Feasibility Study to Evaluate the Safety of the Autologous GrOwnValve Transcatheter Pulmonary Heart Valve

Study Overview
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Brief Summary
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Aim of this study is to investigate the clinical safety of a novel pediatric heart valve.

Detailed Description
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Defective or diseased pulmonary heart valves do not recover. If left untreated, pediatric and adult patients alike, face serious risks of progressive heart failure and death. Due to the insufficient care of children with heart valve defects, the valve replacement with regenerative, remodeling, and growth potential remains an unmet medical need. Therefore, the first pediatric heart valve (GrOwnValve) was developed to overcome the current limitations, which should offer regenerative potential that adapts to the somatic growth of the child. The study aims to investigate the safety and provide the first initial efficacy estimates of the transcatheter implantable GrOwnValve. This first prospective, non-randomized, single center trial in 7 study subjects (≥ 18 years of age) should be conducted to assess the devices safety for clinical application. The novel interdisciplinary solution approach is based on the combination of individualized 3D modeling, viable autologous tissue (contrary to all other prosthetic heart valves on the market), and preservation of the regenerative capacity of the valve replacement by maintaining the vitality of heart valve cells and tissue through the application of a novel crosslinker in the tissue preparation process. The GrOwnValve prothesis has the potential to be the first durable and regenerative heart valve for adults. Fabrication is performed on-demand in the operating room. The trial should be the first clinical investigation assessing this novel heart valve replacement approach. We are aiming for the GrOwnValve to be the standard of care, replacing current solutions.

Official Title
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A First-in-Human Feasibility Study to Evaluate the Safety (and Short Term Effectiveness) of the Autologous GrOwnValve Transcatheter Pulmonary Heart Valve [GECT]

Conditions
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Pulmonary Valve Insufficiency

Intervention / Treatment
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* Device: GrOwnValve - novel heart valve replacement approach


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years, Intact appropriate tissue (preferably: Pericardium for pericardiectomy via thoracoscopy or thoracotomy; other option fascia lata, rectus fascia, or diaphragm), Any of the following by transthoracic echocardiography and/or Cardiac Magnet Resonance Imaging: For patients in New York Heart Association (NYHA) Classification II, III, or IV: Moderate (3+) or severe (4+) pulmonary regurgitation AND/OR mean systolic gradient across PV or RVOT ≥ 35 mmHg For patients in NYHA Classification I: Severe (4+) pulmonary regurgitation with RV dilatation or dysfunction and/or mean PV or RVOT systolic gradient ≥ 40 mmHg Written informed consent provided by study subjects and/or their parents or legal guardians as approved and required by the respective institutional review board and agrees to its provisions, and obtained before any research related test is performed Exclusion Criteria: Lack of pericardium, or other appropriate tissue Active endocarditis or myocarditis or within 3 months before the screening date Patient or guardian unwilling or unable to provide written informed consent or comply with follow-up requirements Obstruction of the central veins (including the superior and inferior vena cava, bilateral iliac veins) such that the ensemble delivery system cannot be advanced to the heart via a transvenous approach from either femoral vein or internal jugular Pre-existing mechanical heart valve in any position Requires emergency surgery Need for concomitant additional mitral and tricuspid valves surgery Recipient of transplanted organs or currently an organ transplant candidate Pulmonary hypertension Connective tissue disorders Coronary artery disease Immunosuppressive disease Estimated survival less than 6 months Fertile females unable to take adequate contraceptive precautions, pregnant, or are currently breastfeeding an infant Acute myocardial infarction within 30 days to the screening date Stroke confirmed by CT, cerebrovascular accident (CVA), or transient ischemic attack (TIA) within 6 months before the screening date Hemodynamic or respiratory instability requiring inotropic or/and mechanical circulatory support, or mechanical ventilation within 30 days before the screening date Severe left ventricular systolic dysfunction with ejection fraction ≤ 20% or evidence of an intra-cardiac mass, thrombus, or vegetation assessed by echocardiography before the screening date Renal insufficiency with creatinine level 2.5 mg/dl within 60 days before the screening date Leukopenia with WBC <3.5 x 109/L anemia with Hgb <10 g/dl, or thrombocytopenia with platelet count <50x103/l accompanied by a history of bleeding diathesis or coagulopathy within 60 days before the screening date Adult subject is an illicit drug user, alcohol abuser, prisoner, untreated psychiatry (limited compliance), or unable to give informed consent Clinical Research | ECS - full application | Application template | CR.2-A2 |Mar. 2021 3/25 Major or progressive non-cardiac disease (liver failure, renal failure, cancer)that has a life expectancy of less than one year Inability to comply with all of the study procedures and follow-up visits Patients requiring pre-stenting for dilatation RV outflow greater than 30mm or that a 30mm stent can be used

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
Interventional Model Description: Non-inferiority analysis with standard of current medical care
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Implantation of autologous GrOwnValve<br>Implantation of autologous GrOwnValve via minimal-invasive transcatheter technique into patients with high-grade pulmonary valve insufficiency and right ventricular dilatation. | Device: GrOwnValve - novel heart valve replacement approach<br>* The autologous GrOwnValve is implanted into a stent before it is implanted via minimal-invasive transcatheter technique into the patients with high-grade pulmonary valve insufficiency and right ventricular dilatation. Control intervention/Reference test: Since the study is designed for investigating the safety of the procedure, there will not be a control group. However, the outcomes will be compared as a non-inferiority analysis with the standard of current medical care (Edwards SAPIEN 3 or Medtronic's Melody, both bioprosthetic transcatheter pulmonary valves).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | (valve-related, sudden, cardiac, and all-cause death) | Up to 5 Years Follow-Up | 
| Major bleeding | Assessment if device-related major bleeding has occured by laboratory + echo + CT | Up to 1 Year Follow-Up | 
| Reoperation | Questioning if device-related re-operation occured | Up to 5 Years Follow-Up | 
| Acute device-related complications | Measurement tool: Spiroergometry o Parameters: cardiac rhythm, load duration, reason for termination, Heart rate at rest, blood pressure, maximum load level, VE/VCO2, PetCO2, VE/VCO2 slope, VO2, Respiratory rate, VD/VT, SpO2, RER, Borg score, FEV1, FVC | Up to 5 Years Follow-Up | 
| Oxygen supply | Measurement tool: Spiroergometry Parameters: cardiac rhythm, load duration, reason for termination, Heart rate at rest, blood pressure, maximum load level, VE/VCO2, PetCO2, VE/VCO2 slope, VO2, Respiratory rate, VD/VT, SpO2, RER, Borg score, FEV1, FVC | Up to 5 Years Follow-Up | 
| Valve opening and closure behavior | Measurement tool: Echocardiography + Magnetic resonance imaging Parameter: 1.) blood flow velocity / stenosis, 2.) stiff leaflet, 3.) valve opening area Decision rule: blood flow velocity >4 m/s, abnormal or no leaflet motion when compared to neighboring leaflets, > 0.70 for 17 diameter, > 0.85 for 19, > 1.05 for 21, > 1.25 for 23, > 1.45 for 25, > 1.70 for 27, 1.95 for 29, and 2.25 for 31 mm annulus diameter | Up to 5 Years Follow-Up | 
| Valve closure behavior | Measurement tool: Echocardiography + Magnetic resonance imaging Parameter: 1.) vena contracta, 2.) Proximal Isovelocity Surface Area (PISA) radius, 3.) Effective regurgitation orifice area (EROA=2π*r2*Va/Vmax), (iv) sagging leaflet Decision rule: 1.) less than or equal to 15% of the diameter of PA/stent at a Nyquist limit of 0.5-0.6 m/s, frame rate >20/sec, gain adjusted, sector small, 2.) equal or minor to 4 mm at a Nyquist limit of 0.2-0.4 m/s, frame rate >20/sec, gain adjusted, variance off, sector small, 3.) < or equal to 3% of the total cross-sectional area of the valve, 4.) n.a | Up to 5 Years Follow-Up | 
| Heart rhythm | Assessment if new or higher grade of cardiac arrhythmia occured, i.e. newly ventricular extra systoly | Up to 5 Years Follow-Up | 
| Position and condition of the stent and structures | Measurement tool: Echocardiography + Magnetic resonance imaging + computed tomography Parameter: 1.) GrOwnValve annulus, 2.) no broken struts of the valve stent Decision rule: 1.) +/- 1.5 mm from the native pulmonary valve annulus, 2.) n.a. | Up to 1 Year Follow-Up | 
| Blood flow | Assessment of backflow and volume of blood by echo + MRI | Up to 1 Year Follow-Up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Availability of pericardium or other tissue for preparation of autologous pulmonary valve graft | Visual assessment of pericardium | Procedure (intra-operatively) | 
| Post-procedure length of stay | Post-procedure hospital stay in days. | Up to day of discharge ( ≤ 30 days) | 
| Ventilation time | Timepoints: Procedure Assessment: How long was the ventilation time for each patient within the allocation? | Procedure (intra-operatively) | 
| Freedom from conduction disturbances and arrhythmias need for permanent pacemaker implantation | Timepoints: Procedure + Discharge + Visit 1 Assessment: Is the implantation of a permanent pacemaker necessary due to disturbances or arrhythmias? | Up to 3 months Follow-Up | 
| (Re-)Hospitalization | Timepoints: Discharge, Visit 1, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, Visit 8 Assessment: Is a (Re-)Hospitalization necessary due to procedure- or device-related complications? | Up to 60 months (5 years) Follow-Up | 
| Comparison of pericardiectomy (if applicable) via thoracoscopy vs. thoracotomy | Timepoints: Procedure Assessment: How was the pericardiectomy conducted, via thoracoscopy or thoracotomy | Procedure (intra-operatively) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medical Need, Heart Valve Replacement, Pulmonary Valve, Congenital Heart Diseases, Transcatheter Valve, Durable, One-time-solution, Autologous Living Tissue