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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Non-diabetic Nephropathy

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Placebo to Aliskiren
* Drug: Hydrochlorothiazide (HCTZ)
* Drug: Placebo to Hydrochlorothiazide (HCTZ)
* Drug: Ramipril


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)+HCTZ/Ram+Ali/Ram<br>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<br>* Aliskiren 150 mg (Tablet)<br>Drug: Placebo to Aliskiren<br>* Aliskiren 150 mg Matching Placebo (Tablet)<br>Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 25mg (Capsule)<br>Drug: Placebo to Hydrochlorothiazide (HCTZ)<br>* HCTZ 25mg (Capsule) Matching Placebo<br>Drug: Ramipril<br>* Ramipril 10mg (Tablet)<br>|
| Experimental: Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)/Ram+Ali + HCTZ/Ram<br>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<br>* Aliskiren 150 mg (Tablet)<br>Drug: Placebo to Aliskiren<br>* Aliskiren 150 mg Matching Placebo (Tablet)<br>Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 25mg (Capsule)<br>Drug: Placebo to Hydrochlorothiazide (HCTZ)<br>* HCTZ 25mg (Capsule) Matching Placebo<br>Drug: Ramipril<br>* Ramipril 10mg (Tablet)<br>|

What is the study measuring?
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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 |