A Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

NCT01643330 | Completed Phase 2 DMC

• 2 other identifiers: CELL-0042012-001700-37
• Study Type: interventional
• Target: 250
• Locations: 10 countries
• Sites: 54

Brief Summary

The purpose of this trial is to assess whether MYDICAR can reduce the frequency and/or delay heart failure related hospitalizations in persons with advanced heart failure when added to their maximal and optimized therapy.

Conditions

Ischemic Cardiomyopathy; Non-ischemic Cardiomyopathy; Heart Failure; Cardiomyopathies

Keywords

Cardiomegaly; Heart Diseases; Cardiovascular Diseases

Outcome Measures

Primary Outcomes (1)

• Time to recurrent events (heart failure [HF]-related hospitalizations, ambulatory worsening HF) in the presence of terminal events (all-cause death, heart transplant, mechanical circulatory support device [MCSD] implantation)

  From administration up to 12 months

Secondary Outcomes (1)

• Time-to-terminal event (all-cause death, heart transplant, MCSD implantation) in the presence of recurrent events.

  From administration up to 12 months

Study Arms (2)

AAV1/SERCA2a (MYDICAR)

EXPERIMENTAL

Intracoronary infusion

Genetic: AAV1/SERCA2a (MYDICAR)

Placebo

PLACEBO COMPARATOR

Intracoronary infusion

Genetic: Placebo

Interventions

AAV1/SERCA2a (MYDICAR) GENETIC

Single intracoronary infusion 1 x 10\^13 DNase Resistant Particles (DRP) MYDICAR

AAV1/SERCA2a (MYDICAR)

Placebo GENETIC

Single intracoronary infusion

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Negative neutralizing AAV1 antibodies (NAb) (titer \<1:2 or equivocal) within 90 days of screening.
• years of age, inclusive, at the time of signing the informed consent.
• Chronic systolic HF due to 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. If a subject has not undergone coronary angiography within 2 months, this criterion may be assessed after the subject is randomized and undergoes angiography just prior to the planned infusion of investigational medicinal product.
• Hypertrophic cardiomyopathy is excluded.
• Toxic and alcoholic cardiomyopathies are allowed as long as toxin or alcohol exposure has been eliminated and a sufficient amount of limit has elapsed to rule-out spontaneous recovery.
• Left ventricular ejection fraction (LVEF) ≤35% anytime during the 60-day window prior to administration of investigational medicinal product.
• Diagnosis of New York Heart Association (NYHA) class II, III or IV HF for a minimum of 90 days prior to screening.
• Individualized, maximal, optimized HF therapy consistent with American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC) practice guidelines for the treatment of chronic heart failure (ACC/AHA/ESC HF guidelines) and as updated from time to time:
• Medical therapy as appropriate to the individual subject including oral diuretic, angiotensin-converting enzyme (ACE) inhibitor (or angiotensin-receptor blocker (ARB) if ACE intolerant) and, as tolerated, beta blocker at approved dosages as labeled in the respective package insert. The choice of beta blocker is limited to those approved for heart failure in all participating countries (bisoprolol, carvedilol or sustained release metoprolol succinate). Unless contraindicated or not tolerated, the addition of an aldosterone antagonist should be considered in the absence of hyperkalemia and significant renal dysfunction and according to evolving standards; the final decision is at the discretion of the investigator. Dosing of the above medications must be stable for a minimum of 30 days prior to screening, although up- or down-titration of diuretics, as medically indicated, is permitted. Enrollment of any subject with any deviation from this combination must be preapproved by the medical monitor.
• Resynchronization therapy, if clinically indicated according to ACC/AHA/ESC HF guidelines, must have been implanted at least 6 months prior to screening.
• Implantable cardioverter defibrillator (ICD), if clinically indicated according to ACC/AHA/ESC HF guidelines, must have been implanted a minimum of 30 days prior to screening.
• Cardiac rehabilitation should be consistent with the Agency for Health Care Policy and Research Clinical Practice Guideline, Number 17, Cardiac Rehabilitation. This does not imply that the potential candidate must be enrolled in a cardiac rehabilitation program at screening or in the future.
• All women of childbearing potential must have a negative urine pregnancy test prior to administration of investigational medicinal product and agree to use adequate contraception (defined as oral or injectable contraceptives, intrauterine devices, surgical sterilization or a combination of a condom and spermicide) or limit sexual activity to vasectomized partner for 3 months after administration of investigational medicinal product. Men capable of fathering a child must agree to use barrier contraception (combination of a condom and spermicide) or limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3 months after administration of investigational medicinal product.
• Ability to understand and comply with study requirements as evidenced by providing signed written informed consent form and Release of Medical Information Form.
• Presence of at least one of the following risk factors:

You may not qualify if:

• Subjects meeting any of the following criteria will be excluded from the study:
• Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening.
• Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete LV aneurysm.
• Cardiac surgery, percutaneous coronary intervention (PCI) or valvuloplasty within 30 days prior to screening.
• Myocardial infarction (MI) (e.g., ST elevation MI \[STEMI\] or large non-STEMI) within 90 days prior to screening. Large non-STEMI shall be defined \>3x upper limit of normal (ULN) for creatinine kinase (CK)-MB or \>5x ULN for troponin.
• Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted left ventricular assist device (LVAD) or cardiac shunt.
• Likely need for an immediate heart transplant or LVAD implant due to hemodynamic instability.
• Known hypersensitivity to contrast agents used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography.
• Significant, in the opinion of the investigator, left main or ostial right coronary luminal stenosis.
• Liver function tests (alanine amino transferase \[ALT\], aspartate aminotransferase \[AST\], alkaline phosphatase) \>3x ULN within 30 days prior to investigational medicinal product administration 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 or current glomerular filtration rate (GFR) ≤20 mL/minute/1.73 m\^2 estimated by Modification of Diet in Renal Disease (MDRD) calculation.
• Bleeding diathesis or thrombocytopenia defined as platelet count \<50,000 platelets/μL.
• Anemia defined as hemoglobin \<9 g/dL, provided that there is no evidence of bleeding.
• Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count \<1000 cells/mm\^3.
• Previous participation in a study of gene transfer; however, if the study was unblinded or documentation otherwise exists that the subject was randomized to the placebo control group and did not receive active gene transfer agent, the subject may be considered for this study.

Sponsors & Collaborators

• Celladon Corporation: lead

Study Sites (54)

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Birmingham, Alabama, United States

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La Jolla, California, United States

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Long Beach, California, United States

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San Diego, California, United States

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Sylmar, California, United States

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Newark, Delaware, United States

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Jacksonville, Florida, United States

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Miami, Florida, United States

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Augusta, Georgia, United States

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Iowa City, Iowa, United States

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Alexandria, Louisiana, United States

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Boston, Massachusetts, United States

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Kansas City, Missouri, United States

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St Louis, Missouri, United States

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New York, New York, United States

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The Bronx, New York, United States

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Winston-Salem, North Carolina, United States

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Columbus, Ohio, United States

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Oklahoma City, Oklahoma, United States

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Philadelphia, Pennsylvania, United States

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Charleston, South Carolina, United States

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Rapid City, South Dakota, United States

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Germantown, Tennessee, United States

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Tullahoma, Tennessee, United States

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Houston, Texas, United States

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San Antonio, Texas, United States

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Salt Lake City, Utah, United States

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Tacoma, Washington, United States

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Waukesha, Wisconsin, United States

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Aalst, Belgium

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Leuven, Belgium

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Aalborg, Denmark

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Coppenhagen, Denmark

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Hvidovre, Denmark

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Bad Nauheim, Germany

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Berlin, Germany

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Cologne, Germany

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Dresden, Germany

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München, Germany

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Budapest, Hungary

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Debrecen, Hungary

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Ashkelon, Israel

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Holon, Israel

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Jerusalem, Israel

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Rehovot, Israel

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Groningen, Netherlands

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Gdansk, Poland

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Wroclaw, Poland

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Zabrze, Poland

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Malmo, Sweden

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Örebrö, Sweden

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Stockholm, Sweden

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Glasgow, United Kingdom

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London, United Kingdom

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Related Publications (7)

• 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 BACKGROUND

• 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 BACKGROUND

• 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

• 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 BACKGROUND

• Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Pogoda JM, Provost R, Guerrero J, Hajjar RJ, Zsebo KM. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure. Gene Ther. 2016 Mar;23(3):313-9. doi: 10.1038/gt.2015.109. Epub 2015 Dec 24.

  PMID: 26699914 BACKGROUND

• Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Desai AS, Barnard D, Bouchard A, Jaski B, Lyon AR, Pogoda JM, Rudy JJ, Zsebo KM. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016 Mar 19;387(10024):1178-86. doi: 10.1016/S0140-6736(16)00082-9. Epub 2016 Jan 21.

  PMID: 26803443 RESULT

• Greenberg B, Yaroshinsky A, Zsebo KM, Butler J, Felker GM, Voors AA, Rudy JJ, Wagner K, Hajjar RJ. Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b). JACC Heart Fail. 2014 Feb;2(1):84-92. doi: 10.1016/j.jchf.2013.09.008. Epub 2014 Jan 25.

  PMID: 24622121 DERIVED

MeSH Terms

Conditions

Heart Failure; Cardiomyopathies; Cardiomegaly; Heart Diseases; Cardiovascular Diseases

Condition Hierarchy (Ancestors)

Hypertrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Call 1-858-366-4288

  Celladon Corporation

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• 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: July 16, 2012
• First Posted: July 18, 2012
• Study Start: July 1, 2012
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2016
• Last Updated: March 24, 2016

Record last verified: 2016-02

Locations

PL (3); DE (5); SE (3); DK (3); NL (1); BE (2); US (29); GB (2); IL (4); HU (2)