VA NEPHRON-D: Diabetes iN Nephropathy Study (VA NEPHRON-D)

May 8, 2015 updated by: US Department of Veterans Affairs

CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D Study)

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. 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. The investigators 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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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

Enrollment (Actual)

1448

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Puerto Rico
      • San Juan, Puerto Rico, 00921
        • VA Medical Center, San Juan
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85012
        • Carl T. Hayden VA Medical Center
    • Arkansas
      • Little Rock, Arkansas, United States, 72205-5484
        • Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock
    • California
      • Loma Linda, California, United States, 92357
        • VA Medical Center, Loma Linda
      • Palo Alto, California, United States, 94304-1290
        • VA Palo Alto Health Care System
    • Connecticut
      • West Haven, Connecticut, United States, 06516
        • VA Connecticut Health Care System (West Haven)
    • Florida
      • Gainesville, Florida, United States, 32608
        • North Florida/South Georgia Veterans Health System
      • Miami, Florida, United States, 33125
        • VA Medical Center, Miami
      • Tampa, Florida, United States, 33612
        • James A. Haley Veterans Hospital, Tampa
    • Illinois
      • Hines, Illinois, United States, 60141-5000
        • Edward Hines, Jr. VA Hospital
    • Indiana
      • Indianapolis, Indiana, United States, 46202-2884
        • Richard Roudebush VA Medical Center, Indianapolis
    • Iowa
      • Iowa City, Iowa, United States, 52246-2208
        • VA Medical Center, Iowa City
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • VA Maryland Health Care System, Baltimore
    • Minnesota
      • Minneapolis, Minnesota, United States, 55417
        • VA Medical Center, Minneapolis
    • Missouri
      • Kansas City, Missouri, United States, 64128
        • VA Medical Center, Kansas City MO
      • St Louis, Missouri, United States, 63106
        • VA Medical Center, St Louis
    • Nebraska
      • Omaha, Nebraska, United States, 68105-1873
        • VA Medical Center, Omaha
    • New Jersey
      • East Orange, New Jersey, United States, 07018
        • VA New Jersey Health Care System, East Orange
    • New Mexico
      • Albuquerque, New Mexico, United States, 87108-5153
        • New Mexico VA Health Care System, Albuquerque
    • New York
      • Buffalo, New York, United States, 14215
        • VA Western New York Healthcare System at Buffalo
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • VA Medical Center, Durham
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • VA Medical Center, Cleveland
    • Oregon
      • Portland, Oregon, United States, 97201
        • VA Medical Center, Portland
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15240
        • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
    • South Carolina
      • Charleston, South Carolina, United States, 29401-5799
        • Ralph H Johnson VA Medical Center, Charleston
      • Columbia, South Carolina, United States, 29209
        • WJB Dorn Veterans Hospital, Columbia
    • Tennessee
      • Memphis, Tennessee, United States, 38104
        • VA Medical Center, Memphis
      • Nashville, Tennessee, United States, 37212-2637
        • VA Medical Center
    • Texas
      • Dallas, Texas, United States, 75216
        • VA North Texas Health Care System, Dallas
    • Virginia
      • Richmond, Virginia, United States, 23249
        • Hunter Holmes McGuire VA Medical Center
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53295-1000
        • Zablocki VA Medical Center, Milwaukee

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Combination of ARB and ACEI
Combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB)
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)
Drug: losartan
50 or 100mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From enrollemnt to time of first primary event, up to 4.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From enrollment to time of first event, up to 4.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

US Department of Veterans Affairs

Investigators

  • Study Chair: Linda Fried, MD MPH, VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2008

Primary Completion (Actual)

September 1, 2014

Study Completion (Actual)

October 1, 2014

Study Registration Dates

First Submitted

November 7, 2007

First Submitted That Met QC Criteria

November 7, 2007

First Posted (Estimate)

November 8, 2007

Study Record Updates

Last Update Posted (Estimate)

May 29, 2015

Last Update Submitted That Met QC Criteria

May 8, 2015

Last Verified

May 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 565

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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