Non-ischemic Preservation of the Donor Heart in Heart Transplantation

• ClinicalTrials.gov Identifier: NCT03991923
• Recruitment Status: Recruiting
• First Posted: June 19, 2019
• Last Update Posted: August 23, 2022
• Sponsor: XVIVO Perfusion
• Information provided by (Responsible Party): XVIVO Perfusion

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Heart Transplantation	Device: XVIVO heart preservation devices; Device: Standard ICSS	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Non-ischemic Preservation of the Donor Heart in Heart Transplantation - a Randomized, Controlled, Multicenter Trial
• Actual Study Start Date: November 25, 2020
• Estimated Primary Completion Date: January 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 30 days mortality and 30 days graft dysfunction [ Time Frame: 30 days ]
   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.

Secondary Outcome Measures :

1. 1 year mortality and 1 year graft dysfunction [ Time Frame: 1 year ]
   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.
2. 30 days and 1 year mortality and graft dysfunction [ Time Frame: 30 days and 1 year ]
   The individual variables included in the composite primary endpoint at 30 days and 1 year analyzed as time-to-first-event.
3. CKMB [ Time Frame: 3 days ]
   Creatine kinase MB (CKMB) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal
4. TnI [ Time Frame: 3 days ]
   Tropinin I (TnI) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal
5. ProBNP [ Time Frame: 3 days ]
   Pro Brain Natriuretic Protein (ProBNP) at 6 ±2 h, 24 ±6 h, 48±6 h and 72±6 h after cross clamp removal
6. Stay in ICU [ Time Frame: 1 year ]
   Length of Stay at Intensive Care Unit, reported as number of days
7. Cardiac Transplant Events [ Time Frame: 1 year ]
   Incidence of Major Adverse Cardiac Transplant Events
8. Postoperative use of mechanical circulatory support [ Time Frame: 1 year ]
   Incidence of use of postoperative mechanical circulatory support, reported as number of days
9. Postoperative duration of mechanical circulatory support [ Time Frame: 1 year ]
   Duration of use of postoperative mechanical circulatory support, reported as number of days
10. Overall success/failure 30 days [ Time Frame: 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.
11. Overall success/failure 1 year [ Time Frame: 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.
12. ECHO data (Left ventricular ejection fraction) [ Time Frame: 24 hours ]
    ECHO data with Left ventricular ejection fraction in percentage within 24 hours after transplantation
13. ECHO data (Left ventricular ejection fraction) [ Time Frame: 1 week ]
    ECHO data with Left ventricular ejection fraction in percentage 1 week after transplantation
14. ECHO data (Left ventricular ejection fraction) [ Time Frame: 6 months ]
    ECHO data with Left ventricular ejection fraction in percentage 6 months after transplantation
15. ECHO data (Left ventricular ejection fraction) [ Time Frame: 1 year ]
    ECHO data with Left ventricular ejection fraction in percentage 1 year after transplantation
16. ECHO data (Right ventricular ejection fraction) [ Time Frame: 24 hours ]
    ECHO data with Right ventricular ejection fraction in percentage within 24 hours after transplantation
17. ECHO data (Right ventricular ejection fraction) [ Time Frame: 1 week ]
    ECHO data with Right ventricular ejection fraction in percentage 1 week after transplantation
18. ECHO data (Right ventricular ejection fraction) [ Time Frame: 6 months ]
    ECHO data with Right ventricular ejection fraction in percentage 6 months after transplantation
19. ECHO data (Right ventricular ejection fraction) [ Time Frame: 1 year ]
    ECHO data with Right ventricular ejection fraction in percentage 1 year after transplantation
20. ECHO data (Tricuspid annular plane systolic excursion) [ Time Frame: 24 hours ]
    ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm within 24 hours after transplantation
21. ECHO data (Tricuspid annular plane systolic excursion) [ Time Frame: 1 week ]
    ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 1 week after transplantation
22. ECHO data (Tricuspid annular plane systolic excursion) [ Time Frame: 6 months ]
    ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 6 months after transplantation
23. ECHO data (Tricuspid annular plane systolic excursion) [ Time Frame: 1 year ]
    ECHO data with Tricuspid annular plane systolic excursion (TAPSE) in mm 1 year after transplantation

Other Outcome Measures:

1. Serious adverse device effects [ Time Frame: 1 year ]
   Incidence of any serious adverse device effects.
2. Adverse device effects [ Time Frame: 1 year ]
   Incidence of any adverse device effects
3. Device dysfunction resulting in loss of transplantable heart [ Time Frame: 12 hours ]
   Number of transplantable hearts lost due to device dysfunction
4. Intra operative details; duration of ECC [ Time Frame: 12 hours ]
   Duration of ECC in minutes
5. Intra operative details; duration of cross clamp [ Time Frame: 12 hours ]
   Duration of cross clamp in minutes
6. Intra operative details; duration of surgery [ Time Frame: 12 hours ]
   Duration of surgery in minutes
7. Intra operative details; attempts to wean off ECC [ Time Frame: 12 hours ]
   Number of attempts to wean off ECC
8. Intra operative details; need for inotropic support [ Time Frame: 12 hours ]
   Need for inotropic support (inotropic score)
9. Intra operative details; need for pulmonary vasodilator [ Time Frame: 12 hours ]
   Need for pulmonary vasodilator
10. Intra operative details; defibrillations [ Time Frame: 12 hours ]
    Number of defibrillations
11. Intra operative details; arryhythmias [ Time Frame: 12 hours ]
    Occurence of arryhythmias
12. Intra operative details; conduction abnormalities [ Time Frame: 12 hours ]
    Number of conduction abnormalities
13. Intra operative details; Left ventricular ejection fraction (LVEF) [ Time Frame: 12 hours ]
    LVEF in percentage
14. Intra operative details; Right ventricular ejection fraction (RVEF) [ Time Frame: 12 hours ]
    RVEF in percentage
15. Intra operative details; Mitral valve regurgitations [ Time Frame: 12 hours ]
    Grade of mitral valve regurgitations
16. Intra operative details; Tricuspid valve regurgitations [ Time Frame: 12 hours ]
    Occurence of tricuspid vavle regurgitations
17. Arterial blood gas lactate [ Time Frame: 6 hours ]
    Arterial blood gas lactate at 6 hours
18. Arterial blood gas lactate [ Time Frame: 24 hours ]
    Arterial blood gas lactate at 24 hours
19. Pro-BNP during follow up [ Time Frame: 1 year ]
    Pro-BNP at predefined time points during follow-up.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Marina Fredholm, M.Sc.; +46 (0)73-3929502; marina.fredholm@xvivogroup.com

Contact: Andreas Wallinder, MD, PhD; +46 (0)73-5192142; andreas.wallinder@xvivogroup.com

Locations

Austria

Allgemeines Krankenhaus der Stadt Wien; Recruiting

Wien, Austria

Contact: Andreas Zuckerman

Belgium

UZ Leuven; Recruiting

Leuven, Flemish Brabant, Belgium, 3000

Contact: Filip Rega +3216344260 filip.rega@uzleuven.be

France

Institut de cardiologie, Chirurgie thoracique et cardiovasculaire La Pitié Salpetrière; Recruiting

Paris, Paris Cedex, France, 75651

Contact: Guillaume Lebreton

Hôpital Bichat Claude-Bernard; Recruiting

Paris, France

Contact: Marylou Para

Germany

Klinikum der Universität München; Recruiting

München, Bavaria, Germany, 81377

Contact: Sebastian Michel

Deutschen Herzzentrum Berlin; Recruiting

Berlin, Brandenburg, Germany, 13353

Contact: Christoph Knosalla

Universitätsklinik der Ruhr-Universität Bochum; Recruiting

Bad Oeynhausen, Germany

Contact: Rene Schramm

Universitätsklinikum Düsseldorf; Recruiting

Duesseldorf, Germany

Contact: Udo Boeken

Hannover Medical School; Recruiting

Hanover, Germany

Contact: Fabio Ius

Italy

Azienda osedalaria di Padova; Recruiting

Padova, Padova PD, Italy, 35121

Contact: Gino Gerosa

Spain

Hospital Puerto de Hierro; Recruiting

Madrid, Majadahonda Madrid, Spain, 28222

Contact: Alberto Forteza

Sweden

Sahlgrenska University Hospital; Recruiting

Gothenburg, Västra Götalands Regionen, Sweden, 412 34

Contact: Göran Dellgren

United Kingdom

Freeman Hospital; Not yet recruiting

Newcastle, Newcastle Upon Tyne, United Kingdom, NE77DN

Contact: Stephen Clark

Queen Elisabeth Hospital; Not yet recruiting

Birmingham, United Kingdom, B152TH

Contact: Aaron Ranasinghe

Royal Papworth Hospital; Not yet recruiting

Cambridge, United Kingdom

Contact: Marius Berman

Sponsors and Collaborators

XVIVO Perfusion

Investigators

• Principal Investigator: Filip Rega, MD, PhD; UZ Leuven

More Information

• Responsible Party: XVIVO Perfusion
• ClinicalTrials.gov Identifier: NCT03991923
• Other Study ID Numbers: NIHP2019
• First Posted: June 19, 2019
• Last Update Posted: August 23, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by XVIVO Perfusion:

Non Ischemic Heart Preservation (NIHP); Ischemic cold static storage of donor hearts (ICSS)