Article Text

Protocol
Non-ischaemic preservation of the donor heart in heart transplantation: protocol design and rationale for a randomised, controlled, multicentre clinical trial across eight European countries
  1. Janne Brouckaert1,
  2. Göran Dellgren2,
  3. Andreas Wallinder3,
  4. Filip Rega1
  1. 1Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium
  2. 2Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
  3. 3XVIVO Perfusion AB, Gothenburg, Sweden
  1. Correspondence to Dr Filip Rega; filip.rega{at}uzleuven.be

Abstract

Introduction Ischaemic cold static storage (ICSS) is the gold standard in donor heart preservation. This ischaemic time frame renders a time constraint and risk for primary graft dysfunction. Cold oxygenated heart perfusion, known as non-ischaemic heart preservation (NIHP), theoretically limits the ischaemic time, while holding on to the known advantage of hypothermia and cardioplegia, a low metabolic rate.

Methods and analysis The NIHP 2019 study is an international, randomised, controlled, open, multicentre clinical trial in 15 heart transplantation centres in 8 European countries and includes 202 patients undergoing heart transplantation, allocated 1:1 to NIHP or ICSS. Enrolment is estimated to be 30 months after study initiation. The patients are followed for 12 months after transplantation.

The primary objective is to evaluate the effect of NIHP on survival, allograft function and rejection episodes within the first 30 days after transplantation. The secondary objectives are to compare treatment groups with respect to survival, allograft function, cardiac biomarkers, rejection episodes, allograft vasculopathy, adverse events and adverse device effects within 12 months.

Ethics and dissemination This protocol was approved by the Ethics Committee (EC) for Research UZ/KU Leuven, Belgium, the coordinating EC in Germany (Bei Der LMU München), the coordinating EC in the UK (West Midlands—South Birmingham Research), the EC of Hospital Puerta de Hierro, Madrid, Spain, the EC of Göteborg, Sweden, the coordinating EC in France, the EC of Padova, Italy and the EC of the University of Vienna, Austria. This study will be conducted in accordance with current local regulations and international applicable regulatory requirements according to the principles of the Declaration of Helsinki and ISO14155:2020. Main primary and secondary outcomes will be published on modified intention-to-treat population and per-protocol population.

Trial registration number NCT03991923.

  • Heart failure
  • Cardiac surgery
  • Cardiology
  • TRANSPLANT SURGERY
  • TRANSPLANT MEDICINE
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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • A large randomised, controlled, open, multicentre clinical trial comparing the use of non-ischaemic heart preservation (NIHP) versus conventional ischaemic cold static storage (ICSS) in heart transplantation.

  • NIHP is a promising new strategy using continuous hypothermic oxygenated perfusion of the graft, avoiding ischaemic damage to the preserved heart prior to transplantation.

  • It is hypothesised that NIHP can optimise donor heart preservation, thereby minimising ischaemia-reperfusion injury in heart transplantation, and improving heart transplant outcomes compared with ICSS.

  • Follow-up will be conducted and reported at 30 days and at 1 year.

  • Randomisation of the recipients is performed when a matching donor heart is allocated, but before final acceptance of the donor heart. When the donor heart is not deemed suitable for transplantation during the organ procurement procedure, the already randomised recipient remains in the assigned study group on the waiting list. If study criteria are met at the time of the next donor heart allocation, the donor heart will be procured according to the original randomisation.

Introduction

Ischaemic cold static storage (ICSS) is the gold standard for preserving and transporting a heart donated after brain death prior to transplantation. The duration of the ischaemic time correlates directly to the recipient outcome.1 2 This effect is even more pronounced using hearts from older donors.3 The important time constraint that comes along with the process of transplantation is costly and results in important logistical limitations. Therefore, new techniques to prolong the acceptable preservation time for donor hearts can simplify logistics, improve survival after transplantation and increase the donor pool worldwide.

Ischaemia in heart donation after brain death occurs when the donor heart is arrested through the administration of a cold cardioplegic solution and persists during subsequent transportation to the recipient site. This results in tissue hypoxaemia, acidosis and microvascular dysfunction. Reperfusion with warm oxygenated blood exacerbates graft damage through ischaemia-reperfusion injury, leading to apoptosis and necrosis of the affected cardiomyocytes. The resulting graft injury and subsequent cell degradation enhance the immune responses.4

Longer ischaemic time (>4 hours) negatively impacts both short-term and long-term survival. According to the International Society of Heart and Lung Transplantation (ISHLT) registry, up to 60% of deaths that occur during the first 30 days after heart transplantation (HT) are due to graft failure and multiorgan dysfunction.5 A major cause of early death after HT is severe primary graft dysfunction (PGD), of which the duration of graft ischaemia is identified as an important and independent risk factor. Only 48% of the HT recipients who developed severe PGD postoperatively survived to 1-year post-transplant. Longer ischaemic time is also known to aggravate the ischaemia-reperfusion injury on HT and continues to impact survival after transplantation beyond the immediate postoperative course.6 Moreover, the impact of longer ischaemic time on survival is amplified with increasing donor age, because heart allografts from older donors appear to be more vulnerable to graft ischaemia.3 7

At present, there is little consensus about what type of preservation solution to use for cardioplegic arrest and ICSS. The most commonly used heart preservation solutions for ICSS are Celsior, University of Wisconsin (UW), Custodiol (HTK) and St. Thomas solution (Plegisol). Supplemented XVIVO heart solution (SXHS) is a hyperoncotic cardioplegic solution supplemented with catecholamines, hormones and cocaine, intended to be used both for the cold cardioplegic flush of the donor heart on heart procurement and for machine perfusion of the heart using the XVIVO heart box. SXHS is expected to improve preservation and is used together with continuous oxygenated perfusion of the heart graft at 8°C, in all constituting non-ischaemic heart preservation (NIHP).8 9

Pressure-controlled oxygenated perfusion of the heart graft in the XVIVO heart box has ensued through an aortic cannula with cold (8°C) cardioplegic nutrition-hormone supplemented solution containing red blood cells. The XVIVO heart box with sterile disposable consists of an oxygenator, a reservoir, a heater-cooler unit, a gas mixer, a leucocyte filter and a pressure-controlled roller pump. During graft perfusion, temperature, perfusion pressure and flow are monitored. In the event of a device failure, the heart graft remains stored in a stable hypothermic environment and might still be transplanted.8–10

NIHP combines the advantages of hypothermia, cardioplegia and oxygenated perfusion. Therefore, the heart graft is reoxygenated in a controlled fashion while cellular metabolism is reduced. This limits graft damage and it is hypothesised that it might minimise the ischaemia-reperfusion injury.10–12 The use of NIHP for heart preservation may improve short-term and long-term post-transplantation outcomes.

Preclinical studies demonstrated successful transplantations after 24 hours of NIHP.8 In a porcine model of orthotopic HT, implementing 24 hours of NIHP, all 10 test group recipients were successfully weaned off extracorporeal circulation (ECC) at 17–35 min postreperfusion and had stable haemodynamics during the 24-hour post-transplantation observation period. In contrast, the control group (ICSS) recipients were difficult to wean off ECC and all died within 1 hour after weaning.8

Längin et al describe how heart preservation by NIHP obtained significantly improved survival in genetically modified pig-to-baboon orthotopic cardiac xenotransplantation. By using improved donor heart preservation techniques (NIHP), the important and fatal perioperative cardiac xenograft dysfunction was avoided.12 13 Optimal oxygenated preservation of the cardiac xenograft by NIHP is of utmost importance and was applied in the first pig-to-human cardiac xenotransplantation reported in 2022.14

Nilsson et al reported the first in human use of NIHP in HT. They performed a prospective, open-label, non-randomised phase II study comparing NIHP to ICSS. In this report (NCT03150147) 6 patients received a donor heart preserved by the NIHP method, compared with a control group of 25 patients where the donor heart was preserved by ICSS. All of the NIHP patients had an event-free survival during the first 6 months, compared with 18 of the ICSS patients (72%). These results provide initial evidence that the NIHP devices and methodology are safe in a clinical context.10

Given the importance of limiting graft ischaemia in HT and the promising results using NIHP in preclinical and clinical trials, we are conducting an international, randomised, controlled, open, multicentre clinical trial to evaluate the use of heart graft preservation by NIHP on short-term and long-term survival, allograft function, rejection episodes and allograft vasculopathy, compared with standard ICSS in HT using heart donation after brain death.8–10 13 We hypothesise that avoiding ischaemia and providing essential elements for the normal physiology of the donor heart will translate into less organ damage and improved clinical outcome compared with ICSS.

Methods and analysis

Study design

The purpose of this randomised controlled trial (RCT) is to evaluate if NIHP using the XVIVO heart preservation devices is safe and superior to conventional ICSS of hearts donated after brain death. The primary hypothesis is that NIHP improves early and late post-transplantation outcomes, such as survival, development of PGD and rejection episodes.

The NIHP2019 trial is an international, randomised, controlled, open, multicentre clinical trial, with a target recruitment of 202 patients. On 25 November 2020, the first study patient underwent HT with heart preservation using NIHP. The estimated study completion date is 1 May 2024. The NIHP group (test) and ICSS group (control) are allocated in 1:1 proportion. Blinding is not possible to apply. However, pathologists evaluating grades of rejection on biopsies, as well as other investigators performing echocardiograms and coronary angiographies, will not be informed about the treatment group. The Standard Protocol Items with Recommendations for Interventional Trials (SPIRIT) were used.15 The participating centres and prinicpal investigators (PIs) are summarised in online supplemental material: list of PI’s NIHP2019.

Patient selection

Recipient and donor inclusion and exclusion criteria are summarised in table 1.

Table 1

Summary of the donor and recipient inclusion and exclusion criteria

Study intervention

When the donor heart is preserved by ICSS, the heart is flushed with a cold crystalloid cardioplegic solution, placed in multiple sterile organ bags containing this cardioplegic preservation solution and transported on ice. The exact type of cardioplegic solution depends on site-specific standards.

When the donor heart is preserved by NIHP, the heart is flushed with cold SXHS, followed by continuous hypothermic oxygenated perfusion in the XVIVO heart box. The perfusate consists of SXHS, which is a hyperoncotic cardioplegic solution supplemented with catecholamines, hormones and cocaine. At preparation of the XVIVO heart box, a sterile disposable is primed with the SXHS, heparin, insulin, antibiotics and two units (300–500 mL) of packed red blood cells. This perfusate is continuously oxygenated using carbogen gas. At organ procurement, the donor heart is arrested using cold SXHS as cardioplegic flush. After cardiectomy, a perfusion cannula is placed in the ascending aorta of the graft and a soft vent is placed through the mitral valve to prevent left ventricle distension during perfusion. The heart graft is connected to the device, followed by a deairing flush. Pressure-controlled perfusion at a set pressure (20 mm Hg) is started and the donor heart is submerged in the hypothermic perfusion solution (8°C). The coronary flow rate is dependent on the size of the heart and the vascular resistance but is typically 100–250 mL/min. The XVIVO heart box containing the perfused donor heart weighs around 30 kg and can be easily transported. Temperature, perfusion pressure and flow are monitored during all stages of graft perfusion. Perfusion is fully automated, and no interventions are needed during the perfusion. In the event of a device failure, the heart graft remains stored in a stable hypothermic environment and might still be transplanted.8 9

Study groups

All patients receive detailed written and verbal information about the purpose of the study and the study design by their physician at the time of enlistment for transplantation. It is emphasised that participation is voluntary, by signing an informed consent form, and that withdrawal at any time is possible without providing a specific reason. The only difference between the study groups is the method of donor heart preservation prior to HT. There will be no difference in waiting list time, surgery or follow-up. The burden of the intervention and time required to participate in the trial is limited and similar to standard HT.

Randomisation with 1:1 proportion is done through a web-based computer program with balancing on the following baseline variables:

  • Donor age <40 years or ≥40 years.

  • Donor and recipient gender.

  • Recipient age <60 years or ≥60 years.

  • Recipient preoperative ventricular assist device.

When a donor heart is identified, accepted according to standard organ assessment procedures and matched to a patient enrolled in the study, randomisation to either ICSS (control group) or NIHP (test group) is performed. This allows time to prime the XVIVO heart system before transportation of the procurement team to the donor site. If priming of the device would be performed before randomisation, this would create an unacceptable waste of material and banked blood when the patient is randomised to the ICSS arm. On the other hand, priming the XVIVO heart system after final donor heart acceptance at the donor site could potentially result in increased ischaemic times, as the donor heart would be stored by ICSS during priming of the device. Therefore, randomisation is done after matching of the donor heart to the recipient, but before final organ acceptance. This means that there is the possibility of on-site organ rejection when the patient has already been randomised. If last minute organ rejection occurs, details of the assessment and rejection will be recorded and the randomised recipient remains in the assigned group. If study criteria are met at the time of the next donor offer, the donor heart will be procured according to the original randomisation. All randomised patients will be followed until they either receive a heart, are removed from the transplant waiting list or develop an exclusion criteria for the trial. After HT, the patients will be followed for 12 months starting from the transplant date. An overview (figure 1) displays the allocation, randomisation and transplantation process.

Figure 1

Overview as a guide through the allocation, randomisation and transplantation process. HT, heart transplantation; ICSS, ischaemic cold static storage; NIHP, non-ischaemic heart preservation; XHS, XVIVO heart solution.

Both ICSS and NIHP patient groups will receive standard medical care, based on clinical practice protocols and on the patients’ individual medical needs. The patient’s short-term follow-up is 30 days and the long-term follow-up is 12 months.

Data collection

Preoperative data are collected, including demographic information, medical history and status at time of transplant. Detailed donor history is collected, including demographic information, medical history and data from the current hospitalisation.

Procedural data with procurement and preservation time points, perfusion or ICSS details, such as the type of preservation solution (ICSS) or any adverse device effects and perfusion data (NIHP) are recorded.

During transplantation, baseline blood samples are taken at induction to perform cardiac enzyme analysis and measurement of organ function. Intraoperative parameters and details specific to the HT are recorded. A transoesophageal echocardiography is performed to assess ventricular and valvular function. The presence of PGD is assessed at fixed time points. Postoperatively, a cardiac ultrasound is performed at defined time points. Duration of stay at the intensive care unit, date and time of hospital discharge will be recorded.

All patients will undergo post-transplantation assessments according to the standard clinical schedule, including follow-up myocardial biopsies graded for rejection according to the ISHLT classification.16 At 1-year post-transplantation, a coronary angiogram will be performed to assess the development of cardiac allograft vasculopathy (CAV). Coronary artery pathology will be reported according to the ISHLT recommended nomenclature for cardiac graft vasculopathy.17 All data will be manually collected and transferred to an elctronic case report form (eCRF).

Study outcomes

A summary of the primary, secondary, technical safety and exploratory endpoints can be found in table 2. Additionally, a copy of the trial registry outcome measures can be found in online supplemental material.

Table 2

Summary of the primary, secondary, technical and exploratory endpoints

The primary endpoint is defined as time-to-first-event of either cardiac-related death, moderate or severe PGD of the left ventricle or PGD of the right ventricle,5 acute cellular rejection ≥2R (according to the 2005 ISHLT consensus16), or graft failure requiring mechanical circulatory support or retransplantation within 30 days.

PGD must occur within the first 24 hours after completion of the HT and cannot be related to a discernable cause (such as acute rejection, sepsis or bleeding) to fulfil the definition. PGD-LV includes left ventricular failure and biventricular failure; and PGD-RV includes only right ventricular failure. Definitions of PGD are summarised in table 3.5

Table 3

Overview of primary graft dysfunction (PGD) definitions5

The key secondary endpoint is defined as time-to-first-event of either any cause of death, moderate or severe PGD (of the left or right ventricle),5 acute cellular rejection ≥2R (according to the 2005 ISHLT consensus16), graft failure requiring mechanical circulatory support or retransplantation or CAV≥1 (according to the 2010 ISHLT consensus17), within 12 months.

Multiple donor and recipient-related factors interplay and affect graft function. The ISHLT criteria include a subjective component where graft dysfunction, caused by factors not directly related to the function of the allograft, should not be classified as PGD. In the current trial, all reported events of PGD as well as any use of mechanical circulatory support will be assessed and classified by an independent, blinded adjudication committee. The same committee will classify the cause of death as related to or not to a failing allograft. If a donor heart is perfused on the investigational device or transported on ICSS but not transplanted, the same committee will assess if the reason for not using the heart was related to the use of the device. The committee will have access to all collected study data, adverse event (AE) reports and medical records after blinding and deidentification. The committee may further request any additional, relevant clinical information to be provided.

Logistical aspects of surgical transplant RCT

The complex logistics inherently involved in the donation and transplantation process required randomisation of the recipients before final acceptance of the donor heart. At the time of designing the trial, three different options were assessed for managing the scenario where a donor heart is rejected for transplantation at the final organ assessment. These options were: (a) exclusion of the randomised recipient from the trial, (b) rerandomisation of the recipient at the time of the next donor allocation or (c) to respect the initial randomisation where the randomised recipient remains in the assigned study group. The latter option was deemed as most methodologically sound, despite the potential caveat of investigators being aware of the allocated treatment arm for a few subjects on the waiting list at the moment of a donor heart offer. However, this strategy implies that a randomised, but not yet transplanted, subject may develop exclusion criteria while awaiting a new donor heart allocation, or that the next donor may not fulfil study criteria, or that the allocated treatment may not be available at the time of the donor offer. In these scenarios, the subject will be excluded from the main analysis (modified intention to treat (mITT) and per protocol (PP)) of the trial but still followed for safety and included in the overall analysis performed on the ITT population.

Statistical analysis plan

The statistical analysis plan (SAP) will be finalised and signed off before the database lock. Any changes or additional analyses will be documented in an amendment to the SAP.

Study populations

The ITT principle, in which all subjects will be included in their assigned treatment groups regardless of preservation method, will be used for the ITT analyses.

  • Important to note is that the ITT population will likely include patients who were never transplanted, due to randomisation prior to on-site evaluation of the donor heart. Therefore, this population cannot be used for the main analyses.

  • The mITT population consists of all patients who were randomised and transplanted while fulfilling inclusion and exclusion criteria at the time of transplantation and will be used for the primary outcome, secondary outcomes and other analyses when appropriate.

The PP population will consist of all transplanted subjects without major protocol violations who were randomised and transplanted while fulfilling inclusion and exclusion criteria at the time of transplantation with the allocated treatment available at the time of the donor procedure. The PP population will be used for the primary outcome, secondary outcomes and other analyses when appropriate. The safety population will consist of all patients who were randomised and underwent HT. Patients will be allocated to the actual treatment group in the safety analyses.

The technical safety donor heart population will consist of all donor hearts that were deemed suitable for HT. Donor organs that were declined after or during transport and subsequently never transplanted will be included in this population.

General methods

All main analyses will be performed on the mITT and PP populations and complementary analyses will be performed on the PP population. The primary analysis and all secondary analyses of time-to-event variables between the two randomised groups will be analysed unadjusted with the log-rank test, and the results will be displayed with Kaplan-Meier graphs. Event incidence will be portrayed through event rates, calculated as the total a number of events divided by the total number of follow-up time. To estimate the precision, 95% CIs will be computed using the exact Poisson limits. The magnitude of the effect size will be described by HRs derived from Cox proportional hazards models. In time-to-event models, where not all causes of death are included, competing risk will be considered.

The study used optimal allocation based on donor age, gender of the donor, recipient age, gender of the recipient and recipient preoperative ventricular assist device (yes/no). For adjusted analysis between the two randomised groups regarding time-to-event variables, multivariable Cox proportional hazards models will be used adjusted for the stratification variables. If the proportional hazard assumption is not fulfilled for some covariates, then these variables will be stratified for in the multivariable Cox model.

If any confounding variables are identified, those that exhibit significant associations with both the outcome and the treatment group, complementary analyses will be conducted adjusting for these statistically identified confounders. For unadjusted comparison between the two randomised groups, Fisher’s exact test will be used for dichotomous variables, Fisher’s non-parametric permutation test for continuous variables, Mantel-Haenszel χ2 trend test for ordered categorical variables and χ2 test for non-ordered categorical variables. For analyses of number of events, Poisson regression models will be considered.

For all unadjusted and adjusted analyses between the two groups, mean differences and ratios with 95% CI will be calculated whenever possible. All significance analyses will be two sided and conducted at the 5% significance level if not otherwise stated.

Standard methods for descriptive analysis will be used. Continuous variables will be described with mean, SD, median, first quartile, third quartile and categorical variables with numbers and percentages.

Sample size determination

Based on registry data and current incidences of post-transplantation morbidity among the participating centres, it is anticipated that the control group in the study will experience the primary composite endpoint at a rate of 35% within 30 days. We expect that the NIHP group will achieve a 60% reduction in the primary endpoint. To ensure a minimum power of 80%, with a two-sided log-rank test at a significance level of 0.05; 101 evaluable patients will need to be included in each group.

For the key secondary composite endpoint, it is anticipated that the control group will have a frequency of 45% at 12 months. We assume that the NIHP group will achieve a 60% reduction in the secondary endpoint. By enrolling 101 patients in each group and using a two-sided log-rank test, we will achieve a power of at least 93%.

Primary efficacy analysis

The primary analysis time to composite endpoint at 30 days will be tested between the two groups with log-rank test at significance level of 0.05. HR with 95% CI will be calculated with Cox proportional hazards model. Kaplan-Meier graphs will be used to graphically present the data. The adjudicated primary endpoint will be used in the analyses, regardless of its correspondence with the investigator’s assessment.

Following sensitivity and complementary analyses will be additionally performed:

  • Handling death for other reasons than cardiac-related as competing risk, tested by Gray’s test.

  • Replacing cardiac-related component with any cause of death, tested by log-rank test.

  • Adjusted for optimal allocation variables, tested by Cox proportional hazards model.

  • Adjusted for potential statistically identified confounders, tested by Cox proportional hazards model.

  • Event-free survival at 30 days, tested by Fisher’s exact test.

Secondary efficacy analyses

If the primary analysis yields a significant result, the probability mass from this initial test will be transferred to the key secondary analysis, which pertains to the time to composite endpoint at 365 days. The same methodology employed for the primary variable will be applied in this case. If this key secondary analysis also produces significant results, then both results will be considered confirmed. For the other secondary variables, the p values will be given for descriptive purposes and no multiplicity adjustment will be performed. These analyses will be considered exploratory. The adjudicated secondary endpoints will be used in the analyses, regardless of its correspondence with the investigator’s assessment.

Exploratory analyses of interactions with treatment effect

Analysis of interaction of treatment effect will be performed on the mITT population for variables potentially affecting post-transplantation outcomes of the primary and selected secondary endpoints, including transplant centre, length of ischaemic time (≤ vs >4 hours), donor and recipient characteristics, intraoperative variables (eg, duration of ECC and cross-clamp, echocardiographic findings). For all baseline variables with significant interaction (p<0.10), subgroup analyses will follow.

Safety analyses

The incidence of AEs will be presented overall and per system organ class and preferred term coded by MedDRA for each treatment group for the safety population. AEs will be presented by seriousness, including a separate listing of deaths, severity and relation to treatment.

Data monitoring and quality assurance

Data monitoring and source data verification are predefined in the trial monitoring plan to ensure quality assurance. Web-based central monitoring by data management will ensure continuous review of data and support on site monitoring. Local monitors, independent of the investigational trial sites, will be responsible for all aspects of the monitoring process including site initiation, training, device accountability, regulatory documentation, periodic monitoring visits or remote monitoring sessions, site compliance and site close-out visits. At each study site, 100% source data verification will be performed by the monitor on the first three transplanted subjects and for every fifth of the subsequently transplanted subjects. Periodic monitoring visits will begin after the first subject is transplanted and will regularly occur until investigation closure. As a minimum, periodic monitoring of each site will occur twice a year.

Independent data and safety monitoring board

An independent data and safety monitoring board (DSMB) is appointed consisting of physicians and statisticians. A first safety analysis will be performed when the first 30 patients have been enrolled and followed for 30 days. Subsequent safety analyses will be performed at regular time intervals during the trial. The study will be suspended if suspicion of an unacceptable risk to patients arises, based on AE/serious AE reporting primarily, during the study or when so instructed by ethics committee or regulatory authority.

Patient and public involvement

Neither patients nor the public were involved in the design and conduct of the study and they will not be involved in interpretation, reporting or dissemination of the trial.

Ethics and dissemination

This protocol has been approved by the Ethics Committee (EC) for Research UZ/KU Leuven in Belgium (reference: S62936), the coordinating EC in Germany (Bei Der LMU München, reference: 19-0935 fed), the coordinating EC in the UK (West Midlands—South Birmingham Research EC, reference: 20/WM/0171 and 267036), the EC of Hospital Puerta de Hierro in Madrid, Spain (reference: 65/19), the EC of Göteborg, Sweden (reference: Dnr 2020-02537), the coordinating EC in France (reference: 20.00945.254028), the EC of Padova, Italy (reference: 4925/AO/20 and AOP1975) and the EC of the University of Vienna, Austria (reference: 1300/2021). This study will be conducted in accordance with current local regulations of the individual participating centres and international applicable regulatory requirements according to the principles of the World Medical Association Declaration of Helsinki and the ISO14155:2020.

This clinical trial will establish whether the use of NIHP is safe and preferred for donor heart preservation prior to HT. A DSMB will closely monitor the trial for safety.

The main primary and secondary outcomes will be published on mITT and PP populations. The final results will be presented at major meetings and regional seminars and published in journals. The study will generate two main articles in peer-reviewed journals, presenting 30-day and 1-year results, respectively.

All data will be collected, coded and anonymised in an online tool. All registered investigators can access this online tool. If important protocol modifications would occur, these will be communicated to all participating centres.

Ethics statements

Patient consent for publication

Acknowledgments

The authors thank Michiel Marynissen for the preliminary work in preparing the manuscript.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Twitter @JanneBrouckaert

  • Contributors JB wrote the first draft of the manuscript. Thorough review and adjustments by all authors: JB, GD, AW and FR.

  • Funding This study is sponsored by XVIVO Perfusion AB, Göteborg, Sweden, providing responsibility by providing the material to perform non-ischaemic heart preservation and institutional financial funding to cover the costs added to the investigational site related to the execution of the trial.

  • Competing interests AW is employed by the Sponsor.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.