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

Heart Failure, Congestive Clinical Trial

— CUPID  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00454818
• Other study ID #: CELL-001
• Secondary ID: CUPID Trial
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 30, 2007
• Last updated: August 19, 2014
• Start date: March 2007
• Est. completion date: August 2012

Study information

• Verified date: August 2014
• Source: Celladon Corporation
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: August 2012
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Dilated Cardiomyopathy
• Heart Failure
• Heart Failure, Congestive

Intervention

Genetic:
• MYDICAR Phase 1 (Open-label, Serial Dose-Escalation Study)
MYDICAR administered by antegrade epicardial coronary artery infusion

Procedure:
• Placebo Infusion
Saline; epicardial coronary artery infusion

Genetic:
• MYDICAR Phase 2 (Placebo-controlled, Randomized Study)
MYDICAR administered by antegrade epicardial coronary artery infusion

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Cardiopulmonary Research Science and Technology Institute, Medical City Dallas Hospital	Dallas	Texas
United States	Shands Hospital at University of Florida	Gainesville	Florida
United States	Methodist Hospital	Houston	Texas
United States	Mid America Heart Institute, Saint Luke's Hospital	Kansas City	Missouri
United States	University of Wisconsin	Madison	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	Columbia University Hospital	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	University of Medicine and Dentistry of New Jersey	Newark	New Jersey
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center, Presbyterian-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	San Diego Cardiac Center	San Diego	California
United States	University of California at San Diego Medical Center	San Diego	California
United States	St. Louis University Hospital	St. Louis	Missouri
United States	Tennessee Center for Clinical Trials & Harton Regional Medical Center	Tullahoma	Tennessee
United States	Wake Forest University	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Celladon Corporation

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View 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. — View 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 perc — View 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 Percutane — View 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- — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Phase 2: Length of Cardiovascular-related Hospitalizations at 12 Months	Mean number of days in the hospital for cardiovascular-related complications. All hospitalizations were evaluated and classified by the blinded Clinical Endpoints Committee.	12 months	Yes
Other	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	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 12 months	No
Other	Phase 2: Change in 6-minute Walk Test (6MWT) From Baseline to Month 12	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 12 months	No
Other	Phase 2: Change in Peak Maximum Oxygen Consumption (VO2) From Baseline to Month 12	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 12 months	No
Other	Phase 2: Change in Absolute Levels of N-terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) From Baseline to Month 12	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 12 months	No
Other	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	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 12 months	No
Other	Phase 2: Change in Absolute Left Ventricular End Systolic Volume (LVESV) From Baseline to Month 12	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 12 months	No
Other	Phase 1 and Phase 2: All Subject Deaths Through 36 Months	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.	36 months	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No