Renoprotection in Early Diabetic Nephropathy in Pima Indians

NCT00340678 | Completed Phase 3 Results DMC

• 2 other identifiers: 999995037OH95-DK-N037
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 1

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.

Conditions

Diabetic Nephropathy

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 6 years

Secondary Outcomes (1)

• Glomerular Volume

  6 years after first treatment

Study Arms (4)

Normoalbuminuria Losartan

EXPERIMENTAL

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

Normoalbuminuria Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Microalbuminuria Losartan

EXPERIMENTAL

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

Microalbuminuria Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Losartan DRUG

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.

Also known as: Cozaar, MK-954, DuP 753

Microalbuminuria Losartan; Normoalbuminuria Losartan

Placebo DRUG

Treatment with placebo corresponding to each dose of losartan.

Microalbuminuria Placebo; Normoalbuminuria Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

NIDDK, Phoenix

Phoenix, Arizona, 85014, United States

Location

Related Publications (10)

• 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.

  PMID: 3862110 BACKGROUND

• 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.

  PMID: 3011862 BACKGROUND

• 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.

  PMID: 2681929 BACKGROUND

• 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.

  PMID: 23545707 RESULT

• Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2024 Apr 29;4(4):CD006257. doi: 10.1002/14651858.CD006257.pub2.

  PMID: 38682786 DERIVED

• 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.

  PMID: 34437304 DERIVED

• 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.

  PMID: 34027894 DERIVED

• 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.

  PMID: 31573977 DERIVED

• 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.

  PMID: 27612501 DERIVED

• 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.

  PMID: 22718189 DERIVED

MeSH Terms

Conditions

Diabetic Nephropathies; Diabetes Mellitus, Type 2

Interventions

Losartan

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Results Point of Contact

• Title: Dr. Robert Nelson
• Organization: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

rnelson@phx.niddk.nih.gov

(602) 200-5205

Study Officials

• Robert G Nelson, M.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2006
• First Posted: June 21, 2006
• Study Start: August 1, 1995
• Primary Completion: May 1, 2012
• Study Completion: March 1, 2014
• Last Updated: March 25, 2021
• Results First Posted: November 19, 2013

Record last verified: 2013-10

Locations

US (1)