Non-ischemic Preservation of the Donor Heart in Heart Transplantation

Study Overview
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Brief Summary
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The study intends to compare standard ischemic cold static storage (ICSS) of retrieved hearts intended to be transplanted, to non-ischemic heart preservation (NIHP) in a randomized clinical multicentre trial. The primary hypothesis is that the non-ischemic hypothermic cardioplegic preservation (NIHP) is safe and superior to ischemic cold static storage (ICSS) of donor hearts. The study will investigate the safety and superiority of the new methodology in terms of improved immediate and prolonged organ function in adult heart transplanted patients.

Detailed Description
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This study will investigate if non-ischemic heart preservation (NIHP) with the XVIVO heart preservation devices could improve clinical outcome of patients receiving hearts after use of the technology compared to after use of standard cold ischemic preservation. This will be investigated in a European multicentre randomized controlled clinical trial. For technical reasons, blinding to the involved clinical personnel is not possible, however, biopsies will be blinded to study pathologists. The trial will include 202 recipients that have been randomized through their heart donor. The primary outcome of the study is a clinically relevant composite including graft survival, primary graft dysfunction, rejection and use of circulatory mechanical support, within 30 days and also including Cardiac Allograft Vasculopathy within 12 months. As secondary outcomes, molecular markers related to cardiac injury CKMB, ProBNP and TNI will be investigated as well as markers of the inflammatory response. Safety aspects such as effect on other organs and machine defects will also be monitored. The study population is adults, listed for heart transplantation and donors accepted as heart donors according to standard hospital procedures. Specific recipient exclusion criteria related to pre-transplant ECMO support, patients undergoing pre-transplant desensitization protocol, patients with Grown-Up Congenital Heart Disease, patients with severe kidney or liver dysfunction, patients with septicaemia, and patients diagnosed with Systemic Lupus Erythematous, sarcoidosis or amyloidosis are excluded. Cardiac death donors and donors with previous sternotomy are excluded. The study hypothesis is that NIHP better preserves the endothelium and myocyte function of the heart resulting in improved short- and medium-term recipient outcome, without inducing any new significant risks to the retrieved heart or the recipient. This is believed to be accomplished through continuous oxygenation of the heart via perfusion of the coronary arteries using an optimized preservation solution, mimicking the normal environment for the endothelium.

Official Title
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Non-ischemic Preservation of the Donor Heart in Heart Transplantation - a Randomized, Controlled, Multicenter Trial

Conditions
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Heart Transplantation

Intervention / Treatment
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* Device: XVIVO heart preservation devices
* Device: Standard ICSS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria recipient: Age ≥18 years Signed informed consent form Listed for heart transplantation Inclusion criteria donor: Age ≥18 and ≤70 years Accepted as heart donor by the transplant team (Research consent from the donor if required in country) Exclusion Criteria recipient: Previous solid organ transplantation Grown-up congenital heart disease (GUCH) Kidney failure eGFR<40 at listing, calculated by CDK-EPI Creatinine, or ultrafiltration or dialysis or rapidly deteriorating kidney function due to a diagnosed renal disease Coagulopathy due to known hepatic disease or heparin induced thrombocytopenia Subject diagnosed with Systemic Lupus Erythematous, sarcoidosis or amyloidosis Known ongoing septicemia defined as positive blood culture immediately prior to the transplant (including with a durable VAD) Incompatible blood group Not able to understand the information provided during the informed consent procedure Combined organ transplantation candidates Subject already enrolled in another transplant related intervention study Subjects under pre-transplant desensitization protocol (including plasma exchange in conjunction with the transplant surgery) Mechanical circulatory support pre-transplantation (except durable Left ventricular assist device or Intra-aortic balloon pump) Exclusion criteria donor: Previous sternotomy DCD hearts

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-ischemic heart preservation (NIHP)<br>Continous cold cardioplegic perfusion of hearts | Device: XVIVO heart preservation devices<br>* The intervention is to preserve hearts during transportation cold, cardioplegic and non-ischemic, with a high oncotic and hormone supplemented perfusate.<br>|
| Active Comparator: Ischemic cold static storage (ICSS)<br>Standard preservation technique | Device: Standard ICSS<br>* Cold static preservation using standard preservation solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30 days mortality and 30 days graft dysfunction | The Primary End-Point is defined as time-to-first-event of cardiac related death, moderate or severe primary graft dysfunction of the left ventricle or primary graft dysfunction of the right ventricle (according to Kobashigawa et al., 2014), acute cellular rejection ≥2R (according to Stewart et al., 2005) or graft failure (use of mechanical circulatory support or retransplantation) within 30 days. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 year mortality and 1 year graft dysfunction | The key secondary endpoint is defined as time-to-first-event of either any cause of death, moderate or severe PGD-LV or PGD-RV (according to Kobashigawa et al., 2014), acute cellular rejection ≥2R (according to Stewart et al., 2005) or graft failure (use of mechanical circulatory support or retransplantation) or CAV ≥ 1 (according to Mehra, 2010) within 12 months. | 1 year | 
| 30 days and 1 year mortality and graft dysfunction | The individual variables included in the composite primary endpoint at 30 days and 1 year analyzed as time-to-first-event. | 30 days and 1 year | 
| CKMB | Creatine kinase MB (CKMB) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal | 3 days | 
| TnI | Tropinin I (TnI) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal | 3 days | 
| ProBNP | Pro Brain Natriuretic Protein (ProBNP) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal | 3 days | 
| Stay in ICU | Length of Stay at Intensive Care Unit, reported as number of days | 1 year | 
| Cardiac Transplant Events | Incidence of Major Adverse Cardiac Transplant Events | 1 year | 
| Postoperative use of mechanical circulatory support | Incidence of use of postoperative mechanical circulatory support, reported as number of days | 1 year | 
| Postoperative duration of mechanical circulatory support | Duration of use of postoperative mechanical circulatory support, reported as number of days | 1 year | 
| Overall success/failure 30 days | Success is defined as a recipient that are transplanted and alive at 30 days without any of the complication in the primary endpoint before 30 days. | 30 days | 
| Overall success/failure 1 year | Success is defined as a recipient that are transplanted and alive at 1 year without any of the complication given in key secondary endpoint before 1 year. | 1 year | 
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage within 24 hours after transplantation | 24 hours | 
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage 1 week after transplantation | 1 week | 
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage 6 months after transplantation | 6 months | 
| ECHO data (Left ventricular ejection fraction) | ECHO data with Left ventricular ejection fraction in percentage 1 year after transplantation | 1 year | 
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage within 24 hours after transplantation | 24 hours | 
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage 1 week after transplantation | 1 week | 
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage 6 months after transplantation | 6 months | 
| ECHO data (Right ventricular ejection fraction) | ECHO data with Right ventricular ejection fraction in percentage 1 year after transplantation | 1 year | 
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm within 24 hours after transplantation | 24 hours | 
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 1 week after transplantation | 1 week | 
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 6 months after transplantation | 6 months | 
| ECHO data (Tricuspid annular plane systolic excursion) | ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 1 year after transplantation | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Ischemic Heart Preservation (NIHP), Ischemic cold static storage of donor hearts (ICSS)