Pilot Study of COR-1 in Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of COR-1 in combination with standard therapy in patients with heart failure. The safety and tolerability of COR-1 will also be assessed.

Detailed Description
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In patients with dilated cardiomyopathy (heart is weakened and enlarged), the presence of anti-beta1-receptor autoantibodies has been shown to predict more depressed left ventricular function, increased prevalence of serious ventricular arrhythmias, sudden cardiac death, and cardiovascular mortality. In animal models, COR-1 cyclopeptide has been shown to bind to, and therefore decrease, the anti-beta1-receptor autoantibody titre. This study will investigate the safety and effectiveness of COR-1 treatment in patients with dilated cardiomyopathy. This study will be a randomized (the study treatment is assigned by chance), double-blind, (neither investigator nor patient knows the treatment that the volunteer receives), multicenter (study is conducted in more than one center) placebo-controlled (one of the treatments is inactive), parallel group study (patients in different treatment groups receive medication at the same time) in men and women who have heart failure due to dilated cardiomyopathy. Eligible patients should also have a left ventricular ejection fraction of less than or equal to 45% (measurement of the percentage of blood leaving the heart each time it contracts) and should be positive for anti-beta1-receptor autoantibodies. The study will consist of 3 phases: a screening phase, a double-blind treatment period, and a follow-up phase. Patients will be randomly assigned to 1 of 4 treatment groups: 20 mg COR-1, 80 mg COR-1, 160 mg COR-1, or placebo (inactive medication). Each patient will receive 1 intravenous dose (medication is injected into a vein) every 4 weeks for a total of 6 months. Patients will come to the study center each time they receive study medication and will remain at the center for 2 to 3 hours following the injection. Blood samples will be drawn at time points during the screening, treatment, and follow-up periods. Patients will return to the study center for follow-up visits at 3 months following completion of the 6-month treatment period. Patients will participate in the study for approximately 9 months. Patient safety will be monitored. The study drug (COR-1) is being investigated for the treatment of heart failure.

Official Title
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COR-1, an Anti-Beta1 Receptor Antibody Cyclopeptide in Heart Failure: a Phase II, Multicentre, Randomised, Double-Blind and Placebo-Controlled Study With Parallel Groups

Conditions
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Cardiomyopathy, Dilated

Intervention / Treatment
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* Drug: 0.9 % sodium chloride
* Drug: COR-1
* Drug: Standard therapy for heart failure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed heart failure due to dilated cardiomyopathy with left ventricular ejection fraction < 45% Presence of anti-beta1-receptor autoantibodies New York Heart Association (NYHA) class II to III heart failure Symptomatic heart failure for >1 year and < 8 years Treatment with adequate doses of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta-blockers, and optional aldosterone antagonists according to guidelines for at least six months (with the exception of lack of tolerability of any of these drugs) and at stable doses for 2 months prior to screening Exclusion Criteria: Ischemic heart disease characterized by >= 50% coronary artery stenosis and/or history of myocardial infarction Third or higher degree valvular defect Any disease requiring immunosuppressive drugs (except for <= 5 mg/day prednisone-equivalent dose) or any clinically relevant disorder of the immune system History of severe allergies and increased risk for anaphylactic shock (e.g., bronchial asthma) History of, or currently active illness, considered to be clinically significant by the Investigator or any other illness that the Investigator considers should exclude the patient from the study or that could interfere with the interpretation of the study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: 0.9 % sodium chloride<br>* Monthly intravenous injection for 6 months<br>Drug: Standard therapy for heart failure<br>* All patients will continue to receive standard therapy for heart failure (ie, in accordance with guidelines) throughout the study.<br>|
| Experimental: 20 mg COR-1<br> | Drug: COR-1<br>* Monthly intravenous injection for 6 months<br>Drug: Standard therapy for heart failure<br>* All patients will continue to receive standard therapy for heart failure (ie, in accordance with guidelines) throughout the study.<br>|
| Experimental: 80 mg COR-1<br> | Drug: COR-1<br>* Monthly intravenous injection for 6 months<br>Drug: Standard therapy for heart failure<br>* All patients will continue to receive standard therapy for heart failure (ie, in accordance with guidelines) throughout the study.<br>|
| Experimental: 160 mg COR-1<br> | Drug: COR-1<br>* Monthly intravenous injection for 6 months<br>Drug: Standard therapy for heart failure<br>* All patients will continue to receive standard therapy for heart failure (ie, in accordance with guidelines) throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Month 6 | The LVEF is a fraction of blood (in percent) pumped out of the left ventricle of the heart (the main pumping chamber). Ejection fraction percentages greater than (>) 55% are considered normal. It was measured by biplane echocardiography (central assessment). | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Local Left Ventricular Ejection Fraction (LVEF) at Month 9 | The LVEF is a measure of how much blood is pumped out of the left ventricle of the heart (the main pumping chamber). Ejection fraction percentages greater than (>) 55% are considered normal. It was measured by biplane echocardiography (local assessment). | Baseline and Month 9 | 
| Change From Baseline in N-Terminal Pro B-Type Natriuretic Peptide (NT-ProBNP) Level at Month 6 | The NT-ProBNP is a biomarker (a biologic molecule) that has been shown to predict cardiac events. | Baseline and Month 6 | 
| Change From Baseline in Central Transmitral Flow Velocity Time Integral (VTI) at Month 6 | Transmitral flow VTI measures how blood flows through the heart. This was measured by echocardiogram. Most of the values for transmitral flow VTI were not provided in the reports from central core echocardiographic laboratory due to technical reasons. | Baseline and Month 6 | 
| Change From Baseline in Central Tissue E-Wave Doppler Mitral Annular Velocity at Month 6 | Tissue doppler mitral annular velocity is a measure of how well the heart fills with blood. This was measured by echocardiogram. Most of the values for E-wave were not provided in the reports from central core echocardiographic laboratory due to technical reasons. | Baseline and Month 6 | 
| Change From Baseline in Distance Walked During Six-minute Walk Test at Month 6 | A standardized 6-minute walk test was performed and the distance covered in 6 minutes was measured. | Baseline and Month 6 | 
| Number of Participants With New York Heart Association (NYHA) Classification of Disease Progression | Disease progression (morbidity) was measured by the NYHA classification. The NYHA classification assesses the severity of symptoms of heart failure as judged by the investigator and is comprised of 4 stages. Stage I- No symptoms/limitation in ordinary physical activity (for example, shortness of breath when walking, climbing stairs); Stage II-Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity; Stage III- Marked limitation in activity due to symptoms, even during less-than-ordinary activity, (for example, walking short distances [20-100 m]), comfortable only at rest; and Stage IV- Severe limitations in activity/experiences symptoms while at rest (mostly bedbound participants). | Baseline and Month 6 | 
| Change From Baseline in Minnesota Living With Heart Failure Questionnaire Score at Month 6 | Minnesota living with heart failure questionnaire is a self-administered, disease-specific measure of health related quality of life (QOL) that assesses participant's perceptions of the influence of heart failure on physical, socioeconomic and psychological aspects of life. Participants responded to 21 items using a six-point response scale (0-5). The total summary score can range from 0-105 with a lower score reflecting better heart failure related QOL. | Baseline and Month 6 | 
| Change From Baseline in Holter Electrocardiography (ECG) Parameters (Heart Rate) at Month 6 | A Holter monitor is a portable device which monitors the electrical activity (electrocardiography) of the heart. Mean heart rate, maximum heart rate and minimum heart rate were evaluated. | Baseline and Month 6 | 
| Number of Participants With Holter Electrocardiography (ECG) Parameters | A Holter monitor is a portable device which monitors the electrical activity (electrocardiography) of the heart. Block, Heart rhythm, AV junctional, Ventricular, Lown classification, Results were evaluated. | Baseline and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-beta1-receptor autoantibodies, COR-1, Heart failure