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”

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.

Study Type: Interventional

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

Study Primary Completion Date: July 2013

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 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.

Intervention(s) in this Clinical Trial

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

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Combination of an angiotensin converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB)
• Active Comparator: 2
  • Mono therapy arm. Standard treatment with angiotensin receptor blocker (ARB)

Primary Measures

• 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
  • Time Frame: up to the last follow-up date of the study
    Safety Issue?: No

Secondary Measures

• 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 Frame: up to the last follow-up date of the study
    Safety Issue?: No

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. Current use of ACEI/ARB comibination
• 8. Current use of Lithium
• 9. Severe (end-stage) comorbid disease
• 10. Prisoner
• 11. Age <18
• 12. Estimated glomerular filration 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 >180/90
• 17. Can not stop any proscribed medications after enrollment

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Department of Veterans Affairs

Overall Clinical Trial Officials and Contacts

Linda Fried, MD MPH Study Chair VA Pittsburgh Health Care System  

Overall Contact: Jane Zhang, PhD (203) 932-5711 jane.zhang@va.gov

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00555217

Study ID Number: 565

ClinicalTrials.gov Identifier: NCT00555217

Health Authority: United States: Federal Government