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

NCT ID: NCT00454818

Last Updated: 2014-08-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-03-31
• Study Completion Date: 2012-08-31

Brief Summary

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

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.

Conditions

Heart Failure, Congestive; Dilated Cardiomyopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

MYDICAR Very Low Dose

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.

Group Type: EXPERIMENTAL

MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

MYDICAR Low Dose

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)

Group Type: EXPERIMENTAL

MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

MYDICAR Mid Dose

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).

Group Type: EXPERIMENTAL

MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

MYDICAR High Dose

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).

Group Type: EXPERIMENTAL

MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

Intervention Type: GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

Placebo infusion

A single dose of placebo (Sodium Chloride Injection, USP) administered by antegrade epicardial coronary artery infusion.

Group Type: PLACEBO_COMPARATOR

Placebo Infusion

Intervention Type: PROCEDURE

Saline; epicardial coronary artery infusion

Interventions

MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)

MYDICAR administered by antegrade epicardial coronary artery infusion

Intervention Type: GENETIC

Placebo Infusion

Saline; epicardial coronary artery infusion

Intervention Type: PROCEDURE

MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

MYDICAR administered by antegrade epicardial coronary artery infusion

Intervention Type: GENETIC

Other Intervention Names

AAV1/SERCA2a; AAV1/SERCA2a

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celladon Corporation

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Brian Jaski, MD

Role: PRINCIPAL_INVESTIGATOR

San Diego Cardiac Center

Donna Mancini, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University Hospital

Randall Starling, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Mariell Jessup, MD

Role: STUDY_CHAIR

University of Pennsylvania

Thomas Cappola, MD, ScM

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Daniel Pauly, MD

Role: PRINCIPAL_INVESTIGATOR

Shands Hospital, University of Florida at Gainesville

Barry London, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh Medical Center

Barry Greenberg, MD

Role: PRINCIPAL_INVESTIGATOR

University of California at San Diego Medical Center

A. G. Kfoury, MD

Role: PRINCIPAL_INVESTIGATOR

Intermountain Medical Center

Stephen Archer, MD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

Andrew Kao, MD

Role: PRINCIPAL_INVESTIGATOR

Mid America Heart Institute, Saint Luke's Hospital

Paul J. Hauptman, MD

Role: PRINCIPAL_INVESTIGATOR

St. Louis University Hospital

Jill Kalman, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Douglas W. Losordo, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Eric J. Eichhorn, MD, FACC

Role: PRINCIPAL_INVESTIGATOR

Cardiopulmonary Research Science and Technology Institutte, Medical City Dallas Hospital

Stephanie H. Dunlap, DO

Role: PRINCIPAL_INVESTIGATOR

University of Cincinnati

Vinay Thohan, MD

Role: PRINCIPAL_INVESTIGATOR

Wake Forest University

Maryl R. Johnson, MD

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Mark Dunlap, MD

Role: PRINCIPAL_INVESTIGATOR

MetroHealth Medical Center

Joaquin E. Cigarroa, MD

Role: PRINCIPAL_INVESTIGATOR

Oregon Health and Science University

Dinesh K. Gupta, MD

Role: PRINCIPAL_INVESTIGATOR

Tennessee Center for Clinical Trials, Harton Regional Medical Center

Marc Klapholz, MD

Role: PRINCIPAL_INVESTIGATOR

University of Medicine and Dentistry of New Jersey

Guillermo Torre, MD

Role: PRINCIPAL_INVESTIGATOR

The Methodist Hospital Research Institute

Locations

University of California at San Diego Medical Center

San Diego, California, United States

San Diego Cardiac Center

San Diego, California, United States

Shands Hospital at University of Florida

Gainesville, Florida, United States

Northwestern University

Chicago, Illinois, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Mid America Heart Institute, Saint Luke's Hospital

Kansas City, Missouri, United States

St. Louis University Hospital

St Louis, Missouri, United States

University of Medicine and Dentistry of New Jersey

Newark, New Jersey, United States

Mount Sinai Medical Center

New York, New York, United States

Columbia University Hospital

New York, New York, United States

Wake Forest University

Winston-Salem, North Carolina, United States

University of Cincinnati

Cincinnati, Ohio, United States

MetroHealth Medical Center

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center, Presbyterian-Shadyside Hospital

Pittsburgh, Pennsylvania, United States

Tennessee Center for Clinical Trials & Harton Regional Medical Center

Tullahoma, Tennessee, United States

Cardiopulmonary Research Science and Technology Institute, Medical City Dallas Hospital

Dallas, Texas, United States

Methodist Hospital

Houston, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

University of Wisconsin

Madison, Wisconsin, United States

Countries

United States

References

Horowitz JD, Rosenson RS, McMurray JJ, Marx N, Remme WJ. Clinical Trials Update AHA Congress 2010. Cardiovasc Drugs Ther. 2011 Feb;25(1):69-76. doi: 10.1007/s10557-011-6285-9.

Reference Type: BACKGROUND

PMID: 21340529 (View on PubMed)

Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, Greenberg B, Pauly DF, Patten R, Starling R, Mancini D, Jessup M. Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail. 2008 Jun;14(5):355-67. doi: 10.1016/j.cardfail.2008.02.005. Epub 2008 May 27.

Reference Type: BACKGROUND

PMID: 18514926 (View on PubMed)

Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ; Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) Trial Investigators. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail. 2009 Apr;15(3):171-81. doi: 10.1016/j.cardfail.2009.01.013.

Reference Type: RESULT

PMID: 19327618 (View on PubMed)

Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ; Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 2011 Jul 19;124(3):304-13. doi: 10.1161/CIRCULATIONAHA.111.022889. Epub 2011 Jun 27.

Reference Type: RESULT

PMID: 21709064 (View on PubMed)

Zsebo K, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M, Hajjar RJ. Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ Res. 2014 Jan 3;114(1):101-8. doi: 10.1161/CIRCRESAHA.113.302421. Epub 2013 Sep 24.

Reference Type: RESULT

PMID: 24065463 (View on PubMed)

Other Identifiers

CUPID Trial

Identifier Type: REGISTRY

Identifier Source: secondary_id

CELL-001

Identifier Type: -

Identifier Source: org_study_id