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

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

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01129557

Enrollment

Registered

2010-05-24

Start date

2009-09-30

Completion date

2012-12-31

Last updated

2014-05-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetic Nephropathy, Focal Segmental Glomerulosclerosis, Glomerulonephritis, Membranous, Glomerulopathy (Obesity-associated), Hypertensive Nephrosclerosis, IgA Nephropathy, 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, 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.

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.

Interventions

DRUGAliskiren

DRUGValsartan

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol.	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

Measure	Time frame	Description
Urine Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	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.	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.	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.	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.	Baseline and Final (9 month)	Compares baseline and final (9 month) serum creatinine for subjects with and without aldosterone breakthrough
Serum Aldosterone Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	Baseline, 3-, 6-, and 9-months	Mean serum aldosterone at baseline, 3-, 6-, and 9-months.
Pre- and Post-treatment 24-hour Urine Protein in Subjects With and Without Aldosterone Breakthrough.	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.	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.	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.	Baseline and Final (9 month)	Compares baseline and final (9 month) serum aldosterone for subjects with and without aldosterone breakthrough
Pre- and Post-treatment Serum Potassium in Subjects With and Without Aldosterone Breakthrough.	Baseline and Final (9 month)	Compares baseline and final (9 month) serum potassium for subjects with and without aldosterone breakthrough

Countries

United States

Participant flow

Participants by arm

Arm	Count
Diovan Diovan (Valsartan), an angiotensin receptor blocker (ARB) 320 mg by mouth once daily for 9 months	15
Tekturna Tekturna (Aliskiren), a direct renin inhibitor (DRI) 300 mg by mouth once daily for 9 months	17
Tekturna+Diovan Tekturna (Aliskiren), a direct renin inhibitor (DRI) 150 mg by mouth once daily for 9 months & Diovan (Valsartan), an angiotensin receptor blocker (ARB) 160 mg by mouth once daily for 9 months	14
Total	46

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	1	2	2
Overall Study	Novartis terminated study early	3	3	2

Baseline characteristics

Characteristic	Diovan	Tekturna	Tekturna+Diovan	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	2 Participants	2 Participants
Age, Categorical Between 18 and 65 years	15 Participants	17 Participants	12 Participants	44 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	2 Participants	3 Participants	1 Participants	6 Participants
Race/Ethnicity, Customized Black or African American	1 Participants	1 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized More than one race	4 Participants	4 Participants	2 Participants	10 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Unknown or Not Reported	0 Participants	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized White	8 Participants	8 Participants	9 Participants	25 Participants
Sex: Female, Male Female	4 Participants	6 Participants	4 Participants	14 Participants
Sex: Female, Male Male	11 Participants	11 Participants	10 Participants	32 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	2 / 17	1 / 15	2 / 14
serious Total, serious adverse events	0 / 17	0 / 15	0 / 14

Outcome results

Primary

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.

Time frame: 9 months

Arm	Measure	Value (NUMBER)
Diovan	Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol.	3 participants
Tekturna	Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol.	3 participants
Tekturna + Diovan	Cumulative Incidence of Aldosterone Breakthrough in Subjects Who Completed the 9-month Study Protocol.	3 participants

Secondary

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

Mean 24-hour urine sodium (mmol/day) at baseline, 3-, 6-, and 9-months. (given as reference to interpret contemporaneous plasma & urine aldosterone measurements.)

Time frame: Baseline, 3-, 6-, and 9-months

Arm	Measure	Value (MEAN)	Dispersion
Diovan	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	158 mmol/day	Standard Deviation 67
Tekturna	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	180 mmol/day	Standard Deviation 81
Tekturna + Diovan	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	188 mmol/day	Standard Deviation 66
9 Months: Subjects Without Aldosterone Breakthrough	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	169 mmol/day	Standard Deviation 70
Baseline: Subjects With Aldosterone Breakthrough	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	258 mmol/day	Standard Deviation 98
3 Months: Subjects With Aldosterone Breakthrough	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	220 mmol/day	Standard Deviation 65
6 Months: Subjects With Aldosterone Breakthrough	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	250 mmol/day	Standard Deviation 102
9 Months: Subjects With Aldosterone Breakthrough	Mean 24-hour Urine Sodium Over Time During 9-month Treatment Course in Subjects With and Without Aldosterone Breakthrough.	200 mmol/day	Standard Deviation 54

Secondary

Pre- and Post-treatment 24-hour Urine Protein in Subjects With and Without Aldosterone Breakthrough.

Compares baseline and final (9 month) 24-hour urine protein for subjects with and without aldosterone breakthrough