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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00660309

Enrollment

Registered

2008-04-17

Start date

2008-04-30

Completion date

2009-12-31

Last updated

2012-08-29

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

Conditions

Type 2 Diabetes Mellitus

Keywords

Type 2 diabetes mellitus, renal disease, hypertension, renal blood flow, retinal blood flow, aliskiren, irbesartan, captopril

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.

Interventions

DRUGAliskiren

Aliskiren 300 mg tablets

DRUGIrbesartan

Irbesartan 300 mg tablets

DRUGCaptopril

Captopril 25 mg tablet

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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/

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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

Measure	Time frame	Description
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	23
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.	22
Total	45

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	0
Overall Study	Withdrawal by Subject	0	3

Baseline characteristics

Characteristic	Aliskiren	Irbesartan	Total
Age Continuous	56.5 years STANDARD_DEVIATION 11.2	57.7 years STANDARD_DEVIATION 8.14	57.1 years STANDARD_DEVIATION 9.73
Sex: Female, Male Female	6 Participants	10 Participants	16 Participants
Sex: Female, Male Male	17 Participants	12 Participants	29 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	2 / 45	5 / 22	5 / 21
serious Total, serious adverse events	0 / 45	0 / 22	0 / 21

Outcome results

Primary

Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan

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.

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

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan	37.18 mL/min/1.73m^2	Standard Deviation 36.19
Irbesartan	Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan	35.88 mL/min/1.73m^2	Standard Deviation 35.53

Primary

Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan

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.

Population: 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	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan	24.62 mL/min/1.73m^2	Standard Deviation 52.93
Irbesartan	Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan	24.22 mL/min/1.73m^2	Standard Deviation 38.23

Primary

Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan

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) .

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan	-5.67 mL/min/1.73m^2	Standard Deviation 49.1
Irbesartan	Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan	-13.08 mL/min/1.73m^2	Standard Deviation 27.01

Primary

Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan

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.

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan	-12.74 mL/min/1.73m^2	Standard Deviation 37.05
Irbesartan	Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan	-14.67 mL/min/1.73m^2	Standard Deviation 35.75

Secondary

Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan

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.

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan	10.52 mL/min/1.73m^2	Standard Deviation 11.22
Irbesartan	Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan	10.16 mL/min/1.73m^2	Standard Deviation 10.1

Secondary

Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril

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.

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril	11.29 mL/min/1.73m^2	Standard Deviation 15.33
Irbesartan	Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril	7.41 mL/min/1.73m^2	Standard Deviation 12.39

Secondary

Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril

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.

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

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril	43.32 mL/min/1.73m^2	Standard Deviation 42.78
Irbesartan	Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril	40.13 mL/min/1.73m^2	Standard Deviation 31.7

Secondary

Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan

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.

Population: 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	Measure	Group	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan	Single dose effect [N=13, 13]	-0.32 µL/min	Standard Deviation 1.37
Aliskiren	Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan	Multiple dose effect [N=13, 11]	0.29 µL/min	Standard Deviation 1.46
Irbesartan	Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan	Single dose effect [N=13, 13]	0.43 µL/min	Standard Deviation 2.32
Irbesartan	Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan	Multiple dose effect [N=13, 11]	0.35 µL/min	Standard Deviation 2.18

Secondary

Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan

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.

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan	8.69 mL/min/1.73m^2	Standard Deviation 9.61
Irbesartan	Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan	2.96 mL/min/1.73m^2	Standard Deviation 6.98

Secondary

Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan

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) .

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan	1.05 mL/min/1.73m^2	Standard Deviation 10.24
Irbesartan	Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan	-5.67 mL/min/1.73m^2	Standard Deviation 10

Secondary

Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan

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.

Arm	Measure	Value (MEAN)	Dispersion
Aliskiren	Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan	-1.71 mL/min/1.73m^2	Standard Deviation 9.38
Irbesartan	Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan	-8.68 mL/min/1.73m^2	Standard Deviation 7.05

Secondary

Change in Plasma Angiotensin I After Captopril, Aliskiren or Irbesartan

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.