Ruboxistaurin in New York Heart Failure Classification III-IV Patients

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.

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.

Study Overview

• Status: Withdrawn
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Ruboxistaurin

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Center for Research and Education at The Christ Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, 30-75 years of age, inclusive
2. 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
3. Patient must have had adequate therapy for acute decompensated HF (heart failure) episode prior to enrollment

Exclusion Criteria:

1. Patients with acute coronary syndrome
2. Resynchronization therapy initiated less than 90 days prior to enrollment
3. (LVAD) left ventricular assist device or heart transplantation expected within the next 3 months
4. Patients on hemodialysis or end stage renal disease (ESRD)
5. Patients with serum albumin less than 3 g/dL or evidence of liver cirrhosis
6. Patients with uncontrolled arterial hypertension (systolic blood pressure > 180 or diastolic blood pressure >110)
7. Patients with severe valvular heart disease
8. Patients with acute myocarditis
9. Patients with serum creatinine >3.0 mg/dl or BUN >70 mg/dL
10. Patients with hemodynamic instability or significant active arrhythmias
11. Patients currently on intravenous inotropic therapy or those that have received inotropic therapy within the last 24 hours prior to study enrollment
12. Patients currently on CYP3A inhibitors, or patients that have taken CYP3A inhibitors within 3 months prior to enrollment
13. Patients with ongoing ischemia
14. Patients who have had a myocardial infarction within 30 days prior to study enrollment
15. Patients who are pregnant, nursing, or planning to become pregnant during the study period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Tennessee
• Collaborators: The Christ Hospital
• Investigators: Principal Investigator: John L Jefferies, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2017
• Primary Completion (Actual): January 1, 2022
• Study Completion (Actual): January 1, 2022

Study Registration Dates

• First Submitted: May 10, 2016
• First Submitted That Met QC Criteria: May 10, 2016
• First Posted (Estimate): May 11, 2016

Study Record Updates

• Last Update Posted (Actual): June 6, 2022
• Last Update Submitted That Met QC Criteria: June 1, 2022
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Ruboxistaurin
• Other Study ID Numbers: 2013-7007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No