Back to results

Renoprotection in Early Diabetic Nephropathy in Pima Indians

Primary Purpose

Diabetic Nephropathy

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Losartan

Placebo

About this trial

This is an interventional treatment trial for Diabetic Nephropathy focused on measuring Angiotensin II Receptor Antagonist, Therapeutic Trial, Glomerular Filtration Rate, Kidney Biopsy, Non-Insulin Dependent Diabetes Mellitus

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

NIDDK, Phoenix

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Normoalbuminuria Losartan

Normoalbuminuria Placebo

Microalbuminuria Losartan

Microalbuminuria Placebo

Arm Description

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.

Subjects with normal urinary albumin excretion were treated with placebo corresponding to each dose of 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.

Subjects with Microalbuminuria were treated with placebo corresponding to each dose of losartan.

Outcomes

Primary Outcome Measures

Number of Participants With Decline in GFR

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

Full Information

NCT ID

NCT00340678

First Posted

June 19, 2006

Last Updated

March 2, 2021

Sponsor

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

1. Study Identification

Unique Protocol Identification Number

NCT00340678

Brief Title

Renoprotection in Early Diabetic Nephropathy in Pima Indians

Official Title

Renoprotection in Early Diabetic Nephropathy in Pima Indians

Study Type

Interventional

2. Study Status

Record Verification Date

October 2013

Overall Recruitment Status

Completed

Study Start Date

August 1995 (undefined)

Primary Completion Date

May 2012 (Actual)

Study Completion Date

March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

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

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetic Nephropathy

Keywords

Angiotensin II Receptor Antagonist, Therapeutic Trial, Glomerular Filtration Rate, Kidney Biopsy, Non-Insulin Dependent Diabetes Mellitus

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

170 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Normoalbuminuria Losartan

Arm Type

Experimental

Arm Description

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.

Arm Title

Normoalbuminuria Placebo

Arm Type

Placebo Comparator

Arm Description

Subjects with normal urinary albumin excretion were treated with placebo corresponding to each dose of losartan.

Arm Title

Microalbuminuria Losartan

Arm Type

Experimental

Arm Description

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.

Arm Title

Microalbuminuria Placebo

Arm Type

Placebo Comparator

Arm Description

Subjects with Microalbuminuria were treated with placebo corresponding to each dose of losartan.

Intervention Type

Drug

Intervention Name(s)

Losartan

Other Intervention Name(s)

Cozaar, MK-954, DuP 753

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Treatment with placebo corresponding to each dose of losartan.

Primary Outcome Measure Information:

Title

Number of Participants With Decline in GFR

Description

Time Frame

Up to 6 years

Secondary Outcome Measure Information:

Title

Glomerular Volume

Time Frame

6 years after first treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert G Nelson, M.D.

Organizational Affiliation

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

Official's Role

Principal Investigator

Facility Information:

Facility Name

NIDDK, Phoenix

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85014

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

3862110

Citation

Zatz R, Meyer TW, Rennke HG, Brenner BM. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5963-7. doi: 10.1073/pnas.82.17.5963.

Results Reference

background

PubMed Identifier

3011862

Citation

Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986 Jun;77(6):1925-30. doi: 10.1172/JCI112521.

Results Reference

background

PubMed Identifier

2681929

Citation

Anderson S, Rennke HG, Garcia DL, Brenner BM. Short and long term effects of antihypertensive therapy in the diabetic rat. Kidney Int. 1989 Oct;36(4):526-36. doi: 10.1038/ki.1989.227.

Results Reference

background

PubMed Identifier

23545707

Citation

Weil EJ, Fufaa G, Jones LI, Lovato T, Lemley KV, Hanson RL, Knowler WC, Bennett PH, Yee B, Myers BD, Nelson RG. Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes. Diabetes. 2013 Sep;62(9):3224-31. doi: 10.2337/db12-1512. Epub 2013 Apr 1. Erratum In: Diabetes. 2018 Jan 5;:

Results Reference

result

PubMed Identifier

34437304

Citation

Fort PE, Rajendiran TM, Soni T, Byun J, Shan Y, Looker HC, Nelson RG, Kretzler M, Michailidis G, Roger JE, Gardner TW, Abcouwer SF, Pennathur S, Afshinnia F. Diminished retinal complex lipid synthesis and impaired fatty acid beta-oxidation associated with human diabetic retinopathy. JCI Insight. 2021 Oct 8;6(19):e152109. doi: 10.1172/jci.insight.152109.

Results Reference

derived

PubMed Identifier

34027894

Citation

Reynolds EL, Akinci G, Banerjee M, Looker HC, Patterson A, Nelson RG, Feldman EL, Callaghan BC. The determinants of complication trajectories in American Indians with type 2 diabetes. JCI Insight. 2021 May 24;6(10):e146849. doi: 10.1172/jci.insight.146849. Erratum In: JCI Insight. 2023 Feb 8;8(3):

Results Reference

derived

PubMed Identifier

31573977

Citation

Afshinnia F, Nair V, Lin J, Rajendiran TM, Soni T, Byun J, Sharma K, Fort PE, Gardner TW, Looker HC, Nelson RG, Brosius FC, Feldman EL, Michailidis G, Kretzler M, Pennathur S. Increased lipogenesis and impaired beta-oxidation predict type 2 diabetic kidney disease progression in American Indians. JCI Insight. 2019 Nov 1;4(21):e130317. doi: 10.1172/jci.insight.130317.

Results Reference

derived

PubMed Identifier

27612501

Citation

Tanamas SK, Saulnier PJ, Fufaa GD, Wheelock KM, Weil EJ, Hanson RL, Knowler WC, Bennett PH, Nelson RG. Long-term Effect of Losartan on Kidney Disease in American Indians With Type 2 Diabetes: A Follow-up Analysis of a Randomized Clinical Trial. Diabetes Care. 2016 Nov;39(11):2004-2010. doi: 10.2337/dc16-0795. Epub 2016 Sep 9.

Results Reference

derived

PubMed Identifier

22718189

Citation

Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, Lovato T, Richardson M, Myers BD, Nelson RG. Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int. 2012 Nov;82(9):1010-7. doi: 10.1038/ki.2012.234. Epub 2012 Jun 20.

Results Reference

derived

Learn more about this trial

Renoprotection in Early Diabetic Nephropathy in Pima Indians

We'll reach out to this number within 24 hrs