- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01522898
Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation Patients (CAAN-AF) (CAAN-AF)
Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background: Cardiac Resynchronization Therapy (CRT) is an established treatment in heart failure (HF) patients with ventricular dyssynchrony who remain in sinus rhythm. Available clinical data has shown inferior outcomes of CRT in HF patients with co-existent atrial fibrillation (AF), who comprise up to 27% of HF patients, and are over-represented in advanced HF classes. We hypothesize, based on the results of a systematic review we recently published in the Journal of the American College of Cardiology, that AV nodal ablation may improve survival, heart failure and functional outcomes in CRT recipients with co-existent AF.
Design: This study will be a multicentre, prospective, randomized controlled trial. Patients with ischemic or nonischemic cardiomyopathy heart failure (NYHA II, III or ambulatory class IV), left ventricular dysfunction (EF ≤ 35%), prolonged intraventricular conduction (QRS duration ≥ 120ms), and persistent or permanent AF will be considered for the study. Persistent AF will be defined as patients where obtaining and maintaining sinus rhythm is deemed either not worthwhile, or to be ineffective in the long term, or where both the patient and the physician accept the presence of AF, where rhythm control intervention is, by definition, no longer pursued. Permanent AF is defined as AF where sinus rhythm cannot be restored.
Eligible subjects will be randomized into one of two arms: (1) CRT-D plus AV nodal ablation ("AV nodal ablation arm [AVNA]") or (2) CRT-D alone ("rate control arm").
Enrollment: 590 subjects, with 295 subjects in the AV node ablation arm and 295 subjects in the control arm, will be enrolled. Study patients will undergo stratified randomization at ≥ 30 days after CRT implant. Participants in will sign informed consent and be screened prior to randomisation. After CRT implant, patients will have at least 30 days for optimisation of heart failure therapy, prior to randomisation.
Randomisation: A computer-generated web-based randomisation schedule will be used. Randomisation will be stratified by trial centre. Randomisation is considered the trial entry point.
Outcomes: The primary endpoint is a composite of all cause mortality and non-fatal heart failure events. Secondary endpoints include all-cause mortality, cardiovascular mortality (including classification in terms of suddenness and arrhythmic mechanism by prespecified Hinkle-Thaler criteria), non-fatal heart failure events, 6-minute walking test distance, quality of life, unplanned hospitalization, and ventricular arrhythmias requiring device therapy, inappropriate shocks, cardiovascular MRI prediction of response, percentage pacing and prediction of response to therapy, ventricular reverse remodeling.
Statistical Plan: The study is powered to find a 25% relative reduction in event rate, with sample sizes calculated assuming a two-tailed α=0.05,1-β=0.80, and 10% sample size increment allow for to drop in the event rate (AV nodal ablation arm), drop out or cross-over (feasibly, control to AVNA arm only). It is planned to perform three interim (0.25, 0.5 0.75 information fractions) and a final analysis requiring 295 patients per arm with a final P-value at ≤ 0.045; stopping rules according to the method of O'Brien and Fleming. The boundaries (z scores: ±4.332, ±2.963, ±2.359, ±2.014; and nominal P-values: 0.000015, 0.0031, 0.014, 0.044)) were derived using the statistical package PASS (V12). Outside of these defined analyses, the Data Safety Monitoring Board (DSMB) will have access to data reports and will be able to stop the trial at any time.
All analyses will be based on the intention-to-treat principle. The primary (binary) mortality-outcome will be analysed using the Cochran-Mantel-Haenszel statistic and logistic regression with pre-specified (baseline) covariates. Time-to-event analyses will be initially undertaken by the Kaplan-Meier survival analysis approach. Key secondary outcomes such as all-cause mortality, cardiovascular mortality, unplanned hospitalisation, and rates of ventricular arrhythmia episodes will be analysed using either Cox proportional hazards models or Fine and Gray competing risks regression as appropriate. Continuous secondary outcomes such as the 6-minute walking distance, Short Form 36 (SF36) scores, Minnesota Living with Heart Failure (MLWHF) score will be compared between randomised groups over time using linear mixed effects models.
Significance and Impact: The study will answer a central clinical question directly impacting the care of HF patients with AF, and will be expected to change current HF management guidelines.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Australian Capital Territory
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Canberra, Australian Capital Territory, Australia, 2605
- Canberra Hospital
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New South Wales
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Concord, New South Wales, Australia
- Concord Hospital
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New Lambton, New South Wales, Australia, 2305
- John Hunter Hospital
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Randwick, New South Wales, Australia, 2031
- Prince of Wales Hospital
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Sydney, New South Wales, Australia, 2065
- Royal North Shore Hospital
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Sydney, New South Wales, Australia
- Royal Prince Alfred Hospital
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Perth, WA
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Murdoch, Perth, WA, Australia, 6150
- Fiona Stanley
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Queensland
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Brisbane, Queensland, Australia, 4209
- Royal Brisbane Hospital
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Chermside, Queensland, Australia, 4032
- Prince Charles Hospital
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Douglas, Queensland, Australia, 4814
- Townsville Hospital and Health Service
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Southport, Queensland, Australia, 4213
- Gold Coast University Hospital
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Woolloongabba, Queensland, Australia, 4102
- Princess Alexandra Hospital
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South Australia
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Adelaide, South Australia, Australia, 5000
- Royal Adelaide Hospital
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Bedford Park, South Australia, Australia, 5042
- Flinders Medical Centre
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Tasmania
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Hobart, Tasmania, Australia, 7000
- Royal Hobart Hospital
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Victoria
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Clayton, Victoria, Australia, 3168
- Monash Medical Centre
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Geelong, Victoria, Australia, 3220
- Geelong Hospital
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Heidelberg, Victoria, Australia, 3084
- Austin Hospital
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Melbourne, Victoria, Australia
- The Alfred Hospital
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Melbourne, Victoria, Australia
- Melbourne Private Hospital
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Parkville, Victoria, Australia, 3050
- Royal Melbourne Hospital
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Western Australia
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Perth, Western Australia, Australia, 6009
- Sir Charles Gairdner Hospital
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Perth, Western Australia, Australia
- Royal Perth Hospital
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Cologne, Germany, D-50936
- university clinic of cologne
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St Georg, Germany, 20099
- Asklepios Hospital
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Gebäude 401/k
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Mainz, Gebäude 401/k, Germany, 55131
- Universitätsmedizin Mainz
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Martinistr. 52 Gebäude Ost 50, 8. OG, Raum 842
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Hamburg, Martinistr. 52 Gebäude Ost 50, 8. OG, Raum 842, Germany, 20246
- Universitätsklinikum Hamburg-Eppendorf
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Kuala Lumpur, Malaysia, 50400
- National Heart Institute
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Auckland, New Zealand, 1142
- Auckland City Hospital
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Hamilton, New Zealand, 3240
- Waikato Hospital
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Wellington, New Zealand, 6021
- Wellington Hospital
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Bay Of Plenty
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Tauranga, Bay Of Plenty, New Zealand, 3143
- Tauranga Hospital
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Middlesbrough, United Kingdom
- James Cook University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age ≥ 18 years old
- Persistent (≥ 1 month) or permanent atrial fibrillation. Persistent AF will be where obtaining and maintaining sinus rhythm is deemed either not worthwhile, or to be ineffective in the long term, or where both the patient and physician accept the presence of AF, where rhythm control intervention is, by definition no longer pursued. Permanent AF is defined as atrial fibrillation where sinus rhythm cannot be restored.
- NYHA class II , III or ambulatory class IV heart failure
- Left Ventricular Ejection Fraction (LVEF) ≤ 35% by objective criteria such as echocardiography, or cardiac MRI
- QRS duration on 12-lead ECG ≥ 120ms
- Able and willing to comply with all pre-, post- and follow-up testing and requirements.
Exclusion Criteria:
- age < 18 years
- pregnancy
- previous AV nodal ablation
- Second or third degree AV block
- Inability to provide informed consent
- life expectancy less than 24 months due to co-morbid illness other than heart failure erg cancer, end-stage renal disease, liver failure
- Paroxysmal Atrial Fibrillation that self terminates within 7 days
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Medical Rate Control
Medical Rate Control aimed at ventricular rate target of 90 beats per minute.
Specific medical therapy to be determined for each patient by individual clinician.
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Ventricular Rate Control with target ventricular rate of 90 beats per minute.
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Experimental: AV nodal ablation
AV node ablation performed by percutaneous catheter ablation, with endpoint of complete heart block.
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Percutaneous catheter ablation of the AV node.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
All-cause mortality and non-fatal heart failure events
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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This is a composite of all-cause mortality and non-fatal heart failure events. All-cause mortality will be determined by a designated clinical events committee. Heart Failure events will be documented by clinical data from the hospital In CAAN-AF, a subject will be described as having a "Heart Failure Event" when the subject has symptoms and/or signs consistent with congestive heart failure and:
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
All-cause mortality
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)f recruitment
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All-cause mortality will be determined after adjudication committee review of clinical records, and death certificate data.
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)f recruitment
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Cardiovascular mortality
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Cardiovascular deaths will be classified in terms of suddenness and arrhythmic mechanism according to the Hinkle-Thaler criteria.
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Non-Fatal Heart Failure Events
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Heart Failure events will be documented by clinical data from the hospital In CAAN-AF, a subject will be described as having a "Heart Failure Event" when the subject has symptoms and/or signs consistent with congestive heart failure and:
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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6-minute walking distance
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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6-minute walking distance will be measured according to standard criteria.
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Quality of Life questionnaires
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Quality of life as assessed by the Short Form 36 (SF-36) questionnaire and Minnesota Living with Heart Failure Questionnaire
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Unplanned Hospitalization
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Unplanned hospital admissions will be assessed by a combination of patient self-report, hospital record and/or treating physician interrogation.
The reason, date and duration of hospitalization will be recorded Planned hospitalizations (hospital visits for elective or planned medical interventions) will excluded from this outcome
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Ventricular arrhythmias requiring device therapy
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Ventricular arrhythmias requiring device therapy will be determined by implantable Cardioverter Defibrillator (ICD) interrogation records and clinical records.
At each site, the number, duration and type (VT/VF) of device recorded arrhythmias will be recorded, as well as the need for device therapy (anti-tachycardia pacing and/or ICD shocks).
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Inappropriate shocks
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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The clinical events committee will review clinical records to ascertain if device therapies are appropriate or inappropriate.
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Cardiovascular MRI prediction of response
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Cardiovascular MRI will be performed in subjects eligible for this procedure prior to implantation of CRT device, when available.
Cardiovascular MRI data will be evaluated for the ability to predict clinical CRT response.
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Depression
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Depression will be evaluated in all patients at specified clinical follow-up visits with the Center for Epidemiologic Studies Depression Scale (CES-D questionnaire).
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Ventricular reverse remodelling
Time Frame: Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Left ventricular reverse remodeling will be assessed by echocardiographic parameters including left ventricular end systolic volume, left ventricular ejection fraction.
An echocardiography core laboratory has been established to process images from individual trial sites for this purpose.
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Final-analysis at completion of recruitment and follow-up period (minimum 2 year follow-up)
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Prashanthan Sanders, MBBS PhD, University of Adelaide
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- RAH-HREC-Protocol-#111234
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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