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Renoprotection in Early Diabetic Nephropathy in Pima Indians

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier:
NCT00340678
First received: June 19, 2006
Last updated: July 16, 2014
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Diabetic Nephropathy
Drug: Losartan
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Renoprotection in Early Diabetic Nephropathy in Pima Indians

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Number of Participants With Decline in GFR [ Time Frame: Up to 6 years ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Glomerular Volume [ Time Frame: 6 years after first treatment ] [ Designated as safety issue: No ]

Enrollment: 170
Study Start Date: August 1995
Study Completion Date: March 2014
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Losartan
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.
Drug: Placebo
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.
Drug: Losartan
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.
Drug: Placebo
Treatment with placebo corresponding to each dose of losartan.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00340678

Locations
United States, Arizona
NIDDK, Phoenix
Phoenix, Arizona, United States, 85014
Sponsors and Collaborators
Investigators
Principal Investigator: Robert G Nelson, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier: NCT00340678     History of Changes
Other Study ID Numbers: 999995037, OH95-DK-N037
Study First Received: June 19, 2006
Results First Received: March 26, 2013
Last Updated: July 16, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Angiotensin II Receptor Antagonist
Therapeutic Trial
Glomerular Filtration Rate
Kidney Biopsy
Non-Insulin Dependent Diabetes Mellitus

Additional relevant MeSH terms:
Diabetic Nephropathies
Kidney Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Urologic Diseases
Losartan
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Anti-Arrhythmia Agents
Antihypertensive Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014