Mild Hypothermia and Acute Kidney Injury in Liver Transplantation (MHALT) Trial
Phase: NA
Conditions: Cirrhosis, End Stage Liver Disease, Acute Kidney Injury, Liver Transplant; Complications, Chronic Kidney Diseases, Hepatitis c, Hepatitis B, NASH - Nonalcoholic Steatohepatitis, Alcoholic Cirrhosis, Hepatocellular Carcinoma
Sponsor: University of California, San Francisco

Protocol UCSF IRB # 17-22384 - PI Michael P. Bokoch, M.D., Ph.D. 
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UCSF DEPT. OF ANESTHESIA & PERIOPERATIVE CARE 
Clinical Research Protocol 
MILD HYPOTHERMIA TO PREVENT ACUTE KIDNEY INJURY IN LIVER 
TRANSPLANTATION (MHALT) 
Protocol Number: 
UCSF IRB # 17-22384 
ClinicalTrials.gov ID 
NCT03534141 
Version Date: 
April 2020 
Investigational Product: 
N/A 
IND Number: 
N/A 
Development Phase: 
N/A 
Sponsor: 
Department of Anesthesia and Perioperative Care 
University of California, San Francisco 
500 Parnassus Ave., MUE 4th Floor 
San Francisco, CA 94143-0648 
Funding Organization: 
Dept. of Anesthesia and Perioperative Care, UCSF 
Principal Investigator: 
Name: Michael P. Bokoch, M.D., Ph.D. 
 
Telephone: (650) 387-4314 
Pager: (415) 443-7619 
 
E-mail: Michael.Bokoch@ucsf.edu  
Medical Monitor: 
Name: James Ramsay, M.D. 
Chair, Data Safety Monitoring Board 
Telephone: (415) 502-2298  
 
E-mail: James.Ramsay@ucsf.edu 
 
Coordinating Center: 
UCSF 
 
 

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Approval: 
 
 
 
 
 
 
April 29, 2020 
PI or Sponsor Signature (Name and Title)  
 
 
 
 
 
 
 
 
 
 
 
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   
 
 
 
 
 
 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing University of California, San Francisco, Department of Anesthesia and 
Perioperative Care with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential 
and that this confidentiality requirement applies to all study staff at this site. Furthermore, 
on behalf of the study staff and myself, I agree to maintain the procedures required to 
carry out the study in accordance with accepted GCP principles and to abide by the terms 
of this protocol. 
 
Protocol Number:  UCSF IRB # 17-22384 
 
Protocol Title:   
Mild Hypothermia to Prevent Acute Kidney Injury in Liver Transplantation (MHALT) 
 
Protocol Date:  April 2020 
 
 
 
April 29, 2020 
Investigator Signature  
 
Date 
Michael P. Bokoch, MD, PhD – Assistant Professor of Clinical Anesthesia 
Print Name and Title 
 
 
Site # 
1 of 3 
 
Site Name 
University of California, San Francisco 
Address 
Moffitt-Long Hospital 
 
Department of Anesthesia and Perioperative Care 
 
505 Parnassus Ave. 
 
San Francisco, CA 94143 
Phone Number 
(415) 514-3781 
 

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Site # 
 
 
2 of 3 
Site Name 
Houston Methodist Hospital 
Address 
Sherrie & Alan Conover Center for Liver Disease & Transplantation 
 
Division of Liver Transplantation Surgery  
 
6550 Fannin Street, SM 1661 
 
Houston, TX 77030 
Phone Number (713) 441-6935 
 
Site # 
 
3 of 3 
Site Name 
University of Colorado Hospital 
Address 
Transplant Services – Anschutz Medical Campus 
 
1635 Aurora Court  
 
Mail Stop F-749 
 
Aurora, CO 80045 
Phone Number 
(720) 848-0844 

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TABLE OF CONTENTS 
 
1 
BACKGROUND ................................................................................................ 12 
1.1 
Overview of Non-Clinical Studies ..................................................................................... 12 
1.2 
Overview of Clinical Studies ............................................................................................. 12 
2 
STUDY RATIONALE ....................................................................................... 12 
2.1 
Risk / Benefit Assessment ................................................................................................. 13 
3 
STUDY OBJECTIVES ...................................................................................... 14 
3.1 
Primary Objective .............................................................................................................. 14 
3.2 
Secondary Objectives ......................................................................................................... 14 
4 
STUDY DESIGN ..................................................................................................... 15 
4.1 
Study Overview .................................................................................................................. 15 
5 
Criteria for evaluation ........................................................................................ 16 
5.1 
Primary Efficacy Endpoint ................................................................................................ 16 
5.2 
Secondary Efficacy Endpoints ........................................................................................... 16 
5.3 
Safety Evaluations ............................................................................................................. 17 
5.4 
Other Evaluations .............................................................................................................. 19 
6 
SUBJECT SELECTION .................................................................................... 19 
6.1 
Study Population ................................................................................................................ 19 
6.2 
Inclusion Criteria ............................................................................................................... 19 
6.3 
Exclusion Criteria .............................................................................................................. 19 
7 
Concurrent Medications ..................................................................................... 20 
8 
STUDY TREATMENTS .................................................................................... 20 
8.1 
Method of Assigning Subjects to Treatment Groups ......................................................... 20 
8.2 
Blinding ............................................................................................................................. 20 
8.3 
Formulation of Test and Control Treatments ..................................................................... 20 
9 
STUDY PROCEDURES AND GUIDELINES .................................................. 22 
9.1 
Clinical Assessments ......................................................................................................... 22 
9.2 
Clinical Laboratory Measurements .................................................................................... 23 
9.3 
Research Laboratory Measurements .................................................................................. 23 
10 
EVALUATIONS BY VISIT .................................................................................... 23 
10.1 
Visit 1 (Day 1, before and during LTx) ............................................................................. 23 
10.2 
Visit 2 (Follow-up prior to hospital discharge, window of 2 ± 1 weeks after LTx) ........... 24 
11 
ADVERSE Experience REPORTING AND DOCUMENTATION .............. 24 
11.1 
Adverse Events .................................................................................................................. 24 
11.2 
Serious Adverse Experiences (SAE) .................................................................................. 25 
12 
DISCONTINUATION And Replacement of subjects .................................... 26 
12.1 
Early Discontinuation of Study Treatment ........................................................................ 26 
12.3 
Withdrawal of Subjects from the Study ............................................................................. 26 
12.4 
Replacement of Subjects ................................................................................................... 27 
13 
PRotocol Violations ........................................................................................ 27 

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14 
DATA SAFETY MONITORING ................................................................... 27 
15 
STATISTICAL METHODS AND CONSIDERATIONS .............................. 27 
15.1 
Data Sets Analyzed ............................................................................................................ 28 
15.2 
Demographic and Baseline Characteristics ........................................................................ 28 
15.3 
Analysis of Primary Endpoint ............................................................................................ 28 
15.4 
Analysis of Secondary Endpoints ...................................................................................... 28 
15.5 
Interim Analysis ................................................................................................................. 29 
15.6 
Sample Size and Randomization ........................................................................................ 30 
16 
DATA COLLECTION, RETENTION AND MONITORING ...................... 30 
16.1 
Data Collection Instruments .............................................................................................. 30 
16.2 
Data Management Procedures ........................................................................................... 30 
16.3 
Data Quality Control and Reporting .................................................................................. 31 
16.4 
Archival of Data ................................................................................................................ 31 
16.5 
Availability and Retention of Investigational Records ...................................................... 31 
16.6 
Monitoring ......................................................................................................................... 31 
16.7 
Subject Confidentiality ...................................................................................................... 31 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ... 31 
17.1 
Protocol Amendments ........................................................................................................ 32 
17.2 
Institutional Review Boards and Independent Ethics Committees .................................... 32 
17.3 
Informed Consent Form ..................................................................................................... 32 
17.4 
Publications ........................................................................................................................ 33 
17.5 
Investigator Responsibilities .............................................................................................. 33 
 

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LIST OF ABBREVIATIONS 
ABG 
arterial blood gas 
AE 
adverse event 
AKI 
acute kidney injury 
AKIN 
Acute Kidney Injury Network 
ALF 
acute liver failure 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CRRT 
continuous renal replacement therapy 
CTSI 
Clinical & Translational Science Institute 
DCD 
donor after cardiac death 
DMC 
Data Monitoring Committee 
DNDD 
donor after neurologic determination of death 
EBL 
estimated blood loss 
ECD 
esophageal cooling device 
ELISA 
enzyme-linked immunosorbent assay 
EMR 
electronic medical record 
FDA 
Food and Drug Administration 
FFP 
fresh frozen plasma 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICA 
International Club for Ascites 
ICF 
informed consent form 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
I-R 
ischemia-reperfusion 
IRB 
Institutional Review Board 
IVC 
inferior vena cava 
ITT 
intention-to-treat 
LTx 
liver transplantation 
NGAL 
neutrophil gelatinase-associated lipocalin 
OG 
orogastric 
PI 
Principal Investigator 
pRBC 
packed red blood cells 
RCT 
randomized controlled trial 
RRT 
renal replacement therapy 
SAE 
serious adverse experience 

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sCR 
serum creatinine 
SSI 
surgical site infection 
TEE 
transesophageal echocardiography 

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PROTOCOL SYNOPSIS 
TITLE 
Mild Hypothermia to Prevent Acute Kidney Injury in Liver 
Transplantation (MHALT) 
SPONSOR 
University of California, San Francisco 
FUNDING 
ORGANIZATION 
Department of Anesthesia and Perioperative Care 
NUMBER OF SITES 
3 
RATIONALE 
Patients undergoing liver transplantation (LTx) are at extremely high 
risk of perioperative acute kidney injury (AKI). AKI has enormous 
impact on outcomes and cost after LTx. 68% of patients at UCSF 
sustain some degree of AKI and 12% develop AKI Stage 3 (a three-
fold increase in sCr from baseline or need for dialysis) after LTx. 
Thirty-day and 1-year mortality, graft survival, and progression to 
chronic kidney disease correlate with the presence and severity of 
AKI. Clearly, any intervention that reduces the incidence or severity 
of AKI in this population would have tremendous impact on short and 
long-term outcomes and cost.  
This trial will study mild hypothermia in LTx for prevention of 
AKI. The protocol is based on strong preliminary data from rodent 
studies showing that hypothermia protects renal function in ischemia-
reperfusion models. Recent work from our department has shown that 
mild hypothermia in deceased organ donors improves graft function 
after kidney transplantation. In light of these preliminary data, we 
propose a trial of mild hypothermia to prevent AKI in LTx. 
STUDY DESIGN 
This is a single-blind, randomized controlled trial 
PRIMARY 
OBJECTIVE 
Assess whether or not mild hypothermia has a protective effect on 
early AKI after liver transplantation. 
SECONDARY 
OBJECTIVES 
1. Demonstrate the feasibility of mild hypothermia during liver 
transplantation.  
2. Assess whether or not mild hypothermia reduces early 
biomarkers of AKI during liver transplantation such as 
neutrophil gelatinase-associated lipocalin (NGAL) 
NUMBER OF 
SUBJECTS 
230 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Age ≥ 18 years 
2. LTx from a donor after neurologic determination of death 
(DNDD) 
Exclusion Criteria: 
1. LTx from a donor after cardiac death (DCD) 
2. LTx for acute liver failure (ALF) 
3. Living-donor LTx 
4. Simultaneous liver-kidney transplantation 

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5. Preoperative renal replacement therapy (RRT) 
6. Preoperative intubation and/or mechanical ventilation 
7. Portopulmonary hypertension 
TEST TREATMENT 
AND METHOD OF 
ADMINISTRATION 
Mild hypothermia (34-35 °C) during liver transplantation 
 
Mild hypothermia will be induced using an esophageal cooling device 
(ECD), as well as standard measures after the induction of general 
anesthesia until blood flow is completely restored to the liver. The 
anticipated median duration of mild hypothermia will be 4-5 hours. 
When feasible, the right kidney will also be packed with ice-cold 
sponges to enhance cooling of the renal parenchyma during the 
anhepatic phase of the operation. 
CONTROL 
TREATMENT AND 
METHOD OF 
ADMINISTRATION 
Normothermia (36.5-37.5 °C) during liver transplantation 
 
Normothermia will be maintained using an ECD as well as standard 
measures after the induction of general anesthesia and throughout the 
liver transplant operation. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to one year. 
Screening:  less than 1 day 
Treatment:  less than 1 day (during liver transplantation) 
Follow-up:  1 year 
The total duration of the study is expected to be 36 months.  24 
months for subject recruitment and 12 for final subject follow-up. 
CONCOMMITANT 
MEDICATIONS 
Allowed: N/A 
 
Prohibited: N/A 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
• 
Incidence of acute kidney injury within 72 hours after liver 
transplantation 
SECONDARY 
ENDPOINTS 
• 
Distribution of the stages of acute kidney injury within 72 hours 
after liver transplantation 
• 
Duration of intensive care unit stay 
• 
Duration of hospital stay 
• 
One-year survival rate 
• 
Need for renal replacement therapy within 7-days, at 30-days, and 
at 1 year after transplant 
• 
Persistent renal dysfunction at 90-days and 1-year after transplant 
• 
Change in serum NGAL levels from baseline to 2 hours after 
reperfusion of the portal vein 
• 
Change in urine NGAL levels from baseline to 2 hours after 
reperfusion of the portal vein 
 
OTHER 
EVALUATIONS 
• 
Percentage of intraoperative time within target temperature range 

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• 
Time to reach normothermia upon initiation of re-warming (mild 
hypothermia arm) 
SAFETY 
EVALUATIONS 
• 
Number of units of blood products transfused (packed red blood 
cells, fresh frozen plasma, platelets, and cryoprecipitate) 
• 
Incidence of surgical site infections within 2 weeks of LTx 
• 
Intraoperative vasopressor doses 
PLANNED INTERIM 
ANALYSES  
When 50% of patients have completed the study, an interim analysis 
for efficacy will be conducted by an independent data safety 
monitoring board (DSMB). 
STATISTICS 
Primary Analysis Plan 
Presence or absence of AKI, and the different categories of AKI 
(Stage 1, 2, or 3 or no AKI), will be summarized as frequency and 
percentage. The primary outcome (presence or absence of AKI) will 
be compared between the two arms by a two-sample proportion test. 
The frequency of different categories of AKI (Stage 1, 2, or 3 or no 
AKI) will be analyzed by a chi-square test. Intention-to-treat analysis 
will be performed. 
Rationale for Number 
of Subjects 
The incidence of AKI in LTx patients at UCSF is 68%. Considering 
one interim analysis for efficacy, we estimate a sample size of 101 
subjects per arm is needed to detect a 30% reduction in AKI with 80% 
power at overall a = 0.05 (two-tailed). To allow for approximately 
10% study drop-out or inability to complete the study protocol, we 
plan to enroll a total of 230 subjects. 
 

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1 
BACKGROUND 
This trial proposes a mild hypothermia intervention (34-35 °C) that is pragmatic, simple, 
and non-invasive. Cooling will be performed using an Esophageal Cooling Device (ECD) 
model EnsoETM (Attune Medical) as well as standard measures (forced-air blankets, 
conductive table cooling). The ECD is a Food and Drug Administration (FDA) approved 
device that is placed in a manner identical to a standard orogastric (OG) tube.1-3 The ECD 
will help maintain the core temperature of the anesthetized patient between 34-35 °C 
during LTx. This temperature range is only slightly lower than that typically seen in LTx 
due to passive heat loss. When possible, the surgeon will also apply local cooling (ice-
cold sponges on the surgical field) to the right kidney during the anhepatic phase of the 
operation. After blood flow is fully restored to the liver, the ECD and standard measures 
(forced-air, fluid, and table warmers, plus a heated anesthesia circuit) will be used to 
actively rewarm subjects. 
1.1 
Overview of Non-Clinical Studies 
Extensive rodent work by Dr. Claus Niemann, one of the investigators for the current trial, 
and colleagues has shown the benefits of mild hypothermia for protecting visceral organs 
against ischemia-reperfusion (I-R) injury. Prior work showed that mild hypothermia (33-
34 °C) is protective against hepatic ischemic injury in both obese and lean rats.4-7 In soon 
to be published rodent work, Dr. Niemann's group has shown that mild hypothermia also 
protects the kidney from injury and inflammation induced by renal artery clamping. Other 
researchers have also shown that mild-moderate hypothermia reduces acute kidney injury 
due to I-R.8 
1.2 
Overview of Clinical Studies 
Therapeutic hypothermia has long been investigated as a way to preserve end-organ 
function from ischemic insult, by reducing oxygen consumption, free radical production, 
and inflammation.9 Targeted temperature management has been recommended to preserve 
neurologic function after cardiac arrest10 (although recent data has questioned this 
finding)11 and during circulatory arrest for aortic arch repair.12 Cold renal perfusion may 
reduce AKI during open aortic aneurysm repair.13 Recently, Dr. Niemann's group has also 
shown that mild hypothermia in brain-dead organ donors improves graft function after 
kidney transplantation.14 
The ECD is a US FDA approved device for induction and maintenance of hypothermia 
through a minimally invasive approach.2 The device has been shown to be effective and 
safe for induction and maintenance of hypothermia after out-of-hospital cardiac arrest1 
and in a series of intensive care unit (ICU) patients.3. 
 
2 
STUDY RATIONALE 
As in the general hospitalized population, AKI has enormous impact on outcomes and 
cost after surgery. Numerous, mostly pharmacologic interventions (e.g., dopamine, N-
acetylcysteine), have been investigated for renal-protecting properties in high-risk surgery 
- and none have shown clear benefit.15,16 Most of these studies suffer from heterogeneous 

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populations (i.e., a mix of cardiac, vascular, and other high-risk surgery), imprecise 
definitions of AKI, and a lack of good biomarkers. Patients undergoing LTx are a specific 
population at extremely high risk of perioperative AKI. Thirty-day and 1-year mortality,17-
20 as well as graft survival,21,22 correlate with the presence and severity of AKI. While 
modern surgical technique (partial inferior vena cava cross-clamp) reduces the incidence 
of AKI,23,24 68% of patients at UCSF sustain some degree of AKI and 12% develop AKI 
Stage 3 (a three-fold increase in sCr from baseline or need for dialysis) after LTx. Clearly, 
any intervention that reduces the incidence or severity of AKI in this population would 
have tremendous impact on short and long-term outcomes and cost.  
 
Given the preliminary data from pre-clinical and clinical studies described above (see 
Section 1.1 and 1.2), there is good rationale for a trial of mild hypothermia during LTx as 
a strategy to prevent AKI. The ECD, an FDA-approved device for cooling or warming of 
patients through a minimally invasive approach, will facilitate rapid cooling of patients to 
target temperature (test treatment), maintenance of normothermia (control treatment), and 
re-warming of patients prior to extubation (test treatment). Without the ECD, the current 
standard-of-care measures for intraoperative temperature control (forced air blankets, 
conductive table heater/coolers, fluid warmers, and a heated-humidified anesthesia circuit) 
are unable to achieve the precision needed for this trial. 
 
2.1 
Risk / Benefit Assessment 
As described above, AKI leads to worse outcomes for patients. The severity of AKI, even 
after adjustment for multiple cofounders, correlates with increased mortality, hospital 
length of stay, and cost.25 Even AKI Stage 1, characterized by increases in sCr as small as 
0.3-0.4 mg/dL, is associated with a 70% increase in risk of death. In cases where sCr rises 
≥ 2 mg/dL, the odds ratio for mortality approaches 50 and excess costs exceed $20,000 
per patient. After liver transplant surgery in particular, AKI has enormous impact. Thirty-
day and 1-year mortality, as well as graft survival, correlate with the presence and severity 
of AKI (see above Section 2 for references). 
 
Given the major negative outcomes associated with AKI after liver transplantation, the 
potential benefit of a positive result in this study is extremely high. Preventing or reducing 
the severity of AKI in any given participant would clearly result in direct benefit by 
lowering the risk of outcomes such as mortality, re-hospitalization, graft loss, or chronic 
kidney disease. The results of the study will help define optimal care for future liver 
transplant patients, and possibly for other surgical patients at high risk of AKI (e.g., 
vascular and cardiac surgery). For society at large, a positive result of this trial would 
likely result in significant monetary savings in terms of health care costs and resource 
utilization. By comparison, the risks of the study are mild and include (1) risks of the ECD 
and (2) side effects of hypothermia. 
 
Even though it is removed at the end of surgery, it is possible that placement of the ECD 
could lead to more discomfort, sore throat, or difficulty swallowing due to the larger size 
of the device compared with a standard OG tube. However, the ECD is smaller and softer 
than a transesophageal echo (TEE) probe that is routinely placed during LTx. The 

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incidence of painful swallowing after TEE insertion is 0.1%,26 and the risk of discomfort 
after ECD placement is expected to be even lower. To minimize the risk of discomfort, 
ECDs will be well-lubricated and only placed by study doctors experienced in the 
placement of OG tubes and TEE probes (attending liver transplant anesthesiologists). 
While placement of the ECD could theoretically cause gastrointestinal bleeding from 
varices, placement of larger probes for TEE is generally considered safe during LTx and 
routinely performed by 86% of liver transplant anesthesiologists in the US.27,28 
 
Mild intraoperative hypothermia has few potential risks.29 Currently 23% of patients 
experience temperatures < 35 °C during LTx at UCSF (data not shown), although not in a 
precisely controlled fashion as proposed in this trial. Hypothermia can exacerbate 
coagulopathy and increase transfusion requirements, but this is mainly described at 
temperatures below our proposed range of 34-35 °C. Increased bleeding was NOT seen in 
a large randomized controlled trial (RCT) of cooling to 33 °C in intracranial aneurysm 
surgery.30 Nevertheless, to mitigate the risk of coagulopathy from hypothermia, the 
attending liver transplant surgeon will be asked to rate the degree of coagulopathy on a 
qualitative scale at various points in the operation (see below). If mild hypothermia is felt 
to be contributing to a coagulopathy that is unsafe for the patient, either the attending 
surgeon or anesthesiologist may request abortion of the hypothermia protocol at any point 
in the operation and rewarming of the patient will be initiated. Cardiovascular instability 
was not observed in a secondary analysis of the aneurysm trial mentioned above31 or in 
the trial of brain-dead kidney donors.14 Hypothermia has been reported to increase 
surgical site infections and bacteremia,29,30 but we are confident that this can be prevented 
by active warming prior to case end and the current antibiotic protocols for LTx.  
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to assess whether or not mild hypothermia has a protective 
effect on early AKI after liver transplantation. We hypothesize that mild hypothermia 
will protect against intraoperative AKI during LTx. We will measure the proportion of 
patients that develop AKI in the early post-transplant period (≤ 72 hours) as our primary 
efficacy outcome. This time window is likely to reflect AKI occurring due to 
intraoperative events,22,32 and therefore has potential to be modulated by the study 
intervention. Serum creatinine measurements will be recorded by observers blinded to the 
treatment arm, and the presence and severity of AKI adjudicated according to the latest 
criteria.33,34 
3.2 
Secondary Objectives 
The secondary objectives are: 
• Assess the feasibility of a mild hypothermia protocol during LTx. Cooling will 
be performed using an ECD as well as standard measures. When possible, the 
surgeon will also apply local cooling (ice-cold sponges on the surgical field) to the 
right kidney during the anhepatic phase of the operation. After blood flow is fully 

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restored to the liver, the ECD and standard measures will be used to actively 
rewarm subjects. Feasibility will be assessed by the proportion of patients 
successfully completing the protocol, and the percentage of time spent within the 
target temperature range. 
• Measure biomarkers of AKI during and after mild hypothermia or 
normothermia in LTx. NGAL, a protein elevated in AKI,35 has been described by 
Dr. Niemann's group as an early biomarker of AKI during LTx.24 Serum NGAL 
indicates glomerular injury, while urine NGAL is a marker of distal tubular 
injury.36 Blood and urine samples will be collected for NGAL determination at 
baseline and two hours after reperfusion of the portal vein. 
 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a multi-center, single-blind, RCT.  230 subjects are planned.  Each subject will 
have an ECD placed after induction of general anesthesia and undergo LTx with one of 
two temperature management protocols (Fig. 1).  Each subject will receive only one of the 
two experimental treatments.  Subjects will be randomizaed to one of the two treatments.  
Evaluations will be taken at baseline, and at several intraoperative time points. Data from 
the electronic medical record will be analyzed post-operatively. 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  
The following treatment regimens will be used (Fig. 1): 
• Experimental treatment – Mild hypothermia (34-35 °C). Cooling will be 
initiated after induction of anesthesia and maintained throughout the anhepatic 
phase of LTx (Fig. 1). In all feasible cases the surgeon will cover the peritoneal 
surface over the right kidney, which is exposed during the operation, with ice-cold 
sponges to enhance cooling of the renal parenchyma. Shortly (15 minutes) after the 
portal vein is reperfused, the ECD and other standard measures (forced-air, fluid, 
and table warmers, plus a heated anesthesia circuit) will be used to actively re-
warm the patient (expected warming rate ≥ 1 °C/hour). The goal is to achieve 
normothermia by case end. 
• Control – Normothermia (36.5-37.5 °C). After induction of anesthesia, the ECD 
and standard warming measures will be used to maintain normothermia throughout 
the operation. 
Total duration of subject participation will be approximately 6-10 hours, which is the 
duration of surgery. Subjects will be followed up remotely via the electronic medical 
record (EMR) for 1 year after LTx. 
 

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Figure 1. Scheme of overall study design showing temperature management protocols. 
 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the incidence of AKI within 72 hours after LTx. The 
International Club for Ascites (ICA) 2015 criteria, a revision of the KDIGO criteria for 
patients with cirrhosis, will be used to define AKI.33 The definitions are as follows: 
 
• AKI: increase in sCr ≥ 0.3 mg/dL within a 48 hour time window, or a percentage 
increase ≥ 50% from baseline, or initiation of RRT. 
• Baseline sCr: the most recent value of sCr prior to LTx 
 
A predefined subgroup analysis of the primary outcome will be performed in patients 
undergoing liver transplantation for hepatocellular carcinoma (HCC) with Model for End-
stage Liver Disease exception points. 
 
5.2 
Secondary Efficacy Endpoints 
A. The distribution of the stages of AKI within 72 hours after liver transplantation. The 
ICA 2015 criteria will be used to define the stages of AKI as follows: 
• AKI Stage 1: increase in sCr ≥ 0.3 mg/dL, or an increase in sCr ≥ 1.5-fold and ≤ 
2-fold from baseline. 
• AKI Stage 2: increase in sCr > 2-fold and ≤ 3-fold from baseline. 
• AKI Stage 3: increase in sCr > 3-fold from baseline, or sCr ≥ 4.0 with an acute 
increase of ≥ 0.3 mg/dL, or initiation of RRT 
B. Duration of intensive care unit (ICU) stay. 

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• 
AKI may worsen volume overload, electrolyte abnormalities, and metabolic 
acidosis, all of which can lead to prolongation of ICU stay. 
C. Duration of hospital stay. 
D. One-year survival rate. 
• 
AKI after LTx is a negative predictor of mortality.17,20  
E. Incidence of post-operative renal replacement therapy within 7-days, at 30-days, and 
at 1 year after transplant. 
• 
LTx is a predictor of developing chronic renal failure.37 
F. Persistent renal dysfunction at 90-days and 1-year after transplant. 
• 
Presence of a reduction in GFR by ≥ 25 mL/min or ≥ 50% from baseline 
(Kellum et al.) 
• 
We are aware that patients may not have lab values available from dates 
exactly 30-days, 90-days, and 1-year after the date of transplantation surgery. 
In order to standardize our data collection, we have developed rules to 
determine the appropriate serum creatinine values to record. The rules are as 
follows:  
 
1 year follow up: preferences (in order of preference) for selecting serum 
creatinine value to record: 
1. Serum creatinine value within 1 month after 1-year follow-up 
date.  
2. Serum creatinine value within 1 month before 1-year follow-up 
date.  
3. Serum creatinine value collected at a date after 1-year follow-up 
date that is beyond 1 month but closest to the follow-up date.  
 
30 and 90 day follow up: 
§ The serum creatinine value recorded must have been collected on 
or post the 30 and 90 follow-up dates. Select the serum creatinine 
value on or closest to the 30- and 90-day follow-up dates.  
 
G. Change in serum NGAL levels from baseline (start of surgery) to 2 hours after 
reperfusion of the liver graft (opening of the portal vein). 
• 
NGAL has been shown to be an early marker of AKI in LTx,24 and as such 
has the potential to be modulated by the study intervention 
H. Change in urine NGAL levels from baseline (start of surgery) to 2 hours after 
reperfusion of the liver graft (opening of the portal vein). 
• 
NGAL has been shown to be an early marker of AKI in LTx,24 and as such 
has the potential to be modulated by the study intervention 
 
5.3 
Safety Evaluations 
A. Intraoperative coagulopathy assessment – while it is unlikely that mild 
hypothermia (34-35 °C) will significantly impair the coagulation cascade or 
platelet function to a significant degree,30 we will ask the attending surgeon to 
qualitatively rate the degree of clinical coagulopathy as visualized on the 

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abdominal wall at two intraoperative time points: (1) shortly after incision when 
the abdominal wall retractors are first placed, and (2) 30 minutes after reperfusion 
of the hepatic artery. Coagulopathy will be rated as minimal, mild, moderate, or 
severe. 
B. Blood product transfusions and estimated blood loss – While previous studies 
of mild hypothermia during intracranial aneurysm surgery did not show increases 
in surgical bleeding or blood product transfusions,30 we will record the number of 
packed red blood cell (pRBC), fresh frozen plasma (FFP), platelet, and 
cryoprecipitate units transfused during surgery, as well as the volume of 
autologous cell salvage blood (i.e. “Cell Saver”, which is standard practice at 
UCSF in LTx operations) administered to the patient. The estimated blood loss 
(EBL) will be calculated by the Cell Saver technician and recorded. 
C. Vasopressor doses – Prior studies of mild intraoperative hypothermia have not 
shown increased vasopressor requirements,31 and vasopressor use is extremely 
common during LTx. As a safety evaluation, we will record the total vasopressor 
doses in the pre-anhepatic, anhepatic, and reperfusion phases of LTx. 
D. Arterial blood gases – The acid-base status of the patient undergoing LTx, as 
measured by the base deficit on arterial blood gas (ABG) analysis, reflects the 
overall perfusion of the patient as well as function of the liver graft. ABGs are 
typically drawn at several time points during the LTx operation and these values 
will be recorded. 
E. Incidence of the following adverse events (AEs): 
• Significant bleeding in conjunction with evidence of severe, refractory 
coagulopathy 
o Defined as significant bleeding that is not attributable to vascular injury 
in the presence of ongoing severe clinical coagulopathy despite 
aggressive treatment (fresh frozen plasma 15 mL/kg, cryoprecipitate 
10 units x 2 doses, and the administration of antifibrinolytics). While 
coagulopathy is a clinical diagnosis during LTx, we would consider 
persistent INR > 4 or fibrinogen < 75 mg/dL after the aggressive 
treatment above as laboratory evidence of severe coagulopathy. 
• Severe upper gastrointestinal (GI) bleeding at the time of ECD insertion 
o It is common to have mild upper GI bleeding after insertion of a 
standard orogastric tube during liver transplant, so only blood return of 
> 500 mL will be considered an AE. 
• Severe hypothermia 
o < 33 °C for greater than 30 minutes 
• Oropharyngeal, dental, or esophageal trauma 
• Perforation or damage to the ECD 
• Intraoperative cardiac arrhythmias requiring treatment 31 – excluding 
bradycardia typically seen at the time of reperfusion of the liver graft. 

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• Intraoperative myocardial ischemia or infarction. 
• Discomfort (oropharyngeal pain, dysphagia, odynophagia) - patients will be 
asked about these symptoms post-operatively 
• Surgical site infections (SSIs) – prior to discharge from the hospital after LTx, 
or within two weeks of LTx (whichever comes first).38 
 
5.4 
Other Evaluations 
A. Fluid totals – Fluid intake (crystalloid, colloid, and blood products) and output 
(estimated blood loss, urine output) will be tallied and recorded at defined time 
points in each case: start of surgery (skin incision), clamping of the hepatic artery, 
15 minutes post-reperfusion of the of the portal vein, completion of the hepatic 
artery, completion of the bile duct, and end of surgery (skin closure). 
B. Time at target temperature range – The percentage of time within the target 
core temperature range (34-35 °C for the Experimental Treatment, and 36.5-37.5 
°C for the Control) as measured by bladder temperature, will be calculated. 
 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of liver disease who meet the inclusion and exclusion criteria 
will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
1. Male or female ≥ 18 years of age at the time of LTx. 
2. Undergoing LTx from a donor after neurologic determination of death (DNDD). 
3. Written informed consent obtained from subject or subject’s legal representative and 
ability for subject to comply with the requirements of the study. 
6.3 
Exclusion Criteria 
1. Undergoing LTx from a donor after cardiac death (DCD) 
2. Undergoing LTx for acute liver failure (ALF) 
3. Undergoing LTx from a living donor 
4. Undergoing simultaneous liver-kidney transplantation 
5. Subject has a diagnosis of portopulmonary hypertension (defined as mean pulmonary 
artery pressure ³ 25 mmHg, pulmonary vascular resistance > 3 Woods Units, and 
pulmonary artery wedge pressure < 15 mmHg in the setting of portal hypertension 
without another known cause). 

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6. Subject received RRT, including hemodialysis or continuous renal replacement 
therapy, within a week prior to liver transplantation. 
7. Subject is intubated and/or mechanically ventilated prior to entering the operating 
room LTx. 
8. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
 
7 
CONCURRENT MEDICATIONS 
Not applicable. 
 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Up to 230 eligible patients will be randomly assigned to the Experimental Treatment (mild 
hypothermia) or Control (normothermia) groups in a 1:1 ratio using a block randomization 
scheme with a randomly chosen block size of 6 or 8 for each block. The randomization 
scheme was developed by Randomize.net and is accessed through a secure web portal. 
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to patients.  The following study procedures will be in place to ensure single-blind 
administration of study treatments. 
Access to the randomization code will be strictly controlled. The randomization code will 
not be revealed until the patient has entered the operating room for liver transplantation. 
The study protocol will be completed in its entirety while the patient is in the operating 
room under general anesthesia. Therefore, it will be impossible for the patient to know the 
treatment assignment until the protocol is complete.   
No attempt will be made to blind the study doctors (anesthesiologists), who are 
investigators in the study, to the treatment assignment, as they will be the ones 
administering and monitoring the temperature protocol during LTx.  
Research staff assigned to adjudicate the Primary Outcome (presence or absence of AKI 
within 72 h of LTx) will be blinded to the treatment assignment and the intraoperative 
anesthesia record showing the patient’s core temperature. Only the preoperative and 
postoperative values of sCr will be necessary to adjudicate the Primary Outcome. 
The study blind will be broken on completion of the clinical study and after the study 
database has been locked. 
8.3 
Formulation of Test and Control Treatments 
After induction of general anesthesia, the ECD will be connected to the Gaymar Medi-
Therm III Hyper/Hypothermia Machine and tested for leaks according to the 

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manufacturer’s instructions. Then, it will be lubricated and placed into the esophagus of 
the subject in a manner identical to that of the standard OG tube used in LTx surgery.  
The standard bladder temperature probe used in LTx operations will be connected to the 
PATIENT PROBE jack of the Gaymar Medi-Therm III, which will be used in 
AUTO/Rapid mode. 
In both Study Arms (Mild Hypothermia and Normothermia), the subject will be given 2 
grams of magnesium (Mg) sulfate IV at the beginning of surgery if the preoperative Mg < 
2 mg/dL. This will be done because mild hypothermia may trigger a cold-induced diuresis 
and loss of electrolytes. Therefore, efforts will be made to keep the Mg normal (1.8-2.4 
mg/dL) in both groups. Potassium will also be monitored carefully during surgery and 
replaced at the discretion of the attending anesthesiologist/study doctor. 
 
Experimental treatment – Mild hypothermia (34-35 °C).  
• Cooling will be initiated after induction of anesthesia and maintained throughout 
the anhepatic phase of LTx (Fig. 1). This will be done by selecting a Set Point 
temeperature of 34.8 °C1 on the Gaymar Medi-Therm III. 
• In all feasible cases the surgeon will cover the peritoneal surface over the right 
kidney, which is exposed during the operation, with ice-cold sponges (lap sponges 
soaked in ice water and wrapped around ice cubes) to enhance cooling of the renal 
parenchyma. Local cooling will be applied to the right kidney beginning 
approximately 10 minutes prior to the anhepatic phase. The anhepatic phase is 
defined as application of the inferior vena cava (IVC) clamp and removal of the 
recipient liver.  
• After the portal vein is reperfused, the ECD (by selecting a Set Point temperature 
of 37 °C on the Gaymar Medi-Therm III) and other standard measures (forced-air, 
fluid, and table warmers, plus a heated anesthesia circuit) will be used to actively 
re-warm the patient (expected warming rate ≥ 1 °C/hour). The goal is to achieve 
normothermia by case end. 
 
Control – Normothermia (36.5-37.5 °C). 
• After induction of anesthesia, the ECD (by selecting a Set Point temperature of 37 
°C on the Gaymar Medi-Therm III) and standard warming measures will be used 
to maintain normothermia throughout the operation. 
 
At the end of LTx surgery, the ECD will be removed from the patient prior to emergence 
from general anesthesia, extubation, and/or transport to the ICU. 
 
 
1 The original protocol used a set point of 34.4 °C. However, we found that the core temperature dropped 
significantly (~0.5 °C) during the anhepatic phase (due to the cold liver graft and ice pack on the right 
kidney). Thus, we have modified the Set Point temperature to 34.8 °C.  

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9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening.  Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a 
subinvestigator who is a physician at Screening (this is part of the standard anesthesia 
preoperative assessment prior to liver transplant surgery). New abnormal physical exam 
findings must be documented and will be followed by a physician or other qualified staff 
post-operatively. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse, oximetry and respirations will be performed 
prior to induction of general anesthesia at Screening and continuously while receiving the 
Study Protocol in the OR during LTx. 
9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 

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9.2 
Clinical Laboratory Measurements 
9.2.1 
Arterial Blood Gas 
Arterial blood will be obtained and analyzed by point-of-care testing using an ABL-90 
blood gas analyzer. This is standard of care during LTx at UCSF and no additional ABGs 
will be drawn outside of what is normally required for patient care.  
9.3 
Research Laboratory Measurements 
9.3.1 
Serum NGAL Measurements 
At two time points, baseline (surgical incision) and 2 hours after reperfusion of the portal 
vein, blood will be collected for serum NGAL determination. At each blood draw, two 
serum separator tubes (gold top) will be filled. Each tube requires about 5 mL of blood, 
there will be 2 tubes collected per time point, and 2 time points, for a total of about 20 mL 
of blood (4 tubes). 
After filling with blood, tubes will be inverted 5-times to mix clot activator with blood. 
Samples will sit undisturbed for 30 min to allow clot to form. Samples will be centrifuged 
at 1,000 x g for 15 minutes. Serum will be pipetted into Eppendorf tubes in 2 mL aliquots 
and frozen at £ -20 °C until analysis, which will be performed en batch. 
Serum NGAL determination will be performed using an enzyme-linked immunosorbent 
assay (ELISA) kit according to the manufacturer’s instructions (R&D Systems, Inc.). 
9.3.2 
Urine NGAL Measurements 
At two time points, baseline (surgical incision) and 2 hours after reperfusion of the portal 
vein, urine will be collected for NGAL determination. Approximately 10-15 mL of fresh 
urine will be aspirated from the Foley catheter collection chamber using a syringe, and 
dispensed into a 15-mL sterile tube (Falcon). The urine will be centrifuged at 1,000 x g for 
15 min to pellet any solid material. The supernatant will be pipetted into Eppendorf tubes 
in 2 mL aliquots and frozen at £ -20 °C until analysis, which will be performed en batch. 
Urine NGAL determination will be performed using an ELISA kit according to the 
manufacturer’s instructions (R&D Systems, Inc.). 
 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Day 1, before and during LTx) 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, including a history of acute kidney injury, ascites, or 
hepatic encephalopathy, including diagnosis date, and prior treatments (dialysis, 
continuous renal replacement therapy (CRRT), large volume paracentesis). 
5. 
Record concomitant medications. 

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6. 
Perform a complete physical examination. 
7. 
Perform and record vital signs. 
8. 
Perform and record oximetry. 
9. 
Perform and record results of blood pressure testing. 
10. 
Randomize subject (see Section 8.1). 
11. 
Place ECD after induction of general anesthesia. 
12. 
Implement intraoperative temperature protocol according to randomization (see 
Section 8.3). 
13. 
Collect blood for ABGs (see Section 9.2) and NGAL determination (Section 9.3.1). 
14. 
Collect urine for NGAL determination (see Section 9.3.2). 
15. 
Remove ECD at the end of surgery. 
10.2 Visit 2 (Follow-up prior to hospital discharge, window of 2 ± 1 weeks after 
LTx) 
1. 
Record any Adverse Experiences. 
2. 
Record changes to concomitant medications. 
3. 
Perform complete physical examination. 
4. 
Perform and record vital signs. 
5. 
Perform and record oximetry. 
6. 
If surrogate consent was obtained for the subject, and subject has now regained 
capacity, re-consent the patient for use of study data.  
 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a treatment that does not necessarily have a causal relationship with 
the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the 
administration of an investigational treatment, whether or not related to that 
investigational treatment. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study protocol, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 

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guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Treatment 
The relationship of an AE to the study treatment should be assessed using the following 
the guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known side effect of treatment; or an event that follows a reasonable 
temporal sequence from administration of the treatment; that follows a known or 
expected response pattern to the suspected treatment; that is confirmed by stopping 
or reducing the treatment; and that is not explained by any other reasonable 
hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
treatment; that follows a known or expected response pattern to the suspected 
treatment; that is confirmed by stopping or reducing the treatment; and that is 
unlikely to be explained by the known characteristics of the subject’s clinical state or 
by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
treatment; that follows a known or expected response pattern to that suspected 
treatment; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
treatment. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 

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• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study treatment) 
per UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Treatment  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the surgeon feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation: 
• Subject withdrawal of consent 
• Adverse event that in the opinion of the investigator would be in the best interest 
of the subject to discontinue study treatment 
• Protocol violation requiring discontinuation of study treatment 
 
If a subject is discontinued from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
 
Subjects will also be discontinued from the study treatment if the study doctor is unable to 
place the ECD after three attempts. 
 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 

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Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents. 
 
12.4 
Replacement of Subjects 
Subjects who undergo early discontinuation of the study treatment will not be replaced, 
and such events will be accounted for by intention-to-treat analysis. 
   
Subjects who withdraw from the study will be replaced with a new subject that will be 
independently randomized. 
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
• Early termination of temperature management protocol 
• Removal of ECD prior to the end of surgery 
• Failure to pack the right kidney with ice 
• Inability to maintain target temperature for ³ 1 hour 
• Failure to meet inclusion/exclusion criteria 
• Failure to comply with Good Clinical Practice (GCP) guidelines will also result in 
a protocol violation.  
Protocol violations will be accounted for by intention-to-treat analysis. Withdrawal of the 
subject will not be required, as all study procedures are completed within the first visit at 
the time of LTx. 
14 DATA SAFETY MONITORING 
A Data Safety Monitoring Board (DSMB) has been established to review data relating to 
safety and efficacy, to conduct and review interim analyses, and to ensure the continued 
scientific validity and merit of the study. Interim reviews will be conducted by the DSMB 
for the purpose of monitoring study conduct and assessing patient safety at a minimum of 
every 6 months during the trial. Further details regarding the timing and content of the 
interim reviews is included in the statistical section below. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   

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15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive the study treatment 
will be included in the safety analysis. 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, gender, age, 
height and weight.   
15.3 Analysis of Primary Endpoint 
Both intention-to-treat (ITT) and per-protocol analysis will be performed. All randomized, 
non-withdrawn patients will be included in the ITT analysis. All subjects completing the 
systemic temperature regulation protocol as outlined in Section 8.3 will be included in the 
per-protocol analysis. Subjects who had a protocol violation will be excluded from the 
per-protocol analysis. 
 
The primary outcome (presence or absence of AKI) will be compared between the two 
arms by two-sample proportion test, furthermore, a multiple logistic regression model will 
be utilized where AKI status (present or absence) is considered as the outcome and arms 
along with demographic characteristics (e.g, race, gender, age, etc.) and clinical 
characteristics (such as local cooling, Model for End-Stage Liver Disease score, etiology 
of liver disease, etc.) are considered as predictors and/or covariates.  
 
15.4 Analysis of Secondary Endpoints 
Categorical variables will be summarized as frequency and percentage, and continuous 
variables as median and interquartile range by arm. Categorical variables will be 
compared between the two arms by either chi-square or Fisher's exact test, as 
appropriate.39 Continuous variables will be compared between the two arms by two-
sample t-tests, or Mann-Whitney U tests if the normality assumption does not hold. 
Logistic regression (simple and multiple) will be used to detect variables associated with 
presence or absence of AKI. Patient and graft survival and time-to-event data (such as 
time to disease progression) will be estimated by Kaplan-Meier method and compared 
between the two arms by log-rank tests and cox-proportional hazard model will be applied 
to facilitate incorporating other covariates in the model. Statistical analysis will be 
performed using GraphPad Prism, STATA, and R software. 
 
• 
To check if the frequencies of categories of AKI (Stage 1, 2, or 3 or no AKI) are 
different between the two arms, a chi-square test will be used. Similarly, a multiple 
proportional odds model will be applied when considering AKI in a multi-category 
fashion.   
• 
Duration of intensive care unit stay and hospital stay will be summarized by median 
and interquartile range by arm and compared by two-sample t-tests, or Mann-Whitney 
U tests if the normality assumption does not hold. 

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• 
Patient survival will be estimated by the Kaplan-Meier method and compared between 
the two arms by log-rank tests. A Cox-proportional hazard model will be applied to 
facilitate incorporating other covariates into the model. 
• 
Incidence of post-operative renal replacement therapy within 7-days, at 30-days, and 
at 1 year after transplant will be summarized as frequency and percentage, and 
compared between the two arms by either chi-square or Fisher's exact test, as 
appropriate. 
• 
Incidence of persistent renal dysfunction (defined as a reduction in glomerular 
filtration rate by ³ 25 mL/min or ³ 50% from baseline) at 90-days and 1-year after 
transplant will be summarized as frequency and percentage, and compared between 
the two arms by either chi-square or Fisher's exact test, as appropriate. 
• 
The change in serum NGAL level from baseline to 2 hours after reperfusion of the 
portal vein will be summarized by median and interquartile range by arm and 
compared by two-sample t-tests, or Mann-Whitney U tests if the normality assumption 
does not hold. 
• 
The change in urine NGAL level from baseline to 2 hours after reperfusion of the 
portal vein will be summarized by median and interquartile range by arm and 
compared by two-sample t-tests, or Mann-Whitney U tests if the normality assumption 
does not hold. 
 
Safety and tolerability data will be summarized by treatment group.   
Adverse event rates will be coded by body system and MedDra classification 
term.  Adverse events will be tabulated by treatment group and will include the number of 
patients for whom the event occurred, the rate of occurrence, and the severity and 
relationship to study treatment.   
15.5 Interim Analysis 
15.5.1. Interim Analysis for Efficacy 
A single interim analysis for efficacy is planned for this study after 50% of the required 
patients (101 of the estimated 202) are accrued after accounting for withdrawn subjects. 
Based on the O'Brien-Fleming approach to calculate alpha spending, during the interim 
analysis step, if the p value is < 0.0054, the study will be stopped as the desired efficacy 
will have been achieved; if not, then we will continue the study. If the final p value is < 
0.0492, then we will declare that the AKI status is different between the two arms. 
 
15.5.2. Stopping Rule for Safety 
Based on clinical experience during LTx at UCSF and data from the liver anesthesia 
quality improvement database, AEs listed in Section 5.3E of severity 3 (Severe) or 4 
(Life-threatening) are expected to have a combined incidence of < 5% in study subjects. 
If, during routine DSMB review, an incidence of AEs of severity 3 or 4 of > 10% is 
observed in all study subjects, or in either treatment arm, the trial will be stopped. 

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15.6 Sample Size and Randomization 
 
Considering one interim analysis for efficacy, and given the incidence of AKI in LTx 
patients at UCSF (68%), we estimate a sample size of 101 subjects per arm (n = 202 total) 
is needed to detect a 30% reduction in AKI with 80% power at overall alpha = 0.05 (two-
tailed). 
 
We will aim to enroll 230 total subjects to allow for just over a 10% drop-out rate, since 
some subjects may not be able to complete the protocol and will be withdrawn from the 
study. UCSF is a high-volume center for LTx (> 180 cases per year), the majority of 
which meet our inclusion criteria. Thus, we estimate it will take no more than two years to 
complete study enrollment. The website http://www.swogstat.org was used to perform the 
power calculation, and the power calculation was confirmed by the CTSI at UCSF. 
 
 
 
 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study protocol.   
Study personnel will enter data from source documents corresponding to a subject’s visit 
into the protocol-specific paper CRF when the information corresponding to that visit is 
available.  Subjects will not be identified by name in the study database or on any study 
documents to be collected by the investigator, but will be identified by a subject number 
and initials. 
If a correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
The data will be entered into a validated RedCap database.  The Data Management group 
will be responsible for data processing, in accordance with procedural documentation.  
Database lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 

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16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis.                                      
Query reports (Data Clarification Requests) pertaining to data omissions and 
discrepancies will be forwarded to the Investigators and study monitors for resolution.  
The study database will be updated in accordance with the resolved queries.  All changes 
to the study database will be documented. 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the DSMB or IRB/IEC upon request.  
A file for each subject must be maintained that includes the signed Informed Consent, 
HIPAA Authorization and Assent Form and copies of all source documentation related to 
that subject.  The Investigator must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years after study completion. 
16.6 Monitoring 
Not applicable. 
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will 
identify all study subjects on CRFs and other documentation.  Additional subject 
confidentiality issues (if applicable) are covered in the Clinical Study Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health 

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Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Investigator.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC prior to 
study initiation.  Serious adverse experiences regardless of causality will be reported to 
the IRB/IEC in accordance with the standard operating procedures and policies of the 
IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the 
study.  The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, consent forms, information concerning patient recruitment, or other 
pertinent information) will be submitted to the IRB/IEC.  The IRB/IECs written 
unconditional approval of the study protocol and the informed consent form will be in the 
possession of the Investigator before the study is initiated. This approval must refer to the 
study by exact protocol title and number and should identify the documents reviewed and 
the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
for submission to the IRB/IEC.  The consent form generated by the Investigator must be 
approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will 

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also comply with local regulations. The Investigator will retain an IRB/IEC-approved 
copy of the Informed Consent Form for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
17.4 Publications  
The publication or presentation of any study results shall comply with all applicable 
privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the IRB/IEC except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the DSMB or IRB/IEC any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the DSMB or IRB/IEC. 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and DSMB all changes in the research activity and all 
unanticipated problems involving risks to subjects or others. 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 

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APPENDIX 1. SCHEDULE OF STUDY VISITS 
 
VISIT 1 
(Day 1, before and 
during liver 
transplant) 
VISIT 2 
(Day 2, prior to 
hospital discharge, 
approximately 2 
weeks after LTx)A 
Informed Consent 
X 
XB 
Medical History 
X 
 
Complete Physical Exam 
X 
X 
Height  
X 
 
Weight  
X 
 
Vital Signs  
X 
X 
Oximetry 
X 
X 
Randomization 
X 
 
Administration of Study 
Treatment 
X 
 
Blood and Urine collection 
X 
 
Initiate Subject Diary 
X 
 
Subject Diary Review 
 
X 
Concomitant Medication Review 
X 
X 
Adverse Experiences 
 
X 
A  ±1 week 
B Consent from subject will be obtained for use of study data if the patient lacked capacity and Surrogate Consent was obtained during Visit 1.

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APPENDIX 2. REFERENCES 
 
1. 
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"Esophageal Cooling Device" after cardiac arrest (the COOL study): A feasibility 
and safety study. Resuscitation. 2017;121:54-61. 
2. 
Naiman M, Shanley P, Garrett F, Kulstad E. Evaluation of advanced cooling 
therapy's esophageal cooling device for core temperature control. Expert Rev Med 
Devices. 2016;13(5):423-433. 
3. 
Hegazy AF, Lapierre DM, Butler R, Althenayan E. Temperature control in critically 
ill patients with a novel esophageal cooling device: a case series. BMC Anesthesiol. 
2015;15(1):152. 
4. 
Choi S, Noh J, Hirose R, et al. Mild hypothermia provides significant protection 
against ischemia/reperfusion injury in livers of obese and lean rats. Ann Surg. 
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5. 
Behrends M, Hirose R, Serkova NJ, et al. Mild hypothermia reduces the 
inflammatory response and hepatic ischemia/reperfusion injury in rats. Liver Int. 
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6. 
Niemann CU, Choi S, Behrends M, et al. Mild hypothermia protects obese rats from 
fulminant hepatic necrosis induced by ischemia-reperfusion. Surgery. 
2006;140(3):404-412. 
7. 
Niemann CU, Xu F, Choi S, et al. Short passive cooling protects rats during 
hepatectomy by inducing heat shock proteins and limiting the induction of pro-
inflammatory cytokines. J Surg Res. 2010;158(1):43-52. 
8. 
Delbridge MS, Shrestha BM, Raftery AT, El Nahas AM, Haylor JL. The effect of 
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9. 
Polderman KH. Mechanisms of action, physiological effects, and complications of 
hypothermia. Crit Care Med. 2009;37(7 Suppl):S186-202. 
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Holzer M. Targeted temperature management for comatose survivors of cardiac 
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Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 
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Levitsky J, O'Leary JG, Asrani S, et al. Protecting the Kidney in Liver Transplant 
Recipients: Practice-Based Recommendations From the American Society of 
Transplantation Liver and Intestine Community of Practice. Am J Transplant. 
2016;16(9):2532-2544. 

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16. 
Zacharias M, Mugawar M, Herbison GP, et al. Interventions for protecting renal 
function in the perioperative period. Cochrane Database Syst Rev. 
2013(9):CD003590. 
17. 
Karapanagiotou A, Dimitriadis C, Papadopoulos S, et al. Comparison of RIFLE and 
AKIN criteria in the evaluation of the frequency of acute kidney injury in post-liver 
transplantation patients. Transplant Proc. 2014;46(9):3222-3227. 
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Karapanagiotou A, Kydona C, Dimitriadis C, et al. Acute kidney injury after 
orthotopic liver transplantation. Transplant Proc. 2012;44(9):2727-2729. 
19. 
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transplantation: incidence and mortality. Transplant Proc. 2014;46(6):1819-1821. 
20. 
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liver transplantation. Transplant Proc. 2010;42(9):3634-3638. 
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transplantation: definition and outcome. Liver Transpl. 2009;15(5):475-483. 
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Hilmi IA, Damian D, Al-Khafaji A, et al. Acute kidney injury following orthotopic 
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injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc 
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intraoperative transesophageal echocardiography: a case series of 7200 cardiac 
surgical patients. Anesth Analg. 2001;92(5):1126-1130. 
27. 
Pai SL, Aniskevich S, 3rd, Feinglass NG, et al. Complications related to 
intraoperative transesophageal echocardiography in liver transplantation. 
Springerplus. 2015;4(1):480. 
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Nguyen HP, Zaroff JG, Bayman EO, et al. Perioperative hypothermia (33 degrees 
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cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for 
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Moran SM, Myers BD. Course of acute renal failure studied by a model of 
creatinine kinetics. Kidney Int. 1985;27(6):928-937. 

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33. 
Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury 
in patients with cirrhosis: revised consensus recommendations of the International 
Club of Ascites. Gut. 2015;64(4):531-537. 
34. 
O'Leary JG, Levitsky J, Wong F, Nadim MK, Charlton M, Kim WR. Protecting the 
Kidney in Liver Transplant Candidates: Practice-Based Recommendations From the 
American Society of Transplantation Liver and Intestine Community of Practice. 
Am J Transplant. 2016;16(9):2516-2531. 
35. 
Haase-Fielitz A, Haase M, Devarajan P. Neutrophil gelatinase-associated lipocalin 
as a biomarker of acute kidney injury: a critical evaluation of current status. Ann 
Clin Biochem. 2014;51(Pt 3):335-351. 
36. 
Parikh CR, Zhang WR. Role of Novel Kidney Injury Biomarkers in Perioperative 
Acute Kidney Injury. New York, NY: Springer New York; 2014:25-36. 
37. 
Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a 
nonrenal organ. N Engl J Med. 2003;349(10):931-940. 
38. 
Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the 
incidence of surgical-wound infection and shorten hospitalization. Study of Wound 
Infection and Temperature Group. N Engl J Med. 1996;334(19):1209-1215. 
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Glantz SA. Primer of Biostatistics. 7th ed. New York: McGraw-Hill; 2012.