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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01302899
• Collaborator: (none)
• Enrollment: 8
• Locations: 2
• Arms: 2
• Duration (Months): 11
• Patients Per Site: 4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Non-diabetic Nephropathy	Drug: Aliskiren; Drug: Placebo to Aliskiren; Drug: Hydrochlorothiazide (HCTZ); Drug: Placebo to Hydrochlorothiazide (HCTZ); Drug: Ramipril	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

1. Effect of Aliskiren on Albuminuria as Measured by Urinary Albumin Excretion Rate (UAER) [26 weeks]

   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.

2. Effect of Aliskiren on Albuminuria as Measured by Creatinine Indexed Albumin [26 weeks]

   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.

Secondary Outcome Measures

1. Mean Sitting Systolic Blood Pressure (msSBP) [26 weeks]

   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.

2. Mean Sitting Diastolic Blood Pressure (msDBP) [26 weeks]

   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.

3. Mean Glomerular Filtration Rate (GFR) as Measurement of Renal Function [26 weeks]

   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.

4. Mean Effective Renal Plasma Flow (ERPF) as One of Hemodynamic Assessments [26 weeks]

5. Percentage of Renal Filtration Fraction (RFF) as One of Hemodynamic Assessments [26 weeks]

6. Mean Extracellular Volume (ECV) as One of Hemodynamic Assessments [26 weeks]

7. Plasma Rennin Activity (PRA) [Baseline to week 26]

   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.

8. Plasma Rennin Concentration (PRC) [Baseline to week 26]

   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.

9. Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril [26 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Groningen		Netherlands
2	Novartis Investigative Site	Leeuwarden		Netherlands

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01302899
• Other Study ID Numbers: CSPP100A2260; 2009-012196-10
• First Posted: Feb 24, 2011
• Last Update Posted: Jan 30, 2013
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Kidney Diseases; Albuminuria; Hydrochlorothiazide; Ramipril

Study Results

Participant Flow

Arm/Group Title	Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)+HCTZ/Ram+Ali/Ram	Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)/Ram+Ali + HCTZ/Ram
Arm/Group Description	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.	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.
Period Title: Period 1 (Day 1 to End of Week 6)
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0
Period Title: Period 1 (Day 1 to End of Week 6)
STARTED	4	4
COMPLETED	3	3
NOT COMPLETED	1	1
Period Title: Period 1 (Day 1 to End of Week 6)
STARTED	3	3
COMPLETED	3	3
NOT COMPLETED	0	0
Period Title: Period 1 (Day 1 to End of Week 6)
STARTED	3	3
COMPLETED	3	3
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)+HCTZ/Ram+Ali/Ram	Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)/Ram+Ali + HCTZ/Ram	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	4	4	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.5 (6.76)	58.5 (8.70)	54.5 (8.38)
Sex: Female, Male (Count of Participants)
Female	2 50%	1 25%	3 37.5%
Male	2 50%	3 75%	5 62.5%

Outcome Measures

1. Primary Outcome

Title	Effect of Aliskiren on Albuminuria as Measured by Urinary Albumin Excretion Rate (UAER)
Description	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.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

2. Primary Outcome

Title	Effect of Aliskiren on Albuminuria as Measured by Creatinine Indexed Albumin
Description	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.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

3. Secondary Outcome

Title	Mean Sitting Systolic Blood Pressure (msSBP)
Description	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.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

4. Secondary Outcome

Title	Mean Sitting Diastolic Blood Pressure (msDBP)
Description	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.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

5. Secondary Outcome

Title	Mean Glomerular Filtration Rate (GFR) as Measurement of Renal Function
Description	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.
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

6. Secondary Outcome

Title	Mean Effective Renal Plasma Flow (ERPF) as One of Hemodynamic Assessments
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

7. Secondary Outcome

Title	Percentage of Renal Filtration Fraction (RFF) as One of Hemodynamic Assessments
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

8. Secondary Outcome

Title	Mean Extracellular Volume (ECV) as One of Hemodynamic Assessments
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

9. Secondary Outcome

Title	Plasma Rennin Activity (PRA)
Description	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.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

10. Secondary Outcome

Title	Plasma Rennin Concentration (PRC)
Description	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.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

The study was terminated and consequentially was underpowered for adequate statistical analysis

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	0	0	0	0

11. Secondary Outcome

Title	Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril
Time Frame	26 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all patients who received at least one study drug and had no major protocol deviations that could have impacted safety data.

Arm/Group Title	Ramipril +HCTZ	Ramipril+Aliskiren + HCTZ	Ramipril+Aliskiren	Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period	All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
Measure Participants	8	7	7	6
patients with adverse events	7 175%	5 125%	3 37.5%	4 NaN
patients with serious adverse events	0 0%	0 0%	0 0%	0 NaN
patients with death	0 0%	0 0%	0 0%	0 NaN

Adverse Events

Arm/Group Title	Ramipril +HCTZ		Ramipril+Aliskiren + HCTZ		Ramipril+Aliskiren		Ramipril
Arm/Group Description	All patients were treated for 6 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren (300 mg) + HCTZ 25 mg		All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 x 150 mg) + HCTZ 25 mg * Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period		All patients were treated for 6 weeks with daily doses of ramipril 10 mg + aliskiren 300 mg* (2 tablets of 150 mg) + placebo to 25 mg HCTZ *Patients were started on aliskiren 150 mg for the 1st week and up-titrated to 300 mg (2 x 150 mg) at the beginning of the 2nd week and continued on this dose until the end of the 6th week of the period		All patients were treated for 8 weeks with daily doses of ramipril 10 mg + placebo to 2 x 150 mg aliskiren + placebo to 25 mg HCTZ
All Cause Mortality
	Ramipril +HCTZ		Ramipril+Aliskiren + HCTZ		Ramipril+Aliskiren		Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ramipril +HCTZ		Ramipril+Aliskiren + HCTZ		Ramipril+Aliskiren		Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Ramipril +HCTZ		Ramipril+Aliskiren + HCTZ		Ramipril+Aliskiren		Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)		5/7 (71.4%)		3/7 (42.9%)		4/6 (66.7%)
Cardiac disorders
Angina pectoris	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Palpitations	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Eye disorders
Vision blurred	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Gastrointestinal disorders
Nausea	2/8 (25%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Abdominal pain	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Diarrhea	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dyspepsia	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
General disorders
Fatigue	3/8 (37.5%)		2/7 (28.6%)		2/7 (28.6%)		2/6 (33.3%)
Edema peripheral	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		2/6 (33.3%)
Non-cardiac chest pain	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Infections and infestations
Nasopharyngitis	1/8 (12.5%)		1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Urinary tract infection	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Investigations
Blood pressure increased	0/8 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Renal function test abnormal	0/8 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Metabolism and nutrition disorders
Gout	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hyperkalemia	0/8 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Salt craving	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	3/8 (37.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Back pain	1/8 (12.5%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Nervous system disorders
Dizziness	4/8 (50%)		2/7 (28.6%)		0/7 (0%)		0/6 (0%)
Orthostatic intolerance	0/8 (0%)		2/7 (28.6%)		0/7 (0%)		1/6 (16.7%)
Headache	2/8 (25%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Tension headache	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Renal and urinary disorders
Nocturia	1/8 (12.5%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Dyspnoea	0/8 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Snoring	0/8 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Vascular disorders
Hypotension	0/8 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.