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

ESCAPE-SHF: A Double-blind, Double-dummy, Randomized, Multicenter, Parallel Group Study to Evaluate the Effects of Aliskiren, Ramipril and Combination Treatment on Plasma Concentration of Angiotensin II in Patients With Decompensated Systolic Heart Failure

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00923156

Acronym

ESCAPE-SHF

Enrollment

123

Registered

2009-06-18

Start date

2009-05-31

Completion date

2011-02-28

Last updated

2012-07-26

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

Conditions

Heart Failure

Keywords

Heart failure, Systolic, Aliskiren, Ramipril, Angiotensin II, Ang II, Plasma Renin Activity, PRA, Plasma Renin Concentration, PR,, brain natriuretic peptide, BNP, urinary aldosterone, Escape, Pharmacokinetic, PK

Brief summary

In addition to the blood pressure lowering effects of aliskiren, it may have beneficial effects on blocking the so called RAAS (renin-angiotensin-aldosterone system) at the tissue level. An increase of angiotensin II is associated with progression of heart failure. Although the use of ACE-inhibitors in heart failure shows clinical benefit, an increase in angiotensin II due to an angiotensin II escape phenomenon is not desirable. It is not yet known if a direct renin inhibitor can reduce or even prevent the angiotensin II escape phenomenon associated with the use of an ACE-inhibitor. Therefore the study tested the effects of ramipril, aliskiren and the combination of both on levels of angiotensin II in the blood in patients with systolic heart failure

Interventions

DRUGaliskiren

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

DRUGramipril

2.5 mg , 5.0 mg or 10 mg once daily

DRUGPlacebo to aliskiren

matching placebo to aliskiren in double blind phase

DRUGPlacebo to ramipril

Matching placebo to ramipril capsule in double blind phase

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Decompensated systolic heart failure, left ventricular ejection fraction ≤40% * Brain natriuretic peptide (BNP) level ≥ 100 pg/mL

Exclusion criteria

* Use of Angiotensin Converting Enzyme(ACE) or Angiotensin Receptor Blocker (ARB) inhibitor treatment following the run-in period or requirement of both treatments * Acute heart failure secondary to acute myocardial infarction, acute coronary syndrome or new tachyarrhythmia * Occurrence of unstable angina or myocardial infarction within 12 weeks prior to screening * History of cardiomyopathy such as postpartum, restrictive, infective, hypertrophic obstructive * History of right heart failure due to pulmonary disease * History of untreated second or third degree atrioventricular heart block Other protocol-defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Venous Angiotensin II Levels After 12 Weeks of Treatment	Baseline. 12 Weeks (Day 84, period 2)	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.

Secondary

Measure	Time frame	Description
Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	Baseline,12 weeks (84 days, Period 2)	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.
Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment	Baseline, 12 weeks (Day 84 period 2)	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.
Biomarker Urinary Aldosterone After 12 Weeks of Treatment	Baseline,12 weeks (Day 84 period 2)	24 hour urine collections were performed. Geometric Mean Ratio to baseline at Week 12 for Urinary aldosterone was calculated 24 hours post-dose.
Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration	12 weeks	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.
Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment	Baseline, 12 weeks (84 days, period 2)	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.
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau(AUCtau)	12 weeks	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.
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)	12 weeks	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.
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)	12 weeks	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.
Pharmacokinetic of Aliskiren: The Terminal Elimination Half-life (T½)	12 weeks	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.
Pharmacokinetic of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration	12 weeks	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.

Countries

Germany, Poland, Russia

Participant flow

Pre-assignment details

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.

Participants by arm

Arm	Count
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.	40
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.	42
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.	41
Total	123

Withdrawals & dropouts

Period	Reason	FG001	FG002
Overall Study	Abnormal laboratory values	0	1
Overall Study	Adverse Event	2	1
Overall Study	Death	1	0
Overall Study	Lack of Efficacy	0	1
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Aliskiren	Ramipril	Aliskiren Plus Ramipril	Total
Age Continuous	61.3 years STANDARD_DEVIATION 9	64.3 years STANDARD_DEVIATION 9.91	62.0 years STANDARD_DEVIATION 10.47	62.6 years STANDARD_DEVIATION 9.83
Sex: Female, Male Female	11 Participants	8 Participants	7 Participants	26 Participants
Sex: Female, Male Male	29 Participants	34 Participants	34 Participants	97 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	6 / 42	3 / 40	7 / 41
serious Total, serious adverse events	7 / 42	2 / 40	3 / 41

Outcome results

Primary

Venous Angiotensin II Levels After 12 Weeks of Treatment

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.

Time frame: 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.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Aliskiren	Venous Angiotensin II Levels After 12 Weeks of Treatment	3 hour post-dose (n=40, 38, 38)	0.38 ratio
Aliskiren	Venous Angiotensin II Levels After 12 Weeks of Treatment	0 Hour pre-dose (n=40, 38, 37)	0.91 ratio
Aliskiren	Venous Angiotensin II Levels After 12 Weeks of Treatment	24 hour post-dose (n=40, 38, 38)	0.79 ratio
Ramipril	Venous Angiotensin II Levels After 12 Weeks of Treatment	3 hour post-dose (n=40, 38, 38)	0.44 ratio
Ramipril	Venous Angiotensin II Levels After 12 Weeks of Treatment	0 Hour pre-dose (n=40, 38, 37)	1.08 ratio
Ramipril	Venous Angiotensin II Levels After 12 Weeks of Treatment	24 hour post-dose (n=40, 38, 38)	0.97 ratio
Aliskiren Plus Ramipril	Venous Angiotensin II Levels After 12 Weeks of Treatment	0 Hour pre-dose (n=40, 38, 37)	0.66 ratio
Aliskiren Plus Ramipril	Venous Angiotensin II Levels After 12 Weeks of Treatment	24 hour post-dose (n=40, 38, 38)	0.64 ratio
Aliskiren Plus Ramipril	Venous Angiotensin II Levels After 12 Weeks of Treatment	3 hour post-dose (n=40, 38, 38)	0.38 ratio

Secondary

Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment

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.

Time frame: Baseline, 12 weeks (Day 84 period 2)

Arm	Measure	Value (GEOMETRIC_MEAN)
Aliskiren	Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment	0.96 ratio
Ramipril	Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment	0.84 ratio
Aliskiren Plus Ramipril	Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment	0.78 ratio

Secondary

Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment

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.

Time frame: Baseline, 12 weeks (84 days, period 2)

Arm	Measure	Value (GEOMETRIC_MEAN)
Aliskiren	Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment	2.48 ratio
Ramipril	Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment	0.96 ratio
Aliskiren Plus Ramipril	Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment	4.67 ratio

Secondary

Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment

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.

Time frame: Baseline,12 weeks (84 days, Period 2)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Aliskiren	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	3 hour post-dose (n=40,38,38)	0.07 ratio
Aliskiren	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	0 hour pre-dose (n=40,38,37)	0.14 ratio
Aliskiren	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	24 hour post-dose (n=40,38,38)	0.12 ratio
Ramipril	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	3 hour post-dose (n=40,38,38)	1.50 ratio
Ramipril	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	0 hour pre-dose (n=40,38,37)	1.02 ratio
Ramipril	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	24 hour post-dose (n=40,38,38)	0.90 ratio
Aliskiren Plus Ramipril	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	0 hour pre-dose (n=40,38,37)	0.25 ratio
Aliskiren Plus Ramipril	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	24 hour post-dose (n=40,38,38)	0.16 ratio
Aliskiren Plus Ramipril	Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment	3 hour post-dose (n=40,38,38)	0.15 ratio

Secondary

Biomarker Urinary Aldosterone After 12 Weeks of Treatment

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

Time frame: Baseline,12 weeks (Day 84 period 2)

Arm	Measure	Value (GEOMETRIC_MEAN)
Aliskiren	Biomarker Urinary Aldosterone After 12 Weeks of Treatment	0.83 ratio
Ramipril	Biomarker Urinary Aldosterone After 12 Weeks of Treatment	0.96 ratio
Aliskiren Plus Ramipril	Biomarker Urinary Aldosterone After 12 Weeks of Treatment	0.87 ratio

Secondary

Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)

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.

Time frame: 12 weeks