Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

Study Overview
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Brief Summary
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The study is divided into 2 parts. In the first part, the safety of the gene transfer agent MYDICAR® will be evaluated. In the second part, the ability of MYDICAR® to improve heart function will be studied.

Detailed Description
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The American Heart Association (AHA) 2006 update on heart disease reported that 5 million Americans are believed to have symptomatic heart failure (HF), and 550,000 patients are newly diagnosed each year. The estimated direct and indirect cost of HF in the United States (U.S.) for 2006 will be  $29.6 billion. Heart failure is a disabling chronic disease and the most frequent discharge diagnosis for hospitalization among older adults. Despite the significant resources expended on the treatment of this disease, outcomes remain poor. The five-year survival for individuals diagnosed with heart failure is less than 50%, and in end-stage heart failure, the one-year survival may be as low as 25% regardless of medical therapy. Recent studies suggest that the failing heart is not refractory to treatment, as was previously believed. For example, the observation that a small percentage of subjects with left ventricular assist devices (LVADs) can be permanently weaned from their device strongly suggests that damaged hearts are capable of recovering lost function. Clinical studies of MYDICAR® have not yet been conducted in humans. Celladon Corporation (Celladon) proposes to investigate gene transfer as a method to restore SERCA2a function in heart failure (HF) patients using a recombinant adeno-associated viral vector (AAV), which consists of an AAV serotype 1 capsid and contains the human SERCA2a complementary DNA (cDNA) flanked by Inverted Terminal Repeats (ITR) derived from AAV serotype 2 (AAV1/SERCA2a). MYDICAR® refers to AAV1/SERCA2a drug product intended for administration by percutaneous delivery.

Official Title
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A Phase 1/2 Trial of Intracoronary Administration of MYDICAR® (AAV1/SERCA2a) in Subjects With Heart Failure in Two Stages (Open-Label, Sequential Dose-Escalation Cohorts and Randomized, Double-Blind, Placebo-Controlled, Parallel Cohorts)

Conditions
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Heart Failure, Congestive, Dilated Cardiomyopathy

Intervention / Treatment
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* Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)
* Procedure: Placebo Infusion
* Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic ischemic or non-ischemic cardiomyopathy. Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow. Left ventricular ejection fraction (LVEF) ≤35% Diagnosis of New York Heart Association (NYHA) Class III/IV heart failure for a minimum of 3 months prior to screening Maximal oxygen consumption (VO2 max) ≤20 mL/kg/min within 90 days prior to enrollment An implantable cardioverter defibrillator (ICD) implanted a minimum of 30 days prior to enrollment Treatment with appropriate heart failure therapy as tolerated All women of childbearing potential must have a negative urine pregnancy test prior to administration of investigational product and agree to use adequate contraception. Men capable of fathering a child must agree to use barrier contraception or limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3 months after administration of investigational product. Ability to sign Informed Consent Form (ICF) and Release of Medical Information Form Exclusion Criteria: Any intravenous therapy with positive inotropes, vasodilators, or diuretics within 30 days prior to enrollment Restrictive cardiomyopathy, obstructive cardiomyopathy, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or dyskinetic LV aneurysm Cardiac surgery, percutaneous coronary intervention, or valvuloplasty within 30 days prior to enrollment Clinically significant myocardial infarction (e.g., ST elevation MI [STEMI] or large non-STEMI) within 6 months prior to enrollment Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted LVAD or cardiac shunt Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, heart transplant, conventional revascularization procedure, or valvular repair within 6 months following enrollment Patients with prior coronary artery bypass graft(s) (CABG) will reviewed on a case-by-case basis No evidence of functional or viable myocardium Exercise capacity primarily limited by obesity, peripheral vascular disease, intrinsic pulmonary disease or orthopedic problems and not by underlying heart failure Known hypersensitivity to octafluoropropane (component of the intravenous echocardiography contrast agent, DEFINITY®) or other contrast dyes used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography A left ventricle that is difficult to image or high quality echocardiography is not obtainable at screening Significant left main or ostial right coronary lumenal stenosis in the opinion of the investigator Expected survival <1 year in the investigator's medical opinion Suspected or active viral, bacterial, fungal, or parasitic infection within 48 hours prior to enrollment Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase) >2x Upper Limit of Normal (ULN) within 30 days prior to enrollment or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection) Current or likely need for hemodialysis within 12 months following enrollment Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/μL Anemia defined as hemoglobin <10 g/dL Known AIDS or HIV-positive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3 Previous participation in a study of gene transfer Presence of neutralizing anti-AAV1 antibodies at titer ≥1:2 within 3 months of screening Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the investigational drug administration prior to enrollment Pregnancy or lactation Recent history of psychiatric disease (including drug or alcohol abuse) that is likely to impair subject's ability to comply with protocol-mandated procedures, in the opinion of the investigator Other concurrent medical condition(s) that, while not explicitly excluded by the protocol, could jeopardize the safety of the patient or objectives of the study

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 |
| --- | --- |
| Experimental: MYDICAR Very Low Dose<br>Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 1.4x10e11 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) only. | Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;|
| Experimental: MYDICAR Low Dose<br>Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 6x10e11 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) and MYDICAR Phase 2 (Placebo-controlled, Randomized Study) | Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;|
| Experimental: MYDICAR Mid Dose<br>Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 3x10e12 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) and MYDICAR Phase 2 (Placebo-controlled, Randomized Study). | Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;|
| Experimental: MYDICAR High Dose<br>Single dose of MYDICAR, a viral vector (adeno-associated virus serotype 1 [AAV1]) carrying the gene for sarcoplasmic reticulum Ca++-adenosine triphosphatase (SERCA2a), at a dose of 1x10e13 DNAase resistant particles administered by antegrade epicardial coronary artery infusion. Used in MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study) and MYDICAR Phase 2 (Placebo-controlled, Randomized Study). | Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)<br>* MYDICAR administered by antegrade epicardial coronary artery infusion<br>* Other names: AAV1/SERCA2a;|
| Placebo Comparator: Placebo infusion<br>A single dose of placebo (Sodium Chloride Injection, USP) administered by antegrade epicardial coronary artery infusion. | Procedure: Placebo Infusion<br>* Saline; epicardial coronary artery infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Incidence of Treatment-emergent Adverse Events (TEAE) at 12 Months | Includes all adverse events that occurred from the time of first infusion of the investigational product or placebo to the 12-month visit. The category of TEAEs related to the investigational product (IP) includes TEAEs considered by the investigator to be possibly, probably, or definitely related to the IP. | 12 months | 
| Phase 2: Length of Cardiovascular-related Hospitalizations at 6 Months | Mean number of days in the hospital for cardiovascular-related complications. All hospitalizations were evaluated and classified by the blinded Clinical Endpoints Committee. | 6 months | 
| Phase 2: Change in Symptomatic Efficacy Domains From Baseline to Month 6: New York Heart Association (NYHA) Class and Minnesota Living With Heart Failure Questionnaire (MLWHFQ) Score | NYHA classification is a symptomatic assessment in which the investigator evaluates subjects on a scale ranging from Class I (subjects with no limitation of activities, no symptoms from ordinary activities) to Class IV (subjects who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest). The MLWHFQ is a patient-reported quality of life (QoL) measure in which patients assess the impact of their heart condition on activities in the past month using a Likert scale ranging from 0 (no effect) to 5 (very much effect). Higher scores thus indicate a lower QoL. The maximum (worst) score is 105 and the minimum (best) score is 0. For both measures, changes from baseline with positive values indicate a worsening in symptoms and changes from baseline with negative values indicate an improvement in symptoms. | Baseline to 6 months | 
| Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 6 | The 6MWT measures the distance walked in meters during a 6-minute test. Higher values indicate a better functional status. Changes from baseline with negative values indicate a worsening in function and changes from baseline with positive values indicate an improvement in function. | Baseline to 6 months | 
| Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 6 | Peak VO2 is a measure of maximal oxygen consumption during cardiopulmonary exercise testing; this study used the modified Naughton treadmill protocol. Higher values indicate a better functional status. Changes from baseline with negative values indicate a worsening in function and changes from baseline with positive values indicate an improvement in function. | Baseline to 6 months | 
| Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 6 | NT-proBNP is a biomarker for heart failure. Increased levels of this biomarker are associated with increased mortality and cardiovascular hospitalization in patients with heart failure. | Baseline to 6 months | 
| Phase 2: Change in Percentage of Blood Ejected From the Left Ventricle (LV) (i.e., Left Ventricular Ejection Fraction [LVEF]) From Baseline to Month 6 | Contrast echocardiography was used to determine LVEF. Increases in LVEF are associated with reduced mortality. Changes from baseline with positive values indicate an improvement in heart function and changes from baseline with negative values indicate a worsening of heart function. | Baseline to 6 months | 
| Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) Frm Baseline to Month 6 | Contrast echocardiography was used to determine LVESV. Decreases in LVESV are associated with reduced mortality. Changes from baseline with positive values indicate a worsening in heart function and changes from baseline with negative values indicate an improvement in symptoms. | Baseline to 6 months |