E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to advanced heart failure (NYHA class III/IV) due to systolic dysfunction |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010684 |
E.1.2 | Term | Congestive heart failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine the efficacy of a single intracoronary infusion of 1 x 10e13 DRP MYDICAR® added to an optimal HF regimen in patients with ischemic or dilated cardiomyopathy and NYHA class III/IV symptoms of heart failure (HF) by reducing the frequency and/or delaying HF-related hospitalizations compared to placebo-treated patients |
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E.2.2 | Secondary objectives of the trial |
Assessment of the safety of MYDICAR® by determining the incidence and severity of AEs and changes in laboratory parameters |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Negative neutralizing AAV1 antibodies (NAb) (titer <1:2) 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 dilated 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 investigational product.
4. Left ventricular ejection fraction (LVEF) ≤35% anytime during the 60-day window prior to administration of investigational product.
5. Diagnosis of NYHA class III/IV HF for a minimum of 90 days prior to screening.
6. 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 (ACC/AHA/ESC HF guidelines) and as updated from time to time:
a. Medical therapy 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 (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.
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 according to ACC/AHA/ESC HF guidelines, 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 investigational 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 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 product.
8. Ability to sign informed consent form and Release of Medical Information Form. |
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E.4 | Principal exclusion criteria |
1. Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening.
2. Restrictive cardiomyopathy, obstructive cardiomyopathy, 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 investigational product 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 <10 g/dL.
14. Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3.
15. Current or history of malugnancy except for basal cell carcinoma.
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 Investigational Product:
-Suspected or active viral, bacterial, fungal or parasitic infection within 48 hours prior to investigational product administration. If an infection does occur, defer infusion for up to 28 days until resolved.
-Significant left main or ostial right coronary artery disease, noted during pre-infusion angiography, requiring immediate intervention.
-No major coronary artery with TIMI grade 3 flow.
-Inability to position the coronary catheters in the coronary ostia in a safe and stable manner. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome is the time-to-recurrent HF-related hospitalizations in the presence of terminal events (all-cause death, heart transplant, LVAD implantation). Efficacy will be further assessed by the sensitivity analyses of 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. Sensitivity analyses for the primary endpoint will include the time-to-first clinical event (including all-cause death, heart transplant and LVAD implantation and HF-related/all–cause hospitalization) and the average rate and duration of HF-related/all-cause hospitalization over time on study. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analyses will be performed when the End of Study occurs. The End of Study is based on a minimum length of time and cumulative total number of clinical events. 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 180 adjudicated HF-related hospitalizations have occurred. The End of Study will occur when both conditions have been met, whichever comes later. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy outcome is the analysis of time-to-terminal event (including all-cause death, heart transplant and LVAD implantation) and will be performed simultaneously with the primary endpoint analysis. The sensitivity analyses for this secondary endpoint will be based on various definitions of the study population and time-to-all-cause death analysis. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Analyses will be performed when the End of Study occurs. The End of Study is based on a minimum length of time and cumulative total number of clinical events. 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 180 adjudicated HF-related hospitalizations have occurred. The End of Study will occur when both conditions have been met, whichever comes later. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Denmark |
Germany |
Netherlands |
Poland |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Based on a minimum length of time and cumulative total number of clinical events. Unless discontinued for a terminal event, all subjects must have completed the full 12-Month Active Observation Period. The study will continue until a total of at least 180 adjudicated HF-related hospitalizations have occurred. The End of Study will occur when both conditions have been met, whichever comes later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |