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

Heart Failure Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00923156
• Other study ID #: CSPP100A2252
• Secondary ID: EudraCT 2008-001
• Status: Completed
• Phase: Phase 2
• First received: June 17, 2009
• Last updated: July 19, 2012
• Start date: May 2009
• Est. completion date: February 2011

Study information

• Verified date: July 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Russia: Ministry of Health of the Russian FederationPoland: Ministry of HealthGermany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 123
• Est. completion date: February 2011
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Systolic

Intervention

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
• ramipril
2.5 mg , 5.0 mg or 10 mg once daily
• Placebo to aliskiren
matching placebo to aliskiren in double blind phase
• Placebo to ramipril
Matching placebo to ramipril capsule in double blind phase

Locations

Country	Name	City	State
Germany	Novartis Investigator Site	Bad Krozingen
Germany	Novartis Investigator Site	Berlin
Germany	Novartis Investigator Site	Berlin
Germany	Novartis Investigator Site	Göttingen
Germany	Novartis Investigator Site	Jena
Germany	Novartis Investigator Site	München
Poland	Novartis Investigator Site	Krakow
Poland	Novartis Investigator Site	Lublin
Poland	Novartis Investigator Site	Poznan
Poland	Novartis Investigator Site	Warszawa
Poland	Novartis Investigator Site	Wroclaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigator Site	Moscow
Russian Federation	Novartis Investigator Site	Moscow
Russian Federation	Novartis Investigator Site	Moscow
Russian Federation	Novartis Investigator Site	Moscow

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Germany,  Poland,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline. 12 Weeks (Day 84, period 2)	No
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.	Baseline, 12 weeks (84 days, period 2)	No
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.	Baseline,12 weeks (84 days, Period 2)	No
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.	Baseline, 12 weeks (Day 84 period 2)	No
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.	Baseline,12 weeks (Day 84 period 2)	No
Secondary	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.	12 weeks	No
Secondary	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.	12 weeks	No
Secondary	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.	12 weeks	No
Secondary	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.	12 weeks	No
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.	12 weeks	No
Secondary	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.	12 weeks	No