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

Study Description

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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, 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
Proteinuric Kidney Disease; Diabetic Nephropathy; Hypertensive Nephrosclerosis; IgA Nephropathy; Focal Segmental Glomerulosclerosis; Glomerulopathy (Obesity-associated); Glomerulonephritis, Membranous	Drug: Aliskiren; Drug: Valsartan	Phase 4

Detailed 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

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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

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Tekturna; Tekturna (Aliskiren), a direct renin inhibitor (DRI) 300 mg by mouth once daily for 9 months	Drug: Aliskiren; Other Name: Tekturna
Active Comparator: Diovan; Diovan (Valsartan), an angiotensin receptor blocker (ARB) 320 mg by mouth once daily for 9 months	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	Drug: Aliskiren; Other Name: Tekturna Drug: Valsartan; Other Name: Diovan

Outcome Measures

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Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.)
4. 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.)
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, New York
Columbia University Medical Center
New York, New York, United States, 10032

Sponsors and Collaborators

Columbia University

Novartis Pharmaceuticals

Investigators

Principal Investigator:	Pietro Canetta, MD	Columbia University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Bomback AS, Rekhtman Y, Klemmer PJ, Canetta PA, Radhakrishnan J, Appel GB. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy. J Am Soc Hypertens. 2012 Sep-Oct;6(5):338-45. doi: 10.1016/j.jash.2012.07.003.

Responsible Party:	Pietro Canetta, MD, Instructor in Clinical Medicine, Nephrology, Columbia University
ClinicalTrials.gov Identifier:	NCT01129557 History of Changes
Other Study ID Numbers:	AAAE0863; #IIRP-906 ( Other Identifier: Novartis )
First Posted:	May 24, 2010
Results First Posted:	May 15, 2014
Last Update Posted:	May 15, 2014
Last Verified:	April 2014

Additional relevant MeSH terms:

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