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

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Brief Title

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)

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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Phase 2: Incidence of Treatment-emergent Adverse Events (TEAE) at 12 Months


Condition

Heart Failure, Congestive

Intervention

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

Study Arms / Comparison Groups

 MYDICAR Very Low Dose
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Genetic

Estimated Enrollment

51

Start Date

March 2007

Completion Date

August 2012

Primary Completion Date

August 2010

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
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Brian Jaski, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00454818

Organization ID

CELL-001

Secondary IDs

CUPID Trial

Responsible Party

Sponsor

Study Sponsor

Celladon Corporation


Study Sponsor

Brian Jaski, MD, Principal Investigator, San Diego Cardiac Center


Verification Date

August 2014