Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
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ClinicalTrials.gov Identifier: NCT01129557 |
Recruitment Status :
Terminated
First Posted : May 24, 2010
Results First Posted : May 15, 2014
Last Update Posted : May 15, 2014
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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.
Condition or disease | Intervention/treatment | Phase |
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Proteinuric Kidney Disease Diabetic Nephropathy Hypertensive Nephrosclerosis IgA Nephropathy Focal Segmental Glomerulosclerosis Glomerulopathy (Obesity-associated) Glomerulonephritis, Membranous | Drug: Aliskiren Drug: Valsartan | Phase 4 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 46 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Aldosterone Breakthrough During Diovan (Valsartan), Tekturna (Aliskiren), and Combination (Valsartan+Aliskiren) Anti-hypertensive Therapy in Patients With Proteinuric Kidney Disease |
Study Start Date : | September 2009 |
Actual Primary Completion Date : | January 2012 |
Actual Study Completion Date : | December 2012 |

Arm | Intervention/treatment |
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Active Comparator: Tekturna
Tekturna (Aliskiren), a direct renin inhibitor (DRI) 300 mg by mouth once daily for 9 months
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Drug: Aliskiren
Other Name: Tekturna |
Active Comparator: Diovan
Diovan (Valsartan), an angiotensin receptor blocker (ARB) 320 mg by mouth once daily for 9 months
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Drug: Valsartan
Other Name: Diovan |
Active Comparator: Tekturna & Diovan
Tekturna (Aliskiren), a direct renin inhibitor (DRI) 150 mg by mouth once daily & Diovan (Valsartan), an angiotensin receptor (ARB) 160 mg by mouth once daily for 9 months
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Drug: Aliskiren
Other Name: Tekturna Drug: Valsartan Other Name: Diovan |
- Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol. [ Time Frame: 9 months ]The primary outcome of this study is the 9-month cumulative incidence of aldosterone breakthrough, defined as a sustained increase in 24-hour urine aldosterone above baseline, in each treatment arm.
- 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

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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 glomerulopathy
Exclusion Criteria:
- 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 blocker)
- 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 exclusion)
- 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 health authorities

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01129557
United States, New York | |
Columbia University Medical Center | |
New York, New York, United States, 10032 |
Principal Investigator: | Pietro Canetta, MD | Columbia University |
Responsible Party: | Pietro Canetta, MD, Instructor in Clinical Medicine, Nephrology, Columbia University |
ClinicalTrials.gov Identifier: | NCT01129557 |
Other Study ID Numbers: |
AAAE0863 #IIRP-906 ( Other Identifier: Novartis ) |
First Posted: | May 24, 2010 Key Record Dates |
Results First Posted: | May 15, 2014 |
Last Update Posted: | May 15, 2014 |
Last Verified: | April 2014 |
Kidney Diseases Diabetic Nephropathies Glomerulonephritis, IGA Glomerulonephritis Glomerulosclerosis, Focal Segmental Glomerulonephritis, Membranous Nephrosclerosis Urologic Diseases Diabetes Complications Diabetes Mellitus |
Endocrine System Diseases Nephritis Autoimmune Diseases Immune System Diseases Valsartan Antihypertensive Agents Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Antagonists Molecular Mechanisms of Pharmacological Action |