VA NEPHRON-D: Diabetes iN Nephropathy Study

NCT00555217 | Terminated Phase 3 Results DMC

• 1 other identifier: 565
• Study Type: interventional
• Target: 1,448
• Locations: 2 countries
• Sites: 31

Brief 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.

Conditions

Kidney Disease; Nephropathy; Type 2 Diabetes

Keywords

kidney disease; nephropathy; type 2 diabetes; hyperkalemia; acute kidney injury

Outcome Measures

Primary Outcomes (1)

• 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 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 Outcomes (1)

• 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.

  From enrollment to time of first event, up to 4.5 years

Study Arms (2)

Combination of ARB and ACEI

EXPERIMENTAL

Combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB)

Drug: losartan; Drug: lisinopril

Monotherapy ARB

ACTIVE COMPARATOR

Mono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)

Drug: losartan

Interventions

losartan DRUG

50 or 100mg/day

Combination of ARB and ACEI; Monotherapy ARB

lisinopril DRUG

10, 20 or 40 mg/day

Combination of ARB and ACEI

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• US Department of Veterans Affairs: lead

Study Sites (31)

Carl T. Hayden VA Medical Center

Phoenix, Arizona, 85012, United States

Location

Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock

Little Rock, Arkansas, 72205-5484, United States

Location

VA Medical Center, Loma Linda

Loma Linda, California, 92357, United States

Location

VA Palo Alto Health Care System

Palo Alto, California, 94304-1290, United States

Location

VA Connecticut Health Care System (West Haven)

West Haven, Connecticut, 06516, United States

Location

North Florida/South Georgia Veterans Health System

Gainesville, Florida, 32608, United States

Location

VA Medical Center, Miami

Miami, Florida, 33125, United States

Location

James A. Haley Veterans Hospital, Tampa

Tampa, Florida, 33612, United States

Location

Edward Hines, Jr. VA Hospital

Hines, Illinois, 60141-5000, United States

Location

Richard Roudebush VA Medical Center, Indianapolis

Indianapolis, Indiana, 46202-2884, United States

Location

VA Medical Center, Iowa City

Iowa City, Iowa, 52246-2208, United States

Location

VA Maryland Health Care System, Baltimore

Baltimore, Maryland, 21201, United States

Location

VA Medical Center, Minneapolis

Minneapolis, Minnesota, 55417, United States

Location

VA Medical Center, Kansas City MO

Kansas City, Missouri, 64128, United States

Location

VA Medical Center, St Louis

St Louis, Missouri, 63106, United States

Location

VA Medical Center, Omaha

Omaha, Nebraska, 68105-1873, United States

Location

VA New Jersey Health Care System, East Orange

East Orange, New Jersey, 07018, United States

Location

New Mexico VA Health Care System, Albuquerque

Albuquerque, New Mexico, 87108-5153, United States

Location

VA Western New York Healthcare System at Buffalo

Buffalo, New York, 14215, United States

Location

VA Medical Center, Durham

Durham, North Carolina, 27705, United States

Location

VA Medical Center, Cleveland

Cleveland, Ohio, 44106, United States

Location

VA Medical Center, Portland

Portland, Oregon, 97201, United States

Location

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Pittsburgh, Pennsylvania, 15240, United States

Location

Ralph H Johnson VA Medical Center, Charleston

Charleston, South Carolina, 29401-5799, United States

Location

WJB Dorn Veterans Hospital, Columbia

Columbia, South Carolina, 29209, United States

Location

VA Medical Center, Memphis

Memphis, Tennessee, 38104, United States

Location

VA Medical Center

Nashville, Tennessee, 37212-2637, United States

Location

VA North Texas Health Care System, Dallas

Dallas, Texas, 75216, United States

Location

Hunter Holmes McGuire VA Medical Center

Richmond, Virginia, 23249, United States

Location

Zablocki VA Medical Center, Milwaukee

Milwaukee, Wisconsin, 53295-1000, United States

Location

VA Medical Center, San Juan

San Juan, 00921, Puerto Rico

Location

Related Publications (8)

• 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.

  PMID: 19118120 BACKGROUND

• 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.

  PMID: 24206457 RESULT

• 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.

  PMID: 24552328 RESULT

• 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.

  PMID: 25014549 RESULT

• 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.

  PMID: 25157242 RESULT

• 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.

  PMID: 40548378 DERIVED

• 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.

  PMID: 38682786 DERIVED

• 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.

  PMID: 30445841 DERIVED

MeSH Terms

Conditions

Kidney Diseases; Diabetes Mellitus, Type 2; Hyperkalemia; Acute Kidney Injury

Interventions

Losartan; Lisinopril

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Water-Electrolyte Imbalance; Renal Insufficiency

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Limitations and Caveats

In October, 2012 the DMC recommended that study treatment be stopped primarily because of safety concerns along with low conditional power to detect a treatment effect on the primary outcome.

Results Point of Contact

• Title: Linda Fried, MD, MPH
• Organization: VA Pittsburgh Healthcare System and University of Pittsburgh School of Medicine, Pittsburgh, PA

Linda.Fried@va.gov

412-360-3930

Study Officials

• Linda Fried, MD MPH

  VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2007
• First Posted: November 8, 2007
• Study Start: July 1, 2008
• Primary Completion: September 1, 2014
• Study Completion: October 1, 2014
• Last Updated: May 29, 2015
• Results First Posted: May 29, 2015

Record last verified: 2015-05

Locations

US (30); PR (1)