To Study the Effects of Aliskiren on Albuminuria and Various Biomarkers in Patients With Nephropathy (ARIA)

A Single-blind, Double Dummy, Randomized, Multi-dose, Two Sequence, Crossover, Study to Investigate the Effects of Renin Inhibitor (Aliskiren 300 mg) on Albuminuria in Non-diabetic Nephropathy Patients Treated With Ramipril 10 mg and Volume Intervention (ARIA)

The study is designed to primarily assess the effect of aliskiren on albuminuria in patients with non-diabetic nephropathy when treated with ramipril and volume intervention.

Study Overview

• Status: Terminated
• Conditions: Non-diabetic Nephropathy
• Intervention / Treatment: Drug: Aliskiren; Drug: Placebo to Aliskiren; Drug: Hydrochlorothiazide (HCTZ); Drug: Placebo to Hydrochlorothiazide (HCTZ); Drug: Ramipril

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Novartis Investigative Site
  • Leeuwarden, Netherlands
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects, age 18 years and above
• Patients with chronic kidney disease of non-diabetic origin
• Glomerular filtration rate >30 ml/min/1.73m2
• Patients with a history of hypertension and msSBP (mean systolic blood pressure) of <160 mm Hg and msDBP (mean diastolic blood pressure) <105 mm Hg at screening and baseline.
• Subjects must have a body mass index (BMI) within the range of 18 and 35 kg/m2

Exclusion Criteria:

• Previously treated (within 3 months of screening) with aliskiren or a combination of aliskiren and ramipril.
• Severe hypertension (msDBP ≥110 mmHg and msSBP ≥180 mmHg)
• Pregnant or nursing (lactating) women,
• A medical history of unstable coronary artery disease, myocardial infarction, coronary bypass surgery or cerebrovascular accident within the last six (6) months
• Diabetes mellitus, Heart failure
• High rate of renal function loss
• History of severe hypersensitivity or contraindications to any of the medications or drugs belonging to the similar therapeutic class as the study drugs and the excipients.
• History of liver disease, positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result
• History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result.

Other protocol-defined inclusion/exclusion criteria applied

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)+HCTZ/Ram+Ali/Ram; Period 1(Day 1 to end of week 6): 1 tablet ramipril 10 mg once daily (o.d.) + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule Hydrochlorothiazide (HCTZ) 25 mg o.d. Period 2 (Weeks 7 to 12): 1 tablet ramipril 10 mg o.d.+ 1 tablet aliskiren 150 mg in 1st week of period; thereafter, 2 tablets aliskiren 150mg o.d.+ 1 capsule HCTZ 25 mg o.d. Period 3 (Weeks 13 to 18): 1 tablet ramipril 10 mg o.d. + 2 tablets aliskiren 150mg o.d. + 1 capsule placebo to HCTZ 25 mg o.d. Period 4 (Weeks 19 to 26): 1 tablet ramipril 10 mg o.d. + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule placebo to HCTZ 25 mg o.d.	Drug: Aliskiren; Aliskiren 150 mg (Tablet); Drug: Placebo to Aliskiren; Aliskiren 150 mg Matching Placebo (Tablet); Drug: Hydrochlorothiazide (HCTZ); HCTZ 25mg (Capsule); Drug: Placebo to Hydrochlorothiazide (HCTZ); HCTZ 25mg (Capsule) Matching Placebo; Drug: Ramipril; Ramipril 10mg (Tablet)
Experimental: Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)/Ram+Ali + HCTZ/Ram; Period 1(Day 1 to end of week 6): 1 tablet ramipril 10 mg once daily (o.d.) + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule Hydrochlorothiazide (HCTZ) 25 mg o.d. Period 2 (Weeks 7 to 12): 1 tablet ramipril 10 mg o.d.+ 1 tablet aliskiren 150 mg in 1st week of period; thereafter, 2 tablets aliskiren 150mg o.d.+ 1 capsule placebo to HCTZ 25 mg o.d. Period 3 (Weeks 13 to 18): 1 tablet ramipril 10 mg o.d. + 2 tablets aliskiren 150mg o.d. + 1 capsule HCTZ 25 mg o.d. Period 4 (Weeks 19 to 26): 1 tablet ramipril 10 mg o.d. + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule placebo to HCTZ 25 mg o.d.	Drug: Aliskiren; Aliskiren 150 mg (Tablet); Drug: Placebo to Aliskiren; Aliskiren 150 mg Matching Placebo (Tablet); Drug: Hydrochlorothiazide (HCTZ); HCTZ 25mg (Capsule); Drug: Placebo to Hydrochlorothiazide (HCTZ); HCTZ 25mg (Capsule) Matching Placebo; Drug: Ramipril; Ramipril 10mg (Tablet)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Aliskiren on Albuminuria as Measured by Urinary Albumin Excretion Rate (UAER)	Two 24-hour collections of urine were to be made at each study visit. The arithmetic mean of the two collections were planned to be used in the calculation of summary statistics and the statistical analyses.	26 weeks
Effect of Aliskiren on Albuminuria as Measured by Creatinine Indexed Albumin	Two 24-hour collections of urine were to be made at each study visit. The arithmetic mean of the two collections were planned to be used in the calculation of summary statistics and the statistical analyses.	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Sitting Systolic Blood Pressure (msSBP)	At study entry, blood pressure (BP) was measured in both arms. If there was a clinically relevant difference in readings between arms (≥ 10 mmHg in systolic BP and/or ≥ 5 mmHg in diastolic BP), the arm with higher BP reading was used. If there was no clinically significant difference between arms, the non-dominant arm was used through out study. Systolic blood pressure were assessed after the patient rested quietly in the sitting position for at least 3 minutes. For each sitting assessment, blood pressure was assessed at least 3 times. From these assessments, msSBP was calculated. All BP measurements were to be performed on the same arm.	26 weeks
Mean Sitting Diastolic Blood Pressure (msDBP)	At study entry, blood pressure (BP) was measured in both arms. If there was a clinically relevant difference in readings between arms (≥ 10 mmHg in systolic BP and/or ≥ 5 mmHg in diastolic BP), the arm with higher BP reading was used. If there was no clinically significant difference between arms, the non-dominant arm was used through out study. Diastolic blood pressure were assessed after the patient rested quietly in the sitting position for at least 3 minutes. For each sitting assessment, blood pressure was assessed at least 3 times. From these assessments, msDBP was calculated. All BP measurements were to be performed on the same arm.	26 weeks
Mean Glomerular Filtration Rate (GFR) as Measurement of Renal Function	All patients had to visit the main center for renal function measurements. The measurements were performed using the constant infusion method with I-iothalamate (IOT) and I-hippuran. GFR was calculated as the urinary clearance of IOT.	26 weeks
Mean Effective Renal Plasma Flow (ERPF) as One of Hemodynamic Assessments		26 weeks
Percentage of Renal Filtration Fraction (RFF) as One of Hemodynamic Assessments		26 weeks
Mean Extracellular Volume (ECV) as One of Hemodynamic Assessments		26 weeks
Plasma Rennin Activity (PRA)	Blood biomarkers were obtained from blood samples in all patients at the time points such as baseline, week 6, week 12, week 18 and week 26. Plasma PRA is a direct measure of the formation of Ang I in the plasma.	Baseline to week 26
Plasma Rennin Concentration (PRC)	Blood biomarkers were obtained from blood samples in all patients at the time points such as baseline, week 6, week 12, week 18 and week 26. PRC measures the concentration of immunoactive renin in the plasma.	Baseline to week 26
Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril		26 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: February 9, 2011
• First Submitted That Met QC Criteria: February 22, 2011
• First Posted (Estimate): February 24, 2011

Study Record Updates

• Last Update Posted (Estimate): January 30, 2013
• Last Update Submitted That Met QC Criteria: December 21, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Urination Disorders; Proteinuria; Kidney Diseases; Albuminuria; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Angiotensin-Converting Enzyme Inhibitors; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide; Ramipril
• Other Study ID Numbers: CSPP100A2260; 2009-012196-10 (EudraCT Number)