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:
Novartis Pharmaceuticals
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
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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
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 June 17, 2013