Safety and Efficacy of Induced Pluripotent Stem Cell-derived Engineered Human Myocardium as Biological Ventricular Assist Tissue in Terminal Heart Failure

Study Overview
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Brief Summary
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The BioVAT-HF trial will test the hypothesis that cardiomyocyte implantation via engineered heart muscle (EHM), the proposed investigational medicinal product (IMP; designated Biological Ventricular Assist Tissue or BioVAT), results in sustainable remuscularization and biological enhancement of myocardial performance in the failing heart. EHM are constructed from defined mixtures of induced pluripotent stem cell (iPSC)-derived cardiomyocytes and stromal cells in a bovine collagen type I hydrogel. Comprehensive preclinical testing confirmed the rationale for the clinical translation of the myocardial remuscularization strategy by EHM implantation. The patient target population for EHM therapy is patients suffering from advanced heart failure with reduced ejection fraction (HFrEF; EF: ≤35%) and no realistic option for heart transplantation.

Official Title
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Safety and Efficacy of Induced Pluripotent Stem Cell-derived Engineered Human Myocardium as Biological Ventricular Assist Tissue in Terminal Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Biological: EHM implantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HFrEF (EF ≤ 35%) as assessed by high-resolution echocardiography or MRI No realistic chance or not eligible for heart transplantation At least one hypo- or dyskinetic segment to demark the implant target area 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) with concomitant RV dysfunction, diagnosed using the Tricuspid Annular Plane Systolic Excursion (TAPSE) index <16 mm (Rudski et al. 2010). 18-80 years of age Previous implantation of an ICD or CRT-D with event recorder New York Heart Association (NYHA) Class III or IV under optimal medical therapy Willingness and ability to give written informed consent Female subjects of childbearing potential must agree to use acceptable method(s) of contraception for the full study duration. Exclusion Criteria: Contraindication to immunosuppressive drugs (e.g. known history of unresolved cancer, hepatitis B/C, HIV, HTLV1) Alloimmunisation against EHM implant cells Hypertrophic cardiomyopathy (HCM) Terminal kidney failure (stage 4; GFR <30 ml/min) Terminal liver failure Autoimmune disease History of stroke Reduced life expectancy in the short term due to non-cardiac disease Simultaneous participation in another interventional trial Pregnant or breastfeeding females Known or suspected alcohol and/or drug abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: EHM Implantation<br>All patients will receive EHM implant | Biological: EHM implantation<br>* Implantation of EHM on dysfunctional left or right ventricular myocardium in patients with HFrEF (EF <35%).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target heart wall thickness | Target heart wall thickness (HWT) as determined by high resolution echocardiography and/or CINE-mode MRI (17-segment model). Primary efficacy analyses are based on the changes in HWT between baseline and 2 weeks, 1 month, 3 months, 6 months and 12 months after implantation. To test for a time effect a one-way Repeated Measures ANOVA will be performed for the primary endpoint. In case of detecting a time effect this is followed by Dunnett-type pairwise comparisons to baseline using paired t-Tests. Due to the explorative character of the efficacy analysis testing will be performed at a 10% two-sided significance level. Mean differences will be reported along with 90% confidence intervals. | 12 months | 
| Heart wall thickening fraction | Heart wall thickening fraction (HWTF) as determined by high resolution echocardiography and/or CINE-mode MRI (17-segment model). Primary efficacy analyses are based on the changes in HWTF between baseline and 2 weeks, 1 month, 3 months, 6 months and 12 months after implantation. To test for a time effect a one-way Repeated Measures ANOVA will be performed for the primary endpoint. In case of detecting a time effect this is followed by Dunnett-type pairwise comparisons to baseline using paired t-Tests. Due to the explorative character of the efficacy analysis testing will be performed at a 10% two-sided significance level. Mean differences will be reported along with 90% confidence intervals. | 12 months |