Efficacy of Candesartan on Symptomatic Heart Failure in Treating Diabetic and Hypertensive Patients. - Full Text View

Sponsor:	Takeda Pharma GmbH
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00775840

Purpose

The purpose of this study is to determine the effects of candesartan, once daily (QD), on the N-terminal pro-B-type Natriuretic Peptide laboratory marker in subjects with symptomatic heart failure with diastolic dysfunction.

Condition	Intervention	Phase
Heart Failure	Drug: Candesartan Drug: Placebo	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Candesartan "Added" Therapy for Treatment Optimization of Symptomatic Heart Failure With Diastolic Dysfunction in Diabetic and Hypertensive Patients A Randomized, Placebo-controlled, Double-blind, Parallel-group and Multicenter Clinical Phase III Study Investigating the Effects on NT-proBNP Over 6 Months

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Heart Failure High Blood Pressure

Drug Information available for: Candesartan Candesartan cilexetil

U.S. FDA Resources

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

The change from Baseline in N-terminal pro-B-type Natriuretic Peptide biomarker. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Mean change in N-terminal pro-B-type Natriuretic Peptide (log-transformed). [ Time Frame: Weeks 6 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Short Form-36 Health Survey score. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Cystatin C. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Adiponectin. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Glycosylated Hemoglobin. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Urinary Albumin Excretion. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in estimated Glomerular Filtration Rate and Cystatin C. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Mean Change in New York Heart Association classification results. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Body Weight. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Blood Pressure. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Echocardiograms. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Correlations of N-terminal pro-B-type Natriuretic Peptide with New York Heart Association Classification Results. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Correlations of N-terminal pro-B-type Natriuretic Peptide with short Form-36 Health Survey Score. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Correlations of N-terminal pro-B-type Natriuretic Peptide with Blood Pressure Results. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Subgroup evaluations regarding beta-blocker therapy and New York Heart Association class (II/III). [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Subgroup evaluations in terms of the different possible dosages of study medication. [ Time Frame: Weeks 6 to 24 or Final Visit. ] [ Designated as safety issue: No ]
Subgroup evaluations based on different baseline levels of estimated Glomerular Filtration Rate. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Subgroup evaluations based on different baseline levels of Cystatin C. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Subgroup evaluations based on different baseline levels of N-terminal pro-B-type Natriuretic Peptide. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Comparison from Baseline on the concomitant use of Loop Diuretics. [ Time Frame: Weeks 6 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Transition from sinus rhythm to permanent atrial fibrillation based on electrocardiogram recordings. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Progression of preserved (Left Ventricular Ejection Fraction greater than or equal to 45%) to impaired systolic dysfunction (Left Ventricular Ejection Fraction less than 45%), based on echocardiographic results. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]

Enrollment:	22
Study Start Date:	January 2008
Study Completion Date:	December 2008
Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Candesartan QD + Heart Failure Therapy (with angiotensin-converting enzyme-inhibitors/beta-blockers)	Drug: Candesartan Candesartan up to 32 mg, tablets, orally, once daily and ongoing angiotensin-converting enzyme inhibitor/beta-blocker therapy for up to 24 weeks. Other Name: BLOPRESS®
Placebo Comparator: Placebo QD + Heart Failure Therapy (with angiotensin-converting enzyme-inhibitors/beta-blockers)	Drug: Placebo Candesartan matching-placebo tablets, orally, once daily and ongoing angiotensin-converting enzyme inhibitor/beta-blocker therapy for up to 24 weeks.

Detailed Description:

Heart diseases are the number one cause of death in developed countries and in particular chronic or congestive heart failure is the leading cause of hospitalization in patients older than 65 years. It is still increasing in prevalence and, in spite of significant advances in therapy, mortality rates remain high: 30% to 40% of patients with advanced disease, and 5% to 10% of patients with mild symptoms will die within 5 to 10 years.

A relevant proportion of the heart failure patients (30 - 50%) suffering from edema and dyspnea have normal or minimally impaired left ventricular ejection fraction (preserved left ventricular ejection fraction) with diastolic abnormalities in echocardiography. Features of diastolic dysfunction are the stiffness, the decreased compliance and the impaired relaxation of the left ventricle. As a result, the left ventricle has a limited filling capacity during a normal left atrial pressure.

Hypertension and/or diabetes are the most predisposing conditions whereas left ventricular hypertrophy is regarded as the linking intermediate pathological condition. Moreover, recent studies showed that patients with symptomatic heart failure and an ejection fraction greater than 40% have a poor prognosis with relatively high mortality and hospitalization rates. Thus, in hypertensive patients, diastolic dysfunction has shown to be a predictor of morbidity.

Diastolic dysfunction is also a frequent finding in type 2 diabetes without symptoms and signs of heart disease. As long as it is independent of ischemic heart disease, it is presumably due to diabetic cardiomyopathy. Once aggravated to heart failure, diastolic dysfunction often coexists with systolic dysfunction as a consequence of coronary artery disease with a limited coronary reserve.

This study will determine whether pharmacological intervention into the Renin Angiotensin Aldosterone System exerted by the Angiotensin-Receptor Blocker Candesartan on top of an Angiotensin-Converting Enzyme Inhibitor-based therapy may lead to a significant drop of N-terminal pro-B-type Natriuretic Peptide. This neurohormonal laboratory marker is sufficient enough to simultaneously indicate the improvement of the causing diastolic dysfunction and associated heart failure symptoms as assessed by objective echocardiographic and clinical parameters.

Total time for participants in this study is approximately 26 weeks.

Eligibility

Ages Eligible for Study:	45 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diabetes mellitus type 2 - insulin dependent or orally treated or managed by diet for at least 3 Months.
Normotension or controlled hypertension with sitting Systolic Blood Pressure less than 140 mmHg and/or sitting Diastolic Blood Pressure less than 90 mmHg.
Regular sinus rhythm or atrial fibrillation with a medicamental-achieved rate control of less than 100 bpm as confirmed by electrocardiogram recordings.
Echocardiographic evidence of a preserved Left Ventricular Ejection Fraction greater than or equal to 45% (assessed by the modified Simpson method), with further doppler-echocardiographic criteria for diastolic dysfunction grade I-IV.
New York Heart Association classification of II or III in a stable condition since at least 3 months.
Existing background heart failure therapy with an Angiotensin-Converting Enzyme Inhibitor alone or together with further preparations in a constant regimen since at least 1 month, in case of beta-blockers since at least 3 months.
N-terminal pro-B-type Natriuretic Peptide greater than or equal to 250 pg/ml measured at screening visit or collected from a dated previous laboratory document not older than 3 months.
No previous therapy with Angiotensin-Receptor Blockers during the last 4 weeks prior to the study.
Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria:

Impaired renal function (serum creatinine greater than 2.2 mg/dl or greater than 194 μmol/l).
Known bilateral renal artery stenosis or interventional treatment for renal artery stenosis in the last year.
State after kidney transplantation.
Serum potassium greater than 5.5 mmol/l or glycosylated hemoglobin greater than 9.5 %.
Cor pulmonale or primary pulmonary disease with dyspnea at rest.
Known disposition to episodes of symptomatic hypotension or sitting Systolic Blood Pressure less than 95 mmHg at baseline.
Acute coronary syndrome or any form of unstable chronic Coronary Artery Disease where the indication of a coronary intervention is either planned in short or medium term or can not be clearly excluded for the period of the study.
Any history of: myocardial infarction, previous Percutaneous Transluminal Coronary Angioplasty with revascularization, stent implantation, Coronary Artery Bypass Graft or open heart surgery.
Tachycardia at rest greater than 100 bpm as confirmed by electrocardiogram recordings.
Known clinically relevant rhythm disorders (e.g., tachyarrhythmias, salves of supraventricular or ventricular extrasystoles or atrial fibrillation without ventricular rate control) or symptoms suggesting a significant rhythm disorder (e.g., recurrent syncopes).
Primary valvular diseases and/or restrictive or obstructive cardiomyopathy.
Existing ventricular assist devices.
Relevant liver diseases (cholestasis or alanine aminotransferase/aspartate aminotransferase greater than 2 times the upper limit of normal or gamma- glutamyltransferase greater than 3 times the upper limit of normal).
History of primary hyperaldosteronism, of cancer in the last 5 years or of another wasting disease with life expectancy of less than 2 years.
Known hypersensitivity to Candesartan Cilexetil.
Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
- Need for maintenance therapy with Non-steroidal anti-inflammatory drugs or Cox-2-inhibitors.
- Use of other Angiotensin-Receptor Blockers.
Any history of life-threatening diseases.
History of drug addiction and/or an extensive use of alcohol.
Acute coronary syndrome or unstable angina pectoris and any coronary artery disease that was not stable during the last 3 months prior to inclusion.
Patients who are dependent on a permanently paced pacemaker (i.e. a patient with a device that is not pacing during the echocardiographic examination can enter the study).
Open heart surgery for other reasons than coronary revascularization
Participation in another clinical investigation within 30 days prior to enrolment or for the course of the present study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00775840

Locations

Germany

Bad Friedrichshall, Baden-Württemberg, Germany

Heidelberg, Baden-Württemberg, Germany

Ludwigsburg, Baden-Württemberg, Germany

Bad Homburg, Hessen, Germany

Bad Nauheim, Hessen, Germany

Darmstadt, Hessen, Germany

Frankfurt, Hessen, Germany

Giessen, Hessen, Germany

Kassel, Hessen, Germany

Limburg, Hessen, Germany

Melsungen, Hessen, Germany

Mühlheim, Hessen, Germany

Wiesbaden, Hessen, Germany

Nienburg, Niedersachsen, Germany

Northeim, Niedersachsen, Germany

Weyhe, Niedersachsen, Germany

Essen, Nordrhein-Westfalen, Germany

Gelsenkirchen, Nordrhein-Westfalen, Germany

Gladbeck, Nordrhein-Westfalen, Germany

Langenfeld, Nordrhein-Westfalen, Germany

Paderborn, Nordrhein-Westfalen, Germany

Siegen, Nordrhein-Westfalen, Germany

Bad Kreuznach, Rheinland-Pfalz, Germany

Neukirchen, Saarland, Germany

Coswig, Sachsen-Anhalt, Germany

Dresden, Sachsen, Germany

Hartmannsdorf, Sachsen, Germany

Leipzig, Sachsen, Germany

Leisnig, Sachsen, Germany

Machem, Sachsen, Germany

Markkleeberg, Sachsen, Germany

Riesa, Sachsen, Germany

Wermsdorf, Sachsen, Germany

Erfurt, Thüringen, Germany

Jena, Thüringen, Germany

Nordhausen, Thüringen, Germany

Berlin, Germany

Sponsors and Collaborators

Takeda Pharma GmbH

Investigators

Study Director:

Medical Director

Takeda Pharma GmbH

More Information

No publications provided

Responsible Party:	Medical Director, Takeda Pharma Gmbh, Aachen (Germany)
ClinicalTrials.gov Identifier:	NCT00775840 History of Changes
Other Study ID Numbers:	BLO K026, 2007-003070-26, D-CAN-546, U1111-1113-9515
Study First Received:	October 16, 2008
Last Updated:	June 17, 2010
Health Authority:	European Union: European Medicines Agency

Keywords provided by Takeda Global Research & Development Center, Inc.:

Cardiac Failure
Congestive Heart Failure
Drug Therapy
Hypertension
Diabetes Mellitus

Additional relevant MeSH terms:

Heart Failure
Heart Diseases
Cardiovascular Diseases
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
Candesartan
Candesartan cilexetil
Protease Inhibitors

Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on May 23, 2012