PK and Tolerability of IV and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina
Condition: Heart Failure; Myocardial Ischemia; Angina Pectoris
MeSH terms: Cardiomyopathies; Angina Pectoris; Myocardial Ischemia; Ischemia
Intervention: CK-1827452 24mg and 6 mg iv infusion; CK-1827452 12.5mg capsule; CK-1827452 48 mg and 11 mg iv infusion; CK-1827452 25mg capsule; Placebo iv infusion; Placebo capsule
Intervention description: I.V. infusion for 2 hours at 24mg/hr followed by 18 hours at 6mg/hr; 12.5mg oral immediate release capsule; I.V. infusion for 2 hours at 48mg/hr followed by 18 hours at 11mg/hr; 25mg oral immediate release capsule; Matching placebo iv infusion; Matching placebo oral immediate release capsule
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 94.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study investigates whether symptom-limited exercise capacity in ischemic cardiomyopathy
      patients with angina is deleteriously affected by treatment with CK-1827452.
    

Eligibility criteria:

        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.