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出境医 / 临床实验 / Sequential Hypo- and Normo-thermic Perfusion to Preserve Extended Criteria Donor Livers for Transplantation

Sequential Hypo- and Normo-thermic Perfusion to Preserve Extended Criteria Donor Livers for Transplantation

Study Description
Brief Summary:
Hypothermic machine perfusion (HMP) has been shown to be beneficial to preserve extended criteria donor (ECD) livers for transplantation. Normothermic machine perfusion (NMP) had the same benefits and also the convenience on liver quality assessment. The investigators proposed to do sequential HMP (1-4 hours) and NMP (1-14 hours) on 15 ECD human livers by using an institutional-developed perfusion device for liver transplantation.

Condition or disease Intervention/treatment Phase
Liver Transplantation Device: Liver Machine Perfusion (MP) device Not Applicable

Detailed Description:
Liver transplantation is a successful therapy on the patients with end-stage liver disease, however is limited by the shortage of donor organs. Donor criteria were expanded in the past decades, however the extended criteria donor (ECD) livers may induce a higher risk of complications. Static cold storage (SCS) is the standard procedure for ex vivo liver preservation for about 4 decades, but has the limitation on preserving ECD livers and especially the inconvenience to evaluate liver quality prior to transplantation. Hypothermic (4-8 Celsius degree) machine perfusion (HMP) and Normothermic (35-37 Celsius degree) machine perfusion (NMP) have been shown to be beneficial to preserve extended criteria donor (ECD) livers respectively. NMP also had the convenience on liver quality assessment. The investigators had an institutional-developed device for liver NMP used on 25 patients with the FDA's IDE approval. In the present study the investigators are proposing to expand the use of the device on sequential HMP (1-4 hours) and NMP (1-14 hours) on 15 ECD human livers. This will be a single center prospective pilot study. The liver metabolism and hydrodynamics during perfusion will be recorded. The transplant procedure and post-transplant care will follow the clinical standard of care. The follow-up period is 12 months after transplantation. The primary end point will be the rate of patient survival and primary non function (PNF) within 30 days after transplantation, while the secondary end points will be: Early Allograft Dysfunction (EAD), 6 months patient and graft survival, peak liver function tests in the first 7 days after transplantation, surgical outcomes (operative time, transfusion requirement etc.), rate of post-transplant kidney failure, assessment of histological ischemia reperfusion (liver and bile duct), rate of vascular complications, rate of biliary complications, hospital and ICU length of stay, rejection rate, infection rate, the ability to predict function based on "on-pump" viability markers, and the incidence of adverse effect (AE).
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Fifteen extended criteria donor livers will undergo sequential hypothermic and normothermic machine perfusion preservation prior to transplantation.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Assess Safety and Feasibility of Sequential Hypothermic Oxygenated Machine Perfusion and Normothermic Machine Perfusion to Preserve Extended Criteria Donor Livers for Transplantation
Estimated Study Start Date : March 1, 2021
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : June 30, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: Liver perfusion

Device: Liver Machine Perfusion (MP) Device

The liver grafts will be preserved at hypothermic and normothermic temperature on the institutional-developed Liver MP Device, and have continuous perfusion with oxygen supply in the ex vivo organ preservation phase.

 Device: Liver Machine Perfusion (MP) device
Donor livers will have ex vivo continuous perfusion on the institutional-developed Liver MP device. The temperature of liver grafts will be controlled during perfusion.
Outcome Measures
Primary Outcome Measures :
  1. patient survival at 1 month post-transplant [ Time Frame: 1 month post-transplant ]
    Patient survival will be recorded at 1 month post transplantation.

  2. graft survival at 1 month post-transplant [ Time Frame: 1 month post-transplant ]
    graft survival will be recorded at 1 month post transplantation. The allograft will be considered lost if a patient has a primary non function (PNF), liver re-transplant or in the event of patient death.


Secondary Outcome Measures :
  1. rate of post-transplant early allograft dysfunction (EAD) [ Time Frame: in the first 7 days after transplantation ]
    EAD is defined as the presence of one or more of the following previously defined postoperative laboratory analyses reflective of liver injury and function: bilirubin ≥10mg/dL on post-operative day (POD) 7, international normalized ratio (INR) ≥1.6 on POD 7, and alanine or aspartate aminotransferases (ALT or AST) >2000 IU/L within the first 7 days.

  2. patient survival at 6 month post-transplant [ Time Frame: 6 month post-transplant ]
    patient survival will be recorded at 6 months post transplantation.

  3. graft survival at 6 month post-transplant [ Time Frame: 6 month post-transplant ]
    graft survival will be recorded at 6 month post transplantation. The allograft will be considered lost if a patient has a primary non function (PNF), liver re-transplant or in the event of patient death.

  4. Estimated blood loss at transplant surgery [ Time Frame: during surgery ]
    Estimated blood loss (ml) during transplant surgery

  5. peak alanine aminotransferases in the first 7 days after transplantation [ Time Frame: in the first 7 days after transplantation ]
    peak level (U/L) of alanine aminotransferases in the first 7 days after transplantation

  6. peak aspartate aminotransferases in the first 7 days after transplantation [ Time Frame: in the first 7 days after transplantation ]
    peak level (U/L) of aspartate aminotransferases in the first 7 days after transplantation

  7. total bilirubin on post-operative day 7 [ Time Frame: on post-operative day 7 ]
    total bilirubin (mg/dL) on post-operative day 7

  8. international normalized ratio on post-operative day 7 [ Time Frame: on post-operative day 7 ]
    international normalized ratio on post-operative day 7

  9. Hospital length of stay [ Time Frame: up to 36 weeks ]
    Length of stay (days) in the hospital at the time for transplantation

  10. ICU length of stay [ Time Frame: up to 36weeks ]
    Length of stay (days) in ICU at the time after liver transplantation


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients undergoing liver transplantation
  • Age 18 or older at the time of transplantation
  • Willingness and ability to comply with the study procedures
  • Signed Informed Consent Form

Exclusion Criteria:

  • Recipient of partial grafts (split and living donors)
  • Mentally or legally incapacitated subjects
  • Inability to understand the procedures due to language barriers
  • Multiorgan transplant
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Cristiano Quintini, MD 2164453388 quintic@ccf.org
Contact: Kevin Smith 2164445868 smithk24@ccf.org

Locations
Layout table for location information
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
Contact: Cristiano Quintini, MD    216-445-3388    quintic@ccf.org   
Contact: Mary Bilancini, MS    2164448983    bilancm@ccf.org   
Sponsors and Collaborators
The Cleveland Clinic
Investigators
Layout table for investigator information
Principal Investigator: Cristiano Quintini, MD The Cleveland Clinic
Tracking Information
First Submitted Date  ICMJE July 10, 2019
First Posted Date  ICMJE July 18, 2019
Last Update Posted Date February 8, 2021
Estimated Study Start Date  ICMJE March 1, 2021
Estimated Primary Completion Date June 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • patient survival at 1 month post-transplant [ Time Frame: 1 month post-transplant ]
    Patient survival will be recorded at 1 month post transplantation.
  • graft survival at 1 month post-transplant [ Time Frame: 1 month post-transplant ]
    graft survival will be recorded at 1 month post transplantation. The allograft will be considered lost if a patient has a primary non function (PNF), liver re-transplant or in the event of patient death.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • rate of post-transplant early allograft dysfunction (EAD) [ Time Frame: in the first 7 days after transplantation ]
    EAD is defined as the presence of one or more of the following previously defined postoperative laboratory analyses reflective of liver injury and function: bilirubin ≥10mg/dL on post-operative day (POD) 7, international normalized ratio (INR) ≥1.6 on POD 7, and alanine or aspartate aminotransferases (ALT or AST) >2000 IU/L within the first 7 days.
  • patient survival at 6 month post-transplant [ Time Frame: 6 month post-transplant ]
    patient survival will be recorded at 6 months post transplantation.
  • graft survival at 6 month post-transplant [ Time Frame: 6 month post-transplant ]
    graft survival will be recorded at 6 month post transplantation. The allograft will be considered lost if a patient has a primary non function (PNF), liver re-transplant or in the event of patient death.
  • Estimated blood loss at transplant surgery [ Time Frame: during surgery ]
    Estimated blood loss (ml) during transplant surgery
  • peak alanine aminotransferases in the first 7 days after transplantation [ Time Frame: in the first 7 days after transplantation ]
    peak level (U/L) of alanine aminotransferases in the first 7 days after transplantation
  • peak aspartate aminotransferases in the first 7 days after transplantation [ Time Frame: in the first 7 days after transplantation ]
    peak level (U/L) of aspartate aminotransferases in the first 7 days after transplantation
  • total bilirubin on post-operative day 7 [ Time Frame: on post-operative day 7 ]
    total bilirubin (mg/dL) on post-operative day 7
  • international normalized ratio on post-operative day 7 [ Time Frame: on post-operative day 7 ]
    international normalized ratio on post-operative day 7
  • Hospital length of stay [ Time Frame: up to 36 weeks ]
    Length of stay (days) in the hospital at the time for transplantation
  • ICU length of stay [ Time Frame: up to 36weeks ]
    Length of stay (days) in ICU at the time after liver transplantation
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sequential Hypo- and Normo-thermic Perfusion to Preserve Extended Criteria Donor Livers for Transplantation
Official Title  ICMJE Assess Safety and Feasibility of Sequential Hypothermic Oxygenated Machine Perfusion and Normothermic Machine Perfusion to Preserve Extended Criteria Donor Livers for Transplantation
Brief Summary Hypothermic machine perfusion (HMP) has been shown to be beneficial to preserve extended criteria donor (ECD) livers for transplantation. Normothermic machine perfusion (NMP) had the same benefits and also the convenience on liver quality assessment. The investigators proposed to do sequential HMP (1-4 hours) and NMP (1-14 hours) on 15 ECD human livers by using an institutional-developed perfusion device for liver transplantation.
Detailed Description Liver transplantation is a successful therapy on the patients with end-stage liver disease, however is limited by the shortage of donor organs. Donor criteria were expanded in the past decades, however the extended criteria donor (ECD) livers may induce a higher risk of complications. Static cold storage (SCS) is the standard procedure for ex vivo liver preservation for about 4 decades, but has the limitation on preserving ECD livers and especially the inconvenience to evaluate liver quality prior to transplantation. Hypothermic (4-8 Celsius degree) machine perfusion (HMP) and Normothermic (35-37 Celsius degree) machine perfusion (NMP) have been shown to be beneficial to preserve extended criteria donor (ECD) livers respectively. NMP also had the convenience on liver quality assessment. The investigators had an institutional-developed device for liver NMP used on 25 patients with the FDA's IDE approval. In the present study the investigators are proposing to expand the use of the device on sequential HMP (1-4 hours) and NMP (1-14 hours) on 15 ECD human livers. This will be a single center prospective pilot study. The liver metabolism and hydrodynamics during perfusion will be recorded. The transplant procedure and post-transplant care will follow the clinical standard of care. The follow-up period is 12 months after transplantation. The primary end point will be the rate of patient survival and primary non function (PNF) within 30 days after transplantation, while the secondary end points will be: Early Allograft Dysfunction (EAD), 6 months patient and graft survival, peak liver function tests in the first 7 days after transplantation, surgical outcomes (operative time, transfusion requirement etc.), rate of post-transplant kidney failure, assessment of histological ischemia reperfusion (liver and bile duct), rate of vascular complications, rate of biliary complications, hospital and ICU length of stay, rejection rate, infection rate, the ability to predict function based on "on-pump" viability markers, and the incidence of adverse effect (AE).
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Fifteen extended criteria donor livers will undergo sequential hypothermic and normothermic machine perfusion preservation prior to transplantation.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Liver Transplantation
Intervention  ICMJE Device: Liver Machine Perfusion (MP) device
Donor livers will have ex vivo continuous perfusion on the institutional-developed Liver MP device. The temperature of liver grafts will be controlled during perfusion.
Study Arms  ICMJE Experimental: Liver perfusion

Device: Liver Machine Perfusion (MP) Device

The liver grafts will be preserved at hypothermic and normothermic temperature on the institutional-developed Liver MP Device, and have continuous perfusion with oxygen supply in the ex vivo organ preservation phase.

Intervention: Device: Liver Machine Perfusion (MP) device
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2019) 		15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2023
Estimated Primary Completion Date June 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients undergoing liver transplantation
  • Age 18 or older at the time of transplantation
  • Willingness and ability to comply with the study procedures
  • Signed Informed Consent Form

Exclusion Criteria:

  • Recipient of partial grafts (split and living donors)
  • Mentally or legally incapacitated subjects
  • Inability to understand the procedures due to language barriers
  • Multiorgan transplant
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Cristiano Quintini, MD 2164453388 quintic@ccf.org
Contact: Kevin Smith 2164445868 smithk24@ccf.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04023773
Other Study ID Numbers  ICMJE Sequential perfusion
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Cristiano Quintini, The Cleveland Clinic
Study Sponsor  ICMJE The Cleveland Clinic
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Cristiano Quintini, MD The Cleveland Clinic
PRS Account The Cleveland Clinic
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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