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

NCT01129557 | Terminated Phase 4 Results DMC

• 2 other identifiers: AAAE0863#IIRP-906
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol.

  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.

  9 months

Secondary Outcomes (11)

• Serum Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.

  Baseline, 3-, 6-, and 9-months

• Urine Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.

  Baseline, 3-, 6-, and 9-months

• Serum Potassium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.

  Baseline, 3-, 6-, and 9-months

• Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.

  Baseline, 3-, 6-, and 9-months

• Pre- and Post-treatment Blood Pressure in Subjects With and Without Aldosterone Breakthrough.

  Baseline and Final (9 month)

Study Arms (3)

Tekturna

ACTIVE COMPARATOR

Tekturna (Aliskiren), a direct renin inhibitor (DRI) 300 mg by mouth once daily for 9 months

Drug: Aliskiren

Diovan

ACTIVE COMPARATOR

Diovan (Valsartan), an angiotensin receptor blocker (ARB) 320 mg by mouth once daily for 9 months

Drug: Valsartan

Tekturna & Diovan

ACTIVE COMPARATOR

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; Drug: Valsartan

Interventions

Aliskiren DRUG

Also known as: Tekturna

Tekturna; Tekturna & Diovan

Valsartan DRUG

Also known as: Diovan

Diovan; Tekturna & Diovan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• nd or 3rd degree heart block without a pacemaker or other uncontrolled arrhythmia
• Clinically significant valvular disease
• Known renal artery stenosis
• 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

Sponsors & Collaborators

• Columbia University: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Publications (1)

• 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.

  PMID: 22995802 RESULT

MeSH Terms

Conditions

Diabetic Nephropathies; Glomerulonephritis, IGA; Glomerulosclerosis, Focal Segmental; Glomerulonephritis, Membranous

Interventions

aliskiren; Valsartan

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Glomerulonephritis; Nephritis; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Results Point of Contact

• Title: Andrew Bomback, MD
• Organization: Columbia University Medical Center, Division of Nephrology

asb68@columbia.edu

212-305-5020

Study Officials

• Pietro Canetta, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Instructor in Clinical Medicine, Nephrology

Study Record Dates

• First Submitted: May 21, 2010
• First Posted: May 24, 2010
• Study Start: September 1, 2009
• Primary Completion: January 1, 2012
• Study Completion: December 1, 2012
• Last Updated: May 15, 2014
• Results First Posted: May 15, 2014

Record last verified: 2014-04

Locations

US (1)