VA NEPHRON-D: Diabetes iN Nephropathy Study
Information source: Department of Veterans Affairs
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Kidney Disease; Nephropathy; Type 2 Diabetes
Intervention: losartan (Drug); lisinopril (Drug)
Phase: Phase 3
Status: Terminated
Sponsored by: Department of Veterans Affairs Official(s) and/or principal investigator(s): Linda Fried, MD MPH, Study Chair, Affiliation: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Summary
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.
Clinical Details
Official title: CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D Study)
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment
Primary outcome: 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
Secondary outcome: 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.
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
Locations and Contacts
VA Medical Center, San Juan, San Juan 00921, Puerto Rico
Carl T. Hayden VA Medical Center, Phoenix, Arizona 85012, United States
Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock, Little Rock, Arkansas 72205-5484, United States
VA Medical Center, Loma Linda, Loma Linda, California 92357, United States
VA Palo Alto Health Care System, Palo Alto, California 94304-1290, United States
VA Connecticut Health Care System (West Haven), West Haven, Connecticut 06516, United States
North Florida/South Georgia Veterans Health System, Gainesville, Florida 32608, United States
VA Medical Center, Miami, Miami, Florida 33125, United States
James A. Haley Veterans Hospital, Tampa, Tampa, Florida 33612, United States
Edward Hines, Jr. VA Hospital, Hines, Illinois 60141-5000, United States
Richard Roudebush VA Medical Center, Indianapolis, Indianapolis, Indiana 46202-2884, United States
VA Medical Center, Iowa City, Iowa City, Iowa 52246-2208, United States
VA Maryland Health Care System, Baltimore, Baltimore, Maryland 21201, United States
VA Medical Center, Minneapolis, Minneapolis, Minnesota 55417, United States
VA Medical Center, Kansas City MO, Kansas City, Missouri 64128, United States
VA Medical Center, St Louis, St Louis, Missouri 63106, United States
VA Medical Center, Omaha, Omaha, Nebraska 68105-1873, United States
VA New Jersey Health Care System, East Orange, East Orange, New Jersey 07018, United States
New Mexico VA Health Care System, Albuquerque, Albuquerque, New Mexico 87108-5153, United States
VA Western New York Healthcare System at Buffalo, Buffalo, New York 14215, United States
VA Medical Center, Durham, Durham, North Carolina 27705, United States
VA Medical Center, Cleveland, Cleveland, Ohio 44106, United States
VA Medical Center, Portland, Portland, Oregon 97201, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA, Pittsburgh, Pennsylvania 15240, United States
Ralph H Johnson VA Medical Center, Charleston, Charleston, South Carolina 29401-5799, United States
WJB Dorn Veterans Hospital, Columbia, Columbia, South Carolina 29209, United States
VA Medical Center, Memphis, Memphis, Tennessee 38104, United States
VA Medical Center, Nashville, Tennessee 37212-2637, United States
VA North Texas Health Care System, Dallas, Dallas, Texas 75216, United States
Hunter Holmes McGuire VA Medical Center, Richmond, Virginia 23249, United States
Zablocki VA Medical Center, Milwaukee, Milwaukee, Wisconsin 53295-1000, United States
Additional Information
Related publications: Fried LF, Duckworth W, Zhang JH, O'Connor T, Brophy M, Emanuele N, Huang GD, McCullough PA, Palevsky PM, Seliger S, Warren SR, Peduzzi P; VA NEPHRON-D Investigators. Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D). Clin J Am Soc Nephrol. 2009 Feb;4(2):361-8. doi: 10.2215/CJN.03350708. Epub 2008 Dec 31.
Starting date: July 2008
Last updated: May 8, 2015
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