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

NCT00923156 | Completed Phase 2 Results

• 2 other identifiers: CSPP100A2252EudraCT 2008-001035-35
• Study Type: interventional
• Target: 123
• Locations: 3 countries
• Sites: 16

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

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

Outcome Measures

Primary Outcomes (1)

• 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)

Secondary Outcomes (10)

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

  Baseline, 12 weeks (84 days, period 2)

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

  Baseline,12 weeks (84 days, Period 2)

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

  Baseline, 12 weeks (Day 84 period 2)

• Biomarker Urinary Aldosterone After 12 Weeks of Treatment

  Baseline,12 weeks (Day 84 period 2)

• Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration

  12 weeks

Study Arms (3)

Aliskiren

EXPERIMENTAL

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; Drug: ramipril; Drug: Placebo to ramipril

Ramipril

EXPERIMENTAL

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; Drug: Placebo to aliskiren

Aliskiren plus Ramipril

EXPERIMENTAL

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; Drug: ramipril

Interventions

aliskiren DRUG

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

Aliskiren; Aliskiren plus Ramipril

ramipril DRUG

2.5 mg , 5.0 mg or 10 mg once daily

Aliskiren; Aliskiren plus Ramipril; Ramipril

Placebo to aliskiren DRUG

matching placebo to aliskiren in double blind phase

Ramipril

Placebo to ramipril DRUG

Matching placebo to ramipril capsule in double blind phase

Aliskiren

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (16)

Novartis Investigator Site

Bad Krozingen, 79189, Germany

Location

Novartis Investigator Site

Berlin, 12207, Germany

Location

Novartis Investigator Site

Berlin, 13353, Germany

Location

Novartis Investigator Site

Göttingen, 37057, Germany

Location

Novartis Investigator Site

Jena, 07747, Germany

Location

Novartis Investigator Site

München, 80336, Germany

Location

Novartis Investigator Site

Krakow, 31-501, Poland

Location

Novartis Investigator Site

Lublin, 20-090, Poland

Location

Novartis Investigator Site

Poznan, 61-848, Poland

Location

Novartis Investigator Site

Warsaw, 02-507, Poland

Location

Novartis Investigator Site

Wroclaw, 50-981, Poland

Location

Novartis Investigator Site

Moscow, 117292, Russia

Location

Novartis Investigator Site

Moscow, 119620, Russia

Location

Novartis Investigator Site

Moscow, 121309, Russia

Location

Novartis Investigator Site

Moscow, 121552, Russia

Location

Novartis Investigative Site

Moscow, Russia

Location

Related Publications (1)

• 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.

  PMID: 33089502 DERIVED

MeSH Terms

Conditions

Heart Failure; Systolic Murmurs

Interventions

aliskiren; Ramipril

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Heart Murmurs; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: May 1, 2009
• Primary Completion: February 1, 2011
• Study Completion: February 1, 2011
• Last Updated: July 26, 2012
• Results First Posted: March 5, 2012

Record last verified: 2012-07

Locations

DE (6); RU (5); PL (5)