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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Celladon Corporation
ClinicalTrials.gov Identifier:
NCT00454818
First received: March 30, 2007
Last updated: August 1, 2013
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
Heart Failure, Congestive
Dilated Cardiomyopathy
Genetic: MYDICAR®
Procedure: Placebo Infusion
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of Intracoronary Administration of MYDICAR® (AAV1/SERCA2a) in Subjects With Heart Failure Divided Into Two Stages: Stage One Open-Label, Sequential Dose-Escalation Cohorts and Stage Two Randomized, Double-Blind, Placebo-Control, Parallel Cohorts

Resource links provided by NLM:


Further study details as provided by Celladon Corporation:

Primary Outcome Measures:
  • Safety and Activity/Efficacy [ Time Frame: 6, 9 and 12 Months ] [ Designated as safety issue: Yes ]
    Safety: incidence and severity of AEs, and fatal and non-fatal CV events. Efficacy: peak VO2, 6MWT, echo assessments, NT-proBNP, NYHA Class, MLWHFQ; time to death, LVAD implant or heart transplant and total number of days in hospital.


Secondary Outcome Measures:
  • Additional Safety and Activity/Efficacy [ Time Frame: 6, 9 and 12 Months ] [ Designated as safety issue: Yes ]
    Safety: non-CV or unknown fatal events, non-heart-failure-related or non-CV-related hospitalization, and time to first treatment-emergent SAE. Efficacy: BNP, Uric Acid and GDF-15 levels; other echo parameters; rate of hospitalizations per patient-year; days dead, on LVAD, with transplant or in hospital.


Enrollment: 51
Study Start Date: March 2007
Study Completion Date: August 2012
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MYDICAR Very Low Dose
1.4x10e11 DRP
Genetic: MYDICAR®
1.4x10e11 DRP; antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Experimental: MYDICAR Low Dose
6x10e11 DRP
Genetic: MYDICAR®
6x10e11 DRP; antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Experimental: MYDICAR Mid Dose
3x10e12 DRP
Genetic: MYDICAR®
3x10e12 DRP; antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Experimental: MYDICAR High Dose
1x10e13 DRP
Genetic: MYDICAR®
1x10e13 DRP; antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Placebo Comparator: Placebo
Placebo
Procedure: Placebo Infusion
Saline; epicardial coronary artery infusion

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 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chronic ischemic or non-ischemic cardiomyopathy. Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with TIMI grade 3 flow.
  • Left ventricular ejection fraction (LVEF) ≤35%
  • Diagnosis of 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 (ALT, 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00454818

Locations
United States, California
San Diego Cardiac Center
San Diego, California, United States, 92123
University of California at San Diego Medical Center
San Diego, California, United States, 92103
United States, Florida
Shands Hospital at University of Florida
Gainesville, Florida, United States, 32608
United States, Illinois
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
Northwestern University
Chicago, Illinois, United States, 60611
United States, Missouri
Mid America Heart Institute, Saint Luke's Hospital
Kansas City, Missouri, United States, 64111
St. Louis University Hospital
St. Louis, Missouri, United States, 63110
United States, New Jersey
University of Medicine and Dentistry of New Jersey
Newark, New Jersey, United States, 07101
United States, New York
Columbia University Hospital
New York, New York, United States, 10032
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, North Carolina
Wake Forest University
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45267
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
MetroHealth Medical Center
Cleveland, Ohio, United States, 44109
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh Medical Center, Presbyterian-Shadyside Hospital
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
Tennessee Center for Clinical Trials & Harton Regional Medical Center
Tullahoma, Tennessee, United States, 37388
United States, Texas
Cardiopulmonary Research Science and Technology Institute, Medical City Dallas Hospital
Dallas, Texas, United States, 75230
Methodist Hospital
Houston, Texas, United States, 77030
United States, Utah
Intermountain Medical Center
Murray, Utah, United States, 84157
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Celladon Corporation
Investigators
Principal Investigator: Brian Jaski, MD San Diego Cardiac Center
Principal Investigator: Donna Mancini, MD Columbia University Hospital
Principal Investigator: Randall Starling, MD The Cleveland Clinic
Study Chair: Mariell Jessup, MD University of Pennsylvania
Principal Investigator: Thomas Cappola, MD, ScM University of Pennsylvania
Principal Investigator: Daniel Pauly, MD Shands Hospital, University of Florida at Gainesville
Principal Investigator: Barry London, MD University of Pittsburgh
Principal Investigator: Barry Greenberg, MD University of California at San Diego Medical Center
Principal Investigator: A. G. Kfoury, MD Intermountain Medical Center
Principal Investigator: Stephen Archer, MD University of Chicago
Principal Investigator: Andrew Kao, MD Mid America Heart Institute, Saint Luke's Hospital
Principal Investigator: Paul J. Hauptman, MD St. Louis University Hospital
Principal Investigator: Jill Kalman, MD Mount Sinai School of Medicine
Principal Investigator: Douglas W. Losordo, MD Northwestern University
Principal Investigator: Eric J. Eichhorn, MD, FACC Cardiopulmonary Research Science and Technology Institutte, Medical City Dallas Hospital
Principal Investigator: Stephanie H. Dunlap, DO University of Cincinnati
Principal Investigator: Vinay Thohan, MD Wake Forest School of Medicine
Principal Investigator: Maryl R. Johnson, MD University of Wisconsin, Madison
Principal Investigator: Mark Dunlap, MD MetroHealth Medical Center
Principal Investigator: Joaquin E. Cigarroa, MD Oregon Health and Science University
Principal Investigator: Dinesh K. Gupta, MD Tennessee Center for Clinical Trials, Harton Regional Medical Center
Principal Investigator: Marc Klapholz, MD University of Medicine and Dentistry of New Jersey
Principal Investigator: Guillermo Torre, MD The Methodist Hospital System
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Celladon Corporation
ClinicalTrials.gov Identifier: NCT00454818     History of Changes
Other Study ID Numbers: CELL-001, CUPID Trial
Study First Received: March 30, 2007
Last Updated: August 1, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Cardiomyopathy, Dilated
Heart Failure
Cardiomyopathies
Cardiomegaly
Heart Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on April 16, 2014