A Clinical Study to Evaluate Renal Hemodynamic Responses to Aliskiren in Patients With Type 2 Diabetes Mellitus

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00660309
• Collaborator: (none)
• Enrollment: 45
• Location: 1
• Arms: 2
• Duration (Months): 20
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

The study objective was to assess the effect of single and multiple doses of aliskiren on renal plasma flow, glomerular filtration rate and to compare the effects of single and multiple doses of aliskiren versus captopril or irbesartan on renal blood flow, glomerular filtration rate, and retinal blood flow in patients with type 2 diabetes mellitus.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Aliskiren; Drug: Irbesartan; Drug: Captopril	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: An Open-label, Randomized, Parallel-group Study to Evaluate the Acute and Steady-state Renal Hemodynamic Responses to Aliskiren in Patients With Type 2 Diabetes Mellitus
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aliskiren On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	Drug: Aliskiren; Aliskiren 300 mg tablets; Other Names: SPP100 ; Drug: Captopril; Captopril 25 mg tablet
Active Comparator: Irbesartan On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.	Drug: Irbesartan; Irbesartan 300 mg tablets; Drug: Captopril; Captopril 25 mg tablet

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan [Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.]

   Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. The measure of the single dose effect (SDE) for aliskiren and irbesartan was calculated as Day 2 peak - Day 2 baseline RPF. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept.

2. Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan [Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) .]

   Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. This multiple dose effect at steady state (MDE_SS) was calculated as Day 15 baseline - Day 2 baseline. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values.

3. Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan [Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and Day 15: 1, 2, 3, 4 and 5 hours post-dose.]

   Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. This maximum multiple dose effect (MDE_Max) was calculated as Day 15 peak - Day 2 baseline. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept.

4. Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan [Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose.]

   Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) was calculated as Day 15 peak - Day 2 peak. Peak RPF was obtained using a moving average concept.

Secondary Outcome Measures

1. Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril [Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.]

   Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. The measure of the single dose effect (SDE) for captopril was calculated as Day 1 peak - Day 1 baseline RPF. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept.

2. Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril [Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.]

   Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. The measure of the single dose effect (SDE) for captopril was calculated as Day 1 peak - Day 1 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept.

3. Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan [Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.]

   Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. The measure of the single dose effect (SDE) for aliskiren and irbesartan was calculated as Day 2 peak - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept.

4. Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan [Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) .]

   Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. This multiple dose effect at steady state (MDE_SS) was calculated as Day 15 baseline - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values.

5. Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan [Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and Day 15: 1, 2, 3, 4 and 5 hours post-dose.]

   Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. This maximum multiple dose effect (MDE_Max) was calculated as Day 15 peak - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept.

6. Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan [Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose.]

   Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) was calculated as Day 15 peak - Day 2 peak GFR. Peak GFR was obtained using a moving average concept.

7. Change in Plasma Renin Concentration (PRC) After Captopril, Aliskiren or Irbesartan [Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.]

   The following plasma renin concentration effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.

8. Change in Plasma Pro-renin Concentration After Captopril, Aliskiren or Irbesartan [Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.]

   The following plasma pro-renin concentration effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.

9. Change in Plasma Renin Activity (PRA) After Captopril, Aliskiren or Irbesartan [Predose and 5 hours post dose on Days 1, 2 and 15.]

   PRA was measured by the trapping method and the following effects assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 baseline / Day 2 baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.

10. Change in Plasma Angiotensin I After Captopril, Aliskiren or Irbesartan [Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.]

    The following angiotensin I effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.

11. Change in Plasma Angiotensin II After Captopril, Aliskiren or Irbesartan [Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.]

    The following angiotensin II effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.

12. Change in Serum Aldosterone After Captopril, Aliskiren or Irbesartan [Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.]

    The following serum aldosterone effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.

13. Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan [Baseline (Day 1), Day 2 and Day 15.]

    Retinal blood flow was assessed using the laser Doppler technique. The blood flow in the superior temporal retinal artery in one of the eyes of each study participant was determined. The Single dose effect of aliskiren or irbesartan was measured as the change/difference between Day 2 and baseline measurements. The Multiple dose effect of aliskiren or irbesartan wsas measured as the change/difference between Day 15 and Day 2 measurements

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hypertensive, male and females of non-child bearing potential patients, with type 2 diabetes mellitus (T2DM) (diagnosed at least 8 weeks before Screening), with or without renal impairment; estimated glomerular filtration rate (eGFR) ≥ 40 mL/min/1.73 m^2, documented at least 3 months before the study start, aged 18-75 years with a minimum body weight of 50 kg and having an appropriate intravenous access as determined by the study staff, able to communicate well were enrolled in the study.

• Patients must be on a stable dose of hypoglycemic medications for at least 8 weeks prior to the study.

• Patients must be medically able to discontinue anti- hypertensive medications for the duration of the study.

Exclusion Criteria:

• Patients with type 1 diabetes mellitus or uncontrolled T2DM (HbA1C> 11%), eGFR <40 mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal Disease (MDRD) formula), renal disease not caused by diabetes or hypertension, serum potassium < 3.5 or > 5.1 mEq/L, heart failure (New York Heart Association (NYHA) Class II-IV) or history of acute/decompensated heart failure within the 6 months prior to dosing, history of myocardial infarction, unstable angina pectoris, coronary bypass surgery, or any percutaneous coronary intervention (PCI) during the 6 months prior to the baseline visit, history of malignancy including leukemia and lymphoma within past five years, hypertensive encephalopathy any time in the past or cerebrovascular accident within the 6 months prior to the baseline visit, or with history of drug or alcohol abuse within the 12 months prior to dosing were excluded from the study.

• Patients with glaucoma, or prior ocular surgery.

• Patients with renal disease not caused by diabetes or hypertension.

• Patients with history of clinically significant drug or atopic allergy, acute or chronic respiratory disease, history of malignancy, or history of myocardial infarction, unstable angina pectoris, coronary bypass surgery, or any coronary intervention (percutaneous coronary intervention; PCI) during the 6 months prior to the study.

• Patients who had used any prescription drugs which may affect the renin-angiotensin-aldosterone system or with known effect on renal hemodynamics within 2 weeks prior to dosing and during the study, over-the-counter (OTC) medication within two (2) weeks prior to dosing,

• Any surgical or medical condition which may jeopardize the patient in case of participation in the study.

• Participation in any clinical investigation within 4 weeks prior to the study.

• Donation or loss of 400 mL or more of blood within 8 weeks prior to the study.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigator Site	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Novartis

Investigators

• Principal Investigator: Novartis, Novartis investigator site

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT00660309
• Other Study ID Numbers: CSPP100A2329
• First Posted: Apr 17, 2008
• Last Update Posted: Aug 29, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by Novartis: Type 2 diabetes mellitus; renal disease; hypertension; renal blood flow; retinal blood flow; aliskiren; irbesartan; captopril
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Irbesartan; Captopril

Study Results

Participant Flow

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Period Title: Overall Study
STARTED	23	22
Treated With Aliskiren or Irbesartan	22	21
Pharmacodynamic Analysis Set	22	20
COMPLETED	21	19
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Aliskiren	Irbesartan	Total
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.	Total of all reporting groups
Overall Participants	23	22	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.5 (11.20)	57.7 (8.14)	57.1 (9.73)
Sex: Female, Male (Count of Participants)
Female	6 26.1%	10 45.5%	16 35.6%
Male	17 73.9%	12 54.5%	29 64.4%

Outcome Measures

1. Secondary Outcome

Title	Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril
Description	Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. The measure of the single dose effect (SDE) for captopril was calculated as Day 1 peak - Day 1 baseline RPF. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept.
Time Frame	Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
Mean (Standard Deviation) [mL/min/1.73m^2]	43.32 (42.78)	40.13 (31.70)

2. Secondary Outcome

Title	Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril
Description	Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. The measure of the single dose effect (SDE) for captopril was calculated as Day 1 peak - Day 1 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept.
Time Frame	Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	16
Mean (Standard Deviation) [mL/min/1.73m^2]	11.29 (15.33)	7.41 (12.39)

3. Primary Outcome

Title	Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan
Description	Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. The measure of the single dose effect (SDE) for aliskiren and irbesartan was calculated as Day 2 peak - Day 2 baseline RPF. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept.
Time Frame	Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
Mean (Standard Deviation) [mL/min/1.73m^2]	37.18 (36.19)	35.88 (35.53)

4. Primary Outcome

Title	Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan
Description	Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. This multiple dose effect at steady state (MDE_SS) was calculated as Day 15 baseline - Day 2 baseline. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values.
Time Frame	Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) .

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	21	18
Mean (Standard Deviation) [mL/min/1.73m^2]	-5.67 (49.10)	-13.08 (27.01)

5. Primary Outcome

Title	Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan
Description	Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. This maximum multiple dose effect (MDE_Max) was calculated as Day 15 peak - Day 2 baseline. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept.
Time Frame	Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and Day 15: 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	21	18
Mean (Standard Deviation) [mL/min/1.73m^2]	24.62 (52.93)	24.22 (38.23)

6. Primary Outcome

Title	Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan
Description	Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) was calculated as Day 15 peak - Day 2 peak. Peak RPF was obtained using a moving average concept.
Time Frame	Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	21	18
Mean (Standard Deviation) [mL/min/1.73m^2]	-12.74 (37.05)	-14.67 (35.75)

7. Secondary Outcome

Title	Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan
Description	Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. The measure of the single dose effect (SDE) for aliskiren and irbesartan was calculated as Day 2 peak - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept.
Time Frame	Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	16
Mean (Standard Deviation) [mL/min/1.73m^2]	10.52 (11.22)	10.16 (10.10)

8. Secondary Outcome

Title	Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan
Description	Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. This multiple dose effect at steady state (MDE_SS) was calculated as Day 15 baseline - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values.
Time Frame	Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) .

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	21	15
Mean (Standard Deviation) [mL/min/1.73m^2]	1.05 (10.24)	-5.67 (10.00)

9. Secondary Outcome

Title	Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan
Description	Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. This maximum multiple dose effect (MDE_Max) was calculated as Day 15 peak - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept.
Time Frame	Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and Day 15: 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	21	14
Mean (Standard Deviation) [mL/min/1.73m^2]	8.69 (9.61)	2.96 (6.98)

10. Secondary Outcome

Title	Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan
Description	Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) was calculated as Day 15 peak - Day 2 peak GFR. Peak GFR was obtained using a moving average concept.
Time Frame	Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set consisted of all patients with available PD data and no major protocol deviations with impact on PD data. Analysis includes patients for whom data were available.

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	21	14
Mean (Standard Deviation) [mL/min/1.73m^2]	-1.71 (9.38)	-8.68 (7.05)

11. Secondary Outcome

Title	Change in Plasma Renin Concentration (PRC) After Captopril, Aliskiren or Irbesartan
Description	The following plasma renin concentration effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.
Time Frame	Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
SDE after captopril [N=22, 20]	1.18	0.92
SDE after aliskiren/irbesartan [N=22, 20]	2.53	1.04
Steady State Trough Effect [N= 21, 19]	4.41	2.35
Steady State Peak Effect [N=21, 19]	4.81	2.06
Accumulation of Peak Effect [N= 21, 18]	1.93	1.91

12. Secondary Outcome

Title	Change in Plasma Pro-renin Concentration After Captopril, Aliskiren or Irbesartan
Description	The following plasma pro-renin concentration effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.
Time Frame	Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
SDE after captopril [N=22, 20]	0.97	1.01
SDE after aliskiren/irbesartan [N=22, 20]	0.93	0.96
Steady State Trough Effect [N= 21, 19]	1.07	1.20
Steady State Peak Effect [N=21, 19]	1.10	1.13
Accumulation of Peak Effect [N= 21, 18]	1.17	1.18

13. Secondary Outcome

Title	Change in Plasma Renin Activity (PRA) After Captopril, Aliskiren or Irbesartan
Description	PRA was measured by the trapping method and the following effects assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 baseline / Day 2 baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.
Time Frame	Predose and 5 hours post dose on Days 1, 2 and 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
SDE after captopril [N=22, 20]	1.47	1.19
SDE after aliskiren/irbesartan [N=22, 20]	0.09	1.30
Steady State Trough Effect [N= 21, 19]	0.12	3.79
Steady State Peak Effect [N=21, 18]	0.07	3.28
Accumulation of Peak Effect [N= 21, 18]	0.95	2.67

14. Secondary Outcome

Title	Change in Plasma Angiotensin I After Captopril, Aliskiren or Irbesartan
Description	The following angiotensin I effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.
Time Frame	Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
SDE after captopril [N=22, 19]	2.20	1.54
SDE after aliskiren/irbesartan [N=22, 20]	0.14	0.83
Steady State Trough Effect [N= 21, 19]	0.24	2.67
Steady State Peak Effect [N=21, 18]	0.14	2.21
Accumulation of Peak Effect [N= 21, 18]	1.06	2.71

15. Secondary Outcome

Title	Change in Plasma Angiotensin II After Captopril, Aliskiren or Irbesartan
Description	The following angiotensin II effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.
Time Frame	Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
SDE after captopril [N=22, 19]	0.31	0.34
SDE after aliskiren/irbesartan [N=22, 20]	0.26	1.23
Steady State Trough Effect [N= 21, 19]	0.43	4.05
Steady State Peak Effect [N=21, 18]	0.17	3.05
Accumulation of Peak Effect [N= 21, 18]	0.69	2.49

16. Secondary Outcome

Title	Change in Serum Aldosterone After Captopril, Aliskiren or Irbesartan
Description	The following serum aldosterone effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour.
Time Frame	Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	22	20
SDE after captopril [N=22, 20]	0.58	0.75
SDE after aliskiren/irbesartan [N=22, 20]	0.66	0.65
Steady State Trough Effect [N= 21, 19]	0.81	0.82
Steady State Peak Effect [N= 21, 18]	0.60	0.64
Accumulation of Peak Effect [N= 21, 18]	0.93	1.02

17. Secondary Outcome

Title	Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan
Description	Retinal blood flow was assessed using the laser Doppler technique. The blood flow in the superior temporal retinal artery in one of the eyes of each study participant was determined. The Single dose effect of aliskiren or irbesartan was measured as the change/difference between Day 2 and baseline measurements. The Multiple dose effect of aliskiren or irbesartan wsas measured as the change/difference between Day 15 and Day 2 measurements
Time Frame	Baseline (Day 1), Day 2 and Day 15.

Outcome Measure Data

Analysis Population Description

PD analysis set. This assessment was only conducted at sites with available Canon Laser Blood Flowmeter. The number of patients with data available included in each analysis is indicated by 'N' [Aliskiren, Irbesartan].

Arm/Group Title	Aliskiren	Irbesartan
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.	On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
Measure Participants	13	13
Single dose effect [N=13, 13]	-0.32 (1.37)	0.43 (2.32)
Multiple dose effect [N=13, 11]	0.29 (1.46)	0.35 (2.18)

Adverse Events

Time Frame	Study duration (14 days) and 30-days follow-up period.
Adverse Event Reporting Description	All patients that received at least one dose of study drug were included in the safety analysis set.
Arm/Group Title	Captopril 25 mg		Aliskiren 300 mg		Irbesartan 300 mg
Arm/Group Description	On Day 1 participants received a single oral dose of 25 mg captopril.		Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days.		Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days.
All Cause Mortality
	Captopril 25 mg		Aliskiren 300 mg		Irbesartan 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Captopril 25 mg		Aliskiren 300 mg		Irbesartan 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/22 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Captopril 25 mg		Aliskiren 300 mg		Irbesartan 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/45 (4.4%)		5/22 (22.7%)		5/21 (23.8%)
General disorders
CHEST PAIN	0/45 (0%)		0/22 (0%)		2/21 (9.5%)
Investigations
BLOOD PRESSURE INCREASED	0/45 (0%)		2/22 (9.1%)		0/21 (0%)
Nervous system disorders
DIZZINESS	0/45 (0%)		2/22 (9.1%)		0/21 (0%)
HEADACHE	2/45 (4.4%)		3/22 (13.6%)		4/21 (19%)

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.