Ruboxistaurin in New York Heart Failure Classification III-IV Patients

Study Overview
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Brief Summary
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This study evaluates the effect of ruboxistaurin for its safety, tolerability, and effectiveness in treating adult patients with heart failure. Patients will receive 1 dose of oral ruboxistaurin.

Detailed Description
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Ruboxistaurin is a drug initially developed for treatment of diabetic peripheral retinopathy. The proposed indication for ruboxistaurin in this study is the treatment of adult patients with New York Heart Failure Association (NYHA) Class III-IV heart failure. Ruboxistaurin is a protein kinase c-alpha (PKC-alpha) inhibitor and thus will produce an inotropic effect in the heart which holds the potential to improve cardiac function.

Official Title
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A Prospective Phase I/II Dose Escalation Pilot Analysis of Ruboxistaurin (LY333531) for Safety in New York Heart Failure Classification III-IV Patients, As Well As For Efficacy in Acutely Augmenting Cardiac Function.

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Ruboxistaurin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 30-75 years of age, inclusive NYHA Class III-IV heart failure (HF) confirmed left ventricular systolic dysfunction with left ventricular ejection fraction (LVEF) <40% as assessed by noninvasive imaging studies such as echocardiography or cardiac MRI within the last 6 months admitted with decompensated heart failure and almost ready for clinical discharge Patient must have had adequate therapy for acute decompensated HF (heart failure) episode prior to enrollment Exclusion Criteria: Patients with acute coronary syndrome Resynchronization therapy initiated less than 90 days prior to enrollment (LVAD) left ventricular assist device or heart transplantation expected within the next 3 months Patients on hemodialysis or end stage renal disease (ESRD) Patients with serum albumin less than 3 g/dL or evidence of liver cirrhosis Patients with uncontrolled arterial hypertension (systolic blood pressure > 180 or diastolic blood pressure >110) Patients with severe valvular heart disease Patients with acute myocarditis Patients with serum creatinine >3.0 mg/dl or BUN >70 mg/dL Patients with hemodynamic instability or significant active arrhythmias Patients currently on intravenous inotropic therapy or those that have received inotropic therapy within the last 24 hours prior to study enrollment Patients currently on CYP3A inhibitors, or patients that have taken CYP3A inhibitors within 3 months prior to enrollment Patients with ongoing ischemia Patients who have had a myocardial infarction within 30 days prior to study enrollment Patients who are pregnant, nursing, or planning to become pregnant during the study period

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruboxistaurin 64 mg<br>ruboxistaurin, 64 mg as 1 capsule by mouth with water, 1 time administration | Drug: Ruboxistaurin<br>* Dose escalation trial. 1st ten patients to receive 64 mg, next 10 patients to receive 128 mg, next 10 patients to receive 256 mg.<br>* Other names: LY333531;|
| Experimental: Ruboxistaurin 128 mg<br>ruboxistaurin, 128 mg as 2 capsules by mouth with water, 1 time administration | Drug: Ruboxistaurin<br>* Dose escalation trial. 1st ten patients to receive 64 mg, next 10 patients to receive 128 mg, next 10 patients to receive 256 mg.<br>* Other names: LY333531;|
| Experimental: Ruboxistaurin 256 mg<br>ruboxistaurin, 256 mg as 4 capsules by mouth with water, 1 time administration | Drug: Ruboxistaurin<br>* Dose escalation trial. 1st ten patients to receive 64 mg, next 10 patients to receive 128 mg, next 10 patients to receive 256 mg.<br>* Other names: LY333531;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients with a new onset, clinically significant arrhythmia or conduction system disease, | EKG and continuous holter monitoring will be performed. Determination of clinically significant arrhythmia will be determined by a blinded electrophysiologist; intent to treat population | 48 hours | 
| Percent of patients with significant prolongation in the corrected QT (QTc) interval | Interpreted by a blinded electrophysiologist. A significant QTc prolongation will be defined as an increase from normal baseline (<440 msec) to greater than 440 msec OR an increase of equal to or more than 5% from baseline for those subjects with a baseline QTc of >440 msec.; Intent to treat population | 24 hours | 
| Percent of patients with significant increase in liver function tests | An abnormal change in liver function tests will be defined as an increase to 2x the upper limits of normal for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) OR a 50% increase from baseline values. Intent to treat population | 12 hours | 
| Percent of patients with a significant increase in serum creatinine not explained by diuretic use. | An abnormal change in serum creatinine will be defined as a 50% increase from baseline values. Of note, changes in Blood Urea Nitrogen (BUN) and creatinine may be secondary to diuretic use and intravascular volume depletion. Intent to treat population | 12 hours | 
| Percent of patient with a significant increase in serum creatine phosphokinase (CPK) levels | An abnormal change in serum CPK will be defined as an increase to 2x the upper limits or normal OR a 50% increase from baseline values. Intent to treat population | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients experiencing at least one adverse event | Adverse events will be assessed up to 30 days post study drug administration. Intent to treat population | 30 days | 
| Change in cardiac contractility as assessed by echocardiography. | Transthoracic echocardiogram performed at baseline and 4 hours. Intent to treat population. Efficacy | 4 hours | 
| Change in self-reported well-being, fatigue and dyspnea | All subjects will undergo assessment of self-reported global well-being, fatigue and dyspnea via a visual-analogue scale that ranges from 0-100. Intent to treat population | 8 hours, 24 hours |