A Randomized Controlled Trial Comparing Non-ischemic to Ischemic Preservation in Adult Cardiac Transplantation
Condition: Transplant; Failure, Heart
Study type: Interventional

Summary: 
      The overall aim of this proposal is to compare a new state-of-the-art ex-vivo organ
      preservation method with standard ischemic cold static storage of donor hearts in adult
      cardiac transplantation.

      Standard heart preservation before transplantation consists of cold ischemic storage of the
      heart. Clinical studies has shown that the morbidity and mortality risk increases with
      extension of the allograft ischemic time over four hours. For each additional hour the
      mortality risk increase with 25% the first year. This time constrained is costly and results
      in severe logistical problems, leading to loss of transplantable organs.

      Initially the study is prospective, single-institution, open-label, non-randomised trial
      comparing the NIHP method with the conventionally SCS in adult heart transplanted patients at
      Skane University Hospital, Lund, Sweden. Six patients will be transplanted using the
      non-ischemic hypothermic cardioplegic perfusion. These will be compared with contemporary
      control patients transplanted with standard ischemic cold static storage. The results will be
      analysed and reported.

      After the initially six patients have been completed, the study will become a single center,
      prospective, open, blinded endpoint, randomized, controlled clinical trial including 34
      patients.

      The primary end-point is a composite of mortality, primary graft dysfunction (PGD), need for
      extra corporal support, or acute cellular rejection (ACR) within 30- days post-transplant.
      PGD and ACR will be accessed blinded.An improved preservation of the transplanted organ will
      reduce the major limitations for survival in the early post-transplant period such as
      non-specific graft failure and acute rejection. Furthermore, it will make it possible to
      increase the donor pool.
    

Detailed description: 
      SURVEY OF THE FIELD

      Ischemia and reperfusion (I/R)-elicited tissue injury contributes to morbidity and
      mortality4. In organ transplantation, it is a major challenge. The imbalance in metabolic
      supply and demand within the ischemic organ results in tissue hypoxia and microvascular
      dysfunction4. The following reperfusion enhances the activation of innate and adaptive immune
      responses resulting in a cell death programs4,5. Furthermore, it has been report that miRNA
      expression profile for heart transplantation is associated with I/R injury. Standard heart
      preservation before transplantation consists of cold ischemic storage of the heart. Clinical
      studies have shown that the mortality risk increases sharply with extension of the allograft
      ischemic time over 4 hours. For each additional hour, the mortality risk increase with 25%
      the first year. Different myocardial cardioplegic preservation solutions and an ex-vivo
      perfusion machine have been developed. That technique includes use of whole blood from
      deceased donor and a normothermic beating heart consuming nutrients during the preservation.
      Despite some promising experimental results, no consistent differences in outcome have been
      found. Improved preservation of the endothelium of the coronary arteries is instrumental to
      achieve improved patient short and long term outcome. A damaged endothelium could result in
      cardiac allograft vasculopathy (CAV) and increases the risk of ACR. Therefore, prolonged time
      and improved storage of the donor heart would save lives.

      PURPOSE AND AIM

      The overall aim of this study is to compare a new state-of-the-art organ preservation
      technique, non-ischemic continous/intermittent hypothermic cardioplegic perfusion (NICHCP),
      on immediate and long term heart allograft function and rejection episodes, with standard
      ischemic cold static storage (ICSS) of donor hearts in adult cardiac transplantation.

      A new ex-vivo heart perfusion technique where the heart is perfused during explantation,
      using an independent portable heart-lung-machine, has been developed by Prof. Steen's
      research group3. Pre-clinical studies have shown that the new technology using NICHCP of
      donor hearts can be safely applied for 24 hours in pigs, however this new perfusion technique
      has never been used on man.

      The primary hypothesis is that the NICHCP is superior to ischemic cold static storage of
      donor hearts. The primary end-point is a composite of mortality, primary graft dysfunction,
      need for extra corporal mechanical support, or Acute Cellular Rejection (ACR) ≥ grade 2
      within 30-days.

      RESEARCH QUESTION

      The study will investigate the superiority of the new methodology (NICHCP) in terms of
      improved immediate and prolonged organ function. More specifically, it is hypothesized that
      the weaning period of cardio-pulmonary bypass, will be shorter, the need for inotropic
      support reduced, and the major limitations for survival in the early post-transplant period
      such as non-specific graft failure, multiorgan failure, ACR, and infection will decrease.
      Furthermore, in the late post-transplant period, it is hypothesized that the development of
      CAV and immunosuppressive side effects, such as malignancy, will be reduced.

      WORK PLAN

      In the initial phase, it is excepted that 1 - 2 patients will be enrolled per month. During
      the randomized part of the study It is expected to enroll 1 - 4 patients per month. With that
      pace, the study is completed within about 24 months. The patient short term follow-up is 30
      days and long term follow up is 12 months. For short-term-analysis purpose the study is
      considered completed as the last patient of the study has passed 30-days post-surgery. The
      long-term study will continue to monitor the patients for 12 months. Adverse events will be
      recorded even if occurring after completion of the study and all patients will be followed
      throughout life according to standard clinical care.

      If this is successful, this will be introduced as standard among other national and
      international collaborators. The investigators estimate that this technique will be the
      golden standard within 5 years.

      STUDY DESIGN

      Initially the study is a prospective, single-institution, open-label, non-randomised trial.
      Here, six patients will be transplanted with the NICHCP method. These will be compared with
      contemporary control patients transplanted with standard ICSS. An interim assessment will be
      performed when these six patients has passed 180-days post-transplant. The results from this
      study will be analysed and published. A report will be sent to the Ethical review bord for an
      approval to continue with the second part of the study.

      After six patients have been transplanted with the NICHCP method and a new approval has been
      achieved from the local ethical board, the study will become a single center, prospective,
      open, blinded endpoint, randomized, controlled clinical trial. The continued study will
      comprise 17 patients in the test group and 17 control patients. The main outcomes will be
      reported on intention to treat basis. PGD and ACR assessment will be performed by a blinded
      access. Listed heart recipients (aged >18 years) at Skåne University Hospital will be
      screened. Patients who full-fill all inclusion and no exclusion criteria will be included
      after they signed the informed consent form. In the initial phase, it is excepted that 1-2
      patients will be enrolled per month. During the randomized part of the study it is expected
      to enroll 1-4 patients per month. With that pace, the study is completed within 24 months.
      The patient short term follow-up is 30 days and long term follow up is 12 months. For
      short-term-analysis purpose the study is considered completed as the last patient of the
      study has passed 30-days post-surgery. The long-term study will continue to monitor the
      patients for 12 months. Adverse events will be recorded even if occurring after completion of
      the study and all patients will be followed throughout life according to standard clinical
      care.

      STATISTICAL ANALYS PLAN

      Descriptive statistics will be presented as means, standard deviations, medians and inter
      quartile ranges for the continuous variables and as counts and percent for categorical
      variables. An alpha level of 5% will be used for all analyses, unless otherwise stated.
      Demographics will be tabulated overall and by treatment group. The results from the
      laboratory analysis will be calculated based on continuous variables. All data analyses will
      be performed on data available. After three of the patients have been enrolled a safety
      assessment will be performed. An interim assessment of the initial six patients in the test
      group will be performed when all six patients has passed 30-days post-transplant or expired.
      A protocol deviation is any event where investigator or study personnel did not conduct the
      study per the protocol or applicable laws. All deviations will be reported to the Principal
      Investigator (regardless of cause or prior approval) and will be noted on the eCRF form.

      CLINICAL AND SCIENTIFIC IMPLICATIONS

      The use of an ex-vivo machine for the preservation of a donor heart requires more resources
      than the technology used today, such as special equipment, suitable transportation and bank
      blood to prime the perfusion module. Compared with cold static techniques for preservation,
      this will initially be costly. However, this must be weighed against the value of more donor
      hearts become available for transplant and cost savings in the form of shorter time to
      perform the surgery, reduced incidence of the primary graft dysfunction (PGD), less need for
      expensive mechanical cardiac support post-transplant, shortened hospitalization and
      longer-term risk reduction of chronic rejection. The costs of complications directly
      connected to the transplant is cost driven, especially if the recipient develops PGD
      requiring mechanical circulatory support with a prolonged ICU stay. Furthermore, in the
      future the transplantation can be scheduled to day-time surgery and complexed high risk cases
      can be done with the highest competence available without time limitation. An improved
      preservation of the transplanted organ will reduce the major limitations for survival in the
      early post-transplant period such as PGD. Furthermore, it will make it possible to increase
      the donor pool. Theoretically in the nordic countries, this would enable international organ
      sharing with Europe and the eastern United States. This expansion of the donor pool is one of
      the main potential benefits of this device.
    

Intervention name(s): Non-ischemic preservation; Ischemic cold static storage
Intervention type(s): Other; Other
Intervention description(s): The device is a portable heart-lung machine; an automatic pressure and flow-controlled perfusion system. The heart is submerged in a solution and the medium is circulated in the heart, at a temperature of 8°C.; Standard ischemic cold static storage; a crystalloid solution (cardioplegia) is used to stop and preserve the heart. Cardioplegia is given. The heart is storage i a transport box containing ice to keep the temperature around 8°C.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Initially the study is a single center, prospective, open, blinded endpoint, non-randomized, controlled clinical trial. Six patients will be transplanted with the NICHCP method. These will be compared with contemporary control patients transplanted with standard ICSS (N=25). An analyze will be performed when these six patients has passed 180-days post-transplant. The result will be reported.
After the the initially study has been completed, the study will become a single center, prospective, open, blinded endpoint, randomized, controlled clinical trial. The continued study will comprise 17 patients in the test group and 17 control patients. The main outcomes will be reported on intention to treat basis. PGD and ACR assessment will be performed by a blinded access. Randomisation will be computer generated.
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Other
Keywords: Organ preservation; Survival; Graft function; Reperfusion injury; Heart transplantation