Ignite Creation Date:
2024-05-06 @ 3:57 PM
Last Modification Date:
2024-10-26 @ 2:00 PM
Study NCT ID:
NCT04812054
Status:
UNKNOWN
Last Update Posted:
2021-04-13
First Post:
2021-03-16
Brief Title:
Dual Hypothermic Oxygenated Machine Perfusion in Liver Transplantation Using Allografts From Donors After Brain Death
Sponsor:
Medical University of Warsaw
Organization:
Medical University of Warsaw
Study Overview
Official Title:
Improving Quality of Livers Procured for Transplantation From Deceased Donors Using Hypothermic Machine Perfusion
Status:
UNKNOWN
Status Verified Date:
2021-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This will be a randomized study on the effects of hypothermic oxygenated machine perfusion in patients undergoing liver transplantations from donors after brain death with allocation of patients to either end-ischemic hypothermic oxygenated machine perfusion group at least 2 hours of allograft perfusion at 12 degrees Celsius though hepatic artery and portal vein prior to implantation or simple cold storage group in a 13 ratio The primary outcome measure of the study will be model for early graft dysfunction MEAF score A total number of 104 patients including 26 in the hypothermic perfusion group and 78 in simple cold storage group will be included Data on potential risk factors for worse allograft function and increased ischemia-reperfusion injury will be collected perioperatively Circulating levels of proinflammatory cytokines IL-2 IL-10 TNFα nuclear damage HMGB-1 8-OHdG serum activity of transaminases gamma-glutamyl-transpeptidase bilirubin concentration and INR will be assessed in the perioperative period Wedge allograft biopsies will be performed 90 minutes post-reperfusion to evaluate activation of innate immunity TLR4 activation of endothelium vWF P-selectin hepatocyte necrosis hepatocyte apoptosis TUNEL assay ATP content and oxidative damage malondialdehyde content Further wedge biopsies will be performed at the end of simple cold storage and at the beginning and after two hours of perfusion to determine steatosis and ATP content During the perfusion perfusate samples will be periodically tested for lactate sodium and potassium concentration CO2 partiall pressure and flavin mononucleotide concentration Patients will be closely monitored in the postoperative period for allograft function and secondary end-points 2-year recipient and graft survival 2-year incidence of biliary complications and 90-day complication rate Both groups will be compared with respect to the primary and secondary end-points circulating levels of IL-2 IL-10 TNFα HMGB-1 8-OHdG activity of transaminases and gamma-glutamyl-transpeptidase and findings in post-reperfusion allograft biopsies Further changes of hepatic steatosis and hepatic ATP content during perfusion will be evaluated and the results of perfusate analyses will be tested as predictors of allograft function in the post-transplant period
Detailed Description:
This will be a parallel randomized controlled study on the effects of end-ischemic hypothermic oxygenated machine perfusion in liver transplantations from donors after brain death Patients will be randomized to either hypothermic perfusion or simple cold storage 13 ratio The primary end-point will be model for early graft dysfunction MEAF score a recently validated continuous measure of allograft function in the early period after liver transplantation calculated using serum alanine transaminase ALT activity international normalized ratio for prothrombin time INR and serum bilirubin concentration within 3 first postoperative days In the original study the mean MEAF score was 501 with a standard deviation of 199 The primary hypothesis of this study is reduction of the mean MEAF score from 5 to 35 using hypothermic oxygenated machine perfusion With the thresholds for type I error of 005 and power of 090 respectively 13 allocation ratio and a standard deviation of 199 the number of patients required to detect such difference is 26 in the hypothermic perfusion group and 78 in the simple cold storage group 104 in total The inclusion criteria will comprise age 18 years deceased-donor liver transplantation and provision of informed consent Exclusion criteria will comprise donation after cardiac death and either reduced or split graft Secondary outcome measures will include 2-year recipient and graft survival 2-year incidence of biliary complications and complications in the 90-day postoperative period classified by type and their severity according to the Clavien-Dindo grading system
Following provision of informed consent recipients will be randomly assigned in a 13 ratio to either hypothermic perfusion group or simple static cold storage group In the hypothermic perfusion group allografts will be subject to end-ischemic hypothermic oxygenated perfusion at 12 degrees Celsius through both hepatic artery and portal vein after a period of simple cold storage at 4 degrees Celsius and immediately prior to implantation The perfusion will last at least 2 hours and the period will be prolonged in case of ongoing hepatectomy in order to perform graft implantation immediately after perfusion Two wedge allograft biopsies will be performed at the beginning and after 2 hours of perfusion for the assessment of micro- and macrovesicular steatosis and ATP content Samples of the perfusate will be taken at the beginning and every 30 minutes for the assessment of sodium potassium and lactate concentration CO2 partial pressure and FMN Perfusate temperature portal and arterial flow and portal and arterial resistance will be closely monitored during the procedure In the simple cold storage group the allografts will be stored in perfusate at 4 degrees Celsius from the procurement until implantation At the end of simple cold storage a wedge biopsy will be taken for the assessment of micro- and macrovesicular steatosis and ATP content In both groups during the back-table procedure the allograft will be flushed with 1 litre of perfusate through the portal vein At the end of flushing a sample of perfusate will be taken from the right hepatic vein for assessment of FMN and lactate concentration
In both groups clinical anthropometric and laboratory pre-transplant data will be collected This includes indication for transplantation Child-Turcotte-Pugh classification presence of hepatitis B and C virus infection model for end-stage liver disease MELD score without exception points patient weight height body mass index and waist circumference serum bilirubin creatinine glucose and albumin concentration INR and serum activity of transaminases Relevant donor and procurement data will be collected including donor age height body mass index cause of death ethnicity serum sodium and bilirubin concentration serum activity of transaminases INR and extraction time Donor risk index will be calculated in every case Duration of cold ischemia and several intraoperative parameters will be collected including duration of warm ischemia intraoperative transfusions serum sodium and potassium changes occurrence of post-reperfusion syndrome and duration of operation A wedge biopsy will be performed in all patients 90 minutes after portal reperfusion for histological assessment of ischemia-reperfusion injury Suzuki score apoptosis endothelial activation vWF and P-selectin activation of innate immunity TLR4 oxidative injury MDA and ATP content Blood samples will be collected immediately prior to reperfusion 90 minutes after reperfusion and at first postoperative day for the assessment of proinflammatory cytokines TNFα IL-2 IL-10 nuclear damage HMGB1 8-OHdG and hepatocyte and cholangiocyte injury transaminases and GGT activity Following transplantation all patients will be strictly followed according to the centre protocol with the assessment of serum activity of transaminases and GGTP bilirubin and creatinine concentration and INR twice daily within the first 3 postoperative days and daily or once every 2-3 days according to the clinical assessment thereafter All complications occurring during the 90-postoperative period will be recorded including primary non-function early allograft dysfunction biliary leaks rejection episodes and vascular complications After hospital discharge patients will be followed-up according to the center protocol with regular appointments in the outpatient clinic every 2 weeks within first 2 months post-transplantation every month up to 6 months every 2-3 months up to 1 year and every 3-6 months thereafter Occurrence of all complications particularly biliary complications will be recorded Both groups will be compared with respect to primary and secondary outcome measures other pre-defined clinical outcomes allograft injury and ATP content before implantation and signs of ischemia-reperfusion injury oxidative damage apoptosis ATP content activation of innate immunity and endothelial activation in allograft biopsies after reperfusion Comparisons will also include pro-inflammatory cytokine release circulating markers of nuclear injury and other laboratory markers of allograft function and injury Analyses of perfusate samples and allograft biopsies obtained before and after reperfusion is planned in order to determine both the impact of hypothermic perfusion on hepatic ATP content and mitochondrial injury FMN Further results of perfusate analyses particularly FMN will be evaluated for potential association with clinical outcome measures results of post-reperfusion allograft biopsies assessment and serum markers of allograft function injury and inflammatory response in order to determine its role in pre-transplant assessment of allograft viability
Following provision of informed consent recipients will be randomly assigned in a 13 ratio to either hypothermic perfusion group or simple static cold storage group In the hypothermic perfusion group allografts will be subject to end-ischemic hypothermic oxygenated perfusion at 12 degrees Celsius through both hepatic artery and portal vein after a period of simple cold storage at 4 degrees Celsius and immediately prior to implantation The perfusion will last at least 2 hours and the period will be prolonged in case of ongoing hepatectomy in order to perform graft implantation immediately after perfusion Two wedge allograft biopsies will be performed at the beginning and after 2 hours of perfusion for the assessment of micro- and macrovesicular steatosis and ATP content Samples of the perfusate will be taken at the beginning and every 30 minutes for the assessment of sodium potassium and lactate concentration CO2 partial pressure and FMN Perfusate temperature portal and arterial flow and portal and arterial resistance will be closely monitored during the procedure In the simple cold storage group the allografts will be stored in perfusate at 4 degrees Celsius from the procurement until implantation At the end of simple cold storage a wedge biopsy will be taken for the assessment of micro- and macrovesicular steatosis and ATP content In both groups during the back-table procedure the allograft will be flushed with 1 litre of perfusate through the portal vein At the end of flushing a sample of perfusate will be taken from the right hepatic vein for assessment of FMN and lactate concentration
In both groups clinical anthropometric and laboratory pre-transplant data will be collected This includes indication for transplantation Child-Turcotte-Pugh classification presence of hepatitis B and C virus infection model for end-stage liver disease MELD score without exception points patient weight height body mass index and waist circumference serum bilirubin creatinine glucose and albumin concentration INR and serum activity of transaminases Relevant donor and procurement data will be collected including donor age height body mass index cause of death ethnicity serum sodium and bilirubin concentration serum activity of transaminases INR and extraction time Donor risk index will be calculated in every case Duration of cold ischemia and several intraoperative parameters will be collected including duration of warm ischemia intraoperative transfusions serum sodium and potassium changes occurrence of post-reperfusion syndrome and duration of operation A wedge biopsy will be performed in all patients 90 minutes after portal reperfusion for histological assessment of ischemia-reperfusion injury Suzuki score apoptosis endothelial activation vWF and P-selectin activation of innate immunity TLR4 oxidative injury MDA and ATP content Blood samples will be collected immediately prior to reperfusion 90 minutes after reperfusion and at first postoperative day for the assessment of proinflammatory cytokines TNFα IL-2 IL-10 nuclear damage HMGB1 8-OHdG and hepatocyte and cholangiocyte injury transaminases and GGT activity Following transplantation all patients will be strictly followed according to the centre protocol with the assessment of serum activity of transaminases and GGTP bilirubin and creatinine concentration and INR twice daily within the first 3 postoperative days and daily or once every 2-3 days according to the clinical assessment thereafter All complications occurring during the 90-postoperative period will be recorded including primary non-function early allograft dysfunction biliary leaks rejection episodes and vascular complications After hospital discharge patients will be followed-up according to the center protocol with regular appointments in the outpatient clinic every 2 weeks within first 2 months post-transplantation every month up to 6 months every 2-3 months up to 1 year and every 3-6 months thereafter Occurrence of all complications particularly biliary complications will be recorded Both groups will be compared with respect to primary and secondary outcome measures other pre-defined clinical outcomes allograft injury and ATP content before implantation and signs of ischemia-reperfusion injury oxidative damage apoptosis ATP content activation of innate immunity and endothelial activation in allograft biopsies after reperfusion Comparisons will also include pro-inflammatory cytokine release circulating markers of nuclear injury and other laboratory markers of allograft function and injury Analyses of perfusate samples and allograft biopsies obtained before and after reperfusion is planned in order to determine both the impact of hypothermic perfusion on hepatic ATP content and mitochondrial injury FMN Further results of perfusate analyses particularly FMN will be evaluated for potential association with clinical outcome measures results of post-reperfusion allograft biopsies assessment and serum markers of allograft function injury and inflammatory response in order to determine its role in pre-transplant assessment of allograft viability
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 201934ENZ500433 | OTHER_GRANT | National Science Centre Poland | None |