Clinical trial NCT00555217: VA NEPHRON-D: Diabetes iN Nephropathy Study
Official title: CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Kidney Disease
Nephropathy
Type 2 Diabetes
Keywords: kidney disease
nephropathy
type 2 diabetes
hyperkalemia
acute kidney injury
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2007-11-08
Enrollment: 1448
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: 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
timeFrame: From enrollemnt to time of first primary event, up to 4.5 years
Secondary outcomes:
measure: 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.
timeFrame: From enrollment to time of first event, up to 4.5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Carl T. Hayden VA Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock
state: Arkansas
city: Loma Linda
country: United States
facility: VA Medical Center, Loma Linda
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: West Haven
country: United States
facility: VA Connecticut Health Care System (West Haven)
state: Connecticut
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System
state: Florida
city: Miami
country: United States
facility: VA Medical Center, Miami
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans Hospital, Tampa
state: Florida
city: Hines
country: United States
facility: Edward Hines, Jr. VA Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Richard Roudebush VA Medical Center, Indianapolis
state: Indiana
city: Iowa City
country: United States
facility: VA Medical Center, Iowa City
state: Iowa
city: Baltimore
country: United States
facility: VA Maryland Health Care System, Baltimore
state: Maryland
city: Minneapolis
country: United States
facility: VA Medical Center, Minneapolis
state: Minnesota
city: Kansas City
country: United States
facility: VA Medical Center, Kansas City MO
state: Missouri
city: St Louis
country: United States
facility: VA Medical Center, St Louis
state: Missouri
city: Omaha
country: United States
facility: VA Medical Center, Omaha
state: Nebraska
city: East Orange
country: United States
facility: VA New Jersey Health Care System, East Orange
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico VA Health Care System, Albuquerque
state: New Mexico
city: Buffalo
country: United States
facility: VA Western New York Healthcare System at Buffalo
state: New York
city: Durham
country: United States
facility: VA Medical Center, Durham
state: North Carolina
city: Cleveland
country: United States
facility: VA Medical Center, Cleveland
state: Ohio
city: Portland
country: United States
facility: VA Medical Center, Portland
state: Oregon
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Charleston
country: United States
facility: Ralph H Johnson VA Medical Center, Charleston
state: South Carolina
city: Columbia
country: United States
facility: WJB Dorn Veterans Hospital, Columbia
state: South Carolina
city: Memphis
country: United States
facility: VA Medical Center, Memphis
state: Tennessee
city: Nashville
country: United States
facility: VA Medical Center
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System, Dallas
state: Texas
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center
state: Virginia
city: Milwaukee
country: United States
facility: Zablocki VA Medical Center, Milwaukee
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: VA Medical Center, San Juan
Study officials:
affiliation: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
name: Linda Fried, MD MPH
role: STUDY_CHAIR
References:
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.
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 treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903. doi: 10.1056/NEJMoa1303154. Epub 2013 Nov 9.
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. No abstract available.
citation: 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.
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. Front Endocrinol (Lausanne). 2014 Aug 11;5:128. doi: 10.3389/fendo.2014.00128. eCollection 2014.
citation: 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.