PK and Tolerability of IV and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina
PK and Tolerability of IV and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina
This study investigates whether symptom-limited exercise capacity in ischemic cardiomyopathy
 patients with angina is deleteriously affected by treatment with CK-1827452.
The primary objective of this study is to assess the effect of intravenous (i.v.) CK-1827452
 on symptom-limited exercise tolerance in patients with ischemic cardiomyopathy and angina.
 The secondary objectives are to assess the tolerability of CK-1827452 administered three
 times daily (tid) to steady state in an immediate-release (IR), blend-in-capsule oral
 formulation to outpatients with ischemic cardiomyopathy and angina and to assess CK-1827452
 plasma concentrations at trough and 1 hour after dosing with CK-1827452 administered tid to
 steady state in an IR, blend-in-capsule oral formulation to outpatients with ischemic
 cardiomyopathy and angina.
Inclusion Criteria:

 1. The patient has signed an Informed Consent Form/Patient Information Sheet for this
 study approved by the governing Institutional Review Board (IRB) or Independent Ethics
 Committee (IEC).

 2. The patient is at least 18 years old.

 3. The patient has ischemic heart disease documented by any one or more of the following:

 -  A history of myocardial infarction documented by elevated CPK-MB, troponin I or
 T, or the presence of electrocardiographic Q waves consistent with myocardial
 infarction.

 -  Coronary angiography demonstrating at least 1 major epicardial coronary artery
 (i.e., left main, left anterior descending, left circumflex, or right coronary
 artery) with a stenosis of at least 60% diameter or greater but excluding
 stenosis of the left main coronary artery unless revascularized by coronary
 artery bypass grafting.

 4. The patient has a history of ≥ 1 episode of exercise induced angina within 2 months
 prior to the initial screening visit.

 5. The patient has been taking a beta blocker and an ACE inhibitor (and/or an ARB) for at
 least 4 weeks. If prescribed, diuretics must have been administered for at least 4
 weeks prior to the initial screening visit.

 6. The patient is NYHA Class II-III at the time of enrollment and has been so for ≥ 3
 months prior to the initial screening visit.

 7. The patient has a history of a left ventricular ejection fraction (LVEF) ≤ 35%.

 8. The patient has a history of EITHER a left ventricular end-diastolic diameter ≥ 55 mm,
 OR a left ventricular end-diastolic diameter index ≥ 32 mm/m2.

 9. The patient can be expected to complete at least 4 minutes of a Modified Naughton ETT
 (see Appendix B).

 10. For female patients only: The patient is post-menopausal (≥ 1 year) or sterilized, or
 if she is of childbearing potential, she is not breastfeeding, her pregnancy test is
 negative, she has no intention to become pregnant during the course of the study, and
 she is using contraceptive drugs or devices.

 Exclusion Criteria:

 1. The patient has acute myocarditis; clinically significant restrictive, constrictive,
 or hypertrophic obstructive cardiomyopathy; or clinically significant congenital heart
 disease.

 2. The patient has a SBP > 160 mmHg, documented on at least 3 separate occasions, at
 least 10 minutes apart.

 3. The patient has a DBP > 90 mmHg, documented on at least 3 separate occasions, at least
 10 minutes apart.

 4. The patient has levels of troponin I or T, or CPK-MB > the upper limit of normal at
 any time from 6 weeks prior to the Initial Screening Visit (Visit 1) and up to
 randomization.

 5. The patient has severe aortic or mitral stenosis.

 6. The patient has had an acute coronary syndrome, transient ischemic attack, or
 revascularization procedure within 6 weeks of the Initial Screening Visit (Visit 1).

 7. The patient has significant co-morbid conditions (i.e., lung disease, arthritis,
 peripheral vascular disease) that may limit his or her treadmill exercise capacity.

 8. The patient has renal impairment defined by a calculated creatinine clearance < 30
 cc/min or a need for renal replacement therapy.

 9. The patient has known hepatic impairment defined by a total bilirubin > 3 mg/dL, or an
 ALT or AST > 2 times the upper limit of normal.

 10. The patient has received an investigational drug or device within 30 days or 5
 half-lives, whichever is greater, of randomization.

 11. The patient weighs > 120 kg.

 12. The patient has a body temperature > 38 ° C, confirmed by at least 2 successive
 measurements, at least 10 minutes apart.

 13. The patient has any laboratory abnormality which, in the opinion of the investigator,
 should preclude his or her participation in the study.

 14. The patient has had any prior treatment with CK-1827452.