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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

March 30, 2007
August 1, 2013
March 2007
August 2010   (final data collection date for primary outcome measure)
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.
Safety as measured by the incidence and severity of adverse events, all-cause mortality, progression of heart failure leading to hospitalization, and/or IV inotrope, vasodilator, and/or diuretic administration.
Complete list of historical versions of study NCT00454818 on ClinicalTrials.gov Archive Site
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.
Efficacy based on changes from baseline to 3, 6, 9 and 12 months in VO2 max, 6-minute walk test, echocardiographic assessments, NT-proBNP level, NYHA Classification, and Quality of Life assessed by Minnesota Living with Heart Failure Questionnaire.
Not Provided
Not Provided
 
Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure
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

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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Heart Failure, Congestive
  • Dilated Cardiomyopathy
  • Genetic: MYDICAR®
    1.4x10e11 DRP; antegrade epicardial coronary artery infusion
    Other Name: AAV1/SERCA2a
  • Procedure: Placebo Infusion
    Saline; epicardial coronary artery infusion
  • Genetic: MYDICAR®
    6x10e11 DRP; antegrade epicardial coronary artery infusion
    Other Name: AAV1/SERCA2a
  • Genetic: MYDICAR®
    3x10e12 DRP; antegrade epicardial coronary artery infusion
    Other Name: AAV1/SERCA2a
  • Genetic: MYDICAR®
    1x10e13 DRP; antegrade epicardial coronary artery infusion
    Other Name: AAV1/SERCA2a
  • Experimental: MYDICAR Very Low Dose
    1.4x10e11 DRP
    Intervention: Genetic: MYDICAR®
  • Experimental: MYDICAR Low Dose
    6x10e11 DRP
    Intervention: Genetic: MYDICAR®
  • Experimental: MYDICAR Mid Dose
    3x10e12 DRP
    Intervention: Genetic: MYDICAR®
  • Experimental: MYDICAR High Dose
    1x10e13 DRP
    Intervention: Genetic: MYDICAR®
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Procedure: Placebo Infusion

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
51
August 2012
August 2010   (final data collection date for primary outcome measure)

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
Both
18 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00454818
CELL-001, CUPID Trial
Yes
Celladon Corporation
Celladon Corporation
Not Provided
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
Celladon Corporation
August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP