VA NEPHRON-D: Diabetes iN Nephropathy Study

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*2 in individuals with an estimated GFR greater than or equal to 60
ml/min/1.73m*2; reduction in estimated GFR of greater than 50% in individuals with an
estimated GFR less than 60 mL/min/1.73m*2; progression to end-stage renal disease (defined
as need for dialysis, renal transplant or an eGFR less than 15 ml/min/1.73m*2) 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*2);
reduction in estimated GFR of more than 30 ml/min/1.73m*2 (for individuals with a baseline
estimated GFR greater than or equal to 60 ml/min/1.73m*2) 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*2).

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*2 in individuals with an estimated GFR greater than or
equal to 60 ml/min/1.73m*2; reduction in estimated GFR of greater than 50% in individuals
with an estimated GFR less than 60 ml/min/1.73m*2; progression to end-stage renal disease
(defined as need for dialysis, renal transplant or en eGFR less than 15 ml/min/1.73m*2)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*2). 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.

Inclusion Criteria:

1. Type 2 diabetes

2. Albuminuria >300mg/gram creatinine

3. Stage 2 or 3 CKD (eGFR 30 to <90 mg/min/1.73m*2 )

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/1.73m*2

13. HbA1c >10.5%

14. Patient refusal

15. Participation in a concurrent interventional study

16. Blood pressure >180/95

17. Unwilling to stop any proscribed medications after enrollment