Liver Transplantation
Conditions
Brief summary
A multicenter randomized controlled trial to compare the efficacy of ex-vivo normothermic machine profusion with static cold storage in human liver transplantation.
Interventions
OTHERStandard of Care (Ice)
Sponsors
North American Science Associates Ltd.
OrganOx Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is 18 years of age or greater * Subject is registered as an active recipient on the United Network for Organ Sharing (UNOS) waiting list for liver transplantation * Subject, or legally authorized representative, is able and willing to give informed consent and HIPAA authorization * Subject is able and willing to comply with all study requirements
Exclusion criteria
* Subject requiring all of the following at the time of transplantation: oxygen therapy, inotropic support, renal replacement therapy * Subject has acute/fulminant liver failure * Subject undergoing simultaneous transplantation of more than one organ * Subject is pregnant or nursing * Concurrent enrollment in another clinical trial. Subjects enrolled in clinical trials or registries where only measurements and/or samples are taken (NO TEST DEVICE or TEST DRUG USED) are allowed to participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Early Allograft Dysfunction (EAD) | 7 Days | EAD is a binary outcome defined by the presence of one of the following 3 outcomes: * Serum bilirubin ≥ 10 mg/dL at day 7 post-transplant * International normalized ratio (INR) ≥ 1.6 at day 7 post-transplant * Alanine Aminotransferase (ALT) or Aspartate Transaminase (AST) \> 2000 IU/L within the first 7 days post-transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Primary Non-Function | 10 Days | Primary Non-Function is defined in this study as irreversible graft dysfunction requiring emergency liver replacement during the first 10 days after liver transplantation. |
| Number of Participants With Graft Survival | 6 Months | — |
| Number of Participants With Subject Survival | 6 Months | — |
| Number of Participants With Post-Reperfusion Syndrome | 1 Day | Post-Reperfusion Syndrome is defined in this study as a decrease in mean arterial pressure (MAP) of more than 30% from the baseline value for more than one minute during the first five minutes after reperfusion. |
| Measure Biochemical Liver Function Via Bilirubin | 6 Months | — |
| Measure Biochemical Liver Function Via Gamma-Glutamyl Transferase (GGT) | 6 Months | — |
| Measure Biochemical Liver Function Via Alanine Aminotransferase (ALT) | 6 Months | — |
| Measure Biochemical Liver Function Via Aspartate Transaminase (AST) | 6 Months | — |
| Assessment of the Health Economic Implications Via Length of ICU Stay and Length of Hospital Stay | 6 Months | — |
| Measure Biochemical Liver Function Via International Normalized Ratio (INR) | 6 Months | The international normalized ratio (INR) is a laboratory measurement of how long it takes blood to form a clot. It is calculated using the following formula: INR = (PT \[test\] / PT \[control\])\^ISI INR = international normalized ratio PT \[test\] = tested prothrombin time PT \[control\] = control prothrombin time ISI = international sensitivity index |
| Measure Biochemical Liver Function Via Lactate | Days 1-7 | — |
| Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | 1 Day | Overall Degree of Ischemia Reperfusion Injury (IRI) was categorized as: * None/Minimal: None or Polymorphonuclear Leukocytes (PMNs) in sinusoidal zone 3 with rare hepatocellular necrosis * Mild: Polymorphonuclear Leukocytes (PMNs) in sinusoidal zone 3 with ≥ 1 cluster of necrotic hepatocytes * Moderate/Severe: Clusters of hepatocellular necrosis in \> 50% of lobules or 60% of parenchyma or panlobular necrosis in \> 1 lobule |
| Number of Participants With Biliary Investigations and Biliary Interventions | 6 Months | — |
| Number of Livers Randomized But Not Transplanted | 1 Day | — |
| Number of Livers That Did Not Experience a Safety Event | 10 Days | Number of livers that did not experience at least one of the following safety events: * Early Allograft Dysfunction (EAD) * Discard of a Retrieved Liver * Primary Non-Function (PNF) |
| Compare Quality of Life Via the EQ-5D-5L Quality of Life Questionnaire | 6 Months | The EQ-5D-5L Questionnaire is the standard layout for recording an adult person's current self-reported health state. It consists of a standard format for respondents to record their health state according to the EQ-5D-5L descriptive system and the EQ Visual Analog Scale (VAS). EQ-5D-5L index scores range from 0 to 1.0 on a scale where 0 = death and 1.0 = perfect health. EQ-5D-5L is the name of the instrument and is not an acronym. |
| Measure Biochemical Liver Function Via Alkaline Phosphatase (ALP) | 6 Months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normothermic Machine Perfusion (NMP) Following the routine retrieval procedure of the liver, it will be placed on the OrganOx metra for Normothermic Machine Perfusion (NMP) for transport per the Investigational Plan and the Instructions For Use.
Normothermic Machine Perfusion (NMP) | 136 |
| Standard of Care (Ice) Following the routine retrieval procedure of the liver, it will be placed in ice-cold perfusion solution within an ice box for transport as dictated by logistics and local policy.
Standard of Care (Ice) | 131 |
| Total | 267 |
Baseline characteristics
| Characteristic | Normothermic Machine Perfusion (NMP) | Total | Standard of Care (Ice) |
|---|---|---|---|
| Age, Continuous | 57.4 Years STANDARD_DEVIATION 10.5 | 57.3 Years STANDARD_DEVIATION 10.6 | 57.2 Years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 28 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 121 Participants | 239 Participants | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 14 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) White | 127 Participants | 246 Participants | 119 Participants |
| Region of Enrollment United States | 136 participants | 267 participants | 131 participants |
| Sex: Female, Male Female | 43 Participants | 91 Participants | 48 Participants |
| Sex: Female, Male Male | 93 Participants | 176 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 136 | 4 / 131 |
| other Total, other adverse events | 125 / 136 | 123 / 131 |
| serious Total, serious adverse events | 95 / 136 | 93 / 131 |
Outcome results
Primary
Percentage of Participants With Early Allograft Dysfunction (EAD)
EAD is a binary outcome defined by the presence of one of the following 3 outcomes: * Serum bilirubin ≥ 10 mg/dL at day 7 post-transplant * International normalized ratio (INR) ≥ 1.6 at day 7 post-transplant * Alanine Aminotransferase (ALT) or Aspartate Transaminase (AST) \> 2000 IU/L within the first 7 days post-transplant
Time frame: 7 Days
Population: There was one subject excluded from the primary endpoint analysis as there was only an attempt to transplant a randomized liver. The subject was deemed unable to proceed with the liver transplant and was followed through 30-days post-transplant for adverse event collection only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Percentage of Participants With Early Allograft Dysfunction (EAD) | 20.6 percentage of participants |
| Standard of Care (Ice) | Percentage of Participants With Early Allograft Dysfunction (EAD) | 23.7 percentage of participants |
Secondary
Assessment of the Health Economic Implications Via Length of ICU Stay and Length of Hospital Stay
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normothermic Machine Perfusion (NMP) | Assessment of the Health Economic Implications Via Length of ICU Stay and Length of Hospital Stay | Length of ICU Stay | 4.6 Days | Standard Deviation 7.5 |
| Normothermic Machine Perfusion (NMP) | Assessment of the Health Economic Implications Via Length of ICU Stay and Length of Hospital Stay | Total Length of Hospital Stay | 14.3 Days | Standard Deviation 17.1 |
| Standard of Care (Ice) | Assessment of the Health Economic Implications Via Length of ICU Stay and Length of Hospital Stay | Length of ICU Stay | 4.2 Days | Standard Deviation 6.2 |
| Standard of Care (Ice) | Assessment of the Health Economic Implications Via Length of ICU Stay and Length of Hospital Stay | Total Length of Hospital Stay | 13.3 Days | Standard Deviation 18.1 |
Secondary
Compare Quality of Life Via the EQ-5D-5L Quality of Life Questionnaire
The EQ-5D-5L Questionnaire is the standard layout for recording an adult person's current self-reported health state. It consists of a standard format for respondents to record their health state according to the EQ-5D-5L descriptive system and the EQ Visual Analog Scale (VAS). EQ-5D-5L index scores range from 0 to 1.0 on a scale where 0 = death and 1.0 = perfect health. EQ-5D-5L is the name of the instrument and is not an acronym.
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normothermic Machine Perfusion (NMP) | Compare Quality of Life Via the EQ-5D-5L Quality of Life Questionnaire | 0.9 score on a scale | Standard Deviation 0.1 |
| Standard of Care (Ice) | Compare Quality of Life Via the EQ-5D-5L Quality of Life Questionnaire | 0.8 score on a scale | Standard Deviation 0.1 |
Secondary
Measure Biochemical Liver Function Via Alanine Aminotransferase (ALT)
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via Alanine Aminotransferase (ALT) | 23.0 IU/L |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via Alanine Aminotransferase (ALT) | 21.0 IU/L |
Secondary
Measure Biochemical Liver Function Via Alkaline Phosphatase (ALP)
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via Alkaline Phosphatase (ALP) | 94.0 IU/L |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via Alkaline Phosphatase (ALP) | 92.0 IU/L |
Secondary
Measure Biochemical Liver Function Via Aspartate Transaminase (AST)
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via Aspartate Transaminase (AST) | 24.0 IU/L |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via Aspartate Transaminase (AST) | 20.0 IU/L |
Secondary
Measure Biochemical Liver Function Via Bilirubin
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via Bilirubin | 0.6 mg/dL |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via Bilirubin | 0.5 mg/dL |
Secondary
Measure Biochemical Liver Function Via Gamma-Glutamyl Transferase (GGT)
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via Gamma-Glutamyl Transferase (GGT) | 38.5 IU/L |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via Gamma-Glutamyl Transferase (GGT) | 34.0 IU/L |
Secondary
Measure Biochemical Liver Function Via International Normalized Ratio (INR)
The international normalized ratio (INR) is a laboratory measurement of how long it takes blood to form a clot. It is calculated using the following formula: INR = (PT \[test\] / PT \[control\])\^ISI INR = international normalized ratio PT \[test\] = tested prothrombin time PT \[control\] = control prothrombin time ISI = international sensitivity index
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via International Normalized Ratio (INR) | 1.0 No Units |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via International Normalized Ratio (INR) | 1.0 No Units |
Secondary
Measure Biochemical Liver Function Via Lactate
Time frame: Days 1-7
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Measure Biochemical Liver Function Via Lactate | 1.4 mmol/L |
| Standard of Care (Ice) | Measure Biochemical Liver Function Via Lactate | 1.5 mmol/L |
Secondary
Number of Livers Randomized But Not Transplanted
Time frame: 1 Day
Population: The analysis population for this outcome reflects all livers randomized in the study; therefore, the number analyzed is greater than the participants enrolled.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Livers Randomized But Not Transplanted | 56 Livers |
| Standard of Care (Ice) | Number of Livers Randomized But Not Transplanted | 61 Livers |
Secondary
Number of Livers That Did Not Experience a Safety Event
Number of livers that did not experience at least one of the following safety events: * Early Allograft Dysfunction (EAD) * Discard of a Retrieved Liver * Primary Non-Function (PNF)
Time frame: 10 Days
Population: The analysis population for this outcome reflects all livers retrieved in the study; therefore, the number analyzed is greater than the participants enrolled, but less than the total livers randomized. There was one subject where there was only an attempt to transplant a randomized liver as the subject was deemed unable to proceed with the liver transplant.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Livers That Did Not Experience a Safety Event | 147 Livers |
| Standard of Care (Ice) | Number of Livers That Did Not Experience a Safety Event | 137 Livers |
Secondary
Number of Participants With Biliary Investigations and Biliary Interventions
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Participants With Biliary Investigations and Biliary Interventions | Biliary Investigations | 14 Participants |
| Normothermic Machine Perfusion (NMP) | Number of Participants With Biliary Investigations and Biliary Interventions | Biliary Interventions | 12 Participants |
| Standard of Care (Ice) | Number of Participants With Biliary Investigations and Biliary Interventions | Biliary Investigations | 16 Participants |
| Standard of Care (Ice) | Number of Participants With Biliary Investigations and Biliary Interventions | Biliary Interventions | 11 Participants |
Secondary
Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies
Overall Degree of Ischemia Reperfusion Injury (IRI) was categorized as: * None/Minimal: None or Polymorphonuclear Leukocytes (PMNs) in sinusoidal zone 3 with rare hepatocellular necrosis * Mild: Polymorphonuclear Leukocytes (PMNs) in sinusoidal zone 3 with ≥ 1 cluster of necrotic hepatocytes * Moderate/Severe: Clusters of hepatocellular necrosis in \> 50% of lobules or 60% of parenchyma or panlobular necrosis in \> 1 lobule
Time frame: 1 Day
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Pre-Reperfusion | None/Minimal | 123 Participants |
| Normothermic Machine Perfusion (NMP) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Pre-Reperfusion | Mild | 10 Participants |
| Normothermic Machine Perfusion (NMP) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Pre-Reperfusion | Moderate/Severe | 0 Participants |
| Normothermic Machine Perfusion (NMP) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Post-Reperfusion | None/Minimal | 100 Participants |
| Normothermic Machine Perfusion (NMP) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Post-Reperfusion | Mild | 29 Participants |
| Normothermic Machine Perfusion (NMP) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Post-Reperfusion | Moderate/Severe | 4 Participants |
| Standard of Care (Ice) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Post-Reperfusion | Mild | 24 Participants |
| Standard of Care (Ice) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Pre-Reperfusion | None/Minimal | 117 Participants |
| Standard of Care (Ice) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Post-Reperfusion | None/Minimal | 93 Participants |
| Standard of Care (Ice) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Pre-Reperfusion | Mild | 5 Participants |
| Standard of Care (Ice) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Post-Reperfusion | Moderate/Severe | 5 Participants |
| Standard of Care (Ice) | Number of Participants With Evidence of Ischemia-Reperfusion Injury Via Comparison of Pre-Reperfusion Biopsies to Post-Reperfusion Biopsies | Pre-Reperfusion | Moderate/Severe | 0 Participants |
Secondary
Number of Participants With Graft Survival
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Participants With Graft Survival | 124 Participants |
| Standard of Care (Ice) | Number of Participants With Graft Survival | 122 Participants |
Secondary
Number of Participants With Post-Reperfusion Syndrome
Post-Reperfusion Syndrome is defined in this study as a decrease in mean arterial pressure (MAP) of more than 30% from the baseline value for more than one minute during the first five minutes after reperfusion.
Time frame: 1 Day
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Participants With Post-Reperfusion Syndrome | 8 Participants |
| Standard of Care (Ice) | Number of Participants With Post-Reperfusion Syndrome | 19 Participants |
Secondary
Number of Participants With Primary Non-Function
Primary Non-Function is defined in this study as irreversible graft dysfunction requiring emergency liver replacement during the first 10 days after liver transplantation.
Time frame: 10 Days
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Participants With Primary Non-Function | 1 Participants |
| Standard of Care (Ice) | Number of Participants With Primary Non-Function | 2 Participants |
Secondary
Number of Participants With Subject Survival
Time frame: 6 Months
Population: The overall number of participants analyzed reflects participants in each arm who were eligible to be included in the analysis and had complete data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normothermic Machine Perfusion (NMP) | Number of Participants With Subject Survival | 121 Participants |
| Standard of Care (Ice) | Number of Participants With Subject Survival | 123 Participants |