E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
E.1.2 | System Organ Class | 100000004849 |
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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 |
to assess safety and efficacy of Engineered Human Myocardium (EHM) in patients with terminal heart failure (HFrEF EF <35%) with or without RV dysfunction (TAPSE <16 mm)
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E.2.2 | Secondary objectives of the trial |
to assess effects of EHM-grafts on disease-specific events and symptoms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Heart failure with reduced ejection fraction (HFrEF with EF ≤ 35%) as assessed by high-resolution echocardiography and MRI or CT. 2. At least one hypo- or dyskinetic segment to demark the implant target area. 3. Stable disease condition allowing for an elective left-lateral mini-thoracotomy (for LV applications) or open-chest surgery (for RV applications) for a clinically indicated intervention on the LV (e.g., coronary bypass surgery, valve repair, mechanical circulatory support device implantation) with concomitant RV dysfunction, diagnosed using the Tricuspid Annular Plane Systolic Excursion (TAPSE) index <16 mm (Rudski et al. 2010). 4. 18-80 years of age 5. Previous implantation of an ICD or CRT-D with event recorder 6. New York Heart Association (NYHA) Class III or IV under optimal medical therapy 7. Willingness and ability to give written informed consent 8. Female subjects of childbearing potential must agree to use acceptable method(s) of contraception for the full study duration. |
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E.4 | Principal exclusion criteria |
1. Contraindication to immunosuppressive drugs (e.g. known history of unresolved cancer, hepatitis B/C, HIV, HTLV1) 2. Contraindication to TachoSil® (e.g. hypersenstitivity to human fibrinogen, human thrombin, horse collagen, human albumin, Riboflavin, Natriumchloride, Natriumcitrate, L-Arginin-Hydrochloride) 3. Hypertrophic cardiomyopathy (HCM) 4. Terminal kidney failure (stage 4; GFR <30 ml/min) at the time of enrolment 5. Terminal liver failure (Child-Pugh stage C; score >10) at the time of enrolment 6. Autoimmune disease 7. History of disabling stroke 8. Reduced life expectancy in the short term due to non-cardiac disease 9. Any condition that excludes adherence to study protocol (in particular lack of adherence to prescribed medication) 10. Simultaneous participation in another interventional trial 11. Pregnant or breastfeeding females 12. Known or suspected alcohol and/or drug abuse |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety Endpoint • Part A (Dose Escalation steps): Adverse events related to the procedure, including in particular arrhythmic events and worsening of disease progression within 28 days (based on a comparison of data obtained during visit 2 and visit 7) • Part B: Adverse events related to the procedure, including in particular arrhythmic events and worsening of disease progression within the whole study duration
Primary efficacy endpoint: • Evidence for structural and functional muscular augmentation of target myocardium determined as enhanced target heart wall thickness (HWT) and thickening fraction (HWTF) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key secondary endpoint: • Recurrent HF hospitalizations
Further secondary endpoints: • Left ventricular ejection fraction (EF) • Change in heart failure medication • Functional status in patients as determined by cardiopulmonary stress testing (VO2max), six-minute walk test (6MWT), and hand-grip strength measurements • Patient reported outcomes assessed by NYHA classification, quality of life score (KCCQ, EQ-5D, QoL-VAD), and study adherence motivation (PHQ-9, HAF-17, ESSI, LOT-R, ULS-8, medication adherence, Trust/Mistrust in medical staff) • All-cause and cardiovascular mortality
Secondary Safety Endpoints: • Frequency of major adverse cardiac events (MACE; non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) • Frequency and severity of arrhythmic events • Incidence of immune rejection (allograft DNA, CK/CK-MB, cTnT. DSA) • Incidence of mechanical perturbation of ventricular function by EHM graft • Change in patient reported outcomes assessed by NYHA classification, quality of life score (MLHFQ, KCCQ, EQ-5D), and physical score (SF-36) • All-cause and cardiovascular mortality
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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 | |
E.8.9.1 | In the Member State concerned days | |