Clinical trial NCT00454818: Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Heart Failure, Congestive
Dilated Cardiomyopathy
Lead sponsor: Celladon Corporation
Sponsor class: INDUSTRY
First posted: 2007-04-02
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Phase 2: Incidence of Treatment-emergent Adverse Events (TEAE) at 12 Months
timeFrame: 12 months
measure: Phase 2: Length of Cardiovascular-related Hospitalizations at 6 Months
timeFrame: 6 months
measure: 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
timeFrame: Baseline to 6 months
measure: Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 6
timeFrame: Baseline to 6 months
measure: Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 6
timeFrame: Baseline to 6 months
measure: Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 6
timeFrame: Baseline to 6 months
measure: 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
timeFrame: Baseline to 6 months
measure: Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) Frm Baseline to Month 6
timeFrame: Baseline to 6 months
Secondary outcomes:
Other outcomes:
measure: Phase 2: Length of Cardiovascular-related Hospitalizations at 12 Months
timeFrame: 12 months
measure: 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
timeFrame: Baseline to 12 months
measure: Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 12
timeFrame: Baseline to 12 months
measure: Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 12
timeFrame: Baseline to 12 months
measure: Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 12
timeFrame: Baseline to 12 months
measure: 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
timeFrame: Baseline to 12 months
measure: Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) From Baseline to Month 12
timeFrame: Baseline to 12 months
measure: Phase 1 and Phase 2: All Subject Deaths Through 36 Months
timeFrame: 36 months
Locations:
city: San Diego
country: United States
facility: University of California at San Diego Medical Center
state: California
city: San Diego
country: United States
facility: San Diego Cardiac Center
state: California
city: Gainesville
country: United States
facility: Shands Hospital at University of Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Kansas City
country: United States
facility: Mid America Heart Institute, Saint Luke's Hospital
state: Missouri
city: St. Louis
country: United States
facility: St. Louis University Hospital
state: Missouri
city: Newark
country: United States
facility: University of Medicine and Dentistry of New Jersey
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Hospital
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center, Presbyterian-Shadyside Hospital
state: Pennsylvania
city: Tullahoma
country: United States
facility: Tennessee Center for Clinical Trials & Harton Regional Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Cardiopulmonary Research Science and Technology Institute, Medical City Dallas Hospital
state: Texas
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: San Diego Cardiac Center
name: Brian Jaski, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University Hospital
name: Donna Mancini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Randall Starling, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Mariell Jessup, MD
role: STUDY_CHAIR
affiliation: University of Pennsylvania
name: Thomas Cappola, MD, ScM
role: PRINCIPAL_INVESTIGATOR
affiliation: Shands Hospital, University of Florida at Gainesville
name: Daniel Pauly, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Medical Center
name: Barry London, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California at San Diego Medical Center
name: Barry Greenberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Intermountain Medical Center
name: A. G. Kfoury, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Stephen Archer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mid America Heart Institute, Saint Luke's Hospital
name: Andrew Kao, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Louis University Hospital
name: Paul J. Hauptman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Jill Kalman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Douglas W. Losordo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiopulmonary Research Science and Technology Institutte, Medical City Dallas Hospital
name: Eric J. Eichhorn, MD, FACC
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cincinnati
name: Stephanie H. Dunlap, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University
name: Vinay Thohan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Maryl R. Johnson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MetroHealth Medical Center
name: Mark Dunlap, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oregon Health and Science University
name: Joaquin E. Cigarroa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tennessee Center for Clinical Trials, Harton Regional Medical Center
name: Dinesh K. Gupta, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Medicine and Dentistry of New Jersey
name: Marc Klapholz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Methodist Hospital Research Institute
name: Guillermo Torre, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.