Signaling Mechanisms and Vascular Function in Diabetes Mellitus

Ruboxistaurin is being tested to see if it is effective in treating certain diabetic complications, such as diseases of the blood vessels.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Ruboxistaurin; Drug: Placebo

Detailed Description

To test the hypothesis that activation of protein kinase C impairs vascular reactivity in patients with diabetes.

A major cause of death and disability in patients with diabetes mellitus is atherosclerosis. Endothelial dysfunction is an important, if not primary, factor in atherogenesis. Nitric oxide is an important substance made and released by the endothelium. Many prior studies in animals and humans have shown that the ability of the blood vessel to dilate is impaired in diabetes. This process of vasodilation is mediated by a substance, nitric oxide, which is thought to be highly susceptible to destruction by oxidant molecules. In previous studies, we found that acute administration of the antioxidant, vitamin C, improves endothelium-dependent vasodilation in blood vessels of patients with type 1 and type 2 diabetes. This suggests that by scavenging oxidants, such as superoxide, vitamin C may reduce the destruction of nitric oxide and thereby preserve endothelial function. Additional mechanisms, including activation of a substance called protein kinase C, and oxidant stress from excess soluble peroxides may be present in diabetes and interact with oxidant stress to cause endothelial dysfunction in patients with diabetes. Accordingly, we would like to study both of these mechanisms to determine their contribution to endothelial dysfunction.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with diabetes mellitus will be eligible if they are receiving dietary treatment for hyperglycemia, sulfonylureas, metformin or insulin

Exclusion Criteria:

• Any diabetic subject with a HgbA1C level of <7% or >11%
• Evidence of atherosclerosis
• symptoms of angina
• symptoms of claudication
• symptoms of cerebrovascular ischemia
• findings of arterial occlusive disease, as would be suggested by decreased pulses, asymmetric blood pressure, bruits or reduced limb pressure measurements
• hypertension defined as a systolic blood pressure > = 150 mmHg and a diastolic blood pressure >= 95 mmHg; (allowable blood pressure medications for diabetic subjects include calcium channel blockers, alpha and beta adrenergic blockers, and diuretics)
• hypercholesterolemia, defined as total cholesterol levels greater than 75th percentile for age and sex and LDL cholesterol levels >130mg/dL.
• renal insufficiency (serum creatinine >1.5 mg/dL for men; >1.2 mg/dL for women)
• hepatic dysfunction defined as liver enzyme abnormalities > two times the upper limit of normal
• chronic pulmonary disease
• congestive heart failure
• pregnancy (or subjects planning to become pregnant);
• history of cigarette smoking within the last five years;

• history of clinically significant coronary artery or cerebrovascular disease (defined as MI or stroke within 6 months, or presence of unstable angina)

  • use of any, vasoactive, cardioactive, or non-steroidal anti-inflammatory medications within 24 hours of vascular testing visits

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; Placebo	Drug: Placebo; 1 tab po QD for 2 weeks
Active Comparator: 1; Ruboxistaurin	Drug: Ruboxistaurin; 32 mg daily for 2 weeks; Other Names: LY-333531

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To test the hypothesis that activation of protein kinase Cß (PKCß) impairs vascular reactivity in patients with diabetes mellitus	one testing visit every 4 weeks for 8 weeks

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start: May 1, 1999
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: September 26, 2008
• First Submitted That Met QC Criteria: September 29, 2008
• First Posted (Estimate): September 30, 2008

Study Record Updates

• Last Update Posted (Estimate): September 30, 2008
• Last Update Submitted That Met QC Criteria: September 29, 2008
• Last Verified: September 1, 2008

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Ruboxistaurin
• Other Study ID Numbers: 1999-P-003331Ruboxistaurin