VA NEPHRON-D Study

Condition(s) targeted: Kidney Disease; Nephropathy; Type 2 Diabetes

Intervention: losartan (Drug); lisinopril (Drug); losartan (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Department of Veterans Affairs

Official(s) and/or principal investigator(s):
Linda Fried, MD MPH, Study Chair, Affiliation: VA Pittsburgh Health Care System

Overall contact:
Jane Zhang, PhD, Phone: (203) 932-5711, Ext: 3779, Email: jane.zhang@va.gov

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. This combination has been shown in one study of non-diabetic kidney disease to decrease the risk of disease progression. 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. We 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.

Official title: CSP #565 - Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy VA NEPHRON-D Study: Nephropathy iN Diabetes Study

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver), Active Control, Parallel Assignment, Efficacy Study

Primary outcome: A composite endpoint of reduction in estimated GFR of 30ml/min/1.73mxm in individuals w/a baseline estimated GFR >= 60 ml/min/1.73mxm, reduction in estimated GFR >50% in individuals w/ baseline estimated GFR <60ml/min/1.73mxm; ESRD or death

Secondary outcome: 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

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. 73mxm in individuals with an estimated GFR greater than or equal to 60 ml/min/1. 73mxm; reduction in estimated GFR of greater than 50% in individuals with an estimated GFR less than 60 mL/min/1. 73mxm; progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR less than 15 mL/min/1. 73mxm) 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. 73mxm); reduction in estimated GFR of more than 30 ml/min/1. 73mxm (for individuals with a baseline estimated GFR greater than or equal to 60 ml/min/1. 73mxm) or progression to end-stage renal disease (defined as need for dialysis, renal transplant or an eGFR of less than 15 ml/min/1. 73mxm).

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. 73mxm in individuals with an estimated GFR greater than or equal to 60 ml/min/1. 73mxm; reduction in estimated GFR of greater than 50% in individuals with an estimated GFR less than 60 ml/min/1. 73mxm; progression to end-stage renal disease (defined as need for dialysis, renal transplant or en eGFR less than 15 ml/min/1. 73mxm)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. 73mxm). 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 three-year period and the maximum length of follow-up is 5 years. The planned study duration is 5 years with 3 years of accrual and 2-5 years of follow-up for all enrolled patients.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Type 2 diabetes

2. Albuminuria >300mg/gram creatinine

3. Stage 2 or 3 CKD (eGFR 30 to <90 mg/min/1. 73mxm )

4. Able to give informed consent

5. Telephone contact available

Exclusion Criteria:

1. History of intolerance to ACEI or ARB

2. Serum potassium level >5. 5 meq/L

3. Receiving sodium polystyrene sulfonate (Kayexalate)

4. Pregnancy, breast feeding, planning to become pregnant or sexually active and not using birth control

5. Renal transplant recipient

6. Suspected non-diabetic kidney disease

7. Inability to discontinue current use of ACEI/ARB combination

8. Current use of Lithium

9. Severe (end-stage) comorbid disease

10. Prisoner

11. Age <18

12. Estimated glomerular filtration rate (GFR) <30 or >=90 ml/min/1. 73mxm

13. HbA1c >10. 5%

14. Patient refusal

15. Participation in a concurrent interventional study

16. Bood pressure >180/95

17. Cannot stop any proscribed medications after enrollment

Jane Zhang, PhD, Phone: (203) 932-5711, Ext: 3779, Email: jane.zhang@va.gov

VA Medical Center, San Juan, San Juan 00921, Puerto Rico; Recruiting
Julio E. Benabe, MD, Phone: 787-641-2907, Email: julio.benabe@va.gov

Carl T. Hayden VA Medical Center, Phoenix, Arizona 85012, United States; Recruiting
Penelope L Baker, MD, Phone: 602-277-5551, Ext: 7277, Email: penelope.baker@va.gov
William Duckworth, MD, Sub-Investigator

VA Medical Center, Loma Linda, Loma Linda, California 92357, United States; Recruiting
James I McMillan, MD, Phone: 909-583-6090, Email: james.mcmillan2@va.gov

VA Palo Alto Health Care System, Palo Alto, California 94304-1290, United States; Active, not recruiting

VA Connecticut Health Care System (West Haven), West Haven, Connecticut 06516, United States; Recruiting
Susan Crowley, MD, Phone: 203-932-5711, Ext: 3950, Email: susan.crowley@va.gov

VA Medical Center, Bay Pines, Bay Pines, Florida 33708, United States; Recruiting
Nash Purohit, MD, Phone: 727-398-6661, Ext: 4094, Email: nash.purohit@va.gov

VA Medical Center, Miami, Miami, Florida 33125, United States; Terminated

North Florida/South Georgia Veterans Health System, Gainesville, Florida 32608, United States; Terminated

James A. Haley Veterans Hospital, Tampa, Tampa, Florida 33612, United States; Recruiting
Alfredo Pequero, MD, Phone: 813-978-5947, Email: alfredo.pequero@va.gov

Edward Hines, Jr. VA Hospital, Hines, Illinois 60141-5000, United States; Recruiting
Nicholas Emanuele, MD, Phone: 708-202-8387, Ext: 21415, Email: nicholas.emanuele@va.gov

Richard Roudebush VA Medical Center, Indianapolis, Indianapolis, Indiana 46202-2884, United States; Recruiting
Amale Lteif, MD, Phone: 317-988-2077, Email: amlteif@iupui.edu

VA Medical Center, Iowa City, Iowa City, Iowa 52246-2208, United States; Recruiting
Bradley S. Dixon, MD, Phone: 319-356-1626, Email: bradley-dixon@uiowa.edu

VA Maryland Health Care System, Baltimore, Baltimore, Maryland 21201, United States; Recruiting
Stephen Seliger, MD, Phone: 410-505-7000, Ext: 5231, Email: stephen.seliger@va.gov

VA Medical Center, Jamaica Plain Campus, Boston, Massachusetts 02130, United States; Recruiting
James Kaufman, MD, Phone: 857-364-5613, Email: james.kaufman@va.gov

VA Medical Center, Minneapolis, Minneapolis, Minnesota 55417, United States; Recruiting
King W Ma, MD, Phone: 612-467-2098, Email: king.ma@va.gov

VA Medical Center, Kansas City MO, Kansas City, Missouri 64128, United States; Recruiting
Archana Goel, MD, Phone: 816-861-4700, Ext: 56593, Email: archana.goel@va.gov

VA Medical Center, St Louis, St Louis, Missouri 63106, United States; Recruiting
Rajalakshmi Gopalakrishnan, MD, Phone: 314-652-4100, Ext: 53085, Email: rajalakshmi.gopalakrishnan@va.gov

VA Medical Center, Omaha, Omaha, Nebraska 68105-1873, United States; Recruiting
Robert J. Anderson, MD, Phone: 402-955-4045, Email: robert.anderson4@va.gov

VA New Jersey Health Care System, East Orange, East Orange, New Jersey 07018, United States; Recruiting
Mark Zimering, MD, Phone: 973-647-0180, Ext: 4426, Email: mark.zimering@va.gov

New Mexico VA Health Care System, Albuquerque, Albuquerque, New Mexico 87108-5153, United States; Recruiting
Karen Servilla, MD, Phone: 505-265-1711, Ext: 4846, Email: karen.servilla@va.gov

VA Western New York Healthcare System at Buffalo, Buffalo, New York 14215, United States; Recruiting
James Lohr, MD, Phone: 716-862-3204, Email: james.lohr@va.gov

VA Medical Center, Durham, Durham, North Carolina 27705, United States; Recruiting
Wissam Kourany, MD, Phone: 919-286-0411, Ext: 7634, Email: wissam.kourany@va.gov

VA Medical Center, Cleveland, Cleveland, Ohio 44106, United States; Recruiting
Richard Ty Miller, MD, Phone: 216-791-3800, Ext: 5198, Email: richard.miller5@va.gov

VA Medical Center, Portland, Portland, Oregon 97201, United States; Recruiting
Suzanne G Watnick, MD, Phone: 503-220-3450, Email: suzanne.watnick@va.gov

VA Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15240, United States; Recruiting
Linda Fried, MD MPH, Phone: 412-688-6181, Email: linda.fried@va.gov
William Duckworth, MD, Phone: (602) 277-5551, Ext: 6358, Email: William.Duckworth@va.gov
Linda Fried, MD MPH, Study Chair
Mohan Ramkumar, MD, Sub-Investigator

VA Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15240, United States; Recruiting
Mohan Ramkumar, MD, Phone: 412-360-3910, Email: mohan.ramkumar@va.gov

Ralph H Johnson VA Medical Center, Charleston, Charleston, South Carolina 29401-5799, United States; Recruiting
Maria Lopes-Virella, MD, Phone: 834-792-2529, Email: virellam@musc.edu

WJB Dorn Veterans Hospital, Columbia, Columbia, South Carolina 29209, United States; Recruiting
Steven J. Rosansky, MD, Phone: 803-776-4000, Ext: 7116, Email: steven.rosansky@va.gov

VA Medical Center, Memphis, Memphis, Tennessee 38104, United States; Recruiting
Barry Wall, MD, Phone: 901-577-7487, Email: barry.wall@va.gov

VA Medical Center, Nashville, Tennessee 37212-2637, United States; Recruiting
Stephen N Davis, MD, Phone: 615-936-1649, Email: steve.davis@vanderbilt.edu

VA North Texas Health Care System, Dallas, Dallas, Texas 75216, United States; Recruiting
Robert F. Reilly, MD, Phone: 214-857-1908, Email: robert.reilly2@va.gov

Hunter Holmes McGuire VA Medical Center, Richmond, Virginia 23249, United States; Recruiting
Franklin J. Zieve, MD, Phone: 804-675-5151, Email: franklin.zieve@va.gov

Zablocki VA Medical Center, Milwaukee, Milwaukee, Wisconsin 53295-1000, United States; Recruiting
Samuel Blumenthal, Phone: 414-384-2000, Ext: 42830, Email: samuel.blumenthal@va.gov

Starting date: July 2008
Ending date: July 2013
Last updated: June 17, 2009