Multicenter Automatic Defibrillator Implantation Trial - Chemotherapy-Induced Cardiomyopathy

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 QRS duration) 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.

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 LVEF with a 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 device according to one of the following options
in currently available guidelines:

1. Class 1: 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

2. Class 2a1: LVEF less than or equal to 35% AND sinus rhythm AND LBBB with a QRS
duration 120-149ms AND NYHA class II, III or ambulatory IV symptoms on
guideline-directed medical therapy

3. Class 2a2: LVEF less than or equal to 35% AND sinus rhythm AND Non-LBBB with a
QRS duration greater than or equal to 150ms AND 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/CRT-D 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 AF (atrial fibrillation), 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