A Phase 1/2 Study of High-dose Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

NCT02346422 | Terminated Phase 1 DMC

• 1 other identifier: CELL-009
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 4

Brief Summary

The purpose of this trial is to characterize the safety profile and preliminary activity of high-dose MYDICAR® in persons with advanced heart failure when added to their maximal and optimized therapy.

Conditions

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

Keywords

Heart Failure; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Cardiomegaly; Gene Therapy

Outcome Measures

Primary Outcomes (1)

• Phase 1 and Phase 2: Safety profile of MYDICAR (proportion of subjects who complete the study; adverse event; concomitant medication use and changes in heart failure-related medications; incidence and event rates of hospitalizations

  The primary objective of the study is to characterize the safety profile of MYDICAR. Safety outcomes will include proportion of subjects who complete the study; adverse event incidence, severity and relationship to investigational medicinal product or cardiac catheterization procedure; concomitant medication use and changes in heart failure-related medications; incidence and event rates of hospitalizations, ambulatory worsening of heart failure, myocardial infarction, stroke, mechanical circulatory support device (MCSD) implantation, heart transplant, and death; changes from baseline in laboratory tests, 12-lead electrocardiogram, and physical examination including weight and vital signs; and changes from baseline in implantable cardioverter defibrillator interrogation parameters.

  24 months

Other Outcomes (9)

• Phase 2: Rates of recurrent events (defined as hospitalizations for failure of the native heart that has not been implanted with an MCSD and/or ambulatory worsening failure of the native heart that has not been implanted with an MCSD)

  24 months

• Phase 2: Rates of terminal events (defined as all-cause death, MCSD implantation, or transplant)

  24 months

• Phase 2: Change from baseline in left ventricular end systolic volume (LVESV)

  12 months

Study Arms (2)

MYDICAR

EXPERIMENTAL

Single intracoronary infusion 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 2.5 x 10\^13 DRP. Administered in MYDICAR Phase 1 and MYDICAR Phase 2.

Genetic: MYDICAR Phase 1; Genetic: MYDICAR Phase 2

Placebo

PLACEBO COMPARATOR

Single intracoronary infusion of placebo (Sodium Chloride Injection, USP) (Placebo Phase 2 only).

Genetic: Placebo Phase 2 only

Interventions

MYDICAR Phase 1 GENETIC

Single dose of MYDICAR

Also known as: AAV1/SERCA2a

MYDICAR

MYDICAR Phase 2 GENETIC

Single dose of MYDICAR

Also known as: AAV1/SERCA2a

MYDICAR

Placebo Phase 2 only GENETIC

Single dose of placebo

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:

• Unless otherwise specified, screening must be performed within 30 days prior to enrollment (phase 1) or enrollment/randomization (phase 2) except as noted below. Subjects must meet the following criteria to be eligible for the study:
• AAV1 neutralizing antibodies (NAb) negative (titer \<1:2 or equivocal) within 60 days prior to screening.
• Age 18-80 years, inclusive, at the time of signing the first informed consent.
• Chronic ischemic or non-ischemic cardiomyopathy, except for hypertrophic cardiomyopathy. Toxic or alcoholic cardiomyopathies are allowed as long as toxin or alcohol exposure has been eliminated and a sufficient amount of time has elapsed to rule out spontaneous recovery. Similarly, patients with viral or peripartum cardiomyopathy will not be enrolled until sufficient time has elapsed to rule out spontaneous recovery. Subjects with ischemic cardiomyopathy must have at least 1 major coronary vessel with thrombolysis in myocardial infarction (TIMI) grade 3 flow. (If a subject has not undergone recent coronary angiography, TIMI flow may be assessed during the study angiography just prior to investigational medicinal product \[IMP\] infusion).
• Left ventricular ejection fraction ≤35%.
• Diagnosis of New York Heart Association class III/IV heart failure (HF) for a minimum of 60 days prior to screening.
• For phase 2 only, the presence of at least one of the following risk factors:
• Hospitalization for HF within 6 months of screening, or in lieu of hospitalization, at least 2 outpatient interventions for the intended treatment of signs and symptoms of worsening HF (e.g., intravenous \[IV\] diuretics, peripheral ultrafiltration).
• N-terminal prohormone brain natriuretic peptide (NT-proBNP) \>1200 pg/mL within 30 days of screening; if subject is in atrial fibrillation, NT-proBNP \>1600 pg/mL within 30 days of screening.
• Individualized, maximal, optimized HF therapy consistent with American College of Cardiology/American Heart Association practice guidelines for the treatment of chronic heart failure (ACC/AHA 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, if ACE intolerant, angiotensin-receptor blocker and beta blocker at approved dosages as labeled in the respective package insert and optimized for the subject.
• The choice of beta blocker is limited to those approved for HF (bisoprolol, carvedilol or metoprolol succinate). Metoprolol tartrate is not approved for HF and is not allowed.
• 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. However, 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.
• Patients requiring IV diuretics during this period will be required to undergo an additional 30 day period of stabilization on oral diuretics.

You may not qualify if:

• Subjects meeting any of the following criteria will be excluded from the study:
• De novo diagnosis of heart failure.
• Any IV therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening or enrollment.
• Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete left ventricular aneurysm.
• Cardiac surgery, percutaneous coronary intervention, valvuloplasty or valve replacement within 30 days prior to screening.
• Myocardial infarction (e.g., ST elevation myocardial infarction \[STEMI\] or large non-STEMI) within 90 days prior to screening. Large non-STEMI shall be defined \>3x the upper limit of normal (ULN) for creatinine kinase test or \>5x ULN for troponin.
• Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), mechanical circulatory support device (MCSD) or cardiac shunt.
• Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, conventional revascularization procedure or valvular repair in the 6 months following treatment.
• Likely need for an immediate heart transplant or MCSD implant due to hemodynamic instability.
• Known hypersensitivity to radiopaque agents used for angiography; history of or likely need for, high dose corticosteroid pretreatment prior to contrast angiography.
• Significant, in the opinion of the investigator, left main or ostial right coronary luminal stenosis.
• Liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) \>3x ULN, total bilirubin \>2x ULN 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) formula for calculating the GFR MDRD calculation.
• Bleeding diathesis or thrombocytopenia defined as platelet count \<75,000 platelets/μL.
• Anemia defined as hemoglobin \<9 g/dL.

Sponsors & Collaborators

• Celladon Corporation: lead

Study Sites (4)

Unknown Facility

La Jolla, California, United States

Location

Unknown Facility

San Diego, California, United States

Location

Unknown Facility

Kansas City, Missouri, United States

Location

Unknown Facility

New York, New York, United States

Location

Related Publications (3)

• 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

• 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

MeSH Terms

Conditions

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

Condition Hierarchy (Ancestors)

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

Study Officials

• Call 1-858-366-4081

  Celladon Corporation

  STUDY DIRECTOR

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: January 15, 2015
• First Posted: January 27, 2015
• Study Start: April 1, 2015
• Primary Completion: June 26, 2015
• Last Updated: January 31, 2017

Record last verified: 2017-01

Locations

US (4)