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

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

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

Brief 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, aldos

Detailed Summary: 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.
Sponsor: Columbia University

Current Primary Outcome: Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol. [ Time Frame: 9 months ]

Original Primary Outcome: Cumulative incidence of aldosterone breakthrough [ Time Frame: 9 months ]

Current Secondary Outcome:

• Serum Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline, 3-, 6-, and 9-months ]
  Mean serum aldosterone at baseline, 3-, 6-, and 9-months.
• Urine Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline, 3-, 6-, and 9-months ]
  Mean urine aldosterone at baseline, 3-, 6-, and 9-months.
• Serum Potassium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline, 3-, 6-, and 9-months ]
  Mean serum potassium at baseline, 3-, 6-, and 9-months. (given as reference to interpret contemporaneous plasma & urine aldosterone measurements.)
• Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline, 3-, 6-, and 9-months ]
  Mean 24-hour urine sodium (mmol/day) at baseline, 3-, 6-, and 9-months. (given as reference to interpret contemporaneous plasma & urine aldosterone measurements.)
• Pre- and Post-treatment Blood Pressure in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) blood pressure for subjects with and without aldosterone breakthrough
• Pre- and Post-treatment Serum Creatinine in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) serum creatinine for subjects with and without aldosterone breakthrough
• Pre- and Post-treatment Serum Potassium in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) serum potassium for subjects with and without aldosterone breakthrough
• Pre- and Post-treatment 24-hour Urine Protein in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) 24-hour urine protein for subjects with and without aldosterone breakthrough
• Pre- and Post-treatment 24-hour Urine Sodium in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) 24-hour urine sodium for subjects with and without aldosterone breakthrough
• Pre- and Post-treatment 24-urine Aldosterone in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) 24-hour urine aldosterone for subjects with and without aldosterone breakthrough
• Pre- and Post-treatment Serum Aldosterone in Subjects With and Without Aldosterone Breakthrough. [ Time Frame: Baseline and Final (9 month) ]
  Compares baseline and final (9 month) serum aldosterone for subjects with and without aldosterone breakthrough

Original Secondary Outcome:

• Mean change in urine aldosterone and plasma aldosterone [ Time Frame: 3-, 6-, and 9-months ]
  Secondary outcome #1: Mean change in urine aldosterone and plasma aldosterone at 3-, 6-, and 9-months of each treatment arm
• Mean change in 24-hour proteinuria [ Time Frame: at 3-, 6-, and 9-months ]
  Secondary outcome #2: Mean change in 24-hour proteinuria at 3-, 6-, and 9-months of each treatment arm
• Less than 10% decline in proteinuria [ Time Frame: 9 months ]
  Secondary outcome #3: Number and percentage of patients, in each treatment arm, with <10% decline in proteinuria over study period
• Greater than 50% decline in proteinuria [ Time Frame: 9 months ]
  Secondary outcome #4: Number and percentage of patients, in each treatment arm, with >50% decline in proteinuria over study period
• Change in office blood pressure measurement [ Time Frame: at 3-, 6-, and 9-months ]
  Secondary outcome #5: Mean change at 3-, 6-, and 9-months of each treatment arm in office blood pressure measurement

Information By: Columbia University

Dates:
Date Received: May 21, 2010
Date Started: September 2009
Date Completion:
Last Updated: April 16, 2014
Last Verified: April 2014