VA NEPHRON-D: Diabetes iN Nephropathy Study (VA NEPHRON-D)
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ClinicalTrials.gov Identifier: NCT00555217 |
Recruitment Status :
Terminated
(It was stopped primarily because of safety concerns along with low conditional power to detect a treatment effect on the primary outcome.)
First Posted : November 8, 2007
Results First Posted : May 29, 2015
Last Update Posted : May 29, 2015
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Condition or disease | Intervention/treatment | Phase |
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Kidney Disease Nephropathy Type 2 Diabetes | Drug: losartan Drug: lisinopril | Phase 3 |
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/1.73m*m in individuals with an estimated baseline GFR greater than or equal to 60 ml/min/1.73m*m; reduction in estimated GFR of greater than 50% in individuals with an estimated baseline GFR less than 60 mL/min/1.73m*m; progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR less than 15 ml/min/1.73m*m) 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/1.73m*m); reduction in estimated GFR of more than 30 ml/min/1.73m*m (for individuals with a baseline estimated GFR greater than or equal to 60 ml/min/1.73m*m) or progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR of less than 15 ml/min/1.73m*m).
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/1.73m*m in individuals with an estimated GFR greater than or equal to 60 ml/min/1.73m*m; reduction in estimated GFR of greater than 50% in individuals with an estimated GFR less than 60 ml/min/1.73m*m; progression to end-stage renal disease (defined as need for dialysis, renal transplant or en eGFR less than 15 ml/min/1.73m*m)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/1.73m*m). 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 tolerate ARB 100mg/day 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 period of 4.25 years and the maximum length of follow-up is 6.25 years. The planned study duration is 6.25 years with 4.25 years of accrual and 6.25 years of follow-up for all enrolled patients. The intervention was stopped on November 7, 2012 for safety concerns after an interim analysis. Patients are still under passively follow-up without intervention.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 1448 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Double (Participant, Care Provider) |
Primary Purpose: | Treatment |
Official Title: | CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D Study) |
Study Start Date : | July 2008 |
Actual Primary Completion Date : | September 2014 |
Actual Study Completion Date : | October 2014 |

Arm | Intervention/treatment |
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Experimental: Combination of ARB and ACEI
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 |
Active Comparator: Monotherapy ARB
Mono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)
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Drug: losartan
50 or 100mg/day |
- A Composite Endpoint of Reduction in Estimated GFR of 30ml/Min/1.73m*m in Individuals w/a Baseline Estimated GFR >= 60 ml/Min/1.73m*m, Reduction in Estimated GFR >50% in Individuals w/ Baseline Estimated GFR <60ml/Min/1.73m*m; ESRD or Death [ Time Frame: From enrollemnt to time of first primary event, up to 4.5 years ]Time to the first event of reduction in estimated GFR of 30ml/min/1.73m*m in individuals w/a baseline estimated GFR >= 60 ml/min/1.73m*m, reduction in estimated GFR >50% in individuals w/ baseline estimated GFR <60ml/min/1.73m*m; ESRD or death.
- A Renal Composite Endpoint, Defined as; Reduction in Estimated GFR of >50% (for Individuals With Baseline GFR <60) or Reduction in GFR of >30 (for Individuals With Baseline GFR >= GFR 60) or ESRD. [ Time Frame: From enrollment to time of first event, up to 4.5 years ]Time to the first event of reduction in estimated GFR of >50% (for individuals with baseline GFR <60) or reduction in GFR of >30 (for individuals with baseline GFR >= GFR 60) or ESRD.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Type 2 diabetes
- Albuminuria >300mg/gram creatinine
- Stage 2 or 3 CKD (eGFR 30 to <90 mg/min/1.73m*2 )
- Able to give informed consent
- Telephone contact available
Exclusion Criteria:
- History of intolerance to ACEI or ARB
- Serum potassium level >5.5 meq/L
- Receiving sodium polystyrene sulfonate (Kayexalate)
- Pregnancy, breast feeding, planning to become pregnant or sexually active and not using birth control
- Renal transplant recipient
- Suspected non-diabetic kidney disease
- Inability to discontinue current use of ACEI/ARB combination
- Current use of Lithium
- Severe (end-stage) comorbid disease
- Prisoner
- Age <18
- Estimated glomerular filtration rate (GFR) <30 or >=90 ml/min/1.73m*m
- HbA1c >10.5%
- Patient refusal
- Participation in a concurrent interventional study
- Blood pressure >180/95
- Unwilling to stop any proscribed medications after enrollment

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00555217

Study Chair: | Linda Fried, MD MPH | VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA |
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | US Department of Veterans Affairs |
ClinicalTrials.gov Identifier: | NCT00555217 |
Other Study ID Numbers: |
565 |
First Posted: | November 8, 2007 Key Record Dates |
Results First Posted: | May 29, 2015 |
Last Update Posted: | May 29, 2015 |
Last Verified: | May 2015 |
kidney disease nephropathy type 2 diabetes hyperkalemia acute kidney injury |
Kidney Diseases Diabetes Mellitus, Type 2 Diabetes Mellitus Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Urologic Diseases Losartan Lisinopril Anti-Arrhythmia Agents |
Antihypertensive Agents Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Antagonists Molecular Mechanisms of Pharmacological Action Angiotensin-Converting Enzyme Inhibitors Protease Inhibitors Enzyme Inhibitors Cardiotonic Agents Protective Agents Physiological Effects of Drugs |