A Multicenter Randomized Controlled Trial to Compare the Efficacy of Ex-vivo Normothermic Machine Perfusion With Static Cold Storage in Human Liver Transplantation
Phase: NA
Conditions: Liver Transplantation
Sponsor: OrganOx Ltd.

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WP01 US Trial Protocol 
A multicenter randomized controlled trial to compare the efficacy of ex-
vivo normothermic machine perfusion with static cold storage in human 
liver transplantation 
 
 
IDE Ref: 
G140243 
Protocol Version: 
WP01 Version 10.0: (24 June 2016) 
National 
Principal 
Investigator: 
Stuart Knechtle, MD 
Professor of Surgery 
Department of Surgery 
Duke University 
2100 Erwin Rd, Durham, NC 27705, USA 
stuart.knechtle@duke.edu  
+1 919 613 9687 
 
Sponsor/Manufacturer: 
 
US Sponsor: 
 
US Agent: 
 
OrganOx Ltd. 
 
NAMSA  
 
NAMSA  
Funder: 
OrganOx Ltd. 
 
Confidentiality Statement: 
This document contains confidential information that must not be disclosed 
to anyone other than the Sponsor, the US Sponsor, the Investigative Team, 
and members of the FDA/IRB unless authorized to do so. 
 
Conflicts of Interest: 
None 
 
 
 
 
 

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STUDY SYNOPSIS 
Trial Title 
A multicenter randomized controlled trial to compare the efficacy of ex-vivo 
normothermic machine perfusion with static cold storage in human liver 
transplantation 
Short Title 
WP01 – Normothermic liver preservation 
Clinical Phase 
Pivotal  
Trial Design 
Multicenter open-label randomized controlled trial 
Investigative Sites 
Subjects will be enrolled at up to 15 investigative sites 
Trial Participants 
Deceased DBD and DCD liver donors and adult liver transplant recipients 
Planned sample size 
266 transplanted livers (minimum of 120 per arm), with approximately 356 
randomized livers 
Follow-up duration 
Subjects will be followed for 12 months post-transplant procedure. The primary 
endpoint analysis will be completed at 6 months post-transplant procedure.  
Planned trial period 
36 months 
 
Objectives 
Outcome measures/endpoints 
Primary 
To compare the effect of NMP to SCS in 
preventing preservation-related graft 
injury 
Severity of immediate graft injury as 
measured by early allograft dysfunction 
(EAD). 
Secondary 
To compare graft and subject survival 
between NMP and SCS livers. 
Primary non-function rates: irreversible 
graft dysfunction requiring emergency 
liver replacement during the first 10 
days after liver transplantation. 
 
Graft survival rates at 30 days, 3 months, 
and 6 months following transplantation.  
Subject survival rates at 30 days, 3 
months, and 6 months following 
transplantation. 
To compare evidence of post-
reperfusion syndrome between NMP 
and SCS livers on transplantation. 
Assess mean arterial pressure (MAP) 
pre- and post-reperfusion in the context 
of vasopressor use. 
To compare biochemical liver function 
between NMP and SCS livers. 
Bilirubin, GGT, ALT, AST, ALP and INR at 
days 1-7, day 30, month 3, and month 6 
post-transplant.   
Lactate at days 1-7 while the subject is in 
ICU. 
To compare evidence of ischemia-
reperfusion injury between NMP and 
SCS livers. 
Post-reperfusion biopsies will be 
compared to baseline pre-reperfusion 
biopsies and graded according to 
standard histological criteria. 

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To compare evidence of biliary 
complications between NMP and SCS 
livers.  
Incidence of biliary investigations and/or 
interventions between 7 days and 6 
months post-transplant. 
To assess the feasibility and safety of 
NMP as a method of organ storage and 
transportation. 
Incidence of livers randomized but not 
transplanted and reasons for not-
transplanting.  
To compare organ utilization between 
NMP and SCS livers. 
Incidence of one or more of the 
following per randomized liver: (i) EAD; 
(ii) discard (non-transplant) of a 
retrieved liver; (iii) primary non-function.  
To assess the health economic 
implications of normothermic liver 
perfusion. 
Logistical and healthcare costs (length of 
stay in ICU and hospital) and quality of 
life measures. 
Device name 
OrganOx metra® 
Device 
manufacturer 
OrganOx Ltd, Oxford, UK 
Length of time 
device has been in 
use 
Since February 2013 (in two European clinical studies)   
 

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INVESTIGATOR SIGNATURE PAGE 
 
I agree to conduct this clinical study in accordance with the design and specific provisions of this protocol and 
will only make changes in the protocol after notifying the US Sponsor. 
I understand that I may terminate or suspend enrollment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects as advised by the Data Safety Monitoring Board (DSMB). This 
study may be terminated by the Sponsor/Manufacturer or US Sponsor, with or without cause. 
I agree to personally conduct or supervise this investigation and to ensure that all associates, colleagues, and 
employees assisting in the conduct of this study are informed about their obligations in meeting these 
commitments. 
I will conduct the study in accordance with applicable Good Clinical Practice, and the moral, ethical and 
scientific principles that justify medical research.  The study will be conducted in accordance with all relevant 
laws and regulations relating to clinical studies and the protection of patients.   
I will ensure that the requirements relating to FDA review and approval are met.   
I agree to maintain adequate and accurate records and to make those records available for audit and 
inspection in accordance with relevant regulatory requirements. 
I agree to promptly report to the FDA, the IRB (per their reporting guidelines), and US Sponsor any changes in 
the research activity and all unanticipated problems involving risks to human subjects or others.  Additionally, I 
will not make any changes in the research without regulatory approval, except where necessary to ensure the 
safety of study participants. 
 
 
 
Signature…………………………………………………………………… 
 
 
Name………………………………………………………………………… 
 
 
Date…………………………. 

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CONTENTS 
Study Synopsis .................................................................................................................................................... 2 
Protocol Sign-Off................................................................................................................................................. 4 
Investigator Signature Page ................................................................................................................................ 5 
Contents ............................................................................................................................................................. 6 
Abbreviations .................................................................................................................................................... 12 
1. Administrative Information .......................................................................................................................... 14 
1.1 Title ......................................................................................................................................................... 14 
1.2 Trial Registration ..................................................................................................................................... 14 
1.3 Protocol Version ..................................................................................................................................... 14 
1.3.1 Current Version ................................................................................................................................ 14 
1.3.2 Previous Versions ............................................................................................................................. 14 
1.4 Study Funding ......................................................................................................................................... 14 
1.5 Sponsor ................................................................................................................................................... 14 
1.6 Trial Personnel ........................................................................................................................................ 14 
1.6.1 National Principal Investigator......................................................................................................... 14 
1.6.2 Database Design .............................................................................................................................. 14 
1.6.3 Trial Statistician................................................................................................................................ 14 
1.6.4 Trial Histopathologist ....................................................................................................................... 14 
1.7 Roles and Responsibilities....................................................................................................................... 15 
1.7.1 Sponsor Responsibilities .................................................................................................................. 15 
1.7.2 Investigator Responsibilities ............................................................................................................ 16 
1.8 Committees ............................................................................................................................................ 17 
1.8.1 Data Safety Monitoring Board (DSMB) ............................................................................................ 17 
1.8.2 Clinical Events Committee (CEC) ...................................................................................................... 17 
2. Introduction .................................................................................................................................................. 18 
2.1 Background and Rationale ...................................................................................................................... 18 
2.1.1 Liver Transplantation – A Successful Therapy ................................................................................. 18 
2.1.2 Liver Failure Epidemiology ............................................................................................................... 18 
2.1.3 The Donor Shortage ......................................................................................................................... 18 
2.1.4 Approaches to the Donor Organ Shortage ...................................................................................... 18 
2.1.4.1 Living Donation ............................................................................................................................. 19 
2.1.4.2 Higher Risk Donor Organs ............................................................................................................. 19 
2.1.4.3 Donation After Circulatory Death (DCD) ....................................................................................... 19 

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2.1.4.4 Viability Assessment ..................................................................................................................... 20 
2.1.4.5 Ex Vivo Reconditioning ................................................................................................................. 20 
2.1.5 Cold Storage ..................................................................................................................................... 20 
2.1.6 Machine Perfusion ........................................................................................................................... 21 
2.1.7 Hypothermic Machine Perfusion (HMP) .......................................................................................... 21 
2.1.8 Normothermic Machine Perfusion (NMP) ....................................................................................... 21 
2.1.9 Preclinical Investigations ................................................................................................................. 22 
2.2 Phase 1 Clinical Trial Data ....................................................................................................................... 23 
3. Objectives ..................................................................................................................................................... 24 
3.1 Hypothesis .............................................................................................................................................. 24 
3.2 Objectives and Outcome Measures/Endpoints ...................................................................................... 24 
3.2.1 Primary Objective ............................................................................................................................ 24 
3.2.2 Primary Outcome Measure/Endpoint ............................................................................................. 24 
4. Trial Design ................................................................................................................................................... 25 
5. Participant Identification .............................................................................................................................. 26 
5.1 Study Setting ........................................................................................................................................... 26 
5.2 Trial Participants ..................................................................................................................................... 26 
5.2.1 CMS Reimbursement ....................................................................................................................... 26 
5.3 Eligibility Criteria ..................................................................................................................................... 27 
5.3.1 Donor Criteria .................................................................................................................................. 27 
5.3.1.1 Donor Inclusion Criteria ................................................................................................................ 27 
5.3.1.2 Donor Exclusion Criteria ............................................................................................................... 27 
5.3.2 Recipient Criteria ............................................................................................................................. 27 
5.3.2.1 Recipient Inclusion Criteria ........................................................................................................... 27 
5.3.2.2 Recipient Exclusion Criteria .......................................................................................................... 27 
6. Trial Procedures ............................................................................................................................................ 27 
6.1 Recruitment ............................................................................................................................................ 27 
6.2 Informed Consent ................................................................................................................................... 28 
6.2.1 Recipient Consent ............................................................................................................................ 28 
6.2.2 Donor Consent ................................................................................................................................. 28 
6.3 Screening and Eligibility Assessment ...................................................................................................... 29 
6.3.1 Recipient Assessment ...................................................................................................................... 29 
6.3.2 Donor Assessment ........................................................................................................................... 29 
6.4 Randomization and Blinding ................................................................................................................... 29 
6.4.1 Sequence Generation ...................................................................................................................... 29 

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6.4.2 Allocation Concealment Mechanism ............................................................................................... 29 
6.4.3 Implementation ............................................................................................................................... 29 
6.4.4 Blinding/Masking ............................................................................................................................. 29 
6.5 Pre-Study Baseline Assessments ............................................................................................................ 29 
6.5.1 Donor Demographics ....................................................................................................................... 29 
6.5.2 Recipient Demographics .................................................................................................................. 30 
6.5.3 Quality of Life Questionnaire (EQ-5D-5L) ........................................................................................ 30 
6.6 Trial Interventions................................................................................................................................... 30 
6.6.1 NMP Group (Investigational metra® Device) ................................................................................... 30 
6.6.2 SCS Group ........................................................................................................................................ 31 
6.6.3 Recording of Operative and Perfusion Parameters ......................................................................... 31 
6.6.3.1 Donor Timings ............................................................................................................................... 31 
6.6.3.1.1 DBD Donor Timings .................................................................................................................... 31 
6.6.3.1.2 DCD Donor Timings .................................................................................................................... 31 
6.6.3.1.3 DBD/DCD Donor Timings Randomized to NMP ......................................................................... 31 
6.6.3.2 Preservation Parameters for All Randomized Livers .................................................................... 31 
6.6.3.3 Operative Parameters ................................................................................................................... 32 
6.6.3.4 Histological Parameters ................................................................................................................ 32 
6.7 Concomitant Care ................................................................................................................................... 32 
6.8 Study Visits .............................................................................................................................................. 33 
6.8.1 Inpatient Stay ................................................................................................................................... 33 
6.8.1.1 Biochemical Assessments ............................................................................................................. 33 
6.8.1.2 Additional Assessments ................................................................................................................ 33 
6.8.1.3 Safety Assessments ....................................................................................................................... 33 
6.8.1.4 Immunosuppression ..................................................................................................................... 33 
6.8.2 Day 30 Post-Transplant Procedure .................................................................................................. 33 
6.8.2.1 Biochemical Assessments ............................................................................................................. 34 
6.8.2.2 Additional Assessments ................................................................................................................ 34 
6.8.2.3 Safety Assessments ....................................................................................................................... 34 
6.8.2.4 Immunosuppression ..................................................................................................................... 34 
6.8.3 Month 3 Post-Transplant Procedure ............................................................................................... 34 
6.8.3.1 Biochemical Assessments ............................................................................................................. 34 
6.8.3.2 Additional Assessments ................................................................................................................ 35 
6.8.3.3 Safety Assessments ....................................................................................................................... 35 
6.8.3.4 Immunosuppression ..................................................................................................................... 35 

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6.8.4 Month 6 Post-Transplant Procedure ............................................................................................... 35 
6.8.4.1 Biochemical Assessments ............................................................................................................. 35 
6.8.4.2 Additional Assessments ................................................................................................................ 35 
6.8.4.3 Safety Assessments ....................................................................................................................... 36 
6.8.4.4 Immunosuppression ..................................................................................................................... 36 
6.8.5 Month 12 Post-Transplant Procedure ............................................................................................. 36 
6.9 Participant Retention .............................................................................................................................. 36 
6.10 Definition of the End of the Trial .......................................................................................................... 36 
7. The OrganOx metra® Device ......................................................................................................................... 37 
7.1 Device Description .................................................................................................................................. 37 
7.1.1 The OrganOx metra® Base Unit ....................................................................................................... 37 
7.1.2 Disposable Set .................................................................................................................................. 37 
7.1.3 Perfusion Solutions .......................................................................................................................... 37 
7.2 Device Safety .......................................................................................................................................... 38 
7.3 Device Labelling ...................................................................................................................................... 38 
7.4 Device Accountability ............................................................................................................................. 38 
7.5 Device Maintenance ............................................................................................................................... 38 
7.6 Device Logistics ....................................................................................................................................... 39 
7.6.1 Logistical Considerations ................................................................................................................. 39 
7.6.2 Logistical Arrangements for Study Sites .......................................................................................... 39 
8. Data Monitoring and Safety Reporting ......................................................................................................... 39 
8.1 Data Monitoring ..................................................................................................................................... 39 
8.1.1 Data Safety Monitoring Board ......................................................................................................... 39 
8.1.2 Interim Analyses .............................................................................................................................. 39 
8.2 Adverse Events ....................................................................................................................................... 39 
8.2.1 Definitions ........................................................................................................................................ 39 
8.2.2 Adverse Event Severity Definitions .................................................................................................. 40 
8.2.3 Anticipated Adverse Events ............................................................................................................. 40 
8.2.4 Device Deficiency ............................................................................................................................. 40 
8.2.4.1 
Device Failures .......................................................................................................................... 41 
8.2.4.2 
Device Malfunctions ................................................................................................................. 41 
8.2.4.3 
Use Errors ................................................................................................................................. 41 
8.2.5 Procedures for Recording Adverse Events ....................................................................................... 41 
8.2.6 Reporting Procedures for All Adverse Events .................................................................................. 41 
8.3 Study Suspension or Early Termination .................................................................................................. 42 

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9. Statistics ........................................................................................................................................................ 42 
9.1 Description of  Statistical Methods ......................................................................................................... 42 
9.1.1 General Statistical Considerations ................................................................................................... 42 
9.1.2 Conditional Phase Analyses ............................................................................................................. 43 
9.1.3 Study Cohorts for Analyses .............................................................................................................. 43 
9.1.4 Primary Outcome ............................................................................................................................. 43 
9.1.5 Secondary Outcomes ....................................................................................................................... 44 
9.1.6 Safety Analyses ................................................................................................................................ 44 
9.1.7 Subgroup Analyses ........................................................................................................................... 44 
9.1.8 Poolability Analysis .......................................................................................................................... 44 
9.1.9 Missing Data .................................................................................................................................... 45 
9.2 Sample Size ............................................................................................................................................. 45 
9.3 Additional Analyses and Deviation from the Statistical Analysis Plan .................................................... 45 
10. Data Collection and Management .............................................................................................................. 45 
10.1 Data Collection Methods ...................................................................................................................... 45 
10.1.1 Source Data .................................................................................................................................... 45 
10.1.2 Data Recording .............................................................................................................................. 46 
10.2 Data Management ................................................................................................................................ 46 
10.2.1 Data Forms and Data Entry ............................................................................................................ 46 
10.2.2 Discrepancies and Missing Data .................................................................................................... 46 
10.2.3 Security and Backup of Data .......................................................................................................... 46 
10.2.4 Data Access .................................................................................................................................... 46 
10.2.5 Data Retention ............................................................................................................................... 46 
11. Quality Assurance, Audit and Training........................................................................................................ 46 
11.1 Monitoring ............................................................................................................................................ 46 
11.2 Quality Assurance Auditing and Inspection .......................................................................................... 47 
11.3 Local Investigator and Site Personnel Training ..................................................................................... 47 
11.4 Study Documentation ........................................................................................................................... 47 
12. Protocol Deviations ..................................................................................................................................... 47 
12.1 Definitions ............................................................................................................................................. 47 
12.2 Reporting of Protocol Deviations .......................................................................................................... 48 
13. Ethical and Regulatory Considerations ....................................................................................................... 48 
13.1 IRB and FDA Approval ........................................................................................................................... 48 
13.2 Protocol Amendments .......................................................................................................................... 48 
13.3 
Reporting .......................................................................................................................................... 48 

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13.3.1 Sponsor Reports............................................................................................................................. 48 
13.3.2 Investigator Reports ...................................................................................................................... 49 
13.4 Participant Confidentiality .................................................................................................................... 50 
13.5 Expenses and Benefits .......................................................................................................................... 50 
14. Dissemination Policy ................................................................................................................................... 51 
14.1 Data Analysis and Release of Results .................................................................................................... 51 
14.2 Primary Outcome Publications ............................................................................................................. 51 
Appendix A1: Timeline for Interventions and Assessments During the Study ............................................. 52 
Appendix A2: Protocol Amendments ........................................................................................................... 54 
References ........................................................................................................................................................ 55 
 
 

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ABBREVIATIONS 
AE 
 
Adverse Event 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Aminotransferase 
AST 
 
Aspartate Transaminase 
ATP 
 
Adenosine Triphosphate 
BMI 
 
Body Mass Index 
CEC 
 
Clinical Events Committee 
CFR 
 
Code of Federal Regulations 
CIT 
 
Cold Ischemia Time 
CMS 
 
Centers for Medicare & Medicaid Services 
CRF 
 
Case Report Form 
CVA 
 
Cerebrovascular Accident 
DBD 
 
Donation after Brain Death 
DCD 
 
Donation after Circulatory Death 
DPMP 
 
Donors per Million Population per Year 
DRI 
 
Donor Risk Index 
DSMB 
 
Data Safety Monitoring Board 
EAD 
 
Early Allograft Dysfunction 
ECD 
 
Extended Criteria Donor 
eCRF 
 
Electronic Case Report Form 
EDC 
 
Electronic Data Capture 
ERCP 
 
Endoscopic Retrograde Cholangiopancreatography 
FDA 
 
Food & Drug Administration 
GCP 
 
Good Clinical Practice 
GGT 
 
Gamma-Glutamyl Transferase 
GST 
 
Glutathione S-Transferase 
H0 
 
Null Hypothesis 
HA 
 
Alternative Hypothesis 
HCC 
 
Hepatocellular Carcinoma 
HCV 
 
Hepatitis C Virus 
HD 
 
Hemodialysis 
HDF 
 
Hemodiafiltration 
HF 
 
Hemofiltration 
HMP 
 
Hypothermic Machine Perfusion 

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HTK 
 
Histidine-Tryptophane-Ketoglutarate  
IC 
 
Ischemic Cholangiopathy 
ICU 
 
Intensive Care Unit 
IDE 
 
Investigational Device Exemption 
IFU 
 
Instructions for Use 
INR 
 
International Normalized Ratio 
IRB 
 
Institutional Review Board 
ISO 
 
International Organization for Standardization 
IVC 
 
Inferior Vena Cava 
MAP 
 
Mean Arterial Pressure 
MELD 
 
Model for End Stage Liver Disease 
MRCP 
 
Magnetic Resonance Cholangiopancreatography 
NMP 
 
Normothermic Machine Perfusion 
OPO 
 
Organ Procurement Organization 
OPTN 
 
Organ Procurement and Transplantation Network 
PNF 
 
Primary Non-Function 
PT 
 
Prothrombin Time 
PTC 
 
Percutaneous Transhepatic Cholangiogram 
RRT 
 
Renal Replacement Therapy 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SBP 
 
Systolic Blood Pressure 
SCS 
 
Static Cold Storage 
SRTR  
 
Scientific Registry of Transplant Recipients 
UADE 
 
Unanticipated Adverse Device Effect 
UNOS 
 
United Network for Organ Sharing 
UW 
 
University of Wisconsin Preservation Solution 

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1. ADMINISTRATIVE INFORMATION 
1.1 TITLE 
“A multicenter randomized controlled trial to compare the efficacy of ex-vivo normothermic machine 
perfusion with static cold storage in human liver transplantation.” 
1.2 TRIAL REGISTRATION 
This trial protocol is registered with clinicaltrials.gov in accordance with regulations.  The national clinical trial 
identifier is NCT02775162. 
1.3 PROTOCOL VERSION 
1.3.1 CURRENT VERSION 
Version number: WP01 Version 10.0 
Issue date: 24 June 2016 
1.3.2 PREVIOUS VERSIONS 
Details of previous versions and amendments to this protocol are detailed in Appendix A2. 
1.4 STUDY FUNDING 
OrganOx Ltd 
1.5 SPONSOR 
The trial is sponsored by OrganOx Ltd. 
The US Sponsor and US Agent is NAMSA.  
The Sponsor/Manufacturer will approve this protocol prior to study commencement. 
1.6 TRIAL PERSONNEL 
1.6.1 NATIONAL PRINCIPAL INVESTIGATOR 
National Principal Investigator: 
Stuart Knechtle MD; Duke University 
 
1.6.2 DATABASE DESIGN 
US Sponsor will be responsible for developing and maintaining the trial database and electronic case report 
forms. The database will have reporting functionality in order to capture data entry and verification, which the 
trial data manager will utilize. 
1.6.3 TRIAL STATISTICIAN 
The NAMSA statistician will be responsible for the development of the statistical analysis plan and the 
subsequent analysis of trial data. 
1.6.4 TRIAL HISTOPATHOLOGIST 
Histopathology will be carried out by a central laboratory in accordance with a study laboratory 
manual.  
 
  

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1.7 ROLES AND RESPONSIBILITIES 
1.7.1 SPONSOR RESPONSIBILITIES  
 
General responsibilities (§812.40)  
Sponsors are responsible for selecting qualified investigators and providing them with the 
information that they need to conduct the investigation properly. They must also ensure proper 
monitoring of the investigation and IRB review and approval, submit an IDE application to FDA for 
significant risk device studies, and inform the IRB and FDA promptly of any significant new 
information about the investigation. 
 
FDA and IRB approval (§812.42)  
A sponsor cannot begin an investigation or any part of an investigation until an IRB and FDA have 
both approved the application or supplemental application. 
 
Selecting Investigators (§812.43)  
A sponsor is responsible for selecting investigators qualified by training and experience to investigate 
the device. 
 
Selecting Monitors (§812.43)  
A sponsor must select monitors qualified by training and experience to monitor the investigational 
study in accordance with the IDE and other applicable FDA regulations. 
 
Device Control (§812.43)  
A sponsor can ship investigational devices only to qualified investigators participating in the 
investigation. 
 
Investigator Agreements (§812.43)  
A sponsor must obtain a signed agreement from each participating investigator that includes: 
o 
The investigator's curriculum vitae,  
o 
A statement of the investigator's relevant experience, including the dates, location, extent, 
and type of experience, where applicable,  
o 
An explanation of the circumstances that led to termination of a study if the investigator 
was involved in an investigation or other research that was terminated,  
o 
A statement of the investigator's commitment to:  
 
Conduct the investigation in accordance with the agreement, the investigational 
plan, the IDE and other  applicable FDA regulations, and conditions of approval 
imposed by the reviewing IRB or FDA,  
 
Supervise all testing of the device involving human subjects  
 
Ensure that the requirements for obtaining informed consent are met. 
 
Sufficient accurate financial disclosure information to allow a sponsor to submit a 
complete and accurate certification or disclosure statement as required under 21 
CFR 54, Financial Disclosure by Clinical Investigators. A sponsor shall also obtain a 
commitment from the clinical investigator to promptly update this information if 
any relevant changes occur during the course of the investigation and for one year 
following completion of the study.  
 
Informing Investigators (§812.45)  
A sponsor must supply all investigators participating in the investigation with copies of the 
investigational plan and a report of prior investigations of the device. 
 
Monitoring (§812.46) 
Securing Compliance: A sponsor who discovers that an investigator is not complying with the signed 
agreement, the investigational plan, the IDE requirements, any other applicable FDA regulations, or 
any conditions of approval imposed by the reviewing IRB or FDA must promptly either secure 
compliance, or discontinue shipments of the device to the investigator and terminate the 
investigator's participation in the investigation. A sponsor must also require that the investigator 

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dispose of or return the device, unless this action would jeopardize the rights, safety, or welfare of a 
subject.  
Unanticipated Adverse Device Effects: A sponsor must immediately conduct an evaluation of any 
unanticipated adverse device effect. A sponsor who determines that an unanticipated adverse device 
effect presents an unreasonable risk to subjects must terminate all investigations or parts of the 
investigations presenting that risk as soon as possible. Termination must occur no later than 5 
working days after a sponsor makes this determination and no later than 15 working days after a 
sponsor first received notice of the effect.  
Resumption of Terminated Studies: a sponsor may not resume a terminated investigation without IRB 
and FDA approval. A sponsor may not resume a terminated investigation without IRB approval.  
 
Sponsor records (§812.140)  
A sponsor must maintain accurate and complete records relating to the investigation. These records 
include: 
o 
All correspondence including required reports,  
o 
Records of shipment of the device,  
o 
Records of disposition of the device,  
o 
Signed investigator agreements including financial disclosure information,  
o 
Records concerning complaints and adverse device effects whether anticipated or not,  
o 
Any other records that FDA requires to be maintained by regulation or by specific 
requirement for a category of investigation or a particular investigation. 
 
Sponsor Reports (§812.150)  
A sponsor must provide the following reports in a timely manner to FDA, the IRB's, and/or the 
investigators. 
o 
Unanticipated Adverse Device Effects  
o 
Withdrawal of IRB Approval  
o 
Withdrawal of FDA Approval  
o 
Current List of Investigators  
o 
Progress Reports  
o 
Recalls and Device Disposition  
o 
Final Report  
o 
Use of device without Informed Consent  
o 
Significant Risk Device Determination  
1.7.2 INVESTIGATOR RESPONSIBILITIES  
 
The investigator is responsible for protecting the rights, safety, and welfare of subjects. An 
investigator must conduct the investigation in accordance with the signed agreement with the 
sponsor, the investigational plan, the IDE regulations and other applicable FDA regulations, and any 
conditions of approval imposed by an IRB and FDA. (§812.100) 
 
While awaiting approval, an investigator may determine whether or not potential subjects would be 
interested in participating in an investigation, but cannot request written informed consent or allow 
any subjects to participate before obtaining IRB and FDA approval.  (§812.110) 
 
An investigator is responsible for obtaining informed consent under 21 CFR Part 50. 
 
Supervision of device use: An investigator can permit use of the investigational device only with 
subjects under his/her supervision and must not supply an investigational device to any person not 
authorized under the regulations to receive it.  (§812.110)  
 
Financial Disclosure (§812.110) 
The clinical investigator must disclose to the sponsor sufficient accurate financial information to allow 
the IDE applicant (or sponsor) to submit certification or disclosure of financial interests under 21 CFR 

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54. The investigator must update the information if any relevant changes occur during the course of 
the investigation and for one year following completion of the study. 
 
Device Disposal (§812.110) 
Upon completion or termination of a clinical investigation or the investigator's part of the 
investigation or at the sponsor's request, an investigator must return to the sponsor any remaining 
supply of the device or dispose of the device as the sponsor directs. 
 
Records (§812.140) 
The investigator must maintain accurate and complete records relating to the investigation. These 
records include: 
o 
All correspondence including required reports, 
o 
Records of receipt, use, or disposition of the investigational device, 
o 
Records of each subject's case history and exposure to the device, 
o 
The protocol and documentation (date and reason) for each deviation from the protocol, 
o 
Any other records that FDA requires to be maintained by regulation or by specific 
requirement for a category of investigation or a particular investigation. 
 
Investigator Reports (§812.150) 
The investigator must provide the following reports in a timely manner to the sponsor and/or the IRB: 
o 
Unanticipated Adverse Device Effects 
o 
Withdrawal of IRB Approval 
o 
Progress Reports 
o 
Deviations from the Investigational Plan 
o 
Failure to obtain Informed Consent 
o 
Final Report 
 
The Investigators will be responsible for: 
o 
Identification and recruitment of patients to the study 
o 
Conducting clinical procedures in accordance with the protocol and standard operating 
procedures 
o 
Data collection and completion of electronic CRFs 
o 
Follow-up of study participants 
1.8 COMMITTEES 
1.8.1 DATA SAFETY MONITORING BOARD (DSMB) 
The DSMB will be appointed to monitor the conduct of the study and subject safety by periodically reviewing 
data from the study. The DSMB will oversee the overall safety of the current and future study subjects by 
protecting them from avoidable harm. The DSMB will review adverse events and other relevant study data and 
will make recommendations regarding continuation of the study to the US Sponsor.  
1.8.2 CLINICAL EVENTS COMMITTEE (CEC) 
The CEC is composed of transplant surgeons or other clinicians with relevant expertise who are not 
participating in this study, and who do not have significant investment with the study Sponsor/Manufacturer 
or US Sponsor.  The CEC is charged with the review and classification of adverse events (AEs), including deaths.  
The CEC will establish rules outlining the minimum data required and the algorithm followed in order to 
classify AEs.  All members of the CEC will meet regularly to review and classify AEs.  All appropriate data will be 
reviewed by the CEC. The CEC will forward a report of event review and classifications as outlined in the CEC 
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2. INTRODUCTION 
2.1 BACKGROUND AND RATIONALE 
2.1.1 LIVER TRANSPLANTATION – A SUCCESSFUL THERAPY 
Liver transplantation is the only effective treatment for many patients with liver disease. For patients with liver 
failure, techniques for supporting liver function provide only limited and temporary benefit as a bridge to 
transplantation or liver regeneration in the case of acute liver failure. In contrast to kidney dialysis support in 
renal failure, there is no artificial means to support a patient with liver failure for an extended period. Since 
the first clinical case in 1963, transplantation of the liver has developed to an established and standardized 
procedure as cure for acute and chronic liver disease. The results of liver transplantation have greatly 
improved and patient survival rates of over 90% at one year and 70% at five years are routinely achieved for 
elective liver transplantation. As a result, liver transplantation has become the mainstay of treatment for an 
increasing spectrum of patients with chronic liver disease, metabolic liver disease, acute liver failure and some 
liver cancers.   
2.1.2 LIVER FAILURE EPIDEMIOLOGY 
In the US cirrhosis is the most common indication for liver transplantation (42%), other indications include 
cancer (22%), and acute hepatic necrosis (4%) [www.srtr.org – 2012 annual report]. The main causes for 
cirrhosis in the US are virus related cirrhosis and alcoholic liver disease. It is predicted that HCV-related 
hepatocellular carcinoma (HCC) will continue to increase during the next decade, despite the impact of new 
drug treatments for this infection. Meanwhile, the incidence of liver disease related to both obesity and 
alcohol consumption is expected to increase despite health campaigns. It is very likely that the demand for 
donor livers suitable for transplantation will continue to rise, exacerbating the existing organ shortage. 
2.1.3 THE DONOR SHORTAGE 
Over the last two decades, liver transplantation has become a victim of its own success: many more patients 
are referred for transplantation, but the number of suitable grafts from deceased organ donors has increased 
more slowly. The donor organ shortage constitutes a serious risk for patients with liver failure. It is the 
principal cause of increasing waiting lists and the death of patients on the waiting list worldwide. In 2012, 
6,256 patients underwent liver transplantation in the USA, but 10,143 patients were added to the waiting list, 
and there was a mortality rate of 19% on the waiting list.  This shortfall is typical of liver transplantation 
services around the world. In many countries, a patient is now more likely to die on the waiting list for a 
transplant than in the 12 months after the operation. 
Great efforts have been made in recent years to increase the referral of organ donors, but an increasing 
proportion of deceased donors are suboptimal. These include donors declared dead by cardiovascular criteria 
(‘donation after circulatory death’, DCD) and other ‘extended criteria’ organ donors (older age, steatosis, etc.). 
There has been a much smaller increase in the number of standard criteria (‘ideal’) organ donors, including 
younger donors declared dead by neurological criteria (‘donation after brain death’, DBD). This is reflected in 
the utilization of donor organs – in 2012, 74% of solid organ donors in the USA resulted in a liver transplant 
(OPTN data). 
2.1.4 APPROACHES TO THE DONOR ORGAN SHORTAGE 
Organ donor rates in other countries range widely: using 2011 data, the highest rate occurred in Spain with 
35.3 donors per million population per year (DPMP), compared to the UK (17 DPMP) and the USA (25 DPMP). 
It is generally accepted that these discrepancies are due not only to cultural distinctions but also due to 
political and legal differences. There is debate as to whether the situation is simpler in those countries that 
practice “presumed consent” (opting out) [1]. Most countries, however, practice a system of “opting in,” 
whereby consent must be sought from the family of the donor. 

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Due to the critical shortage of donor organs, clinicians are continually searching for ways to overcome the 
discrepancy between demand and availability of donor livers for transplantation. Additional sources of organs 
include those from living donors, organs from DCD (donation after circulatory death) donors (previously known 
as ‘non-heart-beating donors’) and other less-than-optimal (‘higher risk’) deceased donors.  
2.1.4.1 LIVING DONATION  
Living donation is one potential means to increase the number of liver transplants, using surgical techniques 
developed for ´liver splitting´ (a technique for using a single liver for transplantation into two recipients). The 
major limitations of this technique include, first, the fact that most patients do not have a willing and suitable 
living donor, and, second, real concerns about the risks to the healthy donor. The reported risk of donor death 
is estimated at 0.2% but the risk of serious complications is much higher [2]. For these and other reasons living 
donor transplantation has had limited impact on the shortage of donor livers for transplantation in most 
countries (only 246 such transplants were performed in the USA in 2012). 
2.1.4.2 HIGHER RISK DONOR ORGANS 
Much emphasis is now placed on optimizing the condition of those organs that are available, to enable an 
increased number of higher risk organs to be transplanted safely. The use of a higher risk organ does 
constitute a greater risk to the recipient, with a higher probability that the organ will never function and 
require immediate replacement (primary non-function; PNF), that it will function poorly and place the patient 
at risk of other complications (early allograft dysfunction; EAD) or that it will lead to later complications 
including multiple stricturing of the biliary tree (ischemic cholangiopathy; IC). 
The serious effects of the organ shortage, with many patients dying on the waiting list, has led to increased 
interest in using donor livers which were formerly thought unsuitable for transplantation. The use of these 
´extended criteria donors´ (ECD; also called ‘marginal’ or ‘high risk’) donor livers for liver transplantation is now 
seen as essential if liver transplant units are to address the demand. Several donor parameters have been 
identified as relative risk factors for poor outcome, including age; steatosis; DCD donation; split livers; 
prolonged cold ischemia time (>12 hours). These were all developed using North American data and 
formulated into an algorithm known as the ‘Donor Risk Index’ (DRI) [3], and later validated using European 
data [4]. 
2.1.4.3 DONATION AFTER CIRCULATORY DEATH (DCD) 
For many years (following the establishment of brain death criteria) in most countries, deceased donor organs 
were almost exclusively sourced from donors declared dead by neurological criteria (donation after brain 
death, DBD). In such cases the donor remains on ventilatory support and cardiopulmonary function is 
maintained until the donor has been transferred to the operating room, preliminary dissection has been 
performed, cannulae placed and the organs are ready for cooling. This enables organs to be removed with 
minimal interruption to oxygenation before cooling and preservation. In contrast, in the case of DCD donors, 
death is certified after cardiac arrest using cardiovascular parameters; this causes an inevitable period of 
oxygen deprivation between cardiac arrest and cold preservation of the organs. DCD donors have been 
classified as ‘uncontrolled’, in which death is not predicted (typically after failed resuscitation in an emergency 
room) and ‘controlled’ in which death is anticipated (typically under circumstances where life-support is 
withdrawn from a patient in whom continued treatment has been deemed to be futile). 
In the latter situation, because death is anticipated and the transplant team can be mobilized in advance, the 
period of ‘warm ischemia’ sustained by the donor organs is usually much shorter; livers from this source have 
been transplanted in substantial numbers in recent years, although very selectively, but with higher rates of 
primary non-function and other post-operative complications than DBD livers, with worse long-term graft 
survival [5-7].  This increase in complications results in an increased cost incurred with DCD transplantation [8]. 
In contrast, livers from uncontrolled DCD are not generally used for transplantation because of a high rate of 
primary non-function in the experience of those centers that have attempted this [9]. It has been estimated, 

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however, that effective use of these potential donors would add greatly to the number of organ donors [10]. 
This contrasts with the situation in renal transplantation in which organs from uncontrolled DCD have been 
used by some centers with outcomes that compare well with those from controlled DCD donors [11]. 
Following renal transplantation, a period of ‘delayed graft function’ is acceptable because it is possible to 
support the patient with dialysis whilst the transplanted organ recovers from the ischemic injury; an 
equivalent delay in initial function of a transplanted liver is fatal without urgent re-transplantation. 
2.1.4.4 VIABILITY ASSESSMENT 
The safety and utility of DCD liver transplantation would be greatly improved by a reliable test to quantify the 
ischemic/preservation injury and assess viability in order to predict the outcome after transplantation. Even 
after careful pre-retrieval donor selection, up to 45% of retrieved livers from DCD donors are discarded due to 
doubts about viability [12]. In the US in 2013  6,449 of 7,137 (90%) of all deceased donor livers retrieved were 
actually transplanted, falling to 360 of 492 (73%) for livers from DCD donors (SRTR data). In addition to these 
losses, many DCD donor organs are declined without being retrieved because of concerns about risk factors.  
An effective means of pre-transplant viability assessment would not only allow greater use of higher risk 
donors but also minimize the risk of primary non-function by identifying and excluding non-viable organs 
before subjecting a patient to the risk of surgery. 
2.1.4.5 EX VIVO RECONDITIONING 
A further strategy in the quest to use higher risk donor organs successfully is that of ‘reconditioning’ after 
retrieval – using techniques to reverse the injury sustained by the organ before and during the process of 
retrieval and treating the organ in such a way as to minimize the immediate damage that occurs after 
transplantation (ischemia-reperfusion injury). Treatment of the organ during preservation has major logistic 
and ethical advantages over any attempt to achieve the same effects by treating the donor (in many countries 
therapeutic interventions before declaration of death that are of no potential benefit to the donor are not 
permitted).  Many cytoprotective strategies have been tested in experimental models of transplantation and 
several have been shown to have therapeutic potential, including various antioxidants, inflammation 
inhibitors, vasodilating agents, inhibitors of chemotaxis or neutrophil infiltration. 
At the moment the flow of oxygenated blood ceases, the supply of oxygen, cofactors, and nutrients stops 
along with the means of disposal of metabolic waste products. Anaerobic metabolism continues (at a 
temperature-dependent rate), leading to depletion of energy stores, mainly adenosine tri-phosphate (ATP), 
with a concomitant build-up of an acidotic milieu. ATP is required for energy-dependent cellular functions, 
including the integrity of sodium/potassium pumps that maintain electrolyte balance across cell membranes 
and ATP depletion leads to loss of trans-cellular electrolyte gradients, cell swelling, influx of free calcium, and 
the subsequent activation of phospholipases. The breakdown of ATP during ischemia also generates substrates 
for the production of reactive oxygen intermediates on reperfusion and initiates the cascade of ischemic 
injury. Prevention of ATP depletion is therefore an important target of innovative preservation methods. It has 
been shown that providing an oxygen supply to the organ can prevent ATP depletion and preserve viability 
following cardiac arrest in a porcine liver transplant model [13]. 
2.1.5 COLD STORAGE 
Organs retrieved for transplantation undergo injury at several consecutive stages: 1) warm ischemia prior to 
preservation, 2) cold preservation injury, 3) ischemic rewarming during surgical implantation and 4) 
reperfusion injury. These consecutive events lead to a cumulative cellular injury that may not be compatible 
with recovery after transplantation.  
Standard clinical practice involves flushing and cooling the liver in situ with preservation solution; University of 
Wisconsin [UW] solution is used most commonly although Histidine-Tryptophane-Ketoglutarate [HTK] solution 
is also widely used. Typically several litres of cold preservation fluid are used both in situ and after removing 
the organ from the donor and before packing for transport and storage. Additional cooling may be provided by 

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topical frozen saline slush both in situ and ex situ. After retrieval, the organ is placed in sterile plastic bags for 
transportation and stored in an ice-box in preservation solution until transplantation.  Although the available 
preservation solutions differ in chemical composition, the function is essentially the same: to prevent cellular 
swelling and death caused by fluid shifts as the membrane ion-exchange pumps cease operating in the cold 
environment. Although cold preservation slows metabolism by 1.5- to 2-fold for every 10°C drop in 
temperature, considerable metabolic activity still occurs at 1°C. This leads to accumulation of metabolic 
products which act as substrates for metabolism that takes place when the organ is re-perfused with 
oxygenated blood – the basis of the ischemia-reperfusion phenomenon [14] 
In organs retrieved from DCD donors the deleterious effects of cold ischemia are superimposed on the injury 
sustained during warm ischemia, which causes rapid depletion of ATP. There are some differences in the 
pattern of injury sustained during warm and cold ischemia; the latter causes initial injury to sinusoidal 
endothelial cells whereas warm ischemia is more damaging to hepatocytes and cholangiocytes.  
Cold storage causes injury to the graft regardless of other factors. It has been known for many years that 
extended preservation time with cold preservation solution has a deleterious effect on organ viability [15, 16] 
with a clear correlation between cold-ischemia time and post-operative primary graft function. The rate of 
primary non-function was reported in a large registry analysis as 5.8% [17], although individual center reports 
show a range of incidence. Although a strong correlation has been shown between preservation injury and 
subsequent acute rejection [18], this has not been confirmed in other reports [19]. Preservation injury is a 
more critical issue in higher risk donor organs - whereas good quality livers can tolerate preservation periods 
even up to 18 hours, higher risk grafts must be implanted much more quickly in order to reduce the risk of 
potentially fatal graft dysfunction after transplantation. 
2.1.6 MACHINE PERFUSION 
Early in the history of organ preservation and transplantation, pioneers in the field investigated machine 
perfusion. In the first half of the twentieth century, for example, Carrel perfused organs with normothermic, 
oxygenated serum and demonstrated gross viability for several days [20]. A number of early successful clinical 
liver transplants carried out by Dr. Thomas Starzl, used machine perfusion with diluted blood under cold 
hyperbaric conditions [21]. This technique never gained popularity, partly due to its complexity and logistic 
challenges but also the subsequent introduction of effective cold flush preservation solutions.  Subsequent 
research into extracorporeal machine perfusion largely centered on liver support [22]. 
2.1.7 HYPOTHERMIC MACHINE PERFUSION (HMP) 
It has been demonstrated experimentally by several groups that hypothermic machine perfusion of the kidney 
significantly improves the preservation compared with static cold storage, in terms of immediate graft function 
and medium-term outcome of deceased kidneys and DCD organs specifically [23, 24]. The mechanism of 
benefit is not fully understood, but probably relates both to the removal of metabolic products as well as the 
delivery of oxygen (although in the absence of formal oxygenation or specialist oxygen carrier molecules, 
oxygen delivery is likely to be limited).  
HMP offers the additional benefit of some (limited) assessment of pre-transplant organ viability by 
measurement of perfusion pressures and also perfusate αGST levels and other biomarkers as a marker of 
cellular injury. It also provides the potential for local therapeutic intervention. Several groups have claimed 
advantages with hypothermic machine perfusions in liver transplantation and the first human clinical study of 
ex-vivo liver HMP has been published [25, 26]. 
2.1.8 NORMOTHERMIC MACHINE PERFUSION (NMP) 
There is accumulating evidence of the superiority of a more physiological approach using oxygenated blood at 
normal body temperature. Several studies demonstrate that the quality of preservation can be improved 
substantially by warm perfusion, by combining the avoidance of cooling with the maintenance of a supply of 

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oxygen and nutrition [27, 28]. These data are mainly based on organ retrieval, preservation, ex-situ-evaluation 
and transplantation in large animal models (pigs). In the experimental setting normothermic perfusion has 
been shown to resuscitate porcine livers subjected to 60 to 90 minutes of warm ischemia [14, 29]. Warm 
perfusion has the added advantage of allowing more effective viability assessment of the organs while on the 
circuit (using multiple perfusion dynamic and biochemical parameters), contrasting with the more limited 
parameters available on the hypothermic circuit [27]. Preclinical liver transplant experiments in the pig model 
from a number of centers [27, 28, 30] have shown that the normothermically preserved liver can be 
transplanted reliably and successfully after warm ischemic injuries that do not allow survival using cold 
preservation. If these results were translated into clinical practice, this would generate a large new source of 
donor organs. 
Normothermic perfusion has been shown as feasible in the setting of human renal transplantation [31], with a 
potential benefit of a reduction in the rate of delayed graft function in organs retrieved from extended criteria 
donors [32]. 
2.1.9 PRECLINICAL INVESTIGATIONS  
The experimental precursor to the proposed normothermic perfusion system was developed more than 15 
years ago and the method of perfusion of the isolated pig liver with autologous blood has since been 
extensively tested and refined, although the overall design of the perfusion circuit remains unchanged [33]. 
The circuit incorporates a centrifugal pump, membrane oxygenator, and heat exchanger. Arterial perfusion is 
directly pumped and the portal vein is perfused via a soft-shell reservoir using gravitational force. The addition 
of various substrates to the perfusion solution enables maintenance of metabolic function [34, 35]. 
The initial preservation experiments were carried out to compare preservation by warm perfusion with 
conventional cold preservation [29]. Porcine livers were retrieved and stored for a period of 24 hours, either 
flushed with UW solution and placed in an icebox or attached immediately to the preservation circuit. Both 
groups of livers were then reperfused on the circuit for 24 hours (as a surrogate for transplantation) and 
markers of cellular injury and of synthetic and metabolic liver function were measured. These experiments 
demonstrated significant superiority of normothermic machine perfusion in terms of hemodynamic, 
biochemical and histological parameters.  
Subsequent experiments investigated the use of oxygenated, normothermic perfusion in an experimental 
setting that reflected the clinical situation of DCD donor organ retrieval [14]. Perfusion with normothermic 
blood was again compared with static cold storage after 60 min of warm ischemia. Normothermic perfused 
livers demonstrated recovery of function by synthetic function, substrate utilization and perfusion 
hemodynamics. Furthermore these livers displayed less cellular injury as shown by hepatocellular enzymes. In 
contrast, cold stored livers showed no evidence of viability during reperfusion and massive necrosis on 
histological examination. 
It is recognized that the combination of warm ischemia and conventional cold preservation leads to a poor 
outcome in DCD liver transplantation [7]. In the experimental setting, it is possible to institute warm perfusion 
with minimal exposure of the organ to cooling. However, in contrast, the logistics of clinical multi-organ 
retrieval in a distant donor hospital are complex and would be simplified by a period of cold preservation prior 
to normothermic preservation. This would enable the liver to be retrieved in the normal way, transported in 
an ice box and then attached to the perfusion machine once back at the base hospital. This scenario was 
simulated in the same experimental model by inserting a period of cold preservation prior to normothermic 
preservation [36]. Porcine livers were subjected to 60 minutes of warm ischemia and then assigned to either 
normothermic preservation for 24 hours or cold preservation in University of Wisconsin solution for 4 hours 
followed by 20 hours normothermic preservation to achieve a total preservation time of 24 hours [36]. Livers 
that underwent normothermic preservation throughout had superior bile production, metabolic activity (base 
deficit and greater glucose use), and less hepatocellular damage (transaminase levels), and sinusoidal 
endothelial cell dysfunction (hyaluronic acid). The histology of livers that had been exposed to 4 hours of cold 

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preservation before normothermia showed more necrosis and destruction of architecture. A similar study 
investigated 60 minutes of warm ischemia followed by 60 minutes of cold preservation before 23 hours of 
normothermic perfusion [37]. This also showed evidence of increased hepatocellular injury, sinusoidal cell 
injury, but no detriment in terms of protein synthesis (factor V), bile production or histological features. These 
studies, therefore, demonstrated the need for the warm preservation device to be transportable so that 
normothermic preservation can be instituted with a minimal period of cooling at the time of organ retrieval.  
In order to confirm these results in a preclinical model of organ transplantation, a series of liver transplants in 
a pig model was performed [27]. In these experiments pig livers were cold-preserved or warm-preserved 
(using the same machine perfusion methodology as before) for either 5 hours or 20 hours, followed by liver 
transplantation. As a model of DBD and DCD clinical scenarios, organs were cold-perfused in situ either at the 
time of cessation of circulation (as in a DBD organ donation) or after 40 and 60 minutes of warm ischemia 
(simulating DCD organ donation). The two preservation times were selected because 5 hours is comfortably 
within, and 20 hours substantially beyond, the limit of the conventional cold preservation technology in pigs 
(in which a generally accepted limit for survival is 12 hours). Similarly the 40 and 60 minute periods of warm 
ischemia are considerably longer than would be acceptable in current clinical practice where warm ischemia 
rarely exceeds 30 minutes. Indeed, success at 40 minutes would raise the realistic prospect of transplantation 
of donor livers from uncontrolled DCD donors. 
There was no difference in outcome between the two groups at 5 hours of preservation. After 20 hours of 
preservation, there were significant advantages consistently in warm compared to cold preservation of both 
DBD and DCD organs. These advantages applied to postoperative enzyme release and animal survival. Notably, 
in the 20 hour warm-preserved groups, there was no difference in survival or postoperative transaminase 
levels in recipients of DBD compared to DCD (40 minute warm ischemia) donor organs (86% versus 83%). At 60 
minutes of warm ischemia and 20 hours normothermic preservation, however, there were no survivors. 
Analysis of hemodynamic, synthetic and metabolic parameters showed that those groups of livers that 
subsequently went on to successful transplant were predictable before transplantation on the basis of portal 
flow/pressure, acid-base homeostasis and several other biochemical parameters [27]. It may be concluded 
that normothermic perfusion, in this context, is not only a more effective means of organ preservation than 
conventional cold storage, but also that this method can be configured to provide an effective means of 
viability assessment [38]. 
The prototype version of the automated clinical investigation device has been tested and demonstrated to be 
effective during pre-clinical studies in which human livers, discarded as unsuitable for transplantation, were 
perfused for 24 hours. 13 such livers were perfused with human blood and the perfusion characteristics and 
control algorithms have been shown to be equally applicable to human as to pig livers (manuscript in 
preparation). More recently, the clinical trials device has been tested, using livers declined for clinical 
transplantation, and all key functional aspects of the device shown to be operational, including particularly 
transport to the donor hospital, automation and 24 hour perfusion. 
2.2 PHASE 1 CLINICAL TRIAL DATA 
A pilot clinical trial was opened at King’s College Hospital in 2012 and extended to the Queen Elizabeth 
Hospital, Birmingham in 2013. Between February and December 2013, 20 subjects underwent liver 
transplantation using donor organs preserved throughout by normothermic perfusion. Sixteen livers (80%) 
were from DBD and 4 (20%) were from DCD (Maastricht category III) donors. The indication for transplantation 
was chronic liver failure except one recipient who underwent re-transplantation for hepatic artery thrombosis. 
The underlying etiology of liver disease was hepatitis C virus infection (n=6), alcoholic liver disease (n=5), 
primary sclerosing cholangitis (n=3), primary biliary cirrhosis (n=2), ɑ1-antitrypsin deficiency (n=1), non-
alcoholic steatohepatitis (n=1), chronic autoimmune hepatitis (n=1) and other cholangiopathic disease (n=1). 
Two matched control subjects were identified for each test subject using pre-set criteria. The median recipient 
MELD score was 12 (7 – 27) in NMP vs. 14 (6 – 25) in matched controls.  

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Median NMP time was 9.31 (range from 3.5 to 18.5) hours. Median cold ischemia time (CIT) in the matched 
controls was 8.9 (range 4.2 – 11.4) hours. The period of NMP was governed by the logistic considerations 
(mainly other transplants). There was evidence of stable hemodynamics, synthetic and metabolic function 
throughout all perfusions with maintenance of pH between 7.2 and 7.4 (unsupported). Bile production 
commenced after the first hour and was maintained, with an upward trend, throughout NMP. Hepatic arterial 
and portal venous flows were consistent throughout. 
Median ITU and hospital stays were similar between the test and control groups overall and when analyzed as 
DBD and DCD subsets. All grafts and subjects in the NMP group survived the first 30 days but 1 recipient of a 
DBD liver in the matched control group died on day 0 from a cardiovascular event. There was no primary non-
function in either group. Three subjects (15%) demonstrated EAD in the NMP group compared to 9 (22.5%) in 
the control group. This difference was more pronounced in the DCD subset (1 (25%) vs. 4 (50%) subjects). EAD 
in the NMP group was due to: day 7 bilirubin of 211 (liver 8, donor age 77); peak AST of 2158 (liver 15 pre-
retrieval AST of 1300); peak AST of 4681 (liver 16, DCD, age 53, WIT 27 minutes). There was a statistically 
significant difference in peak AST levels (417 vs. 902, p=0.034), numerically more pronounced in the DCD 
cohort (422 vs. 1894, p=0.283). In all these cases, perfusion parameters were stable with good acid-base 
maintenance (indicators of good outcome). Postoperatively, all subjects made good recoveries.  
3. OBJECTIVES 
3.1 HYPOTHESIS 
Normothermic machine perfusion (NMP) is superior to static cold storage (SCS) of human liver allografts for 
reduction of preservation injury. 
3.2 OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
3.2.1 PRIMARY OBJECTIVE 
To compare the effect of NMP to SCS in the prevention of preservation injury and graft dysfunction, as 
measured by early allograft dysfunction (EAD). 
3.2.2 PRIMARY OUTCOME MEASURE/ENDPOINT 
The severity of immediate graft injury as measured by early allograft dysfunction (EAD) [40]. The study will be 
powered to demonstrate a reduction in EAD from 25% to 10% in NMP versus SCS. EAD is a binary outcome 
defined by the presence of one of the following 3 outcomes: 
1. Serum bilirubin ≥ 10 mg/dL at day 7 post-transplant 
2. International normalized ratio ≥ 1.6 at day 7 post-transplant 
3. ALT or AST > 2000 IU/L within the first 7 days post-transplant 
 
 
Objectives 
Outcome measures/endpoints 
Primary 
To compare the effect of NMP to SCS in 
preventing preservation-related graft 
injury 
Severity of immediate graft injury as 
measured by early allograft dysfunction 
(EAD). 

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Secondary 
To compare graft and subject survival 
between NMP and SCS livers. 
Primary non-function rates: irreversible 
graft dysfunction requiring emergency 
liver replacement during the first 10 
days after liver transplantation. 
 
Graft survival rates at 30 days, 3 months, 
and 6 months following transplantation.  
Subject survival rates at 30 days, 3 
months, and 6 months following 
transplantation. 
To compare evidence of post-
reperfusion syndrome between NMP 
and SCS livers on transplantation. 
Assess mean arterial pressure (MAP) 
pre- and post-reperfusion and 
requirement for vasopressor use. 
To compare biochemical liver function 
between NMP and SCS livers. 
Bilirubin, GGT, ALT, AST, ALP and INR at 
days 1-7, day 30, month 3, and month 6 
post-transplant.  
Lactate at days 1-7 while the subject is in 
ICU. 
To compare evidence of ischemia-
reperfusion injury between NMP and 
SCS livers. 
Post-reperfusion biopsies will be 
compared to baseline pre-reperfusion 
biopsies and graded according to 
standard histological criteria. 
To compare evidence of biliary 
complications between NMP and SCS 
livers.  
Incidence of biliary investigations and/or 
interventions between 7 days and 6 
months post-transplant. 
To assess the feasibility and safety of 
NMP as a method of organ storage and 
transportation. 
Incidence of livers randomized but not 
transplanted and reasons for not-
transplanting. 
To compare organ utilization between 
NMP and SCS. 
 
Incidence of one or more of the 
following per randomized liver: (i) EAD; 
(ii) discard (non-transplant) of a 
retrieved liver; (iii) primary non-function. 
To assess the health economic 
implications of normothermic liver 
perfusion. 
Logistical and healthcare costs (length of 
stay in ICU and hospital) and quality of 
life measures. 
 
4. TRIAL DESIGN 
This is a randomized controlled, non-blinded, clinical trial comparing SCS versus NMP for organ preservation 
prior to liver transplantation. Following assessment of donor and recipient eligibility and recipient informed 
consent, the donor liver will be randomized to either NMP or SCS.  At the end of preservation, the liver will be 
transplanted and the enrolled recipient subject managed according to standard local practice and protocols. 
Subjects are considered enrolled in the study when there is an attempt to transplant a randomized liver. 
Enrolled subjects who are transplanted with a randomized liver will participate in the study for a duration of 12 
months. If there is an attempt to transplant a randomized liver, but the liver is ultimately not transplanted, the 

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subject will be followed for 30 days following the attempt for adverse events and will then be exited from the 
study. Subjects who are matched to a liver that is randomized, but there is no attempt to transplant the liver 
will not be considered enrolled. An attempt to transplant a liver is considered when there is knife-to-skin 
contact in the operating room during the recipient transplant procedure. A subject is considered to be 
transplanted when there is reperfusion of the donor liver in the recipient subject.  
If the intended original recipient did not receive the randomized liver, the liver will be offered to the next 
recipient in accordance to the UNOS matching sequence.  All attempts by the investigational team will be 
made to allocate the randomized liver to a local recipient who has consented and meets inclusion/exclusion 
criteria for the study.  In situations where this is not possible, emergency use procedures may be followed in 
accordance to FDA regulations should the liver be randomized to the investigational device arm (NMP).    
Primary and secondary outcomes will be analyzed and reported after all available transplanted subjects have 
completed the 6 month post-transplant follow-up visit. Subjects will continue to be followed for 12 months 
post-transplant for safety. Upon completion of all 12 month post-transplant follow-up visits, a final clinical 
study report will be completed and all subjects exited from the study. 
5. PARTICIPANT IDENTIFICATION 
5.1 STUDY SETTING 
Recruitment will take place in up to 15 investigational centers which are UNOS member liver transplant 
centers. 
5.2 TRIAL PARTICIPANTS 
Participants will be 18 years of age or older and active on the waiting list for liver-only transplantation at any of 
the participating transplant centers. 
5.2.1 CMS REIMBURSEMENT 
Based on the target study population, approximately 30% of subjects enrolled will utilize CMS/Medicare 
reimbursement during their participation. It is not anticipated that the device under investigation will treat a 
Medicare population different than the demographics found in the investigators' general population for this 
same condition, including populations eligible for Medicare due to age (e.g., 65 years or older), disability, or 
other eligibility status. The demographics of recipients outside of age alone are found to be similar between 
Medicare and Non-Medicare populations. According to the American Liver Foundation, at least 30 million 
people, or one in 10 Americans, have some form of liver disease. More than one million Americans are 
infected with hepatitis B and four million Americans have hepatitis C. In addition, about 21,000 Americans are 
diagnosed with primary liver cancers, one of the few cancers on the rise in the U.S. The Centers for Disease 
Control and Prevention (CDC) stated that more than 75 percent of adults with hepatitis C are born between 
1945 and 1966 and it is estimated that one in every 33 “baby boomers” has viral hepatitis and are five times 
more likely to have hepatitis C. While these numbers indicate a rise in the incidence of liver disease, it is 
anticipated the number of liver transplants will also rise in both the Medicare and Non-Medicare 
populations. The number of liver transplants has increased by 10% in all ages and 7.3% in the Medicare 
population in the last ten years. The recipient outcome measures are not only related to the underlying 
conditions of the recipient but also the donor. Several demographic measures (e.g., age, weight, 
race/ethnicity, functional status, geography, etc.), cause of death, function of liver, and recovery time and 
logistics will impact the outcome of the recipient. Thus the results of the study are expected to be 
generalizable to the Medicare eligible population and a logistic regression model will be used to examine the 
possible explanatory effect of Medicare recipient status.  
 

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5.3 ELIGIBILITY CRITERIA 
All eligibility criteria must be met at the time of a recipient being matched to a donor and the donor liver 
receiving a randomization assignment. 
5.3.1 DONOR CRITERIA 
5.3.1.1 DONOR INCLUSION CRITERIA 
1. DBD donor aged 40 years or greater 
2. DCD donor aged 16 years or greater  
3. Liver allograft from donation after brain death (DBD) or donation after circulatory death (DCD) donors 
5.3.1.2 DONOR EXCLUSION CRITERIA  
1. Living donor liver 
2. Liver intended for split transplant 
3. Liver which Investigator is unwilling to randomize to either arm 
5.3.2 RECIPIENT CRITERIA 
5.3.2.1 RECIPIENT INCLUSION CRITERIA   
1. Subject is 18 years of age or greater 
2. Subject is registered as an active recipient on the UNOS waiting list for liver transplantation 
3. Subject, or legally authorized representative, is able and willing to give informed consent and HIPAA 
authorization 
4. Subject is able and willing to comply with all study requirements (in the opinion of the Investigator) 
5.3.2.2 RECIPIENT EXCLUSION CRITERIA  
1. Subject requiring all of the following at the time of transplantation: 
a. Oxygen therapy via a ventilator/respirator 
b. Inotropic support 
c. 
Renal replacement therapy 
2. Subject has acute/fulminant liver failure (UNOS status 1A) 
3. Subject undergoing simultaneous transplantation of more than one organ (e.g., liver and kidney) 
4. Subject is pregnant (as confirmed by urine or serum pregnancy test) or nursing 
5. 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. 
6. TRIAL PROCEDURES 
The participant timeline is illustrated in Appendix A1.  The following section provides details of this timeline 
and all study procedures. 
6.1 RECRUITMENT 
The emergency nature of liver transplantation means that once a potential recruit/study subject is called in for 
a transplant there will only be a 3-4 hour window for the consent and screening process to occur. This does 
not allow sufficient time for the potential subject to fully consider his/her participation in the study. For this 
reason, all patients who fulfil the entry criteria and who are on the UNOS waiting list for liver transplantation 
at the participating centers should be provided with full information either during a routine clinic 
appointment, inpatient admission, or a mailed copy of the Informed Consent Form in accordance with local IRB 
policy. Informed consent will then be requested at the time the patient is admitted for transplantation. 

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Alternatively, depending on local factors (including the size of waiting list) it may logistically be possible for 
patients to be informed and to provide consent while on the waiting list (in advance of the donor organ 
becoming available). 
6.2 INFORMED CONSENT 
6.2.1 RECIPIENT CONSENT 
Prior to being enrolled in the clinical study, subjects (or their legally authorized representative) must consent 
to participate after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them and per the requirements in 21 CFR Part 50.  
Detailed information will be given both verbally and in the informed consent document that includes 
information about the study and the consent form will be prepared and given to the subject. This document 
will contain all the elements required by the 21 CFR Part 50.25 regulation for subject information and informed 
consent, and any additional elements required by local regulations. The document must be in a language 
understandable by the subject. Subjects are free to withdraw consent at any time, irrespective of their initial 
consent.   
After reading the informed consent document, the participant (or their legally authorized representative) must 
sign and date the current approved version of the informed consent form before any study specific procedures 
are performed. Written and verbal versions of the informed consent form will be presented to the participants 
detailing the exact nature of the study, the implications and constraints of the protocol, and any risks involved 
in taking part. It will be clearly stated that the participant is free to withdraw from the study at any time for 
any reason without prejudice to future care, and with no obligation to give the reason for withdrawal. The 
participant will be allowed as much time as possible to consider the information, and the opportunity to 
question the Investigator, or other members of the clinical or research team, to decide whether to participate 
in the study. 
 
The study coordinator at each center will maintain a list of consenting subjects. 
 
Any use of the device without obtaining informed consent shall be promptly reported (no later than 5 working 
days) to the US Sponsor and the IRB.  
 
A copy of the signed consent document must be offered to the subject. The original signed consent document 
will be retained by the Investigator.  
 
The Investigator will not perform any exams or testing specifically required only for the clinical study until valid 
consent has been obtained.  
 
The Investigator may inform the subject’s primary physician about the subject’s participation in the trial if the 
subject has a primary physician and if the subject agrees to the primary physician being informed. 
6.2.2 DONOR CONSENT 
Authorization from the donor family will be obtained per standard practices from the retrieving Organ 
Procurement Organization (OPO). 
During the course of the study, donor details will be kept anonymous (specific study identification codes will 
be used for each study donor).  Donor data will only be made available to authorized staff of the study 
Sponsor, its authorized representatives, and the FDA. 
 
 

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6.3 SCREENING AND ELIGIBILITY ASSESSMENT 
6.3.1 RECIPIENT ASSESSMENT 
All consented subjects on the transplant waiting list in participating centers will be screened for suitability for 
transplantation; beyond fulfilling the inclusion/exclusion criteria listed above, further screening assessment is 
not required as part of the trial and the subject will be followed per standard of care. Upon the offer of a 
suitable donor organ, consent will be requested as described in section 6.2.1, if it has not already been 
obtained.   
6.3.2 DONOR ASSESSMENT 
On reciept of an organ offer, the local recipient investigative site staff will ascertain baseline demographic 
information from the offering OPO to assess eligibility of the liver for inclusion in the trial. The decision 
whether to transplant a liver in this study remains solely the responsibility of the Investigator. 
6.4 RANDOMIZATION AND BLINDING  
6.4.1 SEQUENCE GENERATION 
Donor livers will be randomly assigned to NMP or SCS with 1:1 allocation as per a computer generated 
randomization schedule using variable block randomization using the following stratification factors: 
participating (recipient) center and by donor type (DBD or DCD). The randomization schedule will be created 
by the study statistician, and will remain confidential.  
6.4.2 ALLOCATION CONCEALMENT MECHANISM 
Allocation concealment will be ensured by use of central computerized randomization.  Allocation will not be 
revealed until the subject has been recruited to the trial and donor and recipient inclusion/exclusion criteria 
have been recorded.  Random permuted block length will be used; block sizes will not be disclosed. 
6.4.3 IMPLEMENTATION 
Prior to randomization, the local Investigator will confirm the availability of the investigational metra® device. 
Once informed consent has been verified from the potential recipient of an organ and recipient and donor 
inclusion and exclusion criteria has been confirmed, the local recipient investigative site staff will proceed with 
randomization.  Recipients will be considered enrolled in the study once a randomized liver has been assigned 
and there is an attempt to transplant the randomized liver. 
6.4.4 BLINDING/MASKING 
While it is not possible to blind the local Investigators to the method of organ preservation, Histopathologists 
at the central laboratory interpreting the biopsy specimens will remain blinded to the randomization group to 
the extent possible. 
6.5 PRE-STUDY BASELINE ASSESSMENTS  
Pre-study baseline assessments to be completed include the following: 
6.5.1 DONOR DEMOGRAPHICS 
Retrieving OPOs/investigational sites will collect donor information per the Organ Procurement and 
Transplantation Network (OPTN) Policy.  
In addition to the OPTN Policy requirements listed in Section 2.11.B, the following will be collected: 
1. Age 

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2. Sex 
3. Race 
4. Ethnicity 
5. Cause of death (CVA, hypoxia, trauma, other) 
6. Type of donor (DBD, DCD) 
7. Donor height 
8. Donor risk index (DRI) [3] 
9. Last and peak serum AST 
10. Last and peak serum sodium 
11. Last and peak GGT 
12. Length of ICU stay 
13. BMI 
6.5.2 RECIPIENT DEMOGRAPHICS 
Recipient demographics to be recorded will include, but not be limited to, the following: 
1. Age 
2. Sex 
3. Race 
4. Ethnicity 
5. Etiology of liver disease 
6. Indication for transplant 
7. MELD score  
8. UNOS status 
9. BMI 
10. Relevant medical history 
11. Relevant social history 
6.5.3 QUALITY OF LIFE QUESTIONNAIRE (EQ-5D-5L) 
Recipient will complete the Quality of Life Questionnaire (measured by means of the EQ-5D-5L).  
6.6 TRIAL INTERVENTIONS 
6.6.1 NMP GROUP (INVESTIGATIONAL METRA® DEVICE) 
If the liver is randomized to the NMP group, arrangements will be made to transport the device to the donor 
hospital (see section 7.6).  The recipient coordinator will also arrange for 3 units of donor-type red blood cells 
to be available for use in the OrganOx metra® device.  Following the routine retrieval procedure at the donor 
hospital the liver will be placed in ice-cold perfusion solution (according to local protocol) on the back-table, 
and prepared for cannulation. The procedure for preparing the device for use and placing the organ on the 
device is described in detail in the metra® Instructions for Use (IFU) document.  The device is then transported 
to the recipient transplant center per local logistics.  The procedure for removing the liver from the device is 
also described in the IFU.  Transplantation and reperfusion of the liver proceed as per the usual practice of the 
transplanting center.  The duration of machine perfusion will be dictated by logistics and local policy, but 
should not be less than 4 hours or more than 24 hours. At the end of the perfusion, a sample of perfusate will 
be taken for analysis of free hemoglobin and will be processed in accordance with the laboratory manual for 
analysis. 
If cannulation proves impossible, the liver will be transported using standard static cold storage as described 
below.  Results will be analyzed in the randomized group per the principals of intention-to-treat.  
At the request of the Principal Investigator from the site, a representative from OrganOx that is trained on the 
OrganOx metra® may: 

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 
Provide technical expertise on the use and functionality of the OrganOx metra® device and 
testing that will be conducted as part of the study 
 
Be present during the procurement of the donor liver and recipient procedure 
 
Prepare the system for use and assist with use of the OrganOx metra® device 
6.6.2 SCS GROUP 
Following the routine retrieval procedure, the liver will be placed in ice-cold perfusion solution (according to 
local protocols) on the back-table, followed by storage in cold perfusion solution within an ice box.  The organ 
will be transported to the recipient center per local logistics, and removed from storage prior to 
transplantation for standard back-table preparation.  The duration of cold storage will be dictated by logistics 
and local policy. 
6.6.3 RECORDING OF OPERATIVE AND PERFUSION PARAMETERS 
The procurement and transplant research teams will record the following data: 
6.6.3.1 DONOR TIMINGS 
6.6.3.1.1 DBD DONOR TIMINGS 
The following times will be recorded for DBD donors: 
1. Brain Death declaration (date and time) 
2. Cessation of donor circulation (cross clamp date and time) 
3. Start of cold perfusion 
4. Liver removal and placement on ice 
5. Removal from ice (recipient operation) 
6. Portal reperfusion 
7. Arterial reperfusion 
6.6.3.1.2 DCD DONOR TIMINGS 
The following times will be recorded for DCD donors: 
1. Withdrawal of support (oxygen therapy and/or inotropic if applicable) 
2. Onset of functional warm ischemia (SBP < 50 mmHg) 
3. Time of Cardiac Death 
4. Start of cold perfusion 
5. Liver removal and placement on ice 
6. Removal from ice (recipient operation) 
7. Portal reperfusion 
8. Arterial reperfusion 
6.6.3.1.3 DBD/DCD DONOR TIMINGS RANDOMIZED TO NMP 
In addition to all above parameters, the following will be recorded for all donor livers randomized to NMP: 
1. Initiation of normothermic machine preservation 
2. Cessation of normothermic machine perfusion (cold flush) 
6.6.3.2 PRESERVATION PARAMETERS FOR ALL RANDOMIZED LIVERS 
The following preservation parameters will be collected for all randomized livers:  
1. Degree of steatosis (graded mild, moderate, severe) – surgeon’s assessment at time of retrieval 
2. Quality of in-situ perfusion (graded poor, moderate, good) 
3. Perfusion parameters for NMP livers (these are logged automatically by the device): 
a. Arterial, and IVC pressures (mmHg) 

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b. Arterial, portal and caval flow rates (ml/min) 
c. 
pO2, pCO2 and pH 
d. Blood temperature (oC), glucose (mmol/L) and bile production (ml/h) 
4. Perfusate ALT and AST (for NMP livers) 
5. Lactate values and time obtained at the following time points (for NMP livers):  
a. After approximately 15 minutes of NMP  
b. Following arrival at the transplant hospital 
c. 
Following the end of NMP  
6. Perfusion solution used for in situ and back-bench  perfusion (all livers) 
Perfusion solution used for organ transport (SCS livers only) 
7. Glucose values measured using i_STAT or similar FDA approved diagnostic device at the following 
time points (for NMP livers): 
a. Approximately after 15 minutes of NMP  
b. Approximately every 4 hours thereafter during perfusion 
At the end of preservation a sample of perfusate/storage solution will be taken for microbiological culture (SCS 
and NMP groups). 
6.6.3.3 OPERATIVE PARAMETERS 
These will include: 
1. Total operative time: defined as time from knife-to-skin to wound closure. 
2. Anastomotic time (secondary warm ischemia): defined as time between removal of organ from 
ice (SCS) or perfusion device (NMP) to organ reperfusion (whichever is first of portal or arterial) 
3. Occurrence of post-reperfusion syndrome (defined 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 [41, 42]) 
4. Use of vasopressors prior to and after reperfusion 
5. Intraoperative transfusion of blood and blood products (measured in units) 
6. The use of veno-venous bypass or porto-caval shunts 
7. Type of caval anastomosis: end-to-end caval replacement, piggyback (end-side or side-side) 
6.6.3.4 HISTOLOGICAL PARAMETERS  
Graft biopsies will be completed on both groups and will be taken: 
1. Pre-Storage (Baseline): Before being placed for storage in either NMP or SCS  
2. Post-Storage:  
a. Following storage in either NMP or SCS 
b. Immediately prior to abdominal closure  
 
The post-storage biopsies will be compared to the pre-storage (baseline) biopsy, examined for evidence of 
reperfusion injury, and graded according to standard histological criteria [39, 43]. For this analysis a central 
core laboratory will be used where the histopathologist will be blinded to the method of storage. 
6.7 CONCOMITANT CARE 
All other aspects of the retrieval procedure will be carried out according to local policies and national 
guidelines. 
Recipient management including the transplantation procedure, postoperative care, immunosuppression and 
other medications, and post-transplant monitoring will follow local protocols. 
 

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6.8 STUDY VISITS 
6.8.1 INPATIENT STAY 
Subjects will be assessed daily by their clinical team and managed according to standard local protocols (refer 
to Appendix A1 for Visit Windows). 
6.8.1.1 BIOCHEMICAL ASSESSMENTS  
The following biochemical outcomes will be recorded where the first measurements should be taken between 
12 and 24 hours of reperfusion: 
1. Daily samples for the first 7 days post-transplant, to include: 
a. Total serum bilirubin (measured in mg/dL) 
b. Serum alkaline phosphatase (ALP; measured in IU/L) 
c. 
Serum gamma-glutamyl transferase (GGT; measured in IU/L)* 
d. Serum aspartate transaminase (AST; measured in IU/L) 
e. Serum alanine aminotransferase (ALT; measured in IU/L) 
f. 
PT/International normalized ratio (INR) 
g. 
Serum albumin (measured in g/dL)* 
h. Serum creatinine (measured in mg/dL)* 
2. Daily serum lactate (measured in mmol/L) while admitted to ICU* 
*Only collected if Standard of Care 
6.8.1.2 ADDITIONAL ASSESSMENTS 
The following additional data will be collected and recorded: 
1. Length of stay in high level care (ICU) (days) 
2. Total length of hospital stay (days) 
3. Total number of ventilation days post-transplant  
4. Requirement for renal replacement therapy (Hemodialysis (HD), Hemodiafiltration (HDF), 
Hemofiltration (HF)) 
5. Primary non-function: irreversible graft dysfunction requiring emergency liver replacement during the 
first 10 days after liver transplantation. 
6.8.1.3 SAFETY ASSESSMENTS 
The following safety data will be collected and recorded: 
1. Recipient infection (documented positive microbiological culture, pathological lesion, or clinical 
criteria met) 
2. Biopsy-proven acute rejection episodes 
3. Biliary investigations (MRCP, ERCP, PTC)  
4. Biliary interventions (surgical, radiological, or endoscopic) 
5. Hepatic vascular complications (e.g., hepatic artery stenosis, hepatic artery thrombosis, portal vein 
thrombosis, portal vein stenosis) 
6. Acute Hemorrhage (requiring transfusion of two or more units of red blood cells) 
7. Reoperation for graft related complications 
8. Adverse event(s) 
6.8.1.4 IMMUNOSUPPRESSION 
Details of induction and maintenance immunosuppression at day 7 post-transplant will be recorded. 
6.8.2 DAY 30 POST-TRANSPLANT PROCEDURE 

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This visit will, where possible, coincide with a routine outpatient appointment.  If the recipient is an inpatient, 
assessment will be made in hospital where appropriate (refer to Appendix A1 for Visit Windows). 
6.8.2.1 BIOCHEMICAL ASSESSMENTS 
The following biochemical outcomes will be recorded at day 30 post-transplant: 
1. Total serum bilirubin (measured in mg/dL) 
2. Serum alkaline phosphatase (ALP; measured in IU/L) 
3. Serum gamma-glutamyl transferase (GGT; measured in IU/L)* 
4. Serum aspartate transaminase (AST; measured in IU/L) 
5. Serum alanine aminotransferase (ALT; measured in IU/L) 
6. PT/International normalized ratio (INR) 
7. Serum albumin (measured in g/dL)* 
8. Serum creatinine (measured in mg/dL)* 
*Only collected if Standard of Care 
6.8.2.2 ADDITIONAL ASSESSMENTS 
The following additional data will be collected and recorded: 
1. Graft and subject survival at day 30 post-transplant 
2. Requirement for renal replacement therapy (HD, HF, HDF) for more than a total of five days 
3. Length of hospital stay 
4. Readmissions 
5. Healthcare resource use (by means of hospital admissions data and medical records) 
6.8.2.3 SAFETY ASSESSMENTS 
The following safety data will be collected and recorded: 
1. Recipient infection (documented positive microbiological culture, pathological lesion, or clinical 
criteria met) 
2. Biopsy-proven acute rejection episodes 
3. Biliary investigations (MRCP, ERCP, PTC)  
4. Biliary interventions (surgical, radiological, or endoscopic) 
5. Hepatic vascular complications (e.g., hepatic artery stenosis, hepatic artery thrombosis, portal vein 
thrombosis, portal vein stenosis) 
6. Reoperation for graft related complications 
7. Adverse event(s) 
6.8.2.4 IMMUNOSUPPRESSION 
Details of maintenance immunosuppression at day 30 post-transplant will be recorded. 
6.8.3 MONTH 3 POST-TRANSPLANT PROCEDURE 
This visit will, where possible, coincide with a routine outpatient appointment.  If the recipient is an inpatient, 
assessment will be made in hospital where appropriate (refer to Appendix A1 for Visit Windows). 
6.8.3.1 BIOCHEMICAL ASSESSMENTS 
The following biochemical outcomes will be recorded at month 3 post-transplant: 
1. Total serum bilirubin (measured in mg/dL) 
2. Serum alkaline phosphatase (ALP; measured in IU/L) 
3. Serum gamma-glutamyl transferase (GGT; measured in IU/L)* 
4. Serum aspartate transaminase (AST; measured in IU/L) 

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5. Serum alanine aminotransferase (ALT; measured in IU/L) 
6. PT/International normalized ratio (INR) 
7. Serum albumin (measured in g/dL)* 
8. Serum creatinine (measured in mg/dL)* 
*Only collected if Standard of Care 
6.8.3.2 ADDITIONAL ASSESSMENTS 
The following additional data will be collected and recorded: 
1. Graft and subject survival at month 3 post-transplant 
2. Requirement for renal replacement therapy (HD, HF, HDF) for more than a total of five days  
3. Readmission(s) 
4. Healthcare resource use (by means of hospital admissions data and medical records). 
6.8.3.3 SAFETY ASSESSMENTS 
The following safety data will be collected and recorded: 
1. Recipient infection (documented positive microbiological culture, pathological lesion, or clinical 
criteria met) 
2. Biopsy-proven acute rejection episodes 
3. Biliary investigations (MRCP, ERCP, PTC)  
4. Biliary interventions (surgical, radiological, or endoscopic) 
5. Hepatic vascular complications (e.g., hepatic artery stenosis, hepatic artery thrombosis, portal vein 
thrombosis, portal vein stenosis) 
6. Reoperation for graft related complications 
7. Adverse event(s) 
6.8.3.4 IMMUNOSUPPRESSION 
Details of maintenance immunosuppression at month 3 post-transplant will be recorded. 
6.8.4 MONTH 6 POST-TRANSPLANT PROCEDURE  
This visit will, where possible, coincide with a routine outpatient appointment.  If the recipient is an inpatient, 
assessment will be made in hospital where appropriate (refer to Appendix A1 for Visit Windows). 
6.8.4.1 BIOCHEMICAL ASSESSMENTS 
The following biochemical outcomes will be recorded at month 6 post-transplant: 
1. Total serum bilirubin (measured in mg/dL) 
2. Serum alkaline phosphatase (ALP; measured in IU/L) 
3. Serum gamma-glutamyl transferase (GGT; measured in IU/L)* 
4. Serum aspartate transaminase (AST; measured in IU/L) 
5. Serum alanine aminotransferase (ALT; measured in IU/L) 
6. PT/International normalized ratio (INR) 
7. Serum albumin (measured in g/dL)* 
8. Serum creatinine (measured in mg/dL)* 
*Only collected if Standard of Care 
6.8.4.2 ADDITIONAL ASSESSMENTS 
The following additional data will be collected and recorded: 
1. Graft and subject survival at month 6 post-transplant 
2. Requirement for renal replacement therapy (HD, HF, HDF) for more than a total of five days 
3. Readmission(s) 

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4. Healthcare resource use (by means of hospital admissions data and medical records). 
5. Quality of life (measured by means of the EQ-5D-5L questionnaire). 
6.8.4.3 SAFETY ASSESSMENTS 
The following safety data will be collected and recorded: 
1. Recipient infection (documented positive microbiological culture, pathological lesion, or clinical 
criteria met) 
2. Biopsy-proven acute rejection episodes 
3. Biliary investigations (MRCP, ERCP, PTC)  
4. Biliary interventions (surgical, radiological, or endoscopic) 
5. Hepatic vascular complications (e.g., hepatic artery stenosis, hepatic artery thrombosis, portal vein 
thrombosis, portal vein stenosis) 
6. Reoperation for graft related complications 
7. Adverse event(s) 
6.8.4.4 IMMUNOSUPPRESSION 
Details of maintenance immunosuppression at month 6 post-transplant will be recorded. 
6.8.5 MONTH 12 POST-TRANSPLANT PROCEDURE  
This visit will, where possible, coincide with a routine outpatient appointment, but may be completed 
remotely via telephone.  If the recipient is an inpatient, assessment will be made in hospital where appropriate 
(refer to Appendix A1 for Visit Windows). 
1. Graft and subject survival at month 12 post-transplant 
2. Requirement for renal replacement therapy (HD, HF, HDF) for more than a total of five days  
3. Readmission(s) 
4. Healthcare resource use (by means of hospital admissions data and medical records). 
6.9 PARTICIPANT RETENTION 
All transplanted subjects completing the 12 month follow-up assessment will be regarded as having completed 
the study.  All subjects will be encouraged to complete study follow-up, and all reasonable efforts will be made 
to ensure completeness of follow-up.  Measures include ensuring that assessments are made, where possible, 
at routine hospital visits rather than additional appointments so those subjects do not incur extra financial 
costs (e.g., travelling costs) as a result of study participation. 
Every effort should be made to secure follow-up data on enrolled subjects. A subject will be considered Lost to 
Follow-Up if there are three documented contact attempts made (via phone, email, or certified mail) 
requesting follow-up with no response.  
It is understood that study subjects may withdraw consent for study participation at any time irrespective of 
their reasons.  The Investigators may also withdraw a subject from the study in order to protect the subject’s 
safety and/or if they are unwilling or unable to comply with the required study procedures. 
In the event of a subject withdrawing from the trial, the reason for withdrawal must be documented on the 
eCRF.  
6.10 DEFINITION OF THE END OF THE TRIAL 
The investigational trial will end after completion of the 12 month post-transplant follow-up visit for all 
available transplanted subjects in the trial and a final study report will be generated. Primary and secondary 
outcomes will be analyzed and reported after all available transplanted subjects have completed the 6 month 
post-transplant follow-up visit. Subjects will continue to be followed for 12 months post-transplant for safety. 

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Upon completion of all 12 month post-transplant follow-up visits, a final clinical study report will be completed 
and all subjects exited from the study. 
The procedures for the early termination/suspension of the study at one or more clinical sites (as a 
consequence of safety or compliance concerns) are detailed in section 8.3. 
7. THE ORGANOX METRA® DEVICE 
7.1 DEVICE DESCRIPTION 
7.1.1 THE ORGANOX METRA® BASE UNIT 
The OrganOx metra® normothermic perfusion device incorporates a centrifugal pump, an oxygenator, oxygen 
concentrator, heat exchanger, reservoir, flow probes, pressure sensors, infusions and blood gas analyzer 
together with tubing and connector components. The device is comprised of three main components: 
1. Reusable base unit which contains software and hardware 
2. Disposable plastic circuit 
3. Set of perfusion solutions suitable for 24 hours of perfusion 
7.1.2 DISPOSABLE SET 
The disposable set used with the core base unit of the OrganOx metra® contains all the disposables used with 
each organ recovery on the metra® and comprises: 
1. A tubing set, including a blood reservoir, perfusion lines, a blood oxygenator/heat exchanger and 
centrifugal pump-head together with flow and pressure sensors. 
2. A liver bowl which is pre-connected to the tubing set to contain the organ while on the device. 
3. Cannulae for the celiac artery, portal vein, and inferior vena cava with easy connection attachment to the 
perfusion circuit. 
4. A cannula and connection point for bile collection 
5. Blood gas sensors for monitoring pO2, pCO2, and pH by means of on-line blood gas analysis. 
7.1.3 PERFUSION SOLUTIONS 
For the present study none of the additives necessary to perfuse and maintain the organ during the storage 
process, with the exception of sodium taurocholate, are included and will be sourced locally (OrganOx will 
provide a list of recommended suppliers in the Instructions for Use (IFU) document). These solutions include 
bolus injections (given at the start of perfusion) and the maintenance infusions (given throughout perfusion). 
The primary perfusion fluid for the liver comprises packed red blood cells, supplemented by albumin to 
normalize the hematocrit and osmolality.  
Before connection of the liver the blood-based perfusate is supplemented with: 
1. Antibiotic – e.g., Cefuroxime  
2. Heparin. 
3. Calcium gluconate. 
During the perfusion the following are infused at a constant rate: 
1. Nutrition – (Clinimix E) amino acids plus electrolytes. 
2. Insulin.  
3. Bile Salts. 
4. Flolan® (epoprostenol Prostacyclin). 
The primary fluid for perfusing the organ is packed red cells supplied per local arrangements and 
supplemented by albumin solution to normalize the hematocrit and osmolality. Further additions are made to 

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the perfusate to support the liver (in a similar mode to current preservation solutions such as Viaspan® or 
those used in machine preservation devices such as the Waters RM3® or the Organ Recovery Systems 
LifePort®). All solutions required will be attached to the circuit during set-up and before the liver is attached. 
The investigational study team will provide the solutions necessary for perfusion with the metra®. Solutions 
are prepared immediately before the organ is attached to the device and contain sufficient solution for 24 
hours of operation, the intended maximum perfusion time for a liver on the device. 
Sodium Taurocholate (bile salts) will be prepared in advance by the investigative site’s pharmacy in accordance 
with the Instructions for Use.   
 
7.2 DEVICE SAFETY 
In designing the metra®, OrganOx has made every attempt to maintain the current practices of organ retrieval 
and transplant teams, in order to minimize the risk of complications or errors that would prevent a successful 
retrieval. From a regulatory standpoint, it is important to note that the metra® is an organ preservation system 
and its use does not involve direct connection to either the donor or recipient at any time. 
The device has been designed according to ISO 13485, the standard that stipulates the requirements for a 
comprehensive management system for the design and manufacture of medical devices. In addition ISO 14971 
specifies a process for a manufacturer to identify the hazards associated with medical devices to estimate and 
evaluate the associated risks, to control these risks, and to monitor the effectiveness of the controls. As part of 
the development of the device an extensive risk analysis has been undertaken and the risks identified and 
minimized in accordance with this standard. As a result, any remaining risk can only be investigated in the 
context of clinical transplant studies.  
OrganOx has deliberately designed the operation of the device such that it will require minimal changes to 
current transplant clinical practice. Also, the perfusion methodology is based on the principle that all the 
perfusion solutions, additives, and packed red cells must be removed from the organ prior to transplant. 
Therefore following the completion of the perfusion, the perfusate is flushed out of the organ with HTK 
solution (or the preferred preservation solution of the transplanting center). 
7.3 DEVICE LABELLING 
All components of the OrganOx metra® system (reusable base unit and disposable set) will be labelled 
“CAUTION  Investigational device. Limited by Federal (or United States) law to investigational use”. Labelling 
will also include the Sponsor/Manufacturer name, contact details, and a unique trial identifier. 
Additional labelling requirements will be followed in accordance with OPTN Policy Section 16.0. 
7.4 DEVICE ACCOUNTABILITY 
Device accountability will be undertaken at each local site throughout the study for the reusable unit(s) and 
disposable sets (sterilization/assembly batch number and disposable set number). The manufacturer and lot 
number for each perfusion solution will also be recorded on the eCRF. The site will maintain a log of the 
retained unit, disposable sets, and perfusion solutions used throughout the study recording the lot number 
used against each subject (on the eCRF).  
At the end of each procedure the OrganOx metra® and any unused disposable and perfusion solutions will be 
removed from the donor hospital and returned to the investigative site.  
7.5 DEVICE MAINTENANCE 
Device cleaning and routine maintenance will be the responsibility of the local Investigator storing the device.  
Full details for cleaning and routine maintenance required will be provided in the Instructions for Use (IFU), 
and appropriate training will be provided as part of the device training described in section 11.3. 

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7.6 DEVICE LOGISTICS 
7.6.1 LOGISTICAL CONSIDERATIONS 
A number of logistic factors must be considered in using the OrganOx metra®: 
1. The device is large, and therefore, may not fit in normal retrieval transportation depending on local 
procedures. 
2. The device has a battery life of 2.5 hours, and so the mode of transport should provide a means of 
providing AC power. 
3. The device requires the manual measurement and entry of perfusate glucose every 4 hours during 
perfusion. 
7.6.2 LOGISTICAL ARRANGEMENTS FOR STUDY SITES 
The OrganOx metra® device will be stored and maintained at the investigative site, or an approved delegated 
site. When an eligible donor organ is offered to the investigative site for a subject who consents to take part in 
the study, the recipient investigational study team will use the online randomization tool to enter required 
information and randomize the liver to either the treatment or control arm. 
The recipient investigational study team will then contact the lead retrieval surgeon to inform him/her of the 
randomization assignment.  If the liver has been randomized to machine perfusion, the recipient study team 
will arrange dispatch of the device to the donor hospital. The investigational study team will also arrange for 3 
units of donor-type packed red cells to be available.  
8. DATA MONITORING AND SAFETY REPORTING 
8.1 DATA MONITORING 
8.1.1 DATA SAFETY MONITORING BOARD 
The trial will have a Data Safety Monitoring Board (DSMB), which consists of at least four independent 
members including clinicians with relevant expertise and a statistical expert, independent from the 
Investigators and the funding source. The DSMB will periodically review accruing data to safeguard the 
interests of the trial participants, potential participants, and future patients and assess the safety of the 
interventions.   
A separate DSMB charter will contain full details of the committee and its roles and reporting structure. 
8.1.2 INTERIM ANALYSES 
Interim analyses of primary and secondary outcomes are not planned. These will only be performed if 
requested by the DSMB on the grounds of participant safety.  
An initial safety assessment is planned to occur following the completion of the 30-day follow-up visit for the 
first 10 subjects enrolled in the study.  The initial safety data will be submitted to the FDA to request expanded 
enrollment in the study.   
8.2 ADVERSE EVENTS 
8.2.1 DEFINITIONS 
An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) whether or not related to the study 
intervention.  
A Serious Adverse Event (SAE) is defined as an adverse event that: 

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 
Led to death 
 
Resulted in serious deterioration in the health of the subject that results in: 
o 
Life-threatening illness or injury, or 
o 
Permanent impairment of a body structure or a body function, or 
o 
The need for inpatient care or prolongation of hospitalization, or 
o 
Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
Planned hospitalization for a pre-existing condition, or a procedure required by the trial protocol, without 
serious deterioration in health, is not considered a serious adverse event. 
An Unanticipated Adverse Device Effect (UADE) is defined as any adverse device effect which, by its nature, 
incidence, severity or outcome, has not been identified in section 8.2.3. 
8.2.2 ADVERSE EVENT SEVERITY DEFINITIONS 
The following definitions will be used to determine the severity rating for all adverse events: 
Mild: awareness of signs or symptoms, that does not interfere with the subject’s usual activity or is transient 
that resolved without treatment and with no sequelae. 
Moderate: a sign or symptom, which interferes with the subject’s usual activity. 
Severe: incapacity with inability to do work or perform usual activities. 
8.2.3 ANTICIPATED ADVERSE EVENTS 
General 
 
Infection (chest, urine, blood, bile, wound, abdominal) 
 
Fluid collection (abdominal, pleural) 
 
Rejection 
 
Renal dysfunction 
 
Hepatic dysfunction 
 
Cardiac failure 
 
Respiratory failure 
Events related to the disease / condition / surgery 
 
Early graft dysfunction 
 
Admission for suspected rejection 
 
Occurrence and treatment of abdominal or wound infection 
 
Respiratory failure requiring mechanical ventilation 
 
Hospitalization for pre-existing condition that has not deteriorated.  
 
Clinically significant abnormal laboratory finding or other abnormal assessments that is associated 
with the disease being studied (unless judged by the Investigator as more severe than expected for 
the subject’s condition).  
 
Death 
The Investigator will exercise his/her medical judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant. However, if in the opinion of the Investigator, the frequency 
or severity of the event is greater than would be expected then it must be reported. 
8.2.4 DEVICE DEFICIENCY 

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A device deficiency is defined as inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety, or performance.  Device deficiencies include device failures, device malfunctions, and use 
errors.  Device deficiencies resulting in SAEs will be managed as detailed in section 8.2.5.  
Device deficiencies that did not lead to an adverse event, but could have led to a medical occurrence if suitable 
action had not been taken, or intervention had not been made or if circumstances had been less fortunate will 
also be managed as detailed in section 8.2.5. 
 
8.2.4.1 DEVICE FAILURES  
A device failure has occurred when the device is used in accordance with the IFU, but does not perform as 
described in the IFU and also negatively impacts treatment of the study subject.  
8.2.4.2 DEVICE MALFUNCTIONS 
A device malfunction occurs when an unexpected change to the device that is contradictory to the IFU is 
observed, which may or may not affect device performance.  
8.2.4.3 USE ERRORS  
A device use error is an act or omission of an act that results in a different medical device response than 
intended by the manufacturer or expected by the user. Use error includes slips, lapses, and mistakes.  An 
unexpected physiological response of the subject does not itself constitute a use error. 
8.2.5 PROCEDURES FOR RECORDING ADVERSE EVENTS 
It is the responsibility of the local Investigator to ensure that all adverse events (AEs, SAEs, UADEs, and device 
deficiencies) occurring during the course of the study are recorded. This may include but not be limited to: 
 
A description of the event 
 
The dates of the onset and resolution 
 
Action taken 
 
Outcome 
 
Assessment of relatedness to the device 
 
Assessment of relatedness to the transplant procedure 
 
Severity 
 
Whether the AE is serious or not 
 
Whether the AE arises from device deficiency, device malfunction, or use error 
Adverse events that occur during the course of the study should be treated by established standards of care 
that will protect the life and health of the study subjects. 
It is the responsibility of the local Investigator to collect all directly observed adverse events and all adverse 
events spontaneously reported by the subject. In addition, each subject should be questioned about adverse 
events at each visit.  Adverse events should be recorded on provided adverse event data collection forms. 
8.2.6 REPORTING PROCEDURES FOR ALL ADVERSE EVENTS 
It is the responsibility of the local Investigator to ensure that all adverse events which fall into the categories of 
SAEs and UADEs are reported to the sponsor and IRB, as required, as soon as possible after becoming aware of 
the event but no later than 10 working days.   
The Investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse 
device effect during an investigation as soon as possible, but no later than 10 working days after the 
Investigator first learns of the effect (812.150). 

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The sponsor shall immediately conduct an evaluation of any unanticipated adverse device effect. If the 
sponsor determines that an unanticipated adverse device effect presents an unreasonable risk to subjects, 
sponsor will terminate all investigations or parts of investigations presenting that risk as soon as possible. 
Termination should occur no later than 5 working days after the sponsor makes this determination and no 
later than 15 working days after the sponsor first received notice of the effect (812.46(b)).  
The sponsor shall conduct an evaluation of an unanticipated adverse device effect under 812.46(b) shall report 
the results of such evaluation to FDA and to all reviewing IRB's and participating Investigators within 10 
working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such 
additional reports concerning the effect as FDA requests (812.150). 
8.3 STUDY SUSPENSION OR EARLY TERMINATION 
The DSMB or sponsor may recommend suspension or termination of the study either at an individual 
investigative site or the entire study for significant and documented reasons. An Investigator, IRB, or FDA may 
suspend or prematurely terminate participation in the study at the investigative sites for which they are 
responsible. If suspicion of an unacceptable risk to subjects arises during the study, or when so instructed by 
the IRB or regulatory authorities, the sponsor shall suspend the study while the risk is assessed. The sponsor 
shall terminate the study if an unacceptable risk is confirmed. 
During the Conditional phase, the study will be limited to 20 enrolled subjects. Based on data collected for the 
first 20 subjects through 30-day follow-up, if the number of subjects experiencing an event (EAD or 30-day PNF 
or 30-day subject death) is greater in the NMP arm than that in the SCS arm by three the study will be 
suspended. 
The sponsor shall consider terminating or suspending the participation of a particular study site or Investigator 
in the study if monitoring or auditing identifies serious or repeated deviations on the part of an Investigator. 
If suspension or premature termination occurs, the terminating party shall justify its decision in writing and 
promptly inform the other parties with whom they are in direct communication. The Principal Investigator and 
sponsor shall keep each other informed of any communication received from either the institutional review 
board (IRB) and/or a regulatory authority. 
If, for any reason, the sponsor suspends or prematurely terminates the study at an individual investigative site, 
the sponsor shall inform the FDA as appropriate and ensure that the IRB is notified, either by the Principal 
Investigator or by the sponsor. If the suspension or premature termination was in the interest of safety, the 
sponsor shall inform all other Investigators. 
If suspension or premature termination occurs, 
a) The Sponsor/Manufacturer shall remain responsible for fulfilling the obligations from the study 
protocol and existing agreements for following subjects enrolled in the study as applicable, and 
b) The Principal Investigator or authorized designee shall promptly inform the enrolled subjects at 
his/her 
study 
site, 
if 
appropriate, 
and 
follow 
written 
instructions 
provided 
by 
the 
Sponsor/Manufacturer and the US Sponsor. 
9. STATISTICS 
This section provides a summary of the planned statistical analyses; additional detail will be contained in the 
Statistical Analysis Plan. In any apparent instances of ambiguity or disparity, the terms and procedures of the 
Statistical Analysis Plan (SAP) govern trial analyses. 
9.1 DESCRIPTION OF  STATISTICAL METHODS 
9.1.1 GENERAL STATISTICAL CONSIDERATIONS 

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All statistical analyses will be performed using SAS version 9.3 or above (SAS Institute, Cary, N.C.) or another 
validated statistical software package. Unless otherwise specified, the data will be summarized in tables 
presenting the mean, standard deviation, and number of subjects in a group for continuous data, or presenting 
count and percentage analyzed using ANOVA with adjustment for categorical data, as appropriate.  
In general, binary data will be assessed using the chi-squared test (or Fisher’s Exact, if appropriate) or logistic 
regression to adjust for potential confounders. Continuous outcomes will be compared using the T-test if 
normally distributed, or by the Mann-Whitney U test.  Time-to-event outcomes will be analyzed using survival 
analysis methods, such as Kaplan-Meier or Cox proportional hazards regression model with calculation of 
hazard ratios.  Outcomes will be reported with 95% confidence intervals and p-values to 3 decimal places.  
Unless otherwise specified, a p-value of less than 0.05 will be regarded as statistically significant. 
9.1.2 CONDITIONAL PHASE ANALYSES 
Data will be summarized on initial safety when the first 10 subjects have completed 30-day post-transplant 
follow-up, although no formal statistical comparisons will be performed. This summary will be strictly for FDA 
review to continue enrollment in the study.   
9.1.3 STUDY COHORTS FOR ANALYSES 
A modified intent-to-treat (mITT) analysis will be performed for all outcomes as the primary analysis.  
Transplanted subjects (a subject who has been reperfused with a donor liver) will be analyzed in the groups to 
which the liver received is randomly assigned, irrespective of whether the assigned method of preservation is 
actually used.  Practically, this means that if a liver intended by randomization for machine perfusion for any 
reason undergoes cold storage, it will be analyzed in the assigned machine perfusion group.  Because analyses 
require data post-transplant, the analysis will exclude recipients for whom were matched to a liver that was 
randomized, but were not transplanted for any reason.  In the case of DCD livers in which the retrieval did not 
proceed, the reason will be documented along with associated DCD recovery time points.  In all other cases 
the reason for the liver not proceeding to transplantation will be documented and a narrative summary of this 
data performed.  In cases of emergency use, where the liver is unable to be transplanted into the initial 
intended recipient and is instead re-allocated to a recipient that is not enrolled in the study, data will not be 
collected beyond what is provided to UNOS through the UNET database, and therefore, these subjects will not 
be included in any outcome analyses that are performed.  Recipient safety data on subject and graft survival, 
in these instances, will be summarized and reported separate from the study cohort on data available up to 
one-year post-transplant.  
As additional, supportive, analyses of the outcomes, a per-protocol (PP) cohort will be considered. This cohort 
will include all subjects who were followed according to the protocol procedures with no major deviations 
(beyond not being treated in the arm they were assigned to). 
9.1.4 PRIMARY OUTCOME 
The intervention (NMP) will be compared against control (SCS) for all primary and secondary outcomes in the 
mITT population.  
Primary outcome, difference in EAD, will be analyzed using a logistic model with adjustment for stratification 
factors. The hypothesis is: 
H0: EADNMP ≥ EADSCS 
HA: EADNMP < EADSCS 
In other words, the EAD for the NMP group is less than the EAD for the SCS group. 
EAD is a binary outcome defined by the presence of one of the following 3 outcomes [40]: 
1. Serum bilirubin ≥ 10 mg/dL at day 7 post-transplant 

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2. International normalized ratio ≥ 1.6 at day 7 post-transplant 
3. ALT or AST > 2000 IU/L within the first 7 days post-transplant 
 
The primary analysis will be a logistic model, adjusted for participating (recipient) center using SAS PROC 
LOGISTIC or a similar procedure. Significance for the treatment effect will be assessed by the p-value 
associated with the F-test statistic for the treatment group assignment. 
 
9.1.5 SECONDARY OUTCOMES 
The following endpoints will be considered secondary endpoints for the study and will be summarized using 
the appropriate analyses described in section 9.1.1: 
1. To compare graft and subject survival between NMP and SCS livers 
2. To compare evidence of post-reperfusion syndrome between NMP and SCS livers on transplantation 
3. To compare biochemical liver function between NMP and SCS livers 
4. To compare evidence of ischemia-reperfusion injury between NMP and SCS livers 
5. To compare evidence of biliary complications between NMP and SCS livers 
6. To assess the feasibility and safety of NMP as a method of organ storage and transportation 
7. To compare organ utilization between NMP and SCS livers 
8. To assess the health economic implications of normothermic liver perfusion 
 
Additionally, a logistic model will be used to examine the possible explanatory effects of baseline subject 
characteristics (in the presence of the treatment indicator variable), namely:  race, age, gender, and number of 
liver transplants received (primary or secondary).   
Secondary analysis may be stratified by recipient center and donor type (DBD or DCD) for exploratory 
purposes.  
9.1.6 SAFETY ANALYSES 
Safety data will be collected and reported on for those recipients that are matched to a randomized liver and 
there is an attempt to transplant the randomized liver. 
9.1.7 SUBGROUP ANALYSES 
Subgroup analyses will be performed for donor type (DCD vs. DBD), by donor risk index (DRI), and by duration 
of machine preservation in the NMP arm of the trial.   
Full details of the proposed statistical analysis will be outlined in a separate Statistical Analysis Plan (SAP).    
9.1.8 POOLABILITY ANALYSIS 
Poolability analyses will be performed on the primary endpoint to assess whether results are poolable across 
participating centers.  
A logistic model with EAD as the dependent (outcome) variable will be reported using a binary treatment 
indicator variable and site by treatment interaction term(s) as independent variables to assess poolability of 
data across sites. Absence of statistically significant interaction term(s) (using a p-value of 0.1 as the cut-off) 
will be taken as evidence of poolability across the sites. Any interaction term that is statistically significant will 
trigger an examination of the data at the relevant site to determine the underlying reason(s). Since the power 
associated with testing for a significant interaction is likely to be low, the difference between the two 
treatment groups will be reported descriptively for each investigational site.  A similar approach will be used to 
assess poolability across donor types. 
 
 

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9.1.9 MISSING DATA 
The extent and types of missing data for key study variables will be assessed as part of sensitivity analyses, and 
reported upon.  
Withdrawals from the trial after transplantation will be documented as per section 6.10, and a narrative 
summary of withdrawals will be performed.  Recipients in the mITT population with incomplete EAD data after 
transplantation will be included in primary endpoint analysis using imputation methods for missing data.  The 
individual components of EAD will be imputed using baseline subject characteristics as well as all available 
components of EAD collected during study follow-up. Additional sensitivity analyses could include “completers 
only,” last observation carried forward, and/or mixed models. 
 
For all secondary endpoints, data will be summarized for those recipients with available data.  In the instances 
where data is collected only if standard of care, results will be summarized for those recipients with available 
data where collection was standard of care.  The following variables are collected only as standard of care;  
a. Serum gamma-glutamyl transferase (GGT; measured in IU/L) 
b. Daily serum lactate (measured in mmol/L) while admitted to ICU 
 
9.2 SAMPLE SIZE 
It is expected that normothermic machine perfusion will be more effective than static cold storage in terms of 
EAD. Olthoff et al. (2010), who developed the EAD definition, showed an EAD incidence of 23%, based on data 
from 300 liver transplants from 3 US centers between 2004 and 2005 [40]. Estimates of EAD rates in DCD 
donors have been shown to be closer to 40% [44]. EAD incidence data from livers transplanted using machine 
perfusion is limited. Using hypothermic machine perfusion Guarrera et al. showed a decrease in EAD incidence 
from 25% to 5% in a prospective cohort pilot study of 20 livers compared to matched controls [25]. The UK 
pilot study of 20 liver transplants using normothermic machine perfusion showed a decrease in EAD incidence 
from 22.5% to 15% compared to matched controls. Based on all the available data this study has been 
powered to demonstrate a reduction in EAD from 25% to 10% in NMP versus SCS. The sample size estimate is 
based on a one-sided significance level of 0.025 and power of 90%. The pooled Z-test is the test statistic, and 
the assumption of the covariate distribution is that the difference between the two proportions is zero. The 
final sample size of 266 transplanted livers (minimum of 120 in each arm), will be achieved by randomizing 
approximately 356 transplanted livers (assumes approximately 25% attrition).  Recipients that receive a 
reallocated liver but are not enrolled in the study (cases of emergency use) will not contribute to the final 
sample size of 266 transplanted livers. 
9.3 ADDITIONAL ANALYSES AND DEVIATION FROM THE STATISTICAL ANALYSIS PLAN 
Additional analyses may be performed as appropriate. In the final report, such analyses will clearly be 
described as post-hoc or exploratory. Any deviation from the original statistical analysis plan will require 
justification in the final study report. 
10. DATA COLLECTION AND MANAGEMENT 
10.1 DATA COLLECTION METHODS 
10.1.1 SOURCE DATA 
Source documents are where data are first recorded, and from which participants’ eCRF data are obtained.  
These include, but are not limited to, hospital records (from which medical history and previous and 
concurrent medication may be summarized into the eCRF), clinical and office charts, laboratory reports, 

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pharmacy records, subject diaries or logs, microfiches, radiographs, correspondence, device accountability 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, and at medico-technical departments involved in the clinical investigation. 
All documents will be stored safely in confidential conditions.  On all trial-specific documents, other than the 
signed consent, the participant will be referred to by the trial participant number/code, not by name. 
10.1.2 DATA RECORDING 
Data collection will be achieved using an electronic data capture (EDC) system.  Data will be input by local 
study Investigators/coordinators trained in the use of the system prior to receiving log-in details. 
All blood samples will be analyzed in local laboratories and results recorded in common units. 
 
10.2 DATA MANAGEMENT 
10.2.1 DATA FORMS AND DATA ENTRY 
As described in section 10.1.2, data will be entered into an electronic data capture (EDC) system. Validation 
rules will ensure that data are entered in the correct format, within valid ranges and minimize the chance of 
missing data.  Data already entered will be retrievable for viewing.  The extent of an individual user’s activity in 
the database will be limited by privileges associated with his/her log-in and password. 
All electronic data will be stored in a secure fashion on password protected servers, with data identified only 
by the unique participant study ID.  Identification of study participants, if required for safety reasons, will be 
available at the study site. 
10.2.2 DISCREPANCIES AND MISSING DATA 
Visual and electronic data review will be performed to identify potential discrepancies and missing data. 
Manual and automatic queries will be created in the EDC system by NAMSA and will be issued to the study site 
to address. The Investigators/coordinators will be responsible for resolving the queries in the database. 
10.2.3 SECURITY AND BACKUP OF DATA 
The database will reside on a server hosted by the EDC provider.  All changes made to the data will be 
captured in an electronic audit trail and available for review.  The EDC software has been designed to meet 
regulatory compliance for deployment as part of a validated system compliant with laws and regulations 
applicable to the conduct of clinical studies pertaining to the use of electronic records and signatures. 
Database backups are performed regularly. 
10.2.4 DATA ACCESS 
Access to the database will be controlled by username and password.  NAMSA will be responsible for assigning 
users access to the database.   
10.2.5 DATA RETENTION 
The study sponsor will store all data captured in the database for at least 15 years following study close-out. 
11. QUALITY ASSURANCE, AUDIT AND TRAINING 
11.1 MONITORING 
The sponsor will be responsible for the local Investigator’s compliance with the trial protocol and for 
performing source document verification. 

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At the site initiation visit the sponsor will review the study protocol and all associated study documentation 
and procedures with the Investigator and study personnel. Applicable local site personnel will receive training 
for device use and use of the data collection tool, as appropriate to their role, as described in section 11.3. 
During the course of the study, the sponsor will maintain regular contact with the investigative sites and 
conduct central monitoring, on-site monitoring visits, and source data verification on a regular basis to ensure 
compliance with this study protocol.  All subject consent forms will be monitored, and source data will be 
monitored as specified in the Monitoring Plan.  
The Investigator and study personnel must set aside a reasonable amount of his/her time for these visits and 
the time of the relevant site personnel. 
 
11.2 QUALITY ASSURANCE AUDITING AND INSPECTION  
During the course of the study, the sponsor may appoint quality assurance personnel to audit the 
administration and conduct of the study at the study site. These procedures are in accordance with Good 
Clinical Practice (GCP) to ensure that complete, accurate, and timely data are collected, that the trial protocol 
requirements are followed and that all complications and adverse events are reported in a timely manner. The 
FDA could potentially conduct audits/inspections. 
The Investigator and the relevant site personnel must set aside a reasonable amount of his/her time for study 
related monitors, audits, and inspection by the authorized representatives of the sponsor, IRB, FDA, and 
institution compliance and quality assurance groups, and provide adequate access to all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data, etc.). 
11.3 LOCAL INVESTIGATOR AND SITE PERSONNEL TRAINING 
All key site personnel must undergo relevant training in advance of the site initiation in accordance with Good 
Clinical Practice (GCP) guidelines.  Such training will be documented.  
In addition, training on the investigational device will be provided in advance of recruitment of the first 
subject.  A record of all device training will be maintained.  All personnel involved in randomization and data 
entry will also be trained in the use of the online randomization and data collection tool by members of the 
clinical trials unit, and records of such training will be maintained. 
11.4 STUDY DOCUMENTATION 
It is the responsibility of the local Investigator to maintain complete, accurate, and current study records. Each 
Investigator will be provided with an Investigator site file, access to the online case reporting system, and 
other associated study specific documentation by the trial management team. Such records will be maintained 
during the course of the study and for a period of 2 years after the latter of the following two dates: The date 
on which the investigation is terminated or completed, or the date that the records are no longer required for 
purposes of supporting a premarket approval application or notice of completion of a product development 
protocol.   
12. PROTOCOL DEVIATIONS 
12.1 DEFINITIONS 
The Investigators shall conduct this study in accordance with this protocol and any conditions of 
approval/notification imposed by the FDA.  Failure to comply with and/or inability to meet these regulations 
may jeopardize further participation of the Investigator or investigative site in this clinical study.   

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A “protocol deviation” is a failure to adhere to the requirements specified in this study protocol.  Examples 
may include, but are not limited to, the enrollment of a study subject who does not meet all of the 
inclusion/exclusion criteria specified in section 5.3, missed study procedures, or missed study visits. 
12.2 REPORTING OF PROTOCOL DEVIATIONS 
Investigators should report protocol deviations to the sponsor as soon as possible and in accordance with 21 
CFR 812.150. 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 IRB AND FDA APPROVAL 
This protocol and the template informed consent form will be submitted to the FDA for approval. This 
protocol, the site-specific informed consent form, and any materials supplied to the subject, will be submitted 
to the investigative site’s IRB for approval.  Before the study can begin, each Investigator must have written 
evidence of IRB approval and the sponsor must have approval from the FDA. 
Once approval has been granted, the Investigator is responsible for ensuring that he/she complies with the 
terms of the approval, namely with adverse event reporting, protocol deviation reporting, notification of 
amendments, interim, annual, and final reports on the progress of the study. 
13.2 PROTOCOL AMENDMENTS 
Any change or addition to this study protocol which may impact the conduct of the study, potential benefit to 
the subject or may affect subject safety, including changes of study objectives, study design, subject 
population, sample sizes, study procedures or significant administrative aspects will require a formal written 
amendment to the study protocol. 
All amendments to the protocol will be notified to the local regulatory authorities and IRBs for approval.  
Approved amendments will be circulated promptly to all Investigators by the trial management team. 
Amendments will be tracked by version number and date in Appendix A2 of this document. 
13.3 
REPORTING 
13.3.1 SPONSOR REPORTS 
The following reports are required by the sponsor under §812.150. All reports to FDA should be identified as 
IDE Reports. 
 
Unanticipated Adverse Device Effects 
The sponsor must report the results of an evaluation of an unanticipated adverse device effect to FDA and all 
reviewing IRBs and investigators within 10 working days after the sponsor first receives notice of the adverse 
effect. 
 
Withdrawal of IRB Approval 
The sponsor must notify FDA and all reviewing IRBs and participating investigators of the withdrawal of IRB 
approval of an investigation (or any part of an investigation) within 5 working days of receipt of the withdrawal 
of approval. 
 
Withdrawal of FDA Approval 
The sponsor must notify all reviewing IRBs and participating investigators of any withdrawal of FDA approval 
within 5 working days after receipt of the notice. 
 

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 
Current List of Investigators  
Every six months the sponsor must submit to FDA a current list of the names and addresses of all investigators 
participating in a significant risk device investigation. 
 
Progress Reports (or Annual Reports) 
At regular intervals and at least yearly, the sponsor must provide progress reports to all reviewing IRBs. For a 
significant risk device, the sponsor must also submit the progress report to FDA.  A suggested format is 
provided below. 
 
Recalls and Device Disposition 
The sponsor must notify FDA and all reviewing IRB’s of any request that an investigator return, repair, or 
dispose of any unit of an investigational device. The notice must be made within 30 working days after the 
request is made and must state why the request was made. 
 
Final Report 
The sponsor must notify FDA and all reviewing IRBs within 30 working days of the completion or termination of 
the investigation. The sponsor must also submit a final report to FDA and all reviewing IRBs and participating 
investigators within 6 months after the completion or termination of the investigation. A suggested format is 
provided by FDA.   
 
Failure to Obtain Informed Consent 
Sponsors must submit a copy of any report by an investigator of the use of a device without first obtaining 
informed consent. The report must be made to FDA within 5 working days after receipt of the notice of such 
use. 
 
Significant Risk Device Determination 
If an IRB determines that the device is a significant risk device and not a non-significant risk device as the 
sponsor had proposed to the IRB, a report must be submitted to FDA within 5 working days after the sponsor 
learns of the IRB’s determination. 
 
Other Reports  
The sponsor must provide accurate, complete, and current information about any aspect of the investigation 
upon request from the reviewing IRB or FDA. 
13.3.2 INVESTIGATOR REPORTS 
The investigator must provide the following reports to the sponsor in a timely manner under §812.150. 
 
Unanticipated Adverse Device Effects 
The investigator must submit to the sponsor and the reviewing IRB a report of any unanticipated adverse 
device effect as soon as possible but no later than 10 working days after the investigator first learns of the 
effect. 
 
Withdrawal of IRB Approval 
The investigator must report to the sponsor a withdrawal of approval of the reviewing IRB within 5 working 
days. 
 
Progress Reports 
The investigator must submit progress reports to the sponsor and the reviewing IRB at regular intervals but no 
less than on a yearly basis. 

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 
Deviations from the Investigational Plan 
The investigator must notify the sponsor and the reviewing IRB of any deviation from the investigational plan 
to protect the life or physical well-being of a subject in an emergency. The notice must be provided as soon as 
possible but no later than 5 working days after the emergency occurred. If it is not an emergency, prior 
approval from the sponsor is required for changes in or deviations from the investigational plan. If the change 
or deviation may affect the scientific soundness of the investigational plan or the rights, safety, or welfare of 
the subject, the sponsor is required to obtain prior IRB approval and also to obtain FDA approval for a 
significant risk device investigation by submitting an IDE supplement. 
o 
 If an investigator uses a device without obtaining informed consent, the investigator must 
report the use to the sponsor and to the reviewing IRB within 5 working days after the use 
occurs. 
o 
Final Report: The investigator must submit a final report to the sponsor and to the reviewing 
IRB within 3 months after termination or completion of the investigation. 
o 
Other Reports: The investigator must provide accurate, complete, and current information 
about any aspect of the investigation upon request from the reviewing IRB or FDA. 
 
Investigator Annual Progress Reports and Final Reports 
The IDE regulations do not specify the content of the annual progress or final reports. Therefore, the contents 
of these reports may largely be dictated by the sponsor. With respect to reports to the IRB, the IRB itself may 
specify what information it wishes to be included in these reports. Because FDA does require the information 
listed below, it is suggested that, at a minimum, the annual progress and final reports to the sponsor and the 
IRB include the following items: 
 
IDE number 
 
Device name 
 
Indications for use 
 
Brief summary of study progress in relation to investigational plan 
 
Number of subjects enrolled 
 
Number of devices received, used, and, in the final report, the final disposition of unused devices 
 
Brief summary of results and, in the final report, conclusions 
 
Summary of anticipated and unanticipated adverse device effects 
 
Description of any deviations from investigational plan 
 
Reprints of any articles published by the investigator in relation to the study 
  
13.4 PARTICIPANT CONFIDENTIALITY 
All study-related information will be stored securely both at the study sites and with the trial management 
team.  Written information will be stored in locked filing cabinets in areas with limited access.  All 
documentation and specimens will be identified by a unique study ID number to maintain participant 
confidentiality.   
Participant’s information will not be released outside of the study without the written consent of the 
participant, except as necessary by regulatory authorities. 
13.5 EXPENSES AND BENEFITS 
Where possible, study visits and investigations will be conducted during routine hospital attendances.   
 
 

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14. DISSEMINATION POLICY 
14.1 DATA ANALYSIS AND RELEASE OF RESULTS 
By conducting the study, the local Investigators agree that all information provided by the sponsor and trial 
management team will be maintained by the local Investigators and the site personnel in strict confidence.  It 
is understood that the confidential information provided to local Investigators will not be disclosed to others 
without authorization from the sponsor and/or trial management team. 
The scientific integrity of the study requires that all data must be analyzed study-wide and reported as such.   
14.2 PRIMARY OUTCOME PUBLICATIONS 
At the conclusion of the study, a multi-center manuscript led by the national study Principal Investigator will 
be prepared with the assistance of OrganOx and NAMSA for publication in a reputable scientific journal. The 
publication of the principal results from any single center experience within the trial is not allowed until the 
preparation and publication of the multi-center results as indicated in the Clinical Trial Agreement. Exceptions 
to this rule require the prior approval of OrganOx. For the purposes of timely abstract presentation and 
publication, secondary publications will be delegated to the appropriate principal authors, and final analyses 
and manuscript review for all multi-center data and/or single-center experience reports will require review 
from 
OrganOx.

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APPENDIX A1: TIMELINE FOR INTERVENTIONS AND ASSESSMENTS DURING THE STUDY 
Activity 
Pre-study 
Screening 
Pre-study 
Baseline 
Pre-
storage 
Pre-
reperfusion 
Post-reperfusion 
Postoperative 
 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D10 
D30 
M3 
M6 
M12 
Visit Windows 
 
 
 
 
 
12-24h 
24-48h 
48-72h 
72-96h 
96-120h 
120-
144h 
144-
168h 
216-
240h 
+/-7d 
+/- 
14d 
+/-14d 
+/- 30d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor & recipient 
demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perfusion 
parameters/samples  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lactate values 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical variables 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Graft biopsy 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum AST 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum ALT 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum ALP 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Total Serum Bilirubin 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum GGT** 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
PT/INR 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum Albumin** 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum Creatinine** 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum lactate(*)(**) 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Medication Log 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Primary non-function 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Graft survival 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject survival 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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* Serum lactate will be recorded daily while the recipient is admitted to high level (ICU) care. 
** Only collected if Standard of Care 
Quality of life 
measure 
(EQ-5D-5L) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Resource use 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Safety outcomes 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Readmissions 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
RRT Requirement 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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APPENDIX A2: PROTOCOL AMENDMENTS 
Version 
Date 
Amendments 
1.0 
26/11/2014 
Original Version 
2.0 
10/07/2015 
Amended primary endpoint and other modifications 
3.0 
4.0 
5.0        
6.0             
7.0       
8.0                     
01/10/2015 
07/09/2015   
02/11/2015 
20/11/2015 
23/11/2015 
16/12/2015   
Amended post-transplant follow up visits 
FDA review questions 
FDA A001 
Fixing grammatical errors 
Updated interventions and assessments table 
IDE number added to first page 
9.0 
22/03/2016 
FDA A003 
10.0 
24/06/2016 
FDA A004 
 
 
 
 
 
 
 

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