Study Results
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View full resultsBasic Information
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TERMINATED
PHASE3
1448 participants
INTERVENTIONAL
2008-07-31
2014-10-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Combination of ARB and ACEI
Combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB)
losartan
50 or 100mg/day
lisinopril
10, 20 or 40 mg/day
Monotherapy ARB
Mono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)
losartan
50 or 100mg/day
Interventions
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losartan
50 or 100mg/day
lisinopril
10, 20 or 40 mg/day
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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US Department of Veterans Affairs
FED
Responsible Party
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Principal Investigators
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Linda Fried, MD MPH
Role: STUDY_CHAIR
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Locations
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Carl T. Hayden VA Medical Center
Phoenix, Arizona, United States
Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock
Little Rock, Arkansas, United States
VA Medical Center, Loma Linda
Loma Linda, California, United States
VA Palo Alto Health Care System
Palo Alto, California, United States
VA Connecticut Health Care System (West Haven)
West Haven, Connecticut, United States
North Florida/South Georgia Veterans Health System
Gainesville, Florida, United States
VA Medical Center, Miami
Miami, Florida, United States
James A. Haley Veterans Hospital, Tampa
Tampa, Florida, United States
Edward Hines, Jr. VA Hospital
Hines, Illinois, United States
Richard Roudebush VA Medical Center, Indianapolis
Indianapolis, Indiana, United States
VA Medical Center, Iowa City
Iowa City, Iowa, United States
VA Maryland Health Care System, Baltimore
Baltimore, Maryland, United States
VA Medical Center, Minneapolis
Minneapolis, Minnesota, United States
VA Medical Center, Kansas City MO
Kansas City, Missouri, United States
VA Medical Center, St Louis
St Louis, Missouri, United States
VA Medical Center, Omaha
Omaha, Nebraska, United States
VA New Jersey Health Care System, East Orange
East Orange, New Jersey, United States
New Mexico VA Health Care System, Albuquerque
Albuquerque, New Mexico, United States
VA Western New York Healthcare System at Buffalo
Buffalo, New York, United States
VA Medical Center, Durham
Durham, North Carolina, United States
VA Medical Center, Cleveland
Cleveland, Ohio, United States
VA Medical Center, Portland
Portland, Oregon, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Pittsburgh, Pennsylvania, United States
Ralph H Johnson VA Medical Center, Charleston
Charleston, South Carolina, United States
WJB Dorn Veterans Hospital, Columbia
Columbia, South Carolina, United States
VA Medical Center, Memphis
Memphis, Tennessee, United States
VA Medical Center
Nashville, Tennessee, United States
VA North Texas Health Care System, Dallas
Dallas, Texas, United States
Hunter Holmes McGuire VA Medical Center
Richmond, Virginia, United States
Zablocki VA Medical Center, Milwaukee
Milwaukee, Wisconsin, United States
VA Medical Center, San Juan
San Juan, , Puerto Rico
Countries
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References
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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.
Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O'Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903. doi: 10.1056/NEJMoa1303154. Epub 2013 Nov 9.
Fried LF, Emanuele N, Zhang JH. Combined angiotensin inhibition in diabetic nephropathy. N Engl J Med. 2014 Feb 20;370(8):779. doi: 10.1056/NEJMc1315504. No abstract available.
Chen SS, Seliger SL, Fried LF. Complete inhibition of the renin-angiotensin-aldosterone system; where do we stand? Curr Opin Nephrol Hypertens. 2014 Sep;23(5):449-55. doi: 10.1097/MNH.0000000000000043.
Zimering MB, Zhang JH, Guarino PD, Emanuele N, McCullough PA, Fried LF; Investigators for the VA NEPHRON-D. Endothelial cell autoantibodies in predicting declining renal function, end-stage renal disease, or death in adult type 2 diabetic nephropathy. Front Endocrinol (Lausanne). 2014 Aug 11;5:128. doi: 10.3389/fendo.2014.00128. eCollection 2014.
Tamargo CL, Coca SG, Thiessen Philbrook H, Hu DG, Ix JH, Shlipak MG, Fried LF, Gutierrez OM, Waikar SS, Schrauben SJ, Schelling JR, Ganz P, Kimmel PL, Greenberg JH, Deo R, Takakura A, Vasan RS, Bonventre JV, Parikh CR. The distal nephron biomarkers associate with diabetic kidney disease progression. JCI Insight. 2025 Jun 23;10(12):e186836. doi: 10.1172/jci.insight.186836. eCollection 2025 Jun 23.
Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2024 Apr 29;4(4):CD006257. doi: 10.1002/14651858.CD006257.pub2.
Huang Y, Fried LF, Kyriakides TC, Johnson GR, Chiu S, Mcdonald L, Zhang JH. Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial. Clin Trials. 2019 Feb;16(1):81-89. doi: 10.1177/1740774518813121. Epub 2018 Nov 16.
Other Identifiers
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565
Identifier Type: -
Identifier Source: org_study_id
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