Efficacy of Candesartan on Symptomatic Heart Failure in Treating Diabetic and Hypertensive Patients.

Condition(s) targeted: Heart Failure

Intervention: Candesartan and heart failure therapy with angiotensin-converting enzyme-inhibitors/beta-blockers. (Drug); Heart failure therapy with angiotensin-converting enzyme-inhibitors/beta-blockers. (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Takeda Pharma GmbH

Official(s) and/or principal investigator(s):
Medical Director, Study Director, Affiliation: Takeda Pharma GmbH

Overall contact:
Medical Adviser Clinial Research, Phone: +49 800 8253325

The purpose of this study is to determine the effects of Candesartan on the N-terminal pro-B-type Natriuretic Peptide laboratory marker in subjects with symptomatic heart failure with diastolic dysfunction.

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

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Primary outcome: The change from Baseline in N-terminal pro-B-type Natriuretic Peptide biomarker.

Secondary outcome:

Mean change in N-terminal pro-B-type Natriuretic Peptide (log-transformed).

The change from Baseline in Short Form-36 Health Survey score, Adiponectin, Cystatin C, glycosylated hemoglobin, Urinary Albumin Excretion and kidney function (based on estimated Glomerular Filtration Rate and Cystatin C).

Mean change for New York Heart Association, body weight, blood pressure and echocardiographic results.

Correlations of N-terminal pro-B-type Natriuretic Peptide with New York Heart Association class, short Form-36 Health Survey score and blood pressure results.

Subgroup evaluations regarding beta-blocker therapy and New York Heart Association class (II/III).

Subgroup evaluations in terms of the different possible dosages of study medication.

Subgroup evaluations based on different baseline levels of estimated Glomerular Filtration Rate, Cystatin C and N-terminal pro-B-type Natriuretic Peptide.

Comparison from Baseline on the concomitant use of loop diuretics.

Transition from sinus rhythm to permanent atrial fibrillation based on electrocardiogram recordings.

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.

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.

In order to show that heart failure therapy with Candesartan may have a comparable effect in heart failure patients with diastolic dysfunction as already seen in patients with heart failure and depressed left ventricular systolic function, this study will be carried out as a randomized, placebo-controlled, double-blind, parallel-group, multicenter and confirmatory trial of clinical phase III with a placebo group using a study collective standardized for background heart failure treatment. 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.

Minimum age: 45 Years. Maximum age: N/A. Gender(s): Both.

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.

Medical Adviser Clinial Research, Phone: +49 800 8253325

Berlin, Germany; Recruiting

Bad Friedrichshall, Baden-Württemberg, Germany; Recruiting

Heidelberg, Baden-Württemberg, Germany; Recruiting

Ludwigsburg, Baden-Württemberg, Germany; Recruiting

Kassel, Hessen, Germany; Recruiting

Mühlheim, Hessen, Germany; Recruiting

Darmstadt, Hessen, Germany; Recruiting

Melsungen, Hessen, Germany; Recruiting

Frankfurt, Hessen, Germany; Recruiting

Bad Homburg, Hessen, Germany; Recruiting

Limburg, Hessen, Germany; Recruiting

Bad Nauheim, Hessen, Germany; Recruiting

Giessen, Hessen, Germany; Recruiting

Wiesbaden, Hessen, Germany; Recruiting

Northeim, Niedersachsen, Germany; Recruiting

Nienburg, Niedersachsen, Germany; Recruiting

Weyhe, Niedersachsen, Germany; Recruiting

Langenfeld, Nordrhein-Westfalen, Germany; Recruiting

Gladbeck, Nordrhein-Westfalen, Germany; Recruiting

Essen, Nordrhein-Westfalen, Germany; Recruiting

Siegen, Nordrhein-Westfalen, Germany; Recruiting

Gelsenkirchen, Nordrhein-Westfalen, Germany; Recruiting

Paderborn, Nordrhein-Westfalen, Germany; Recruiting

Bad Kreuznach, Rheinland-Pfalz, Germany; Recruiting

Neukirchen, Saarland, Germany; Recruiting

Wermsdorf, Sachsen, Germany; Recruiting

Leisnig, Sachsen, Germany; Recruiting

Leipzig, Sachsen, Germany; Recruiting

Dresden, Sachsen, Germany; Recruiting

Hartmannsdorf, Sachsen, Germany; Recruiting

Machem, Sachsen, Germany; Recruiting

Riesa, Sachsen, Germany; Recruiting

Markkleeberg, Sachsen, Germany; Recruiting

Coswig, Sachsen-Anhalt, Germany; Recruiting

Erfurt, Thüringen, Germany; Recruiting

Nordhausen, Thüringen, Germany; Recruiting

Jena, Thüringen, Germany; Recruiting

Starting date: January 2008
Ending date: December 2008
Last updated: October 16, 2008