Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
Information source: Columbia University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Proteinuric Kidney Disease; Diabetic Nephropathy; Hypertensive Nephrosclerosis; IgA Nephropathy; Focal Segmental Glomerulosclerosis; Glomerulopathy (Obesity-associated); Glomerulonephritis, Membranous
Intervention: Aliskiren (Drug); Valsartan (Drug)
Phase: Phase 4
Sponsored by: Columbia University
Official(s) and/or principal investigator(s):
Pietro Canetta, MD, Principal Investigator, Affiliation: Columbia University
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
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.
Official title: Aldosterone Breakthrough During Diovan (Valsartan), Tekturna (Aliskiren), and Combination (Valsartan+Aliskiren) Anti-hypertensive Therapy in Patients With Proteinuric Kidney Disease
Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol.
Serum Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.
Urine Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.
Serum Potassium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.
Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment Blood Pressure in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment Serum Creatinine in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment Serum Potassium in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment 24-hour Urine Protein in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment 24-hour Urine Sodium in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment 24-urine Aldosterone in Subjects With and Without Aldosterone Breakthrough.
Pre- and Post-treatment Serum Aldosterone in Subjects With and Without Aldosterone Breakthrough.
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.
Minimum age: 18 Years.
Maximum age: N/A.
- Proteinuria > 300 mg/day
- Normal to mildly reduced kidney function (eGFR > 45 ml/min/1. 73m2)
- Systolic blood pressure >130 mm Hg
- Diastolic blood pressure >70 mm Hg
- Diagnoses of diabetic nephropathy, hypertensive nephrosclerosis, IgA nephropathy,
focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis,
membranous nephropathy, fibrillary glomerulonephritis, or obesity-associated
- Concomitant use of cyclosporine (which can interact with aliskiren)
- Inability to undergo 6 week washout period if already on RAAS-blocking drug(s)
(includes renin inhibitor, ACE-inhibitor, ARB, and mineralocorticoid receptor
- eGFR < 45 ml/min/1. 73m2
- Urine protein excretion < 300 mg/day
- Serum K > 5. 0 mEq/l
- Systolic blood pressure > 170 mm Hg or < 130 mm Hg after washout period
- Diastolic blood pressure > 110 mm Hg or < 70 mm Hg after washout period
- Congestive heart failure NYHA class III and IV
- History of any cardiovascular events (stroke, TIA, MI, unstable angina, CABG, PCI,
CHF hospitalization) in 3 months prior to study visit 1
- 2nd or 3rd degree heart block without a pacemaker or other uncontrolled arrhythmia
- Clinically significant valvular disease
- Known renal artery stenosis
- Any surgical or medical condition that might significantly alter the pharmacokinetics
of the study drugs (n. b. bariatric surgery > 6 months prior to visit 1 is not an
- History or evidence of drug or alcohol abuse within the last 12 months
- Any concurrent life threatening condition with a life expectancy less than 2 years
- Pregnant or nursing (lactating) women
- Women of child-bearing potential unless postmenopausal for at least 1 year,
surgically sterile, or using effective methods of contraception as defined by local
Locations and Contacts
Columbia University Medical Center, New York, New York 10032, United States
Starting date: September 2009
Last updated: April 16, 2014