Safety and Efficacy Study of Once and Twice Daily Doses of MCC-135 in Subjects With Congestive Heart Failure.

Study Overview
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Brief Summary
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The purpose of this study is to determine the effect of two different doses of MCC-135, once daily (QD) or twice daily (BID), on the disease state and the quality of life in subjects with congestive heart failure.

Detailed Description
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In recent years the usefulness of angiotensin converting enzyme inhibitors and vasodilators as well as beta-blockers has been realized in the treatment of heart failure. Multi-center studies clinical trials have shown some benefit of angiotensin converting enzyme inhibitors on the morbidity and mortality of heart failure subjects, and physicians are also prescribing angiotensin converting enzyme inhibitors for the initial treatment of subjects with left ventricular dysfunction. Some subjects do not respond to angiotensin converting enzyme inhibitors and intolerance to these compounds has also been observed. Despite the significant reduction in mortality observed in limited controlled studies, the 5-year mortality of subjects with congestive heart failure continues to be high, indicating that there is a significant therapeutic gap in the treatment of this disease. MCC-135 is being studied to assess its usefulness as a supplement or replacement to current treatment and to provide subjects with specific and predictable therapy that will reverse the remodeling of the diseased heart and markedly improve the subject's survival. The current study is an exploratory clinical trial to determine the efficacy of two doses and two dose regimens of MCC-135 when compared to placebo by evaluating improvement in the subject's plasma b-type (brain) natriuretic peptide levels, regular rate (heart rate) variability and clinical signs and symptoms.

Official Title
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A Phase II, Double-Blind, Randomized, Exploratory, Placebo-Controlled Study of Efficacy, Safety, and Tolerability of MCC-135 Comparing QD vs BID Doses in Subjects With Congestive Heart Failure, NYHA Class II/III

Conditions
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Congestive Heart Failure

Intervention / Treatment
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* Drug: MCC-135
* Drug: MCC-135
* Drug: MCC-135
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion: 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. Having a clinical diagnosis consistent with congestive heart failure, of at least 6 months duration and clinically stable for the last month. Has a left ventricular ejection fraction less than or equal to 40%. Has Plasma b-type (brain) natriuretic peptide levels greater than or equal to 200 pg/ml at screening. Meeting the following requirements for current concomitant medication: Must be using an angiotensin converting enzyme inhibitor or Angiotensin II receptor antagonists therapy for at least 1 month prior to the screening visit. If using beta-blockers, must have commenced treatment at least 4 months prior to the screening visit. All other cardiac medications must have been introduced at least one month prior to the screening visit. Exclusion: Heart failure primarily due to: Obstructive valvular disease Malfunctioning artificial heart valve Congenital heart disease Pericardial disease Uncontrolled thyroid disease Amyloidosis Severe pulmonary disease Restrictive or obstructive cardiomyopathy Known active myocarditis Terminal heart failure or on waiting list for transplant. Atrio-ventricular block except for first-degree atrio-ventricular block. A history of or currently sustained ventricular tachycardia. Subjects with atrial fibrillation and/or requiring pacemakers (including bi-ventricular pacing). Presence of pulmonary embolism. Acute myocardial infarction, unstable angina, coronary revascularization or major surgery during the last 6 weeks prior to screening. Episode of syncope or cardiac arrest during the last 6 weeks prior to screening. Requiring treatment with the following therapies: Anti-arrhythmics (Amiodarone/beta-blockers are permitted) Calcium sensitizers Catecholamines Phosphodiesterase inhibitors Is currently participating in another investigational study or who have participated in an investigational study (including MCC-135) during the 2 months prior to the screening visit Has a history of drug or alcohol abuse, as defined by Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria, within the past two years. Has significant, moderate-severe renal dysfunction or disease, confirmed by serum creatinine of greater than 2mg/dl (180 micromol/L). Serum potassium levels at entry confirmed below 3.5mmol/L. Known severe symptomatic primary pulmonary disease in the last 5 years e.g. asthma, chronic obstructive pulmonary disease. Concurrent severe disease (including significant hepatic, metabolic or other systemic disease) or any medical condition that, in the opinion of the investigator, would compromise the subject's safety or their successful participation in the study. History of multiple drug allergies or with a known allergy to the study drug or any medicine chemically related to the study drug. Individuals who are morbidly obese. 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: Anti-arrhythmics (Amiodarone/beta-blockers are permitted) Calcium sensitizers Catecholamines Phosphodiesterase inhibitors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MCC-135 50 mg BID<br> | Drug: MCC-135<br>* MCC-135 50 mg, tablets, orally, twice daily for up to 12 weeks<br>|
| Experimental: MCC-135 100 mg QD<br> | Drug: MCC-135<br>* MCC-135 100 mg, tablets, orally, once daily for up to 12 weeks<br>|
| Experimental: MCC-135 200 mg QD<br> | Drug: MCC-135<br>* MCC-135 200 mg, tablets, orally, once daily for up to 12 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* MCC-135 placebo-matching tablets, orally, once daily for up to 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the serum levels of brain natriuretic peptide |  | At Final Visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Minnesota living with heart failure questionnaire score |  | At Final Visit. | 
| Regular rate (heart rate) variability as measured by 24-hour Holter monitoring |  | At Final Visit. | 
| Disease progression status measured by New York Heart Association class |  | At Final Visit. | 
| Disease progression status measured by Global Clinical Status |  | At Final Visit. | 
| Disease progression status measured by Clinical Composite |  | At Final Visit. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congestive Heart Failure, Cardiac Failure, Heart Decompensation, Drug Therapy