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.
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.
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 continue to meet the eligibility 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.
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 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
Jacques Durr, MD, Phone: 727-398-6661, Ext: 5253, Email: jacques.durr@va.gov
VA Medical Center, Miami, Miami, Florida 33125, United States; Recruiting
Jennifer Marks, MD, Phone: 305-575-3525, Email: jennifer.marks@va.gov
North Florida/South Georgia Veterans Health System, Gainesville, Florida 32608, United States; Recruiting
Suzanne Quinn, MD, Phone: 352-376-1611, Ext: 5228, Email: suzanne.quinn@va.gov
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
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; Not yet 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
Mohan Ramkumar, MD, Phone: (412) 688-6181, Email: mohan.ramkumar@va.gov
Linda Fried, MD MPH, Study Chair
Mohan Ramkumar, MD, Sub-Investigator
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; Not yet 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; Not yet recruiting
Adrianna Hung, MD
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
