Multicenter Automatic Defibrillator Implantation Trial - Chemotherapy-Induced Cardiomyopathy

Study Overview
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Brief Summary
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The purpose of this trial or study is to determine if cardiac resynchronization therapy (CRT) can be a benefit to people who have impaired heart function due to past treatment with chemotherapy and/or chest radiation. The investigators are looking to enroll approximately 30 eligible subjects with heart failure in this trial. All patients enrolled and registered in the study will be implanted with a cardiac resynchronization therapy device that includes an implantable cardiac defibrillator (CRT-D). Clinical histories, physical exams, and external device testing will be collected both at the time of enrollment in the trial and during follow-up study visits. Following implantation of the CRT-D, patients will be contacted by phone at 3 months and will have a scheduled clinic visit follow-up at 6 months.

Detailed Description
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With the advent of new therapies and an increasing number of long-term cancer survivors, the incidence and consequently the interest in chemotherapy-induced cardiomyopathy (CHIC) have been increasing. CHIC is a dose-dependent cardiomyopathy and presents as congestive heart failure several months to years after the administration of chemotherapy and/or chest radiation that includes the heart. Greater than one-half of the patients exposed to just this class of drugs will show evidence of cardiac dysfunction, with 5% presenting with overt symptomatic heart failure. The overall incidence of CHIC is significantly underestimated as within the US alone, greater than 60,000 patients receive just anthracyclines every year. Despite this, there is little data on their response to conventional heart failure therapy. There is some preliminary evidence from two small, retrospective case-series suggesting that patients with CHIC and evidence of conduction tissue disease (i.e. a wide electrocardiographic depolarization duration (QRS) may significantly benefit from cardiac resynchronization therapy (CRT). MADIT-CHIC is a multicenter, non-randomized, prospective observational study. The primary aim is to determine if CRT-D (Defibrillator) in high-risk patients with chemotherapy-induced cardiomyopathy will significantly improve left ventricular ejection fraction (LVEF) by echocardiography within 6 months of initiating CRT without adversely affecting mortality. The study will last 6 months and will be conducted in 10-15 clinical centers in the United States. Following implantation of the CRT-D device (Defibrillator), patients will be followed for 6 months. The first follow-up contact will be by phone at which time study personnel will review the patient's health status. The last study contact will be a 6-month clinic visit. At the 6-month visit, the patient's health status will be reviewed, the functioning of the CRT-D (Defibrillator) will be tested and an echocardiogram will be conducted. After the 6-month visit, the study-required follow-up will have been completed and patients will continue to have CRT-D (Defibrillator) clinical follow-up based on their physicians direction. During the course of the study, Subjects will as outlined in the inclusion criteria continue on stable optimal pharmacologic therapy for the cardiac condition that is guideline-based and may include one or more of the following medications: Loop diuretics, Angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blocker (ARB), Aldosterone antagonists and/or Beta-blockers unless the subject is not indicated, contraindicated, or is intolerant of medication.

Official Title
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Multicenter Automatic Defibrillator Implantation Trial - Chemotherapy-Induced Cardiomyopathy

Conditions
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Cardiomyopathy

Intervention / Treatment
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* Device: Three-lead CRT-D (Defibrillator)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 (or of legal age to give informed consent specific to state and national law) up to 80 years of age Male or Female Without clinical heart failure at initiation of chemotherapy/radiation-induced treatment for an underlying malignancy, but developed clinical heart failure (cardiomyopathy: reduced left ventricular ejection fraction (LVEF) with a left bundle branch block (LBBB)-type of conduction disturbance; see next inclusion item) 6 months or more after initiation of the chemotherapy without other evident cause of the cardiomyopathy. Eligible for implantation of a CRT-D (cardiac resynchronization therapy-defibrillator) device according to one of the following options in currently available guidelines: Class 1: Left ventricular ejection fraction (LVEF) less than or equal to 35% AND sinus rhythm AND LBBB (left bundle branch block) with a QRS (electrocardiographic depolarization duration) duration greater than or equal to 150ms AND NYHA (New York Heart Association) class II, III or ambulatory IV symptoms on guideline-directed medical therapy Class 2a1: Left ventricular ejection fraction (LVEF) less than or equal to 35% AND sinus rhythm AND left bundle branch block (LBBB) with a QRS (electrocardiographic depolarization duration) duration 120-149ms AND New York Heart Classification (NYHA) class II, III or ambulatory IV symptoms on guideline-directed medical therapy Class 2a2: Left ventricular ejection fraction (LVEF) less than or equal to 35% AND sinus rhythm AND Non-left bundle branch block (LBBB) with a QRS(electrocardiographic depolarization duration) duration greater than or equal to 150ms AND New York Heart Classification (NYHA) class III or ambulatory IV symptoms on guideline-directed medical therapy On stable optimal pharmacologic therapy for the cardiac condition that is guideline-based and may include one or more of the following medications: Loop diuretics, Angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blocker (ARB), Aldosterone antagonists and/or Beta-blockers unless the subject is not indicated, contraindicated, or is intolerant of medication. Exclusion Criteria: Currently implanted pacemaker or implantable cardioverter defibrillator (ICD) device Previous implant with a CRT (cardiac resynchronization therapy)/CRT-D (cardiac resynchronization therapy-defibrillator) device Cardiac condition not presumed to be caused by chemotherapy Documented symptoms or hemodynamically unstable ventricular tachyarrhythmia On active chemotherapy (must be at least 6 calendar months after last chemotherapy) Permanent or chronic Atrial Fibrillation (AF), or cardioversion for AF within the past 3 calendar months before consent date Structural heart disease such as congenital heart disease, valvular heart disease, e.g., rheumatic valvular heart disease, amyloid heart disease, etc. Coronary artery bypass graft surgery or percutaneous coronary intervention within the past 3 calendar months before consent date Enzyme positive myocardial infarction within the past 3 calendar months prior to consent date Unstable angina requiring hospitalization, with diagnostic work up and intervention within the past 3 months prior to consent date Angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future Class IV and expected to undergo transplant within study duration Current or past history of drug addiction or abuse that caused cardiomyopathy Pregnant or plans to become pregnant during the course of the trial. Recent cerebral vascular accident or transient ischemia attack within the previous 3 months prior to consent date Presence of any disease, other than the subject's cardiac or cancer disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., uremia, liver failure, active malignant disease, etc. Participating in any other clinical trial Unwilling or unable to cooperate with the protocol Lives at such a distance from the clinic that travel for follow-up visits would be unusually difficult Does not anticipate being a resident of the area for the scheduled duration of the trial Unwilling to sign the consent for participation Physician does not allow participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: CRT-D (Defibrillator)<br>Implantation of a three-lead CRT-D (Defibrillator) in all registered patients | Device: Three-lead CRT-D (Defibrillator)<br>* The three-lead CRT-D (Defibrillator) will consist of a pulse generator, a right atrial lead, a right ventricular lead and a left ventricular lead.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Left Ventricular Ejection Fraction | The primary endpoint will be the change in left ventricular ejection fraction (LVEF) from baseline to six months | 6 months post implant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All-Cause Mortality | Number of Participants with All-Cause Mortality in CRT-D patients | 6 months post implant | 
| Effects of CRT Therapy on Left Ventricular Volume at End Diastole | Determine based on echocardiogram study if CRT therapy improves left ventricular volume at end diastole (LVEDV) between baseline and six months | 6 months post implant | 
| Effects of CRT Therapy on Left Ventricular Volume at End Systole | Determine based on echocardiogram study if CRT therapy improves left ventricular volume at end systole (LVESV) between baseline and six months | 6 months post implant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemotherapy-induced cardiomyopathy, Heart failure, Cardiac resynchronization therapy