Trial Outcomes & Findings for Effects of Aliskiren, Ramipril, and the Combination on Levels of Angiotensin II in Patients With Decompensated Systolic Heart Failure (NCT NCT00923156)

NCT ID: NCT00923156

Last Updated: 2012-07-26

Results Overview

Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric mean ratio to baseline at Week 12 for Venous angiotensin II levels was calculated in patients with decompensated systolic heart failure (SHF) and left ventricular ejection fraction ≤40% at 0 hour pre-dose, 3 hours and 24 hours post-dose.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 123 participants
• Primary outcome timeframe: Baseline. 12 Weeks (Day 84, period 2)
• Results posted on: 2012-07-26

Participant Flow

Patient enrolled to 4 week open label run-in phase (period 1) to up-titrate ramipril dose. 123 patients were randomized on Day 1 of Period 2 in a double-blind fashion to one of the three (1:1:1) treatment arms. The double-blind period was for 12 weeks.

Participant milestones

Measure	Aliskiren In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Overall Study STARTED	40	42	41
Overall Study COMPLETED	40	38	38
Overall Study NOT COMPLETED	0	4	3

Reasons for withdrawal

Measure	Aliskiren In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Overall Study Adverse Event	0	2	1
Overall Study Abnormal laboratory values	0	0	1
Overall Study Withdrawal by Subject	0	1	0
Overall Study Death	0	1	0
Overall Study Lack of Efficacy	0	0	1

Baseline Characteristics

Effects of Aliskiren, Ramipril, and the Combination on Levels of Angiotensin II in Patients With Decompensated Systolic Heart Failure

Baseline characteristics by cohort

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril n=42 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril n=41 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.	Total n=123 Participants Total of all reporting groups
Age Continuous	61.3 years STANDARD_DEVIATION 9.00 • n=5 Participants	64.3 years STANDARD_DEVIATION 9.91 • n=7 Participants	62.0 years STANDARD_DEVIATION 10.47 • n=5 Participants	62.6 years STANDARD_DEVIATION 9.83 • n=4 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	8 Participants n=7 Participants	7 Participants n=5 Participants	26 Participants n=4 Participants
Sex: Female, Male Male	29 Participants n=5 Participants	34 Participants n=7 Participants	34 Participants n=5 Participants	97 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline. 12 Weeks (Day 84, period 2)

Population: Pharmacodynamic (PD) Analysis Set: Subjects with any available PD data and no major protocol deviations with impact on PD data. Only patients with a value at both baseline and post-dose are included. In each category "n" indicates patients with observations at that time point.

Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric mean ratio to baseline at Week 12 for Venous angiotensin II levels was calculated in patients with decompensated systolic heart failure (SHF) and left ventricular ejection fraction ≤40% at 0 hour pre-dose, 3 hours and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril n=42 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril n=41 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Venous Angiotensin II Levels After 12 Weeks of Treatment 0 Hour pre-dose (n=40, 38, 37)	0.91 ratio Interval 0.52 to 1.59	1.08 ratio Interval 0.64 to 1.81	0.66 ratio Interval 0.37 to 1.18
Venous Angiotensin II Levels After 12 Weeks of Treatment 3 hour post-dose (n=40, 38, 38)	0.38 ratio Interval 0.23 to 0.62	0.44 ratio Interval 0.24 to 0.78	0.38 ratio Interval 0.22 to 0.66
Venous Angiotensin II Levels After 12 Weeks of Treatment 24 hour post-dose (n=40, 38, 38)	0.79 ratio Interval 0.44 to 1.41	0.97 ratio Interval 0.59 to 1.6	0.64 ratio Interval 0.34 to 1.24

SECONDARY outcome

Timeframe: Baseline, 12 weeks (84 days, period 2)

Population: Pharmacodynamic (PD) Analysis Set: Subjects with any available PD data and no major protocol deviations with impact on PD data. Only patients with a value at both baseline and post-dose are included.

Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at 12 weeks for PRC was calculated at 0 hour pre-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril n=38 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril n=37 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment	2.48 ratio Interval 1.67 to 3.66	0.96 ratio Interval 0.71 to 1.3	4.67 ratio Interval 2.8 to 7.78

SECONDARY outcome

Timeframe: Baseline,12 weeks (84 days, Period 2)

Population: Pharmacodynamic (PD) Analysis Set: Subjects with any available PD data and no major protocol deviations with impact on PD data. Only patients with a value at both baseline and post-dose are included. In each category "n" indicates patients with observations at that time point.

Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at Week 12 for tPRA was calculated at 0 hour pre-dose, 3 hour and 24 hour post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril n=42 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril n=41 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment 0 hour pre-dose (n=40,38,37)	0.14 ratio Interval 0.08 to 0.24	1.02 ratio Interval 0.68 to 1.52	0.25 ratio Interval 0.15 to 0.41
Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment 3 hour post-dose (n=40,38,38)	0.07 ratio Interval 0.04 to 0.14	1.50 ratio Interval 0.86 to 2.61	0.15 ratio Interval 0.09 to 0.24
Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment 24 hour post-dose (n=40,38,38)	0.12 ratio Interval 0.07 to 0.22	0.90 ratio Interval 0.58 to 1.4	0.16 ratio Interval 0.11 to 0.25

SECONDARY outcome

Timeframe: Baseline, 12 weeks (Day 84 period 2)

Population: Pharmacodynamic (PD) Analysis Set: Subjects with any available PD data and no major protocol deviations with impact on PD data. Only patients with a value at both baseline and post-dose are included.

Peripheral venous blood was collected after 30 minutes of rest in the sitting position for analysis of biomarkers. Geometric Mean Ratio to baseline at Week 12 for BNP was calculated at 0 hours pre-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril n=38 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril n=37 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment	0.96 ratio Interval 0.8 to 1.16	0.84 ratio Interval 0.69 to 1.03	0.78 ratio Interval 0.64 to 0.95

SECONDARY outcome

Timeframe: Baseline,12 weeks (Day 84 period 2)

Population: Pharmacodynamic (PD) Analysis Set: Subjects with any available PD data and no major protocol deviations with impact on PD data. Only patients with a value at both baseline and post-dose are included.

24 hour urine collections were performed. Geometric Mean Ratio to baseline at Week 12 for Urinary aldosterone was calculated 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril n=37 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril n=36 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Biomarker Urinary Aldosterone After 12 Weeks of Treatment	0.83 ratio Interval 0.64 to 1.08	0.96 ratio Interval 0.78 to 1.18	0.87 ratio Interval 0.63 to 1.21

SECONDARY outcome

Timeframe: 12 weeks

Population: All subjects with evaluable PK parameter data and no major protocol deviations with impact on PK data were included in the PK data analysis.

Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration	1.50 Hour Full Range 1.7896 • Interval 0.42 to 7.97	—	—

SECONDARY outcome

Timeframe: 12 weeks

Population: All subjects with evaluable PK parameter data and no major protocol deviations with impact on PK data were included in the PK data analysis.

Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Pharmacokinetic of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration	257.2 ng/mL Standard Deviation 270.23	—	—

SECONDARY outcome

Timeframe: 12 weeks

Population: All subjects with evaluable PK parameter data and no major protocol deviations with impact on PK data were included in the PK data analysis.

Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau(AUCtau)	1707 hr*ng/mL Standard Deviation 1321.9	—	—

SECONDARY outcome

Timeframe: 12 weeks

Population: All subjects with evaluable PK parameter data and no major protocol deviations with impact on PK data were included in the PK data analysis.

Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=40 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)	3041 hr*ng/mL Standard Deviation 1669.1	—	—

SECONDARY outcome

Timeframe: 12 weeks

Population: All subjects with evaluable PK parameter data and no major protocol deviations with impact on PK data were included in the PK data analysis.

Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=19 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)	3502 hr*ng/mL Standard Deviation 1907.5	—	—

SECONDARY outcome

Timeframe: 12 weeks

Population: All subjects with evaluable PK parameter data and no major protocol deviations with impact on PK data were included in the PK data analysis.

Blood samples (2 mL) for the determination of aliskiren concentration in plasma were collected using an indwelling cannula inserted in a forearm vein. Samples were collected at week 12 (day 84): pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose.

Outcome measures

Measure	Aliskiren n=19 Participants In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren Plus Ramipril In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Pharmacokinetic of Aliskiren: The Terminal Elimination Half-life (T½)	31.02 hour Standard Deviation 10.624	—	—

Adverse Events

Ramipril

Serious events: 7 serious events

Other events: 6 other events

Deaths: 0 deaths

Aliskiren

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Ramipril + Aliskiren

Serious events: 3 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ramipril n=42 participants at risk In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren n=40 participants at risk In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril + Aliskiren n=41 participants at risk In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Cardiac disorders Acute myocardial infarction	2.4% 1/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Cardiac disorders Adams-Stokes syndrome	0.00% 0/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	2.4% 1/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Cardiac disorders Bradycardia	0.00% 0/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	2.4% 1/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Cardiac disorders Cardiac failure	9.5% 4/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	5.0% 2/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Cardiac disorders Cardiac failure chronic	2.4% 1/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Cardiac disorders Myocardial infarction	0.00% 0/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	2.4% 1/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Gastrointestinal disorders Abdominal pain	0.00% 0/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	2.5% 1/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
General disorders Sudden death	2.4% 1/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Hepatobiliary disorders Cholecystitis	2.4% 1/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug

Other adverse events

Measure	Ramipril n=42 participants at risk In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received ramipril 10 mg capsule o.d and matching placebo of aliskiren tablet.	Aliskiren n=40 participants at risk In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (Period 2), patients received aliskiren (150 mg once daily) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site and matching placebo of ramipril capsules.	Ramipril + Aliskiren n=41 participants at risk In open label run-in phase (period 1), patients started with ramipril 2.5 mg or 5.0 mg capsule once daily (o.d) depending on previous treatment with RAAS blockers and up-titrated to ramipril 10 mg capsule o.d by end of period 1. In double blind phase (period 2), patients received ramipril (10 mg once daily capsule) and aliskiren (150 mg once daily tablet) up titrated to 300 mg once daily after 1 week of treatment following a clinical safety patient assessment at the study site.
Cardiac disorders Tachycardia	0.00% 0/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	2.5% 1/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	12.2% 5/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Infections and infestations Nasopharyngitis	4.8% 2/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	0.00% 0/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	7.3% 3/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug
Investigations Electrocardiogram QT prolonged	9.5% 4/42 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	5.0% 2/40 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug	2.4% 1/41 Reported adverse events summarized events of the run-in period and double blind period. All serious adverse (SAEs) events were not suspected to be related to study drug

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER