Non-ischemic Preservation of the Donor Heart in Heart Transplantation

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Transplantation
• Intervention / Treatment: Device: XVIVO heart preservation devices; Device: Standard ICSS

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 Type: Interventional
• Enrollment (Actual): 230
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marina Fredholm, M.Sc.; Phone Number: +46 (0)73-3929502; Email: marina.fredholm@xvivogroup.com
• Study Contact Backup: Name: Andreas Wallinder, MD, PhD; Phone Number: +46 (0)73-5192142; Email: andreas.wallinder@xvivogroup.com

Study Locations

• Austria
  • Wien, Austria
    • Allgemeines Krankenhaus der Stadt Wien
• Belgium
  • Flemish Brabant
    • Leuven, Flemish Brabant, Belgium, 3000
      • UZ Leuven
• France
  • Paris, France
    • Hopital Bichat Claude-Bernard
  • Paris Cedex
    • Paris, Paris Cedex, France, 75651
      • Institut de cardiologie, Chirurgie thoracique et cardiovasculaire La Pitié Salpetrière
• Germany
  • Bad Oeynhausen, Germany
    • Universitätsklinik der Ruhr-Universität Bochum
  • Duesseldorf, Germany
    • Universitätsklinikum Düsseldorf
  • Hanover, Germany
    • Hannover Medical School
  • Bavaria
    • München, Bavaria, Germany, 81377
      • Klinikum der Universität München
  • Brandenburg
    • Berlin, Brandenburg, Germany, 13353
      • Deutschen Herzzentrum Berlin
• Italy
  • Padova PD
    • Padova, Padova PD, Italy, 35121
      • Azienda osedalaria di Padova
• Spain
  • Majadahonda Madrid
    • Madrid, Majadahonda Madrid, Spain, 28222
      • Hospital Puerto de Hierro
• Sweden
  • Västra Götalands Regionen
    • Gothenburg, Västra Götalands Regionen, Sweden, 412 34
      • Sahlgrenska University Hospital
• United Kingdom
  • Birmingham, United Kingdom, B152TH
    • Queen Elisabeth Hospital
  • Cambridge, United Kingdom
    • Royal Papworth Hospital
  • Newcastle Upon Tyne
    • Newcastle, Newcastle Upon Tyne, United Kingdom, NE77DN
      • Freeman Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: XVIVO Perfusion
• Investigators: Principal Investigator: Filip Rega, MD, PhD, UZ Leuven

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2020
• Primary Completion (Actual): August 31, 2023
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 18, 2019
• First Posted (Actual): June 19, 2019

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Non Ischemic Heart Preservation (NIHP); Ischemic cold static storage of donor hearts (ICSS)
• Other Study ID Numbers: NIHP2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No