Renal and Peripheral Hemodynamic Function in Patients With Type 1 Diabetes Mellitus

Diabetes Mellitus, Type 1 Clinical Trial

Official title: The Effect of Protein Kinase C Inhibition on Renal and Peripheral Hemodynamic Function in Patients With Type 1 Diabetes Mellitus

Status Completed

Clinical Trial Summary

Protein kinase C (PKC), an enzyme in the body, has been implicated in the process of diabetic microvascular complications. The purpose of this study will be to evaluate the renal hemodynamic and peripheral vascular effects of PKC inhibition with ruboxistaurin mesylate (an inhibitor of PKC) in patients with Type 1 diabetes mellitus and evidence of early nephropathy. In this pilot study, 21 patients with type 1 diabetes were planned to be randomized to LY333531 or placebo in a 2:1 fashion, after an initial period of testing. After 8 weeks of study drug, patients were retested.

Clinical Trial Description

This is a pilot study with 3 parts. Twenty-one patients with type 1 diabetes will be randomized to LY333531 or placebo in a 2:1 fashion. Each patient will be studied on four occasions, while euglycemic and while hyperglycemic without PKC inhibition and while euglycemic and hyperglycemic after an eight-week period of PKC inhibition.

Study Part 1: The impact of PKC inhibition on the renal and peripheral hemodynamic response to hyperglycemia On the evening prior to the first study day, the study participants will be admitted to an in-patient research facility with overnight plasma glucose levels maintained at 4-6 mmol/L using a modified glucose clamp technique. The next day, baseline measures of endothelial function and vascular compliance, mean arterial pressure (MAP), and renal function, including glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal blood flow (RBF), filtration fraction (FF) and renal vascular resistance (RVR) will be obtained using inulin and para-aminohippurate. In all diabetic subjects, euglycemia or hyperglycemia will be maintained by modified overnight glucose clamping techniques. During the second day of the study, capillary blood glucose will be maintained at 9-11 mmol/l overnight, and the renal and peripheral vascular hemodynamic measurements will be repeated the following day. The subjects will then be given the PKC-inhibitor LY333531 (or placebo) for 6 weeks, after which the study will be repeated. The first dose of LY333531 will be taken at 0800 hrs the day after the completion of Study 1 The dose will consist of 32 mg PO OD. Study participants will monitor their capillary blood glucose levels on a four times daily schedule.

Study Part 2: The impact of PKC inhibition on the response to Ang II On the evening prior to the first study day, the study participants will be admitted to an in-patient research facility with overnight plasma glucose levels maintained at 4-6 mmol/L using a modified glucose clamp technique. The next day, baseline measures of renal function, including GFR, ERPF, RBF, FF and RVR will be obtained. Graded Ang II infusion will be administered, and the response of MAP, GFR, RPF, RBF, FF and RVR will be measured. The subjects will then be given the PKC-inhibitor LY333531 (or placebo) for 8 weeks, as previously described, after which the study will be repeated.

Study Part 3: The impact of PKC inhibition on proteinuria . Subjects will collect a 24 hour urine sample for protein / albumin excretion. They will subsequently be randomized to receive either the PKC inhibitor LY333531 or placebo, using a table of random numbers. After 8 weeks treatment, the 24 hour urine sample will again be collected. ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

• NCT number: NCT00297401
• Study type: Interventional
• Source: Chromaderm, Inc.
• Status: Completed
• Phase: Phase 3
• Start date: March 2006
• Completion date: November 2007