Renoprotection in Early Diabetic Nephropathy in Pima Indians

This investigation is a randomized, double-blinded, placebo-controlled clinical trial in adult diabetic Pima Indians with normal urinary albumin excretion (albumin-to-creatinine ration less than 30 mg/g) or microalbuminuria (albumin-to-creatinine ration = 30-299 mg/g) to test the hypothesis that blockade of the renin-angiotensin system with the angiotensin receptor blocker (ARB) losartan can prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care.

One hundred seventy subjects were recruited for the study, all of whom had type 2 diabetes for at least 5 years, serum creatinine concentrations less than 1.4 mg/dl, and no evidence of non-diabetic renal diseases. Ninety-two of the subjects had normal urinary albumin excretion at baseline and other 78 had microalbuminuria. Subjects in each albumin excretion group were randomized to treatment with either the angiotensin II receptor antagonist, losartan, or placebo. Measurements of glomerular filtration rate (GFR), renal plasma flow (RPF) and fractional clearances of albumin and IgG will be made initially, at one month, and at 12-month intervals from baseline thereafter. A kidney biopsy was performed after six years in 111 subjects. Morphometric analysis of renal biopsies was used to determine differences in glomerular structure between treatment groups.

Study Overview

Status

Completed

Intervention / Treatment

Detailed Description

This investigation is a randomized, double-blinded, placebo-controlled clinical trial in adult diabetic Pima Indians with normal urinary albumin excretion (albumin-to-creatinine ratio < 30 mg/g) or microalbuminuria (albumin-to-creatinine ratio = 30-299 mg/g) to test the hypothesis that blockade of the renin-angiotensin system with the angiotensin receptor blocker (ARB) losartan can prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care.

One hundred seventy subjects were recruited for the study, all of whom had type 2 diabetes for at least 5 years, serum creatinine concentrations < 1.4 mg/dl, and no evidence of non-diabetic renal diseases. Ninety-two of the subjects had normal urinary albumin excretion at baseline and the other 78 had microalbuminuria. Subjects in each albumin excretion group were randomized to treatment with either the angiotensin II receptor antagonist, losartan, or placebo. Measurements of glomerular filtration rate (GFR), renal plasma flow (RPF) and fractional clearances of albumin and immunoglobulin G (IgG) were made initially, at one month, and at 12-month intervals from baseline thereafter. A kidney biopsy was be performed after six years in 111 subjects. Morphometric analysis of renal biopsies was used to determine differences in glomerular structure between treatment groups.

The major outcome measure was a decline in GFR to less than or equal to 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of < 120 ml/min. Other measures of renoprotection were assessed, including group differences in 1) change in albumin excretion, 2) change in serum creatinine concentration, and 3) glomerular morphology in all subjects as outlined above.

Study Type

Interventional

Enrollment (Actual)

170

Phase

  • Phase 3

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

    • Arizona
      • Phoenix, Arizona, United States, 85014
        • NIDDK, Phoenix

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

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:

Volunteers from the Gila River Indian Community who meet the eligibility criteria will be invited to participate.

To be eligible for participation in the study, subjects must meet the following criteria:

  • Aged 18-65.
  • Diagnosis of type 2 diabetes greater than or equal to 5 years.
  • Serum creatinine concentration less than to 1.4 mg/dl.
  • Serum potassium concentration less than or equal to 5.5 milliequivalents (mEq)/L.
  • At least 2 of 3 weekly screening urinary albumin-to-creatinine ratios less than 300 mg/g. All screening tests are to be within 3 months of enrollment.
  • Willingness, after receiving a thorough explanation of the study, to participate.

EXCLUSION CRITERIA:

Subjects will be excluded for the following reasons:

  • Clinically significant disorders of the liver, cardiovascular disease, cerebrovascular disease, peripheral vascular disease, pulmonary diseases, renal-urinary disorders, gastrointestinal disorders, or hematocrit levels less than or equal to 30 percent in women or less than or equal to 35 percent in men.
  • Renovascular or malignant hypertension; uncontrolled hypertension despite treatment with three antihypertensive drugs; or hypertension that is being treated with antihypertensive medicines and the primary care physician or the patient refuses to adopt the blood pressure treatment regimen outlined in the study protocol.
  • Hematuria of unknown etiology.
  • Chronic debilitating disorders with or without treatment that would interfere with the assessment of kidney function or that might reduce the chances of survival for a sufficient length of time to evaluate efficacy of treatment.
  • Currently receiving a drug regimen that includes: steroids, immunosuppressants, or investigational new drugs.
  • Pregnancy. Women of childbearing potential must have a negative pregnancy test prior to entry and every three months during the study.
  • Evidence of inability to empty the bladder.
  • Hypersensitivity to angiotensin-converting enzyme inhibitors (ACEi), ARBs, or iodine.
  • Bleeding disorders, since kidney biopsies could not be performed safely in these individuals.
  • Massive obesity with body mass index greater than or equal to 45 kg/m(2).
  • Non-diabetic renal disease.
  • Conditions that are likely to interfere with informed consent or compliance with the protocol.

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: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Normoalbuminuria Losartan
Subjects with normal urinary albumin excretion were treated with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.
Treatment with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.
Other Names:
  • Cozaar
  • MK-954
  • DuP 753
Placebo Comparator: Normoalbuminuria Placebo
Subjects with normal urinary albumin excretion were treated with placebo corresponding to each dose of losartan.
Treatment with placebo corresponding to each dose of losartan.
Experimental: Microalbuminuria Losartan
Subjects with microalbuminuria were treated with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.
Treatment with losartan began at 50 mg daily, with the dose increasing to 100 mg daily after 1 week if symptomatic hypotension did not develop.
Other Names:
  • Cozaar
  • MK-954
  • DuP 753
Placebo Comparator: Microalbuminuria Placebo
Subjects with Microalbuminuria were treated with placebo corresponding to each dose of losartan.
Treatment with placebo corresponding to each dose of losartan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Decline in GFR
Time Frame: Up to 6 years
Participants were monitored for up to 6 years. This is the number of participants who had a decline in GFR to less than or equal to 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of less than 120 ml/min during the time of observation.
Up to 6 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Glomerular Volume
Time Frame: 6 years after first treatment
6 years after first treatment

Collaborators and Investigators

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

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

August 1, 1995

Primary Completion (Actual)

May 1, 2012

Study Completion (Actual)

March 1, 2014

Study Registration Dates

First Submitted

June 19, 2006

First Submitted That Met QC Criteria

June 19, 2006

First Posted (Estimate)

June 21, 2006

Study Record Updates

Last Update Posted (Actual)

March 25, 2021

Last Update Submitted That Met QC Criteria

March 2, 2021

Last Verified

October 1, 2013

More Information

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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