A Study of CK-1827452 Infusion in Stable Heart Failure

Study Overview
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Brief Summary
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This study will assess the safety, tolerability, and pharmacodynamics of CK-1827452 infusion in patients with stable heart failure.

Official Title
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A Phase II, Multi Center, Double-Blind, Randomized, Placebo Controlled, Dose-Escalation, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of CK-1827452 in Patients With Stable Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: Placebo
* Drug: Placebo
* Drug: CK-1827452
* Drug: Placebo
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452
* Drug: CK-1827452


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patient is male, or female of non-childbearing potential (two years post-menopausal or surgically sterilized) Female patients must have a negative urine pregnancy test prior to entry into the study Patient is 18 years old or greater Patient has given signed informed consent Patient is considered to be in suitable health in the opinion of the investigator, as determined by: A pre-study physical examination with no clinical abnormalities which in the opinion of the investigator would preclude participation in the study other than physical symptoms or signs consistent with stable heart failure An electrocardiogram (ECG) with no abnormalities in the opinion of the investigator that would impair assessment of stopping criteria Patient has pre-study clinical laboratory findings that are within normal range, or if outside of the normal range, should not preclude participation in the study in the opinion of the investigator (see Exclusion Criteria, below, for exceptions) Patient has a documented diagnosis of heart failure with an ejection fraction of less than 40% Patient has been on a stable dose of a beta blocker and an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin II receptor blocker) for at least 4 weeks. If prescribed, diuretics must have been administered according to a consistent regimen for at least 4 weeks Patient is currently in sinus rhythm Patient has interpretable echocardiographic images on a screening echocardiogram Exclusion Criteria Patient has been hospitalized for heart failure, myocardial infarction, coronary revascularization, or another cardiac indication within the last 6 weeks Patient has a current history of alcohol use which in the opinion of the investigator would preclude participation in the study Patient has a current history of drug abuse Patient has donated blood or blood products within 30 days prior to screening Patient has Canadian Cardiovascular Society (CCS) Class III or IV angina Patient has significant obstructive valvular disease or significant congenital heart disease Patient has had a valve replacement Patient is pacemaker dependent Patient is on chronic anti-arrhythmic therapy, with the exception of amiodarone Patient is currently taking, or has taken in the last 7 days, a CYP3A4 inhibitor or inducer medication Patient has a history of hypertrophic obstructive cardiomyopathy Patient weighs > 120 kg Patient has a supine resting systolic blood pressure < 95 mmHg after 3 minutes rest Patient has a supine resting heart rate ≥ 100 beats per minute after 3 minutes rest Patient has an Modification of Diet in Renal Disease (MDRD) estimate of Glomerular Filtration Rate (GFR) ≤ 35 ml/min/1.73 m2 Patient has a potassium < 3.5 mEq/L or > 5.5 mEq/L Patient has a sodium ≤ 133 mEq/L Patient has a urea > 15 mmole/L Patient has a troponin I or T at screening that is detectable at the investigative site's clinical laboratory Patient has a hemoglobin < 11 gm/dL in males or < 10 gm/dL in females Patient has an alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALKP) or total bilirubin (TBILI) > 3 times the upper limit of normal Patient is, in the opinion of the investigator, not suitable to participate in the study Patient has participated in any clinical study with an investigational drug within three months prior to the first day of dosing with the exception of coronary stent studies Patient has ever received CK-1827452

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | Drug: CK-1827452<br>* IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h<br>Drug: Placebo<br>* IV infusion for 2 hours<br>|
| Experimental: Cohort 2<br>4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | Drug: CK-1827452<br>* IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.75 mg/kg/h followed by 1 hour at 0.375 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h<br>Drug: Placebo<br>* IV infusion for 2 hours<br>|
| Experimental: Cohort 3<br>4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | Drug: Placebo<br>* IV infusion for 24 hours<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.25 mg/kg/h followed by 23 hours at 0.025 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.5 mg/kg/h followed by 23 hours at 0.05 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 1.0 mg/kg/h followed by 23 hours at 0.1 mg/kg/h<br>|
| Experimental: Cohort 4<br>4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart. | Drug: CK-1827452<br>* IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h followed by 22 hours at 0.025 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h followed by 22 hours at 0.05 mg/kg/h<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h followed by 22 hours at 0.1 mg/kg/h<br>Drug: Placebo<br>* IV infusion for 24 hours<br>|
| Experimental: Cohort 5<br>2 treatment periods with a 72 hour infusion. The 2 treatment periods are randomly assigned and consist of 1 dose level of CK-1827452 (with dose de-escalation possible depending on tolerability) and 1 placebo treatment. Treatment period 2 occurs at least 7 days after the conclusion of period 1. | Drug: CK-1827452<br>* IV infusion for 1 hour at 1.0 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h<br>Drug: Placebo<br>* IV infusion for 72 hours<br>Drug: CK-1827452<br>* IV infusion for 1 hour at 0.75 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations | Pooled analysis of the echocardiographic measure systolic ejection time from echocardiograms taken at all timepoints. The systolic ejection time is the period during which the aortic valve is open and blood is flowing across the valve. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452. | 4 days | 
| Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations | Pooled analysis of the echocardiographic measure fractional shortening from echocardiograms taken at all timepoints. Fractional shortening is the percentage of change from baseline in the left ventricular cavity dimension with systole. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452. | 4 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CK-1827452 Maximum Observed Plasma Concentration (Cmax) | Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion | 2 days | 
| CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast) | Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion | 2 days |