International Randomized Trial to Evaluate The Effectiveness of The Portable Organ Care System (OCS™) Liver For Preserving and Assessing Donor Livers for Transplantation (OCS Liver PROTECT Trial)
Phase: NA
Conditions: Liver Transplantation, Liver Preservation for Transplant
Sponsor: TransMedics

Tran sMedics Confidential 
OCS-Liver 092014 
INVESTIGATIONAL PLAN/PROTOCOL 
International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care 
System (OCSTM) Liver for Preserving and Assessing Donor Livers for Transplantation 
(OCS Liver PROTECT Trial) 
Sponsor: 
Sponsor Primary Contact: 
Sponsor Secondary Contact: 
OCSTM 
Liver 
PROTECT 
Trial 
Number OCS-L VR-092014 
May 20, 2016 
TransMedics , Inc. 
200 Minuteman Road, Suite 302 
Andover , MA 01810 
Waleed Hassanein, MD 
President & CEO 
Phone: (978) 552-0901 
Fax: (781) 998-0354 
Email: whassanein@transmedics .com 
Tamer Khayal, MD 
Chief Medical Officer 
Phone: (978)552-0902 
Fax: (978) 552-0978 
Email: tkhayal@transmedics.com 
.CONFIDENTIAL - PROPRIETARY INFORMATION 
Protocol Rev 
Issue Date 
1.0 
Sept 30, 2014 
1.1 
Jan 12, 2014 
1.2 
June 18, 2015 
1.3 
December 15, 2015 
1.4 
May 20, 2016 
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TransMedic s Confiden tial 
OCS-Liver 0920 I 4 
TABLE OF CONTENTS 
OCS™ LIVER PROTECT TRIAL SYNOPSIS ......................................................................... 5 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ....................................... 12 
1.1. Liver Transplantatio n and Current Clinical Challenges .................................................. 12 
1.2. Potential Clinical Solutions to Overcome Limitation in Donor Liver Utilization .......... 13 
1.3. Subject emollment and health insurance ...................................... ................................... 14 
1 .4. Summary of Prior Testing and Investigations ................................................................. 14 
1.4.1. OCSTM Liver Engineering Testing .................................................................... .. 14 
1.4.2. Independent Pre-Clinical Testing of Normothermic Machine Perfusion 
for Donor Livers ......................................................................... ............... 14 
1.4.3. OCS™ Liver Pre-Clinical Testing ...................................................................... 18 
1.4.3.1. Phase 1 Ex-vivo OCS Liver Perfusion for up-to 12 homs ........................ .18 
1.4.3.2. Phase 2 Simulated Transplants After OCS Liver Perfusion: ..................... 21 
1 .4.4. Clinical Feasibility Testing of Ex-vivo normothermic Liver Perfusion: ............. 25 
2. 
DEVICE DESCRIPT ION ................... ............................................................................... 26 
3. 
TRI.AL OBJECTIVES ........................................ .......................................................... ..... 27 
3.1. Type of the Trial ..................................................................... ......................................... 27 
3.2. Trial Size and Subject Follow-up ................................... ................................................. 27 
4. 
TRIAL ENDPOINTS ............................................................................................... .......... 28 
4.1. Primary Effectivene ss Endpoint ................................ ...................................................... 28 
4.2. Seconda1y Effectiveness and OCS Donor Liver Assessment Endpoints ........................ 28 
4.3. Other Endpoints ...................................................................................... ......................... 28 
4.4. Safety Endpoint ....................... .......................... .............................................................. 29 
5. 
TRIAL POPULATION ....................................................... ............................................... 29 
5.1. Donor Eligibility Criteria .................................. .................. ............................................ 29 
5.1.1. Donor Inclusion Criteria ............................... ...................................................... .29 
5.1.2. Donor Exclusion Criteria ............................................................................. ........ 29 
5.2. Recipient Eligibility Criteria ....................................... ......................................... ........... 30 
5.2.1. Recipient Inclusion Criteria ................................................................................. 30 
5.2.2. Recipient Exclusion Criteria ........................................... ..................... ................ 30 
6. 
PRE-OPERATIVE TRIAL PROCEDURES .............................................. ..................... 30 
6.1. Subject Identification ....................................... ................................................................ 30 
6.2. Recipient Day of Transplant Assessment. ....................................................... ................ 30 
6.3. Donor Screening and Acceptance .................................................................................. . 31 
6.4. Donor Liver Retrieval and OCS Preservation and Assessment ..................................... . 32 
6.5. Donor Liver Acceptance for Transplantation .................................................................. 35 
7. 
TRANSPLANT, IMMEDIATE POST-OPERATIVE AND LONG TERM 
FOLLOW-UP ............................................................................................................ 35 
7.1. Transplant Details .......................... .................................................................................. 35 
7.2. Post-transplan t Functional Assessments Day O - Day 30: .......................................... .... 36 
7.3. Long Term Follow- up: 6 and 12 & 24 months ............................................................... .37 
7.3.1. 6 and 12-Month Follow-up ................................... ............................................... 37 
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TransMedics Conlidential 
OCS-Liver 092014 
7.3.1.1. 24-Month Follow-up ................................................... ............................... 37 
8. 
EVALUATION OF ADVERSE EVENTS ................................................................. ...... 37 
8.1. Evaluation of Liver Graft-Related Adverse Events ......................................................... 37 
8.2. Serious Adverse Events (SAEs) .................................................... .................................. 38 
8.3. Anticipated and Unanticipated Adverse Events .............................................................. 38 
8.4. Unanticipated Adverse Device Effect (UADE) ............................................................. .40 
8.5. Recording and Repo1iing of Adverse Event.. .................................... ............................. .40 
8.6. Relationship of an Adverse Events to OCSTM Liver (OCS) or Standard of Care 
(Control) ................................................................................................................... 40 
8.7. Severity ...................................... .................................................................................. · .... 41 
8.8. Pre-Existing Conditions ................................................................................................... 41 
9. 
ST A TISTICAL METHODS .................................. ................ ............................................ 41 
9.1. General ............................................................................................................................ 41 
9.2. Analysis Populations .............................................................................. ......................... 41 
9.2. l . Per Protocol Population ...................................................................................... .41 
9 .2.2. Modified Intent-to-Treat Population ............................................. ..................... .41 
9.2.3. As Treated Population ................................ ......................................................... 42 
9 .2.4. Donor Liver Population .............................. ........................................................ .42 
9.3. Analysis of Effectiveness Endpoints ................................................................... ........... .42 
9 .3 .1. Primary Effectiveness Endpoint .................................... ................................... ... 42 
9.3.2. Secondruy Effectiveness and OCS Donor Liver Assessment Endpoints ............ 43 
9.4. Analysis of Safety .................................................................................................. .......... 44 
9.5. Randoinization ................................................................................................................. 45 
9.6. Sample Size Determinati on ........................................................... ........................ .......... 46 
9.7. Sample Size Re-Estimat ion ................................................................... ......................... .46 
9.8. Interin1 Analyses ............................................................................. ................................. 46 
9.9. Statistical Analysis Plan ........................... ......................................... ........................... ... 46 
10. 
RISK ANALYSIS ............................................................................................................... 46 
10.1. Potential Risks ................................... ................................................... ..................... . 47 
10.2. Manner in Which the Potential Risks Have Been Minimized .................................... 47 
10.3. Potential Benefits ........................................................................................................ 48 
10.4. 
Risks Benefits Ratio ........................................................ .......................... ................. 48 
11. 
DEVICE/SITE MANAGEMENT ............................................................... ...................... 48 
11. l. 
Packaging and Labeling .................................................... .......................................... 48 
11.2. 
Storage .............................................. .................................... .................................... .. 48 
I 1.3. Accountability ............................................................................................................. 48 
11 .4. Device Complaints and Malfunctions ............................................................. .......... .48 
12. 
REGULA TORY / ETHICS ............................................................................ ................... 49 
12.1. Institutional Review Boards (IRB) or Ethics Committee (EC) .................................. 49 
12.2. [nformed Consent ....................................................................................................... 49 
13. 
DATA COLLECTION/RECORDS/REPORTS ............................................................. .49 
13.1. Investigator Records .................... ..................... ..................................... ..................... 49 
13.2. Investigator Reports ............................................................................................ ........ 50 
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TransMedics Confidential 
OCS-Liver 0920 14 
13.3. Data Collection ........................................................ ................................................... 51 
13.4. Source Docun1ents ............................. ......................................................................... 51 
13.5. 
Archiving of Record s .................................................................................................. 51 
13.6. 
Sponsor Records and Reports30T .............................................................................. 51 
13.7. Final Study report .................................. .......................... ........................................... 51 
14. 
CLINICAL MONITORING ............................................................................................. 52 
14.1. Monitoring ....................................................................................... ..................... ...... 52 
14.2. Pre-Trial Monitoring Procedures ................................................ ................................ 52 
14.2. 1. Selection of Monitors ................ .............................. ............................ ................ 52 
14.2.2. Initiation Visit. ..................................................................................................... 52 
14.3. Periodic Monitoring Visits ....................................................................................... .. 53 
14.4. 
Frequency of Monitoring Visits ............................................................................. ..... 53 
14.5. Trial Completion Visit ................................................................................................ 53 
14.6. Reports of Monitoring Visits ...................................................................................... 53 
14. 7. Additional Auditing ........................................................ ............................................ 54 
14.8. Protocol Deviations ....................................................................... ........................... .. 54 
14.9. Medical Monitor ......................................................... ................................................ 54 
14.10. 
Stopping Rule ........................................................................................................... 54 
14.11. Data Monitoring Board ............................................................................................ 55 
14.12. 
Investigator Training ................................................................................................ 56 
15. 
CONFIDENTIALITY ........................................................................................................ 56 
16. 
AMENDMENT POLICY .................................................................................................. 56 
17. 
REFERENCES ...................................................... ............................................................. 57 
APPENDIX 1. 
LIVER TISSUE BIOPSY, BILE DUCT SPECIMEN , & 
SCORING PROTOCOL .......................................................................................... 59 
APPENDIX 2. 
APPENDIX 3. 
SCHEDULE OF CLINICAL ASSESSMENTS .................................... 61 
DRAFT PATIENT INFORMED CONSENT FORM 
TEMP LA TE .............................................................................................................. 62 
APPENDIX 4. 
DRAFT ELECTRONIC CASE REPORT FORMS ............................. 63 
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TransMedics Confidential 
OCS-Liver 092014 
OCS™ LIVER PROTECT TRIAL SYNOPSIS 
Protocol Title 
Objectives 
Trial Design 
Trial Size 
Screening and 
Treatment 
Donor Liver Eligibility 
Criteria 
Recipient 
Eligibility Criteria 
International Randomized Trial to Evaluate The Effectivenes s of The Portable 
Organ Care System (OCS™) Liver For Preserving and Assessing Donor Livers for 
Transplantation (OCS™ Liver PROTECT Trial) 
To evaluate the effectiveness of the OCS™ Liver to preserve and assess donor 
livers intended for transplantation 
A prospective, "Phased Pivotal," international randomized trial. The trial will have 
two parts, (Part A rolling into large Part B, assuming stopping rule is not triggered): 
• 
Part A: Include the first 20 randomized transplanted liver recipients with 
pre-specified stopping rule to ensure safety; 
• 
Pait B: assuming no stopping rule was triggered, the trial enrollment will 
continue beyond the initial 20 transplanted recipients in Pait A into Patt B, 
while the data from the first 20 subjects is being reviewed. All of the final 
analyses of the study will be based on the pooled data from Parts A and B. 
A maximum of25 participating sites worldwide to enroll 300 transplant ed Liver 
recipient s 
Primary Liver tran splant candidates will be screened for trial eligibility. Every 
eligible candidate will be asked to pa1ticipate. Eligible liver transplan t candidates 
will be randomized to receive a donor liver preserved either on OCS™ Liver (OCS) 
or using cold preservation solution (Control) 
Donor livers will be screened for trial eligibility. Eligible donor livers will be 
preserved either using the OCS™ Liver system (OCS) or cold flush and storage 
using cold preservation solut ion (Control) 
Inclusion 
Donor meets at least one of the following: 
• 
Donor age 2:40 years old; or 
• 
Expected total cross clamp/co ld ischemic time 2:6 hours ; or 
• 
Donor after circulatory death (DCD) with age :S55 years old; or 
• 
Steatotic liver >0% and :S40% macrosteatosis at time of retrieval (based 
on retrieval biopsy readout (only if the donor liver was clinically 
suspected to be fatty by the retrieval surgeon at time of liver retriev al) 
Exclusion 
Donor Livers will be excluded if they meet any of the following criteria: 
• 
Living donors 
• 
Liver intended for split transplan ts 
• 
Positive sero logy (HIV, Hepati tis B surface antigen & C) 
• 
Presence of moderate or severe traumatic liver injury, or anatomical liver 
abnormalities that would compromise ex-vivo perfusion of the donor liver 
(i.e., accessory blood vessels or other abnorma l anatomy that require 
surg ical repair) and livers with active bleeding (e.g., hematoma s) 
• 
Donor livers with macrosteatosis of >40% based on retrieval biopsy 
readout 
Inclusion 
Recipients are required to meet all the following criteria on the day of transplant: 
• Registered primary Liver transplant candidate, male or female 
Page 5 of63 

TransMedics Confidential 
Pl"imary Effectiveness 
Endpoint 
Secondary 
Effectiveness and OCS 
Donor Liver 
Assessment Endpoints 
Other Endpoints 
OCS-Liver 0920 14 
• A ge ?J 8 years old 
• Signed: I) written informed consent documen t and 2) authorization to use 
and disclose protected health informa tion 
Exclusion 
Recipients will be excluded if they meet any of the following criteria on the day of 
transplant: 
• Acute, fulminant liver failure 
• Prior solid organ or bone marrow transplant 
• Chronic use of hemodialy sis or diagnosis of chronic renal failure, defined 
as chronic serum creatinine of>3 mg/dl for >2 weeks and/or requirin g 
hemodialysis 
• Multi-or gan transplant 
• Venti lator dependent 
• Dependent on> 1 IV inotrop e to maintain hemodynamic s 
Incidence of Early liver Allograft Dysfunction (EAD) or primary non-function, 
defined as presence of one or more of the following criteria: 
• 
AST level >2000 IU/ml within the first 7 postoperative days; 
• 
Bilirubin 2:10 mg/di on postop erative day 7; 
• 
fNR 2:1.6 on postoperative day 7; or 
• 
Primary non-functioning graft within the first 7 days (defined as irreversib le 
graft dysfunction requirin g emergency liver re-tran splantat ion or death, in 
the absence of immuno logic or surgical causes) 
• 
OCS donor liver assessment during perfusion, defined as, among donor 
livers preserved using OCS for the entire preservation period, the 
propo1tion of livers on which measurements of all of the following durin g 
perfusion will be available on OCS device before transplant 
o 
La ctate level (every two hour s) 
o 
Average bile production rate (based on total bile prod uction volume 
and duration of OCS perfusion) 
o 
Hepatic Attery Pressure (continuous ly) 
o 
Portal Vein Pressure (continuou sly) 
• 
Patient survival at day-30 post-transplantation 
• 
Patie nt survival at initial hospital discharge post liver transp lantation 
• 
Length of initial post-tra nsplant ICU stay 
• 
Length of initial post-tran splant hospita l stay 
• 
Evidence of ischemic biliary comp lications diagnosed at 6 and at 12 months 
• 
Exten t of reperfusion syndrome as assessed based on the rate of decrease of 
lactate over the follow ing time points: 
o 
During anhepat ic phase immediately before reperfusion of the 
transplanted liver 
o 
30-40 minute s after hepatic att ery and po1tal vein reperfusion of the 
transplanted liver 
o 
90-120 minutes after reperfusion of the transp lanted liver 
• 
Pathology sample score for liver tissue samples taken at the following time 
points (applies to both OCS and Control arms): 
o 
Donor liver pre-retrieval 
o 
Post-OCS and Control preservation at the end of back preparation 
and immediate ly before the sta1t of re-implantation 
o 
Post reperfusion 90-120 after reperfusion of the transp lanted liver 
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TransMedic s Con fidential 
OCS-Liver 0920 14 
I 
I 
(prior to abdominal closure) 
I 
Safety Endpoints 
Safety will be analyzed principally by examination of the frequency of liver graft-
related serious adverse events (SAEs) up to the 30-day follow-up after 
transplantation. This endpoint is defined as the average number of liver graft-
related serious adverse events through the 30-days post-liver transplantation per 
subject , consisting of the following serious adverse events (at most one per type per 
person): 
• 
Primary non-function (defined as irreversible graft dysfunction requiring 
emergency liver re-tran splantation or death with the first 10 days, in the 
absence of immuno logic or sW"gical causes); 
• 
Ischemic biliary comp lications (ischemic biliary strictures , and non-
anastomotic bile duct leaks); 
• 
Vascular complications (Liver graft-related coagulopathy, hepatic aitery 
stenosis, hepatic artery thrombosis and po1tal vein thrombosis); 
• 
Liver allograft infections (liver abscess, cholangitis , etc.) 
Follow-up 
All patients will be followed for a minimum of 30 days post liver transplant. 
Patients will be followed for a maximum of (24 months) 2 years post-transp lant. 
The following data will be collected at 6 and 12 months: 
• Patient and graft survival 
• Incidence of ischemic biliary compl ications and method of diagnosis 
• Liver graft related SAEs at 6 months only 
• Liver graft related re-hospitalized after initial discharge, and, if yes, the 
primary reason/diagnosis for the hospitalizat ion and the length of stay 
The following data will be collected at 24 months: 
• 
Patient and graft survival 
Analysis Populations 
• 
The Per Protocol (PP) Population will consist of all randomized subjects who 
are transplanted and have no major protocol violations and for whom the donor 
liver received the complete preservation procedure as per the randomization 
assignment. In analyses based on the PP Population , subjects will be analyzed 
as random ized. The primary analysis of effectiveness will be based on the PP 
Population. 
• 
The Modified Intent-to-Treat Population (mlTT) will consist of all randomized 
subjects who are transplanted. In analyses based on the mlTT Population, 
subjects will be analyzed as randomized. The mlTT analyses will be considered 
secondary analyses of effect iveness. 
• 
The As Treated Population (AT) will consist of all treated subjects, i.e., all 
subjects who are transplanted in the study with a donor liver preserved with 
either OCS or Control. In analyses based on this population, subjects will be 
analyzed as treated. A subject who receives a liver with some preservation with 
OCS and some with standa rd of care will be analyzed according to the initia l 
preservation. After the initiation of preservation, any switchover in preservation 
method shou ld be recorded as a protocol deviation and those subjects will not be 
considered part of the AT population. Analyses of safety endpoints will be 
performed based on the AT Population. 
• 
The Dono r Liver Population will consist of all donor livers for which the 
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TransMedics Confidential 
OCS-Liver 092014 
potential recipient was randomized and which have preservation initiated using 
OCS or Control. Tn some of the analyses based on this population , livers will be 
analyzed as randomized; in others, the y will be analyzed as treated. For the 
analyses based on the actual treatment of the liver, a liver with some 
preservation with OCS and some with standard of care will be analyzed 
according to the initial preservation. 
Effectiveness Analysis 
The primary effectiveness endpoint for this study is Early Liver Allograft 
Dysfunction (EAD), defined as presentation of one or more of the following 
criteria: 
• 
AST leve l >200 0 ill /ml within the first 7 postoperative days; 
• 
Bilirubin 2:10 mg/dl on postoperative day 7; 
• 
INR 2:1.6 on postoperative day 7; or 
• 
P1imary non-functioning graft within the first 7 days 
The primary hypothesis for this study is that the OCS treatment is non-inferior to 
the standard of care treatm ent with respect to this endpoint. The non-inferiority 
margin 8 is taken to be 0.075. If non-inferiorit y is demon strate d using a 
significance level of 0.05, a two-sided test of superiority will be performed. 
The primary effectiveness endpoint will be analyzed by calculating, for each 
treatment group, the sample proportion of subjects meeting the primary 
effectiveness endpoint, as well as an exact (Clopper-Pearson) 
95% confidence 
interval for the corresponding population propo1tion. The 95% upper bound of the 
exac t unconditional one-sided confidence interval based on Farrington and Manning 
score statistic will be calculated for the difference between the two population 
propo1tions (OCS - Control). An upper confidence limit less than 8 = 0.075 will 
result in rejection of the null hypothesis in favor of the alternative hypoth esis and 
the demon stratio n of non-inferio rity of OCS to Control for the primary 
effectiveness endpoint. In the event non-inferiority is demonstrated, Fisher's exact 
test (two-sided) will be used to test for superio rity. 
This endpoint will be analyzed using the Per Protocol and mITT Population s. The 
Per Protocol analy sis will be considered the primary analysis. Multiple imputation 
methods will be used for data imputation for any patients with missing values for 
thi s endpoint. 
The secondary effectiveness and OCS donor liver assessment endpoints for this 
trial, listed in the order in which they will be tested using the fixed sequence testin g 
procedure , are as follows: 
• 
OCS Measurements during organ perfusion 
• 
Patient survival at day-30 post-transplantation 
• 
Patient survival at initial hospital discharge post liver transplantation 
The hypot hesis for the endpoint of OCS donor liver assessment durin g perfusion is 
that , among donor I ivers preserv ed using OCS for the entire preservation period, the 
propo1tion of liver s on which measurem ents of lactate level, average bile production 
rate, Hepatic Artery and Portal Vein Pressure during perfusion are ava ilable on OCS 
device before transplant is at least 85%. This endpoint will be analyzed by 
calculating the sample propo1tion of donor liver s meeting the endpoint, as we ll as 
an exact 95% one-s ided lower confidence bound for the corresponding population 
proportion. A lower confidence bound great er tha n 0.85 will result in the 
demonstration that the true proportion is greater than 0.85 for the OCS donor liver 
Page 8 of 63 

TransMedics Confidentia l 
Safety Analysis 
OCS-Live r 092014 
assessment endpoint 
Each secondary effectiveness endpoint will be summa rized using counts and 
percentages and an exact 95% confidence interval for the true percentage based on 
the binomial distribution. The secondary effectiveness endpoints will be analyzed 
using the PP and the mlTT Populations. The Per Protocol analysis will be 
considered the primary analysis. 
The primary hypothesis for the first seconda ry effectiveness endpoint is that the 
OCS treatment is non-inferior to the standard of care treatment. The non-infer iority 
margin is taken to be 0.075. Tbis endpoint will be analyzed by calculating the 95% 
upper confidence limit based on the normal approximation for the difference 
between the two population proportion s (Contro l - OCS). An upper confidence 
limit less than 8 = 0.075 will result in reject ion of the null hypothesis in favor of the 
alternative hypothesis and demonstration of non-inferiority of OCS to Contro l. In 
the event non-inferiority is demonstrated, Fisher 's exact test (two-sided) will be 
used to test for superiority. 
The second secon dary effectiveness endpoint, patient survival at initial hospital 
discharge post liver transplantation, will be analyzed in a manner analogous to the 
first seconda ry effect iveness endpoint with the same non-inferior ity margin of 
0.075. 
Beca use fixed sequence testing will be used for the seconda 1y endpoints, no 
adjustment for the multiplicity of these endpoints needs to be made. The endpoint s 
will be tested in the order listed above. The test for non-inferiority for the first 
secondary effectiveness endpoint will be performed only if the null hypothesis has 
been rejected for the OCS donor liver assessment endpoint. The test for non-
inferiority for the second seconda ry effectiveness endpoint will be perform ed only 
if the null hypot hesis has been rejected in favor of the alternat ive hypothesis ofnon -
inferiority of the OCS treatment to the Contro l treatment for the first secondary 
effectiveness endpoint. Similarly, the test for superiority for the second seco ndary 
effectiveness endpoint will be performed only if the nu LI hypothesis of equality has 
been rejected in favor of super iority of the OCS treatment to the Contro l treatment 
for the first secondary effectiveness endpoint (and non-inferiority has been 
demonstrated for the given seconda ry effectiveness endpo int). 
These endpoints will be analyzed using the Per Protocol and mITT Populations , 
with the Per Protoco l analysis being considered the primary analysis. Multiple 
imputation methods will be used for data imputation for patients with missing 
values for these endpoints. 
Safety will be analyzed principally by examinat ion of the frequency of liver graft-
related serious adverse events (SAEs) up to the 30-day follow-up after 
transplantation. This endpoint is defined as the average number of liver graft-
related serious adverse events through the 30 days post-liver transplantat ion per 
subject, consisting of the following serious adverse events (at most one per type per 
person): 
• Primary non-function (defined as irreversib le graft dysfunction requiring 
emergency liver re-transplantation or death with the first 10 days, in the 
absence of immunologic or surgica l causes); 
• Iscbemic biliary comp lications (ischemic biliary strictures , and non-
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TransMedics Confidential 
Randomization 
I 
Sample Size 
Determination 
OCS-Liver 0920 14 
anastomotic bile duct leaks); 
• Vascular complications (Liver graft -related coagulopathy , hepatic a1tery 
stenosis, hepatic artery thromb osis and portal vein thrombo sis); 
• Liver allograft infection s (liver abscess, cholangitis, etc.) 
This endpoint will be summarized by treatment group using descriptive statistics. 
For each treatment group, a 95% confidence interval for the mean based on the t-
distribution will be presented. Also, a 95% confidence interva l based on the t-
distribution wi ll be presented for the difference in means betw een the two 
treat ment s. 
For the number of liver graft-related SAEs, the hypo thesis is that the OCS treatment 
is non-inf erior to the standard of care tre atmen t. The non-in feriori ty ma rgin is taken 
to be 1.00. The safety endpoin t will be analy zed using a one-s ided , two-sample t-
test with an alpha level of0.05. If non-inferi ority is demonstrated , a corresponding 
(two-sided) test of sup eriorit y will be pe1formed. 
This endpo int will be analyzed based on the As Treated Population. 
In addition, the number s and percentages of subje cts experiencing at least one liver 
graft-rela ted AE, at least one ( definitel y or probably-related) device-related AE, at 
least one unanticipated AE, and at least one serious AE, and the number and 
percentage of death s wi 11 al I be tabulated by treatment group. Also, the number of 
liver graft- related adverse events and the number and percentage of subjec ts 
expe riencing liver graft -related adverse events wi ll be tabulated by system organ 
class and preferred term using MedDRA . A similar analysis will be perfo rmed for 
liver graft-related SAEs. AEs will also be tabulated at the event leve l by system 
organ class and preferred term and the relationship of the adverse eve nt to the 
device using counts and percent ages. Similar analyses wi ll be performed by the 
seve rity of the adverse event. 
The numbe rs and percentages of donor livers in the Donor Liver Population that are 
treated as randomized and transp lanted, treated not as randomized and transplanted, 
treated as randomi zed and not transplanted , and treated not as random ized and not 
tran splanted will be presented. For livers that are treated not as randomized , the 
reason will also be summarized using counts and percentages. 
Both of these 
ana lyses will be don e based on the randomiz ed treatment for the liver, but the 
fol lowing analyses wi ll be based on the actual treatme nt of the liver. For livers that 
are not transplanted , the reason(s) for non-t ransplan tation (including device failure) 
will be summari zed using counts and percentages. The numbe r and percentage of 
donor livers in the Donor Liver Pop ulatio n for which these was a device failu re will 
also be presented. 
After confomation of eligibilit y, obt aining informed consent , and a matc hing donor 
liver is identifi ed, potential liver transp lant recipients will be randomized 1 :I to 
have their donor livers preser ved using either the OCS Live r perfusion or the 
standard cold static preservatio n technique (Contro l) using cold flush and storage. 
Randomization will be performed through the Interactive Web Respon se System 
(TWRS). Subjects who are not tran splanted with the matching donor liver will be 
re-ra ndomi zed and treated as a new subiect. 
The samp le size for this trial was determined based on the effec tiveness endpo int, 
Early Liver Allograft Dysfunction (EAD) in the first 7 days post liver 
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TransMedics Confidential 
OCS-Livcr 092014 
transplantation. The sample size calculation assumed a non-inferiority , test based 
on the upper bound of the Exact unconditional one-sided confidence interval for the 
difference in proportions using Farrington and Manning score statistic. An alpha 
level of 0.05, a non-inferiority margin of 0.075, a 1: 1 allocation, true proportions for 
the primary effectiveness endpoint of0.2 for the OCS treatment and 0.25 for the 
Contro l treatment , and power of 80%. Based on these specifications, the required 
sample size was determined to be 144 transp lanted recipients per treatment group, 
or 288 total transplanted subjects. To ensure an adequate number of subjects in the 
Per Protoco l Population, the samp le size was increa sed to a total of300 transplanted 
subjects. Subjects will be enrolled until there are either 290 subjects in the Per 
Protocol Population or a total of 300 transplanted subjects, whichever comes first. 
Sample Size Re-
A sample size re-estimation will be performed for the purpose of confirming the 
estimation 
current sample size is sufficient for testing for non-inferiority for the primary 
effectiveness endpoint and to assess the feasibility of demonstrating superiority . It 
will be conducted after there are 200 transplanted subjects to allow for a possible 
upwards adjustment in sample size. The sample size will not be increased by more 
than 150 subjects. 
Trial Sponsor 
TransMedics , Inc. 
200 Minuteman Road , Suite 302 
Andover , MA, USA O 1810 
Page 11 of 63 

TransMedics Confidential 
OCS-Liver 092014 
1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Liver Transplantation and Current Clinical Challenges 
Over the last two decades liver transplantation has evolved as the gold standard for h·eating end-
stage liver failure disease and those with tumors of hepatic origin in the setting of liver 
dysfunction. The success ofliver h·ansplantation is now its primary obstacle, as the pool of 
donor livers fails to keep pace with the growing number of patients added to the national liver 
transplant waiting list. As of August 2014, there are nearly 16,000 patients listed on the U.S. 
national waiting list for liver transplantation, yet only 6,200 patients were transplanted in 2013 
depriving thousands of patients the gift of new Livers to treat their end-stage Liver disease, 
according to the Organ Procurement and Transplant Network (OPTN) 1 database. In addition, 
this significant discrepancy between supply and demand results in approximately 20% of patients 
either dying or becoming too sick to receive a liver transplantation (see Figure 1 below). 
Figure 1: 
U.S. National Liver Transplant Waiting List Dynamics 2009-2011. Source: OPTN 
2011/Scientific Registry of Transplant Recipients (SRTR) 2011 Annual Report: 
Transplant data 2011. 
2010 2011 2012 
Patients at start of year 
14,956 15,360 15,428 
Patients added during year 
10,349 10,359 10,143 
Patients removed during year 
9,925 10,272 10,281 
Patients at end of year 
15,380 15,447 15,290 
Removal reason 
Deceased donor transplant 5,450 
5,539 
5,468 
Livino donor transplant 
209 
187 
192 
Patient died 
2,458 
2,506 
2.187 14% 
Patient refused transplant 
53 
60 
73 
Improved, 
tx not 'needed 
552 
541 
644 
Too sick to transolant 
362 
482 
815 5% 
Other 
841 
957 
902 
-
----
-
The current teclmique for liver preservation using cold flush and storage of donor livers plays a 
major role in the above large and growing clinical problem in liver transplantation due to the 
following severe limitations: 
• It subjects the donor livers to significa nt time-dependent ischemic injmy 2'3 and 
subsequent reperfusion injury that may impair liver function post-transp lant. This 
causes h·ansplanting physicians to only select for procurement those Livers most 
likely to withstand the potential damage associated with cold storage preservation. It 
also imposes significant time and geographical limitations on the liver reh·ieval 
process, adversely impacting the utilization of available donor livers. In addition, this 
time-dependent ischemic injmy has been directly coll'elated to post- h·ansplant 
complications. 
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TransMedics Confidential 
OCS-Liver 092014 
• 
It lacks any perfusion capabilities to maintain the liver in a near-physiologic 4 (in-
vivo-like) environment after the donor liver is retrieved from the body of the donor. 
This limitation results in significant underntilization of the donor livers with fatty 
cells (macrosteatotic livers). This further limits the use of these donor livers that 
otherwise are functioning normally in the body of the donor. 
• 
It lacks any ability to evaluate organ metabolic state and function after procurement 
and preservation to determine the suitability of the donor Livers for transplantation 4 .• 
This significantly limits the utilization of donor livers that are subjected to the 
negative, non-physiologic conditions of brain death in the donor. More impo1tantly, 
it severely limits the utilization of donor livers classified as donors after circulatory 
death (DCDs). 
1.2. 
Potential Clinical Solutions to Overcome Limitation in Donor Liver 
Utilization 
Over the past 10+ years, there has been a global focus on ex-vivo organ perfusion in a near 
physiologic condition as a promising technique to overcome the cunent challenges in organ 
preservation and to potentially increase utilization of donor organs (liver, lung, heart and kidney) 
that are currently not used due to sho1tcomings of cold storage. 13 
Isolated liver perfusion has been extensively studied for over 25+ years using a variety of 
different perfusates and perfusion temperatures. More recently, there has been an international 
focus in the liver transplant clinical and scientific community on normothermic liver perfus ion 
using blood based perfusate to minimize the negative impacts of cold ischemic preservation on 
donor livers for transplantation. In addition, by maintaining livers in an active metabolic and 
functioning state, donor livers from hemt beating or DCD donors can be assessed ex-vivo for 
suitability for transplantation. 
The TransMedics ' Organ Care System (OCS™) Liver technology is a portable system for ex-
vivo perfusion and assessment of the donor Livers for transplantation. The OCS™ Liver 
maintains the donor liver in a metabolically active and functioning state (producing bile), by 
perfusing the liver with wmm oxygenated and nutrient enriched blood based perfusion solution. 
The OCS™ Liver is intended to significantly reduce ischernia and reperfusion injuries on the 
donor Livers and enable metabolic and functional assessment of donor livers to assess their 
suitability for transplantation . The OCS™ Liver may enable the following clinical advantages: 
• 
Reduction of the ischemia and reperfusion injuries on the donor Livers during 
preservation, thus, eliminating the significant logistical and geographical barriers to 
Liver transplantation that currently exist with cold storage preservation. 
• 
Optimization of donor Liver ex-vivo environment by optimizing oxygen and substrate 
delivery , while also maintaining nem· nmmotherrnic condition to avoid the negative 
impact of cold temperature on fatty livers. 
• 
Ex-vivo assessment of donor liver metabolic and functional state utilizing standm·d 
clinical tests of liver enzymes, bile production and lactate metabolism. This could 
enable the transplanting clinical team to judge the suitability of the donor liver for 
transplantation and substantially minimizing the risk of transplanting questionable 
donor Uvers into recipients. 
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TransMedics Confidential 
OCS-Liver 092014 
1.3. 
Subject enrollment and health insurance 
Approximate ly 30-40% of liver transplant recipients have their care paid for by Medicare due to 
their age or disability status. Therefore, it is expected that Medicare patients will consent to 
participate in this study. Since Medicare patients in need of transplantation do not differ from 
transplant candidates receiving coverage from other payors , Medicare patients will be treated in 
the same manner as all other study Subjects and will realize the same potential benefits and risks 
experienced by all other Subjects in the study. 
1.4. 
1.4.1. 
Summary of Prior Testing and Investigations 
OCS™ Liver Engineering Testing 
The OCSTM Liver device components have been CE marked for Heait and lung perfusion and 
TransMedics is currently in the process of expa11ding our CE mark indication for liver perfusion . 
The OCS™ system and perfusion modules have tmdergone extensive preclinical testing to 
demonstrate its safety, effectiveness, and readiness for clinical use. The Liver Perfusion Set has 
also been evaluated and tested in accordance with ISO-10993 "Biological Evaluation of Medical 
Devices," including evaluations for acute toxicity, irritation, sensitization, cytotoxicity, 
hemolys is, genotoxicity, and pyrogenicity. These test results demonstrated that the device and 
its materials are biocompatible and suitable for their intended use. The Liver Perfusion Set will 
be provided sterile using validated methods, and is appropriately packaged to maintain sterility. 
The OCS has also undergone extensive preclinical bench testing for: electrical safety; 
electromagnetic compatibility; and validation and verification testing (including validation of the 
device software). All tests and results have demonstrated that the OCS meets its expected 
performance specifications and is safe and suitable for clinical use. 
1.4.2. 
Independent Pre-Clinical Testing of Normothermic Machine Perfusion for 
Donor Livers 
Isolated liver perfusion has been extensively studied for over 25+ years using a variety of 
different perfusates and perfusion temperatures. More recently, there has been an international 
focus in the liver transplant clinical and scientific community on normothermic liver perfusion 
using blood based perfusate to mininlize the negative impacts of cold ischemic preservation on 
donor livers for transplantation. In addition, by maintaining livers in an active metabolic and 
functioning state, donor livers from DCD donors can be assessed ex-vivo for suitability for 
transplantation. The following is a summary of relevant clinical and scientific published studies 
supporting the concept of ex-vivo near-normothermic machine perfusion using blood-based 
perfusate for donor livers : 
• 
In 2001, Schon MR et al. 17 reported successful swine liver transplantation after 4 
hours of nonnothennic ex-vivo blood based perfusion of both the hepatic arte1y and 
po1tal vein. This report demonstrated that normothennic perfusion groups had better 
metabolic function and histological picture for livers that were immediately perfused 
after harvest as well as livers that were subjected to 1 hour of wann ischemia (to 
simulate DCD donors), prior to n01mothe1mic machine perfusion . The metabolic 
function of the liver was assessed ex-vivo by measuring serial AST , GGT levels (see 
Figure 2 below) as well as bile production. The perfusate mix used for this study 
consisted of: 
-
Swine blood 
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TransMedics Confidential 
OCS-Liver 092014 
-
Buffered electrolyte solution 
-
Heparin 
-
NaHCO3 for buffers 
Figure 2: 
Sl1on et al, AST and GGT levels during 4 hours of ex-vivo machine perfusion for 
group 3= heart beating swine livers and group 6= DCD swine livers. 
700 
500 
000 
-H 
--0-- group 3 
400 
-6-
group6 
600 
300 
400 
~ 300 
,k--
! 200 
200 
100 
,_ 
"! 
-11 
Iii 50 ~ 
~ 
40 r 
~ 40 
< 
30 
20 
20 
10 
0 
0 
ti 
~ 
~ .. ~ 
._'<> 
'I,"' 
,.,.,,. ~"' 
ti 
·S-
~~ 
·S-
.._'<> 
n,"' ,.,., "'"' 
., 
._<, 
,§> 
"fl 
.i, 
,§>fl 
• 
In 2002, Butler AJ, Friend PJ, et al.6 reported successful extracorporeal porcine liver 
perfusion for up 72 hours using swine blood as perfusate. The swine livers were 
perfused by cannulating the hepatic artery and the portal vein. Liver metabolic 
function was well preserved as evidence of stable pH of the perfusate, stable ALT and 
alkaline phosphatase levels (see Figure 3 below). In addition, bile production was 
well maintained up to 10 hours of perfusion , then significantly dropp,ed due to lack of 
bile salts/acids in the circuit and bile sludge noticed/repmied by the author. The 
perfusate mix used for this study consisted of: 
-
Swine whole blood 
-
Colloid solution 
-
Antibiotics 
-
Methylprednisolone steroid 
-
NaHC0. 3. for buffer 
-
Heparin 
-
Vitamins and trace elements 
-
Prostacyclin for vasodilatation 
-
Calcium chloride 
-
Taurocholic acid for bile salts 
-
Parenteral nutrition solution supplemented with amino acids 
-
Insulin 
l'age 15 of63 

TransMedics Confidential 
OCS-Liver 092014 
Figure 3: 
A •• ,---
---
----
• 
II 
;., 
)U 
1• 
~} 
fl,) 
I ll 
,0 
• 
Ill 
i';I 
>• 
,. 
Fig. 3 
. l\lau·kcrs of liver lnjw-y nud ruuctiou 
Cn= 61 during 1!>'.Crncorporenl liver perruslon. 
CA) ALT (se1·u01 gluCnmic py.-u,i c 
lrnn snruiunsl! ) le vels (normnl porcin e rang e 31-68 UIL ) nnd nlknlin c pho"J'hn(ns
c lc,·cls (normal porcin e rang e 180-813 U/L ). 
Ul> Dile output mcnsured os ml of bile produced per hour ond tol.ol hilirubin expres sed in 1.cmoVL (normal porcin e rnnge up 
lo 0-17.1 µmol/LI . CC) Orygeu consumption 
c ulc ulu1ed by Urn Fl ek <--quutlou nnd expr ess ed us ml O,lmln/Uvcr. 
• 
In 2009, Brachman J., et al.7 repmted the successful preservation of hemt beating and 
DCD swine livers using blood based, no1mothermic ex-vivo machine perfusion for 
up-to 20 hours and subsequent transplantation. This study demonstrated a clear trend 
towards better liver function in the normothermic perfusion groups as compared to 
cold storage for both heart beating and DCD livers. In addition, this report suggested 
that bile production; AST levels and portal vein pressure as potential ex-vivo 
perfusion predictors for post-transplant viability in pigs. The perfusate mix used for 
this study consisted of: 
Swine whole blood 
Colloid solution 
Antibiotics 
Methylprednisolone steroid 
NaHCO.3. for buffer 
Heparin 
Vitamins and trace elements 
Prostacyclin for vasodilatation 
Calcium chloride 
Tamocholic acid for bile salts 
Parenteral nutrition solution supplemented with amino acids 
Insulin 
• 
In 2011, Fondevila, et al. 8 reported successful transplantation of swine DCD livers 
after 90 minutes of cardiac an-est by using ex-vivo normothermic blood based 
perfusion (NMP) of donor swine livers. This repo1t demonstrated that when 
nonnothermic ex-vivo perfusion was used it resulted in 100% survival of the swine 
post-transplantation as compared to 83% when in-vivo NMP was used and 0% when 
cold storage was used. This report demonstrated good histological pictures of all 
Page 16 of63 

TransMedics Confidential 
OCS-Liver 092014 
livers perfused using ex-vivo normothennic blood based perfusion. The perfusate 
mix used for this study consisted of: 
-
Swine whole blood 
NaHCO3 for buffer 
Heparin 
• 
In 2014, Liu Q, et al.9- 11 reported that n01mothermic machine perfu sion (NMP) is 
superior to cold storage (CS) for preservation of swine DCD livers after 10 hours of 
preservation followed by simulated transplantation. This study evaluated ex-vivo 
liver enzymes during NMP as well as perfusion parameters ; hepatic a1tery and pmtal 
vein flow and pressure as signs of liver metabolic activitie s (see Figme 4 below). 
During simulated transplantation phase , liver function was assessed using liver 
enzyme levels as markers to hepatocellular injury and showed clear advantage of 
NMP vs. CS (see Figure 5 below). The perfu sate mix used for this study consisted of: 
Swine whole blood 
-
Colloid solution 
Antibiotics 
Methy lprednisolone steroid 
-
NaHCO 3 for buffer 
Heparin 
-
Prostacyclin for vasodilatation 
-
Calcium Gluconate 
-
Taurocholic acid for bile salts 
-
Parenteral nutrition solution supplemented with amino acids 
-
Insulin 
Figure 4: 
Enzyme release during NMP 
1000 
aoo I 
____ 
• __ ___.._,,. 
----- · 
-· -
+ AST 
~ 600 I 
•✓ • ·• 
___. 
_ ______...--t • ALT 
400 ,/
, .,,.,,---
j 
1 
• 
LOH 
200 ~ 1· 
0 '-
~
~--
-
-~ ,. 
NMP lime (hours) 
Flows and Pressures during NMP 
100 
0 ,._ 
g~ 
so 
~E 
:, S 60 
.s t! 
5; 40 
E; 
icl: 20 
£ 
0 
, 
.--• ___ 
_..- .1.- _co
,.. 
0 ~---
• 
' 
• ---
-----
--
-
IO 
NMP time (hours) 
+ HA flow 
.,_ PV nO\Y 
• 
HApr enur ~ 
-
PVpreuure 
F_ig, 4 
~nzyme release a.nd heruodynamlcs durtn g NMP. 111c enzymes 1n the perfusalc Increased ma.Inly during the early phnsc of 
NMP and then gmdwilly reached a plateau . TI1c mean HA and PV prcs~W"CS and nows were stable during the entire NMl' phase. 
Page 17 of6 3 

TransMedics Confiden tial 
OCS-Liver 092014 
1.4.3. 
Figure 5: 
AST 
COO() 
iiO'JO -H•-rt-
<000 
§ 30» 
20)0 t,,,1--+-
1000 
0 
- . --- . • 
• 
• 
11 
24 
0 
0 
10000 
LOH 
:lOO 
F>"-o
.oia 
250 
200 
-t
/ 
j 
.. - I 
2();0 
• -../ 
e Hso 
100 
r 
0 
• 
- • -
• -
· -
• --
• 
0 
12 
hours 
18 
.....-cs group 
---- NMP group 
ALT 
•- ·- •-
• 
-
- • 
12 
18 
24 
Bile production 
I 
P=O.OOt 
- -• 
j 
-+ 
I 
~ 4" 
.. 
hour, 
Fig, 5 
OuU'0llff 
(» htp3 l~llul.u 
Inj ury and bl!(' produrUoo durtftt rtpul\J.Jloo. 1bt CS·ptt.K.I'\~ Uvus had slg,1!.lk.ultly hlgJ1w 
ASr, ALT, nnd LOH le'\•lli In U1'"' perfuw..e (P < O.05) n.ud much leu bU'"' prod uetJon tn ttlfUp;ttl.Son With Uu: r,.'M P•pRR.n'l'd l!l•rrs nft('r 
rt:o.t.JfUjlO ll. 
OCS™ Liver Pre-Clinical Testing 
The OCS™ Liver System has been extensively tested in the large swine animal model and has 
demonstrated excellent results in maintaining liver function ex-vivo. The OCS liver preclinical 
testing was conducted in two distinct phases/steps. 
1.4.3.1. 
• 
Phase 1 Ex-vivo OCS Liver Perfusion for up-to 12 hours 
28 consecutive large swine studies were conducted using ex-vivo OCS Liver 
perfusion to maintain livers for up to 12 hours. The perfusate used to perfuse these 
28 livers was identical to the one described in the publi shed scientific and clinical 
literatm e above. The OCS perfusat e consisted of: 
Swine washed blood cells 
-
Colloid solution using 25% albumen 
-
Buffered crystalloid solution (PlasmaLyte™) 
-
Antibiotic s (gram negative and gram positive coverage) 
-
Steroids - methylpredni solone and dexamethasone 
-
NaHCO .3. for buffer 
-
Heparin 
-
Calcium Gluconat e 
-
Vitamins and trace elements 
-
Parenteral nutrition solution supplemented with amino acids 
-
Insulin 
Page 18 of6 3 

TransMedics Conlid ential 
OCS-Liver 092014 
-
Prostacyclin for vasodilatation - as needed 
-
Taurocholic acid for bile salts - as needed 
• 
Liver function on OCS was evaluated using the identical parameters that were 
described in the above published independent scientific and clinical literature: 
-
Perfusion parameters - Hepatic Aliery Pressure (HAP); Po1ial Vein Pressure 
(PVP) 
-
Markers of liver injury: Liver enzymes 
-
Marker of liver metabolism: Lactate level 
-
Marker for liver function: Bile production 
-
Histopathology to evaluate parenchymal and bile duct injury 
Figure 6: 
OCS Liver perfusion paramete1·s over 12 hours of ex-vivo perfusion demonstrating 
CD 
:r: 
E 
.§. 
C. 
cl: 
:r: 
stable and near physiologic HA and PV pressures 
120 ~----------------
-
-
-
-------~ 
6 
OCS Liver Perfusion Parameters (mean± SE) 
20 -+------
--1
- - -
-
- -
-
-
5 
CD 
:r: 
E 
4 .§. 
C. 
~ 
3 
o--~-~-~~-~-~-~--~-~-~-~--~----
2 
0 
60 
120 
180 
240 
300 
360 
420 
480 
540 
600 
660 
720 
OCS Liver Perfusion Time (min.) 
~
Hepatic Artery Pressure (HAP) 
~
Portal Vein Pressure (PVP) 
Page 19 of63 

TransMedics Confidential 
OCS-Liver 092014 
Figure 7: 
Donor liver AST levels during OCS Liver perfusion demonstrating a positive trend 
towards base line (BL) levels indicating normal liver function and no evidence of 
injury. Lactate levels trending down indicating normal liver metabolic function and 
a sign of adequate perfusion 
250 -r----------------, 
5.0 ~-------------~ 
~ 150 
g 
AST level on OCS (mean:!: SE) 
OCS Liver Lactate Level (mean :!: SE) 
4.5 +------------------! 
4.0 
:; 15° 
3.0 _,_ __
___ __ 
....., _______ 
_, 
E 
~ 100 •l- _..--------
-1-- -- -1 
.§. 2.5 --
•·-----
-- --
-----< 
:i 
fl 
~ 2.0 
Figure 8: 
50 +- -+ -------------
-! 
BL 
2Hr 
4Hr 
6Hr 
8Hr 
l0Hr 
12Hr 
0.0 -~---~----------.--< 
BL 0.5Hr 2Hr 
4Hr 
6Hr 
8Hr 
l0Hr 
12Hr 
OCS Liver Perfusion Time (hours) 
OCS Liver Perfusion Time (hours) 
Total bile production during OCS Liver perfusion measured hourly showing steady 
and consistent bile production by the liver indicating that liver function is well 
maintained 
300 
Total Bile Production on ocs (mean ± SE) 
250 
"in 
e 200 
C 
0 
~ 150 
,:s 
0 a: 100 
~ 
iii 
·so 
0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
OCS Liver Perfusion Time (hours) 
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TransMedics Confidential 
OCS-Liver 092014 
Figure 9: 
Histological examination of A) Parenchymal tissue and B) Bile duct tissue shows 
normal liver sinusoidal structure with no evidence of necrosis or ischemia and 
normal bile duct epithelial cells indicating adequate perfusion and lack of ischemic 
injury after 12 hours of OCS Liver machine perfusion 
1.4.3.2. 
Phase 2 Simulated Transplants After OCS Liver Perfusion: 
This group of studies focused on evaluating donor swine liver in a simulated transplant model 
after 8 hours of ex-vivo OCS Liver perfusion using identical perfusate to the one used in Phase 1 
OCS pre-clinical studies above. The simulated transplant procedure used whole blood from a 
different animal without any modifications and livers were studied for 4 hours in the simulated 
transplant condition. Liver function was assessed using identical parameters to the ones 
measured in Phase 1. Post-transplant histological samples were evaluated in an identical fashion 
to the phase 1 animal studies, looking at both liver parenchyma and bile duct samples. Below 
are the summary results of these simulated transplanted studies. 
Figure 10: 
OCS Liver preservation and post-transplant perfusion parameters demonstrating 
stable and neat· physiologic HA and PV pressures and stability of perfusion 
OCS liver Perfusion Parameters (mean ± SE) 
120 ~-----------'-----'-------.-
6 
100 
~80 
E 
!,60 
Q. 
<( 
J::40 ·1-------------
-~ 
4 
3 
20 +-----------
--
--
-1· 1 
o +--..-,--,--,--,--,--,--,--,-..-,--,--,--,--,-~
o 
10 
60 
110 
160 
210 
260 
310 
360 
410 
460 
OCS Uver Perfusion Time (min.) 
J: 
E 
.§. 
~ 
Q. 
..,_ Hepatic Artery Pressure (HAP) 
120 
100 ·-
5 
_ 
80 .. 
J: 
E 
!_ 60 
Q. 
<( 
J: 40 
J: 
E 
------------------+ 
3E 
0.. > 
+--------------
---<· 2 0.. 
20 +---------------
1 
10 
60 
110 
160 
210 
OCS liver Perfusion Time (min.) 
..,.
Portal Vein Pressure (PVP) 
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TransMedics Confidential 
OCS-Liver 092014 
Figure 11: 
OCS Liver preservation and post-transplant AST liver enzyme levels showing a 
positive trend towards base line (BL) levels indicating normal liver function aDd no 
evidence of injury. 
Figure 12: 
6 
2S0 .----------------, 
250 ,--
--
-------------
AST Level on OCS (mean ±SE) 
Post Tx. AST Level (mean ±SE) 
200 -!-----------------
1S0 
l 
~-
T 
T 
~ 
T 
I;; 100 
I 
I 
I 
<( --
~ 
.L 
.I. 
50 •- --
---------------< 
so 
o~~------------~_, 
o~-------~--~--~~ 
BL 
2hr 
4hr 
6hr 
8hr 
0.5hr 
1hr 
2hr 
3hr 
4hr 
ocs UVer Perfusion 
Time Hour 
OCS Uver Perfusion 
Time Hour 
OCS Liver preservation and post-transplant Lactate levels showing a Lactate levels 
trending down indicating normal liver metabolic function and a sign of adequate 
perfusion. 
OCS-Llver lactate level (mean ± SE) 
6 
Post Tx. lactate level (mean± SE) 
s +------------------i 
5 
4 
? 
0 
E 3 
.§. 
:J .. 
t: 
2 
!I 
1 . 
o~~- - ------------..--< 
BL 
O.SHr lHr 
2Hr 
3Hr 
4Hr 
SHr 
6Hr 
7Hr 
8Hr 
0 
BL 
15 min 
1hr 
2hr 
3hr 
4hr 
OCS Liver Perfusion llme (Hour) 
ocs Liver Perfusion llme (Hour) 
Page 22 of 63 

TransMedics Confidential 
OCS-Liver 092014 
Figure 13: 
Figure 14: 
Total bile production during simulated transplant measured houl'ly showing steady 
and consistent bile production by the liver indicating that liver function is well 
maintained 
120 -
Total BIie Production on OCS (mean± SE) 
100 
.ii' 1 80 
C 
0 'fl 60 
::I 
"Cl 
0 .. 
Cl. 40 
~ 
iii 
20 
0 
0 
1 
2 
3 
4 
5 
Simulated Transplant (hours) 
Histological examination of A) Parenchymal tissue and B) Bile duct tissue shows 
normal liver sinusoidal structure with no evidence of necrosis or ischemia and 
norma·l bile duct epithelial cells indicating adequate perfusion and lack of ischemic 
injury after 8 hours of preservation on OCS liver system, 45 minutes of cold storage 
and 4 hours of simulated h·ansplantation 
In addition, we have compared the OCS arm to a control arm of 8 hours cold stored swine livers 
using standard of care cold preservation solution. The control arm was also assessed in a 
simulated animal transplant model identical to the one described above. Liver function was 
assessed using identical parameters to the ones measmed in Phase 1. Below are the summary 
results of the OCS vs. Control group during simulated transplant phase. 
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TransMedics Confidential 
OCS-Liver 092014 
Figure 15: 
Lactate and AST levels fo1· OCS vs. Control arms during 4 hours of simulated 
transplantation. 
The data demonstrates that OCS perfused swine live1·s had a 
:::; 
...... 
0 
E 
.§. 
.l!l 
tl 
!I 
10 -
9 
8 
7 
6 
5 
4 
3 
2 
1 
0 
0 
significantly better metabolic function, as evidenced by their ability to metabolize 
Lactate to baseline levels as compared to cold stored livers where lactate continued 
to rise to significantly high levels. In addition, the OCS perfused swine livers had a 
significantly lower AST levels throughout the 4 hour transplant phase as compared 
to rising level of AST in the cold storage group. This indicates significantly less liver 
injury to the graft in the OCS group as compared to the cold stored group. 
Simulated Transplant Lactate Levels 
(mean± SE) 
30 
60 
90 
120 150 180 210 240 270 
Simulated Transplant Time (min) 
1400 
1200 
1000 
< 800 
2. 
~ 600 
400 
200 
0 
·I--
Simulated Transplant AST Levels 
(mean± SE) 
-
,---
~ 
~ 
~ 
-
-
-
-
~ -
0 
30 
60 
90 
120 150 180 210 240 270 
Simulated Transplant Time (min) 
-
cold Storage Group (n=6) -
ocs Perfusion Group (n=6) 
-
cold Storage Group (n=G) 
-
ocs Perfusion Group 
Page 24 of6 3 

TransMcdics Confidentia l 
OCS-Liver 092014 
Figure 16: 
Total Bile Production for OCS vs. Control arms during 4 hours of simulated 
transplantation. 
The above graph demonstrates that OCS perfused swine livers had 
a higher bile production rate as compared to Cold stored livers. This indicates 
better liver graft function in the OCS group vs. Cold group 
1.4.4. 
160.0 
140.0 
120.0 
100.0 
::. 
.§. 80.0 
., 
iii 
60.0 
40.0 
20.0 
o.o 
Simulated Transplant Total Bile Production 
(mean± SE) 
1 Hr STX 
2 Hr STX 
3 Hr STX 
4 Hr STX 
OCS Perfusion Time (hours) 
---
Total Bile - Cold Arm 
~
Total Bile - OCS Arm 
Clinical Feasibility Testing of Ex-vivo normothermic Liver Perfusion: 
In 2014, Friend P, et al. repmted the successful clinical feasibility of normothermic machine 
perfusion in 20 clinical liver transplants in a UK trial using the Metra liver perfusion device. The 
Metra device shares identical characteristics to the OCS Liver perfusion device. In addition, the 
donor inclusion criteria represented a mix of routine, DCD and steatotic donor livers which is a 
true reflection of current realities in clinical liver transplantation. More importantly, this study 
used an identical cellular perfusate and additives to the one described in the scientific/clinical 
literatme and the OCS Liver perfusate. It included: 
• 
Type specific packed red blood cells (pRBCs) 
• 
Colloid solution 
• 
Buffered crystalloid solution 
• 
Antibiotics (gram negative and gram positive coverage) 
• 
Methylprednisolone steroid 
• 
NaHCO.3. for buffer 
• 
Heparin 
• 
Vitamins and trace elements 
• 
Prostacyclin for vasodilatation 
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• 
• 
• 
• 
Calcium chloride 
Tamocholic acid for bile salts 
Parenteral nutrition solution supplemented with amino acids 
Insulin 
The summmy clinical results me presented in the table below. 
OCS-Liver 092014 
Friend, et al. Reported ClinicaJ Outcomes 
Normothermic 
Cold Storage Matched 
Machine Perfusion 
Control 
30-Day graft survival, n (%) 
20 (100%) 
37 (97.5%) 
30-day patient survival, 11 (%) 
20 (100%) 
J (97.5%) 
3-month patient survival, 11 (%) 
20 (100%) 
39 (97.5%) 
Primary non-function rate 
0 (0) 
0 (0) 
Ear ly Allograft Dysfunction , n (%) 
3 (15%) 
9 (22.5%) 
Peak AST within 7 days, (IU/L), median 
417 
902 
(range) 
(84-4681) 
(218-8786) 
Initial Post-Tx. ICU stay (days), median 
3 (1-8) 
3 (1-41) 
(range) 
Hospital Stay (days), median (range) 
12 (6-34) 
14 (8-88) 
Source: Rising Star Symposium, international Liver Transplant Society, June 5, 2014, London, England; Abstract 0-1 , Human 
Liver Transplantation Using Normothennic Machine Preservation, Friend P, et al. 
Sunrise Symposia; New Dimensions in Liver Transplantation, 
World Transplant Congress, July 31, 2014, San Francisco, CA, 
U.S.A.; Nonnothermic Machine Preservation 
of the Liver, Friend P, et al. 
Based on the above overwhelming supportive pre-clinical , scientific and clinica l evidence of 
safety, feasibility and potential benefits of wmm machine perfusion for liver transplantation 
using identical perfusion protocols/perfusates to the OCS liver technology, we m·e proposing to 
proceed with a pivotal prospective clinical investigation of the OCS liver technology to compare 
its outcomes to cold static storage in liver transplant recipients. 
2. 
DEVICE DESCRIPTION 
The OCS™ Liver System is an integrated portable platform designed to maintain donor Livers in 
a near physiologic , nmmothermic perfusion state . The OCS™ Liver System consists of: 
• 
• 
The Portable Console & Monitor: This is a compact electromechanical device that 
contains an integrated pulsatile perfusion pump, batteries, blood warmer, pressure , 
flow and saturation meters. In addition, it has an integrated wireless monitor that 
allows the clinical operator to control and display critical perfusion pm·mneters of the 
preserved donor Livers. 
Single Use Sterile Perfusion Set: At the core of the OCS™ Liver is a sterile, 
biocompatible perfusion module that maintains the organ's physiologic environment 
m1d has embedded sensors to optimize and monitor the Liver perfusion parameter s 
and bile production. In addition, the perfusion module enables perfusate sampling in 
order to monitor the Liver's metabolic condition. 
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OCS-Liver 092014 
Figure 17: 
System Components 
3. 
TRIAL OBJECTIVES 
To compare the safety and effectiveness of the OCS™ Liver (OCS) vs. standard cold storage 
(Control) to preserve and assess donor Livers having one or more of the following 
characteristics: 
• 
Donor age 2:40 years old; or 
• 
Expected cross clamp time 2:6 hours; or 
• 
Donor after circulatory death (DCD) with age :S55 years old; or 
• 
Steatotic liver >0% and :S40% macrosteatosis at time ofretrieval ( on pre-retrieval 
histology) 
3.1. 
Type of the Trial 
A prospective, multi-center , randomized, controlled Phased Pivotal trial with transplanted 
recipients assigned to either the OCS Liver arm (OCS - treatment) or standard of care cold 
storage mm (SOC - control). The trial will have two pmts . (Pait A rolling into large Pait B, 
assuming stopping rule is not triggered): 
• 
Pait A: Include the first 20 randomized transplanted liver recipients with pre-
specified stopping rule to ensme safety; 
• 
Pait B: assuming no stopping rnle was triggered , the trial emollment will continue 
beyond the initial 20 transplanted recipients in Pait A into Pait B, while the data from 
the first 20 subjects is being reviewed. All of the final analyses of the study will be 
based on the pooled data from Parts A and B. 
3.2. 
Trial Size and Subject Follow-up 
This trial will be conducted at no more than 25 institutions, in the United States and worldwide 
(Europe , Australia and Canada) and will include up to 300 transplanted Liver recipient s. The 
number of subjects was determined as described in the statistical analysis section ohhis 
Investigational Plan/Protocol. All subjects will be followed for a minimum of 30 days post-
transplant Patients will be followed for a maximum of 24 months from the date of 
transplantation. The summary of the follow-up is in Appendix 2 as follows: 
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• 
AH subjects will be followed from transplant to discharge 
• 
30-day patient and graft survival will be documented on day-30 post-transplant eCRF 
• 
6, 12, and 24 months patient follow-up 
4. 
TRIAL ENDPOINTS 
4.1. 
Primary Effectiveness Endpoint 
Incidence of Early liver Allograft Dysfunction (EAD) or primary non-function, defined as 
presence of one or more of the following criteria: 
• 
AST level>2000 IU/ml witrun the first 7 postoperative days; 
• 
Bilirubin ~10 mg/dl on postoperative day 7; 
• 
INR ~1.6 on postoperative day 7; or 
• 
Primary non-functioning graft within the first 7 days 
4.2. 
Secondary Effectiveness and OCS Donor Liver Assessment 
Endpoints 
• 
OCS Measurements during organ perfusion 
• 
Patient survival at Day 30 post-transplantation 
• 
Patient survival at initial hospital discharge post liver trnnsplantation 
4.3. 
Other Endpoints 
• 
Length of initial post-transplant ICU stay 
• 
Length of initial post-transplant hospital stay 
• 
Evidence of ischemic biliary complications diagnosed at 6 and at 12 months post-
transplant 
• 
Extent of reperfusion syndrome as assessed based on the rate of decrease of lactate 
over the following time points: 
-
During anhepatic phase immediately before reperfusion of the transplanted liver 
-
30-40 minutes after hepatic artery and portal vein reperfusion of the transplanted 
liver 
-
90-120 minutes after reperfusion of the transplanted liver 
• 
Pathology sample score for liver tissue samples taken at the following time points 
(applies to both OCS and Control arms): 
-
Donor liver pre-retrieval 
-
Post-OCS and Control preservation at the end of back preparation and 
immediately before the start of re-implantation 
-
90-120 minutes after reperfusion of the transplanted liver 
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4.4. 
Safety Endpoint 
Safety will be analyzed principally by examination of the frequency of liver graft-related serious 
adverse events (SAEs) up to the 30-day follow-up after transplantation. This endpoint is defined 
as the average number ofliver graft-related serious adverse events through the 30 days post-liver 
transplantation per subject, consisting of the following serious adverse events (at most one per 
type per person): 
• 
Primary non-function (defined as irreversible graft dysfunct ion requiring emergency 
liver re-transplantation or death with the first 10 days, in the absence of immunologic 
or surgical causes) 
• 
Ischemic biliary complications (ischemic biliary strictures, and non-anastomotic bile 
duct leaks) 
• 
Vascular complications (Liver graft-related coagulopathy , hepatic artery stenosis, 
hepatic artery thrombosis and p01tal vein thrombosis) 
• 
Liver allograft infections (liver abscess, cholangitis, etc.) 
5. 
TRIAL POPULATION 
The trial will include 300 Liver transplant recipients , at up to 25 investigational sites in the USA 
and worldwide (Europe, Australia and Canada). 
5.1. 
5.1.1. 
Donor Eligibility Criteria 
Donor Inclusion Criteria 
Donor liver meets at least one of the following: 
5.1.2. 
• 
Donor age 2:40 years old; or 
• 
Expected total cross clamp/cold ischemic time 2:6 hours ; or 
• 
Donor after circulatory death (DCD) with age ~55 years old; or 
• 
Steatotic liver >0% and ~40% macrosteatosis at time of retrieval (based on retrieval 
biopsy readout only if the donor liver was clinically suspected to be fatty by the 
retrieval surgeon at time of liver retrieval) 
Donor Exclusion Criteria 
Donor Livers will be excluded if they meet any of the following criteria: 
• 
Living donors 
• 
Liver intended for split transplants 
• 
Positive serology (HIV, Hepatitis B surface antigen & C) 
• 
Presence of moderate or severe traumatic liver injury, or anatomical liver 
abnormalities that would compromise ex- vivo preservation of the donor liver (i.e., 
accessory blood vessels or other abn01mal anatomy that require surgical repair) and 
livers with active bleeding (e.g., hematomas) 
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• 
Donor livers with macrosteatosis of> 40% based on retrieval biopsy readout 
5.2. 
Recipient Eligibility Criteria 
5.2.1. 
Recipient Inclusion Criteria 
Recipients are required to meet all the following criteria on the day of transplant: 
• 
Registered primary Liver transplant candidate, male or female 
• 
Age 2:.18 years old 
• 
Signed: 1) written informed consent document and 2) authorization to use and 
disclose protected health information 
5.2.2. 
Recipient Exclusion Criteria 
Recipients will be excluded if they meet any of the following criteria on the day of transplant: 
• 
Acute, fulminant liver failure 
• 
Prior solid organ or bone ma.iTow transplant 
• 
Chronic use of hemodial ysis or diagnosis of chronic renal failure, defined as chronic 
serum creatinine of>3 mg/dl for >2 weeks and/or requiring hemodialysis 
• 
Multi-organ transplant 
• 
Ventilator dependent 
• 
Dependent on > 1 IV inotropic support to maintain hemod ynamics 
6. 
PRE-OPERATIVE TRIAL PROCEDURES 
6.1. 
Subject Identification 
All patients on the liver transplant waiting list who a.i·e being treated by trial investigators will be 
identifie d. Those patients who initially appear eligible for the trial will have the trial thoroughly 
explained to them , be invited to participate, and will be asked to sign an info1med consent for 
pa.iticipation in the trial prior to treatment. When a matching donor Liver becomes available , the 
inclusion and exclusion criteria will be re-verified. When a final decision is made at the 
recipient site to transplant the Liver , the recipient will be assigned a subject identification 
number. 
6.2. 
Recipient Day of Transplant Assessment 
The purpose is to conduct a final assessment of whether the potential consent ed recipient still 
meets the eligibility criteria. The following infmmation will be verified and recorded on the day 
of transplant: 
• 
Eligibility: Investigator will review and confnm that the potential consented 
recipient continues to meet all inclusion criteria and no exclus ion criteria. 
• 
Demographics/Characteristics: 
-
Date of birth or Age 
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-
Gender, body mass index 
-
Race and Ethnicity 
-
Blood type and RH factor 
-
Recipient Model for End-stage Liver Disease (MELD) Score 
-
Recipient ID 
• 
Baseline Liver Function Tests: 
Bilirubin levels 
-
Aspartate aminotransferase (AST) 
-
Alanine aminotransferase (ALT) 
-
Gamma-glutamyl transpeptidase (GGT) 
-
Alkaline phosphatase 
-
International normalized ratio (INR) 
-
Serum Lactate level 
• 
Recipient Risk Factors & Medical History: 
-
Indication for transplantation: The primary etiology of Liver failure will be 
recorded 
-
History of Hepatitis C 
-
Histmy of liver cancer 
-
Histmy of diabetes 
6.3. 
Donor Screening and Acceptance 
Using the inclusion and exclusion criteria, the investigator or a member of her/his transplant 
team will evaluate the donor and the quality and suitability of the Liver for the trial. The 
following evaluations will be conducted and recorded: 
• 
Organ Donor Identification Number and Type of Registry ( e.g. UNOS ID, 
Eurotransplant ID, etc.) 
• 
Demographics: Age, Date of birth (if available), gender, race, and ethnicity 
• 
Donor Characteristics: Blood type & RH factor, body mass index 
• 
Donor's Cause of Death: 
-
Cause of death and date and time of pronouncement of brain death 
-
If the donor is a DCD donor, total time in minutes from discontinuation of support 
to cardiac stand still 
• 
Medical History: 
-
Active infection, positive serology for CMV, HIV, Hepatitis B or C, malignant 
tumors, and Liver disease 
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OCS-Liver 092014 
-
History of diabetes (if available) 
• 
Donor Liver Assessment: The donor Liver will be assessed p1ior to procurement 
and acceptance using the following methods: 
-
Liver Enzymes : the following tests will be collected if available: 
• 
Bilirnbin levels; 
• 
Aspmiate aminotransferase (AST); 
• 
Alanine aminotransferase (ALT); 
• 
Gamma-glutamyl transpeptidase (GGT); 
• 
Alkaline phosphatase; 
• 
International no1malized ratio (INR); 
• 
Lactate level ; 
-
Liver Biopsy (see Appendix L): A needle biopsy will be collected from all 
donor livers at time of retrieval at time of cross clamp in the donor . Only donor 
livers that are clinically suspected to be fatty by retrieval team visualization, will 
require a pre-retrieval biopsy readout to estimate the degree of macrosteatosis and 
confitm eligibility (>0 and .'.S40% macrosteato sis). 
• 
Eligibility: The donor will be evaluated to document whether the eligibility criteria 
are met. All eligibility criteria for not accepting a donor Liver at final assessment 
before retrieval will be recorded. Any other clinical reasons for not accepting donor 
liver at final assessment before retrieval will be recorded . 
6.4. 
Donor Liver Retrieval and OCS Preservation and Assessment 
After final evaluation of the donor Liver in donor's abdomen and upon acceptance into the trial, 
the investigators will retrieve and preserve the donor Liver according to the following proto col: 
• 
Initial Liver Flush in Donor Body: all donor Livers will be flushed using cold 
Belzer UW® solution or Custodio!® HTK preservation solutions according to the 
institution 's standmd of care practice and the manufacturer instruction for use. 
• 
OCS Liver Back Table Flush: All donor livers randomi zed to be perfused on OCS 
Liver system will be flushed on the back table using cold PlasmaL yte® solution 
supplemented with sodium bicarbonate (NHCO3) 10 mml/L, Epoprostenol Sodium 2 
mics/L , and Methylprednisolone ~ 160 rng/L flush below , according to the followin g 
protocol: 
-
Hepatic Artery : 1 liter flush at ~50-70 rnmHg pressme bag 
-
Po..tal Vein: 2 liters gravity drain 
• 
OCS™ Liver Perfusion: The OCS™ Liver system will be primed using the 
following: 
OCS Li-ver Perfusate Composition 
Recommended Dose 
Packed Red Blood Cells (pRBCs)* 
4-8 units 
Albumin 25% 
400 mis 
PlasmaLyte® solution 
700-800 mis 
Methy I predn isolone 
500 mgs 
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OCS Liver Perfusate Composition 
Recommended Dose 
Dexametha sone 
20 mgs 
Sodium Bicarbonate (NaHC0. 3.) 8.4% 
70mmol 
Adult Multi vitamin s for infusi on 
1 unit 
e.g., INFUV ITE® 
Calcium Gluconate 10% (100 mg/ml) 
10 mis 
Antimicrob ials: 
Gram positive antibiotic 
l gm 
e.g., Cefazo lin 
Gram negative antibiotic 
100 mg 
e.g., Cirprofloxacin 
* type specific (or O negative blood group), pathogen free, leukocyte and platelet reduced 
• 
OCS™ Liver Perfusion Additives: In addition to the above OCS Liver perfusate , 
the following will be infused to the perfusate mix using an ex-vivo solution pump: 
OCS Liver Perfusate Additives 
Continuous Infusion Mix 
Dose 
Total parenteral nutriti on (TPN) Mix: 
30 ml/hr 
CLINIM/X E TPN (4.25%Amino Acid I 10% Dextrose); PLUS 
insulin 30 JU 
Glucose 25 gms 
Heparin 40,000 units 
As Needed Additives 
Dose 
Prostacyclin infusion as need ed to control Hepatic artery pressure 
0-20 mies/hr 
e.g., Epoprostenol Sodium 0.5 mg 
Bile Salts 
3 ml/hr 
e.g., Taurocholic acid sodi um (1 gm/50 ml) 
NaHC0. 3. 8.4% to correct metabo lic acidosis 
1.5 rneq/ 1 base excess 
• 
Bile Salt Preparation: All study sites will be provided sealed Gamma-sterilized 
vials of 1 gm of Taurocho lic acid sodium in salt form to be mixed prior to retrieva l 
according to the following steps:: 
-
Add 50 ml of sterile water for injection using aseptic techniqu e 
-
Mix well to ensure all salt is dissolved 
At the time of use the OCS operator will spike the stopper of the vial using a sterile 
OCS infusion line and connect to the OCS infusion delivery system. 
• 
The OCS™ Liver Preservation Parameters: Donor livers will be perfused on the 
OCS Liver device with OCS parameters maintained within the following ranges 
-
Hepatic Aliery Pressure (mean HAP): 75-100 mmHg 
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-
Hepatic Artery Flow (HAF): 300-700 ml/mm 
-
Pmtal Vein Pressme (mean PVP): 4-8 mmHg 
-
Portal Vein Flow (PVF): 700-1700 ml/min 
-
Perfusate Temperatme (Temp): 34°C 
-
Oxygen gas flow 400-700 ml/min 
-
Circulating arterial Lactate (Lact) trend: trending down over time 
• 
Lactate and Liver Enzyme Levels During OCS Liver Perfusion Sampling 
Scheme: The organ retrieval team will collect samples from the arterial pmt of the 
OCS perfusion circuit to measure lactate level using a standard blood analyzer 
according to the following protocol: 
-
OCS Baseline arterial sample within the first 10-30 min ofliver instrnmentation. 
• 
Lactate 
• 
Liver enzymes: AST, ALT , GGT, total bilirubin , and ALP 
-
Lactate samples will continue to be collected from the device at approximately 
hourly intervals until lactate level is trending down, at this time, lactate samples 
should be done every 2 hours or after any active HAF or HAP adjustments. 
-
OCS Final aiterial sample before cooling liver on OCS 
• 
Lactate 
• 
Liver enzymes: AST, ALT, GGT, total bilirubin, and ALP 
• 
Final Liver Cooling and Flush Arrest on OCS: all donor Livers on OCS will be 
cooled and flushed on the OCS using cold PlasmaLyte ® solution supplemented with 
sodium bicai·b olone onate (NHCO3) 10 mml/L , Epoprostenol Sodium 2 mics/L, and 
Methylprednis ~ 160 mg/L flush below, according to the following protocol: 
-
Hepatic Artery: 1 liter flush at ~50-70 mmHg pressure bag 
-
Portal Vein: 2 liters gravity drain 
• 
Liver Biopsy (see Appendix 1.): a needle biopsy will be collected from donor livers 
preserved on OCS or control on the back table , post preservation, immediately before 
re-implantation. 
• 
OCS Preservation Information: the following info1mation will be collected 
-
Device Information (serial number etc.) 
-
Device Malfunction( s) 
-
OCS system data collected by the device during the preservation run and 
upload ed into the EDC database 
• 
Donor Retrieval Details: The following information will be collected at time of 
Liver retrieval 
-
Date and time of cross clamp of donor amta 
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• 
OCS Details (Liver Instrumentation details): 
Total cold ischemia time between initial donor cross clamp and start of OCS™ 
Liver perfusion 
• 
OCS Parameters and Enabled Measurements: The following OCS™ Liver 
perfusion parameters and Liver metabo lic conditions will be recorded: 
-
HAP 
-
HAF 
-
PVP 
-
PVF 
-
Total Bile volume 
-
OCS Liver arterial lactate level 
6.5. 
Donor Liver Acceptance for Transplantation 
All donor livers that are preserved on OCS or Control are expected to be transplanted into a 
matching consented recipient. Any decision to turn down Livers after the Livers have been 
retrieved, preserved on either OCS™ Liver or cold storage should be done with notification to 
the Site PI and the donor Liver examined by the transplant center's qualified liver transplant 
pathologist and/or tissue slides/samples to be sent to core lab for the study for fruther 
examination . All reasons for turning down a donor liver after it has been preserved will be 
collected in the eCRFs. 
7. 
TRANSPLANT, IMMEDIATE POST-OPERATNE AND LONG 
TERM FOLLOW-UP 
7.1. 
Transplant Details 
The following information concerning the transplant procedme will be collected: 
• 
The organ recipient unique post-tran splant patient identifier 
• 
Total cross clamp duration in minutes (from donor cross-clamp application to 
removal of cross-clamp in the recipient) 
• 
Total cold ischemia time will be collected (Control= total cross clamp time; OCS = 
cold ischemic time pre and post OCS Liver perfusion) 
• 
Any surgical complications encountered during smgery 
• 
Use of circulatory bypass will be recorded 
• 
Type of liver anastomosis 
-
Bicaval anastomosis; or 
-
Piggyback anastomosis 
• 
The total amount of any blood product and clotting factors transfusion will be 
collected (pRBCs, Fresh Frozen Plasma (FFP), platel ets, etc.) 
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• 
Any inotropic suppmt needed to maintain hemodynamics will be collected for both 
arms 
• 
A liver tissue biopsy will be collected from Right lobe of the transplanted liver 
immediately before abdominal closure in the recipient. The biopsy will be collected 
according to Liver Biopsy protocol in Appendix 1. 
7.2. 
Post-transplant Functional Assessments Day O - Day 30: 
• 
Early Liver Allograft Dysfunction (EAD) Surveillance in the first 7 days: 
-
AST level >2000 IU/ml within the first 7 postoperative days; 
-
Bilirubin 2':.l 0 mg/dl on postoperative day 7; 
-
INR 2':.1.6 on postoperative day 7; or 
-
Primaiy non-functioning grnft within 7days 
• 
Inotropic Support to Maintain Hemodynamics at TO, T24 and 48 and 72 hours 
after ICU admission (if applicable) will be collected 
• 
Initial use of Mechanical Respiratory Support: duration of initial post-transplant 
invasive ventilator support will be recorded from the time of initial admission to ICU 
post-Liver transplant until extubation. 
• 
Initial Post-Transplant ICU Stay: Intensive cat'e unit (ICU) admission time, and 
date and tin1e when clinical order for ICU discharge is written . 
• 
Renal Replacement Therapy: Need for dialysis treatments in the first 10 days post 
liver transplantation for patients that did not have renal replacement prior to 
transplantation 
• 
Immunosuppression Medications: The type of immunosuppression medication and 
dose will be recorded at day 7 and at time of discharge from the hospital. 
Immunosuppression induction will be recorded if applicable. 
• 
Patient and Graft Survival at Day 30 and At Initial Hospital Discharge: Patient 
and graft survival will be assessed on day 30 post-transplant and at initial hospital 
dischai·ge post-liver transplantation. 
• 
Adverse Events: All Liver graft-related serious adverse events and any Liver graft-
related adverse events will be followed and documented until the investigator 
designates the event to be either resolved or its effect on the patient 's condition 
stabilized. 
• 
Medications: Medications used to treat all serious Liver graft-related adverse event 
(SAE)-related will be recorded in the u-ial electronic database until the SAE is 
resolved. 
These follow-ups will be attempted within± 3 days of the designated periods except for the 
Early Liver Allograft Dysfunction (EAD) Surveillance , in the first 7 days which must be 
collected at the designated times . The evaluations may be conducted over several days. 
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7.3. 
Long Term Follow-up: 6 and 12 & 24 months 
Follow-up data collection will be conducted at approximately 6, 12, and at 24 months post-
transplant. 
7.3.1. 
6 and 12-Month Follow-up 
At approximately 6 and 12 months post-transplant, the patient will be evaluated at an office visit 
if this is the institution's standard of care, and, if not, by phone contact by the site. The patient's 
medical record may be reviewed to confinn patient's answers. This follow up will collect 
information on: 
• 
Patient and graft survival; 
• 
Liver graft related SAEs (6 months only); 
• 
Liver graft related re-hospitalized after initial discharge, and, if yes, the primary 
reason/diagnosis for the hospitalization and the length of stay; 
• 
Information will also be collected on any diagnosis of ischemic biliary complications 
and, if so, the method of diagnosis and treatment. 
The 6 and 12-month follow-up will be collected within± 1 month of the designated period and 
will be recorded on the 6 and 12 month follow-up electronic form. 
7.3.1.1. 
24-Month Follow-up 
At approximate ly 24 months post-transplant, the patient will be evaluated at an office visit if this 
is the institution's standard of care, and, if not, by phone contact by the site. The patient's 
medical record may be reviewed to confirm patient's answers. This follow up will collect 
information on: 
• 
Patient and graft survival; 
• 
Results of standard clinical practice or for cause liver biopsy will be collected (if 
applicable) . 
The 24 months follow-up will be collected within± 1 month of the designated period and will be 
recorded on the 24-month follow-up electronic form . 
8. 
EVALUATION OF ADVERSE EVENTS 
8.1. 
Evaluation of Liver Graft-Related Adverse Events 
Liver Graft-Related Adverse Events are those, which have any untoward effect on the health, or 
safety of the patient and that are related to the transplanted Liver function ( except for acute 
rejection) . Liver graft-related adverse events will be collected from the time a subject is 
transplanted with a Liver preserved on OCS or Control until the completion of the 30-day 
follow-up evaluation. A Liver graft-related adverse event will be followed until resolution or 
stabilization of the event. 
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8.2. 
Serious Adverse Events (SAEs) 
An adverse event will be classified as serious if it meets any of the following criteria: 
• 
Results in, leads to, or contributes to, a death; 
• 
Is life-threatening; 
• 
Results in permanent disability or incapacity (i.e., permanent in1pairment of a body 
ft.mction or permanent damage to a body structure); 
• 
Requires in-patient hospitalization or prolongs hospitalization; 
• 
Necessitates medical or surgical intervention to preclude a permanent disability or 
incapacity; 
• 
Results in fetal distress, fetal death or a congenital anomaly/birth defect 
All Liver graft-related SAEs will be followed until their reso lution . 
8.3. 
Anticipated and Unanticipated Adverse Events 
The investigator will assess each adverse event for whether it is anticipated or unanticipated. An 
unanticipated adverse event is defined as any adverse effect on health or safety, or any life-
threatening problem or death caused by, or associated with, a device if that effect, problem or 
death was not previously identified in nature, severity or degree of incidence in the 
investigational plan or application (including a supp lementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the safety, or welfare of 
subjects. 
Adverse events are associated with Liver transplant procedures and have been documented 
within the first 30 days after Liver transplant, and are therefore anticipated. The list of events 
includes, but is not limited to: 
• 
Acute rejection 
• 
Atrial and ventricular arrhythmias 
• 
Bleeding 
• 
Hemodynamic instability 
• 
Death 
• 
Fever 
• 
Early liver allograft dysfunction (EAD) 
• 
Respiratory failure 
• 
Liver primaiy non-function 
• 
Bile lealcs 
• 
Hepatic mte1y thrombosis 
• 
Pmtal vein tlu·ombosis 
• 
Cholangitis 
• 
Liver abscess 
• 
Diaphragmatic injury 
• 
Phrenic nerve injmy 
• 
Sepsis 
• 
Renal dysfunction and/or failure 
• 
Hyperammonaemia 
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• 
Malignancy (post-transplant lymphoproliferative disorder (PTLD) 
• 
Multiple organ failure 
• 
Myocardial infarction 
• 
Neurological dysfunction 
• 
Hepatic dysfunction 
• 
Diabete s due to steroid and anti-rejection medications 
• 
Pancreatitis 
• 
Peptic ulceration 
• 
Gastritis 
• 
Gastro esophageal reflux disease (GERD) 
• 
Aspiration 
• 
Cardiac tamponade 
• 
Pneumo-mediastinum 
• 
Pneumothorax 
• 
Hemothorax 
• 
Ascites 
• 
Pleural effusion 
• 
Venous thromboembolism (deep venous thrombosi s [DVT]) 
• 
Pulmonmy embolism (PE) 
• 
Abdominal wound dehiscence 
• 
Organ deemed not transplantable after retrieval 
• 
Stroke 
• 
Psychosis 
• 
Ileus 
• 
Bowel obstruction 
• 
GI Bleeding (upper or lower) 
• 
Cerebrovascular accident 
• 
Peripheral vascu lar clotting or occlusion due insertion of mechanical support or 
equivalent 
• 
Delirium, confusion and neurological complication s 
• 
Hepatic coma 
• 
Retransplantation 
• 
Limb gangrene due to vascular occlusion due insertion of mechanical support 
• 
Use of mechanical circulatory support 
• 
Coagulopathy 
• 
Blood produ ct transfusion 
• 
Transfusion reaction 
• 
Hyperacute rejection 
• 
Anastomotic site complications; narrowing, bleeding or occlusion 
• 
Bowel thromboembolic complications and gangrene 
• 
Protamine and other anti-heparin medication reaction 
• 
Hepm'in induced thrombocytopenia 
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8.4. 
Unanticipated Adverse Device Effect (UADE) 
An UADE means any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified or encountered before at least once in standard clinical practice, in natme , 
severity , or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
8.5. 
Recording and Reporting of Adverse Event 
All Liver graft-related adverse events and serious adverse events are to be recorded on the 
electronic case report forms until post-transplant day 30 or until initial hospital discharge, 
whichever comes first. The description of the adverse event will include: the date of onset, 
dmation, severity, seriousness, the relationship of the event to the trial treatment, anticipated or 
not, and any treatment required. All serious adverse events occuning during the course of the 
first 30 days post-transplant will be reported to TransMedics, Inc., as well as documented on the 
appropriate electronic case rep01i form(s). For all SA.Es, the investigator is required to supply 
any additional data that may be deemed necessary by the Sponsor. Additionally any serious 
adverse events (SAE) and unanticipated adverse device effects (UADE) should be rep01ied to 
TransMedics, Inc., preferably within 48 hours of the time the investigator learns of the event, but 
in no case later than 5 working days. Liver graft-related A.Es will be recorded up to the 30-day 
follow-up or through hospital discharge only if longer than 30 days. For any particular patient, 
the Independent Medical Monitor if required to protect patient safety may specify a different 
follow-up period. The Sponsor is responsible for the classification and repotiing of Liver graft-
related adverse events to the appropriate regulatory authorities, and for the on-going safety 
evaluation of the trial in accordance with ISO 14155 and governing regulatory requirements. 
8.6. 
Relationship of an Adverse Events to OCS™ Liver (OCS) or 
Standard of Care (Control) 
The investigator will assess the relationship of the AE to the OCS or Control methods of 
preservation. The relationship will be assessed using the following categories: 
• Definitely Related: There is a reasonable causal and temporal relationship between 
preservation with the OCS™ Liver and the adverse event. 
• Probably Related: It is more likely than not that there is a reasonable causal 
relationship between preservation with the OCS™ Liver the adverse event. 
• Possibly Related: There is a reasonable relationship with preservation with the 
OCS™ Liver and the adverse event, but the causal relationship is unclear or lacking. 
• 
• 
Unlikely Related: There is a temporal relationship with preservation with the OCS™ 
Liver and the adverse event, but there is not a reasonable causal relationship between 
the trial device and the event. 
Unrelated: There is no relationship between preservation with the OCS™ Liver and 
the adverse event. 
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8. 7. 
Severity 
The investigator will rate the severity of the adverse event using the following categories: 
• 
Mild: The adverse event is transient and/or easily tolerated by the subject. 
• 
Moderate: The adverse event causes the subject discomfo1t and interrupts the 
subject's usual activities. 
• 
Severe: The adverse event causes considerable interference with the subject's usual 
activities. 
8.8. 
Pre-Existing Conditions 
Pre-existing diseases or conditions will not be repmt ed as adverse events. 
9. 
STATISTICAL METHODS 
9.1. 
General 
Continuous variables will be summarized using descriptive statistics, specifically the mean, 
median, standard deviation, minimum , and maximum. Categorical variab les will be summarized 
using frequencies and percentages. 
9.2. 
9.2.1. 
Analysis Populations 
Per Protocol Population 
The Per Protocol (PP) Population will consist of all randomized subjects who are transplanted 
and have no major protocol violations and for whom the donor liver received the complete 
preservation procedure as per the randomization assignment. The major protocol violations that 
will exclude a subject from this population are the following: 
• 
Ineligible for the study according to the recipient inclu sion and exclusion criteria 
• 
Ineligible for the study according to the donor organ inclusion and exclusion criteria 
• 
Subject is transplanted with a liver with preservation other than that to which the 
subject was randomized 
• 
Failure to complete adequate post-transplant assessments to support the primary, 
secondary or safety endpoints 
• 
Other major protocol violations 
In analyses based on the PP Popu lation, subject s will be analyzed as randomized . The primary 
analysis of effectiveness and of secondary and other endpoints will be based on the PP 
Population . 
9.2.2. 
Modified Intent-to-Treat Population 
The Modified Intent-to-Treat Population (mITT) will consist of all randomi ze subjects who are 
transplanted. In analyses based on mITT Population, subjects will be analyzed as randomized. 
The mITT analyses will be considered secondary analyses of effect iveness. 
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9.2.3. 
As Treated Population 
The As Treated Population (AT) will consist of all treated subjects, i.e., all subjects who are 
transplanted in the study with a donor liver preserved with either OCS or Control. In analyses 
based on this population, subjects will be analyzed as treated. A subject who receives a liver 
with some preservation with OCS and some with standard of care will be analyzed according to 
the initial preservation. After the initiation of preservation , any switchover in preservation 
method should be recorded as a protocol deviation and those subjects will not be considered pmt 
of the AT population. Analyses of safety endpoints will be performed based on the AT 
Population 
9.2.4. 
Donor Liver Population 
The Donor Liver Population will consist of all donor livers for which the potential recipient was 
randomized and which have preservation initiated using OCS or Control. In some of the 
analyses based on this population, livers will be analyzed as randomized ; in others, they will be 
analyzed as treated . For the analyses based on the actual treatment of the liver, a liver with some 
preservation with OCS and some with standard of caTe will be analyzed according to the initial 
preservation. 
9.3. 
9.3.1. 
Analysis of Effectiveness Endpoints 
Primary Effectiveness Endpoint 
The primaiy effectiveness endpoint for this study is Eai·ly Liver Allograft Dysfunction (EAD) , 
defined as presentation of one or more of the following criteria: 
• 
AST level >2000 IU/ml within the first 7 postoperative days; 
• 
Bilirubin 2:10 mg/dl on postoperative day 7; 
• 
INR 2:1.6 on postoperative day 7; or 
• 
Primaty non-functioning graft within the first 7 days 
The primai·y hypothesis for this study is that the OCS treatment is non-inferior to the stai1dard of 
care treatment with respect to this endpoint. The primai·y statistical hypotheses ai·e as follows: 
H10.: n. 1,ocs .2: 1t.1,coNTROL
-+ 8 and 
H11.: 7t.J,OCS 
.< 1t.1,CONTROL 
.+ O, 
where 1t.1,ocs .and 1t.1,coNTROL 
me the true proportions of subjects with Early Liver 
Allograft Dysfunction for the OCS and standard of care treatments , respectively, and 8 is 
the non-inferiority margin which is here taken to be 0.075. If non-inferiority is 
demonstrated using a significance level of 0.05, a two-sided test of superiority will be 
performed. 
The primmy effectiveness endpoint will be analyzed by calculat ing, for each treatment group, the 
sample propmtion of subjects meeting the primaiy effectiveness endpoint , as well as an exact 
(Clopper -Peai·son) 95% confidence interval for the corresponding population propmtion. The 
95% upper bound of the exact unconditional one-sided confidence interval based on the 
Farrington and Maiming score statistic 18 will be calculated for the difference between the two 
population proportions (n.1,ocs .- 1t.1,coNTRO
L-), An upper confidence limit less than 8 = 0.075 will 
result in rejection of the null hypothesis (H10) in favor of the alternative hypothesis (H11) and the 
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demonstration of non-inferiority of OCS to control for the primmy effectiveness endpoint. In the 
event non-inferiority is demonstrated , Fisher 's exact test (two-sided) will be used to test for 
superiority. 
This endpoint will be analyzed using the Per Protocol and mITT Population s. The Per Protocol 
analysis will be considered the primmy analysis. Multiple imputation methods will be used for 
data imputation for any patients with missing values for this endpoint. 
Subgroup analyses of the primary effectiveness endpoint will be performed for the following 
subgroups of patients: 
• 
DCD (donation after circulatory death) patients 
• 
Fatty liver patients 
• 
Other liver patients 
No data imputation or statistical tests will be performed for these subgroup analyses. 
9.3.2. 
Secondary Effectiveness and OCS Donor Liver Assessment Endpoints 
The seconda1y effectiveness endpoints for this trial are as follows: 
• 
OCS Measurements during organ perfusion 
• 
Patient survival at day-30 post-transplantation 
• 
Patient survival at time of initial hospital discharge post-transplantation 
The null and alternative hypotheses for the endpoint of OCS donor liver assessment during 
perfusion are: 
Ho.: n.3. :'.S 0.85 and 
H1.: n.3. > 0.85, 
respectively, where n.3 is the true proportion of livers, among donor livers preserved using 
OCS for the entire preservation period, on which measurements of lactate level, average 
bile production rate, Hepatic Artery and Po1tal Vein Pressure during perfusion will be 
available on OCS device before transplant. 
This secondary endpoint on OCS liver assessment during organ perfusion will be analyzed by 
calculating the sample proportion of donor livers placed on OCS meeting this secondary 
endpoint, as well as an exact (Clopper-Pearson) 95% one-sided lower confidence bound for the 
corresponding population proportion. A lower confidence bound greater than 0.85 will result in 
rejection of the null hypothesis in favor of the alternative hypothesi s and the demonstration that 
the true propo1tion is greater than 0.85 for the OCS donor liver assessment endpoint. 
Each secondmy effectiveness endpoint will be summm·ized using counts and percentages and an 
exact 95% confidence interval for the true percentage based on the binomial distribution. The 
secondmy effectiveness endpoints will be analyzed using the PP Population. 
The statistical hypotheses for the first secondary effectiveness endpoint, patient survival at day-
30 post-transplantation , are as follows: 
H.20.: 1t.2,ocs .:'.S 1t.2,coNTROL-- 8 and 
H21-: n.2,ocs .> n.2 ,coNT ROL .- 8, 
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where n.2,ocs and n.2,coNTROL 
are the true proportions of the subjects surviving to day-30 
post-transplantation for the OCS and standard of care treatments, respectively, and 8 is 
the non-inferiority margin , which is here taken to be 0.075. This endpoint will be 
analyzed by calculating the 95% upper confidence limit based on the normal 
approximation for the difference between the two population proportions (7t.2,coNTROL 
.-
rc.2,ocs)- An upper confidence limit less than 8 = 0.075 will result in rejection of the null 
hypothesis (H 20) in favor of the alternative hypothesis (H21) and demonstration of non-
inferiority of OCS to Control. In the event non-inferiority is demonstrated , Fisher 's exact 
test (two-sided) will be used to test for superiority. 
The second secondary effectiveness endpoint , patient survival at initial hospital discharge post 
liver transplantation, will be analyzed in a manner analogous to the first secondary effectiveness 
endpoint with the same non-inferiority margin of 0.075. 
Because fixed sequence testing will be used for the secondmy endpoints, no adjustment for the 
multiplicity of these endpoints needs to be made. The endpoints will be tested in the order listed 
above. The test for non-inferiority for the first secondaiy effectiveness endpoint will be 
performed only if the null hypothesis has been rejected for the OCS donor liver assessment 
endpoint. The test for non-inferiority for the second secondary effectiveness endpoint will be 
performed only if the null hypothesis has been rejected in favor of the alternative hypothesis of 
non-inferiority of the OCS treatment to the Control treatment for the first secondary 
effectiveness endpoints. Similm·ly, the test for superiority for the second secondary effectiveness 
endpoint will be perfonned only if the null hypothesis of equality has been rejected in favor of 
superiority of the OCS treatment to the Control treatment for the first secondaiy effectiveness 
endpoints (and non-inferiority has been demonstrated for the given secondaiy effectiveness 
endpoint). Due to statistical power limitations , it is not expected that non-inferiority will be 
demonstrated for patient survival at day 30 or at initial hospital dischai·ge. 
These endpoints will be analyzed using the Per Protocol and m.ITT Population s, with the Per 
Protocol analysis being considered the primary analysis. Multiple imputation methods will be 
used for data imputation for patients with missing values for these endpoints. 
Subgroup analyses of the secondary endpoints will be performed for the same subgroups of 
patients as for the primary effectiveness endpoint. No data imputation or statistical tests will be 
performed for these subgroup analyses. 
9.4. 
Analysis of Safety 
Safety will be analyzed principally by examination of the frequency of liver graft-related serious 
adverse events (SAEs) up to the 30-day follow-up after transplantation. This endpoint is defined 
as the average number ofliver graft-related serious adverse events through the 30 days post-liver 
transplantation per subject, consisting of the following serious adverse events (at most one per 
type per person): 
• 
Primary non-function (defined as irrever sible graft dysfunction requiring emergency 
liver re-transplantation or death with the first 10 days, in the absence of immunologic 
or surgical causes); 
• 
Ischemic biliary complications (ischemic bi.limy strictures, and non-anastomotic bile 
duct leaks); 
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• 
Vascular complications (Liver graft-related coagulopathy, hepatic aitery stenosis, 
hepatic artery thrombosis and portal vein thrombosis); 
• 
Liver allograft infections (liver abscess, cholangitis, etc.) 
This endpoint will be summarized by treatment group using descriptive statistics. For each 
treatment group, a 95% confidence interval for the mean based on the t-distribution will be 
presented. Also, a 95% confidence interval based on the t-distribution will be presented for the 
difference in means between the two treatments. 
For the number ofliver graft-related SAEs, the statistical hypotheses are as follows: 
H3o: ~Locs-~ ~CONTROL.+ 8 and 
H3 I: f.-locs. < J.-lcoNTR
01..+ 0, 
where f.-locsalld 
J.-lcoN"rn
o1.are the true mean numbers ofliver graft-related SAEs up to the 30-
day follow-up after transplantation per subject with the OCS and standard of cai·e 
treatments, respectively, and 8 is the non-inferiority margin, which is here taken to be 
1.00. The safety endpoint will be analyzed using a one-sided, two-sample t-test with an 
alpha level of 0.05. If non-inferiority is demonstrated, a corresponding (two-sided) test 
of superiority will be perfo1med. 
This endpoint will be analyzed based on the As Treated Population. 
In addition, the numbers and percentages of subjects experiencing at least one liver graft-related 
AE, at least one (definitely or probably-related) device-related AE, at least one unanticipated AE, 
and at least one serious AE, and the number and percentage of deaths will all be tabulated by 
treatment group. Also, the number ofliver graft-related adverse events and the number and 
percentage of subject s experiencing liver graft-related adverse events will be tabulat ed by system 
organ class and preferred term using MedDRA. A similar analysis will be performed for liver 
graft-related SAEs. AEs will also be tabulated at the event level by system organ class and 
preferred term and the relation ship of the adverse event to the device using counts and 
percentages. Similai· analyses will be perf01med by the severity of the adverse event. 
The numbers and percentages of donor livers in the Donor Liver Population that are treated as 
randomized and transpla11ted, treated not as randomized and transplanted, h·eated as randomi zed 
and not transplanted, and treated not as randomized and not transplanted will be presented. For 
livers that are treated not as randomized, the reason will also be summar ized using counts and 
percentages. Both of these analyses will be done based on the randomized treatment for the 
liver, but the following analyses will be based on the actual treatment of the liver. For livers that 
ai·e not transplanted, the reason(s) for non-transplantation (including device failure) will be 
summarized using counts and percentages. The number and percentage of donor livers in the 
Donor Liver Population for which these was a device failure will also be presented. 
9.5. 
Randomization 
After confirmation of eligibility, obtaining informed consent, and a matching donor liver is 
identified, potential liver transplant recipient s will be randomized 1: 1 to have their donor livers 
preserved using either the OCS Liver perfusion or the stand ard cold static preservation technique 
using cold flush and storage. Randomization will be performed through the Interacti ve Web 
Response System (IWRS). Subjects who are not transplanted with the matching donor liver will 
be re-randomized and treated as a new subject. 
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9.6. 
Sample Size Determination 
The sample size for this trial was determined based on the primary effectiveness endpoint, Early 
Liver Allograft dysfunction (EAD) in the first 7 days post-transplantation. 
The sample size 
calculation assumed a one-sided, normal approximation test for non-inferiority , an alpha level of 
0.05, a non-inferiority margin of 0.075, a 1: 1 allocation , true propmtions for the primaiy 
effectiveness endpoint of 0.2 for the OCS tr·eatment and 0.25 for the Control treatment , and 
power of 80%. Based on these specifications, the required sample size was determined to be 144 
transplanted recipients per treatment group , or 288 total transplant ed subjects. To ensure an 
adequate number of subjects in the Per Protocol Population, the samp le size was increased to a 
total of 300 transplanted subjects. Subjects will be emailed until there are either 290 subjects in 
the Per Protocol Population or a total of 300 transplanted subjects , whichever comes first. 
9.7. 
Sample Size Re-Estimation 
A sample size re-estimation will be performed for the purpose of confirming the current sample 
size is sufficient for testing for non-inferiority for the primaiy effectiven ess endpoint and to 
assess the feasibility of demonstrating superiority . It will be conducted after there are 200 
transplanted subjects to allow for a possible upwards adjustment in sample size. The increase in 
sample size, if any, required in order to obtain 80% conditional power for a test for non-
inferiority for the primaiy efficacy endpoint will be determined . The increase in sample size, if 
any, required to obtain 80% power for a two-sided test for super iority for the primary 
effectiveness endpoint will also be determined. In both cases , conditional power will be 
calculated based on the observed proportions for the primaiy effectiveness endpoint. The sainple 
size will not be increased by more than 150 subje cts. If the required samp le size increase is less 
than or equal to 150 subjects for both the test for non-inferiority and the test for superiority , the 
increase in sample size will be based upon the result for the test for superiority , which will be the 
larger increase. However, if the required sample size increase is less than or equal to 150 
subjects for the test for non-inferiority , but greater than 150 for the test for superiority, the 
increase in samp le size will be based upon the result for the test for non-inferiority. 
If the 
conditional power based upon the planned samp le size is at least 80% for both the test for non-
inferiority and the test for super iority or the required increase in samp le size is greater than 150 
subjects for both cases, the sample size will not be increased. 
9.8. 
Interim Analyses 
For regulatmy purposes, descriptive summaries and/or data listings of key data will be provided 
to the FDA based on the first 10 tra11Splanted liver recipients in Pait A of the study after they 
have comp leted 30 days post-h·ansp lantation and on the 20 transplanted liver recipients in Pait A 
of the study after they have completed 30 days post-transplantation. 
9.9. 
Statistical Analysis Plan 
A fo1mal statistical analysis plan will be prepared and finalized prior to data lock. 
10. 
RISK ANALYSIS 
.This clinical trial has been designed to ensure that the benefits and knowledge gained from the 
trial outweigh the potential risk s to the subjects. The subjects are adults undergoing primary 
Liver transplants. 
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10.1. 
Potential Risks 
The potential risks to subjects from paiticipation in this clinical trial include the following: 
10.2. 
• 
Potential Risks Associated with Liver Transplant Procedures: These risks include 
post-operative complications, such as graft failure, primary graft dysfunction, 
rejection, infection and other organs/systems complications, graft vessel disease (an 
expression of chronic rejection), infection, abnormal kidney function, diabetes, high 
level of cholesterol, high blood pressure , cancer and neurological complications. 
• 
The Potential Risks Associated with the Investigational Device: As with any medical 
device, there is always a risk of extremely rai·e or previously unknown side effects 
developing from the treatment. 
Manner in Which the Potential Risks Have Been Minimized 
The Sponsor has relied upon a number of different means, including the device design, risk 
analysis and management process, preclinical testing, and the clinical protocol itself, to minimize 
the risks to subjects and to protect their safety and welfare. The sponsor has designed the device 
and conducted a risk analysis in accordance with ISO 14971 to minimize and mitigate the risks 
to subjects and users. 
The Sponsor has conducted extensive prnclinical testing of the OCS™ Liver to demonstrate its 
safety, effectiveness and readiness for clinical use. The OCS has undergone extensive 
preclinical and animal studies to demonstrate that the device performs as intended. These studies 
strongly indicate that the OCS™ Liver maintains Liver viability by providing a controlled 
environment that simulates near-normal physiological conditions , and monitors its function. The 
Liver Perfusion Set has been tested for biocompatibility to minimize the risk of adverse tissue 
reactions. These test results demonstrate the device and its materials are biocompatible and 
suitable for their intended use. The Liver Perfusion Set are provided sterile and for single use to 
minimize the risk of infection. The OCS™ Liver has also undergone and continues to undergo 
extensive design verification and validation testing to optimize its perfo1mance and minimize the 
risks associated with its use. Preclinical studies demonstrate the device performs as intended and 
meets its performance specifications including the perfusion pun1p, the blood warmer, and other 
functions. The softwai·e has undergone and continues to undergo extensive testing to 
demonstrate it, and its safety functions and alaims, perform as intended. 
This clinical protocol incorporates several procedures to minimize the risks to subjects and to 
ensure the benefits of the clinical trial outweigh its potential risks. 
• 
Subjects will be monitored before, during and after the operative procedure to help 
ensure their safety. The investigators are members of transplant teains who have 
extensive experience with Liver transplants and who will be trained to use the OCS™ 
Liver to further minimize risk. 
• 
Subjects in the trial will undergo frequent visits and routine monitoring to help detect 
any abnormal changes and to provide appropriate treatment as necessary. 
• 
The trial will be monitored to ensure the identification, documentation, and analysis 
of adverse events; and to ensure compliance with the protocol and procedures that are 
in place for conducting research to protect the safety and well-being of all subjects. 
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10.3. 
Potential Benefits 
The OCS™ Liver system's preservation and assessment capabilities could potentially increase 
the rate of utilization of donor Livers that are currently less utilized due to the limitations of cold 
storage techniques. This could dramatica lly improve the chances of waiting list recipients to 
receive a lifesaving Liver transplant and reduce waiting list time and m01tality. 
In addition, the OCS™ Liver's physiologic preservat ion of donor Livers could result in 
improved shmt and long-term post -transplant outcomes in the f01m of increased survival and 
lower graft dysfunction/rejection rates. 
10.4. 
Risks Benefits Ratio 
Based on the above, the benefits of using OCS™ Liver technology to preserve and assess donor 
Livers to ensme their suitability for Liver transplantation outweigh any potential risks to the trial 
subjects. 
11. 
11.1. 
DEVICE/SITE MANAGEMENT 
Packaging and Labeling 
The OCS™ Liver Perfusion Set and accessories will be supplied sterile and are intended and 
labeled for single use. 
The OCS™ and its components will be clearly labeled as an investigational device according to 
21 CFR 812.5. The labeling provides instructions for use for the device . A copy of the 
Instructions for Use will be provided to each investigational site. 
11.2. 
Storage 
The investigational devices will be stored in a secure place. Access should be sh·ictly lin1ited to 
the investigators and their designees. Neither the investigators nor any designees may provide 
the investigational device to any subject not pmticipating in this h'ial. Special storage 
instructions for the components m·e described below. The OCS™ Liver Perfusion Set should be 
stored at temperatures between -20°C and 50°C, and ambient hurnidity from 10-95%, no 
condensing . 
Note: The OCS™ Liver Pe,fusion Set should be operated at ambient temperatures (10°C to 
35°C), and ambient humidity (20%-90%). 
11.3. 
Accountability 
The investigator or designee will maintain an inventory record of investigational devices 
received , used for treatment, otherwise discm·ded, and returned to the Sponsor to assure FDA and 
the Sponsor that the investigational new device will not be dispensed to any person who is not a 
subject under the terms and conditions set fmth in this protocol. 
11.4. 
Device Complaints and Malfunctions 
The investigator will inform the Sponsor of any complaints or malfunctions during the course of 
the trial. The Sponsor will investigate all device complaints and malfunctions. 
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12. 
REGULATORY I ETIDCS 
This clinical trial will be conducted in accordance with the requirements of the FDA 
Investigational Device Exemptions regulation (21 CFR Parts 50, 56, 812, and 45 CFR pmt 46), 
ISO Standard 14155, and in accordance with good clinical practices. 
12.1. 
Institutional Review Boards (IRB) or Ethics Committee (EC) 
In accordance with the conditions imposed by the reviewing Institutional Review Board (IRB) or 
Ethics Committee (EC) to applicable regulations from Federal agency (i.e. U.S. Food and Drug 
Administration (FDA), with local regulations, prior to initiation of any trial procedures, the 
protocol, informed consent template and device labeling (if requested) will be submitted to each 
site's IRB or EC for review and approval. In addition, any amendments to the protocol or 
informed consent form will be reviewed and approved (if necessary) by the IRB or EC. The 
Sponsor must receive a letter documenting the IRB 's or EC's approval at the clinical site prior to 
the initiation of the trial at that patticular site. 
12.2. 
Informed Consent 
Written informed consent will be obtained from all subjects before any trial-specific procedures 
m·e perfo1med. Informed consent will be obtained and documented prior to initiation of any 
procedures that are performed solely for the purpose of the research trial. 
Investigators have both m1 ethical and legal responsibility to ensure that each patient being 
considered for inclusion in this trial is given a full explanation of the protocol. This will be 
documented via a written inform ed consent form approved as part of the full trial approval 
granted by the Institutional Review Board (IRB) or Ethics Committee (EC) for the site. Each 
informed consent form will include the elements required by 21 CFR Prut 50. The investigator 
agrees to also obtain approval from the Sponsor and IRB/EC for any written info1med consent 
form used in the trial. 
The approved written infmmed consent fmm will be signed and dated by the subject and the 
individual obtaining the consent. The subject will be given a copy of the signed info1med 
consent form. The original will be kept in the patient's file by the investigator. 
A copy of the proposed draft Informed consent template is included as Appendix 3. 
13. 
DATA COLLECTION/RECORDS/REPORTS 
13.1. 
Investigator Records 
Prior to pmticipation in the investigation , the investigator will provide the following 
documentation to the Sponsor: 
• 
Investigator Agreement , signed by the inve stigator and disclosure of any financial 
intere st; 
• 
A copy of the primary investig ator's curriculum vitae (CV), as well as copie s of CVs 
for any co-inve stigators ; 
• 
Written approva l of the trial from the IRB or EC; and, 
• 
A copy of the approved informed consent document. 
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During the trial, investigators will be responsible for complete and accurate ent1y of data into the 
trial's database, and will be required to maintain on file the following accurate, complete and 
current records relating to this trial: 
• 
All relevant correspondences and required reports that pertain to the trial; 
• 
Records ofreceipt , use or disposition of the investigational device, includin g the type 
and quantity of the device; the dates of receipt; the lot number; the names of all 
persons who received , used or disposed of each device; and why and how any units of 
the device have been returned to the Sponsor, repaired, or otherwise disposed; 
• 
Records of each subject's case history and exposure to the device; 
• 
Signed and dated consent forms; 
• 
Relevant observations, including records concerning adverse events, condition of 
each subject upon entering and results of diagnostic tests; 
• 
Protocol, and any amendments; 
• 
Subject recruiting materials; and, 
• 
Investigator curricula vitae. 
The investigator will not dispose of any records relevant to this trial without (1) written 
pennission from the Sponsor and (2) providing an opportunity for the Sponsor to collect such 
records . The investigator will take responsibility for maintaining adequate and accurate 
electronic or hard copy source documents of all observations and data generated during this trial. 
Such documentation is subject to inspection by the Sponsor and regulatmy authorities. 
13.2. 
Investigator Reports 
In accordance with the FDA reporting requirements, the investigators will be required to prepare 
and submit to the Sponsor the following complete, accurate, and tin1ely repo1ts on this 
investigation when necessary : 
• 
The investigator will notify the Sponsor of a subject death occurring during the 
investigation as soon as possible, preferably within 24 hours of learning of the 
subject's death, but in no event later than 48 hours. The investigator will also notify 
the Sponsor immediately of a serious adverse event, preferably within 48 hours of 
learning of the serious adverse event, but in no event later than 5 working days. 
• 
The investigator will notify the Sponsor of any unanticipated adverse device effects 
(UADE) preferably within 48 hours after the investigator first learns of the effect, but 
in no event later than 5 working days. The investigator will notify its IRB or EC of 
any unanticipated adverse device effects as soon as possible, but no later than 10 
working days after the investigator first learns of the effect. 
• 
The investigator will notify the Sponsor of the withdrawal of IRB or EC approval as 
soon as possible , but no later than 5 working days after the investigator first learns of 
the withdrawal 
• 
The investigator will provide cmTent progress reports to the Sponsor and reviewing 
IRB or EC at regular intervals but at least on an annual basis. 
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TransMedics Confidential 
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13.3. 
• 
The investigator will notify the Sponsor and the !RB or EC of any deviation from the 
investigational plan to protect the life and physical well-being of a subject in an 
emergency as soon as possible , but no later than 5 working days after the emergency 
occurred. 
• 
The investigator will notify the Sponsor and IRB or EC that an inf mmed consent was 
not obtained from a subject as soon as possible, but no later than 5 working days after 
such an occurrence. 
• 
The investigator will provide a final summary repmt within 3 months after 
termination or completion of the trial to the IRB or EC. The site trial completion 
repo1t may serve as the trial completion for the Sponsor 
• 
The investigator will provide any other info1mation upon the request of the IRB or 
EC, or the Sponsor. 
Data Collection 
During each subject assessment, an investigator paiticipating in the trial will record progress 
notes to document all significant observations. In addition, any contact with the subject via 
telephone or other means that provides significant clinical information will also be documented 
in the progress notes. For transmission to the Sponsor, information from the trial progress notes 
and other source documents will be promptly entered into the electronic database (eCRFs). 
All data required by the trial protocol will be completely and accurately entered into the trial 
database by the investigator or his or her designate. A copy of draft eCRFs is provided in 
Append ix 4. 
13.4. 
Source Documents 
Source documents are defined as the results of original observation s and activitie s of a clinical 
investigation. Source documents will include, but are not limited to, progress notes, electronic 
data, computer printouts, screening logs, and recorded data from automated instruments. All 
source documents pe1taining to this trial will be maintained by the investigators and made 
available for inspection by authorized persons. 
13.5. 
Archiving of Records 
Essential trial documents must be maintained by the Investigator for at least 2 yeai·s after the last 
marketing approval by a regulatory body, as determined by the Sponsor. The documents should 
be retained for a longer period , however , ifrequired by the applicable regulatory requirements. 
Records will be kept in a secure, dry location controlled by the institution. 
13.6. 
Sponsor Records and Reports. 
The Sponsor will conform to all records and reports requirement s imposed by FDAs regulation s. 
13.7. 
Final Study report 
All study data will be reviewed and monitored throughout the trial. A formal statistical ai1alysis 
will be conducted in which validated data will be produced to suppmt the overall analysis of the 
trial endpoints. The formal statistical data analysis will be shared with the Steering Committee 
and Study Investigators. 
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TransMed.ics Confident ial 
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The Sponsor will work collaboratively with the Steering Committee and Study Investigators to 
publish all posit ive and negative outcomes of the study in peer review journals and at 
national/international scientific conferences within 18 months of the completion of the study 
analysis. If the study is terminated early for any negative or positive findings , the above-
described process will begin at the date of the early termination of the study. 
14. 
14.1. 
CLINICAL MONITORING 
Monitoring 
The Sponsor has ethical, legal and scientific obligations to cmefully follow this tria l in a detailed 
and orderly manner in accordance with established research principles. As pait of a concerted 
effmt to fulfill these obligations (maintain current personal knowledge of the progress of the 
trial), the Sponsor's monitors will visit the center during the trial in addition to maintaining 
frequent telephone and written communications. The following guidelines are provided to 
describe the Sponsor's procedures for monitoring the clinical studies . If the investigator is not 
complying with the signed Investigator Agreement, the protocol, or any condition of the trial, 
(e.g., incomplete data fo1ms) the Sponsor has the right to terminate the investigator's 
paiticipation in the t1ial. The Sponsor is responsible for selecting trial monitors qualified by 
training and experience to conduct monitoring of the trial and for ensuring the quality of the trial 
monitoring visits by the monitor. The Sponsor's general monitoring procedures for 
investigational studies ai·e described below. 
14.2. 
14.2.1. 
Pre-Trial Monitoring Procedures 
Selection of Monitors 
All monitors will be qualified by education, training , and experience. 
14.2.2. 
Initiation Visit 
A monitor will be responsible for determining and documenting that each investigator clearly 
understands and accepts the responsibilities and obligations incmred in conducting a clinical 
trial. The monitor will ensure , prior to trial initiation, that the investigator : 
• 
Understands the requirements for a well-controlled trial. 
• 
Understai1ds the nature of the clinical protocol. 
• 
Understands his/her repmting obligations. 
• 
Understands the requirements for device accountability. 
• 
Understands and accepts the obligations to obtain infmmed consent. 
• 
Understands and accepts the obligation to obtain IRB or EC review and approval of 
the clinical investigati on before it is initiated and to ensure continuing review of the 
trial by the IRB or EC, and to keep the Sponsor info1111ed of all IRB or EC actions 
concerning the trial. 
• 
Has adequate facilities, support staff, and access to an adequate number of suitable 
subjects to conduct the investigation. 
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14.3. 
• 
Has the required documentation on file, includin g IRB or EC approval and a signed 
investigator agreement. 
• 
Financial disclosure infmmation will be obtained. 
Periodic Monitoring Visits 
Monitoring visits will be conducted as scheduled by the sponsor. The monitor should visit each 
site as needed to ensure the following: 
14.4. 
• 
Facilities continue to be adequate and acceptable. 
• 
Infmmed consent has been obtained. 
• 
The protocol is being properly followed. 
• 
The IRB or EC has approved or been notified of any protocol changes. 
• 
Accurate, complete and cunent records are being maintained , and the information 
recorded and submitted to the Sponsor is representative of the subject's record and 
other supporting documentation . 
• 
Accurate , complete and timely adverse event reports are being submitted to the 
Sponsor. 
• 
The reason for a subject's withdrawal from the trial has been documented. 
• 
Reports are being submitted to the IRB or EC and Sponsor. 
• 
The appropriate staff is carrying out trial activities. 
• 
SAEs identified and reported in a timely fashion 
Frequency of Monitoring Visits 
The frequency of monitoring visits will be dete1mined on the basis of several factors, including 
the duration of the trial, number of subjects emolled, number of investigators /sites, complexity of 
the trial, and number of outstanding issues from previous visits. All routine monitoring functions 
will be perfmmed prior to the trial te1mination. 
14.5. 
Trial Completion Visit 
The trial termination visit may be combined with a monitoring visit. The following tasks will be 
completed at the last visit by the monitor. 
• 
Ensure that all electronic forms have been complet ed. 
• 
Ensure that any database queries have been resolved. 
• 
Remind the investigator of the obligation to retain the records. 
14.6. 
Reports of Monitoring Visits 
Monitoring report s will be completed for all visits. Report s will include the date of the visit, list 
of trial personnel present , and a summary of the findings. 
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TransMedics Confidential 
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14.7. 
Additional Auditing 
Regulatory authorities worldwide may also audit the investigator during or after the trial. The 
investigator will contact the Sponsor immediately if this occurs, and will fully cooperate with the 
audits conducted at a reasonable time in a reasonable manner. 
14.8. 
Protocol Deviations 
This trial will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and well-being of a subject requires a protocol deviation, based on 
the judgment of the investigator ( or a responsible, appropriately trained professional designated 
by the investigator). If the deviation from the protocol is necessaiy to protect the life and 
physical well-being of a subject in an emergency, such protocol deviations will be reported to the 
Sponsor and the IRB or EC as soon as possible, but no later than 5 working days after the 
emergency occurred. In the event of a significant deviation from the protocol due to an accident 
or mistake, the investigator or designee will contact the Sponsor at the emliest possible time by 
telephone to discuss the deviation ai1d its impact on the tii.al and subject continuation in the trial. 
These discussions will be documented by the investigator and the Sponsor, reviewed by the 
monitor, and documented on the Protocol Deviation eCRF. 
14.9. 
Medical Monitor 
The Sponsor will utilize an independent Medical Monitor to provide individual serious adverse 
event adjudication for the trial. It is anticipated that the Medical Monitor will meet with the 
Sponsor on a periodic basis, or as needed, depending on the rate of patient accrual. The primaiy 
responsibilities of the Medical Monitor are to: 
14.10. 
• 
Review serious adverse events that occur over the course of the trial and the 
subsequent classification of these adverse events as related to the device 
• 
Review donor and recipient treatment group eligibili ty issues. 
• 
Evaluate possible protocol deviations. 
• 
Provide oversight for issues affecting general patient welfai·e. 
• 
Provide recommendations to extend the length of follow-up past 30 days post-
transplant for a subject experiencing a serious adverse event. 
• 
Review all site Tepmted EAD diagnosis based on the pre-specified protocol criteria 
and actual clinical case of the trial patient. 
Stopping Rule 
The stopping rule will be con.fumed eve1y time a trigger event occurs (i.e., each time a subject in 
either arms has experienced an eai·ly liver dysfunction or death) . In addition , Stopping rule 
analyses will be conducted twice, once after the first 10 transplanted liver recipients in Pait A of 
the sh1dy have completed 30 days post-transplantation and a second time after the 20 
transplanted liver recipients in Pait A of the study have completed 30 days post-transplantation. 
The stopping rule will be based on the occurrence of either emly liver graft dysfunction within 7 
days or death within 30 days post-tran splantation. The null and alternative hypotheses to be 
tested me as follows: 
I-Lio.: 7t. 3,ocs .:::; 1t.3,coNTRO
L and 
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TransMcdics Confide ntial 
OCS -Liver 092014 
JLi 1.: 7t.3,0CS .> 7t.J,CONTROL-, 
where 1t.3,ocs and n.3,coNTROL 
are the tiue proportions of subjects with either early liver 
graft dysfunction within 7 days or death within 30 days post -transplantation for the OCS 
and Contro l treatments, respective ly. A one-sided Fisher's Exact Test will be conducted 
to test the null hypothesis H40, and the study will be stopped if the p-value is less than 
0.15. 
The table below provides an example ind icating the circumstances under which we wou ld stop 
the study and those under which we would continue the study for the analysis to be perfo rmed 
after the 20 transplanted liver recipients in Pait A of the study have completed 30 days post-
transplantation , assuming 10 recipients in each treatment group. 
Conditions Und er which the Study Would be Stoppe d 
Number of 
Number of OCS Patients Experiencing an Eve nt 
CON TROL 
0 
1 
2 
3 
4 
5 
6 
7 
8 
Patients 
Ex pe1·iencin g 
an Even t 
0 
Cont. 
Cont. 
Cont. 
Stop 
Stop 
Stop 
Stop 
Stop 
Stop 
1 
Cont. 
Cont. 
Cont. 
Cont. 
Stop 
Stop 
Stop 
Stop 
Stop 
2 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Stop 
Stop 
Stop 
Stop 
3 
Cont. 
Cont. 
Cont. 
Cont 
Cont. 
Cont. 
Stop 
Stop 
Stop 
4 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Stop 
Stop 
5 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Stop 
6 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
7 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
8 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Cont. 
Key: Note: Cont. = Continue 
TransMedics will be responsib le for implementing the stopping rnle and will stop the trial if a 
stopping rule was triggered until the data is reviewed by the DMB . 
14.11. 
Data Monitoring Board 
An independent Data Safety Monitoring Bom·d (DMB) will be established by the Sponsor to 
periodically assess the progress of the trial, the safety data and the primary effectiveness and 
safety endpoints. The DSMB will make recomme ndations to the Sponsor regarding 
continuation, modification or term ination of the clinical trial. The DMB will review all data 
submitted to them by the Sponsor and may request addit ional informat ion to assist in their 
decision process . They will attend scheduled meetings and issue written minutes of their 
meetings; fmthennore, the appointed Chair will be responsib le for issuing final written 
recommendations. 
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14.12. 
Investigator Training 
Device, protocol and electronic database training will be provided to all the paiticipant 
investigators and supp01t staff prior to patient enrollment in the trial. Device training will be 
conducted at the TransMedics clinical training facility or equivalent training facility. Protocol 
training will include a thorough review of this protocol. Electronic database training will consist 
of an explanation of the structure of the database, the data elements to be collected, simulated use 
of the database, error handling, and instructions regarding the handling of queries. 
15. 
CONFIDENTIALITY 
Confidentiality agreements will be executed prior to the study related activities commencing. 
All information generated in this trial will be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the trial without written prior permission 
from the Sponsor. Authorized regulatory officials and Sponsor personnel ( or their 
representatives) will be allowed full access to inspect and copy the records. All investigational 
devices, subject bodily fluids, and/or other materials collected shall be used solely in accordance 
with this protocol, unless otherwise agreed to in writing by the Sponsor. Subjects will be 
identified only by initials and unique subject numbers on the case report forms. If necessary , 
their full names may be made known to the Sponsor, a regulatory agency , or other authorized 
officials. 
16. 
AMENDMENT POLICY 
The investigator will not make any changes to this protocol without prior written consent from 
the Sponsor and subsequent approval by the IRB or EC, except if the deviation from the protocol 
is necessaiy to protect the life and physical well-being of a subject in an emergency. Such 
protocol deviations will be rep01ted to the Sponsor and the reviewing IRB or EC as soon as 
possible, but no later than 5 working days after the emergency occurred. Any permanent change 
to the protocol, whether it is ai1 overall change or a change for specific trial center(s) , will be 
handled as a protocol amendment. Any amendment to the protocol that appears indicated as the 
trial progresses will be fully discussed by the inve stigator(s) and the Sponsor. If agreement is 
reached regmding the need for an amendment, it will be written by the Sponsor. The written 
amendment will be submitted to the chairman of the IRB or EC responsible for reviewing 
amendments. Except for "administrative letters ," investigators will await IRB or EC approval of 
protocol amendments before implementing the change(s). Administrative letters are defined to 
have no effect on the validity of the data or info1mation resulting from the completion of the 
approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the 
protocol ; the scientific soundness of the investigational plan or protocol; and, the right, safety or 
welfme of the human subjects involved in the investigation. The Sponsor will notify the FDA of 
such changes in a 5-Day Notice. When, in the judgment of the IRB or EC, the investigators 
and/or the Sponsor , the ainendment to the protocol substantiall y alters the trial design and/or 
increases the potential risk to the subject; such changes will be approved by the FDA and the 
IRB and EC. 
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TransMedics ConCidenlial 
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17. 
REFERENCES 
1. OPTN 2011/Scientific Registry of Transplant Recipients (SRTR) 2011 Annual Report: 
Transplant data 2011. 
2. Yuan Zhai, Henrik Petrowsky , et al. Ischemia-Reperfusion Injury in Liver 
Transplantation-From Bench to Bedside. Nat Rev Gastroenterol Hepatol. 2013 February; 
10 (2): 79-89. 
3. Jason A. Wertheim, MD, PhD, Hemik Petrowsky, MD, Et al. major Challenges Limiting 
Liver Transplantation in the United States. Am J Transplant. 2011 September; 11 (9): 
1773-1784. 
4. Thomas Vogel, Jens G. Brockmann, et al. The Role ofNormothennic Extracorporeal 
Perfusion in Minimizing Ischemia Reperfusion Injmy. Transplantation Reviews 26 
(2012) 156-162 
5. Shawn D St Peter, Charles J Imber, Peter Friend. Liver and Kidney Preservation by 
Perfusion. The Lancet, vol 359, February 16, 2002 
6. Jens Brockmann, MD, Srikanth Reddy, FRCS, et al. Normothermic perfusion a New 
Paradigm for Organ Preservation. Annals of Surgery. Volume 250, Number 1, July 2009; 
250:1-6 
7. Andrew J. Butler, Michael A. Rees, et al. Successful Extracorporeal Porcine Liver 
perfusion For 72 Hr. Transplantation. Vol. 73, 1212-1218, No. 8, April 27, 2002 
8. Constantino Fondevila, MD, PhD, Amelia J. Hessheimer, MD, et al. Superior 
Preservation ofDCD Livers With Continuous Normothermic Perfusion . Annals of 
surgery. Volume 254, Number 6, December 2011. 
9. Ahmed Nassar, MD, Qiang Liu, MD, et al. Ex Vivo Normothermic Machine Perfusion Is 
Safe, Simple and Reliable: results From a Large Animal Model. Surgical Innovation 1-9, 
2014 
10. Ahmed Nassar, Qiang Liu, et al. Role ofVasodilation During Normothennic Machine 
Perfusion ofDCD Porcine Livers. Int J Artif Organs 2014; 37 (2): 165-172 
11. Qiang Liu, Ahmed Nassar, et al. Sanguineous Normothermic Machine Perfusion 
Improves Hemodynamics and Biliary Epithelial Regeneration in Donation after Cardiac 
death Porcine Livers. Liver Transplantation 20: 987-999, 2014 
12. Erik Barthel, Falk Rauhfus, et al. The PRAISE Study: A Prospective, Multi-Center, 
Randomized, Double Blinded, Placebo-Controlled Study for the Evaluation of iloprost in 
the early Postoperative Period After liver Transplantation (ISRCTN 12622749). BMC 
Surgery 2013, 13:1 
13. Kim M. Olthoff, Laura Kulik, et al. Validation of a Current Definition of Early Allograft 
Dysfunction in Liver Transplant Recipients and Analysis of Risk factors. Liver 
Transplantation 16(8):943-949, 2010 
14. Hoyer D, et al. Donor Information Based Prediction for Early Allograft Dysfunction and 
Outcome in Liver Transplantation. Liver Int. 2014;1-8. 
15. Deschenes , et al. EARLY ALLOGRAFT DYSFUNCTION AFTER LIVER 
TRANSPLANT A TI ON: A Definition and Predictors of Outcome. Transplantation: 15 
August 1998 - Volume 66 - Issue 3 - pp 302-310 
16. Van Raemdonck D, Neyrinck A, et al. Machine perfusion in organ transplantation: a tool 
for 
ex-vivo graft conditioning with mesenchymal stem cells? Cur Opinion transplant. 
2013 Feb; 18(1): 24-33. 
17. Schon MR, Kollmar 0 , et al. Liver transplantation after organ preservation with 
norn1othermic ext:racorporeal perfusion. Ann Surg. 2001 Jan; 233(1):114-23 . 
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OCS-Liver 092014 
18. Chan, I.S.F, Zhang, Z., 1999. Test-based confidence intervals for the difference of two 
binomial propmiions . Biometrics 55, 1201-1209. 
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APPENDIX 1. LIVER TISSUE BIOPSY, BILE DUCT SPECIMEN, & 
SCORING PROTOCOL 
Liver Parenchyma Tissue Sample: 
• 
Each tissue specimen is a 2.0 cm long 16-gauge needle biopsy taken perpendicular to 
the liver capsule from the right lobe. It should be stressed that the needle NOT be 
inse1ied parallel to the capsule. 
• 
The tissue sample can then be placed in 10% neutral-buffered formalin, which is 
standard at most institutions. 
• 
The specimen container must be CLEARLY LABELED with an anonymous code 
and specimen info1mation. Bar coding is preferable. 
• 
The label should also contain the timing of the biopsy: a) donor pre-retrieval; b) post-
preservation (before implant); and c) post-reperfusion. 
Timing of Liver Biopsy Samples: 
• 
Liver tissue samples taken at the following time points: 
-
Donor liver pre-retrieval. Only donor livers that are clinically suspected to be 
fatty by retrieval team visualization, will require a pre-retrieval biopsy readout to 
estimate the degree of macrosteatosis and confirm eligibility (:S40% 
macrosteatosis) 
-
Post-OCS and Control preservation at the end of back preparation and 
immediately before the stmi of re-implantation 
-
90-120 minutes after reperfusion of the transplanted liver (prior to abdominal 
closure) 
Bile Duct Specimens (if applicable): 
• 
Any tissue trimmed from the bile duct or cystic duct should be placed into 10% 
neutral buffered fmmalin , as above, and CLEARLY LABELED, as to the center and 
pmticipant and location of the sample. For example, 001-001 "distal common bile 
duct trimming." 
Timing of Bile Duct Specimen: 
• 
Pathology sample of common bile duct taken post preservation (applies to both OCS 
and control arms). 
-
Post preservation at the end of back preparation and immediately before the stmt 
of re-implantation OR 
-
Post reperfusion-Prior to biliary anastomosis 
Refer to core lab collection nuuuwl in the PROTECT Study Manual 
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TransMedics Confidential 
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Score 
P ARENCHYMAL CHANGES: 
Total biopsy length: ____ 
mm 
Total number of portal tracts: ____ 
_ 
Biopsy Adequate: Yes 
Overall architectural integrity: 
1. Lobular necrosis: 
1.1 Overall severity: 
1.2 Primary location: 
1.3 Secondary location 
1.4 Tertiary location: 
2. Lobular inflammation : 
2.1 Overall severity: 
2.2 Primary location: 
2.3 Secondary location: 
3. Lobular inflammation type: 
3.1 Primary type: 
normal/intact mild 
moderate 
severe distortion 
()NONE 
() MILD 
()MOD 
()SEV 
()NIA 
( ) Periportal 
() Midzonal 
( ) Perivenular ( ) Panlobular 
( )NA 
( ) Periportal 
( ) Midzonal 
( ) Perivenular ( ) Panlobular 
( )NA 
( ) Periportal 
( ) Midzonal 
( ) Perivenular ( ) Panlobular 
( )NA 
() NONE 
() MILD 
()MOD 
()SEV 
()N IA 
( ) Periportal 
( ) Midzonal 
() Perivenular ( ) Panlobular 
( )NA 
( ) Periportal 
() Midzonal 
() Perivenular ( ) Panlobular 
( )NA 
( ) N eutrophils ( ) Eosinophils 
( ) Macrophage/monocyte 
( ) Lymphocytes 
( ) N eutrophils ( ) Eosinophils 
( ) Macrophage/monocyte 
( ) Lymphocytes 
3.2 Secondary type: 
3.3 Tertiary type: 
( ) N eutrophils ( ) Eosinophils 
( ) Macrophages/monocytes ( ) Lymphocytes 
4. Lobular Steatosis: 
4.1 Overall severity: 
() NONE 
() MILD 
() MOD 
() SEV 
() NIA 
4.2 Predominant distribution: ( ) Periportal ( )Midzonal ( ) Perivenular ( ) Panlobular ( ) NA 
5. Liver Sinusoidal Endothelial Cell (LSEC) integrity/coverage (based on CD31 staining) 
5 .1 Overall percentage of sinusoids covered ___ 
( nearest 10%) 
5.2 Primary LSEC loss: 
() Periportal 
( )Midzonal 
() Perivenular 
5.3 Secondary LSEC loss: 
() Periportal 
( )Midzonal 
() Perivenular 
EXTRA-HEPATIC BILE DUCT CHANGES: 
( ) Panlobular 
( ) Panlobular 
(adapted from Hansen et al Virchows Arch 2012;461 :41-48; and op den Dries _J HepatoL. 2014 Jun;60(6):1172-9): 
1. Surface epithelial loss: 
( ) 0: no loss 
( ) 1: :S 50% 
( ) > 50% 
2. Bleeding: 
( ) 0: no bleeding 
( ) 1: :S 50% 
( ) > 50% 
3. Thrombi: 
( ) 0: no thrombi 
( ) 1: thrombi present 
4. Vascular lesions: 
( ) 0: no lesions 
( ) 1: :S 50% vessels ( ) > 50% vessels 
5. Arteriolonecrosis: 
( ) 0: no lesions 
( ) 1: :S 50% vessels ( ) > 50% vessels 
( )NA 
( )NA 
No 
( ) Plasma cells 
( ) Plasma cells 
( ) Plasma cells 
6. Duct necrosis: 
( ) 0: no lesions 
( ) 1: <25% 
( ) 2: 25-50% 
( ) 3: 50-75% 
( ) > 75% necrosis 
7. Inflammation: 
( ) 0: none; ( ) 1: at least > 10 leukocytes/HPF; 
( ) 2: >50/HPF 
8. Subluminal gland injury: ( ) 0: no injury 
( ) 1: :S 50% ( ) > 50% 
9. Deep gland injury: 
( ) 0: no loss 
( ) 1: :S 50% ( ) > 50% 
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APPENDIX 2. SCHEDULE OF CLINICAL ASSESSMENTS 
Evaluations 
nonor & Liver Assessments 
ocs 
Cold Flush and Storage 
Preservation 
(Control) 
Eligibility & TD 
X 
X 
Demo graphics/Characteristics 
X 
X 
Donor Cause of Death 
X 
X 
Donor Medical & Social History 
X 
X 
Donor Liver Assessment 
X 
X 
Donor Cross Clamp Time and Flush Detail 
X 
X 
Post-Preservation Liver Biop sy and if applicable Bile duct 
X 
X 
specimen 
OCS Preservation Param eters 
X 
OCS Liver Enzymes & Lactate Levels 
X 
Device Malfuncti on (if applicable) 
X 
N on-tran splant Reasons (if applic able) 
X 
X 
Evaluations 
Recipient Schedule of Assessments 
Tx. Day -Day 7 
Discharge 
Day 
Month 6 
Month 
Month 
l'ost-Tx. 
30 
12 
24 
E ligibility & Tnformed Consent 
X 
Random ization 
X 
Demographic/Characteristics 
X 
Medical & Risk Factors 
X 
Transplant Details 
X 
Early Liver Allograft Dysfunction (EAD) Surveillance 
X 
Mechanical Ventilator Suppo1t 
X 
Patient Survival 
X 
X 
X 
X 
X 
X 
Graft Survival 
X 
X 
X 
X 
X 
X 
Immun osuppressive Meds & Induction (if applicable) 
X 
X 
Initial ICU & Hospital Stay 
X 
X 
Liver Graft- Related (AE's & SAE's ) 
X 
X 
X 
Liver Biopsy * 
X 
X 
X 
* ONLY Tes ts regularly scheduled per center standard of care or performed due to a clinical cause at these time-points w ill be 
collected. 
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APPENDIX 3. DRAFT PATIENT INFORMED CONSENT FORM 
TEMPLATE 
(This Page is Intentionally Left Clear) 
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APPENDIX 4. DRAFT ELECTRONIC CASE REPORT FORMS 
(This Page is Intentionally Left Clear) 
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