prior myocarditis.

AADs can reduce VT recurrence, but have significant limitations in treatment of VT in NICM. For example, amiodarone has high rates of side effects/toxicities and a finite effective usage before recurrence. NICM has a young demographic population which AADs are likely not to provide a durable control of VT in the intermediate or long term. ICDs prevent cardiac arrest and sudden death from VT, but do not stop VT occurring. Recurrent VT and ICD therapies decrease QOL, increase hospital visits, mortality, morbidity and risk of death. Improvement in techniques for mapping and ablation of VT have made CA an alternative. Increasing rates of CA for VT in NICM have also been noted. CA in NICM for recurrent VT is technically more challenging due to scar locations, topography and properties, to those in ICM. NICM scars are often clustered around the aortic, mitral, pulmonary or tricuspid valves, more often involve the right ventricle or both ventricles rather than the left ventricular alone. This introduces procedural challenges, albeit acute procedural efficacy or procedural complication rate are not dissimilar to patients with ICM, but long-term recurrence of VT appears to be higher in NICM than ICM.

Currently, there is limited evidence to guide clinicians either toward AAD therapy or CA in patients with NICM. All randomised data for CA vs AAD for recurrent VT is exclusively in patients with ICM. This data shows significant benefit of CA over medical therapy in terms of VT free survival, survival free of VT storm and VT burden. Observational studies suggest that CA is effective in eliminating VT in NICM patients who have failed AADs, resulting in reduction of VT burden and AAD use over long term follow up. Randomised trials of CA vs AADs in ICM provides a proof-of-concept that the benefit of VT ablation is likely translatable to the NICM population, but this has not been formally evaluated in a clinical trial.

Therefore the primary objective is to determine in patients with non-ischemic heart disease and spontaneous or inducible VT, if catheter ablation compared to standard medical therapy with anti-arrhythmic drugs results in a reduction of a composite endpoint of recurrent VT, VT storm and death at a median follow up of 18 months.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93526 0
A/Prof Saurabh Kumar
Address 93526 0
Room 2111, Level 2, Clinical Sciences Corridor,
Westmead Public Hospital, Cnr Darcy and Hawkesbury Roads,
Westmead, NSW, 2145
Country 93526 0
Australia
Phone 93526 0
+61 2 8890 8140
Fax 93526 0
Email 93526 0
saurabh.kumar@health.nsw.gov.au
Contact person for public queries
Name 93527 0
Mr Timothy Campbell
Address 93527 0
Westmead Hospital
Room 2021, Research and Education Network (REN Building)
Cnr Darcy and Hawkesbury Road
Westmead, NSW, 2145
Country 93527 0
Australia
Phone 93527 0
+61 02 8890 7045
Fax 93527 0
Email 93527 0
timothy.campbell@sydney.edu.au
Contact person for scientific queries
Name 93528 0
A/Prof Saurabh Kumar
Address 93528 0
Room 2111, Level 2, Clinical Sciences Corridor,
Westmead Public Hospital, Cnr Darcy and Hawkesbury Roads,
Westmead, NSW, 2145
Country 93528 0
Australia
Phone 93528 0
+61 2 8890 8140
Fax 93528 0
Email 93528 0
saurabh.kumar@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not utilised.
What supporting documents are/will be available?
No other documents available
Summary results
No Results