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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00923156
First received: June 17, 2009
Last updated: July 19, 2012
Last verified: July 2012
  Purpose

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


Condition Intervention Phase
Heart Failure
Drug: aliskiren
Drug: ramipril
Drug: Placebo to aliskiren
Drug: Placebo to ramipril
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Venous Angiotensin II Levels After 12 Weeks of Treatment [ Time Frame: Baseline. 12 Weeks (Day 84, period 2) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, 12 weeks (84 days, period 2) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline,12 weeks (84 days, Period 2) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, 12 weeks (Day 84 period 2) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline,12 weeks (Day 84 period 2) ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 123
Study Start Date: May 2009
Study Completion Date: February 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: aliskiren
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
Drug: ramipril
2.5 mg , 5.0 mg or 10 mg once daily
Drug: Placebo to ramipril
Matching placebo to ramipril capsule in double blind phase
Experimental: 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.

Drug: ramipril
2.5 mg , 5.0 mg or 10 mg once daily
Drug: Placebo to aliskiren
matching placebo to aliskiren in double blind phase
Experimental: 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

Drug: aliskiren
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
Drug: ramipril
2.5 mg , 5.0 mg or 10 mg once daily

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00923156

Locations
Germany
Novartis Investigator Site
Bad Krozingen, Germany, 79189
Novartis Investigator Site
Berlin, Germany, 12207
Novartis Investigator Site
Berlin, Germany, 13353
Novartis Investigator Site
Göttingen, Germany, 37057
Novartis Investigator Site
Jena, Germany, 07747
Novartis Investigator Site
München, Germany, 80336
Poland
Novartis Investigator Site
Krakow, Poland, 31-501
Novartis Investigator Site
Lublin, Poland, 20-090
Novartis Investigator Site
Poznan, Poland, 61-848
Novartis Investigator Site
Warszawa, Poland, 02-507
Novartis Investigator Site
Wroclaw, Poland, 50-981
Russian Federation
Novartis Investigator Site
Moscow, Russian Federation, 117292
Novartis Investigator Site
Moscow, Russian Federation, 121309
Novartis Investigative Site
Moscow, Russian Federation
Novartis Investigator Site
Moscow, Russian Federation, 121552
Novartis Investigator Site
Moscow, Russian Federation, 119620
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00923156     History of Changes
Other Study ID Numbers: CSPP100A2252, EudraCT 2008-001035-35
Study First Received: June 17, 2009
Results First Received: February 1, 2012
Last Updated: July 19, 2012
Health Authority: Russia: Ministry of Health of the Russian Federation
Poland: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Novartis:
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

Additional relevant MeSH terms:
Heart Failure
Heart Failure, Systolic
Heart Diseases
Cardiovascular Diseases
Angiotensin II
Natriuretic Peptide, Brain
Ramipril
Vasoconstrictor Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Natriuretic Agents
Physiological Effects of Drugs
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents

ClinicalTrials.gov processed this record on July 22, 2014