Moderate to advanced heart failure (NYHA class II, III or IV) due to systolic dysfunction MedDRA version: 17.1 Level: LLT Classification code 10010684 Term: Congestive heart failure System Organ Class: 100000004849
Conditions
Interventions
Product Name: MYDICAR® Injection
Product Code: AAV1/SERCA2a
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: AAV1/SERCA2a
Current Sponsor code: AAV1/SERCA2a
Concentration unit: Other
C
Sponsors
Celladon Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Negative AAV1 (NAb) (titer <1:2 or equivocal) within 90 days of screening. 2. 18-80 years of age, inclusive, at the time of signing the informed consent. 3. Chronic systolic HF due to ischemic or non-ischemic cardiomyopathy. Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with 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 IMP. a. Hypertrophic cardiomyopathy is excluded b. Toxic and 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. 4. Left ventricular ejection fraction (LVEF) =35% anytime during the 60-day window prior to administration of IMP. 5. Diagnosis of NYHA class II, III or IV HF for a minimum of 90 days prior to screening. 6. Individualized maximal, optimized HF therapy consistent with American College of Cardiology/American Heart Association and European Society of Cardiology practice guidelines for the treatment of chronic heart failure: a. 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 sence 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. b. Resynchronization therapy, if clinically indicated according to ACC/AHA/ESC HF guidelines, must have been implanted at least 6 months prior to screening. c. Implantable cardioverter defibrillator (ICD), if clinically indicated, must have been implanted a minimum of 30 days prior to screening. d. 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. 7. All women of childbearing potential must have a negative urine pregnancy test prior to administration of IMP 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 IMP. 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 IMP. 8. Ability to understand and comply with study
Exclusion criteria
Exclusion criteria: 1. Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening. 2. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete LV aneurysm. 3. Cardiac surgery, percutaneous coronary intervention or valvuloplasty within 30 days prior to screening. 4. Myocardial infarction (e.g., ST elevation MI [STEMI] or large non-STEMI) within 90 days prior to screening. 5. Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted LVAD or cardiac shunt. 6. Likely need for an immediate heart transplant or LVAD implant due to hemodynamic instability. 7. Prior CABG is not considered ideal for inclusion in the study; however, a potential candidate can be reviewed on a case-by-case basis. Ideally, the orifice of the graft should be easy to engage with a catheter and the graft should perfuse a significant amount of potentially viable myocardium. 8. Known hypersensitivity to contrast agents used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography. 9. Significant, in the opinion of the investigator, left main or ostial right coronary luminal stenosis. 10. Liver function tests (ALT, AST, alkaline phosphatase) >3x Upper Limit of Normal (ULN) within 30 days prior to IMP administration or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection). 11. Current or likely need for hemodialysis within 12 months following enrollment or current GFR =20 mL/minute/1.73 m2 estimated by MDRD calculation. 12. Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/µL. 13. Anemia defined as hemoglobin <9 g/dL, provided that there is no evidence of bleeding. 14. Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3. 15. Diagnosis of, or treatment for, any cancer other than basal cell carcinoma within the last 5 years. (Past medical history of cancer is not exclusionary as long as subject has been disease-free for at least 5 years since the time of diagnosis and treatment). 16. 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. 17. Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the investigational drug administration prior to screening. Exception may be made if the individual is enrolled in a non-therapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment. 18. Pregnant or breast-feeding. 19. Recent history of psychiatric disease, including drug or alcohol abuse, that is likely to impair, in the opinion of the investigator, the subject’s ability to comply with protocol-mandated procedures. 20. Other concurrent medical condition(s) that, while not explicitly excluded by the protocol, could jeopardize the safety of the subject or objectives of the study. Contraindications for Infusion of Inv
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Determine the efficacy of a single intracoronary infusion of 1 x 10e13 DNase Resistant Particles (DRP) MYDICAR® (AAV1/SERCA2a) added to an optimal HF regimen in subjects with ischemic or non-ischemic cardiomyopathy and moderate to advanced symptoms of heart failure (HF) by reducing the frequency of and/or delaying HF-related hospitalizations and episodes of ambulatory worsening HF (recurrent events) compared to placebo-treated subjects.;Secondary Objective: Assessment of the safety of MYDICAR® by determining the incidence and severity of AEs and changes in laboratory parameters;Primary end point(s): The primary efficacy endpoint is the time to recurrent events (hospitalizations related to failure of the native heart that has not been implanted with a mechanical circulatory support device (LVAD, RVAD, BiVAD, TAH and referred to generically as "MCSD")) and ambulatory worsening failure of the native heart that has not been implanted with a MCSD in the presence of terminal events (all-cause death, heart transplant, MCSD implantation) based on the joint frailty model. Efficacy will be further assessed by a sensitivity analysis involving the primary endpoint based on various definitions of the study population, various recurrent and terminal event definitions, and different methods of statistical analysis to assure that study outcome is not due to a specific statistical method, population or event definition. Analyses of the following endpoints will be included in the sensitivity analysis: time-to-first clinical event, defined as all-cause death, heart transplant, MCSD implantation, HF-related hospitalization, and ambulatory worsening HF; and the average rate and duration of HF-related / CV-related / all-cause hospitalizations over time on study. ;Timepoint(s) of evaluation of this end point: Analyses will be performed when a minimum length of time and cumulative total number of clinical events have happened. Unless discontinued for a terminal event, all s | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoint is time to terminal event, defined as allcause death, heart transplant or MCSD implantation, based on the joint frailty model and performed simultaneously with the primary endpoint analysis. A sensitivity analysis for this secondary endpoint will include the following: various definitions of the study population, time-to-allcause death analysis and a statistical approach based on traditional survival analysis (product-limit point estimates and the log rank test).;Timepoint(s) of evaluation of this end point: Analyses will be performed when a minimum length of time and cumulative total number of clinical events have happened. Unless discontinued for a terminal event, all subjects must have completed the full 12-Month Active Observation Period. This is the minimum length of time that must be met. In addition, the study will continue, even if all subjects have completed the Active Observation Period and the Long-Term Follow-Up Period, until a total of at least 186 adjudicated recurrent events (HF-related hospitalization, ambulatory worsening HF) have occurred. The analyses will occur when both conditions have been met, whichever comes later. | — |
Countries
Belgium, Czech Republic, Denmark, Germany, Hungary, Israel, Netherlands, Poland, Sweden, United Kingdom, United States
Contacts
Public ContactVice President, Clinical Operations
Celladon Corporation
Outcome results
None listed