Renoprotection in Early Diabetic Nephropathy in Pima Indians

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00340678
• Collaborator: (none)
• Enrollment: 170
• Location: 1
• Arms: 4
• Duration (Months): 223
• Patients Per Site Per Month: 0.8

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Nephropathy	Drug: Losartan; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Renoprotection in Early Diabetic Nephropathy in Pima Indians
• Study Start Date: Aug 1, 1995
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

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.	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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Decline in GFR [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.

Secondary Outcome Measures

1. Glomerular Volume [6 years after first treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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

Locations

	Site	City	State	Country	Postal Code
1	NIDDK, Phoenix	Phoenix	Arizona	United States	85014

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Robert G Nelson, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00340678
• Other Study ID Numbers: 999995037; OH95-DK-N037
• First Posted: Jun 21, 2006
• Last Update Posted: Mar 25, 2021
• Last Verified: Oct 1, 2013

• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Angiotensin II Receptor Antagonist; Therapeutic Trial; Glomerular Filtration Rate; Kidney Biopsy; Non-Insulin Dependent Diabetes Mellitus
• Additional relevant MeSH terms: Kidney Diseases; Diabetic Nephropathies; Losartan

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled between 1996 and 2001, the last biopsy was performed in 2007, and morphometric evaluation was completed in 2012.
Pre-assignment Detail	Of 313 patients with type 2 diabetes who were screened, 79 were ineligible, 50 declined to participate, and 14 had other reasons that prevented participation despite meeting eligibility requirements.

Arm/Group Title	Normoalbuminuria Losartan	Normoalbuminuria Placebo	Microalbuminuria Losartan	Microalbuminuria Placebo
Arm/Group 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.
Period Title: Overall Study
STARTED	46	46	39	39
COMPLETED	45	46	39	39
NOT COMPLETED	1	0	0	0

Baseline Characteristics

Arm/Group Title	Normoalbuminuria Losartan	Normoalbuminuria Placebo	Microalbuminuria Losartan	Microalbuminuria Placebo	Total
Arm/Group 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.	Total of all reporting groups
Overall Participants	46	46	39	39	170
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.5 (10.6)	41.9 (11.7)	41.8 (8.9)	42.3 (10.9)	41.3 (10.6)
Sex: Female, Male (Count of Participants)
Female	36 78.3%	33 71.7%	28 71.8%	27 69.2%	124 72.9%
Male	10 21.7%	13 28.3%	11 28.2%	12 30.8%	46 27.1%
Region of Enrollment (participants) [Number]
United States	46 100%	46 100%	39 100%	39 100%	170 100%
Diabetes duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.8 (4.7)	10.4 (6.0)	10.3 (5.2)	14.1 (8.4)	10.8 (6.2)
BMI (kg/(m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/(m^2)]	37.4 (8.8)	36.6 (8.0)	34.6 (9.1)	33.8 (7.2)	35.7 (8.3)
Blood pressure, systolic (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	115 (11)	118 (14)	118 (15)	123 (13)	118 (13)
Blood pressure, diastolic (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	75 (7)	75 (7)	77 (9)	77 (7)	76 (7)
Blood pressure, mean (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	88 (7)	89 (9)	90 (10)	92 (8)	90 (9)
HbA1c (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	9.2 (2.0)	8.1 (2.2)	9.5 (2.3)	10.3 (2.1)	9.2 (2.1)
Glomerular filtration rate (GFR) (mL/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min]	171 (38)	152 (40)	166 (43)	168 (43)	164 (41)
Urinary albumin to creatinine ratio (mg/g) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/g]	15	14	66	80	47

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Decline in GFR
Description	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.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	Normoalbuminuria Losartan	Normoalbuminuria Placebo	Microalbuminuria Losartan	Microalbuminuria Placebo
Arm/Group 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.
Measure Participants	45	46	39	39
Number [participants]	2 4.3%	2 4.3%	1 2.6%	4 10.3%

2. Secondary Outcome

Title	Glomerular Volume
Time Frame	6 years after first treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	Normoalbuminuria Losartan	Normoalbuminuria Placebo	Microalbuminuria Losartan	Microalbuminuria Placebo
Arm/Group 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.
Measure Participants	45	46	39	39
Mean (Standard Deviation) [*10^6 cubic microns]	5.4 (1.8)	5.6 (1.1)	6.4 (2.3)	7.0 (3.0)

Adverse Events

Arm/Group Title	Losartan		Placebo
Arm/Group Description	Subjects received losartan		Subjects received placebo
All Cause Mortality
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/84 (3.6%)		6/85 (7.1%)
Blood and lymphatic system disorders
Death from coronary artery disease	1/84 (1.2%)	1	1/85 (1.2%)	1
Death from leukemia	0/84 (0%)	0	1/85 (1.2%)	1
Gastrointestinal disorders
Death from bleeding gastric ulcer	1/84 (1.2%)	1	0/85 (0%)	0
General disorders
Death from multiple myeloma	1/84 (1.2%)	1	0/85 (0%)	0
Hepatobiliary disorders
Death from hepatocellular carcinoma	0/84 (0%)	0	1/85 (1.2%)	1
Death from alcoholic cirrhosis	0/84 (0%)	0	1/85 (1.2%)	1
Social circumstances
Death from automobile accident	0/84 (0%)	0	2/85 (2.4%)	2
Other (Not Including Serious) Adverse Events
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/84 (1.2%)		0/85 (0%)
Renal and urinary disorders
Urethral obstruction after kidney biopsy	1/84 (1.2%)	1	0/85 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.