VA NEPHRON-D: Diabetes iN Nephropathy Study

Type 2 Diabetes Clinical Trial

— VA NEPHRON-D  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00555217
• Other study ID #: 565
• Status: Terminated
• Phase: Phase 3
• First received: November 7, 2007
• Last updated: May 8, 2015
• Start date: July 2008
• Est. completion date: October 2014

Study information

• Verified date: May 2015
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1448
• Est. completion date: October 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Kidney Disease
• Kidney Diseases
• Nephropathy
• Type 2 Diabetes

Intervention

Drug:
• losartan
50 or 100mg/day
• lisinopril
10, 20 or 40 mg/day

Locations

Country	Name	City	State
Puerto Rico	VA Medical Center, San Juan	San Juan
United States	New Mexico VA Health Care System, Albuquerque	Albuquerque	New Mexico
United States	VA Maryland Health Care System, Baltimore	Baltimore	Maryland
United States	VA Western New York Healthcare System at Buffalo	Buffalo	New York
United States	Ralph H Johnson VA Medical Center, Charleston	Charleston	South Carolina
United States	VA Medical Center, Cleveland	Cleveland	Ohio
United States	WJB Dorn Veterans Hospital, Columbia	Columbia	South Carolina
United States	VA North Texas Health Care System, Dallas	Dallas	Texas
United States	VA Medical Center, Durham	Durham	North Carolina
United States	VA New Jersey Health Care System, East Orange	East Orange	New Jersey
United States	North Florida/South Georgia Veterans Health System	Gainesville	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 Medical Center, Kansas City MO	Kansas City	Missouri
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 Medical Center, Memphis	Memphis	Tennessee
United States	VA Medical Center, Miami	Miami	Florida
United States	Zablocki VA Medical Center, Milwaukee	Milwaukee	Wisconsin
United States	VA Medical Center, Minneapolis	Minneapolis	Minnesota
United States	VA Medical Center	Nashville	Tennessee
United States	VA Medical Center, Omaha	Omaha	Nebraska
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	Carl T. Hayden VA Medical Center	Phoenix	Arizona
United States	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania
United States	VA Medical Center, Portland	Portland	Oregon
United States	Hunter Holmes McGuire VA Medical Center	Richmond	Virginia
United States	VA Medical Center, St Louis	St Louis	Missouri
United States	James A. Haley Veterans Hospital, Tampa	Tampa	Florida
United States	VA Connecticut Health Care System (West Haven)	West Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (5)

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. Review. — View Citation

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. — View Citation

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 tre — View Citation

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. — View Citation

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. Fro — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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 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	No