VA NEPHRON-D: Diabetes iN Nephropathy Study

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00555217
First received: November 7, 2007
Last updated: October 20, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Kidney Disease
Nephropathy
Type 2 Diabetes
Drug: losartan
Drug: lisinopril
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
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)

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • 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: February, 2013 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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: up to the last follow-up date of the study ] [ Designated as safety issue: No ]

Estimated Enrollment: 1448
Study Start Date: July 2008
Estimated Study Completion Date: October 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
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: Arm 2
Mono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)
Drug: losartan
50 or 100mg/day

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00555217

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

Publications:
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00555217     History of Changes
Other Study ID Numbers: 565
Study First Received: November 7, 2007
Last Updated: October 20, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
kidney disease
nephropathy
type 2 diabetes
hyperkalemia
acute kidney injury

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Kidney Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Urologic Diseases
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
Losartan
Angiotensin II Type 1 Receptor Blockers
Anti-Arrhythmia Agents
Antihypertensive Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014