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Trial registered on ANZCTR


Registration number
ACTRN12624000995572p
Ethics application status
Submitted, not yet approved
Date submitted
30/03/2024
Date registered
14/08/2024
Date last updated
14/08/2024
Date data sharing statement initially provided
14/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluate the Feasibility and Safety of Long-term Preservation of Human Livers before Transplantation.
Scientific title
Evaluate the Feasibility and Safety of Transplantation of Unsuitable Livers following Long-term Normothermic Perfusion for Adult Liver Transplant Recipient
Secondary ID [1] 311856 0
none
Universal Trial Number (UTN)
Trial acronym
LT-NMP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Transplantation 333395 0
Condition category
Condition code
Surgery 330081 330081 0 0
Other surgery
Oral and Gastrointestinal 330146 330146 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transplantation of initially unsuitable livers following extended organ perfusion is an open-label, non-randomised, prospective, single-arm trial, using normothermic extended organ perfusion (NEOP) to test viability and then transplant marginal livers. It will be conducted at the Australian National Liver Transplant Unit (ANLTU) at Royal prince Alfred Hospital. We propose a parallel phase I/II clinical trial to evaluate simultaneously the safety and efficacy of NEOP. The design uses two linked components assessing: (Aim 1) the safety and feasibility of NEOP as a technique to safely increase the number of transplantable livers and (Aim 2) (once initial safety has been demonstrated) achievement of successful transplantation of the NEOP treated marginal livers. (Aim 1) uses a two-stage adaptive design, requiring up to 54 ‘marginal’ livers to be perfused. (Aim 2) uses a three-stage adaptive design and requires 27 NEOP treated marginal livers to be transplanted. Success is measured by a 90-day graft survival.

The duration of machine perfusion will be dictated by graft viability/function and logistics. Viability criteria are assessed at 4 hours and then every 4 hours up to 96 hours. Graft is perfused until satisfy viability criteria up to 96 hours. Once criteria have been met, the recipient operation will be scheduled to occur as soon as practicable in ‘daylight hours’. Explantation, implantation and reperfusion of the liver will be carried out in using standardised techniques by the on-call transplant surgeon. The liver will remain on the machine until after the explantation has taken place at which point it will be flushed by 2 L of cold HTK immediately prior to implantation.

A red-cell based perfusate is prepared using 4 units of donated packed red cells, 2 units of donated fresh frozen plasma, 200ml of 20% albumin and 1L of normal saline. The system is anticoagulated throughout using enoxaparin (100mg twice daily) and the perfusate is “cleaned” prior to connecting the liver by continuous circulation of perfusate through the dialysis filter and correction of electrolyte abnormalities. Supportive perfusion at physiological conditions is continued, and the grafts are continuously assessed. The organ will be perfused using extended organ perfusion system (EOPS). This system is automated and allow minimal intervention of perfusionist. EOPS autoregulate dyalisis, ventilation, nutrition, acid-base, and glucose. A trained perfusionist will supervises the EOPS>

Controlled rewarming was performed with a 1° increase in temperature per hour for 4 degree celsius (from the initial 32° to 36 degree Celsius) to maintain perfusion in a temperature range conducive to red blood cell survival and minimise the effects of ischaemia reperfusion injury. Organ will be perfused

The same partecipants can be enrolled into each stage , initial safety and transplant efficacy stage. As we have used adaptive designs, there are planned formal interim assessments for both (A) feasibility of NEOP and (B) successful transplantation of rescued livers. Recruitment will continue during interim assessment..

The collection and reporting of adverse events (AEs) will be in accordance with the therapeutic goods administration frame- work for clinical studies. The reporting period for AEs will commence at visit 1 and end at the 24-month follow-up. All AEs, device deficiencies and adverse device event (ADEs) will be reported using the applicable electronic case report form (eCRF). AEs will be reported in accordance with Clavien-Dindo classification of surgical complications.

Two-stage design
Using a Simon’s two-stage design : Interim assessment stage 1A of accrual: 24 marginal grafts will be perfused and assessed in the first stage. Grafts will be transplanted depending on the criteria achieved. The procedure will be considered infeasible if there are fewer than eight recovered livers meet criteria and are transplanted. If more than eight livers are transplanted, we will proceed to Stage 2.
Final stage 2A of accrual: Up to additional 30 marginal grafts will be perfused. We would consider the procedure feasible if there are at least 27 transplanted livers out of 54 perfused livers.

Interim assessment stage 1B: Following transplantation in three patients, the trial will stop early (concluding p=0.73) if there are fewer than two patients achieving 90-day survival. If two or more patients reach the primary end point of 90-day survival, an additional eight transplantations will be performed. Interim assessment stage 2B: Following transplantation in 11 patients (combined first and second stages) the trial will stop early (concluding p=0.73) if there are 7 or fewer successes. If 8 or more patients reach the primary end point, an additional 11 transplantations will be performed. Final stage 3B: Following transplantation in 22 patients in all three stages, the trial will be successful if at least 18 patients reach the primary end-point of 90-day survival.
Intervention code [1] 328315 0
Treatment: Devices
Intervention code [2] 328356 0
Treatment: Surgery
Comparator / control treatment
No control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 337896 0
Any change in the proportion of initially declined livers that can be used for transplantation having been deemed viable following a period of prolonged machine perfusion.
Timepoint [1] 337896 0
90 days Graft survival, 90 days patients survival.
Primary outcome [2] 337897 0
Any change in the number of organs available for liver transplantation and change in logistic of liver transplantation (timing recipient surgery)
Timepoint [2] 337897 0
the number of organs available for liver transplantation (cumulative data) will be assessed at the conclusion of the study. Determine the proportion of livers that will be transplanted in ‘daylight hours’ (start the liver transplant between 0800 and 1300H) compared to transplants in the immediately preceding 3 years.
Secondary outcome [1] 433437 0
Any change in discard rate of livers that would have been declined due to logistics such as an ongoing clinical transplant rather than organ quality alone.
Timepoint [1] 433437 0
Determine the proportion of livers that will be transplanted despite difficult logistic (concomitant liver transplant) compared to transplants in the immediately preceding 3 years.

Eligibility
Key inclusion criteria
Suitable potential LT-NMP trial graft recipients will be identified during their assessment and listing process. Eligible patients will be informed that they would be suitable to receive a graft from the NEOP trial. They will be given the patient information sheets to read more about the trial. If already listed, potential recipients will be identifiedt, contacted and sent the information documents. Informed consent will be obtained from all participants. Enrolling in the trial will not impact the chance of them receiving a standard ‘transplantable’ graft. Patients with all aetiologies of chronic liver disease will be considered for inclusion.
Recipients will meet all the following inclusion criteria to be eligible for participation in the NEOP trial:
• Adult primary liver transplant recipient.
• Patient listed electively (not ‘super-urgent) for transplantation.
• Low to moderate transplant risk candidate, suitable for extended criteria grafts, as assessed by the ANLTU liver transplant listing multidisciplinary team (MDT) meeting (these are usually candidates with MELD score < 20, without cardiovascular comorbidities, with good functional and nutrition status, with patent portal vein and with no history of previous major upper abdominal surgery, for example, patients transplanted for liver cancer).
• Able to undergo the informed consent process.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Recipient exclusion criteria
Subjects who meet any of the following exclusion criteria are excluded from participating in the NEOP trial:
• ‘High-risk patients’ not considered suitable for a marginal graft (these are mainly patients with high MELD score (>20) with cardiovascular comorbidities or renal insufficiency, with poor nutrition and performance status).
• Patients with extensive portal vein thrombosis diagnosed prior to the transplantation.
• Liver re-transplantation.
• Patients with fulminant hepatic failure.
• Patients undergoing transplantation of more than one organ.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample Size Justification
For (1) feasibility of LT-NMP to rescue discarded liver grafts, it is anticipated that LT-NMP will achieve a desirable organ recovery rate of more than 70%. A recovery rate of 30% or less would make this concept to be economically unfeasible. The significance level (a) is set at 0.05, corresponding to the probability of incorrectly rejecting the hypothesis given it is true (type I error), and the power is set at 0.90 (type II error rate, ß = 0.10), corresponding to the probability of correctly deciding the LT-NMP treatment is successful given the true response rate is greater than 50%. Using a Simon’s two-stage design : Interim assessment stage 1A of accrual: 24 marginal grafts will be perfused and assessed in the first stage. Grafts will be transplanted depending on the criteria achieved. The procedure will be considered infeasible if there are fewer than eight recovered livers meet criteria and are transplanted. If more than eight livers are transplanted, we will proceed to Stage 2.
Final stage 2A of accrual: Up to additional 30 marginal grafts will be perfused. We would consider the procedure feasible if there are at least 27 transplanted livers out of 54 perfused livers.
For (2) for viable livers transplanted following LT-NMP, a desirable 90-day graft survival rate is at least 88%, with an undesirable rate of 75%. The mean 90-day graft survival rate for ‘standard’ liver transplants is 96%. An optimal three-stage design will be used to test the null hypothesis that the mean 90-day graft survival rate will be less than 75% (p=0.75) versus an alternative hypothesis that the 90-day graft survival rate will be at least 88% (p=0.88).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/10/2024
Actual
Date of last participant enrolment
Anticipated
3/10/2027
Actual
Date of last data collection
Anticipated
3/06/2029
Actual
Sample size
Target
54
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 26346 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 42319 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 316201 0
Government body
Name [1] 316201 0
Medical Research Future Fund (MRFF) – 2023 Clinician Researchers Applied Research in Health Grant Opportunity
Country [1] 316201 0
Australia
Primary sponsor type
Hospital
Name
Sydney Local Health District
Address
Country
Australia
Secondary sponsor category [1] 318384 0
None
Name [1] 318384 0
Address [1] 318384 0
Country [1] 318384 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315018 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 315018 0
Ethics committee country [1] 315018 0
Australia
Date submitted for ethics approval [1] 315018 0
31/03/2024
Approval date [1] 315018 0
Ethics approval number [1] 315018 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 133438 0
A/Prof Carlo Pulitano
Address 133438 0
Royal Prince Alfred Hospital, Missenden road, Camperdown, NSW 2050
Country 133438 0
Australia
Phone 133438 0
+61 2 9515 7274
Fax 133438 0
Email 133438 0
Carlo.pulitano@sydney.edu.au
Contact person for public queries
Name 133439 0
Carlo Pulitano
Address 133439 0
Royal Prince Alfred Hospital, Missenden road, Camperdown, NSW 2050
Country 133439 0
Australia
Phone 133439 0
+61 2 9515 7274
Fax 133439 0
Email 133439 0
Carlo.pulitano@sydney.edu.au
Contact person for scientific queries
Name 133440 0
Carlo Pulitano
Address 133440 0
Royal Prince Alfred Hospital, Missenden road, Camperdown, NSW 2050
Country 133440 0
Australia
Phone 133440 0
+61 2 9515 7274
Fax 133440 0
Email 133440 0
Carlo.pulitano@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.