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Sponsored by: |
Department of Veterans Affairs |
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Information provided by: | Department of Veterans Affairs |
ClinicalTrials.gov Identifier: | NCT00555217 |
Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. The overall rate of ESRD secondary to diabetes has risen 68% since 1992. Medications that block the renin angiotensin system have been shown to decrease the progression of diabetic nephropathy. The use of an angiotensin receptor blocker (ARB) has been shown to decrease the risk of progression of kidney disease in two studies of individuals with Type 2 diabetes and proteinuria. Despite the use of an ARB, the incidence of renal failure remained high in the treated group in both studies. The combination of an angiotensin converting enzyme inhibitor (ACEI) and ARB can lead to more complete blockade of the renin angiotensin system. This combination has been shown in one study of non-diabetic kidney disease to decrease the risk of disease progression. In diabetic kidney disease, combination therapy has been shown to decrease proteinuria in short-term studies. Although there are encouraging results for improvement in proteinuria there are no data on progression of kidney disease for the use of combination of ACEI and ARB therapy in patients with diabetes. In addition, there could be an increased risk of serious hyperkalemia in individuals with diabetes who receive combination ACEI and ARB. We therefore propose a randomized double blind multi-center clinical trial to assess the effect of combination of ACEI and ARB in patients with diabetes and proteinuria on progression of kidney disease.
Condition | Intervention | Phase |
---|---|---|
Kidney Disease Nephropathy Type 2 Diabetes |
Drug: losartan Drug: lisinopril |
Phase III |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver), Active Control, Parallel Assignment, Efficacy Study |
Official Title: | CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy VA NEPHRON-D Study: Nephropathy iN Diabetes Study |
Estimated Enrollment: | 1850 |
Study Start Date: | July 2008 |
Estimated Study Completion Date: | July 2013 |
Estimated Primary Completion Date: | July 2013 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
Combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB)
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Drug: losartan
50 or 100mg/day
Drug: lisinopril
10, 20 or 40 mg/day
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2: Active Comparator
Mono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)
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Drug: losartan
50 or 100mg/day
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Primary Hypothesis:
To evaluate the combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB) vs. standard treatment with angiotensin receptor blocker on the progression of kidney disease in individuals with Type 2 diabetes and overt nephropathy.
The primary outcome is a composite endpoint of reduction in estimated GFR of 30 ml/min/1.73mxm in individuals with an estimated GFR greater than or equal to 60 ml/min/1.73mxm; reduction in estimated GFR of greater than 50% in individuals with an estimated GFR less than 60 mL/min/1.73mxm; progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR less than 15 mL/min/1.73mxm) or death.
Secondary outcome: a renal composite endpoint, defined as; reduction in estimated GFR of more than 50% (for individuals with a baseline estimated GFR less than 60 ml/min/1.73mxm); reduction in estimated GFR of more than 30 ml/min/1.73mxm (for individuals with a baseline estimated GFR greater than or equal to 60 ml/min/1.73mxm) or progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR of less than 15 ml/min/1.73mxm).
Tertiary outcomes are cardiovascular events (cardiovascular mortality, myocardial infarction, cerebrovascular accident, admission for heart failure), change in albuminuria at 12 months and decline in slope of kidney function.
Study Abstract:
The study is a multi-center, prospective, randomized, parallel group trial to test the efficacy of the combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotension receptor blocker (ARB) vs. standard treatment with angiotension receptor blocker on the combined end-point. The primary outcome is a composite endpoint of reduction in estimated GFR of 30 ml/min/1.73mxm in individuals with an estimated GFR greater than or equal to 60 ml/min/1.73mxm; reduction in estimated GFR of greater than 50% in individuals with an estimated GFR less than 60 ml/min/1.73mxm; progression to end-stage renal disease (defined as need for dialysis, renal transplant or en eGFR less than 15 ml/min/1.73mxm)or death. The study population is individuals with type 2 diabetes and overt nephropathy.
Eligible subjects who consent to participate will be randomized into either the combination therapy arm or the mono therapy arm. The randomization will be stratified by site and within sites by baseline albuminuria (< 1 vs. greater than or equal to 1 gram/gram creatinine) and eGFR (< 60 vs. greater than or equal to 60 ml/min/1.73mxm). All participants will receive open label therapy with losartan, an ARB, as standard of care. Patients not treated with an ACEI or ARB will be initiated on losartan; patients treated with an ACEI or ARB other than losartan (the study ARB) will be converted to losartan (the study ARB) and the dose titrated to 100 mg/day. Individuals who continue to meet the eligibility criteria will be randomized in a 1:1 ratio to the addition of blinded lisinopril (the study ACEI) or placebo. The medication (lisinopril or placebo) will be titrated from an initial dose of 10 mg/day to a target dose of 40 mg/day. After each adjustment in dose, serum chemistries will be evaluated for kidney function and potassium levels. Subjects will be enrolled over a three-year period and the maximum length of follow-up is 5 years. The planned study duration is 5 years with 3 years of accrual and 2-5 years of follow-up for all enrolled patients.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Jane Zhang, PhD | (203) 932-5711 ext 3779 | jane.zhang@va.gov |
Contact: Theresa O'Connor, PhD | (203) 932-5711 ext 3778 | terry.oconnor@va.gov |
Study Chair: | Linda Fried, MD MPH | VA Pittsburgh Health Care System |
Responsible Party: | Department of Veterans Affairs ( Fried, Linda - Study Chair ) |
Study ID Numbers: | 565 |
Study First Received: | November 7, 2007 |
Last Updated: | December 17, 2008 |
ClinicalTrials.gov Identifier: | NCT00555217 |
Health Authority: | United States: Federal Government |
kidney disease Nephropathy type 2 diabetes hyperkalemia |
Losartan Diabetic Nephropathies Metabolic Diseases Lisinopril Diabetes Mellitus Hyperkalemia Endocrine System Diseases |
Angiotensin II Urologic Diseases Diabetes Mellitus, Type 2 Kidney Diseases Endocrinopathy Glucose Metabolism Disorders Metabolic disorder |
Molecular Mechanisms of Pharmacological Action Cardiotonic Agents Physiological Effects of Drugs Enzyme Inhibitors Cardiovascular Agents Antihypertensive Agents Protective Agents |
Pharmacologic Actions Protease Inhibitors Angiotensin II Type 1 Receptor Blockers Therapeutic Uses Angiotensin-Converting Enzyme Inhibitors Anti-Arrhythmia Agents |