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Effects of Aliskiren, Ramipril, and the Combination on Levels of Angiotensin II in Patients With Decompensated Systolic Heart Failure (ESCAPE-SHF)

Primary Purpose

Heart Failure

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
aliskiren
ramipril
Placebo to aliskiren
Placebo to ramipril
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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/exclusion criteria applied

Sites / Locations

  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigator Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Aliskiren

Ramipril

Aliskiren plus Ramipril

Arm Description

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.

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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration
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
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 End of the Dosing Interval Tau(AUCtau)
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)
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)
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)
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.

Full Information

First Posted
June 17, 2009
Last Updated
July 19, 2012
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00923156
Brief Title
Effects of Aliskiren, Ramipril, and the Combination on Levels of Angiotensin II in Patients With Decompensated Systolic Heart Failure
Acronym
ESCAPE-SHF
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2012
Overall Recruitment Status
Completed
Study Start Date
May 2009 (undefined)
Primary Completion Date
February 2011 (Actual)
Study Completion Date
February 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
123 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Aliskiren
Arm Type
Experimental
Arm Description
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.
Arm Title
Ramipril
Arm Type
Experimental
Arm Description
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.
Arm Title
Aliskiren plus Ramipril
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
aliskiren
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
ramipril
Intervention Description
2.5 mg , 5.0 mg or 10 mg once daily
Intervention Type
Drug
Intervention Name(s)
Placebo to aliskiren
Intervention Description
matching placebo to aliskiren in double blind phase
Intervention Type
Drug
Intervention Name(s)
Placebo to ramipril
Intervention Description
Matching placebo to ramipril capsule in double blind phase
Primary Outcome Measure Information:
Title
Venous Angiotensin II Levels After 12 Weeks of Treatment
Description
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)
Secondary Outcome Measure Information:
Title
Biomarker Plasma Renin Concentration (PRC)After 12 Weeks of Treatment
Description
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)
Title
Biomarker Trapping Plasma Renin Activity (tPRA) After 12 Weeks of Treatment
Description
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)
Title
Biomarker B-type Natriuretic Peptide (BNP) After 12 Weeks of Treatment
Description
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)
Title
Biomarker Urinary Aldosterone After 12 Weeks of Treatment
Description
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)
Title
Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration
Description
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
Title
Pharmacokinetic of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration
Description
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
Title
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau(AUCtau)
Description
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
Title
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)
Description
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
Title
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)
Description
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
Title
Pharmacokinetic of Aliskiren: The Terminal Elimination Half-life (T½)
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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/exclusion criteria applied
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigator Site
City
Bad Krozingen
ZIP/Postal Code
79189
Country
Germany
Facility Name
Novartis Investigator Site
City
Berlin
ZIP/Postal Code
12207
Country
Germany
Facility Name
Novartis Investigator Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigator Site
City
Göttingen
ZIP/Postal Code
37057
Country
Germany
Facility Name
Novartis Investigator Site
City
Jena
ZIP/Postal Code
07747
Country
Germany
Facility Name
Novartis Investigator Site
City
München
ZIP/Postal Code
80336
Country
Germany
Facility Name
Novartis Investigator Site
City
Krakow
ZIP/Postal Code
31-501
Country
Poland
Facility Name
Novartis Investigator Site
City
Lublin
ZIP/Postal Code
20-090
Country
Poland
Facility Name
Novartis Investigator Site
City
Poznan
ZIP/Postal Code
61-848
Country
Poland
Facility Name
Novartis Investigator Site
City
Warszawa
ZIP/Postal Code
02-507
Country
Poland
Facility Name
Novartis Investigator Site
City
Wroclaw
ZIP/Postal Code
50-981
Country
Poland
Facility Name
Novartis Investigator Site
City
Moscow
ZIP/Postal Code
117292
Country
Russian Federation
Facility Name
Novartis Investigator Site
City
Moscow
ZIP/Postal Code
119620
Country
Russian Federation
Facility Name
Novartis Investigator Site
City
Moscow
ZIP/Postal Code
121309
Country
Russian Federation
Facility Name
Novartis Investigator Site
City
Moscow
ZIP/Postal Code
121552
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
Country
Russian Federation

12. IPD Sharing Statement

Citations:
PubMed Identifier
33089502
Citation
Wang GM, Li LJ, Tang WL, Wright JM. Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Cochrane Database Syst Rev. 2020 Oct 22;10(10):CD012569. doi: 10.1002/14651858.CD012569.pub2.
Results Reference
derived

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

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