Improving Outcomes in Patients With Kidney Disease Due to Diabetes

March 1, 2010 updated by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Improving Outcomes in Diabetic Nephropathy

Kidney disease affects about one out of three people with diabetes mellitus, a common medical problem. Treatment of kidney disease with medications that lower blood pressure can slow the kidney disease but there is no known cure. This study is designed to test the hypothesis that certain combination-based blood pressure lowering regimens (of FDA approved medications) are better than single agent-based regimens for lowering blood pressure and further slowing or preventing progression of this incurable disease

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The long-range objective of this project is to prevent progression of diabetic nephropathy, the leading cause of end-stage renal disease (ESRD). In most patients diabetic nephropathy progresses inexorably to ESRD despite inhibition of the renin-angiotensin- aldosterone system with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs). The specific aims of this proposal are to: 1) recruit a multiethnic cohort of 78 young adults (ages 20-40) with type 1 (n=36) or type 2 (n=36) diabetes and overt nephropathy (defined as a urine albumin/creatinine ratio > 300 mg albumin/g creatinine) and randomize in a double blind fashion to a control group consisting of ACEI-based therapy alone (ramipril 40 mg once daily) or one of two experimental groups: a) ACEI + ARB (ramipril 40 mg once daily plus losartan 100 mg once daily) or b) ACEI + mineralocorticoid receptor antagonist (MRA) (ramipril 40 mg once daily plus spironolactone 25 mg once daily); 2) conduct a 12-month prospective study to determine if proteinuria is reduced to a greater extent when either the ARB or MRA is added to ACEi-based therapy. This study is powered to detect a 30% greater reduction in 24-hour urine albumin/creatinine ratio in either experimental group versus control (alpha = 0.05, beta=0.10, repeated measures analysis of variance). Secondary endpoints to be examined include: (a) serum potassium and creatinine to assess safety, (b) TGF-beta, as a surrogate marker for ongoing renal injury, (c) plasma renin activity, angiotensin II and aldosterone levels and (d) plasma lipids and lipoprotein composition; and 3) perform repeated ambulatory blood pressure monitoring (ABPM) to examine the renoprotective effect of the 3 different regimens at comparable 24-hour BP of < 125/75 mmHg. The deliverables include: 1) documentation of the safety of maximal dose combination therapy; 2) the feasibility of utilizing 24-hr ABPM to establish BP independent renoprotective effects of specific antihypertensive therapies; and 3) provide preliminary data for future large-scale studies to test efficacy and safety of combining ACEi with MRA therapy on renal outcomes.

Study Type

Interventional

Enrollment (Anticipated)

92

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Dallas, Texas, United States, 75230
        • The University of Texas Southwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Adult male and female subjects aged 20-65 of all ethnic backgrounds.
  • Type I diabetes mellitus defined as sudden onset of insulin requiring diabetes prior to age 20 and at least 5 years duration
  • Type 2 diabetes mellitus defined as onset > 20 years of age and treatment with oral hypoglycemic agent and/or insulin and increased C-peptide level.
  • Seated SBP > 130 mmHg documented at one screening visit or treated SBP < 130 mmHg with a documented history of SBP > 130 mmHg on more than one previous occasion
  • Proteinuria defined as a 24-hour urine albumin/creatinine ratio > 300 mg/g while on an ACE inhibitor with or without non-ARB, non-aldosterone antagonist treatment
  • Ongoing treatment (> 3 months) with an ACE inhibitor or ARB with or without additional antihypertensive therapy (e.g. CCB, a-blocker, b-blocker, clonidine).

Exclusion Criteria:

  • BMI > 45 kg/m2
  • Baseline serum creatinine > 3.0 mg/dl in females and > 4.0 mg/dl in males or creatinine clearance <20 ml/min estimated by Cockcroft-Gault equation (based on age, fasting serum creatinine concentration and ideal body weight in kilograms).
  • Secondary cause of kidney disease other than diabetic nephropathy
  • Serum potassium concentration >5.5 mEq/L on ACE inhibitor therapy 7-10 days prior to randomization
  • Poorly controlled diabetes, i.e. HgbA1C > 11 mg/dl 7-10 days prior to randomization
  • History of allergy to iothalamate or history of renal failure due to contrast nephropathy
  • Stroke or myocardial infarction within the preceding 12 months prior to randomization
  • Coronary revascularization procedure within past 6 months
  • Clinically apparent congestive heart failure defined as clinical signs of heart failure or an ejection fraction of < 40% (and/or depressed LV systolic function by echocardiogram).
  • Terminal disease including cancer and AIDS
  • Documented increase in serum creatinine > 50% of baseline within 3 months prior to the run-in period
  • Renal disease known or in the opinion of the investigator caused by a condition other than diabetes
  • Known adverse reaction to study medications including ACE inhibitors, ARB and spironolactone
  • History of chronic or intermittent gross hematuria
  • Spontaneous 24-hour urine sodium excretion rate exceeding 350 mEq/day
  • AST or ALT greater than 2.5 the upper limit of normal for the laboratory
  • Pregnancy
  • History of autoimmune disease, connective tissue disease or multiple drug allergies
  • Anticipated need for renal replacement therapy within 12 months Inclusion criteria for normal subjects
  • Adult male and female subjects aged 20-65 of all ethnic backgrounds Exclusion criteria for normal subjects
  • Chronic medical conditions, including but not limited to diabetes mellitus, hypertension, chronic kidney disease, and hyperlipidemia.
  • Use of medications for antihypertensive
  • Inability to follow study protocol for any reason

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Change in 24 hour urine albumin to creatinine ratio after 12 months of treatment

Secondary Outcome Measures

Outcome Measure
Changes in:
urine transforming growth factor beta
plasma lipids
lipoprotein levels
plasma aldosterone level

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Robert D Toto, MD, The University of Texas Southwestern Medical Center Dallas

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2003

Study Completion (Actual)

December 1, 2006

Study Registration Dates

First Submitted

September 26, 2006

First Submitted That Met QC Criteria

September 26, 2006

First Posted (Estimate)

September 27, 2006

Study Record Updates

Last Update Posted (Estimate)

March 2, 2010

Last Update Submitted That Met QC Criteria

March 1, 2010

Last Verified

March 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DK063010-04 (completed)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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