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 19, 2014
Last verified: August 2014
  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 Phase 1 (Open-label, Serial Dose-Escalation Study)
Procedure: Placebo Infusion
Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)
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 in Two Stages (Open-Label, Sequential Dose-Escalation Cohorts and Randomized, Double-Blind, Placebo-Controlled, Parallel Cohorts)

Resource links provided by NLM:


Further study details as provided by Celladon Corporation:

Primary Outcome Measures:
  • Phase 2: Incidence of Treatment-emergent Adverse Events (TEAE) at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    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.

  • Phase 2: Length of Cardiovascular-related Hospitalizations at 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Mean number of days in the hospital for cardiovascular-related complications. All hospitalizations were evaluated and classified by the blinded Clinical Endpoints Committee.

  • 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 [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]

    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.


  • Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 6 [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 6 [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 6 [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) Frm Baseline to Month 6 [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Phase 2: Length of Cardiovascular-related Hospitalizations at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Mean number of days in the hospital for cardiovascular-related complications. All hospitalizations were evaluated and classified by the blinded Clinical Endpoints Committee.

  • Phase 2: Change in Symptomatic Efficacy Domains From Baseline to Month 12: New York Heart Association (NYHA) Class and Minnesota Living With Heart Failure Questionnaire (MLWHFQ) Score [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]

    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.


  • Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 12 [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 12 [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 12 [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Percentage of Blood Ejected From the Left Ventricle (LV) (i.e., Left Ventricular Ejection Fraction [LVEF]) From Baseline to Month 12 [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
    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.

  • Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) From Baseline to Month 12 [ Time Frame: Baseline to 12 months ] [ Designated as safety issue: No ]
    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.

  • Phase 1 and Phase 2: All Subject Deaths Through 36 Months [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
    All subject deaths that occurred during the 12-month study or the 24-month follow-up in subjects enrolled in either the Phase 1 or Phase 2 trial. Events occurring after early termination from the trial are listed as occurring during long-term follow-up, but may have been within 12 months. Specifically, two cardiovascular (CV) deaths in placebo subjects occurred following early study termination, but within 12 months of study initiation. These deaths are therefore included under "Deaths within 12 months" but also listed as "Cardiovascular deaths in long-term follow-up." Accordingly, the number of "Cardiovascular deaths in long-term follow-up" for the placebo group is greater than the number of "Deaths after 12 months," as 2 of the deaths occurred within 12 months but after early termination.


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
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)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Experimental: 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)
Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Experimental: 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).
Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Experimental: 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).
Genetic: MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)
MYDICAR administered by antegrade epicardial coronary artery infusion
Other Name: AAV1/SERCA2a
Placebo Comparator: Placebo infusion
A single dose of placebo (Sodium Chloride Injection, USP) administered by antegrade epicardial coronary artery infusion.
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 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.

  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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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:
Jessup M, Greenberg B, Mancini D, et al. 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 [published online ahead of print June 27, 2011]. Circulation 2011. doi:10.1161/CIRCULALTIONAHA.111.022889.

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
Results First Received: June 25, 2014
Last Updated: August 19, 2014
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 August 20, 2014