Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease

Diabetic Nephropathy Clinical Trial

Official title: Aldosterone Breakthrough During Diovan (Valsartan), Tekturna (Aliskiren), and Combination (Valsartan+Aliskiren) Anti-hypertensive Therapy in Patients With Proteinuric Kidney Disease

Status Terminated

Clinical Trial Summary

Primary Hypothesis: Aldosterone breakthrough will occur at a far lower frequency during renin inhibition (0-10% over 9 months), alone or in combination with an ARB, compared to conventional ARB therapy (35-45% over 9 months). The investigators hypothesize that aldosterone breakthrough occurs due to accumulation of active precursor substances, most notably angiotensin II, produced in response to conventional RAAS blockade with ACEinhibitors and ARBs. The investigators believe that direct renin inhibition (DRI) should minimize this accumulation and therefore significantly lower or possibly eliminate the breakthrough effect.

Interruption of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), alone and in combination, has become a leading therapy to slow the progression of chronic heart and kidney disease. Both types of drugs inhibit the formation of aldosterone, a hormone, which has been shown to have harmful effects on patients with chronic heart and kidney disorders. This treatment is effective but not perfect since, even after an initial improvement, many patients become worse over the long term. This may be due to an unexpected increase in aldosterone, a phenomenon called "aldosterone breakthrough."

The purpose of this study is to find out whether the use of a direct renin inhibitor (DRI) alone, or in combination with an angiotensin receptor blocker (ARB), will lessen the occurrence of aldosterone breakthrough since direct renin inhibitors inhibit the formation of aldosterone at a very early step. This study will compare the effectiveness of adding Diovan (valsartan) or Tekturna (aliskiren) or a combination of Diovan and Tekturna to the usual antihypertensive treatment. The investigators will follow blood pressure, aldosterone levels, and urinary protein levels over 9 months to evaluate which of these therapies is most effective for treating hypertension in patients with proteinuric kidney disease.

Clinical Trial Description

This is a randomized, open-label, three-arm study comparing Diovan (valsartan, an ARB), Tekturna (aliskiren, a DRI), and the combination of valsartan + aliskiren (i.e. ARB + DRI). One hundred twenty subjects (40 per arm) will be treated with Tekturna, Diovan, or a combination of both drugs for 9 months on top of their usual antihypertensive treatment. Changes in urinary aldosterone excretion will be monitored during therapy to measure the incidence of aldosterone breakthrough, defined as any sustained positive change from baseline urinary aldosterone excretion by the completion of the 9-month study period. This frequency measure will be compared during ARB, DRI, and ARB + DRI therapy. Changes in urinary protein excretion will also be monitored alongside the urinary aldosterone levels to determine whether aldosterone breakthrough is associated with refractory proteinuria. This is an innovative study that will be the first to (1) examine aldosterone breakthrough during DRI therapy, and (2) explore whether addition of a DRI to an ARB protects against aldosterone breakthrough. In addition, this will be the first study to examine whether DRI therapy (alone or in combination with ARB) is effective therapy for hypertension in patients with non-diabetic proteinuric kidney disease. ;

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetic Nephropathies
• Diabetic Nephropathy
• Focal Segmental Glomerulosclerosis
• Glomerulonephritis
• Glomerulonephritis, IGA
• Glomerulonephritis, Membranous
• Glomerulopathy (Obesity-associated)
• Glomerulosclerosis, Focal Segmental
• Hypertensive Nephrosclerosis
• IgA Nephropathy
• Kidney Diseases
• Nephrosclerosis
• Proteinuric Kidney Disease

• NCT number: NCT01129557
• Study type: Interventional
• Source: Columbia University
• Status: Terminated
• Phase: Phase 4
• Start date: September 2009
• Completion date: December 2012