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

NCT00454818 | Completed Phase 1 Results DMC

• 2 other identifiers: CELL-001CUPID Trial
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 22

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.

Conditions

Heart Failure, Congestive; Dilated Cardiomyopathy

Outcome Measures

Primary Outcomes (8)

• 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

Other Outcomes (8)

• Phase 2: Length of Cardiovascular-related Hospitalizations at 12 Months

  12 months

• 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

  Baseline to 12 months

• Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 12

  Baseline to 12 months

Study Arms (5)

MYDICAR Very Low Dose

EXPERIMENTAL

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 Low Dose

EXPERIMENTAL

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); Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

MYDICAR Mid Dose

EXPERIMENTAL

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); Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

MYDICAR High Dose

EXPERIMENTAL

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); Genetic: MYDICAR Phase 2 (Placebo-controlled, Randomized Study)

Placebo infusion

PLACEBO COMPARATOR

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

Procedure: Placebo Infusion

Interventions

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

MYDICAR administered by antegrade epicardial coronary artery infusion

Also known as: AAV1/SERCA2a

MYDICAR High Dose; MYDICAR Low Dose; MYDICAR Mid Dose; MYDICAR Very Low Dose

Placebo Infusion PROCEDURE

Saline; epicardial coronary artery infusion

Placebo infusion

MYDICAR Phase 2 (Placebo-controlled, Randomized Study) GENETIC

MYDICAR administered by antegrade epicardial coronary artery infusion

Also known as: AAV1/SERCA2a

MYDICAR High Dose; MYDICAR Low Dose; MYDICAR Mid Dose

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Celladon Corporation: lead

Study Sites (22)

University of California at San Diego Medical Center

San Diego, California, 92103, United States

Location

San Diego Cardiac Center

San Diego, California, 92123, United States

Location

Shands Hospital at University of Florida

Gainesville, Florida, 32608, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Mid America Heart Institute, Saint Luke's Hospital

Kansas City, Missouri, 64111, United States

Location

St. Louis University Hospital

St Louis, Missouri, 63110, United States

Location

University of Medicine and Dentistry of New Jersey

Newark, New Jersey, 07101, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Columbia University Hospital

New York, New York, 10032, United States

Location

Wake Forest University

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

MetroHealth Medical Center

Cleveland, Ohio, 44109, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Medical Center, Presbyterian-Shadyside Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Tennessee Center for Clinical Trials & Harton Regional Medical Center

Tullahoma, Tennessee, 37388, United States

Location

Cardiopulmonary Research Science and Technology Institute, Medical City Dallas Hospital

Dallas, Texas, 75230, United States

Location

Methodist Hospital

Houston, Texas, 77030, United States

Location

Intermountain Medical Center

Murray, Utah, 84157, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Related Publications (5)

• 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.

  PMID: 21340529 BACKGROUND

• 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.

  PMID: 18514926 BACKGROUND

• 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.

  PMID: 19327618 RESULT

• 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.

  PMID: 21709064 RESULT

• 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.

  PMID: 24065463 RESULT

MeSH Terms

Conditions

Heart Failure; Cardiomyopathy, Dilated

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Cardiomegaly; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

Limitations of this study include its small sample size and the inability to conclusively prove that the delivered gene was responsible for the observed clinical effects. Larger confirmatory trials are needed.

Results Point of Contact

• Title: Jeffrey J. Rudy, Vice President
• Organization: Celladon Corporation

jrudy@celladon.net

1 858-366-4288

Study Officials

• Brian Jaski, MD

  San Diego Cardiac Center

  PRINCIPAL INVESTIGATOR

• Donna Mancini, MD

  Columbia University Hospital

  PRINCIPAL INVESTIGATOR

• Randall Starling, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

• Mariell Jessup, MD

  University of Pennsylvania

  STUDY CHAIR

• 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 Medical Center

  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

  Icahn School of Medicine at Mount Sinai

  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 University

  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 Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2007
• First Posted: April 2, 2007
• Study Start: March 1, 2007
• Primary Completion: August 1, 2010
• Study Completion: August 1, 2012
• Last Updated: August 20, 2014
• Results First Posted: August 20, 2014

Record last verified: 2014-08

Locations

US (22)