A Randomized, Open-Label, Multicenter, Controlled, Pivotal Study to Assess Safety and Efficacy of ELAD in Subjects With Alcohol-Induced Liver Decompensation (AILD)
Phase: PHASE3
Conditions: Acute Alcoholic Hepatitis
Sponsor: Vital Therapies, Inc.

D4010-308 
CONFIDENTIAL 
 
CONFIDENTIAL 
VTL-308 PROTOCOL (AMENDMENT 1) 
  
Title A Randomized, Open-label, Multicenter, Controlled, Pivotal 
Study to Assess Safety and Efficacy of ELAD® in Subjects 
with Alcohol-Induced Liver Decompensation (AILD) 
IND 005479 
EudraCT 2015-004529-14 
Sponsor Vital Therapies, Incorporated 
15010 Avenue of Science, Suite 200 
San Diego, CA  92128 
  
Amendment 1 20 November 2015 
Original  22 October 2015 
  
  
 
This document is the property of Vital Therapies, Inc. (VTL) and contains information that is 
of a confidential, trade secret and/or proprietary nature.  It is intended for use by clinical 
investigators conducting studies with the ELAD System and no portion may be photocopied, 
disclosed, or transmitted to any person not involved in the clinical investigation of the ELAD 
System without the prior written approval of VTL.  The holder is bound by the terms of 
confidentiality contained in the agreement with VTL pursuant to which the holder has been 
provided access to this document and is responsible for the safekeeping and return of the 
document to VTL upon request. 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
2 
PROTOCOL SYNOPSIS 
Sponsor:  Vital Therapies, Inc., San Diego, CA 
Product Name:  ELAD® 
Protocol Number and Title:  VTL-308, A Randomized, Open-Label, Multicenter, Controlled, Pivotal Study to 
Assess Safety and Efficacy of ELAD in Subjects with Alcohol-Induced Liver Decompensation (AILD) 
Planned Study Centers:  Approximately 40 study centers in the United States and Europe 
Phase of Development:  Phase 3 
Study Objectives: 
The primary objective of the study is to evaluate safety and efficacy of ELAD® with respect to overall survival 
(OS) of subjects with a clinical diagnosis of alcohol-induced liver decompensation (AILD) through at least Study 
Day 91, with follow-up Protocol VTL-308E providing additional survival data up to a maximum of 5 years that 
will be included, as available, through VTL-308 study termination (after the last surviving enrolled subject 
completes Study Day 91). The primary objective will be assessed using a Kaplan-Meier survival analysis of the 
Intent-to-Treat (ITT) population utilizing a log-rank test. 
The secondary objective is to evaluate the proportion of survivors at Study Day 91 using a chi-squared test.   
Study Design:  
VTL-308 is a randomized, open-label, multicenter, controlled, pivotal study of subjects with AILD.  A minimum 
of 150 subjects meeting the eligibility requirements of the study will be randomly assigned in a 1:1 ratio to 
receive either standard of care treatment for AILD (as defined in the protocol) plus treatment with the ELAD 
System (ELAD group) or standard of care treatment for AILD alone (Control group). 
Central randomization will be performed to ensure that neither Sponsor, site, nor study personnel will have any 
foreknowledge of subject treatment assignment.  
Because ELAD treatment must take place in an Intensive Care Unit (ICU), or a Step-Down Unit (SDU) with an 
equivalent standard of care if written pre-approval has been given by VTL, all subjects considered for enrollment 
must be considered eligible for ICU or SDU placement. Control subjects need not be placed in an ICU or SDU 
setting unless deemed necessary by the Investigator due to the severity of their illness. 
Screening evaluations and assessments will be completed for both ELAD and Control subjects and reviewed 
against inclusion/exclusion criteria prior to Randomization.  For both study groups, ELAD-treated and Control, 
the time of Randomization will define the time of study entry (Hour 0, Study Day 1, study baseline) and inclusion 
in the ITT population. Laboratory draws for the first post-randomization blood tests required by the protocol will 
begin with the next standard laboratory draw (typically the following morning). 
In addition to the Screening evaluations, because there will be a delay between Randomization and initiation of 
ELAD treatment, a further assessment to confirm the subject’s safety eligibility will be undertaken. This 
assessment will be conducted in the same manner for both ELAD and Control subjects. Either the principal 
investigator or sub-investigator trained on the study must have evaluated the safety eligibility results and be 
immediately available when ELAD treatment begins in order to assess changes in the subject’s condition since 
Randomization. This is especially important when evaluation changes during the 24 hours preceding initiation of 
ELAD treatment in order to determine whether the subject remains eligible for extracorporeal treatment. 
For all subjects randomized, the following key safety factors must be evaluated within 6 hours prior to ELAD 
treatment initiation, or at End of Study Day 2 (±6 hours) for Control subjects: platelet count, international 
normalized ratio (INR), serum creatinine, evidence of infection unresponsive to antibiotics, hemodynamic 
instability, bleeding status, and status with respect to ventilation, intubation, or need for hemodialysis. These 
factors will be assessed in accord with the pertinent exclusion criteria (2, 3, 4, 7, 9, 10, 15, and 16, relative to the 
safety evaluation time point), and subjects must be assessed within 6 hours prior to ELAD treatment initiation, or 
at End of Study Day 2 (±6 hours) for Control subjects, and subjects must continue to be eligible based on these 
exclusion criteria to remain in the modified intent-to-treat (mITT) population.     
In addition, vital signs will be taken, total bilirubin measured and a MELD score will be calculated.   

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
3 
The standard of care labs may fulfill this requirement provided they are drawn and evaluated within 6 hours prior 
to ELAD treatment initiation.   
 
If an ELAD subject fails to meet these criteria, ELAD treatment will not be initiated, the 
subject will continue to receive standard of care, and the subject will be exluded from the 
modified intent-to-treat (mITT) population.   
 
If a Control subject fails to meet these criteria, the subject will continue to receive standard of 
care, and the subject will be excluded from the mITT population.   
Subjects randomized to the ELAD group will be treated with ELAD for a minimum of 3 days (72 hours).   
ELAD treatment may be interrupted for a period of less than 6 hours then restarted with the same set of cartridges 
provided that, in the opinion of the Investigator, the subject remains eligible for treatment. ELAD treatment may 
be interrupted for a period of more than 6 hours but less than 72 hours, if, for example, to allow for the conduct of 
a diagnostic or therapeutic procedure or for management of an adverse event, or should there be a need to 
interrupt the use of anticoagulants. Should this circumstance arise, a new set of ELAD cartridges must be used if 
treatment of the subject will continue, and the subject must meet the same safety eligibility criteria as are required 
prior to the initiation of treatment (See Section 5.4.2.1.1).   
ELAD treatment will be discontinued and will not be restarted if any of the following discontinuation criteria are 
met. If ELAD treatment is discontinued, subjects will receive standard of care therapy alone and be followed 
through Study Day 91. Discontinuation criteria include the following: 
 
Continued ELAD treatment is judged to be futile, defined as an increase of more than 25% in 
total bilirubin at 72 (+6) hours (includes clinical consideration of impact of artifactual 
hyperbilirubinemia) compared to the most temporal measurement of total bilirubin taken within 
6 hours prior to ELAD initiation. Bilirubin measurements must be taken at least 12 hours after 
any procedure known to artificially alter serum bilirubin (e.g., administration of packed red 
blood cells, plasma exchange);  
 
Subject has been off treatment for more than 72 hours; 
 
Subject has suffered an adverse event that, in the Investigator’s opinion, requires ELAD 
treatment to be discontinued, and/or which cannot be resolved within a period of 72 hours;  
 
Subject has suffered a disseminated intravascular coagulopathy (DIC) event; 
 
Subject develops an indication for hemodialysis; 
 
Subject requires an extracorporeal procedure that takes precedence over ELAD treatment; 
 
Subject has been treated for a maximum of 120 hours within five (5) 24-hour periods regardless 
of treatment interruption;  
 
Subject undergoes orthotopic liver transplantation;  
 
Subject is discharged from the hospital; 
 
The first set of ELAD cartridges has been replaced for any reason and the second set also 
requires replacement, or the subject fails safety eligibility checks for the second set; 
 
Subject or legally-authorized representative withdraws consent for further ELAD treatment; 
 
Investigator decides to stop ELAD treatment;  
 
ELAD System performance issues arise that cannot be resolved within a period of 72 hours; 
 
Subject experiences catheter-related issues that cannot be resolved within a period of 72 hours. 
 
Subjects in both groups will be evaluated throughout the 91-day study period.   
If standard of care therapy as defined by the institution is consistent with discharging the subject home, then the 
subject should be discharged.  Prior to discharge, the subject will be advised to attend all protocol-required visits.  
Instructions for home visits will also be reviewed. 
An extension of this study, VTL-308E, will provide extended follow-up of subjects enrolled in VTL-308 over a 
period of 5 years to determine incidence of survival, cancer, liver transplant, and quality of life. Data obtained 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
4 
from the extension study will provide additional survival data up to a maximum of 5 years that will be included, 
as available, through VTL-308 study termination (after the last surviving enrolled subject completes Study Day 
91). 
Efficacy Analyses 
Primary EfficacyAnalysis: 
Overall survival (OS) of AILD subjects through at least Study Day 91 
OS will be assessed using a Kaplan-Meier survival analysis of the intent-to-treat (ITT) population utilizing a log-
rank test, with follow-up Protocol VTL-308E providing additional survival data up to a maximum of 5 years that 
will be included, as available, through VTL-308 study termination. Model-based estimates and confidence limits 
will be calculated for median survival by treatment group and hazard rates along with the hazard ratio and its 
confidence limits. This analysis will also be carried out on the mITT, Per-Protocol (PP) and Safety populations as 
sensitivity analyses.  Two-tailed alpha for the log-rank test will be set at 0.05. The statistical analysis plan will 
outline the methods used to account for missing data in this and all other analyses.  
Secondary Efficacy Analyses: 
Proportion of Survivors at Study Day 91 
A chi-square test will be used to evaluate the proportion of subjects who survived at End of Study Day 91 based 
on the ITT population. Two-tailed alpha will be set at 0.05. This analysis will also be carried out on the mITT, PP 
and Safety populations as sensitivity analyses.   
Safety Assessment 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and incidences will 
be presented by treatment group using MedDRA Preferred Terms within System Organ Classes for the Safety 
Population.  The following will also be summarized by treatment group: 
 
Adverse Events 
 
Mean Arterial Pressure (MAP) 
 
Clinical laboratory values 
 
The use of concomitant procedures including concomitant blood product administration (e.g., 
whole blood, packed red blood cells, platelets, fresh frozen plasma, albumin, cryoprecipitate)  
 
Concomitant therapies (e.g., intubation, tracheostomy, CVVH/CVVHD, arterial line) 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
5 
Inclusion Criteria 
Subjects must meet ALL inclusion criteria to be eligible for the study: 
1. Age ≥18; 
2. Total bilirubin ≥16 mg/dL (≥273.6 µmol/L); 
3. A clinical diagnosis of alcohol-induced liver decompensation (AILD), based upon lab test or 
medical history or family interview with a causal relationship and temporal association (6 weeks or 
less) of alcohol use and hospital admission for this episode of AILD; 
4. Maddrey score ≥32; 
5. Subjects must have AILD that is severe acute alcoholic hepatitis (sAAH) diagnosed with either: 
a. 
A confirmatory liver biopsy, OR 
b. Two or more of the following:  
i. 
Hepatomegaly, 
ii. 
AST > ALT, 
iii. 
Ascites, 
iv. 
Leukocytosis (WBC count above lab normal at site); 
Note:  Subjects will be classified as either: 
a. 
AILD that is sAAH with no underlying liver disease other than alcoholic liver 
disease, OR 
b. AILD that is sAAH with evidence of underlying liver disease other than 
alcoholic liver disease which must be documented by: 
i. Liver biopsy, AND/OR 
ii. Laboratory findings, AND/OR 
iii. Medical history; 
6. Not eligible for liver transplant during this hospitalization; 
7. Subject or legally-authorized representative must provide Informed Consent; 
8. Subject must be eligible for Standard of Care treatment as defined in the protocol. 
Exclusion Criteria 
Subjects must NOT have any of the exclusion criteria to be eligible for the study: 
1. Age ≥50; 
2. Platelet count <40,000/mm3;  
3. International Normalization Ratio (INR) >2.5; 
4. Serum Creatinine ≥1.3 mg/dL (≥115.04 µmol/L); 
5. MELD score ≥30; 
6. AST >500 IU/L; 
7. Evidence of infection unresponsive to antibiotics (e.g. increased tissue involvement relative to initial 
diagnosis, clinical worsening of symptoms, etc.) indicated by any of the following: 
a. 
Presence of sepsis or septic shock; OR 
b. Positive blood cultures (bacteremia, fungemia) within 72 hours prior to Randomization; OR 
c. 
Presence of spontaneous bacterial peritonitis during the 2 days prior to Randomization; OR 
d. Clinical and radiological signs of pneumonia;  
8. Evidence of reduction in total bilirubin of 20% or more in the previous 72 hours.  Bilirubin 
measurements must be taken at least 12 hours after any procedure known to artificially alter serum 
bilirubin (e.g., administration of packed red blood cells, plasma exchange);  
9. Evidence of hemodynamic instability as defined by the following: 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
6 
a. 
Systolic blood pressure <90 mmHg with evidence of diminished perfusion unresponsive to 
fluid resuscitation and/or low-dose pressor support; OR  
b. Mean arterial pressure (MAP) <60 mmHg with evidence of diminished perfusion 
unresponsive to fluid resuscitation and/or low-dose pressor support; OR  
c. 
Requirement for escalating doses of vasopressor support prior to Screening; OR  
d. Subject on vasopressors, including but not limited to those listed below, at doses above the 
following at Screening or Randomization: 
 
Dobutamine:   
5.0 µg/kg/min 
 
Dopamine: 
2.0 µg/kg/min 
 
Norepinephrine: 
0.02 µg/kg/min 
 
Phenylephrine: 
1.0 µg/kg/min 
 
Vasopressin: 
0.02 U/min 
10. Evidence of active bleeding, major hemorrhage defined as requiring ≥2 units packed red blood cells 
to maintain a stable hemoglobin occurring within 48 hours prior to Randomization, or with banding 
of gastroesophageal varices during the 7 days immediately preceding screening;  
11. Clinical evidence of liver size reduction due to cirrhosis [liver size of the craniocaudal diameter 
(sagittal view) <10 cm when measured on the mid clavicular line (or equivalent measurement) by 
ultrasound, or liver volume <1200 cc as determined by CT or MRI], unless Investigator 
interpretation of the clinical evidenceindicates liver size of <10 cm or volume <1200 cc is not 
considered reduced for the individual subject, and Sponsor agrees;  
12. Occlusive portal vein thrombosis impairing hepatopetal flow, or evidence of bile duct obstruction;  
13. Evidence by physical exam, history, or laboratory evaluation, of significant concomitant disease 
with a life expectancy of less than 3 months, including, but not limited to:  
a. 
Severe acute or chronic cardiovascular, central nervous system, or pulmonary disease; 
b. Cancer that has metastasized or has not yet been treated; 
c. 
Severe metabolic abnormalities that have not been corrected (See Section 5.1.3); 
14. Subject has chronic end-stage renal disease requiring chronic hemodialysis for more than 8 weeks 
(not classified as hepatorenal syndrome); 
15. Subject ventilated or intubated; 
16. Subject on hemodialysis; 
17. Subject has liver disease related to homozygous hemachromotosis, Wilson’s disease, has non-
alcoholic fatty liver disease, or Budd-Chiari Syndrome; 
18. Serological evidence (including viral titers) of active viral hepatitis A, B or C infection. If the 
investigator suspects that the subject may be at risk for viral hepatitis A, B or C, and no serology is 
available, then serologies must be obtained prior to Randomization, as a positive serology would be 
exclusionary; 
19. Pregnancy as determined by serum β-human chorionic gonadotropin (HCG) results, or subjects of 
child-bearing potential not willing to use effective means of contraception, without history of 
medical or surgical sterilization;  
20. Participation in another investigational drug, biologic, or device study within one month of 
enrollment, except for observational studies (the observational study setting should not affect the 
safety and/or efficacy of the VTL-308 clinical trial);  
21. Previous liver transplant;  
22. Previous enrollment in the treatment phase of another ELAD trial;  
23. Have a Do Not Resuscitate or a Do Not Intubate (DNR/DNI) directive (or such local equivalent) or 
any other Advanced Directive limiting Standard of Care in place (the DNR/DNI criterion is not 
applicable in Europe);  
24. Refusal to participate in the VTL-308E follow-up study; 
25. Inability to provide an address for home visits.  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
7 
 
TABLE OF CONTENTS 
1 INTRODUCTION ...................................................................................................................14 
2 STUDY OBJECTIVES ............................................................................................................17 
3 STUDY DESIGN.....................................................................................................................18 
4 STUDY POPULATION ..........................................................................................................21 
4.1 
General Characteristics of the Proposed Study Population .........................................21 
4.2 
Anticipated Number of Research Subjects ..................................................................21 
4.3 
Inclusion Criteria .........................................................................................................21 
4.4 
Exclusion Criteria ........................................................................................................22 
5 STUDY PROCEDURES .........................................................................................................24 
5.1 
Pre-Screening ...............................................................................................................24 
5.1.1 Sponsor Notification ..............................................................................................24 
5.1.2 Pre-Screening Procedures ......................................................................................25 
5.1.3 Pre-Screening Laboratory Abnormalities ..............................................................25 
5.2 
Screening......................................................................................................................26 
5.2.1 Informed Consent...................................................................................................26 
 Informed Consent Process ...............................................................................26 
5.2.2 Sponsor Notification ..............................................................................................26 
5.2.3 Screening Procedures .............................................................................................27 
 PEth Test ..........................................................................................................28 
 Imaging Requirements .....................................................................................28 
5.2.4 Assessment of MELD and Maddrey Scores ..........................................................29 
5.3 
Randomization Process ................................................................................................29 
5.3.1 Interactive Web Response System (IWRS)/EDC Core Details .............................30 
5.3.2 Subject Enrollment and Randomization Procedure ...............................................30 
5.3.3 Other Procedures ....................................................................................................31 
5.4 
Study Treatment ...........................................................................................................32 
5.4.1 Study Treatment Standards of Care .......................................................................32 
 Standard of Care - Nutrition ............................................................................33 
 Standard of Care - Steroid Administration ......................................................33 
 Standard of Care - Ascites ...............................................................................34 
 Standard of Care – Gastroesophageal Varices .................................................35 
 Standard of Care – Hepatic Encephalopathy ...................................................36 
 Standard of Care – Hepatorenal Syndrome (HRS) ..........................................36 
 Standard of Care – Hyponatremia....................................................................36 
 Standard of Care – Spontaneous Bacterial Peritonitis .....................................37 
 Standard of Care - Thrombocytopenia .............................................................38 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
8 
 
Standard of Care – ICU Discharge ............................................................38 
 
Standard of Care – Hepatic Hydrothorax ...................................................38 
5.4.2 Pre-Treatment ........................................................................................................38 
 Pre-ELAD Treatment .......................................................................................38 
 Pre-Control Treatment .....................................................................................40 
5.4.3 Treatment Start.......................................................................................................40 
 ELAD Treatment Start .....................................................................................40 
 Control Treatment Start ...................................................................................41 
5.5 
Evaluations While on Treatment .................................................................................42 
5.5.1 Daily Evaluations through End of Study Day 7 .....................................................42 
5.5.2 Safety Evaluations While on Extracorporeal Treatment (ELAD only) .................43 
 Anticoagulation Therapy during ELAD Treatment .........................................43 
5.5.3 Evaluations 24 Hours after ELAD Treatment Ends (ELAD-treated subjects 
only) .......................................................................................................................44 
5.5.4 Evaluations on Study Days 14, 21, and 28 (+3 days) ............................................45 
5.5.5 Evaluations on Study Day 63 and Study Day 91 (+5 days) ...................................45 
5.5.6 Evaluations at Discharge........................................................................................46 
5.5.7 Evaluations Following Discharge ..........................................................................46 
5.5.8 Missed Visits ..........................................................................................................48 
5.5.9 Early Discontinuation from the Study ...................................................................48 
5.6 
Laboratory Testing .......................................................................................................48 
5.6.1 Blood Culture Samples for Microbiological Testing (ELAD and Control 
subjects) .................................................................................................................48 
5.6.2 Ultrafiltrate Culture Samples for Microbiological Testing (ELAD Subjects 
only) .......................................................................................................................49 
5.6.3 Blood Collection for Future Research (ELAD and Control subjects) ...................50 
5.6.4 Ultrafiltrate Collection for Future Research (ELAD Subjects only) .....................50 
6 ELAD SYSTEM ......................................................................................................................51 
6.1 
ELAD System Use .......................................................................................................51 
6.2 
PRECautions while on ELAD .....................................................................................51 
6.3 
ELAD System Dosage .................................................................................................51 
6.4 
Receipt and Administration of ELAD Cartridges ........................................................51 
6.5 
ELAD Cartridge Replacement .....................................................................................51 
6.6 
Interruption of ELAD Treatment .................................................................................52 
6.7 
Criteria for Discontinuation of ELAD Treatment ........................................................52 
6.8 
ELAD SYSTEM ACCOUNTABILITY ......................................................................52 
6.8.1 Shipment of ELAD Cartridges...............................................................................52 
6.8.2 ELAD Cartridge Inspection and Storage ...............................................................52 
6.8.3 Packaging and Labeling of Cartridges ...................................................................53 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
9 
6.8.4 Dispensing and Accountability of Cartridges ........................................................53 
6.8.5 ELAD System Disposition .....................................................................................53 
6.8.6 Cleaning of Equipment after Discontinuation of ELAD Treatment ......................54 
7 STATISTICS AND METHODS OF DATA ANALYSIS ......................................................55 
7.1 
Sample Size Rationale .................................................................................................55 
7.2 
Populations ...................................................................................................................55 
7.2.1 Safety .....................................................................................................................55 
7.2.2 Efficacy ..................................................................................................................56 
 Intent-to-Treat (ITT) ........................................................................................56 
 Modified Intent-toTreat (mITT) ......................................................................56 
 Per-Protocol (PP) .............................................................................................56 
7.3 
Primary Efficacy Analysis ...........................................................................................56 
7.3.1 Overall Survival (OS) of AILD Subjects through at Least Study Day 91 .............56 
7.4 
Secondary Efficacy Analyses ......................................................................................57 
7.4.1 Proportion of Survivors at Study Day 91 ...............................................................57 
7.5 
Exploratory Efficacy Analysis .....................................................................................57 
7.6 
Safety Assessment .......................................................................................................57 
7.7 
Demographics and Other Baseline Variables ..............................................................57 
8 STUDY DOCUMENTATION ................................................................................................58 
8.1 
Site Documentation ......................................................................................................58 
8.1.1 Laboratory Accreditation .......................................................................................58 
8.1.2 Financial Disclosure...............................................................................................58 
8.1.3 Subject Confidentiality ..........................................................................................58 
8.2 
Pre-Study Site Visits and Site Initiation Visits ............................................................58 
8.3 
Recording of Subject Data ...........................................................................................58 
8.3.1 Electronic Case Report Forms (eCRFs) .................................................................59 
8.3.2 Records Retention ..................................................................................................59 
8.3.3 Concomitant Medications, Procedures and Therapies ...........................................60 
8.4 
Monitoring of the Study ...............................................................................................61 
8.5 
Site Closure ..................................................................................................................61 
9 PHARMACOVIGILANCE AND SAFETY REPORTING ....................................................63 
9.1 
Adverse Events ............................................................................................................64 
9.2 
Definitions....................................................................................................................64 
9.3 
Laboratory Abnormalities as Adverse Events .............................................................66 
9.4 
Reporting of Serious Adverse Events ..........................................................................66 
9.5 
Classification of Adverse Events by Severity ..............................................................68 
9.6 
Classification of Adverse Events by Relationship to Study Treatment .......................68 
9.7 
Sponsor and Investigator Reporting Requirements .....................................................70 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
10 
9.8 
Unanticipated Device Adverse Effects ........................................................................71 
9.9 
Data and Safety Monitoring Board (DSMB) ...............................................................71 
10 HUMAN SUBJECTS AND INFORMED CONSENT ...........................................................72 
10.1 
Institutional Review Board/Ethics Committee ............................................................72 
10.2 
Informed Consent.........................................................................................................72 
11 DISCLOSURE OF DATA/PUBLICATION POLICY ...........................................................74 
12 BIOHAZARD CONTAINMENT ............................................................................................75 
13 ESTABLISHMENT OF REGISTRY FOR SUBJECT FOLLOW-UP – VTL-308E ..............76 
13.1 
VTL-308E Justification ...............................................................................................76 
13.2 
Objectives ....................................................................................................................76 
13.3 
Subject Population .......................................................................................................77 
13.4 
Research Design and Methods .....................................................................................77 
13.5 
Maintaining Confidentiality .........................................................................................79 
14 CRITERIA FOR STUDY DISCONTINUATION ..................................................................80 
15 INVESTIGATOR AGREEMENT...........................................................................................81 
16 REFERENCES ........................................................................................................................82 
 
LIST OF TABLES 
Table 1. 
Schedule of Evaluations and Procedures at Screening for Randomization .......... 84 
Table 2. 
Schedule of Evaluations and Procedures for CONTROL Subjects ...................... 85 
Table 3. 
Schedule of Evaluations and Procedures for ELAD Subjects .............................. 86 
Table 4. 
Schedule of Evaluations and Procedures for Standards of Care (SOC) ............... 88 
 
LIST OF FIGURES 
Figure 1. 
Subject Enrollment Process .................................................................................. 31 
Figure 2. 
Main Study Timeline ............................................................................................ 93 
 
LIST OF APPENDICES 
Appendix A. West Haven Criteria .............................................................................................. 94 
Appendix B. Tool for Determining Capacity to Consent ........................................................... 95 
Appendix C. EQ-5D-5L Quality of Life Questionnaire ............................................................. 96 
Appendix D. Clinical Trial Pharmacovigilance Investigator Guide ......................................... 102 
Appendix E. Anticoagulation Guidelines for the VTL-308 Study .......................................... 111 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
11 
ABBREVIATIONS 
AAH 
Acute Alcoholic Hepatitis 
AASLD 
American Association for the Study of Liver Diseases 
ACLF 
Acute on Chronic Liver Failure 
AE 
Adverse Event 
AILD 
Alcohol-induced liver decompensation 
ALT 
Alanine Aminotransferase 
AOCH 
Acute on Chronic Hepatitis 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
C&S 
Culture and Sensitivity 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
CT 
Computed Tomography 
CVVH 
Continuous Venovenous Hemofiltration 
CVVHD 
Continuous Venovenous Hemodialysis 
DNR/DNI 
Do Not Resuscitate/Do Not Intubate 
DSMB 
Data and Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ECS 
Extracapillary Space 
EDC 
Electronic Data Capture  
EVL 
Endoscopic Variceal Ligation 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
HAV 
Hepatitis A Virus 
HCG 
β-Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HDV 
Hepatitis D Virus 
HE 
Hepatic Encephalopathy 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
12 
HIT 
Heparin-Induced Thrombocytopenia 
HIV 
Human Immunodeficiency Virus 
HRS 
Hepatorenal Syndrome  
ICH 
International Conference on Harmonization 
ICS 
Intracapillary Space 
ICU 
Intensive Care Unit 
INR 
International Normalization Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LAR 
Legally-authorized Representative 
LDH 
Lactate Dehydrogenase 
LTFU 
Lost to follow-up 
MAP 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model of End-stage Liver Disease 
mITT 
Modified Intent-to-Treat 
mTSR 
Modified Treatment Services Review Questionnaire 
NAC 
N-acetylcysteine 
NH3 
Ammonia 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
O2 
Oxygen 
OS 
Overall Survival 
PBR 
Blood return pressure 
PBW 
Blood withdrawal pressure 
PEC 
ELAD cartridge pressure 
PegIFN 
Peginterferon 
Peth 
Phosphatidylethanol  
PF 
Filter pressure 
PFS 
Progression Free Survivors 
PPUG 
Pre ultrafiltrate generator pressure 
PUF 
Ultrafiltrate withdrawal pressure 
PP 
Per Protocol (analysis) 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
13 
PTx 
Pentoxifylline 
RBV 
Ribavirin 
SAAG 
Serum-Ascites Albumin Gradient 
sAAH 
Severe Acute Alcoholic Hepatitis 
SAE 
Serious Adverse Event 
SBP 
Spontaneous Bacterial Peritonitis 
SD 
Study Day 
SDU 
Step-Down Unit 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
TIPS  
Transjugular intrahepatic portosystemic shunt  
TLFB 
Alcohol Timeline Followback Questionnaire 
TTP 
Time to Progression 
UNOS 
United Network for Organ Sharing 
US 
Ultrasound 
USA 
United States of America 
VTL 
Vital Therapies, Inc. 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
14 
1 
INTRODUCTION 
The liver is one of the largest and most metabolically-complex organs in the body, but has a 
remarkable capacity for regeneration in response to injury. Vital Therapies, Inc. (VTL) has 
developed ELAD®, an extracorporeal human hepatic cell-based liver treatment (hereafter 
referred to as the ELAD® System or ELAD®) to improve survival in patients with liver failure 
secondary to acute hepatocellular insult with a temporal and causal relationship to alcohol use, 
and to provide liver support continuously to a subject with compromised liver function. It is 
postulated that this allows time for the subject’s native liver to recover from the acute 
decompensation, stabilize, potentially regenerate and be restored to a functional state, or to 
maintain the subject until a suitable donor organ can be found for transplantation. 
The current configuration of the ELAD System draws blood from the subject via a dual-lumen 
catheter placed in a large vein using an extracorporeal pumping unit, and then separates the 
plasma fluid (ultrafiltrate) from cellular components using a specifically-designed ultrafiltrate 
generator cartridge. While the cellular components are returned to the subject via the venous 
access, the ultrafiltrate is circulated at a high flow rate through the four metabolically-active 
ELAD cartridges. The active ingredients within the ELAD C3A cell cartridges are cloned, 
immortalized human hepatoblastoma cells (VTL C3A cells) derived from a subclone of the 
human hepatoblastoma cell line HepG2. The metabolic activity of ELAD cartridges containing 
VTL C3A cells can be monitored by measuring oxygen and glucose consumption, as well as by 
the production of hepatocyte-specific proteins. 
After circulation through the cartridges, the ultrafiltrate passes through a 0.2-µm pore size filter, 
is recombined with the cellular components of the subject’s blood, and is returned to the subject 
through the dual-lumen catheter. The toxins metabolized by the VTL C3A cells are thereby 
returned to the subject to be excreted by the renal or gastrointestinal system. This circulation is 
maintained continuously for the duration of ELAD treatment, typically between three and 
five days. 
Hepatocellular damage, secondary to a variety of insults (infectious agents, alcohol, exogenous 
drugs, autoimmunity, fatty liver disease, etc.), can result in chronic liver disease if the underlying 
etiology is not effectively treated. This condition is characterized histopathologically by 
increasing degrees of fibrosis and cirrhosis, and frequently remains subclinical and/or 
undiagnosed. Often as a result of a secondary insult, the chronic hepatitis can decompensate, 
leading to a life-threatening disorder known as Acute on Chronic Liver Failure (ACLF) 
(Jalan 2012). 
There are a number of types of ACLF, including acute flare of Chronic Hepatitis B and Alcohol-
induced Liver Decompensation (AILD). AILD is defined as a progressive inflammatory liver 
disease leading to an acute form of alcohol-induced liver injury which arises when the proximate 
cause of the acute decompensation is the consumption of alcohol. A specific, well-defined subset 
of AILD is Severe Acute Alcoholic Hepatitis (sAAH), generally defined as progressive 
inflammatory liver disease leading to an acute form of alcohol-induced liver injury that occurs 
with the consumption of large amounts of alcohol in patients with relatively mild, underlying 
chronic alcoholic liver disease. These sAAH patients typically present with a characteristic 
pattern of jaundice, ascites, hepatomegaly, AST > ALT, and leukocytosis. Liver biopsies in 
sAAH subjects reveal the following histological characteristics: hepatocellular 
damage/ballooning, Mallory bodies, polymorphonuclear infiltration, steatosis, lobular fibrosis, 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
15 
megamitochondria, and bilirubinostasis (Altamirano 2014). However, liver biopsy is deemed to 
be too invasive for routine use in US patients (O’Shea 2010). Various degrees of fibrosis and 
hepatitis are present in AILD patients (Altamirano 2014 and Orrego 1987).   
The damage to the liver from continuing insults causes the gradual development of fibrosis in the 
liver over time, which results in a decrease of both liver function and the ability to regenerate 
after decompensation (Schuppan and Afdhal 2008). The fibrosis progresses to cirrhosis when 
this process has been underway for many years. The progression of fibrosis to cirrhosis results in 
a shrunken liver, distortion of hepatic lobules, and continued loss of hepatocytes (due to 
replacement with fibrotic tissue) that leads to progressive and recurrent episodes of 
decompensation. This progressive loss of hepatocyte mass impairs the liver’s inherent ability to 
regenerate following decompensation. In AILD patients with hepatomegaly, there appears to be 
sufficient hepatocyte mass that may allow hepatic regeneration and reversal of the 
decompensation. They can be discriminated from patients with end-stage liver disease by 
measurements of liver size using imaging techniques such as ultrasound, CT scan, or MRI.   
Treatment options for patients with AILD are limited. In particular, patients with severe sAAH 
(defined as a Maddrey Discriminant Function of >32) have a poor prognosis, with 90-day 
survival of around 50% (Maddrey 1978). Regimens that have been used for the past 40 years, 
including corticosteroids (Morris 2005; Thursz 2015), theophylline (Kendrick 2010) with 
corticosteroids, pentoxifylline (Parker 2013; Lebrec 2010; and Thursz 2015), and infliximab 
(Naveau 2004), have had no significant effect on the long-term survival of patients with AILD.  
Other contraindications to steroid use in patients with AILD include active gastrointestinal 
bleeding, renal failure, acute pancreatitis, active tuberculosis, uncontrolled diabetes, and 
psychosis (Singal 2011; Singh 2015). Subjects who do not respond to seven days of steroid 
therapy (as defined by the Lille score) have a particularly dismal prognosis, with 6-month 
survival rates of less than 25% (Louvet 2007). A recent study of >1100 subjects with a clinical 
diagnosis of sAAH (the STOPAH study) demonstrated a reduction in 28-day mortality in 
subjects administered steroids that did not reach statistical significance, with no improvement in 
survival at 90 days or 1 year. This study also revealed no survival benefit at any time point for 
pentoxifylline relative to placebo (Thursz 2015). 
It has been hypothesized that the common characteristic of subjects that have benefited from 
ELAD treatment is that they have more extensive hepatic reserve capacity than those with end-
stage liver disease accompanied by cirrhosis, thereby having increased potential for liver 
regeneration. However, there is no accepted method to measure liver reserve capacity or to 
quantify liver regeneration. The extent of chronic liver damage must be estimated, for example 
by assessing liver size, medical history and subject condition. Using these parameters, the current 
ELAD clinical trial program has been designed to focus on those subjects without evidence of 
end-stage liver disease, in whom a single course of ELAD treatment of 3-5 days may induce 
stabilization, possibly associated with increasing hepatic reserve secondary to liver regeneration, 
thereby leading to improved survival in the absence of liver transplantation. In addition, data 
from the VTI-208 study have indicated that subjects with secondary organ complications, such as 
acute kidney injury and moderate to severe coagulopathy have an increased mortality risk if 
administered ELAD treatment compared with standard of care therapy and these subjects will be 
excluded from future ELAD clinical trials (Gustot 2015). 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
16 
In a Phase 2 study (VTI-206) of ELAD, AILD was defined based on clinical judgment and 
substantiated by evidence from laboratory tests, medical history, or family interview of a 
temporal association (6 weeks or less) and causal relationship between the use of alcohol and the 
onset of symptoms. Analysis of this predefined subset of subjects in VTI-206 provided 
preliminary evidence that those treated with ELAD along with standard of care may have 
prolonged survival versus standard of care alone. 
VTI-208 was designed to provide data on the safety and clinical utility of the ELAD System in 
the treatment of subjects with AILD. The primary endpoint evaluated overall survival of subjects 
with a clinical diagnosis of alcohol-induced liver decompensation (AILD) up to at least Study 
Day 91, with follow-up Protocol VTI-208E providing additional survival data up to a maximum 
of 5 years that was included, as available, through VTI-208 study termination (after the last 
surviving enrolled subject completed Study Day 91). This was assessed using a Kaplan-Meier 
survival analysis of the ITT population utilizing a log-rank test. The study was conducted at 
40 centers in the US, Australia, and Europe. 
In addition to collecting long-term survival data, VTI-208E will help inform the incidence of 
cancer, liver transplant, and an assessment of quality of life over the extended 5-year follow-up 
period. 
The VTI-208 study included 203 AILD subjects in the ITT population, 96 and 107 subjects 
randomized to ELAD treatment and Control (standard of care only) groups, respectively. The 
Kaplan-Meier analysis of the overall survival (OS) in the ITT population was not statistically 
different. However, in a predefined subset of 120 subjects with MELD scores <28 that consisted 
of 51 and 69 subjects in the ELAD-treated and Control groups, respectively, the Kaplan-Meier 
analysis of the OS did approach statistical significance. In another pre-specified exploratory 
analysis of subjects with less than the median age of 46.9 years, the Kaplan-Meier analysis of the 
OS favored the ELAD treated AILD subjects. These analyses provide the rationale to conduct 
this VTL-308 study in AILD subjects younger than 50 years old who have MELD scores <30.  
Other subset analyses suggest that subjects with acute renal dysfunction, defined as serum 
creatinine ≥1.3 mg/dL and severe coagulopathy (INR >2.5) (Moreau 2013), should be excluded 
from this study.  
The safety profile of ELAD observed in the VTI-208 study was similar to that observed in prior 
ELAD studies. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
17 
2 
STUDY OBJECTIVES 
The primary objective of the study is to evaluate safety and efficacy of ELAD® with respect to 
overall survival (OS) of subjects with a clinical diagnosis of alcohol-induced liver 
decompensation (AILD) through at least Study Day 91, with follow-up Protocol VTL-308E 
providing additional survival data up to a maximum of 5 years that will be included, as available, 
through VTL-308 study termination (after the last surviving enrolled subject completes Study 
Day 91).  The primary objective will be assessed using a Kaplan-Meier survival analysis of the 
Intent-to-Treat (ITT) population utilizing a log-rank test. 
The secondary objective is to evaluate the proportion of survivors at Study Day 91 using a chi-
squared test.   
The exploratory objectives will identify potential differences between treatment groups in factors 
related to standard demographics, selected baseline characteristics, medical history, and standard 
of care. These factors will be prespecified in the SAP, and are based on previously-identified and 
medically-pertinent influences on treatment outcomes in alcoholic liver disease, as well as on 
factors shown to be important in prior studies of ELAD. In addition, the relationship between 
outcomes and ELAD System performance, therapeutic interventions of interest and 
administration of concomitant pharmacotherapies of interest will be assessed in order to help 
inform product labeling and use. Furthermore, changes in certain biomarkers of interest will also 
be evaluated. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
18 
3 
STUDY DESIGN 
VTL-308 is a randomized, open-label, multicenter, controlled, pivotal study of subjects with 
AILD. A minimum of 150 subjects meeting the eligibility requirements of the study will be 
randomly assigned in a 1:1 ratio to receive either standard of care treatment for AILD (as defined 
in the protocol) plus treatment with the ELAD System (ELAD group) or standard of care 
treatment for AILD alone (Control group).   
Central randomization will be performed to ensure that neither Sponsor, site, nor study personnel 
have any foreknowledge of subject treatment assignment.  
Because ELAD treatment must take place in an Intensive Care Unit (ICU), or a Step-Down Unit 
(SDU) with an equivalent standard of care if written pre-approval has been given by VTL, all 
subjects considered for enrollment must be considered eligible for ICU or SDU placement.  
Control subjects need not be placed in an ICU or SDU setting unless deemed necessary by the 
Investigator due to the severity of their illness. 
Screening evaluations and assessments will be completed for both ELAD and Control subjects 
and reviewed against inclusion/exclusion criteria prior to Randomization. For both study groups, 
ELAD-treated and Control, the time of Randomization will define the time of study entry (Hour 
0, Study Day 1, study baseline) and inclusion in the ITT population. Laboratory draws for the 
first post-randomization blood tests required by the protocol will begin with the next standard 
laboratory draw (typically the following morning). 
In addition to the Screening evaluations, because there will be a delay between Randomization 
and initiation of ELAD treatment, a further assessment to confirm the subject’s safety eligibility 
will be undertaken. This assessment will be conducted in the same manner for both ELAD and 
Control subjects.  Either the principal investigator or sub-investigator trained on the study must 
have evaluated the safety eligibility results and be immediately available when ELAD treatment 
begins in order to assess changes in the subject’s condition since Randomization. This is 
especially important when evaluation changes during the 24 hours preceding initiation of ELAD 
treatment in order to determine whether the subject remains eligible for extracorporeal treatment. 
For all subjects randomized, certain key safety factors must be evaluated within 6 hours prior to 
ELAD treatment initiation, or at End of Study Day 2 (±6 hours) for Control subjects: platelet 
count, international normalized ratio (INR), serum creatinine, evidence of infection unresponsive 
to antibiotics, hemodynamic instability, bleeding status, and status with respect to ventilation, 
intubation, or need for hemodialysis. These factors will be assessed in accord with the pertinent 
exclusion criteria (2, 3, 4, 7, 9, 10, 15, and 16 relative to the safety evaluation time point), and 
subjects must continue to be eligible based on these exclusion criteria to remain in the modified 
intent-to-treat (mITT) population.     
In addition vital signs will be taken, total bilirubin measured, and a MELD score will be 
calculated. 
The standard of care labs may fulfill this requirement provided they are drawn within 6 hours 
prior to ELAD treatment initiation.   
 If an ELAD subject fails to meet these criteria, ELAD treatment will not be 
initiated, the subject will continue to receive standard of care, and the subject 
will be exluded from the modified intent-to-treat (mITT) population.   

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
19 
 If a Control subject fails to meet these criteria, the subject will continue to 
receive standard of care, and the subject will be excluded from the mITT 
population.   
Subjects randomized to the ELAD group will be treated with ELAD for a minimum of 3 days 
(72 hours).  
ELAD treatment may be interrupted for a period of less than 6 hours then restarted with the same 
set of cartridges provided that, in the opinion of the Investigator, the subject remains eligible for 
treatment.  ELAD treatment may be interrupted for a period of more than 6 hours but less than 
72 hours, if, for example, to allow for the conduct of a diagnostic or therapeutic procedure or for 
management of an adverse event, or should there be a need to interrupt the use of 
anticoagulants. Should this circumstance arise, a new set of ELAD cartridges must be used if 
treatment of the subject will continue, and the subject must meet the same safety eligibility 
criteria as are required prior to the initiation of treatment (See Section 5.4.2.1.1).   
ELAD treatment will be discontinued and will not be restarted if any of the following 
discontinuation criteria are met.  If ELAD treatment is discontinued, subjects will receive 
standard of care therapy alone and be followed through Study Day 91.  Discontinuation criteria 
include the following: 
 Continued ELAD treatment is judged to be futile, defined as an increase of 
more than 25% in total bilirubin at 72 (+6) hours  (includes clinical 
consideration of impact of artifactual hyperbilirubinemia) compared to the most 
temporal measurement of total bilirubin taken within 6 hours prior to ELAD 
initiation.  Bilirubin measurements must be taken at least 12 hours after any 
procedure known to artificially alter serum bilirubin (e.g., administration of 
packed red blood cells, plasma exchange);  
 Subject has been off treatment for more than 72 hours; 
 Subject has suffered an adverse event that, in the Investigator’s opinion, 
requires ELAD treatment to be discontinued, and/or which cannot be resolved 
within a period of 72 hours;  
 Subject has suffered a disseminated intravascular coagulopathy (DIC) event; 
 Subject develops an indication for hemodialysis; 
 Subject requires an extracorporeal procedure that takes precedence over ELAD 
treatment; 
 Subject has been treated for a maximum of 120 hours within five (5) 24-hour 
periods regardless of treatment interruption;  
 Subject undergoes orthotopic liver transplantation;  
 Subject is discharged from the hospital; 
 The first set of ELAD cartridges has been replaced for any reason and the 
second set also requires replacement, or the subject fails safety eligibility checks 
for the second set; 
 Subject or legally-authorized representative withdraws consent for further 
ELAD treatment; 
 Investigator decides to stop ELAD treatment;  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
20 
 ELAD System performance issues arise that cannot be resolved within a period 
of 72 hours; 
 Subject experiences catheter-related issues that cannot be resolved within a 
period of 72 hours. 
 
Note: Regarding the judgment of futility of treatment based upon increase of bilirubin by 25%, 
Investigators are asked to use clinical judgment in assessing artifactual 
hyperbilirubinemia (e.g., resulting from transfusion of packed red blood cells) before 
discontinuing ELAD treatment if they believe ELAD to still be capable of providing 
clinical benefit.  A call to the Medical Monitor should be made to discuss this, should it 
occur.   
Subjects in both groups will be evaluated throughout the 91-day study period.   
Subjects undergoing orthotopic liver transplantation during ELAD treatment will be evaluated 
exactly the same as any other subject who completed treatment early. The evaluation mandated 
for the first day after treatment will be carried out 24 hours post-transplantation.  All subjects 
(ELAD and Control) receiving a liver transplant will be followed through Study Day 91. 
If the subject (ELAD or Control) withdraws consent from the study at any time during the Study, 
the subject will no longer be monitored by the site through Study Day 91. All efforts should be 
made to ensure subject continues to consent for safety and follow up. 
If standard of care treatment as defined by the institution is consistent with discharging the 
subject home, then the subject should be discharged.  Prior to discharge, the subject will be 
advised to attend all protocol-required visits.  Instructions for home visits will also be reviewed. 
An extension of this study, VTL-308E, will provide extended follow-up of subjects enrolled in 
VTL-308 over a period of 5 years to determine incidence of survival, cancer, liver transplant, and 
quality of life.  Data obtained from the extension study will provide additional survival data up to 
a maximum of 5 years that will be included, as available, through VTL-308 study termination 
(after the last surviving enrolled subject completes Study Day 91). 
A diagram of the study design and timeline is provided in Figure 2. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
21 
4 
STUDY POPULATION 
4.1 
GENERAL CHARACTERISTICS OF THE PROPOSED STUDY 
POPULATION 
Subjects under 50 years of age with a clinical diagnosis of AILD, associated with recent alcohol 
consumption, with elevated bilirubin, and without evidence of secondary organ failure, as 
characterized by acute kidney injury, severe coagulopathy, infection unresponsive to antibiotics, 
hemodynamic instability, recent bleeding and/or the need for intubation.  
4.2 
ANTICIPATED NUMBER OF RESEARCH SUBJECTS 
Approximately 150 subjects meeting the defined eligibility requirements. 
4.3 
INCLUSION CRITERIA 
Subjects must meet ALL inclusion criteria to be eligible for the study: 
1. Age ≥18; 
2. Total bilirubin ≥16 mg/dL (≥273.6 µmol/L); 
3. A clinical diagnosis of alcohol-induced liver decompensation (AILD), based upon lab 
test or medical history or family interview with a causal relationship and temporal 
association (6 weeks or less) of alcohol use and hospital admission for this episode of 
AILD; 
4. Maddrey score ≥32; 
5. Subjects must have AILD that is severe acute alcoholic hepatitis (sAAH) diagnosed 
with either: 
a. A confirmatory liver biopsy, OR 
b. Two or more of the following: 
i. 
Hepatomegaly, 
ii. 
AST > ALT, 
iii. 
Ascites, 
iv. 
Leukocytosis (WBC count above lab normal at site); 
Note:  Subjects will be classified as either: 
a. 
AILD that is sAAH with no underlying liver disease other than 
alcoholic liver disease, OR 
b. 
AILD that is sAAH with evidence of underlying liver disease other 
than alcoholic liver disease which must be documented by: 
i. 
Liver biopsy, AND/OR 
ii. 
Laboratory findings, AND/OR 
iii. 
Medical history; 
6. Not eligible for liver transplant during this hospitalization; 
7. Subject or legally-authorized representative must provide Informed Consent; 
8. Subject must be eligible for Standard of Care treatment as defined in the protocol. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
22 
4.4 
EXCLUSION CRITERIA 
Subjects must NOT have any of the following exclusion criteria: 
1. Age ≥50; 
2. Platelet count <40,000/mm3; 
3. International Normalization Ratio (INR) >2.5; 
4. Serum Creatinine ≥1.3 mg/dL (≥115.04 µmol/L); 
5. MELD score ≥30; 
6. AST >500 IU/L; 
7. Evidence of infection unresponsive to antibiotics (e.g. increased tissue involvement 
relative to initial diagnosis, clinical worsening of symptoms, etc.) indicated by any of 
the following: 
a. Presence of sepsis or septic shock; OR 
b. Positive blood cultures (bacteremia, fungemia) within 72 hours prior to 
Randomization; OR 
c. Presence of spontaneous bacterial peritonitis during the 2 days prior to 
Randomization; OR 
d. Clinical and radiological signs of pneumonia;  
8. Evidence of reduction in total bilirubin of 20% or more in the previous 72 hours.  
Bilirubin measurements must be taken at least 12 hours after any procedure known to 
artificially alter serum bilirubin (e.g., administration of packed red blood cells, 
plasma exchange);   
9. Evidence of hemodynamic instability as defined by the following: 
a. Systolic blood pressure <90 mmHg with evidence of diminished perfusion 
unresponsive to fluid resuscitation and/or low-dose pressor support; OR  
b. Mean arterial pressure (MAP) <60 mmHg with evidence of diminished 
perfusion unresponsive to fluid resuscitation and/or low-dose pressor support; 
OR  
c. Requirement for escalating doses of vasopressor support prior to Screening; 
OR  
d. Subject on vasopressors, including but not limited to those listed below, at 
doses above the following at Screening or Randomization: 
 Dobutamine:   
5.0 µg/kg/min 
 Dopamine: 
2.0 µg/kg/min 
 Norepinephrine: 
0.02 µg/kg/min 
 Phenylephrine: 
1.0 µg/kg/min 
 Vasopressin: 
0.02 U/min 
10. Evidence of active bleeding, major hemorrhage defined as requiring ≥2 units packed 
red blood cells to maintain a stable hemoglobin occurring within 48 hours prior to 
Randomization, or with banding of gastroesophageal varices during the 7 days 
immediately preceding screening;  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
23 
11. Clinical evidence of liver size reduction due to cirrhosis [liver size of the 
craniocaudal diameter (sagittal view) <10 cm when measured on the mid clavicular 
line (or equivalent measurement) by ultrasound, or liver volume <1200 cc as 
determined by CT or MRI], unless Investigator interpretation of the clinical evidence 
indicates liver size of <10 cm or volume <1200 cc is not considered reduced for the 
individual subject, and Sponsor agrees;  
12. Occlusive portal vein thrombosis impairing hepatopetal flow, or evidence of bile duct 
obstruction;  
13. Evidence by physical exam, history, or laboratory evaluation, of significant 
concomitant disease with a life expectancy of less than 3 months, including, but not 
limited to:  
a. Severe acute or chronic cardiovascular, central nervous system, or pulmonary 
disease; 
b. Cancer that has metastasized or has not yet been treated; 
c. Severe metabolic abnormalities that have not been corrected (See 
Section 5.1.3);  
14. Subject has chronic end-stage renal disease requiring chronic hemodialysis for more 
than 8 weeks (not classified as hepatorenal syndrome); 
15. Subject ventilated or intubated; 
16. Subject on hemodialysis; 
17. Subject has liver disease related to homozygous hemachromotosis, Wilson’s disease, 
has non-alcoholic fatty liver disease, or Budd-Chiari Syndrome. 
18. Serological evidence (including viral titers) of active viral hepatitis A, B or C 
infection. If the investigator suspects that the subject may be at risk for viral hepatitis 
A, B or C, and no serology is available, then serologies MUST be obtained prior to 
Randomization, as a positive serology would be exclusionary; 
19. Pregnancy as determined by serum β-human chorionic gonadotropin (HCG) results, 
or subjects of child-bearing potential not willing to use effective means of 
contraception, without history of medical or surgical sterilization;  
20. Participation in another investigational drug, biologic, or device study within one 
month of enrollment, except for observational studies (the observational study setting 
should not affect the safety and/or efficacy of the VTL-308 clinical trial);  
21. Previous liver transplant;  
22. Previous enrollment in the treatment phase of another ELAD trial;  
23. Have a Do Not Resuscitate or a Do Not Intubate (DNR/DNI) directive (or such local 
equivalent) or any other Advanced Directive limiting Standard of Care in place (the 
DNR/DNI criterion is not applicable in Europe);  
24. Refusal to participate in the VTL-308E follow-up study; 
25. Inability to provide an address for home visits.  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
24 
5 
STUDY PROCEDURES 
Schedules of evaluations are presented by study period in Table 1, Table 2, Table 3, and Table 4. 
The pre-screening, screening (inclusion/exclusion criteria assessment), and randomization 
process is a collaboration between the Investigator and the Sponsor Representative to confirm 
subject eligibility and ensure subject safety. The process involves pre-screening through the 
conduct of routine standard medical procedures, subject informed consent (enrollment) followed 
by conduct of the screening assessment (inclusions/exclusion criteria assessment), and 
randomization. The Investigator may contact the Medical Monitor or Chief Medical Officer at 
any time during this process.  
5.1 
PRE-SCREENING 
Pre-Screening is the collection of information to determine subject eligibility before obtaining 
Informed Consent. It includes the review of data obtained from routine standard medical 
procedures to determine if a patient is potentially an eligible subject for enrollment in this study. 
A record of all pre-screened subjects will be maintained by each site on the Pre-Screening Log in 
the Electronic Data Capture (EDC) system. If a subject is found ineligible for study participation 
prior to Screening, the reason(s) for ineligibility will be documented on the Pre-Screening Log 
electronic Case Report Form (eCRF). 
It is possible that a subject who does not initially qualify for the study may have a change in 
status at a later date. If the Investigator believes that the eligibility of the subject has changed, the 
Sponsor Representative should be notified and the subject may be considered again. 
5.1.1 
Sponsor Notification 
Investigational Review Board/Ethics Committee (IRB/EC) or other governing regulatory body 
policy dictates the manner in which medical information may be shared with the Sponsor.  
1. The local policy allows de-identified medical information to be shared with the 
Sponsor prior to obtaining Informed Consent.   
 
OR 
2. The local policy requires Informed Consent to be obtained prior to sharing any de-
identified medical information with the Sponsor. 
When a potential study subject is identified during the pre-screening process, the Investigator or 
designee must notify the Sponsor Representative by calling the Subject Enrollment Mobile 
Phone. Medical information may be shared at this time with the Sponsor according to local 
policy. 
Results of medical information from tests or procedures that have been performed as part of 
routine standard medical care of the patient (and that may be shared with the Sponsor according 
to the local policy during the pre-screening process) must be provided to the Sponsor 
Representative. All personal identifiers (patient names, patient numbers, hospital names 
and locations, etc.) must be removed/redacted from the data prior to sending them to VTL.  
Signed Informed Consent Forms must not be sent. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
25 
5.1.2 
Pre-Screening Procedures 
The results of the tests and assessments listed below, if performed as Standard of Care (SOC) 
within the previous 24 hours, unless otherwise noted (see Section 5.2.3.2 regarding imaging 
requirements), should be reviewed. The below tests and assessments, if unavailable as SOC, 
should NOT be obtained specifically for study review until AFTER a signed Informed Consent 
Form is obtained. An overview of these procedures is presented in Table 1: 
 Demographics (date of birth or age, race, ethnicity, height, weight, gender) 
 Relevant medical history 
 Documented evidence of temporal association (6 weeks or less) of alcohol use 
and hospital admission for this episode of AILD.  Documented evidence 
includes patient or other credible person reporting alcohol use, and/or positive 
blood test  
 Physical exam (performed by a Physician, Physician Assistant or Nurse 
Practitioner if within the scope of practice for institution) 
 Vital signs (blood pressure, heart rate, respiration rate, temperature)  
 Encephalopathy stage [West Haven Criteria, performed by a Physician, 
Physician Assistant, or Nurse Practitioner if within the scope of practice for 
institution (Refer to Appendix A)] unless subject is sedated 
 Liver imaging to determine liver size and confirm the absence of occlusive 
portal vein thrombosis or bile duct obstruction (see Section 5.2.3.2 regarding 
imaging performed no more than six weeks prior to current hospitalization)  
 Routine laboratory evaluations: Creatinine, total bilirubin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), α-fetoprotein   
 Complete Blood Count (CBC): White blood cell count (WBC), hematocrit. 
hemoglobin and platelets 
 Prothrombin time (PT), international normalized ratio (INR) 
 Serum pregnancy test (if applicable) 
 MELD and Maddrey scores will be calculated in accord with Section 5.2.4. 
5.1.3 
Pre-Screening Laboratory Abnormalities 
If during pre-screening, severe metabolic abnormalities are noted, screening and randomization 
should not be considered until these abnormalities have been corrected. Examples of severe 
metabolic abnormalities (See Exclusion Criterion 13) include, but are not limited to: 
 hypoglycemia (serum glucose <50 mg/dL or 2.8 mmol/L)  
 hypocalcemia (serum calcium ≤3.52 mg/dL, ≤0.88 mmol/L, or ≤1.76 mEq/L)  
 hypokalemia (serum potassium <7.8 mg/dL, <2 mmol/L, or <2.0 mEq/L) 
 hypomagnesemia (serum magnesium <1.2 mg/dL, <0.5 mmol/L, or <1.0 
mEq/L) 
 hyponatremia (serum sodium <276 mg/dL, <120 mmol/L, or <120 mEq/L) 
 hypophosphatemia (serum phosphate <0.93 mg/dL, <0.3 mmol/L, or <0.6 
mEq/L)  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
26 
5.2 
SCREENING 
The Screening process includes evaluation of the potential subject based on the 
inclusion/exclusion criteria provided in Section 4. It is the collection of information to determine 
subject eligibility after obtaining Informed Consent. It includes specific procedures to determine 
if a patient is an eligible subject for randomization into this study. Additional laboratory tests not 
required for study eligibility, but that are part of determining baseline laboratory values, must 
also be collected as part of this Screening process. 
If a subject fails the Screening process, the subject’s Screening information is collected in the 
EDC system and the subject will be considered a screen failure and not randomized into the 
study.   
It is possible that a subject who does not initially qualify for the study may have a change in 
status at a later date. If the Investigator believes that the eligibility of the subject has changed, the 
Sponsor Representative should be notified and the subject may be considered again. 
5.2.1 
Informed Consent  
A subject is enrolled in the study when the subject or their legally-authorized representative 
(LAR) has signed the Informed Consent Form. This marks the beginning of the Screening 
process during which study-specific screening procedures may be performed (Section 5.2.3).  
Screening eCRFs in the EDC system will be completed for all enrolled subjects regardless of the 
final eligibility determination. 
 
Informed Consent Process 
The Informed Consent Form (ICF) must be approved by the local IRB/EC or governing 
regulatory body. The ICF must be signed and dated by the subject or LAR and by the person 
obtaining consent. The original signed ICF will be retained in the subject's study records and a 
copy will be provided to the subject or LAR. The informed consent process must be documented 
in the subject's medical record. 
If informed consent is obtained from a subject with altered mental status, capacity for consent 
must be clearly documented in the medical record as assessed by the Investigator or designee. An 
assessment tool for determining capacity for consent is available in Appendix B. If at any time 
during the study the subject regains capacity for consent, this assessment must be documented by 
the investigator and the subject must complete the consent process. If the subject does not agree 
to consent, they will be discontinued from participation in the study. 
During the informed consent process, subjects will also be informed about participation in the 
follow-up registry extension of this study (VTL-308E). Subjects who decline participation in 
VTL-308E are not considered candidates for participation in VTL-308 (Exclusion Criterion 24). 
5.2.2 
Sponsor Notification 
The Investigator or designee must notify the Sponsor Representative by calling the Subject 
Enrollment Mobile Phone after signed Informed Consent is obtained. Medical information may 
be shared at this time with the Sponsor according to local policy. 
Results of medical information from tests or procedures that have been performed as part of the 
Screening Process (inclusion/exclusion criteria assessment) must be provided to the Sponsor 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
27 
Representative. All personal identifiers (patient names, patient numbers, hospital names 
and locations, etc.) must be removed/redacted from the data prior to sending them to VTL.  
Signed Informed Consent Forms must not be sent. 
5.2.3 
Screening Procedures 
The tests and assessments listed below must be performed prior to Randomization, unless 
otherwise noted (see Section 5.2.3.2 regarding imaging requirements). An overview of these 
procedures is presented in Table 1 of this protocol. 
Procedures that are performed one time as part of the Screening process are as follows: 
 Demographics (date of birth or age, race, ethnicity, height, weight, gender) 
 Relevant medical history 
 Documented evidence of temporal association (6 weeks or less) of alcohol use 
and hospital admission for this episode of AILD.  Documented evidence 
includes patient or other credible person reporting alcohol use, and/or positive 
blood test  
 Liver imaging to determine liver size and confirm the absence of occlusive 
portal vein thrombosis or bile duct obstruction (see Section 5.2.3.2 regarding 
imaging performed no more than six weeks prior to current hospitalization)  
 Serologies (if not previously collected during this hospitalization, and 
investigator suspects subject may be at risk) for active viral hepatitis A, B or C 
infection or human immunodeficiency virus (HIV); a positive serology for 
active hepatitis would be exclusionary 
 Serum pregnancy test++ (if applicable) 
++ Note: Subjects who are sexually active, without history of medical or surgical sterilization, 
must agree to practice a form of effective contraception. Instruction should be given that if a 
subject becomes pregnant or impregnates another during participation in the study, they must 
inform the Principal Investigator immediately. Female subjects that become pregnant and report 
this to the Principal Investigator will be followed through to the completion of the pregnancy, 
including delivery and status of the neonate. The partner of a male ELAD-treated subject who is 
impregnated during the time between Randomization to Study Day 91 will not be followed.   
Procedures that are performed as part of the Screening process and which are used as Baseline 
values required for subsequent assessments of change in key parameters are as follows (Note: 
these tests and assessments must be performed within 24 hours prior to randomization): 
 Physical exam (performed by a Physician, Physician Assistant or Nurse 
Practitioner if within the scope of practice for institution) 
 Vital signs (blood pressure, heart rate, respiration rate, temperature)  
 Encephalopathy stage [West Haven Criteria, performed by a Physician, 
Physician Assistant, or Nurse Practitioner if within the scope of practice for 
institution (Refer to Appendix A)] unless subject is sedated 
 Routine laboratory evaluations: BUN, creatinine, total bilirubin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), glucose, sodium, 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
28 
potassium, chloride, carbon dioxide (or bicarbonate), calcium, magnesium, 
phosphate, albumin, total protein, alkaline phosphatase  
 Baseline laboratory evaluations (not used for study eligibility):  partial 
thromboplastin time (PTT), ammonia, lactate, albumin, α-fetoprotein, lactate 
dehydrogenase (LDH) 
 Complete Blood Count (CBC): White blood cell count (WBC), hematocrit, 
hemoglobin, and platelets 
 Prothrombin time (PT), control PT, international normalized ratio (INR) 
 Pulse oximetry and FiO2 (with amount of oxygen and delivery method noted, if 
applicable) 
 PEth Test 
 MELD and Maddrey scores will be autocalculated in accord with Section 5.2.4. 
 
PEth Test 
The PEth test blood sample (finger stick) will be collected to determine whether the subject has 
been drinking alcohol (Center for Substance Abuse Treatment, 2006; Allen 2003; Cluver 2007; 
Miller 2005). This specimen (identifiable by subject number only) will be sent to a central 
laboratory and the results will go directly to the outside data management group that handles the 
Sponsor’s data to prevent any caregivers from knowing the results. Because subjects may want 
this information kept confidential from any caregivers, subjects should be made aware that it is 
for research only and results will not be entered into their medical records or given to any of the 
clinical trial team.   
The kit to carry out the PEth test to determine alcohol use will be provided to the sites by VTL or 
designee and performed by an outside lab: 
United States Drug Testing Laboratories 
1700 South Mount Prospect Road 
Des Plaines, Illinois 60018 
 
Instructions for the test and for sending the samples to United States Drug Testing Laboratories 
will be included with the actual test materials delivered to the investigational site. 
 
Imaging Requirements  
Liver imaging will be used to confirm that there is no evidence of occlusive portal vein 
thrombosis or bile duct obstruction and to assess liver size, either by diameter or by liver volume 
(Exclusion Criteria 11 and 12). To determine subject eligibility for enrollment, the liver must be 
assessed by ultrasound in all subjects, to determine if there is occlusive portal vein thrombosis or 
bile duct obstruction, whether or not the ultrasound measurement is used to assess liver size.  
Liver size may be assessed by ultrasound, CT scan, or MRI. All imaging must be indicative of 
and have a temporal relationship to the subject’s current clinical condition. 
If the imaging is not performed during the current hospitalization, the Investigator or designee 
must document that it is representative of the subject’s current clinical condition. Imaging must 
be performed no more than six weeks prior to the current hospitalization. The Sponsor will 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
29 
request that imaging be repeated if the imaging studies that have been carried out are inadequate 
to ascertain patient safety and/or eligibility. 
5.2.3.2.1 
Measurement of Liver Diameter 
Liver diameter can be assessed using ultrasound, CT or MRI to ensure adequate liver size per 
Exclusion Criterion 11. Imaging must be performed no more than six weeks prior to the current 
hospitalization. The craniocaudal diameter (sagittal view) of the liver must be at least 10 cm 
when measured on the mid-clavicular line. If the mid-clavicular (sagittal) measurement is not 
available, other craniocaudal planes may also be used [e.g., mid-axillary (coronal plane) or 
anterior-posterior (transverse plane)] provided that, in the opinion of the Investigator, the 
measurement is consistent with a mid-clavicular measurement (right lobe of the liver) of at least 
10 cm. If liver size is not routinely measured at the institution, then it is recommended that liver 
measurement and the technique to measure the liver size be added to ultrasound orders for 
potential subjects.  
5.2.3.2.2 
Measurement of Liver Volume 
If the ultrasound is unable to adequately assess liver size, a CT or MRI scan may be performed, 
and the liver volume may be calculated to ensure adequate liver size per Exclusion Criterion 11.  
The CT or MRI scan must be performed no more than six weeks prior to the current 
hospitalization. The liver volume must be at least 1200 cc.  
5.2.4 
Assessment of MELD and Maddrey Scores 
The MELD scoring system accounts for the effects of dialysis, whether it be intermittent 
hemodialysis or continuous hemofiltration.  For the purposes of this protocol, the MELD score 
will be autocalculated when the individual parameters (bilirubin, creatinine, INR, age, dialysis) 
are entered into the eCRFs. MELD and Maddrey scores should not be calculated manually 
outside of the eCRF/EDC system.   
The parameters used to calculate the MELD score must be obtained using lab values from blood 
draws taken within a period of 6 hours of each other. If one of the three parameters for the 
MELD score needs to be reassessed, and the blood draw for this parameter falls outside of a 
period of 6 hours from one or both of the other parameters, then all three parameters have to be 
reassessed using the guidelines above.   
Likewise, calculation of the Maddrey score must be done using laboratory values for the PT and 
total bilirubin collected from blood draws taken within 6 hours of each other. For the purposes of 
this protocol, the Maddrey is autocalculated when entered into the eCRFs and will autopopulate 
once calculation values are entered. These calculations must be done in the eCRF and should not 
be calculated manually. 
5.3 
RANDOMIZATION PROCESS 
After initial subject eligibility has been confirmed by the Sponsor, the Investigator is notified.  
The investigator is now able to complete the randomization process using the EDC system.  
Once randomization occurs, study subjects randomized to the ELAD treatment group should be 
transferred to the ICU (or equivalent) prior to End of Study Day 2. Written preapproval must be 
obtained from VTL prior to ELAD treatment in a Step Down Unit (SDU). 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
30 
The randomization to the ELAD treatment group or Control group will be 1:1. 
Every effort should be made to notify the subject’s personal physician about his/her inclusion in 
this study.  If the subject cannot provide the physician’s contact information, attempts to obtain it 
from the family or LAR should be made.  
5.3.1 
Interactive Web Response System (IWRS)/EDC Core Details 
Subject enrollment will occur via the vendor-supplied EDC eClinical Suite. The system is an 
integrated platform containing the EDC, Adjudication, and Randomization (IWRS) modules. 
The EDC eClinical Suite Randomization module provides secure, confidential, real-time access 
to a centralized randomization list. The potential for bias is reduced by ensuring that neither 
Sponsor, site, nor study personnel will have any foreknowledge of subject treatment assignment.   
Prior to any entry into the system, each user will complete the training required to perform the 
applicable tasks specific to their role and function. 
Controls are in place to limit access to key personnel for the following:  
 Randomization List  
 Randomization Controls  
 Randomization Configuration  
 Randomization 
5.3.2 
Subject Enrollment and Randomization Procedure 
Site personnel will evaluate patients for eligibility. Patients who are not eligible will be recorded 
in the EDC system’s Pre-Screening Failure module. If site evaluation indicates that the patient is 
eligible, the site will add the subject into the EDC system. The site will enter basic information, 
including Informed Consent and Demographic data, and then upload supporting documentation 
of the subject’s eligibility into the EDC system. Once these steps are completed, the EDC system 
automatically notifies the designated Sponsor representative that the subject’s data is available 
for adjudication.   
The Sponsor representative reviews the submitted data and documentation and will either 
approve or reject the subject in the EDC system. The EDC system will automatically notify the 
site of this status update. For approved subjects, the site can proceed to randomization using the 
EDC system’s Randomization module. Rejected subjects are designated as Screen Failures in the 
EDC system. 
The subject will be randomized based on the randomization scheme defined and loaded into the 
system. The subject will be randomized to either the ELAD treatment or control group in a 1:1 
ratio. This information is automatically populated into the EDC system on screen and within the 
audit log, and is available to the site and the sponsor. This information is also provided to the 
designated site and Sponsor team via an automatic system email notification once a subject has 
been randomized. 
See Figure 1 below for a flow diagram of the subject enrollment process. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
31 
Figure 1. 
Subject Enrollment Process 
 
5.3.3 
Other Procedures 
The following samples or procedures should be collected or performed at any time prior to 
starting ELAD treatment for subjects assigned to the ELAD group, and before End of Study Day 
2 for subjects assigned to the Control group. Results are not required prior to initiation of 
treatment, however, if results are known prior to initiating treatment, and there is a positive 
culture result, appropriate treatment per medical judgment should be provided prior to initiating 
Site Screens Subject
Subject meets Criteria
Site Adds Subject to Fusion
Site Completes Required Data Entry
- Visit Details, Demographics, Eligibility
Site marks subject as Ready for Review
via the Adjudication Module
Sponsor reviews subject in Fusion
via the Adjudication Module
Sponsor Rejects Subject
via the Adjudication Module
Subject updates to a Screen Fail
Sponsor Approves Subject
via the Adjudication Module
Sites Randomize Subject 
via the Randomization Module
Subject updates to Enrolled

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
32 
treatment. If results become available after initiation of treatment, appropriate treatment per 
medical judgment should be provided. 
 Blood culture samples (×2)** (See Section 5.6.1) 
 Urine sample for culture and sensitivity (C&S) testing**  
 Sputum sample for C&S testing**, if clinically able to obtain and process 
according to standard Microbiology Department procedures at Institution 
 Peritoneal fluid sample for C&S testing, if ascites present and if one has not 
been done within prior 7 days or is contraindicated 
 Blood collection for outside analysis (consented subjects at participating centers 
only) (See Section 5.6.3) 
 Subject location 
 
**Note: If repeat cultures are not allowed within 48 hours, then those closest to 
randomization will be used. 
5.4 
STUDY TREATMENT 
Study Day 1 begins at the time of Randomization when protocol-specified standard of care 
(SOC) guidelines must be followed and concludes following the next morning’s SOC lab draw.   
Note: The SOC lab draw may be adjusted in order to initiate ELAD treatment within a 6-hour 
window to limit blood draws. Study Day 1, therefore, will be less than 24 hours. Study 
Day 91 is the final study day. All subjects are enrolled into the study with the expectation 
of completing all 91 days of the study.   
5.4.1 
Study Treatment Standards of Care 
To eliminate potential bias, subjects entered into this study will receive the pertinent 
standard of care as defined by this protocol, independent of treatment group 
(ELAD/Control) assignment.  Standard of Care treatment for all subjects, in both the 
ELAD and Control groups, is to be the same.   
For anticoagulation guidelines for the VTL-308 Study please refer to Appendix E. There is also a 
summary table of the standard of care guidelines in Table 4, which were derived from those 
written and endorsed by the American Association for the Study of Liver Diseases (AASLD) and 
the European Association for the Study of the Liver (EASL). 
There will be treatments that do not fall under the SOC listed in this protocol. For those 
treatments, it is imperative that Control and ELAD subjects are managed the same. For example, 
institutional standard of care for severe acute alcoholic hepatitis may involve the administration 
of concomitant medications such as pentoxifylline (PTx) and/or N-acetylcysteine (NAC). If this 
is the case the same SOC must be applied to both treatment groups unless contraindicated. In this 
case the administration of PTx or NAC would be captured in the concomitant medication section 
of the eCRF. 
Any significant deviations from the standards defined below are to be noted in the eCRFs. These 
SOC cover the following conditions/events: 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
33 
 Nutritional support 
 Steroids 
 Ascites 
 Gastroesophageal varices 
 Hepatic encephalopathy 
 Hepatorenal syndrome (HRS) 
 Hyponatremia 
 Spontaneous bacterial peritonitis (SBP) 
 Thrombocytopenia 
 ICU discharge 
 Hepatic Hydrothorax 
 
Standard of Care - Nutrition 
All subjects will receive Dietary consultations within 72 hours of Randomization if this has not 
already occurred. All Dietary consults include weight measurement. Should specialized Dietary 
personnel (Nutritionists) not be routinely available at the investigative site, Investigators will 
provide dietary oversight following the AASLD/EASL guidelines or hospital guidelines for both 
Control and ELAD-treated subjects. Nutritional guidelines that are standard for the hospital will 
be followed while subjects are in-house with particular attention given to vitamin, trace metal, 
and nutritional deficiencies (protein-calorie malnutrion) and overall general nutritional 
supplementation. Dietary follow-up will be given throughout the hospital stay including at 
hospital discharge. Upon discharge, standardized dietary follow-up, including measurement of 
weight, will be provided at each investigational site/clinic visit. 
 
Standard of Care - Steroid Administration 
In accord with AASLD guidelines, all subjects treated on the protocol (ELAD-treated and 
Control subjects), will be administered prednisolone/prednisone (40 mg daily) for 7 days unless 
specifically contraindicated. If steroids are not administered, the rationale for not administering 
steroids (e.g the specific contraindication) must be documented on the eCRF. After 7 days of 
prednisolone/prednisone therapy, subjects will be evaluated to assess whether steroid treatment 
should be continued. Based on clinical judgment and objective measures of clinical response, 
subjects not responding will be discontinued from steroid treatment and the method used to 
evaluate the clinical response, and the reason for termination recorded. Care should be exercised 
in the interpretation of measures such as the Lille score in subjects treated with ELAD due to the 
impact of extracorporeal therapy on serum bilirubin and prothrombin time. To the extent 
possible, the same criteria must be applied to both the ELAD-treated and Control subjects to 
determine continued steroid treatment. If continued use of steroids is judged to be beneficial to 
the subject, steroid use can be continued for up to 28 days (total). All subjects will stop 
prednisolone/prednisone 40 mg daily after 28 days of administration unless the Investigator 
believes that continued use of steroids is warranted. The clinical rationale for extending or 
stopping steroid dosing must be documented on the eCRFs. If steroid treatment is stopped, a 
tapering schema may be followed. The recommended tapering schema would take place over 7 
days. If an alternative tapering schema is adopted, the rationale for adopting the tapering schema 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
34 
must be documented. The treatment period of prednisolone/prednisone at 40 mg/day must take 
into account any prednisolone/prednisone treatment received prior to this hospital admission 
(e.g., treatment from a transferring hospital).  
 
Standard of Care - Ascites 
5.4.1.3.1 
Abdominal Paracentesis 
All subjects with ascites who are entered into the VTL-308 study will undergo an abdominal 
paracentesis during Screening, if clinically indicated (e.g., grades 2 [moderate] or 3 [large] 
ascites, worsening ascites, spontaneous bacterial peritonitis [SBP], etc.) and if one has not been 
done within 7 days prior to Screening. Subjects who had an abdominal paracentesis more than 7 
days before the first day of Screening are to undergo a repeat paracentesis so that it is confirmed 
that patients do not haveSBP prior to Randomization. The purpose of this requirement is to 
assure that subjects are free of SBP since it is a co-morbidity that is associated with an increased 
risk of hepatorenal syndrome (HRS) and gastroesophageal bleeding, as well as a higher 
mortality. If subjects are on ELAD treatment, paracentesis may only be done if heparin 
anticoagulation has been discontinued for a minimum of 12 hours and should not be done if the 
subject has been diagnosed to have hyperfibrinolysis or disseminated intravascular coagulation. 
5.4.1.3.2 
Ascitic Fluid Analysis 
All subjects with ascites treated with abdominal paracentesis entered into the VTL-308 study 
will have an ascitic fluid cell count and differential, ascitic fluid total protein, and serum-ascites 
albumin gradient (SAAG) conducted in the ascitic fluid sample obtained during Screening. The 
SAAG) is calculated by subtracting the ascites albumin from the serum albumin. A high gradient 
(SAAG >1.1 g/dL indicates portal hypertension). If the subject is suspected at Screening to have 
an ascitic bacterial infection due to associated co-morbidities, signs, or symptoms, ascitic fluid 
should be collected at the bedside in aerobic and anaerobic blood culture bottles prior to 
initiation of antibiotics. Post-paracentesis albumin infusion may not be necessary for a single 
paracentesis of <5 liters. 
5.4.1.3.3 
Treatment 
All subjects entered into the VTL-308 study with ascites will be treated with a salt-restricted diet 
(approximately 2000 mg sodium) and an oral dual diuretic regimen consisting of spironolactone 
and furosemide (if clinically indicated) as soon as the subjects are stabilized and are able to eat 
and tolerate oral medications. 
Long-term norfloxacin (or equivalent) is to be administered to subjects with no gastrointestinal 
bleeding or prior history of SBP if the ascitic fluid protein is <1.5 g/dL and at least one of the 
following is present:  serum creatinine ≥1.2 mg/dL; BUN ≥25 mg/dL; serum sodium 
≤130 mEq/L; and Child-Pugh ≥9 points with bilirubin ≥3 mg/dL. 
Cellulitis can explain pain and fever in subjects with cirrhosis and ascites and should be treated 
with diuretics and antibiotics. 
5.4.1.3.4 
Management of Tense Ascites 
Subjects entered into the VTL-308 study who are considered to have tense ascites that should be 
treated with a paracentesis will have this procedure conducted during Screening before 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
35 
Randomization and the paracentesis should be followed with dietary sodium restriction and oral 
diuretics. Subjects who have less than 5 liters of ascitic fluid removed do not need a colloid 
infusion whereas subjects who had 5 or more liters of ascitic fluid removed are to have post-
paracentesis colloid infusion (8 g of serum albumin for every liter of ascitic fluid removed) to 
prevent post-paracentesis circulatory dysfunction. If tense ascites recurs, paracentesis can be 
repeated at any time it is clinically required. 
5.4.1.3.5 
Refractory Ascites 
Refractory ascites is defined as fluid overload that is unresponsive to a sodium-restricted diet and 
high-dose diuretic treatment (400 mg/day spironolactone and 160 mg/day furosemide) or rapid 
recurrence of ascites after a therapeutic paracentesis. Subjects with refractory ascites entered into 
the VTL-308 study are to have the therapeutic paracentesis conducted during Screening (before 
Randomization). In addition, if the volume of ascitic fluid exceeds 5 liters, subjects will be 
required to have a colloid infusion (8 g of serum albumin for every liter of ascitic fluid removed) 
to minimize electrolyte abnormalities and prevent post-paracentesis circulatory dysfunction. 
5.4.1.3.6 
Drugs contraindicated in Patients with Ascites 
The following drugs are contraindicated in patients with ascites: nonsteroidal anti-inflammatory 
drugs (NSAIDs) including aspirin; angiotensin converting enzyme inhibitors and angiotensin 
receptor blockers; α1-adrenergic blockers; dipyridamole; and aminoglycosides alone or in 
combination with ampicillin, cephalothin, or mezlocillin. 
 
Standard of Care – Gastroesophageal Varices 
Note: Subjects with banding of gatroesophageal varices during the 7 days immediately preceding 
screening will not be eligible for enrollment in the study (see Exclusion Criterion 10). 
All subjects with medium/large varices that have not bled but are Child-Pugh A, B, or C will be 
placed on non-selective β-blockers at the maximum tolerated dose sometime during Screening 
but before Randomization, unless there are clinical issues that contraindicate their use. These 
same subjects may be treated with endoscopic variceal ligation but this procedure and the follow-
up endoscopies should be conducted after the subject completes Study Day 7 (Control) or 
completes ELAD treatment.   
Subjects who have had active bleeding and have received blood products prior to Screening must 
be stable with no bleeding and no further need for blood products for 2 days prior to 
Randomization. Subjects who had active bleeding within 2 weeks prior to Randomization should 
be given oral norfloxacin 400 mg twice daily for 7 days (or equivalent); if the antibiotics cannot 
be administered orally, intravenous ceftriaxone 1 g/day for 7 days (or equivalent) is to be 
administered. 
Subjects who have a variceal bleed will be treated according to the AASLD guidelines: blood 
transfusion (maintain hemoglobin level of 8 g/dL); short course of prophylactic antibiotics (e.g., 
oral norfloxacin 400 mg twice daily for 7 days; if the antibiotics cannot be administered orally, 
intravenous ceftriaxone 1 g/day for 7 days - or equivalents); pharmacologic therapy (e.g., 
vasopressin, terlipressin); endoscopy using endoscopic variceal ligation (EVL)/sclerotherapy (if 
EVL is not technically feasible), balloon tamponade (not to exceed 24 hours), or transjugular 
intrahepatic portosystemic shunt (TIPS); bleeding cannot be controlled or recurs despite 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
36 
pharmacologic and endoscopic therapy, if needed.  Subjects who are treated for recurrent 
variceal bleeding while in the study will be treated with non-selective β-blockers and EVL to 
prevent recurrence of bleeding. TIPS may be considered for appropriate subjects. 
Treatment of type 1 gastric varices (extension of esophageal varices along the lesser curvature of 
the stomach) should follow the management guidelines for esophageal varices. Acute gastric 
fundal variceal hemorrhage should be treated with endoscopic obturation with tissue adhesives or 
EVL, and TIPS if bleeding cannot be controlled or recurs, 
 
Standard of Care – Hepatic Encephalopathy 
Subjects whose hepatic encephalopathy (HE) is stabilized at Screening, during the 
hospitalization, or the outpatient visits to Study Day 91 will be treated with prophylactic 
measures to prevent precipitating factors (e.g., variceal bleeding, SBP, HRS, infections), will be 
fed a nutritious diet (protein intake between 1.0 and 1.5 g/kg/day), and will be maintained on an 
adequate daily dose of lactulose to maintain two to three soft bowel movements per day.  
Selective digestive decontamination, for example rifaximin, may also be given. 
 
Standard of Care – Hepatorenal Syndrome (HRS) 
Hepatorenal syndrome (HRS) is to be diagnosed when ascites is present, the serum creatinine is 
>1.5 mg/dL, there is no reduction in serum creatinine after at least 2 days of diuretic withdrawal 
and volume expansion with albumin, there was no shock, no current or recent treatment with 
nephrotoxic drugs, and there is absence of parenchymal kidney disease.  
Type I is characterized by a rapidly progressive reduction in renal function as defined by a 
doubling of the initial serum creatinine to a level >2.5 mg/dL or a 50% reduction of the initial 
24-hour creatinine clearance to a level <20 mL/minute in less than two weeks. Type II does not 
have a rapidly progressive course.  
Subjects who develop Type I HRS after randomization should be placed on pharmacotherapeutic 
SOC in accord with local practice, for example albumin/octreotide/midodrine (MOA) regimen in 
the US or terlipressin/albumin regimen (TA) ex-US. The treatment of Type II HRS that occurs 
after randomization will be driven by the clinical needs of the subject.  
Renal replacement therapy may be useful in subjects who do not respond to MOA or TA, and 
who fulfill criteria for renal replacement therapy. 
VTL requires that subjects who develop Type I HRS after randomization but prior to the start of 
ELAD treatment as well as while on ELAD treatment must be discontinued from ELAD 
treatment and are to be continued on SOC. VTL also requires that subjects on ELAD treatment 
who require renal replacement therapy/hemodialysis are to be discontinued from ELAD 
treatment before renal replacement therapy/hemodialysis is started. 
 
Standard of Care – Hyponatremia 
Even though there is no good evidence as to what level of serum sodium should prompt 
treatment, subjects in this study will be diagnosed to have hyponatremia when the serum sodium 
level is lower than 130 mmol/L per the EASL practice guidelines. Investigators need to 
determine whether the hyponatremia is secondary to hypovolemic hyponatremia (usually 
secondary to excessive diuretic administration) or hypervolemic hyponatremia (related to the 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
37 
expansion of extracellular fluid volume associated with ascites and edema). Hypovolemic 
hyponatremia should be treated (e.g., stopping diuretics, fluid administration as needed per the 
clinical needs) whenever it occurs during the study. Hypervolemic hyponatremia should be 
treated with fluid restriction if it is practical; fluid restriction is necessary unless the serum 
sodium level is <125 mmol/L. 
 
Standard of Care – Spontaneous Bacterial Peritonitis 
All subjects entered into the VTL-308 study are to undergo an abdominal paracentesis for ascitic 
fluid testing, inclusive of culture, if clinical signs or symptoms suggestive of SBP are present 
(e.g., abdominal pain or tenderness, fever, encephalopathy, renal failure, acidosis, or peripheral 
leukocytosis) during the study. Ascitic fluid should be collected at the bedside in aerobic and 
anaerobic blood culture bottles prior to initiation of antibiotics.    
SBP is diagnosed when the ascitic fluid polymorponuclear (PMN) count is ≥250 cell/mm3 and 
the bacterial cultures are positive. Subjects who have an ascetic fluid PMN count ≥250 cell/mm3 
but the bacterial cultures are negative should be diagnosed to have culture-negative neutrocytic 
ascites.  Symptomatic subjects with ascitic fluid PMN counts <250 cells/mm3 are considered to 
have monomicrobial nonneutrocytic bacterascites. 
Empiric therapy with intravenous cefotaxime (or equivalent) is to be started as soon as the cell 
counts are available and continued for 5 days; appropriate subjects can be treated with ofloxacin 
(or equivalent) for 8 days. Subjects eligible for empiric therapy include those with culture-
positive neutrocytic ascites, culture-negative neutrocytic ascites, and monomicrobial non-
neutrocytic bacterascites. Empiric therapy in subjects with culture-positive neutrocytic ascites is 
modified based on the culture and sensitivities. Subjects who develop a recurrence of SBP at any 
time after the resolution of the current episode of SBP are to have a repeat paracentesis and if the 
polymorphonuclear (PMN) cell counts are ≥ 250 cells/mm3and/or clinical signs of SBP are 
present, the subject is to have empiric therapy, which is to be modified as needed when the 
culture and sensitivities are available. All episodes of SBP up to Study Day 91 are to be treated 
using this algorithm.   
 Intravenous ceftriaxone (or other 3rd generation cephalosporin) for 7 days or 
norfloxacin twice daily for 7 days (or equivalent) is to be given to prevent 
bacterial infections in subjects who have gastrointestinal bleeding (variceal 
bleeding) between Study Day 1 and Study Day 91.   
 Subjects who survived a prior episode of SBP prior to entering the VTL-308 
study or the episode of SBP was treated while the subject was in the VTL-308 
study will be started on long-term prophylaxis with daily norfloxacin (or 
trimethoprim-sulfamethoxazole or equivalent); if indicated, long-term antibiotic 
prophylaxis can be started at Randomization or following an episode of SBP 
that occurred between Study Day 1 to Study Day 91.   
 Subjects with cirrhosis and ascites but no gastrointestinal bleeding are to be 
started on long-term prophylaxis with daily norfloxacin (or trimethoprim-
sulfamethoxazole or equivalent) if the ascitic fluid protein is <1.5 g/dL and at 
least one of the following is present: serum creatinine ≥1.2 mg/dL, BUN 
≥25 mg/dL, serum sodium ≤130 mEq/L, and Child-Pugh ≥9 points with 
bilirubin ≥3 mg/dL. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
38 
 
Standard of Care - Thrombocytopenia 
Subjects with a platelet count <20,000/mm3 without any clinical manifestations of bleeding 
during study treatment (ELAD and Control) will receive platelet transfusions based on the 
judgment of the clinical team. If the platelet count is <20,000/mm3 and there are clinical 
manifestations of only localized contained bleeding, the subjects (ELAD and Control) must 
receive platelet transfusions.  Subjects with a platelet count of <20,000/mm3 and generalized 
bleeding are to be promptly assessed and, if on ELAD, considered for treatment discontinuation. 
 
Standard of Care – ICU Discharge 
Subjects may be admitted to the ICU (or SDU where hospital standards allow and VTL 
approves) before or during the VTL-308 study. Therefore, the subjects’ status should be 
continuously reviewed to identify subjects who no longer require ICU care. It is recommended 
that subjects be discharged from the ICU when their physiologic status has stabilized or when 
their physiological status has deteriorated and further interventions are not warranted. It is 
recommended that subjects experiencing alcohol withdrawal receive ICU care until their 
detoxification stage has stabilized (i.e., absence of seizures and delirium requiring intense 
monitoring). In addition, the subject experiencing alcohol withdrawal should be 
hemodynamically stable prior to discharge (i.e., not requiring intense monitoring for vasopressor 
administration or mechanical respiratory support). Continuous and frequent follow-up with the 
subject is recommended on the SDU or medical/surgical unit post-ICU discharge. For discharge 
from the ICU, a general guideline is that the subject is no longer in need of vasopressors, 
mechanical ventilation, or continuous extracorporeal renal treatment. 
 
Standard of Care – Hepatic Hydrothorax 
Hepatic hydrothorax is defined as a large pleural effusion (usually unilateral and right-sided) that 
occurs in a subject with cirrhosis and ascites. The protein concentration in the pleural fluid is 
usually higher than in the ascitic fluid due to differences in the hydrostatic forces in the abdomen 
versus the chest. First-line therapy of hepatic hydrothorax consists of dietary sodium restriction 
and diuretics while TIPS is considered to be second-line treatment when it becomes refractory.  
Chest tube insertion is contraindicated in a subject with hepatic hydrothorax. 
5.4.2 
Pre-Treatment 
Assessments will be carried out for both ELAD and Control subjects. For ELAD subjects, these 
assessments will be conducted in accord with Section 5.4.2.1.1 to determine eligibility for 
extracorporeal safety. For Control subjects, these assessments will be conducted as part of Study 
Day 2 evaluations in accord with Section 5.4.2.2.1. 
 
Pre-ELAD Treatment 
Prior to initiation of the extracorporeal treatment, ELAD subjects will be evaluated in accord 
with Section 5.4.2.1.1. 
5.4.2.1.1 
Pre-ELAD Safety Assessments 
Either the principal investigator or sub-investigator trained on the study must have evaluated the 
safety eligibility results and be immediately available when ELAD treatment begins in order to 
assess changes in the subject’s condition since Randomization. This is especially important when 
evaluating changes during the 24 hours preceeding initiation of ELAD treatment in order to 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
39 
determine whether the subject remains eligible for extracorporeal treatment. When the ELAD 
Specialist confirms that ELAD treatment can begin in 6 hours or less, certain key safety factors 
must be evaluated. The following procedures will be completed (Table 3), and assessed in accord 
with the pertinent Exclusion Criteria 2, 3, 4, 7, 9, 10, 15, and 16 relative to the safety evaluation 
time point:  
 Platelet count 
 International Normalization Ratio (INR) 
 Serum creatinine 
 Evidence of infection unresponsive to antibiotics 
 Hemodynamic instability assessment (blood pressure and MAP) 
 Bleeding status 
 Status with respect to ventilation, intubation, or need for hemodialysis 
 
In addition the following will be done: 
 Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
 Blood samples will be obtained for culture (×2) (See Section 5.6.1) 
 Total bilirubin will be obtained and MELD scores will be calculated in accord 
with Section 5.2.4 
 Partial thromboplastin time (PTT) will be re-evaluated to guide anti-coagulation 
protocols (See Section 5.5.2.1) 
The ELAD Specialist and the Investigator or designee, prior to the initiation of ELAD treatment, 
will review the safety eligibility criteria listed above to ensure that the criteria are met, and that it 
is safe to initiate treatment. In addition, the Investigator or designee must confirm that the subject 
remains eligible for extracorporeal treatment. If these criteria are not met, the Sponsor 
Representative must be notified and ELAD treatment may not be initiated. The Medical Monitor 
or the Chief Medical Officer must be contacted by the Investigator or designee prior to initiation 
of ELAD treatment. All such procedures and evaluations must be recorded in the appropriate 
section(s) of the eCRFs. 
Every effort must be made to initiate ELAD treatment as soon as possible after confirmation of 
the safety procedures.  However, if treatment is delayed for any reason such that the time from 
the conduct of safety procedures is greater than 6 hours, the subject must be reassessed prior to 
the initiation of ELAD treatment in accord with the procedures above.  In that case, the latest 
data would be recorded on the eCRF.  
If the subject is no longer considered eligible for ELAD treatment, the ELAD cartridges will 
either be destroyed according to the institution’s practices, or may be returned to VTL or 
designee.  The reason the subject was deemed a Pretreatment Failure will be noted on the 
appropriate eCRFs. Pretreatment failure in the ELAD group will result in exclusion from the 
mITT population. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
40 
 
Pre-Control Treatment 
Control subjects undergo the same evaluation as ELAD subjects in order to standardize data 
collection. 
5.4.2.2.1 
Pre-Control Safety Assessments 
Either the principal investigator or sub-investigator trained on the study must have evaluated the 
safety eligibility results and be available at the safety eligibility evaluation timepoint for Control 
subjects (End of Study Day 2) (±6 hours) in order to assess changes in the subject’s condition 
since Randomization. The following procedures will be completed (Table 3), and assessed in 
accord with the pertinent Exclusion Criteria 2, 3, 4, 7, 9, 10, 15, and 16 relative to the safety 
evaluation time point:  
 Platelet count 
 International Normalization Ratio (INR) 
 Serum creatinine 
 Evidence of infection unresponsive to antibiotics 
 Hemodynamic instability assessment (blood pressure and MAP) 
 Bleeding status 
 Status with respect to ventilation, intubation, or need for hemodialysis 
 
In addition the following will be done: 
 Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
 Blood samples will be obtained for culture (×2) (See Section 5.6.1) 
 Total bilirubin will be obtained and MELD scores will be calculated in accord 
with Section 5.2.4 
All such procedures and evaluations must be recorded in the appropriate 
section(s) of the eCRFs. 
If the subject is no longer considered eligible, the reason the subject was deemed a Pretreatment 
Failure will be noted on the appropriate eCRFs. Pretreatment failure in the Control group will 
result in exclusion from the mITT population. 
5.4.3 
Treatment Start 
 
ELAD Treatment Start 
Prior to ELAD treatment initiation, subjects will be given 100 mg hydrocortisone (or institutional 
equivalent) and 50 mg diphenhydramine (or institutional equivalent). The timing for 
premedication should be in accord with the institution’s policy for premedication; if ELAD 
cartridges need to be replaced premedication does not need to be repeated. Anticoagulation 
therapy should be considered prior to initiation of ELAD treatment (See Section 5.5.2.1).  
The clinical, laboratory, and hemodynamic assessments will be performed at specified intervals 
during the study treatment period for both the ELAD and Control groups. An overview of 
evaluations during study treatment is presented in Table 2 for Control subjects and Table 3 for 
ELAD subjects. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
41 
The Investigator or designee should assess the subject, per their Institutions SOC guidelines for 
placing a patient on an extracorporeal system, immediately prior to starting the ELAD System 
blood pump. 
All ELAD System management and cartridge placement will be done by ELAD Specialists. Site 
staff will not be responsible for the management of the ELAD System.  
As ELAD may provide some degree of liver function, the dosage of drugs known to be subject to 
liver metabolism should be carefully monitored by the Investigator or designee in accord with 
institutional standard of care. 
5.4.3.1.1 
Catheter Placement 
Prior to initiation of ELAD treatment, a dedicated, dual-lumen, kink-resistent dialysis catheter 
must be placed by an experienced physician, preferably ultrasound-guided, into the right internal 
jugular vein (preferred site), left internal jugular, femoral, or subclavian veins. If available and 
accessible, the interventional radiology team should be involved in complicated cases. Catheters 
should be designed to deliver a minimum of 300 mL/min blood flow to the ELAD System. For 
insertion and care of the catheter, the Centers for Disease Control and Prevention (CDC) or the 
European CDC guidelines (or local equivalent) should be followed.   
5.4.3.1.2 
ELAD Treatment Duration 
Subjects randomized to receive ELAD will be treated with ELAD for a minimum of 3 days 
(72 hours), unless discontinuation criteria are met (See Section 3). At the end of 3 days (72 
hours), a total bilirubin measurement must be taken. If the total bilirubin has increased by 25% or 
more from the measurement within 6 hours prior to initiation of ELAD treatment, ELAD 
treatment must be discontinued. If the bilirubin has not increased by 25% then treatment should 
continue to a maximum of 5 days (120 hours) regardless of treatment interruption (see 
Section 6.6). Bilirubin should be measured at least 12 hours after any procedure known to 
artificially alter serum bilirubin (e.g. administration of PRBCs, plasma exchange).  
Subjects randomized to receive ELAD treatment will also receive standard of care therapy, and 
will receive medical treatment in accordance with the SOC guidelines as delineated in 
Section 5.4.1 of this protocol and those of the institution. For overall ranges of the durations of 
ELAD treatments from past trials (presented in hours) see the Investigator’s Brochure. 
 
Control Treatment Start 
Subjects randomized to Control Treatment will initiate treatment in accord with the protocol-
defined standards of care immediately following randomization.  
The clinical, laboratory, and hemodynamic assessments will be performed at specified intervals 
during the study treatment period for both the ELAD and Control groups. An overview of 
evaluations during study treatment is presented in Table 2 for Control subjects and Table 3 for 
ELAD subjects. 
5.4.3.2.1 
Control Treatment Duration 
Subjects randomized to the Control group receive standard of care therapy alone, and will 
receive medical treatment in accordance with the SOC guidelines as delineated in Section 5.4.1 
of this protocol and those of the institution.  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
42 
5.5 
EVALUATIONS WHILE ON TREATMENT 
All evaluations in this section are for both ELAD and Control subjects, unless specified 
otherwise. 
5.5.1 
Daily Evaluations through End of Study Day 7 
The following procedures will be performed daily through End of Study Day 7, based on 24-hour 
periods following the End of Study Day 1, and must be performed a minimum of 12 hours apart 
and, if specified, either within the defined time window or during the Study Day. Any subject 
discharged from the hospital prior to End of Study Day 7 must return to the study site for the End 
of Study Day 7 evaluation only (+2 days). It is not necessary to have outpatients return for daily 
assessments. There may be instances where the ELAD treatment period is delayed; therefore 
daily evaluations may be extended beyond End of Study Day 7. Additional eCRFs may be added 
in this situation. See Table 2 for evaluations schedules for Control subjects and Table 3 for 
ELAD subjects:  
 Physical examination (performed by a Physician, Physician Assistant, or Nurse 
Practitioner if within the scope of practice for institution)  
 Vital signs (blood pressure, heart rate, respiration rate, temperature) 
 Encephalopathy stage [West Haven Criteria, performed by a study physician, 
Physician Assistant, or Nurse Practitioner if within the scope of practice for 
institution (Refer to Appendix A)] unless subject is sedated 
 Routine laboratory evaluations: BUN, creatinine, glucose, sodium, potassium, 
chloride, carbon dioxide (or bicarbonate), calcium, magnesium, phosphate, 
ALT, AST, bilirubin (total/direct), albumin, total protein, alkaline phosphatase 
 Additional laboratory evaluations:  ammonia, lactate, , α-fetoprotein, lactate 
dehydrogenase (LDH)  
 Complete Blood Count (CBC): white blood cell count (WBC), hematocrit, 
hemoglobin, and platelets 
 Blood collection for outside analysis (consented subjects at participating centers 
only - at End of Study Days 3, 5, and 7) (See Section 5.6.3) 
 Blood culture samples ×2 – at End of Study Day 2 and End of Study Day 4 for 
Control subjects, or within 6 hours prior to ELAD treatment start and Hours 48 
and 96 of treatment for ELAD subjects  
 Ultrafiltrate samples must be drawn as described in Section 5.6.2 and 
Section 5.6.4. 
 PT, PTT, and INR (If heparin is administered, PTT will be assayed in accord 
with the standard anticoagulation therapy protocol at the site.) 
 Pulse oximetry and FiO2 and method of delivery (for inpatients only) 
 MELD score will be autocalculated in accord with Section 5.2.4 
 Adverse events will be monitored continuously from Randomization and 
recorded 
 Concomitant procedures including concomitant blood product administration 
(e.g., whole blood, packed red blood cells, platelets, fresh frozen plasma, 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
43 
albumin, cryoprecipitate) will be monitored continuously from Randomization 
and recorded 
 Concomitant therapies (e.g., intubation, tracheostomy, CVVH/CVVHD, arterial 
line) will be monitored continuously from Randomization and recorded 
 Documentation of all transfers, discharges, readmissions and admissions within 
or outside institution.  All emergency room visits must also be documented 
 For outpatients Study Day 7 only: Follow-up Dietary consult (including weight) 
 
5.5.2 
Safety Evaluations While on Extracorporeal Treatment (ELAD only)  
The following study procedures will be completed during the first 24 hours of ELAD treatment 
(see Table 3): 
 Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
collected between hours 1-3, 6-10, and 14-18  
 PT, PTT, INR, and platelet count collected between hours 6-10, and 14-18  
 If anticoagulants are administered, they will be managed using the standard 
anticoagulation therapy protocol at the site (See Section 5.5.2.1) 
These 24-hour safety evaluations will all be repeated if the ELAD cartridges are replaced during 
treatment (See Section 6.5).  
ELAD Specialists are responsible for all ELAD System management and monitoring. ELAD 
System performance will be monitored through pump speeds and system pressures (PBW, PPUG, 
PUF, PEC, PF, PBR). ELAD cartridge performance will be monitored by measuring oxygen, pH, 
glucose, and temperature.  
The ELAD System Operator’s Manual provides instructions for the management and monitoring 
of the ELAD System during treatment. The ELAD Specialists will document ELAD System 
performance in the ELAD System Monitoring Forms.  
 
Anticoagulation Therapy during ELAD Treatment  
Extracorporeal systems often require anticoagulation therapy. As an example, in subjects with a 
PTT of less than 50 seconds, extracorporeal circuits may clot more frequently than in subjects 
with a spontaneous PTT of more than 50 seconds if no anticoagulant is used. Please refer to 
anticoagulation guidance provided by the Sponsor in Appendix E, and hospital standard of care 
for extracorporeal treatment. 
Since anticoagulation therapy is associated with changes in coagulation parameters which may 
be more profound in patients with liver disease, the use of anticoagulants must be monitored 
according to the study site’s internal procedures for continuous anticoagulation of extracorporeal 
circuits in subjects with increased bleeding risks. 
The Investigator at each site is responsible for assessing the need of each subject for 
anticoagulation therapy prior to ELAD initiation and during ELAD treatment, and may consult 
with the study site’s experts (e.g., intensive care staff, nephrology staff, or perfusionists) to apply 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
44 
the study site’s internal standards for anticoagulation of liver disease subjects on continuous 
extracorporeal circuits. 
The most frequently used anticoagulant for ELAD treatments in the past has been heparin, 
monitored by PTT. Other anticoagulants used in prior ELAD trials include low molecular weight 
(LMW) heparin monitored by anti-factor Xa or prostacyclin. If contraindications against heparin 
occur (e.g., suspected heparin induced thrombocytopenia), hirudin analogs may be considered, 
according to the study site’s internal procedures. The use of either prostacyclin or hirudin 
analogs should be controlled by appropriate laboratory measurements according to the study 
site’s internal standards. 
Since the performance of C3A cells may be affected by decreased ionized calcium, citrate must 
not be used as an anticoagulant. 
The Investigator or designee may contact the Sponsor (Medical Monitor or designee) prior to 
initiation of ELAD treatment and during ELAD treatment to assist in the evaluation of the need 
for, and dosing of, anticoagulants for the ELAD System. 
At the discretion of the Investigator, anticoagulation therapy can be discontinued at any time.  
All coagulation laboratory parameter results obtained during ELAD treatment will be recorded 
on the appropriate eCRF. 
Clotting in the blood circuit may occur. If that happens, the ELAD Specialist will notify the 
Investigator or designee, who is responsible for determining the need for anticoagulation therapy, 
as discussed above. 
5.5.3 
Evaluations 24 Hours after ELAD Treatment Ends (ELAD-treated subjects 
only) 
The following evaluations will be completed during the study day after the study day during 
which ELAD treatment ends, at least 24 hours (±6 hours) after ELAD treatment ends. These 
evaluations may coincide with standard End of Study Day evaluations, and if so, do not need to 
be repeated. 
 Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
 Physical examination (performed by a Physician, Physician Assistant, or Nurse 
Practitioner if within the scope of practice for institution)  
 Encephalopathy stage [West Haven Criteria, performed by a study physician, 
Physician Assistant, or Nurse Practitioner if within the scope of practice for 
institution (Refer to Appendix A)] unless subject is sedated 
 Laboratory evaluations: BUN, creatinine, glucose, sodium, potassium, chloride, 
carbon dioxide (or bicarbonate), calcium, magnesium, phosphate, ALT, AST, 
bilirubin (total/direct), albumin, total protein, alkaline phosphatase 
 Additional required laboratory evaluations:  ammonia, lactate, α-fetoprotein, 
and LDH 
 CBC: WBC count, hematocrit, hemoglobin, and platelets 
 Pulse oximetry and FiO2 and method of delivery 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
45 
 PT, PTT, and INR 
 MELD score will be autocalculated in accord with Section 5.2.4 
 Blood collection for outside analysis (consented subjects at participating centers 
only) (See Section 5.6.3) 
 Subject location 
5.5.4 
Evaluations on Study Days 14, 21, and 28 (+3 days) 
On Study Days 14, 21 and 28 the following evaluations will be completed for all subjects: 
 Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
 Physical examination (performed by a Physician, Physician Assistant, or Nurse 
Practitioner if within the scope of practice for institution) 
 Encephalopathy stage [West Haven Criteria, performed by a study physician, 
Physician Assistant, or Nurse Practitioner if within the scope of practice for 
institution (Refer to Appendix A)] unless subject is sedated 
 Laboratory evaluations: BUN, creatinine, glucose, sodium, potassium, chloride, 
carbon dioxide (or bicarbonate), calcium, magnesium, phosphate, ALT, AST, 
bilirubin (total/direct), albumin, total protein, alkaline phosphatase 
 Additional required laboratory evaluations:  ammonia, lactate, α-fetoprotein, 
and LDH   
 CBC: WBC count, hematocrit, hemoglobin, and platelets 
 PT, PTT, and INR 
 Blood collection for outside analysis (consented subjects at participating centers 
only) (See Section 5.6.3) 
 Documentation of all transfers, discharges, readmissions and admissions within 
or outside institution.  All emergency room visits must also be documented  
 MELD score will be autocalculated in accord with Section 5.2.4 
 Assessment of concomitant medications 
 Concomitant therapies (e.g., intubation, tracheostomy, CVVH/CVVHD,  arterial 
line) will be monitored continuously from Randomization and recorded 
 Assessment of adverse events 
 Follow-up Dietary consult (including weight) 
5.5.5 
Evaluations on Study Day 63 and Study Day 91 (+5 days) 
On Study Days 63 and 91, the following evaluations will be completed for all subjects: 
 Vital signs (blood pressure, heart rate, respiration rate, and temperature) 
 Physical examination (performed by a Physician, Physician Assistant, or Nurse 
Practitioner if within the scope of practice for institution) 
 Encephalopathy stage [West Haven Criteria, performed by a study physician, 
Physician Assistant, or Nurse Practitioner if within the scope of practice for 
institution (Refer to Appendix A)] unless subject is sedated 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
46 
 Laboratory evaluations: BUN, creatinine, glucose, sodium, potassium, chloride, 
carbon dioxide (or bicarbonate), calcium, magnesium, phosphate, ALT, AST, 
bilirubin (total/direct), albumin, total protein, alkaline phosphatase 
 Additional required laboratory evaluations:  ammonia, lactate, α-fetoprotein, 
and LDH 
 CBC: WBC count, hematocrit, hemoglobin, and platelets 
 PT, PTT, and INR 
 Blood collection for outside analysis (consented subjects at participating centers 
only) (See Section 5.6.3) 
 Documentation of all transfers, discharges, readmissions and admissions within 
or outside institution.  All emergency room visits must also be documented  
 MELD score will be autocalculated in accord with Section 5.2.4 
 Assessment of concomitant medications  
 Concomitant therapies (e.g., intubation, tracheostomy, CVVH/CVVHD,  arterial 
line) will be monitored continuously from Randomization and recorded 
 Assessment of adverse events 
 Follow up Dietary consult (including weight)  
 EQ-5D-5L Quality of Life (QOL) questionnaire ONLY if subject is being 
discharged or if it is the Study Day 91 visit 
5.5.6 
Evaluations at Discharge  
In addition to the daily labs above, on the date of discharge the following should also be 
performed: 
 PEth test for alcohol use  
 Discharge Dietary consult, including weight (within 24 hours prior to 
discharge); follow-up Dietary consult (including weight) with each return study 
visit  
 EQ-5D-5L Quality of Life (QOL) questionnaire (within 24 hours prior to 
discharge) 
5.5.7 
Evaluations Following Discharge 
A post-hospital discharge evaluation is any study-defined subject evaluation that takes place 
following discharge from the hospital where study treatment was conducted. It is defined the 
same across both treatment arms.  
All study-scheduled, post-hospital discharge follow-up evaluations will be conducted by an 
Investigator who is blinded to the subject’s treatment assignment unless the subject is currently 
hospitalized. Inpatient evaluations can be carried out by any member of the study team. For 
clarification, study-defined subject evaluations that would be carried out by the Blinded 
Investigator would include the physical exam, encephalopathy assessment (West Haven 
Criteria), assessment of AEs and SAEs, and recommendation of management of the subject’s 
care (inclusive of recommendations for hospital readmission when applicable).   

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
47 
Study participants will be instructed not to tell the Blinded Investigator conducting the post-
discharge evaluations whether or not they received ELAD treatment. This information must be 
reinforced to all subjects after treatment and again upon hospital discharge. They must be 
instructed to NOT divulge their study arm (treatment group) to any study personnel who were 
not a part of their care team while during the treatment phase of the study. 
Decisions for hospital readmission are to be made independently of knowledge of the subject’s 
treatment group. 
Payments will be made to the subject for each post-discharge study site visit and home visit if 
allowed by the individual site/IRB/EC and/or regulatory agency.  
The study site will notify the home visit agency at the time of subject discharge (i.e., at a 
minimum provide subject’s name, address, contact information). The Investigator will provide 
the discharge orders for the home visits to commence. If the subject is discharged to a skilled 
nursing facility (SNF), hospice, or rehabilitation facility, the Investigator will assure discharge 
orders are reflective of the research to be carried out in the facility by the home visit practitioner.  
It is the study site’s responsibility to ensure the home visit will be allowed at the facility. In both 
cases, discharge to home or to another facility, every effort will be made by the home visit 
practitioner to schedule the initial visit within one week of hospital discharge.  Subsequent visits 
will be scheduled weekly (±2 days) thereafter through the End of Study Day 91 (based on the 
original date of discharge not on the day of the previous visit). All study subjects must have a 
valid home address and phone number where they can be reached, or the information of the 
facility to which they are to be transferred.   
The initial home visit will be scheduled for 1 to 2 hours; subsequent visits will be scheduled for 
approximately 1 hour. During the visits, the home visit practitioner will administer two 
questionnaires and collect an alcohol biochemical marker, PEth blood spot test (Center for 
Substance Abuse Treatment 2006; Allen 2003; Cluver 2007; Miller 2005). The home visit 
practitioner’s scope of practice does not extend past the aforementioned duties. During the visit 
if the home visit practitioner, in his/her professional opinion, deems the subject in need of 
immediate medical attention, the home visit practitioner will observe his/her specific agency 
protocol as appropriate and notify the Principal Investigator and/or appropriate healthcare 
provider within 24 hours of the event. Again, as with the Blinded Investigator, the home visit 
personnel are not to be informed of the subject’s treatment group. This must be reinforced with 
the subjects at discharge. 
Initial Weekly Visit (1 to 2 hours) 
Alcohol Timeline Followback Questionnaire (TLFB) 
Modified Treatment Services Review Questionnaire (mTSR) 
Test for alcohol use (PEth) 
Subsequent Weekly Visits through End of Study Day 91 (irrespective of scheduled Study Day 
Evaluations) (1 hour) 
Alcohol Timeline Followback Questionnaire (TLFB) 
Modified Treatment Services Review Questionnaire (mTSR) 
Test for alcohol use (PEth)  
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
48 
The weekly TLFB (Sobell 2003) and mTSR questionnaires (provided separately from this 
protocol) will be completed (unless the subject is unable to do so due to his/her physical state).  
However, as with the blood test to determine if the subject has been drinking, these results will 
not become part of the medical record or be shared with the Principal Investigator or hospital 
staff. 
5.5.8 
Missed Visits 
If a subject misses a scheduled appointment, every effort should be made to reach the subject by 
the study site personnel. The missed visit should be communicated to the home visit provider and 
a concerted effort should be made to contact the subject. If the subject does not return messages 
after at least 3 attempts, and a back-up contact was identified, every effort should be made to 
reach the back-up contact.   
If the back-up contact cannot be reached by phone after at least 3 attempts, a registered letter will 
be sent by the study site personnel to both the study subject and to the back-up contact, 
requesting that they call the site to reconfirm contact information. 
If no information is forthcoming within three weeks of sending the registered letters, the subject 
will be considered lost to follow-up. If at a later time, the subject contacts the study site, or 
survival information is made known, the study visit should be done at that time (or as much of it 
as possible; i.e. documentation of survival outcome), even if it is outside the study window. If the 
back-up contact responds, effort should be made to get the subject’s current contact information 
and confirm outcome, if possible. 
The site should look in their medical records for any information regarding possible death of the 
subject if they get no response to calls. All deaths will be documented on the eCRFs. Deaths that 
occur during the subject’s active participation in VTL-308 will be reported as an outcome of an 
SAE. 
5.5.9 
Early Discontinuation from the Study 
If a subject is removed from the study prematurely, the reason for doing so and the date of early 
discontinuation will be documented in the source documents and the subject’s eCRF. 
Investigator  or study coordinator must clarify if a subject is withdrawing from the treatment part 
of the study and is still willing to be contacted for follow up throughout the 91-day study, as well 
as long term follow-up for 5 years.   
5.6 
LABORATORY TESTING 
5.6.1 
Blood Culture Samples for Microbiological Testing (ELAD and Control 
subjects) 
Blood culture samples will be collected by the Investigator or designee to determine whether the 
subject’s blood has become contaminated. A set of blood culture samples includes one sample to 
be cultured under aerobic conditions, and one sample to be cultured under anaerobic conditions.   
Blood culture samples will be collected to assess for possible microbial contamination in Control 
subjects at the End of Study Day 2 and End of Study Day 4. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
49 
The following applies to blood culture samples collected to assess for possible microbial 
contamination in ELAD-treated subjects: 
1. Two sets of blood culture samples (1 aerobic bottle and 1 anaerobic bottle per set) 
will be collected by the Investigator or designee, prior to first connection to the 
ELAD System, and every 48 hours of ELAD treatment (Hours 0, 48, and 96).   
2. During ELAD treatment, beginning at hour 48, the two sets of blood culture samples 
will be collected at the same time as ultrafiltrate culture samples (See Section 5.6.2). 
3. All blood culture samples will be labeled and processed as per institution policy.  
4. All positive (preliminary or final) blood culture results that were collected prior to or 
during ELAD treatment must be brought to the attention of the Sponsor immediately: 
a. If the ELAD Specialist is on-site, the Investigator or designee must 
communicate the results to the ELAD Specialist, who will be responsible for 
promptly reporting the results to the Medical Monitor.   
OR 
b. If the ELAD Specialist is not on-site, the Investigator or designee must 
communicate the results via phone or text message to the Medical Monitor.  
5. The Medical Monitor will promptly review the relevant information of the positive 
blood culture results.  
5.6.2 
Ultrafiltrate Culture Samples for Microbiological Testing (ELAD Subjects 
only) 
Ultrafiltrate culture samples will be collected by the ELAD Specialist to determine whether the 
ultrafiltrate circuit has become contaminated.  A set of ultrafiltrate culture samples include one 
sample to be cultured under aerobic conditions, and one sample to be cultured under anaerobic 
conditions.   
The following applies to ultrafiltrate culture samples collected to assess for possible microbial 
contamination: 
1. Two sets of ultrafiltrate culture samples (aerobic and anaerobic) will be collected by 
the ELAD Specialist after ELAD cartridges are installed in the ELAD System, just 
prior to starting the ultrafiltrate pump, and every 48 hours of treatment (Hours 0, 48, 
and 96). The ultrafiltrate culture samples are sampled from the ultrafiltrate circuit 
flow before the ELAD cartridges (Pre-ELAD) and after the ELAD cartridges (Post-
ELAD). 
2. The ELAD Specialist will label the ultrafiltrate culture samples as Pre-ELAD and 
Post-ELAD, date, time, and initials. The ELAD Specialist will deliver the samples to 
the investigator or designee for processing per institution policy. 
3. During ELAD treatment, beginning at hour 48, aerobic and anaerobic ultrafiltrate 
culture samples will be collected at the same time as blood culture samples (See 
Section 5.6.1).  
4. All positive (preliminary or final) ultrafiltrate culture results that were collected prior 
to or during ELAD treatment must be brought to the attention of the Sponsor 
immediately: 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
50 
a. If the ELAD Specialist is on-site, the Investigator or designee must 
communicate the results to the ELAD Specialist, who will be responsible for 
promptly reporting the results to the Medical Monitor.   
OR 
b. If the ELAD Specialist is not on-site, the Investigator or designee must 
communicate the results via phone or text message to the Medical Monitor.  
5. The Medical Monitor will promptly review the relevant information of the positive 
ultrafiltrate culture results.  
5.6.3 
Blood Collection for Future Research (ELAD and Control subjects) 
In addition to the collection of ultrafiltrate samples, at certain investigational sites that agree to 
perform additional sampling, blood samples will be collected in accord with procedures 
summarized in Table 1, Table 2 and Table 3 for analysis at a later time. At these sites, this 
procedure will only be carried out if the subject has signed an additional consent allowing this 
added analysis. VTL intends to use the samples to evaluate biomarkers/proteins in order to gain 
further understanding of ELAD’s mechanism of action. Testing results could provide 
information for future development of a safer and more effective version of ELAD. No genetic 
testing will be performed, and if added later, it will not be done without prior additional informed 
consent from the subject. Participating centers must document collection times of samples and 
placement in -70oC freezer on a log provided by the Sponsor. 
5.6.4 
Ultrafiltrate Collection for Future Research (ELAD Subjects only) 
Ultrafiltrate culture samples will be collected by the ELAD Specialist to assess ELAD cartridge 
performance. Please refer to the VTL-308 Laboratory Manual for more details. 
1. A sample volume of 6 mL of ultrafiltrate from the inlet line (UF In), and 6 mL of 
ultrafiltrate from the outlet line (UF Out) will be collected by the ELAD Specialist 
after ELAD cartridges are placed in the ELAD System, just prior to starting the 
ultrafiltrate pump and every 24 hours of treatment (Hours 0, 24, 48, 72, 96, and 120).   
2. Six 1-mL samples will be collected from the ultrafiltrate withdrawal line (UF In), and 
six 1-mL samples will be collected from the ultrafiltrate return line (UF Out). They 
will be collected in separate 2mL vials. 
3. In the event that ELAD treatment is discontinued early, an additional set of six 1-mL 
UF In, and six 1-mL UF Out samples will be collected. 
4. The ELAD Specialist will ensure the samples are properly labeled per the VTL-308 
Laboratory Manual. 
5. The Investigator or designee is responsible for placement of the samples in the -70ºC 
freezer, and documenting such on the ultrafiltrate sample log provided by the 
Sponsor. 
6. The samples will be sent to a Sponsor-designated vendor, by the Investigator or 
designee as outlined in the VTL-308 Laboratory Manual. 
7. The Sponsor may request additional ultrafiltrate culture samples for analysis, up to a 
maximum of 100 mL, in any one 24-hour period. 
8. There will be 100 mL of ultrafiltrate collected from the remaining residual 
ultrafiltrate left in the system after treatment ends. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
51 
6 
ELAD SYSTEM 
6.1 
ELAD SYSTEM USE 
The setup of the ELAD System is described in the ELAD System Operator’s Manual. 
A dedicated, dual-lumen, kink-resistent dialysis catheter must be placed by an experienced 
physician, preferably ultrasound-guided, into the right internal jugular vein (preferred site), left 
internal jugular, femoral, or subclavian veins. If available and accessible, in complicated cases 
the interventional radiology team should be involved. Catheters should be designed to deliver a 
minimum of 300 mL/min blood flow to the ELAD System. For insertion and care of the catheter, 
the Centers for Disease Control and Prevention (CDC) or the European CDC guidelines (or local 
equivalent) guidelines should be followed. 
Extracorporeal systems often require anticoagulation therapy. Refer to Section 5.5.2.1 for 
additional details on anticoagulation. 
It is recognized that there may be some interruptions in continuous treatment for up to 6 hours to 
allow for subject transport (See Section 6.6). All interruptions in ELAD treatment must be 
accurately recorded in the subject’s source documentation. 
All system-related malfunctions will be noted and reported to VTL on the ELAD System 
Incident Report Form for follow-up by the appropriate internal VTL team. 
6.2 
PRECAUTIONS WHILE ON ELAD 
Subjects in this study may require procedures under standard of care that carry a higher risk if 
performed while a subject is heparinized or otherwise anticoagulated. These include, but are not 
limited to, liver biopsies, paracentesis, surgery or dental surgery, insertion of large bore 
intravascular catheters, and/or elective intubation. Such procedures, if elective in character, 
should be performed after discontinuation of anticoagulation which also may require interruption 
of ELAD treatment. Depending on the nature of the intervention, rechecking of the coagulation 
parameters and correction by administration of blood products may be required. 
6.3 
ELAD SYSTEM DOSAGE 
The ELAD System consists of a set of four cartridges, each containing approximately 110 g of 
VTL C3A cells (approximately 440 g total). It is estimated that the mass of cells within 
four cartridges represents approximately 20% to 30% of the native liver hepatocyte mass, a 
residual mass believed to be necessary for survival. 
6.4 
RECEIPT AND ADMINISTRATION OF ELAD CARTRIDGES 
Upon receipt and inspection of the ELAD cartridges by the VTL ELAD Specialist, the system 
will be taken to the bedside and treatment will be started as soon as possible. In all cases, 
treatment should be initiated according to Section 5.4. 
6.5 
ELAD CARTRIDGE REPLACEMENT 
ELAD cartridges may need to be replaced during treatment due to ELAD cartridge performance 
or interruption of treatment greater than 6 continuous hours.  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
52 
If scheduled End of Study Day procedures occur while the subject is awaiting new cartridges, 
those scheduled procedures will be carried out in accordance with the protocol. The 24-hour 
safety evaluations and UF culture and samples performed on treatment day 1 must be repeated if 
the ELAD cartridges are replaced during treatment (see Section 5.5.2, Section 5.6.2, and 
Section 5.6.4). In addition, if ELAD treatment is stopped for more than 6 hours, the Pre-ELAD 
safety assessments (See Section 5.4.2.1.1) in accord with the pertinent Exclusion Criteria 2, 3, 4, 
7, 9, 10, 15, and 16 relative to the safety evaluation time point will be performed. Administration 
of 100 mg hydrocortisone and 50 mg diphenhydramine do not need to be repeated prior to 
initiation of ELAD treatment after cartridge replacement.   
6.6 
INTERRUPTION OF ELAD TREATMENT 
ELAD treatment may be interrupted. If the interruption is for a period of less than 6 hours then 
ELAD may be restarted with the same set of cartridges. If ELAD treatment is interrupted for a 
period of more than 6 hours but less than 72 hours (e.g. to allow for the conduct of a diagnostic 
or therapeutic procedure or for management of an adverse event, or should there be a need to 
interrupt the use of anticoagulants), then a new set of ELAD cartridges must be used if treatment 
of the subject will continue. In order for ELAD treatment to be restarted with a second set of 
cartridges after more than 6 hours, the subject must meet the same safety eligibility criteria as are 
required prior to the initiation of the first set of cartridges (See Section 5.4.2.1.1 and Section 6.5). 
If there is a need to replace ELAD cartridges, the subject’s overall ELAD treatment duration will 
be calculated based from the initial start of treatment. If the subject’s ELAD treatment is 
interrupted for greater than 24 hours, the treatment period may be extended, not to exceed a total 
of 120 treatment hours. The maximum period between stopping treatment and starting with a 
new set of cartridges is 72 hours. 
6.7 
CRITERIA FOR DISCONTINUATION OF ELAD TREATMENT 
ELAD treatment will be discontinued and will not be restarted if any of the discontinuation 
criteria listed in Section 3 are met.  
6.8 
ELAD SYSTEM ACCOUNTABILITY 
6.8.1 
Shipment of ELAD Cartridges 
The ELAD cartridges will be packed in a temperature controlled, secured shipping container to 
maintain temperature within specifications outlined in the ELAD System Operator’s Manual.  
The shipment will be sent to the Investigator or designee by rapid courier. Final ELAD cartridge 
accountability records will be maintained as described in Section 6.8.4. 
6.8.2 
ELAD Cartridge Inspection and Storage 
The ELAD cartridges may be received at the study site by the ELAD Specialist or designee. 
ONLY the ELAD Specialist will open, inspect, and store the ELAD cartridges as per the ELAD 
System Operator’s Manual. ELAD cartridge accountability will be documented as described in 
Section 6.8.4.  
ELAD cartridges may remain stored in a temperature controlled environment for up to 60 hours 
according to the “Begin Use By” date and time indicated on the label. Cartridges that have been 
stored longer than 60 hours before they are used in ELAD treatment will be returned to VTL or 
designee or destroyed by the ELAD Specialist according to the institution’s policies. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
53 
6.8.3 
Packaging and Labeling of Cartridges 
The ELAD cartridges will be labeled with the protocol number, ELAD cartridge identification, 
conditions for storage, subject number, Investigator’s name and telephone number, “Begin Use 
By” date and time (60 hours allotted for transport and storage until installation into ELAD 
System), and “Complete Use By” (date and time after which the cartridges can no longer be used 
for subject treatment). Other labels must not be adhered to the cartridges to obscure any of this 
labeling information. The final label will be adapted to the requirements of the individual 
country where the study is being performed in accordance with local regulations. 
6.8.4 
Dispensing and Accountability of Cartridges 
ELAD cartridges will be dispensed to the study site for subject use. Other labels must not 
obscure the VTL label, especially the cautionary statement on Investigational Use, which is 
required verbatim by law.   
The ELAD Specialist will maintain complete accountability records of all ELAD cartridges 
shipped to the study site. The accountability records are provided to the study site upon 
completion of treatment. The ELAD cartridge accountability log will include the following:  
 Subject Identification Number 
 ELAD cartridge reception, inspection, and storage 
 ELAD cartridge final disposition 
 ELAD cartridge lot number  
 
The ELAD Specialist will also provide the study site with copies of the shipping records of the 
ELAD cartridges and a copy of the Certificate of Analysis as part of the subject’s source 
documentation.   
The ELAD cartridges are to be prescribed only by the Investigator named on the Form FDA 
1572 (or equivalent) and listed on the Delegation of Authority Log. Under no circumstances will 
the Investigator allow the ELAD cartridges to be used other than as directed by this protocol. 
6.8.5 
ELAD System Disposition 
Maintenance and accountability of the ELAD System, non-mechanical materials (disposables) 
and supply cart will be maintained by the ELAD Specialists in accord with the ELAD System 
Operator’s Manual. 
All System-related malfunctions will be noted by the ELAD Specialist and reported to VTL 
according to internal VTL processes. 
ELAD cartridges, ELAD System, and supply cart disposition is recorded on the ELAD System 
Monitoring Forms. This is completed by the ELAD Specialist on site at the end of subject 
treatment. These forms serve as verification of the accountability (including disposition) of the 
ELAD System, cartridges, and supplies, and this information is available to the site personnel in 
the EDC system. 
Each ELAD System and supply cart has a unique identification number that will be used for this 
purpose and will include date of arrival as well as date shipped out of the investigational site. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
54 
Any issues involved with the identity, quality, durability, reliability, safety, or performance of 
the system or any of its components will be recorded on the ELAD System Monitoring Forms by 
the ELAD Specialists. Any investigational product-related subject adverse events will be 
reported as detailed in Section 9. 
6.8.6 
Cleaning of Equipment after Discontinuation of ELAD Treatment 
At the conclusion of the subject’s treatment and the removal of all non-mechanical (disposable) 
materials from the ELAD System, the ELAD Specialists will clean all surfaces of the ELAD 
System using the appropriate disinfectant solution(s) according to the ELAD Bedside Unit 
disinfection procedure. The cleaning of the equipment designated for ELAD treatment will be 
noted on the ELAD Declaration of Decontamination Status Form. 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
55 
7 
STATISTICS AND METHODS OF DATA ANALYSIS 
7.1 
SAMPLE SIZE RATIONALE 
The sample size is based on experience from the VTI-208 study.   
Analysis of the VTI-208 data suggests that in a group of subjects meeting the inclusion criteria 
for VTL-308 it might be reasonably anticipated that the hazard rate in the control group will be 
0.004 and the hazard ratio 0.4 in favor of the ELAD group. Under the assumption of a 
proportional hazards model, this leads to median survival estimates of approximately 175 days 
and 438 days for Control and ELAD subjects, respectively. 
The VTL-308 inclusion criteria have been established to reflect the same study population as that 
enrolled in a subset of the VTI-208 population with baseline criteria including MELD <30, age 
<50, INR ≤2.5, creatinine <1.3 and serum total bilirubin ≥16mg/dL, to define the ITT population, 
with key safety criteria also applied prior to initiation of ELAD treatment and at End of Study 
Day 2 (EOSD 2) in the Control group to establish the mITT population. Applying these criteria 
to the analysis of the primary endpoint of overall survival in the ITT population, and assuming: 
1) that this prospectively-defined population behaves similarly to this subgroup of the VTI-208 
study; 2) the use of a log-rank test comparing two survival curves with a two-sided significance 
level of 0.05; 3) exponential survival curves with proportional hazards; 4) uniform accrual with 
an accrual time of at least 720 days and a minimum follow-up time of 90 days; and 5) a drop-out 
rate of 10%, a sample size for VTL-308 of 75 subjects per group with 1:1 allocation is consistent 
with power of at least 0.95 with estimated median survival times of 175 and 438 days 
respectively. 
Due to the distribution of subjects between the ITT and mITT group it may be necessary to 
enroll more than 150 subjects total in order to ensure that there are a minimum of 75 subjects 
actually treated with ELAD in the ITT population. Consequently, enrollment may continue until 
ELAD treatment has been initiated on 75 subjects.  
The proportional hazards model modified in accord with findings from Study VTI-208 estimates 
that approximately 55 deaths are anticipated as the total number of events required to achieve 
approximately 95% power under these assumptions. If the total number of observed events in the 
ITT primary population is less than this number after all 150 enrolled subjects complete Study 
Day 91, are lost to follow up, withdraw consent, or die before that Study Day, then the study may 
continue until a minimum of 55 deaths are recorded. This provision is intended to ensure that the 
desired power is achieved in the ITT population even if the event rate is lower than would be 
anticipated from the reference study, VTI-208. 
7.2 
POPULATIONS 
7.2.1 
Safety 
This population is defined as all subjects who are randomized and begin treatment including 
standard of care; analyses of this population will be based on actual treatment received. This 
population will include all randomized subjects assigned to the group that most accurately 
reflects the actual treatment that they received. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
56 
As a practical matter this means that a subject deemed an “ELAD-treatment initiation failure” 
that received no ELAD treatment would be assigned to the Control group. A subject that was 
randomized to the Control group yet received ELAD treatment would be assigned to the ELAD 
group. 
7.2.2 
Efficacy 
 
Intent-to-Treat (ITT) 
The ITT population is defined as all subjects who are randomized; analyses of this population 
will be based on assigned randomized treatment. This population will include all randomized 
subjects assigned to the group to which they were randomized irrespective of actual treatment. 
The ITT population will be the primary analysis population. 
 
Modified Intent-toTreat (mITT) 
The mITT population is defined as all subjects who are randomized to the ELAD treatment 
group that subsequently become eligible for treatment initiation and received ELAD treatment, 
and all subjects who are randomized to the Control group that also remained eligible for 
treatment in accord with EOSD 2 evaluations. Treatment assignment will be based on the 
treatment group to which the subject was randomized. 
 
Per-Protocol (PP) 
The PP population will include all randomized subjects assigned based on treatment group 
(ELAD or Control) less those that received <72 hours of treatment (ELAD or Control) and less 
those that had major protocol violations, including but not necessarily limited to the following: 
 Baseline ineligibility 
 Ineligible for ELAD treatment initiation but treated anyway 
 Continued treatment for more than 3 days despite an increase in bilirubin in 
excess of 25% 
 Off treatment for longer than 6 hours with the same set of cells 
 Off treatment for longer than 72 hours with a second set of cells 
 Treated with cartridges >60 hours from harvest (i.e., expired) 
 Received different treatment than their treatment assignment   
 
Those subjects deemed an “ELAD treatment initiation failure” that received no ELAD treatment 
would be excluded from this population (as they received different treatment) as would those 
subjects who died within the first 72 hours (Control or ELAD treatment) or those that received a 
total of less than 72 hours of Control or ELAD treatment for other reasons.  
7.3 
PRIMARY EFFICACY ANALYSIS 
7.3.1 
Overall Survival (OS) of AILD Subjects through at Least Study Day 91 
OS will be assessed using a Kaplan-Meier survival analysis of the intent-to-treat (ITT) 
population utilizing a log-rank test, with follow-up Protocol VTL-308E providing additional 
survival data up to a maximum of 5 years that will be included, as available, through VTL-308 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
57 
study termination. Model-based estimates and confidence limits will be calculated for median 
survival by treatment group and the hazard ratio and its confidence limits. This analysis will also 
be carried out on the mITT, Per-Protocol (PP) and Safety populations as sensitivity analyses. 
Two-tailed alpha for the log-rank test will be set at 0.05. The statistical analysis plan will outline 
the methods used to account for missing data in this and all other analyses.  
The statistical analysis plan will also evaluate differences in standard of care between the groups 
that may affect subject outcome, such as differences in the administration of steroid therapy, and 
define analytical strategies to deal with those differences should they arise.   
7.4 
SECONDARY EFFICACY ANALYSES 
7.4.1 
Proportion of Survivors at Study Day 91 
A chi-square test will be used to evaluate the proportion of subjects who survived at End of 
Study Day 91 based on the ITT population. Two-tailed alpha will be set at 0.05. This analysis 
will also be carried out on the mITT, PP and Safety populations as sensitivity analyses.     
7.5 
EXPLORATORY EFFICACY ANALYSIS 
Exploratory efficacy analyses will be carried out as defined in the SAP. These may include, but 
not be limited to, analyses of efficacy outcomes based on any subgroups, such as those defined 
by medical history and baseline demographics and other baseline characteristics, along with 
region (USA vs. Europe). Additional analyses may be based on the relationship between 
outcomes and ELAD System performance, therapeutic interventions of interest and 
administration of concomitant pharmacotherapies of interest.    
7.6 
SAFETY ASSESSMENT 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and incidences will be compared between treatment groups using MedDRA Preferred Terms 
within System Organ Classes for the Safety Population. The following will also be summarized 
by treatment group: 
 Adverse Events 
 Mean Arterial Pressure (MAP) 
 Clinical laboratory values 
 The use of concomitant procedures including concomitant blood product 
administration (e.g., whole blood, packed red blood cells, platelets, fresh frozen 
plasma, albumin, cryoprecipitate)  
 Concomitant therapies (e.g., intubation, tracheostomy, CVVH/CVVHD, arterial 
line)  
7.7 
DEMOGRAPHICS AND OTHER BASELINE VARIABLES 
Demographic and other baseline variables include age, sex, ethnicity, height, weight, vital signs, 
and all safety and efficacy analyses related to the subject’s condition at Baseline, including all 
laboratory-based evaluations. 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
58 
8 
STUDY DOCUMENTATION 
8.1 
SITE DOCUMENTATION 
8.1.1 
Laboratory Accreditation 
Any laboratory facility to be used for analysis of routine clinical laboratory samples required by 
this protocol must provide evidence of adequate licensure and accreditation. Documentation of 
laboratory certification/accreditation must be collected throughout the study and maintained in 
the site’s regulatory binder. Reference values and/or normal ranges for the test results must be 
provided to VTL. VTL must be notified immediately in writing of any changes occurring in 
reference values during the course of the study. 
8.1.2 
Financial Disclosure 
The Investigator and Sub-Investigators, as identified on Form FDA 1572 (or equivalent), shall 
provide VTL with sufficient financial information to allow VTL to submit accurate certification 
or disclosure statements as required under 21 CFR 312.54. The Principal Investigator shall 
promptly update this information if any relevant changes occur during the course of the 
investigation and for one year following the completion of the study. 
8.1.3 
Subject Confidentiality 
All reports and subject laboratory documents submitted with the eCRFs or SAE reports will be 
identified only by subject initials (where allowed) and study number (coded number) to maintain 
subject confidentiality. All records will be kept confidential to the extent required by law. 
8.2 
PRE-STUDY SITE VISITS AND SITE INITIATION VISITS 
Prior to commencement of the study, representatives of VTL will visit the study site to ensure 
adequacy of facilities to conduct the protocol, and to discuss with the Investigator the general 
obligations regarding studies with investigational new products. Upon satisfactory receipt of all 
necessary documentation (including Form FDA 1572 or equivalent and Financial Disclosure 
Forms), and all pertinent regulatory documents, the VTL or designated monitor will arrange for 
all study material to be delivered to the study site and for the scheduling of a mutually-
convenient appointment. At this meeting, all personnel expected to be involved in the conduct of 
the study will undergo orientation to include review of the study protocol, instructions for eCRF 
completion, and overall responsibilities including those for system accountability and study file 
maintenance. Subject entry must not begin until the site has been informed by the Sponsor that 
they are open for enrollment.   
Training of site personnel regarding study administration, subject management, and ELAD 
treatment will occur prior to or at the site initiation visit and be documented appropriately.   
8.3 
RECORDING OF SUBJECT DATA 
Investigators will provide subject data, which will be collected on individual eCRFs, and will be 
substantiated by source documents at the clinical site and monitored by the Sponsor’s clinical 
research associates (CRAs). The Investigator must maintain a separate subject list containing the 
name, address, and other contact information for each study participant so that they can be easily 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
59 
contacted if necessary. This information will not be provided to VTL but will be kept in a secure 
location at the study center. 
8.3.1 
Electronic Case Report Forms (eCRFs) 
The eCRF will be comprised of a series of electronic forms. Subjects are not to be identified on 
the eCRFs by name.  Subjects will be identified by a unique subject identification number, which 
is assigned sequentially upon registering the subject in the EDC system. The eCRFs should be 
completed in a timely manner (the timeframe required by the study contract/agreement).  
Electronic CRFs are not considered source documents and source documentation must be 
provided by the site. Sufficient training will be provided on the process of entering data into the 
eCRFs. 
It is the obligation of the Investigator to review each page of the eCRFs for accuracy, 
completeness, and legibility before signing the designated and appropriate forms as the study 
authority. Electronic CRFs are to be completed by appropriately trained study personnel. Data 
recorded on eCRFs should be supported by information recorded in the subject’s source 
documentation (e.g., laboratory reports, hospital records, x-ray reports). Electronic CRF 
completion may be formally delegated to other study personnel, but they must be identified on 
the Delegation of Authority Log. 
Prior to initiation of the study, the study monitor will conduct an initiation meeting. The 
appropriate use and completion of all eCRFs will be discussed at that time. Additionally, training 
on the eCRF system will be done with each study site by the EDC vendor responsible for the 
system. 
Completed eCRFs will be reviewed by the monitor to ensure data accuracy, completeness, and 
consistency. Any discrepancies found during the eCRF review are to be clarified by the 
Investigator (or his/her designated staff). This includes eCRF reviews at the site by the Sponsor 
or its designee, or during data validation and quality assurance review of the data by data 
management and other functions. A complete audit trail of the original entries, changes and 
deletions, session dates and times, and the identity of the eCRF user who performed the 
operation will be maintained by the system. 
8.3.2 
Records Retention 
The Investigator must maintain copies of all documents and records relating to the conduct of the 
trial. This documentation includes, but is not limited to, the protocols and amendments, eCRFs, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with health authorities and ECs/IRBs, fully executed consent forms, Investigator curricula vitae, 
monitor visit logs, subject screening and tracking logs, investigational product accountability 
records, laboratory reference ranges, and laboratory certification/ accreditation or quality control 
procedures. Subject files and other source documents, and eCRF data must be kept for a 
minimum time period, as specified below. VTL must be consulted if the Investigator wishes to 
assign the files to someone else, remove them to another location, or is unable to retain them for 
the specified period. 
The Investigator must maintain all trial records for a period of at least two years following the 
date on which the investigational product is approved by FDA or other applicable regulatory 
agency for marketing for the purposes that were the subject of the clinical investigations. If no 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
60 
application is to be filed, records must be retained until two years following the date that the 
study is discontinued and the FDA or other applicable regulatory agency is notified.  If the 
application is not approved by the FDA or other applicable regulatory agency for such 
indication, records must be retained for two years after notification by VTL, of the FDA or other 
applicable regulatory agency decision (or longer if local regulations require). VTL should be 
notified in writing at least 30 days prior to the disposal of any study records related to this 
protocol. 
8.3.3 
Concomitant Medications, Procedures and Therapies 
All concomitant medications administered to the subject from Randomization through Study Day 
91, or until subject discontinuation within this 91-day period, will be recorded in the subject’s 
source documents and transcribed into the eCRF in the EDC system. All blood products and 
procedures administered to the subject from Randomization through Study Day 91, or until 
subject discontinuation within this 91-day period, will be documented in the subject’s source 
documents and recorded on the Concomitant Therapy eCRF. Use of blood products known to 
artificially alter serum bilirubin in the 24 hours prior to Randomization will be recorded in the 
eCRF. If an adverse event requiring concomitant therapy (i.e., medications, blood products, or 
procedures) occurs up to and including Study Day 91, or until subject discontinuation within this 
91-day period, it must be recorded on the appropriate Medication, Blood Product Administration, 
or Therapies and Procedures eCRF. Use of other defined medications of interest will be captured 
for the 6 weeks preceding Randomization 
The following medications are typically administered for the indications shown in parentheses, 
and are considered medications of interest:  
 Albumin [treatment of hepatorenal syndrome (HRS), hypotension, following 
large-volume paracentesis, etc.]; 
 Antibiotics [treatment of infections diagnosed immediately before or while in 
the study, following gastrointestinal bleeding (prevention of infection following 
bacterial translocation), or as prophylaxis or treatment of spontaneous bacterial 
peritonitis (SBP)]; 
 Beta-blockers [prophylaxis or treatment for bleeding gastroesophageal (GE) 
varices, following GE banding, etc.] 
 Blood products [packed red blood cells (PRBCs), platelets, fresh frozen plasma 
(FFP), cryoprecipitate for treatment of clinical bleeding, anemia, coagulopathy, 
etc.];  
 Diuretics (treatment of  ascites); 
 Heparin (or alternative anticoagulation therapy) [for controlling clot formation 
during ELAD treatment as well as prophylaxis for deep vein thrombosis 
(DVTs)]; 
 H2 receptor antagonists [treatment of gastrointestinal bleeding or prophylaxis of 
stress-related mucosal disease (SRMD) bleeding];  
 Lactulose [treatment of hepatic encephalopathy (HE)]; 
 Midodrine (treatment of HRS); 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
61 
 N-acetyl cysteine (treatment of AAH) 
 Nutritional supplements; 
 Octreotide (treatment of HRS); 
 Pentoxifylline (treatment of AAH); 
 Rifaximin (treatment of HE); 
 Steroids (treatment of AAH); 
 Trace metal supplements (treatment of deficiencies of calcium, magnesium, 
etc.); 
 Vasopressors (treatment of hypotension and/or HRS); 
 Vitamins (treatment for vitamin deficiencies e.g., pyridoxal phosphate, 
thiamine, etc.). 
As ELAD may provide some degree of liver function, modification of the dosage of drugs 
known to be subject to liver metabolism should be carefully considered by the treating physician 
in accord with institutional standard of care. Subjects in this study may require procedures under 
standard of care that carry a higher risk if performed while a subject is heparinized or otherwise 
anticoagulated (See Section 6.2). 
8.4 
MONITORING OF THE STUDY 
Throughout the course of the study, VTL or the designated monitor will make periodic contact 
with the Investigator. This will include electronic and on-site visits at appropriate and necessary 
intervals. During these visits, eCRFs will be reviewed for completeness and accuracy, and the 
study conduct will be reviewed for adherence to the protocol. As part of the data review, it is 
required that source documents (e.g., hospital records, office records) will be made available for 
review by the study monitor. The monitor will also perform cartridge and supply accountability 
checks, and will review the Investigator’s study file to ensure completeness of documentation.  
The Investigator or appointed delegate will be available to the monitor during these on-site visits 
and will provide necessary study documents for inspection and will respond to all inquiries that 
may arise as part of this review. On completion of the study, the monitor will arrange for a final 
review of the study files, after which the files should be secured for the appropriate time period 
as specified in Section 8.3.2. The Investigator will also permit inspection of the study files by 
authorized representatives of the Institutional Review Board/Ethics Committee (IRB/EC), VTL 
representatives or their designees, the FDA, or other applicable regulatory agencies. 
8.5 
SITE CLOSURE 
Throughout the course of the trial, the Investigator shall make every reasonable effort to 
maintain the enrollment rate of appropriate subjects at a level previously determined. Should the 
enrollment rate lag, VTL may elect to terminate the study at that site. VTL also has the right to 
terminate the study at any time for non-adherence to the protocol, unavailability of the 
Investigator or his study staff to VTL monitoring representatives, or for administrative reasons. 
The Sponsor reserves the option to terminate the participation of a Principal Investigator or the 
study at any time. Reasons for terminating the study or participation by the Principal Investigator 
include, but are not limited to, the following: 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
62 
 The incidence or severity of AEs in this or other studies with the investigational 
product indicates a potential health hazard to subjects 
 Subject enrollment is unsatisfactory 
 Data recording is inaccurate or incomplete 
 The Investigator does not adhere to the protocol or applicable regulatory 
guidelines in conducting the study 
 The Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC/REB) or Data and Safety Monitoring Board (DSMB) decides to 
terminate or suspend approval for the study or the Investigator 
 The Investigator asks to withdraw from study participation 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
63 
9 
PHARMACOVIGILANCE AND SAFETY REPORTING 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the investigational product, without any judgment about causality. An 
adverse event can arise from any use of the product (e.g., off-label use, use in combination with 
another drug) and from any route of administration, formulation, or dose, including an overdose.   
It is also defined as any untoward effect, or worsening in severity, or increase in frequency of a 
sign, symptom, or clinically-significant laboratory abnormality, that occurs after Randomization, 
regardless of its relationship to the investigational product. This applies to both Control and 
ELAD-treated subjects.   
On the eCRFs, the syndrome or diagnosis should be recorded and not each sign, symptom, 
and laboratory abnormality associated with that syndrome or diagnosis. Adverse events will 
be captured on the eCRFs from Randomization through Study Day 91 or until subject 
discontinuation within this 91-day period. If the subject (ELAD or Control) withdraws consent 
from the study at any time during the Study, the subject will no longer be followed by the site 
through Study Day 91. All efforts should be made to ensure subject continues to consent for 
safety and follow up. All adverse events, regardless of severity and whether or not ascribed to the 
study treatment, will be recorded in the appropriate section of the eCRF. Adverse events will 
include all complications including those associated with: the control treatments; surgical 
procedures; therapeutic or diagnostic procedures (e.g., paracentesis, etc.); catheters [distinguish 
between those related to the ELAD versus other central venous catheters, peripherally inserted 
central catheters (PICC), etc.], blood products (e.g, transfusion reactions, etc.), other concomitant 
drugs (e.g., heparin), in addition to adverse events associated with the ELAD System (VTL C3A 
cells in ELAD cartridges; ELAD System; and ELAD Procedure), or other causes. The onset, 
duration, severity, action taken, relationship to treatment, and outcome of all adverse events will 
be documented in the eCRF. Investigators should use appropriate medical judgment in the 
characterization of a serious adverse event for subjects with AILD. A medical or surgical 
intervention required to treat a recognized sign, symptom, laboratory abnormality, or clinical 
condition associated with AILD may not necessarily be considered a serious adverse event.  
Please refer to the Investigator’s Brochure for the most current ELAD System subject 
experiences. Additionally, Appendix D includes information regarding how to assess relatedness 
to ELAD; whether it should be attributed to the VTL C3A cells, the ELAD System, or to the 
ELAD Procedure. Please refer to this appendix prior to assigning a causal relationship to any 
reported events. 
The Investigator will report serious adverse events (defined consistent with a reportable adverse 
event in accord with local and regional regulations) to the Sponsor within 24 hours of knowledge 
of the event in accordance with this section. The Investigator will also report the event(s) to the 
IRB/EC within 24 hours of knowledge of the event(s) if required by local regulations. 
Subjects experiencing adverse events or clinically-significant laboratory abnormalities will be 
assessed and appropriate evaluations performed until all parameters have returned to baseline 
levels, or are consistent with the subject’s then-current physical condition.   

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
64 
9.1 
ADVERSE EVENTS 
The safety of all subjects enrolled in this study will be monitored throughout the study. Safety 
monitoring will include history and physical examination with vital signs, adverse event 
reporting, and laboratory evaluations. Adverse events will be collected and recorded for subjects 
from Randomization through Study Day 91, or until subject discontinuation within this 91-day 
period.  
ELAD is a combination biologic and medical device product that is regulated as a medicinal 
product in the US and EU where the study is being conducted. However, adverse events need to 
be assessed and reported following both the drug and medical device regional requirements.  
The Investigator is responsible for assessment of all AEs/SAEs for severity and relationship to 
the assigned treatment. All SAEs must be reported by the Investigator to the VTL Designee 
within 24 hours of knowledge. The VTL Designee will report SAEs that meet the criteria for 
expedited reporting (per the Investigator’s Brochure) to the appropriate health authorities in 
accord with regional requirements. The Investigator must submit these expedited reports to their 
IRB/EC in accord with local requirements. Further detail is provided below. 
9.2 
DEFINITIONS 
The following definitions are guided by applicable international regulations and guidelines. 
Adverse Event - (Also referred to as an adverse experience) can be any unfavorable and 
unintended sign [e.g., an abnormal, clinically-significant laboratory finding (see 
Investigator’s Brochure)], symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality. An adverse event can arise from any use of the 
investigational product (e.g., off-label use, use in combination with another drug) and from any 
route of administration, formulation, or dose, including an overdose.  
An adverse event can also be defined as any untoward medical occurrence, unintended disease 
or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, 
users or other persons, whether or not related to the investigational product. 
Note: This definition includes events related to the investigational product (Biologic, Device, 
and Procedure).  
Adverse Device Effect - Adverse event related to the use of an investigational medical device. 
This includes any event resulting from insufficiencies or inadequacies in the instructions for use 
(ELAD System Operator’s Manual), the deployment, the implantation, the installation, the 
operation, or any malfunction of the investigational product, and any event that is a result of a 
use error or intentional misuse. 
Device Deficiency – This is inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device deficiencies include malfunctions, use 
errors, and inadequate labeling. 
Suspected Adverse Reactions - An adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. A "reasonable possibility" means there is evidence to suggest 
a causal relationship between the drug and the adverse event (See Section 9.6).  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
65 
Unexpected - An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed. For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the Investigator’s Brochure as occurring with a class of 
investigational products. 
This definition relies entirely on a listing of the adverse events or suspected adverse reactions in 
the Investigator’s Brochure as the basis for determining if newly acquired information generated 
from clinical trials or reported from other sources is unexpected. The suspected adverse reactions 
listed in the Investigator’s Brochure (i.e., “expected”) are those observed with the investigational 
product and for which a causal relationship between the event and the product is suspected or 
confirmed. These events are listed along with the adverse events experienced by subjects in the 
Control group in some tables, but it is clear which ones occurred in ELAD-treated subjects.  
Thus, adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
Investigator’s Brochure. For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the Investigator’s Brochure. Therefore, all 
deaths are to be reported to the Sponsor. 
Serious Adverse Event (SAE) - An adverse event or suspected adverse reaction is considered 
“serious” if, in the view of either the Investigator or Sponsor, it results in any of the following 
outcomes:  
1. Death, 
2. Serious deterioration in the health of the subject, that either results in: 
a. A life-threatening illness or injury, or 
b. A permanent impairment of a body structure or a body function, or 
c. In-patient hospitalization or prolonged hospitalization, or 
d. Medical or surgical intervention to prevent life-threatenting illness or injury or 
permanent impairment to a body structure or a body function, 
3. Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Note 1: Planned hospitalization for a pre-existing condition, or a procedure required by the 
clinical investigational plan (CIP), or protocol, without serious deterioration in health, 
is not considered a serious adverse event. 
Note 2: This includes device deficiencies that might have led to a serious adverse event if, a) 
suitable action had not been taken, or b) intervention had not been made, or c) if 
circumstances had been less fortunate. These are handled under the SAE reporting 
system. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
66 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition of an SAE. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  
Life-threatening – for the purpose of reporting adverse events, refers to an event in which the 
subject was, in the view of the initial reporter, at immediate risk of death at the time of the event 
as it occurred (i.e., it does not refer to any event which might have resulted in death if it were 
more severe). 
Serious Adverse Device Effect (SADE) – An adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
Unanticipated Serious Adverse Device Effect (USADE) – A serious adverse device effect which 
by its nature, incidence, severity or outcome has not been identified in the current version of the 
Investigator’s Brochure.   
9.3 
LABORATORY ABNORMALITIES AS ADVERSE EVENTS 
Many laboratory abnormalities observed during the course of a study will be encompassed under 
a reported adverse event describing a clinical syndrome (e.g., elevated BUN and creatinine in the 
setting of an adverse event of “renal failure”). In these cases (e.g., an AE of “renal failure”), the 
laboratory abnormality itself (e.g., elevated creatinine) does not need to be recorded as an 
adverse event. Refer to the Investigator’s Brochure for hematology and serum chemistry results 
that occur while the subject is on ELAD treatment that should be reported as AEs (e.g., 
decreased platelet count or increased INR relative to baseline). However, isolated laboratory 
abnormalities (e.g., hyponatremia) should be reported as adverse events if they are considered to 
be clinically-significant by the investigator. Criteria for a “clinically-significant” laboratory 
abnormality are: 
 A laboratory abnormality that leads to a treatment-limiting toxicity (e.g., 
thrombocytopenia that results in study treatment discontinuation or interruption) 
 A laboratory abnormality that results in therapeutic intervention (e.g., protamine 
for a prolonged PTT) 
 Other laboratory abnormality judged by the Investigator to be of any particular 
concern (e.g., detection of fibrin split products). 
 
Significant elevations in α-fetoprotein level is an expected laboratory change in subjects on 
ELAD treatment. This should not be reported as an adverse event. 
9.4 
REPORTING OF SERIOUS ADVERSE EVENTS 
All SAEs defined as being reportable adverse events in accord with 21 CFR 312.32 [that also 
includes the reporting of suspected unexpected serious adverse reactions (SUSARs)], European 
database of Suspected Unexpected Serious Adverse Reactions (Eudraviligance – Clinical Trial 
Module), and serious adverse device effects (SADEs) in accord with 21 CFR 812, in addition to 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
67 
all other local regulations, that occurs in  any subjects participating in this clinical trial, must be 
reported as described below: 
As soon as feasible, but at least within 24 hours of knowledge of a new SAE, the Investigator 
must report the event to the VTL designee. The SAE reporting form should be completed and 
submitted irrespective of the volume of information available about the event, though the 
Investigator is expected to provide as much information as possible.  
Information to be sent to VTL (or designee) includes, where applicable: 
 Pertinent subject medical history 
 Concomitant medications 
 Physical examination results, vital signs and laboratory reports if available 
 Treatment(s) administered 
 Outcome of the event  
 
SAEs should be reported from Randomization through the last day of study participation or 
through Study Day 91. 
Follow-up information to serious adverse events must be provided promptly as it becomes 
known to the Investigator and submitted to the VTL designee. 
The approving IRB/EC must be notified by the Investigator of any fatal, life-threatening and/or 
serious adverse events regardless of cause on a timely basis according to local regulatory 
requirements. In addition, a written report of all SAEs will be submitted by the Investigator per 
local IRB/EC requirements. All subjects with serious adverse events should be followed 
clinically and by the appropriate diagnostic evaluations until the event (1) resolves, (2) an 
outcome is reached, or (3) the event is otherwise explained or stabilized. 
Subjects withdrawn from the study due to an SAE will be followed by the Investigator until the 
outcome is determined and, when appropriate, additional written reports and documentation will 
be provided to the VTL designee. 
All SAEs that occur after the discontinuation of treatment with the ELAD System, regardless of 
relatedness to the study treatment, must be reported to the VTL designee if the onset of the SAE 
occurred from Randomization through the last day of study participation or through Study Day 
91. 
All suspected unexpected serious adverse reactions (SUSARs) related (related is defined as 
possibly related, probably related, and related) to the investigational product which occur during 
this study are subject to expedited reporting. 
All adverse events, regardless of severity, and whether or not related to the study treatment, will 
be recorded in the appropriate section of the eCRF.   
All adverse events beginning after the discontinuation of treatment with the ELAD System, 
whether serious or non-serious and regardless of relatedness to the study treatment, must be 
reported to the Sponsor if the onset of the adverse event occurred during the subject’s study 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
68 
participation (from Randomization through the last day of study participation or through Study 
Day 91). 
All serious adverse events that are unexpected (defined as an adverse event not listed in the 
Investigator’s Brochure) and related (related is defined as possibly related, probably related, and 
related) to the investigational product that occur from Randomizaton through the last day of 
study participation or through Study Day 91 must be reported to the Sponsor in a timely fashion. 
Any death or liver transplant occurring from Randomization through the last day of study 
participation or through Study Day 91, must be reported to the Sponsor regardless of how much 
time has elapsed since the last exposure to investigational product treatment. The cause of death 
must be reported as an SAE, since death is an outcome and not an SAE. A death occurring after 
Study Day 91 that is not reasonably associated with investigational product treatment does not 
require completion of an SAE reporting form. However, both of these events should trigger 
completion of applicable VTL-308E eCRFs for the subject (see Section 13). 
If progression of the underlying disease (i.e., the condition being treated with the investigational 
product) might be reasonably anticipated given the nature and severity of the underlying disease, 
then progression of the underlying disease per se will not constitute an adverse event. However, 
if the progression of the underlying disease meets the criterion for “serious” categorization of 
adverse events (e.g., the underlying disease results in premature death or prolonged 
hospitalization), then it should be reported as an SAE. 
9.5 
CLASSIFICATION OF ADVERSE EVENTS BY SEVERITY  
The Investigator must categorize the severity of each adverse event according to the following 
guidelines: 
 MILD: Awareness of sign or symptom, requires no special medical 
management or attention 
 MODERATE: Tolerable, but requires medical management 
 SEVERE: Intolerable, requires medical management 
9.6 
CLASSIFICATION OF ADVERSE EVENTS BY RELATIONSHIP TO 
STUDY TREATMENT 
For assessing relatedness of an event, the meaning of “reasonable possibility” is made clear by 
providing the following examples of types of evidence that would suggest a causal relationship 
between the investigational product and the adverse event. Associated with the use of the 
investigational product means that there is a reasonable possibility that the event may have been 
caused by the investigational product. Examples of evidence of a causal relationship to the 
investigational product are the following: 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with investigational product exposure (e.g., anaphylaxis, 
angioedema, Stevens-Johnson Syndrome)  
 One or more occurrences of an event that is not commonly associated with 
investigational product exposure, but is otherwise uncommon in the population 
exposed to the investigational product (e.g., tendon rupture).  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
69 
 An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation 
or other events that commonly occur in the study population independent of 
investigational product treatment) that indicates those events occur more 
frequently in the investigational product treatment group than in a concurrent or 
historical control group 
 
The relationship of each adverse event to the study treatment will be assessed by the Investigator 
after careful consideration, and according to the following guidelines: 
Not Related 
This category is applicable to those adverse events which are clearly due to extraneous causes 
(underlying disease, clinical state, concurrent drugs, environment, etc.) and do not meet the 
criteria for relationship listed under Possibly Related, Probably Related, and Related. 
Possibly Related 
This category applies to those adverse events judged to be perhaps related to the study 
investigational product administration. An adverse event may be considered Possibly Related 
when it meets at least one of the following criteria: 
 It follows a reasonable temporal sequence from application of the study 
treatment; 
 It could not readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject; 
 It follows a known or expected response pattern to the study treatment. 
Probably Related 
This category applies to those adverse events judged with a high degree of certainty to be related 
to the study treatment. An adverse event may be considered Probably Related if it meets at least 
two of the following criteria: 
 It follows a reasonable temporal sequence from application of the study 
treatment; 
 It could not be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject; 
 It disappears or decreases on cessation or reduction in study treatment dose.  
There are exceptions when an adverse event does not disappear upon 
discontinuation of the study treatment, yet study treatment relatedness clearly 
exists (e.g., coagulopathy, sepsis, etc.); 
 It follows a known pattern or expected response to the study treatment. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
70 
Related 
This category applies to those adverse events judged to be incontrovertibly related to study 
treatment. Any adverse event may be assigned to this category if it meets at least three of the 
following criteria: 
 It follows a reasonable temporal sequence from application of the study 
treatment; 
 It could not be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject; 
 It disappears or decreases on cessation or reduction in study treatment dose.  
There are exceptions when an adverse event does not disappear upon 
discontinuation of the study treatment, yet study treatment relatedness clearly 
exists (e.g., coagulopathy, sepsis, etc.); 
 It follows a known pattern or expected response to the study treatment. 
 It reappears or worsens when the study treatment is re-administered. 
To standardize the reporting of AEs, all of the Investigator terms used to describe complications 
will be collapsed into primary terms as defined by MedDRA. The incidence of adverse events for 
each study group, therefore, will be organized and summarized by system organ class, preferred 
term, relatedness, and degree of severity. Please see Appendix D regarding information about 
relatedness, including specific attribution to the VTL C3A cells (biologic), the ELAD System 
(device), or to the ELAD procedure. 
9.7 
SPONSOR AND INVESTIGATOR REPORTING REQUIREMENTS 
With regard to regulatory compliance, the specific AE and SAE reporting requirements of 
Investigators and Sponsors participating in this study are governed by the local and regional 
regulations of each Regulatory Authority authorizing the conduct of the trial, and by the ICH.  
This protocol reflects the shortest reporting timelines in these collective regulations, hence 
adhering to compliance at all investigational sites. 
In certain European countries where ELAD is regulated as both a biologic/advanced therapy and 
a device, VTL is required to report all SAEs that have occurred in the trial in compliance with 
the EU MEDDEV 2.7/3 guidelines on Serious Adverse Event reporting. In order to minimize any 
potential compromise to the trial whose primary efficacy endpoint is overall survival and to 
maintain the blind in study conduct, those SAEs that have an outcome of death, or in rare cases 
where death is listed as an event term, will not be reported in the MEDDEV reports. This 
exception in SAE reporting is consistent with the recommendations in ICH Guidance E2A 
Clinical Safety Data Management regarding potential compromise of the clinical investigation if 
the blind is broken. 
Similarly, reporting of deaths and associated statistics in the periodic safety reports, including the 
Development Safety Update Report, required for submission by the Sponsor in compliance with 
local and regional regulations where the trial is being conducted, will be masked to further 
minimize potential compromise to the trial. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
71 
9.8 
UNANTICIPATED DEVICE ADVERSE EFFECTS 
Unanticipated device adverse effects will be reported by the Investigator and by the Sponsor as 
required by local regulations. In addition, the ELAD Specialist will record all device-related 
malfunctions on the ELAD System Clinical Incident Report Form, whether they appear to impact 
the subject and/or ELAD treatment or not, and follow-up by VTL will be conducted. Any broken 
or malfunctioning components caused by shipping or moving the system and/or supply cart are 
also captured on the form. The ELAD Specialist will notify his/her supervisor of all device 
and/or component deficiencies during treatment within a timely manner, in addition to filling out 
the ELAD System Clinical Incident Report Form. Similarly, an ELAD System Clinical Incident 
Report and notification to the supervisor is required if the ELAD Specialist notes an increase in 
the need to replace any specific component(s) during the subject’s treatment. Once reported, 
appropriate action, if required, will be taken by the Sponsor. 
All device issues that do not impact the subject directly are reported by the ELAD Specialists on 
the ELAD System Clinical Incident Report Form and follow-up at VTL is conducted by the Risk 
Evaluation Team. Any deficiencies listed on the form will be discussed with the ELAD 
Specialist’s supervisor within 24 hours. Any incidents believed capable of doing harm to 
subjects, even if they did not in the case reported, will be conveyed to the Risk Evaluation Team 
for immediate assessment and consideration of expedited regulatory and IRB/EC reporting. 
All unanticipated adverse device effects will be reported as SAEs if they meet the reporting 
requirements, as described in Section 9.4. 
9.9 
DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent DSMB will be constituted to include at least one expert hepatologist, and one 
intensivist. An independent statistician will provide the data for DSMB review and consult the 
DSMB for statistical questions. The DSMB will review and interpret safety data from the study 
on a regular basis. The DSMB membership and responsibilities will be documented in a charter 
that will be prepared prior to the first DSMB review meeting. The DSMB reviews will include 
summaries of safety data, such as laboratory data (with special attention to liver function tests), 
serious adverse events, and treatment discontinuation. After each safety review, the DSMB will 
make recommendations to VTL regarding continuing, modifying, or terminating the trial. 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
72 
10 
HUMAN SUBJECTS AND INFORMED CONSENT 
10.1 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
This protocol, the proposed informed consent form, any advertisement for subject recruitment 
and any subject instructional materials must be reviewed and approved by the appropriate 
IRB/EC prior to the start of the study. The proposed informed consent form and any proposed 
advertisement must also be agreed to by VTL. A copy of the IRB/EC approval letter of the 
protocol, any amendments, the informed consent form and any advertisements or subject 
instructional materials must be supplied to VTL prior to starting the study. During the course of 
the study, the Investigator shall make timely and accurate reports to the IRB/EC on the progress 
of the trial, at intervals not exceeding one year, as well as satisfying any other local IRB/EC 
regulations regarding reporting. Protocol deviations/procedure violations will be reported to the 
IRB/EC as required. Copies of all reports and correspondence with the IRB/EC must be provided 
to VTL. Furthermore, at the completion or early termination of the study, a final report should be 
made to the IRB/EC by the Investigator within the applicable IRB/EC time frames. 
The IRB/EC must review any requests for deviations, and reports of deviations, if the deviation 
affects subject's rights, safety and well-being, or the scientific integrity of the clinical 
investigation if local regulations require. Please check with your IRB/EC regarding their specific 
reporting rules. 
Any significant changes or revisions in the study protocol or any changes that may alter subject 
risk must be approved by VTL (and may require FDA or other regulatory agency review and 
approval) and must be approved in writing by the IRB/EC prior to implementation. A protocol 
change intended to eliminate an apparent immediate hazard may be implemented immediately 
provided that VTL is immediately notified and an amendment is subsequently provided by VTL 
and approved by the IRB/EC. Under emergency circumstances, deviations from the protocol to 
protect the rights, safety and well-being of human subjects may proceed without prior approval 
of the Sponsor and the IRB/EC. Such deviations must be documented and reported to the sponsor 
and the IRB/EC as soon as possible. 
The Investigator’s Brochure, protocols, case report forms, informed consent form and other 
subject information, or other clinical investigation documents will be amended as needed 
throughout the clinical investigation. The sponsor will notify the Principal Investigator, or the 
coordinating Investigator of such amendments. The amendments to the protocol and the subject's 
informed consent form shall be notified to, and approved by, the IRB/EC and regulatory 
authorities, if required. The amendment number and date of amendments will be documented. 
It is the Investigator’s obligation to maintain an IRB/EC correspondence file, and to make this 
available for review by VTL representatives as part of the study monitoring process. 
10.2 
INFORMED CONSENT  
The proposed informed consent form, which must be in compliance with the regulations, must be 
reviewed and approved by VTL prior to initiation of the study. The proposed informed consent 
form must contain a full explanation of the purpose, nature and duration of the study, a 
description of the procedures, the possible advantages, risks, alternative treatment options, and a 
statement of confidentiality of subject study records, a statement regarding voluntary 
compensation and availability of treatment in case of injury, an explanation of whom to contact 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
73 
about the research, the subjects rights, and notification that participation is voluntary and refusal 
will involve no penalty or loss of medical benefits. These requirements will be in accordance 
with US Federal Regulations as detailed in 21 CFR 50.25 and the Declaration of Helsinki and 
any applicable local regulations. It should also indicate, by signature, that the subject, or legal 
guardian/legally authorized representative, permits access to relevant medical records by the 
Sponsor and/or the Sponsor’s duly appointed agent and by representatives of the US FDA or 
other applicable regulatory authorities. Additionally, Investigators in states and countries with 
specific regulations regarding subject’s rights have a responsibility to follow and document their 
fulfillment of those regulations. 
The Investigator will be responsible for obtaining written informed consent from potential 
subjects or their subject representative(s) prior to any study-specific screening required for entry 
into this study. During the consent process, the Principal Investigator or appropriate designee(s) 
will verbally inform all subjects or their legally-authorized representative(s) about the purpose, 
nature and duration of this clinical study. The Investigator or appropriate designee will also 
inform all subjects regarding the methods to which they will be subjected and the experimental 
nature of the treatment, as well as the potential risks and benefits that may result from utilization 
of study treatment. Subjects will be informed that they are free to refuse participation in this 
clinical study. If they should participate, it will be made clear that they may withdraw from the 
study at any time without prejudicing further care. Subjects will also be informed of alternative 
methods of treatment should they not wish to participate in this clinical study. The person 
obtaining informed consent from the subject and the subject or their legally-authorized 
representative must sign and date the informed consent document. 
A signed copy of the informed consent will be provided to the subject, and a signed copy will be 
maintained with the subject’s eCRFs, or in the study documentation notebook. The original will 
be retained by the Investigator. 
Subjects participating in this protocol will provide written informed consent at the time of the 
screening visit indicating their understanding of the study. Due to the critical nature of the 
subject’s condition, they may not be able to understand or execute the informed consent at the 
time of Screening. The subject’s legally authorized representative must then sign the subject 
informed consent at the time of subject entry. The reason the subject was unable to personally 
provide consent will be indicated on the consent form signed by the subject’s legally authorized 
representative. Should the subject’s condition improve such that they are able to understand the 
study and provide personal consent, they will be asked to give their consent to continue 
participation. This consent will be documented on a separate form. If the subject is able to 
understand the study and provide informed consent, but is unwilling to continue their 
participation, the subject must be withdrawn from the study. The source documents must note the 
subject’s decision, and this information must be accurately captured in the subject’s eCRFs.  
Consent includes authorization of participation into VTL-308E, the 5-year registry follow-up 
portion of the trial. See Section 13 for more information regarding this. 
Should withdrawal of consent be implemented by the subject or the subject’s legally-authorized 
representative, a written document will be presented to them for signature with the ability to 
check the extent to which consent is withdrawn. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
74 
11 
DISCLOSURE OF DATA/PUBLICATION POLICY 
All information obtained as a result of this study or during the conduct of this study will be 
regarded as the confidential property of VTL. Disclosures (i.e., release of information to any 
third party not noted herein) or any information related to the study, not previously known to be 
public, and/or study results shall not be made either by publication or by oral or poster 
presentation without the express, written consent of VTL. 
VTL intends to have the results of this trial published following study conclusion. The results 
will appear on at least one public database, www.clinicaltrials.gov.  

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
75 
12 
BIOHAZARD CONTAINMENT 
Since the transmission of HIV and other blood-borne infectious agents can occur through contact 
with contaminated needles, blood or blood products, appropriate precautions must be employed 
by all personnel involved in this study, as currently recommended by the Centers for Disease 
Control. Universal Precautions information can be obtained at the following website: 
http://www.cdc.gov/niosh/topics/bbp/universal.html  
 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
76 
13 
ESTABLISHMENT OF REGISTRY FOR SUBJECT FOLLOW-UP – 
VTL-308E 
VTL intends to provide for long-term follow-up of subjects recruited into this trial through 
establishment of a registry which is described in the extension protocol VTL-308E. 
13.1 
VTL-308E JUSTIFICATION 
VTL is conducting clinical trial VTL-308, in which subjects with AILD are treated with ELAD 
and standard of care, or with standard of care alone to assess the safety and efficacy of ELAD 
treatment. 
A hypothetical risk exists that over an extended period of follow up there may be an increased 
incidence of tumor formation in subjects treated with ELAD. However, the underlying disease 
processes in subjects with alcoholic hepatitis also leads to an increased risk of tumor formation 
in the liver and elsewhere. Worldwide, hepatocellular cancer is the fifth most common cancer in 
men and eighth most common cancer in women, varying in accordance to prevalence of hepatitis 
B and C infections, and well over 80% of all primary liver cancers are caused by chronic 
hepatitis infections (Bosch and Diaz 2004). 
The VTL-308 trial monitors subject safety up to 91 days after Randomization. To assess whether 
there is an increased risk of late tumor formation in subjects treated with ELAD, this registry 
protocol segment of VTL-308 extends the safety monitoring period to 5 years.  
VTL-308E is designed to provide a long-term assessment of subject’s outcome in relationship to 
tumor (in particular liver tumor), liver transplant, and overall mortality. The protocol includes 
both control and ELAD-treated subjects to assess the significance of any findings.  
13.2 
OBJECTIVES  
The intent of this protocol is to determine the status of VTL-308 study subjects at 6 months 
(± 2 weeks), 9 months (± 2 weeks), 1 year (± 2 weeks), and then annually for 4 additional years 
(± 2 months) following their participation in the study to assess: 
 Survival 
 Incidence and characterization of tumor (in particular hepatocellular tumor) 
 Incidence of liver transplant  
 Quality of life using a standard, validated questionnaire 
 
Subjects who withdraw prior to Study Day 91 and who continue to consent to be followed in the 
VTL-308E study will be contacted according to the VTL-308E procedures at each of the 
remaining parent study scheduled visits (e.g. Study Day 28, Study Day 63, Study Day 91). VTL 
may request additional unscheduled contacts during the extension period in order to support 
survival analyses, particularly around the time of completing the parent study.  
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
77 
13.3 
SUBJECT POPULATION  
Since this is a follow-up segment to the VTL-308 study, only subjects participating in VTL-308 
will be considered for enrollment into this protocol. Subjects lost to follow-up in VTL-308 will 
be considered as the same, lost to follow-up, for this extension segment of this protocol 
(VTL-308E).  
13.4 
RESEARCH DESIGN AND METHODS 
While consenting for VTL-308, each subject will be consented to participate in the follow-up 
VTL-308E protocol as an extension of the protocol. Once consented, they will provide contact 
information that can be used for 5 years of follow-up (see Section 5.2.1). This will include a 
current address and telephone number as well as that of a contact person who may know their 
whereabouts should they no longer be able to be reached at the phone number or address 
provided. This contact information (e.g. address, telephone number, contact person) will not be 
sent to VTL or to their data management contractors. It will be available to study personnel at the 
investigational site only.  
Additionally, subjects will be asked to notify their study Investigator if they are diagnosed with 
cancer at any time during the 5 years following their VTL-308 participation regardless of when 
the diagnosis is made in reference to their annual follow-up call. They will be given the contact 
information necessary to make the notification. 
The date of Randomization will be logged on an eCRF. Based on that date, at 6 months, 9 
months, 1 year, and then annually for 4 additional years following their date of Randomization, 
subjects will be contacted by phone by the investigative site. VTL will keep a master log of the 
coded subjects and their anniversary dates and will send a reminder to the sites within 2 weeks of 
the time the call should be made. The site will be provided with eCRFs that include the specific 
questions to ask.   
The questions involve the following: 
If the subject responds: 
When the subject is reached by phone, or if the subject calls the site, he/she will be asked the 
following: 
1. Since your last contact with study staff, have you had a liver transplant? 
If yes, obtain the date of the transplant.  
2. Since your last contact with study staff, have you been diagnosed with cancer (that is 
different than any cancer you may have had while in the trial)? If yes, proceed with 
the following questions: 
a. What type of cancer were you diagnosed with? 
b. What was the extent of your metastatic disease (if applicable)? (To be asked 
as has your cancer spread? If so, where?) 
3. Have you changed or do you anticipate changing your contact information? If so, 
please update it now. 
4. Have you changed or do you anticipate changing your contact person or their contact 
information? If so, please update it now. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
78 
5. The EQ-5D-5L Quality of Life questionnaire will be completed. 
 
If the call recipient states the subject has expired: 
If another person answers and states the subject is deceased, the investigative site’s 
designated caller will ask the following: 
6. When did the subject expire? 
7. What was the cause of death? 
8. Was an autopsy performed?  If yes, where can a copy of the report be obtained? 
9. Ask if signed approval can be obtained to access the subject’s medical records that 
have the pertinent information (particularly if cancer was present) if the information 
is not in the medical record at the investigational site. If approval is given, the 
coordinator will send out the appropriate medical records release form for a legally 
appropriate family member to sign. A prepaid FedEx return envelope will be 
included. 
10. Was the subject diagnosed with cancer after being in the VTL-308 study? If so: 
a. What type of cancer was the subject diagnosed with? 
b. What was the extent of the subject’s metastatic disease (if applicable)? Again, 
ask in terms the caller can understand. 
11. Had the subject had a liver transplant? If so, obtain the date of the transplant. 
 
If the subject is deceased, it will be noted on the eCRF and no further follow-up will be 
initiated. Vital Therapies must be made aware of this to update the call reminder list. Call the 
office at +1-858-673-6840 and ask for any of the VTL-308 staff. Deaths, incidences of 
cancer, and liver transplants will not be reported as SAEs, but should be reported to Vital 
Therapies as soon as feasible. 
Subject is not home/available: 
If the subject is unavailable, the caller will find out when to call back to speak to the subject, 
or what a better phone number might be to reach the subject. A call-back number can be left 
for the subject.   
A message can be left on a subject’s voicemail or answering machine/service only if it gives 
no medical information or relationship to the reason of the call. For instance, “This call is for 
John Doe. Please call Jane at 555-555-6655 when you get this message.” No reference to a 
clinic, doctor’s office, etc. should be left unless the subject has previously stated this is 
allowed. 
Subject not located or calls not returned: 
If a subject is no longer at the number given, continues to be unavailable, or does not return 
messages for at least 3 attempts, the person listed as the contact person should be notified for 
information.   
If the contact person cannot be reached by phone (at least 3 attempts), a registered letter will 
be sent to both the study subject and to the contact person requesting contact information for 
them both. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
79 
If no information is forthcoming within 3 weeks of sending the registered letters, the subject 
will be considered lost to follow-up. No further attempts will be made to reach the subject or 
the contact person. VTL should be notified of the lost-to-follow-up status by calling the 
office at +1-858-673-6840 and asking for any of the VTL-308 staff.   
If at a later time, the subject or the contact person responds, the study visit should be done at 
that time, even if it is late. The protocol will resume on the following anniversary, so ensure 
that VTL is made aware of the late contact to keep the subject on the call reminder list. 
The site should look in their medical records for any information regarding possible death of 
the subject if they get no response to calls. All deaths will be noted on the eCRF. 
Prior to calling a subject annually, the previous year’s information will be reviewed to assure no 
subject contact is inadvertently made if the subject has expired and we have been made aware of 
it. 
For subjects lost to follow-up, whether during or after the 91-day parent study, VTL may engage 
a third party vendor that specializes in identifying survival status (e.g. through a search of public 
records). In such cases, this vendor will provide documentation of the survival status to study 
site, who will then enter this new information in the eCRF. 
13.5 
MAINTAINING CONFIDENTIALITY 
All efforts to maintain confidentiality of subject identification will be upheld. VTL will have the 
investigative site personnel call all subjects and maintain the contact information. Identifiable 
subject data will not be stored at VTL nor will it be made available to VTL.   
A coding system will be in place using the coded patient identifiers used in VTL-308 (the subject 
number). Only the investigative site will have the corresponding subject names, phone numbers, 
addresses, and contact information in the event the subject cannot be reached. There will be no 
social security or medical record numbers stored. 
A cover page with the subject identification coded will be completed at the site. This cover page 
will have the subject’s full name, telephone number, and address. It will also have the name, 
telephone number, and address for their back-up contact should they be unreachable. This cover 
page, and any information contained within, will not leave the site or be made available to VTL 
or to the data management company.   
Site staff must be aware of the importance of keeping subject data confidential. In accordance 
with ICH Guideline for Good Clinical Practice, confidentiality of records that could identify 
subjects must be protected, respecting the privacy and confidentiality rules in accordance with 
the applicable regulatory requirement(s). 
Monitor(s), auditor(s), the IRB/EC, and the regulatory authority (ies) will be granted direct 
access to the subject's original medical records for verification of clinical trial procedures and/or 
data, without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations and that, by signing a written informed consent form, the subject or the 
subject's legally acceptable representative is authorizing such access.  
Records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. If the results of the trial 
are published, the subject’s identity will remain confidential. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
80 
14 
CRITERIA FOR STUDY DISCONTINUATION 
This study shall be terminated following completion of study participation of all study subjects 
enrolled, or at the discretion of VTL, or the Data and Safety Monitoring Board (DSMB). If 
during review of safety information it is determined that the study represents higher risk than 
potential benefit, the DSMB will inform the Sponsor if action is required, per the DSMB Charter.  
In addition, if an SAE or ELAD System Clinical Incident is observed of such a nature that it 
represents an immediate, life-threatening risk to ELAD subjects, enrollment into the study will 
be suspended, the occurrence investigated, and IRBs/health authorities notified expeditiously. 
Study enrollment can only be reinitiated if deemed appropriate after review and release by the 
DSMB and health authority notification. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
81 
15 
INVESTIGATOR AGREEMENT 
I have read protocol VTl-308 (incorporating VTL -308E) and its appendices and agree to adhere 
to all requirements in the conduct of the study. 
In signing below I agree: 
 To assume responsibility for the proper conduct of the study at my site 
 To conduct the study in compliance with this protocol, any future amendments, 
and with any other study procedures provided by Vital Therapies, Inc. 
 That I am aware of, and will comply with Good Clinical Practices (GCP) and all 
applicable regulatory requirements 
 To ensure that all persons assisting me with the study are adequately informed 
about the study and of their study-related duties as delegated by me 
 Not to implement any changes to the protocol without written agreement from 
Vital Therapies, Inc. and prior review and written approval from the Ethics 
Committee/Institutional Review Board (EC/IRB) except where necessary to 
eliminate an immediate hazard to study subjects 
 
I acknowledge that failure to adhere to these stipulations may constitute a breach of 
governmental regulations, may invalidate the data and may result in termination of the study at 
my site. 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
Principal Investigator’s Printed Name 
 
 
Institution’s Name 
 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
82 
16 
REFERENCES 
Allen JP, Sillanaukee P, Strid N, Litten RZ. Biomarkers of Heavy Drinking. In: Allen JP, Wilson 
VB, eds: Assessing Alcohol Problems: A Guide for Clinicians and Researchers. 2nd ed. 
Bethesda, MD: NIH Publication No. 03-3745; 2003: 37-53. 
Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. 
Gastroenterology, 2004; 127(5 Suppl 1):S5-S16. 
Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, and Bacon BR.  
Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J 
Gastroenterol, 1999; 94(9), 2467-2474. 
Center for Substance Abuse Treatment.  The Role of Biomarkers in the Treatment of Alcohol 
Use Disorders. Substance Abuse Treatment Advisory. Volume 5, Issue 4, September 2006. 
Cluver JS, Miller PM, Anton, RF. Case Studies of the Utility of Serum Carbohydrate-Deficient 
Transferrin (%CDT) in the Clinical Management of Alcoholics.  J Addict Med, 2007; 1 (1): 44-
47. 
Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, et al.  Clinical Course of acute-on-
chronic liver failure syndrome and effects on prognosis. Hepatology. 2015 Jul; 62(1):243-52. 
Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, et al. Acute-on chronic liver failure. J 
Hepatol, 2012; 57(6), 1336-1348. 
Kendrick SFW, et al, Theophylline Improves Steroid Sensitivity in Acute Alcoholic Hepatitis. 
Hepatology 2010; 52:126-131. 
Lebrec D, Thabut D, Oberti F, Perarnau JM, Condat B, et al.  Pentoxifylline does not decrease 
short-term mortality but does reduce complications in patients with advanced cirrhosis. 
Gastroenterology. 2010 May; 138(5):1755-62. 
Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E,. (2007). The Lille model: A new tool 
for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. 
Hepatology, 2007; 45, 1348-1354. 
Maddrey WC, Boitnott JK, Bedine MS, Weber FL, Mezey E, and White RI. Corticosteroid 
therapy of alcoholic hepatitis. Gastroenterology, 1978; 75, 193-199. 
Miller PM, Dominick C, Anton RF. Carbohydrate-Deficient Transferrin Test: A Tool for 
Detecting Alcohol Abuse.  Current Psychiatry. 2005; 4 (6): 80-87. 
Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, et al.  Acute-on chronic liver failure is a 
distinct syndrome that develops in patients with acute decompensation of cirrhosis.  
Gastroenterology. 2013; 144:1426-1437. 
Morris JM, and Forrest EH. Bilirubin response to corticosteroids in severe alcoholic hepatitis. 
European Journal of Gastroenterology and Hepatology 2005; 17:759–762. 
Naveau S et al, A Double Blind Randomized Controlled Trial of Infliximab Associated with 
Prednisolone in Acute Alcoholic Hepatitis. Hepatology, 2004; 39(5): 1390-1397. 
Orrego H, Blake J, Blendis L, and Medline A. Prognosis of Alcoholic Cirrhosis in the Presence 
and Absence of Alcoholic Hepatitis. Gastroenterology, 1987; 92:208-14. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
83 
O'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American 
Association for the Study of Liver, D., and Practice Parameters Committee of the American 
College of G. Hepatology, 2010; 51(1), 307-328.  
Parker R, Armstrong M, Corbett C, Rowe I, Houlihan D.  Systematic Review: Pentoxifylline for 
the treatment of severe alcoholic hepatitis.  Aliment Pharmacol Ther. 2013; 37: 845-854. 
Schuppan D and Afdhal NH. Liver cirrhosis. Lancet, 2008; 371(9615), 838-851.  
Singal AK, et al. Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis:  
Current status.  World Journal of Hepatology, 2011a; 3(8): 205-210. 
Singh S, Murad MH, Chandar AK, Bongiorno CM, Singal AK, Atkinson SR, Thursz MR, 
Loomba R, Shah VH (2015). Comparative Effectiveness of Pharmacological Interventions for 
Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis. Gastroenterology, 
October:149(4):958-970. e12. doi: 10.1053/j.gastro.2015.06.006. Epub 2015 Jun 16. 
Sobell LC, Sobell MB. Alcohol Consumption Measures. In: Allen JP, Wilson VB, eds: 
Assessing Alcohol Problems: A Guide for Clinicians and Researchers. 2nd ed. Bethesda, MD: 
NIH Publication No. 03-3745; 2003: 75-99. 
Thursz MR, Richardson P, Allison M, Austin A, Bowers M, et al. Prednisolone or Pentoxifylline 
for Alcoholic Hepatitis. New England Journal of Medicine. 2015; 372(17):1619-1628. 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
84 
Table 1. 
Schedule of Evaluations and Procedures at Screening for Randomization 
 
Procedures 
Screening1 
Randomization 
(Start of Study 
Day 1) 
Identify Subject/Notify Vital Therapies 
X 
 
Informed Consent 
X 
 
Demographics (DOB or age, race, ethnicity, gender, height, weight) 
X 
 
Medical History 
X 
 
Physical Exam2 and Vital Signs3 
X 
 
Inclusion/Exclusion Criteria 
X 
 
Encephalopathy Stage (West Haven Criteria)2 
X 
 
Ultrasound 11 
X 
 
Serology for active viral hepatitis A, B, and C4 
X 
 
Laboratory Evaluations5 
X 
 
Complete Blood Count (CBC) 
X 
 
Blood for outside analysis (consented subjects at participating centers ONLY) 6 
X 
 
PT/control PT/PTT/INR 
X 
 
Baseline Laboratory Evaluations12 
X 
 
Test for alcohol use (PEth)  
X 
 
Pulse Oximetry and FiO2 
X 
 
Blood Culture samples (×2)6 
X 
 
Sputum and urine Culture and Sensitivity6 
X 
 
Peritoneal Fluid Culture6 (only if paracentesis has not been done within 7 days prior to 
Screening) 
X 
 
Serum Pregnancy Test (if applicable) 
X 
 
MELD Score and Maddrey Score autocalculated7 
X 
 
Enroll Subject/Notify Vital Therapies 
 
X8 
Adverse Events 
 
X 
Concomitant Medications10 
 
X 
Concomitant Blood Product Administration 
 
X 
Concomitant Fluid Administration 
 
X 
Subject Location9 
 
X 
1 
All Screening evaluations and procedures can be obtained from standard of care if previously performed within 24 hours of Randomization 
unless otherwise specified. 
2 
Performed by a study physician, physician assistant or nurse practitioner if within their scope of practice for institution. 
3 
Blood pressure, heart rate, respiration, temperature. 
4 
Serologies are to be completed at Screening if not previously performed during this hospital admission.  
5 
BUN, creatinine, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, sodium, potassium, chloride, 
carbon dioxide (or bicarbonate), calcium, magnesium, phosphate, albumin, total protein, alkaline phosphatase.  Bilirubin measurements must 
be taken at least 12 hours after any procedure known to artificially alter serum bilirubin.  
6 
 Blood sample, urine sample, sputum sample, and peritoneal fluid sample for Culture and Sensitivity (C&S) testing, and blood for outside 
analysis may be collected at any time after informed consent (unless indicated per standard of care) but before the End of Study Day 2 for 
Control subjects or before start of treatment for subjects randomized to ELAD. 
7 
A MELD Score and Maddrey Score will be autocalculated using these data (see Section 5.2.4).  The MELD Score must be calculated using 
values obtained at the same time point, and from blood draws taken within 6 hours of each other. 
8 
Subject eligibility will continue to be monitored up until the time of initiation of Randomization. Randomization must occur within 24 hours 
of Screening, otherwise Screening evaluations must be repeated. (See Section 5.2.3). 
9 
Documentation of all transfers, discharges, readmissions and admissions within or outside institution. All emergency room visits must also 
be documented. 
10 Steroid use is to be collected for the 6 weeks prior to hospital admission, if possible. 
11 Ultrasound must be performed no more than six weeks prior to the current hospitalization and be indicative of and have a temporal 
relationship to the subject’s current clinical condition (See Section 5.2.3.2). 
12 Ammonia, lactate, albumin, α fetoprotein, lactic dehydrogenase (LDH). 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
85 
Table 2. 
Schedule of Evaluations and Procedures for CONTROL Subjects 
Control Subject Procedures 
End of Study Day 2 
Matched safety 
eligibility check 
(±6 hrs) 
Daily on End of 
Study Day 11 to End 
of Study Day 7 
End of Study 
Day 14, 21, 28 
(+3 days) 
End of Study 
Day 63 and 91 
(+ 5 days) 
Physical Exam3 
 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
Exclusion Criteria check  
X2 
 
 
 
Weight 
 
X (SD 7 outpatient only) 
X14 
X14 
Encephalopathy Stage (West Haven Criteria) 3 
 
X 
X 
X 
Laboratory Evaluations5 
Cr, T bili 
X 
X 
X 
CBC 
Platelets 
X 
X 
X 
PT/PTT/INR 
INR 
X 
X 
X 
Pulse Oximetry, FiO2, delivery method 
(inpatients only) 
 
X 
 
 
Blood culture samples (×2)6  
X6 
X6 
 
 
MELD scores to be calculated7 
X 
X 
X 
X 
Blood for outside assessment8 
 
X 
X 
X 
TLFB and mTSR Questionnaires9 
 
X 
X 
X 
Test for alcohol use (PEth)10 
 
At hospital discharge and at all home health visits 
EQ-5D-5L QOL Questionnaire 
 
At hospital discharge and Day 91 only 
X15 
Continuous monitoring: 
 
 
 
 
Adverse Events11 
 
X 
X 
X 
Concomitant Medications12 
 
X 
X 
X 
Concomitant Therapies12 
 
X 
X 
X 
Subject Location13 
 
X 
X 
X 
Dietary consultation14 
 
X 
X 
X 
1 First morning Standard of Care Labs after Randomization. Study Day 1 may be less than 24 hours in duration; Daily 
assessments must be performed on each Study Day a minimum of 12h apart, if patient discharged prior to end of SD 7 they 
must return for SD 7 evaluations (+2d). 
2 Exclusion Criteria 2, 3, 4, 7, 9, 10, 15, and 16. 
3 Performed by a study physician, physician assistant or nurse practitioner if within their scope of practice for institution. 
4 Blood pressure, heart rate, respiration rate, and temperature.  
5 Blood Urea Nitrogen (BUN), creatinine (Cr), glucose, sodium, potassium, chloride, carbon dioxide (CO2), calcium, 
magnesium, phosphate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (total/direct), albumin, 
total protein, alkaline phosphatase, lactic dehydrogenase (LDH), ammonia (NH3), lactate and α fetoprotein. Bilirubin 
measurements must be taken at least 12 hours after any procedure known to artificially alter serum bilirubin.  
6 Drawn only at End of SD2 (matched safety eligibility check) and End of SD 4.  
7 A MELD Score will be calculated using these data (see Section 5.2.4).  The MELD Score must be calculated using values 
obtained at the same time point, and from blood draws taken within 6 hours of each other. 
8  Only participating sites and consented subjects; draw at Screening, Days 3, 5, 7 (and/or 24 hrs post ELAD), 14, 28, and 91.  
If blood draw is missed at Screening, it must be drawn before End of Study Day 2. 
9 TLFB and mTSR obtained weekly by home visit practitioners for subjects that are outpatients only. Study staff not 
responsible for obtaining TLFB and mTSR. 
10 Blood alcohol testing will be done by home visit personnel if subjects are outpatients.  Study site does one Blood alcohol 
testing (PEth) at hospital discharge only. 
11 AEs will be monitored continuously from after Randomization throughout Study Day 91 and recorded in the eCRFs.  
12 Concomitant medications including concomitant blood product administration (e.g., whole blood, packed red cells, platelets, 
fresh frozen plasma), and concomitant therapies (e.g., intubation, tracheostomy, CVVH/CVVHD, arterial blood gas) will be 
monitored continuously from Randomization through Study Day 91. 
13 Documentation of all transfers, discharges, readmissions and admissions within or outside institution. All emergency room 
visits must also be documented. 
14 Dietary consultation within 72 hrs of Randomization, at discharge, and all outpatient visits (including weight). 
15 EQ-5D-5L Quality of Life Questionnaire (Appendix C) at Day 91 and hospital discharge only. 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
86 
Table 3. 
Schedule of Evaluations and Procedures for ELAD Subjects 
Treated Subject Procedures 
End of SD1  
(Hr 24)1 
 
ELAD Treatment 
Daily on End 
SD2 to End 
SD71, 20 
End of SD  
14, 21, 28 
(+ 3 days) 
End of SD  
63 and 91 
(+ 5 days) 
Safety 
Eligibility  
(-6 Hrs to 
ELAD 
Start)21 
Hr 1-321 
Hr 6-10 
and   
14-1821 
Q 24 Hr 
on ELAD 
24 Hr Post 
ELAD Stop1
(±6 hours) 
Physical Exam3 
X 
 
 
 
 
X 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
 
X 
X 
X 
X 
Exclusion Criteria check  
 
X2 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
X17 
X17 
Encephalopathy Stage (West Haven Criteria) 3 
X 
 
 
 
 
X 
X 
X 
X 
Laboratory Evaluations6 
X 
T Bili7, Cr7 
 
 
 
X 
X 
X 
X 
CBC 
X 
Platelets7 
 
Platelets 
 
X 
X 
X 
X 
PT, PTT18, INR  
X 
INR7, PTT 
 
X 
 
X 
X 
X 
X 
Pulse Oximetry, FiO2,delivery method 
X 
 
 
 
 
X 
X10 
 
 
Blood culture samples (×2)  
 
X 
 
 
X8 
 
 
 
 
Ultrafiltrate Cultures (×2) 
 
X5 
 
 
X8 
 
 
 
 
Ultrafiltrate Sample to assess cartridge performance  
 
X5 
 
 
X 
 
 
 
 
Blood for outside assessment9 
 
 
 
 
 
X 
X 
X 
X 
MELD scores to be calculated11 
X 
X 
 
 
 
X 
X 
X 
X 
TLFB and mTSR Questionnaires12 
 
 
 
 
 
 
X 
X 
X 
Test for alcohol use (PEth)13 
At hospital discharge and all home health visitis 
 
EQ-5D-5L Quality of Life Questionnaire 
At hospital discharge and Day 91 only 
X19 
Adverse Events14 
X 
 
 
 
 
 
X 
X 
X 
Concomitant Medications15 
X 
 
 
 
 
 
X 
X 
X 
Concomitant Therapies15 
X 
 
 
 
 
 
X 
X 
X 
Subject Location16 
X 
 
 
 
 
X 
X 
X 
X 
Dietary Consultation17 
 
 
 
 
 
 
X 
X 
X 
1 First morning Standard of Care Labs after Randomization. Study Day 1 may be less than 24 hours in duration. Daily assessments (including 24-hour post-ELAD stop) must be 
performed on each Study Day, a minimum of 12h apart If patient discharged prior to end of SD7 they must return for SD 7 evaluations (+2d). 
2  Exclusion Criteria 2, 3, 4, 7, 9, 10, 15, and 16. 
3 Performed by a study physician, physician assistant or nurse practitioner if within their scope of practice for institution. 
4 Blood pressure, heart rate, respiration rate, and temperature. 
5 Just before ELAD pump start (hour 0). 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
87 
6 Blood Urea Nitrogen (BUN), creatinine (Cr), glucose, sodium, potassium, chloride, carbon dioxide (CO2), calcium, magnesium, phosphate, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (total/direct), albumin, total protein, alkaline phosphatase, lactic dehydrogenase (LDH), ammonia (NH3), lactate and α fetoprotein . 
Bilirubin measurements must be taken at least 12 hours after any procedure known to artificially alter serum bilirubin. 
7 Results of total bilirubin, creatinine, INR and platelets must be available and reviewed by study physician prior to initiating ELAD treatment.  
8 Blood culture and Ultrafiltrate culture samples drawn at the sample time at Hour 48 and 96 of ELAD Treatment Period only. 
9 Only participating sites and consented subjects; Screening (or before ELAD treatment start), Days 3, 5, 7 (and/or 24 hrs post ELAD), 14, 21, 28, 63 and 91.   
10 FiO2 and pulse oximetry on inpatients only. 
11 MELD Score calculated using these data (see Section 5.2.4).  The MELD Score must be calculated using values obtained at the same time point, and from blood draws taken 
within 6 hours of each other.. 
12 TLFB and mTSR obtained weekly by home visit practitioners for subjects that are outpatients only. Study staff not responsible for obtaining TLFB and mTSR. 
13 Blood alcohol testing will be done by home visit personnel if subjects are outpatients.  Study site does one Blood alcohol testing (PEth) at hospital discharge only. 
14 AEs will be monitored continuously from Randomization throughout Study Day 91 and recorded in the eCRFs. 
15 Concomitant medications including concomitant blood products and concomitant therapies will be monitored from Randomization through Study Day 91. 
16 Documentation of all transfers, discharges, readmissions and admissions within or outside institution. All emergency room visits must also be documented.  
17 Dietary consultation within 72 hrs of Randomization, at discharge, and all outpatient visits (including weight). 
18 If heparin is administered, additional PTT’s will be assayed in accord with the standard anticoagulation therapy protocol at the site. 
19 EQ-5D-5L Quality of Life Qestionnaire (Appendix C) at Day 91 and hospital discharge only. 
20 Additional End of Study Day Visits, beyond End of Study Day 7, will need to be added as necessary if the start of ELAD Treatment is delayed beyond the End of Study Day 3. 
21 To be repeated if ELAD cartridges are replaced. 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
88 
Table 4. 
Schedule of Evaluations and Procedures for Standards of Care (SOC) 
Important Note:  This summary table does not take the place of reading the protocol. It is essential that these SOC guidelines 
be read and followed for study consistency across investigative sites. All study-related procedures done prior to 
Randomization, if done to follow the SOC described here, must have prior subject informed consent. 
 
Standards of Care 
(SOC) for Treated and 
Control Subjects 
Screening 
Randomization (Study Start) through 
Hospitalization 
Post Hospital 
Discharge 
Comments 
Steroids 
Document current and prior 
steroid use, and pertinent 
clinical indications and 
rationale. 
Administer steroids in accord with AASLD 
guidelines (see Section 5.4.1.2) 
Full documentation of steroid administration and 
tapering schema must be obtained in accord with 
Section 5.4.1.2) 
Steroid use post 
discharge must be 
monitored and 
recorded through  
End of Study Day 91 
 
Ascites 
(tense and refractory) 
For specific type, see 
below and see protocol 
If ascites is present, do abd 
paracentesis to rule out 
SBP. 
If fluid removed exceeds 
5 L, administer colloid 
infusion (8 g of serum 
albumin/liter of ascitic fluid 
removed). 
See protocol for testing to 
be done on ascitic fluid. 
Salt-restricted diet/diuretic regimen.  If history of 
SBP or GI bleed, use antibiotic therapy per protocol. 
 
It is essential that 
the guidelines in 
Section 5.4.1.3 be 
reviewed when 
treating ascites. 
See list of drugs 
contraindicated 
with ascites 
Tense Ascites 
 
Salt-restricted diet/diuretic regimen. A dual diuretic 
regimen of spironolactone and furosemide is 
recommended. 
If tense ascites recurs, paracenteses can be repeated 
at any time. 
 
 
Refractory Ascites 
Defined as fluid 
overload that  
1) Is unresponsive to 
sodium-restricted diet 
and high-dose diuretic 
treatment or 
2) Recurs rapidly after 
therapeutic paracentesis.   
 
Serial therapeutic paracenteses are effective in 
controlling ascites even in subjects with no urinary 
sodium excretion if they are performed approx every 
two weeks. 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
89 
Standards of Care 
(SOC) for Treated and 
Control Subjects 
Screening 
Randomization (Study Start) through 
Hospitalization 
Post Hospital 
Discharge 
Comments 
Gastroesophageal 
Varices 
See categories below 
 
 
 
 
Medium/Large Varices 
that have not bled  
 
Place on non-selective β-blockers at the maximum 
tolerated dose. 
May treat with endoscopic variceal ligation, but this 
procedure and the follow-up endoscopies should be 
conducted after subject completes Study Day 7 
(Control) or ELAD treatment (Treated) whenever 
possible. 
 
 
Actively Bleeding 
Varices 
Must be stable with no 
bleeding and no further 
need for blood products for 
2 days prior to 
Randomization. 
Treat according to the AASLD guidelines: blood 
transfusion; short course antibiotics (e.g. PO 
norfloxacin 400 mg bid × 7 days; if the antibiotics 
cannot be admin PO, IV ceftriaxone 1 g/day for 
7 days - or equivalents); drug therapy (e.g., 
vasopressin, terlipressin, etc); endoscopy using 
EVL/sclerotherapy, balloon tamponade, or TIPS, if 
needed.  Subjects treated for recurrent variceal bleed 
while in study to be treated with non-selective 
β-blockers and EVL to prevent recurrence.  TIPS 
may be considered for appropriate subjects. 
 
 
Active bleeding within 
two weeks prior to 
Randomization 
See above 
Oral norfloxacin 400 mg bid for 7 days (or 
equivalent); if the antibiotics cannot be administered 
PO, IV ceftriaxone 1 g/day for 7 days (or equivalent) 
is to be administered. 
 
 
Hepatic 
Encephalopathy 
 
Nutritious diet (protein intake between 1.0 to 
1.5 g/kg/day), and will be maintained on an adequate 
daily dose of lactulose to maintain two to three soft 
bowel movements per day.  Selective digestive 
decontamination, for example, rifaximin, may also 
be given. 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
90 
Standards of Care 
(SOC) for Treated and 
Control Subjects 
Screening 
Randomization (Study Start) through 
Hospitalization 
Post Hospital 
Discharge 
Comments 
Hepatorenal Syndrome 
(HRS) 
 
Type I HRS will be considered for SOC in accord 
with local practice, e.g., albumin/octreotide/midodrine 
or terlipressin/albumin regimen.  If treatment is 
initiated during Screening, eligible subjects can be 
randomized when stable and the regimen is continued 
during study. Treatment of Type II HRS is driven by 
the clinical needs of the subject. 
Renal replacement therapy may be useful in subjects 
who do not respond to vasoconstrictor therapy, and 
who fulfill criteria for renal support. 
VTL requires that subjects who develop Type I HRS 
after randomization but prior to the start of ELAD 
treatment as well as while on ELAD treatment must 
be discontinued from ELAD treatment and are to be 
continued on SOC. VTL also requires that subjects 
on ELAD treatment who require renal replacement 
therapy/hemodialysis are to be discontinued from 
ELAD treatment before renal replacement 
therapy/hemodialysis is started. 
 
 
Hyponatremia 
(sodium level lower than 
130 mmol/L) 
 
Hypovolemic hyponatremia is treated by stopping 
diuretics, and fluid administration as needed per 
clinical needs. Hypervolemic hyponatremia is treated 
with fluid restriction if practical. 
 
 
Spontaneous Bacterial 
Peritonitis 
All ascitic subjects will get 
paracentesis prior to 
Randomization (if not 
previously obtained within 
7 days of Randomization) 
If SBP is suspected, paracentesis is to be performed.  
Follow the algorithm: 
 IV ceftriaxone × 7 days or norfloxacin BID for 7 
days (or equivalent) in subjects who have GI 
bleeding. 
 Subjects surviving an episode prior to the study or 
had SBP was while in the study will start long-
term prophylaxis with daily norfloxacin (or 
trimethoprim-sulfamethoxazole or equivalent); if 
indicated, long-term antibiotic prophylaxis can be 
started at Randomization or following an 
episode of SBP occurring bet.  Study Day 1- 91. 
 Subjects with cirrhosis and ascites but no GI 
bleed are to start on long-term prophylaxis with 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
91 
Standards of Care 
(SOC) for Treated and 
Control Subjects 
Screening 
Randomization (Study Start) through 
Hospitalization 
Post Hospital 
Discharge 
Comments 
daily norfloxacin (or trimethoprim-
sulfamethoxazole or equivalent) if ascitic fluid 
protein is < 1.5g/dL and at least 1 of the 
following is present: serum creatinine ≥ 1.2 
mg/dL, blood urea nitrogen ≥ 25 mg/dL, serum 
sodium ≤ 130 mEq/L, and Child-Pugh ≥ 9 points 
with bilirubin ≥ 3 mg/dL. 
Thrombocytopenia 
 
For a platelet count < 20,000/mm3 without clinical 
manifestations of bleeding during study treatment 
(ELAD and Control) will receive platelet transfusions 
based on the judgment of the clinical team.  If the 
platelet count is < 20,000/mm3 and clinical 
manifestations of only localized contained bleeding, 
(ELAD and Control) subjects are to receive platelets.  
Subjects with platelet count of < 20,000/mm3 and 
generalized bleeding are to be promptly assessed, and if 
on ELAD, considered for treatment discontinuation. 
 
 
Nutritional Support 
 
Dietary consultations within 72 hours of 
Randomization. If not available, the Investigator 
must provide dietary/nutritional supervision. 
Continuous Dietary follow-up throughout and at 
discharge. 
Dietary to see at 
each follow-up visit 
 
ICU Discharge 
 
When physiologic status has stabilized or when 
physiological status has deteriorated and further 
interventions are not warranted. Subjects with 
alcohol withdrawal should receive ICU care until 
their detoxification stage has stabilized (i.e. absence 
of seizures and delirium requiring intense 
monitoring). They should be hemodynamically 
stable prior to discharge (i.e. not requiring intense 
monitoring for vasopressor admin or mechanical 
respiratory support). For discharge from the ICU, a 
general guideline is that the subject is no longer in 
need of vasopressors, mechanical ventilation, or 
continuous extracorporeal renal treatment. 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
92 
Standards of Care 
(SOC) for Treated and 
Control Subjects 
Screening 
Randomization (Study Start) through 
Hospitalization 
Post Hospital 
Discharge 
Comments 
Hepatic Hydrothorax 
 
First-line therapy of hepatic hydrothorax consists of 
dietary sodium restriction and diuretics while TIPS 
is considered to be second-line treatment when it 
becomes refractory. Chest tube insertion is 
contraindicated in a subject with hepatic 
hydrothorax. 
 
 
Post-Hospital Care 
 
Notify Home Visit Agency to arrange post-discharge 
visits 
Weekly home visits 
by outside agency 
 
 

Vital Therapies, Inc. 
 
ELAD® System 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
93 
 
Figure 2. 
Main Study Timeline 
 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
94 
Appendix A. West Haven Criteria 
The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven 
Criteria for semi-quantitative grading of mental status, referring to the level of impairment of 
autonomy, changes in consciousness, intellectual function, behavior, and the dependence on 
therapy. 
Grade 0: (Sub-clinical hepatic encephalopathy) – Lack of detectable changes in personality or 
behavior.  Minimal changes in memory, concentration, intellectual function, and 
coordination. Asterixis is absent. 
Grade 1: Trivial lack of awareness; Euphoria or anxiety; Shortened attention span;  
Impaired performance of addition. 67% of cirrhotic patients may have 'minimal hepatic 
encephalopathy'. 
Grade 2: Lethargy or apathy; Minimal disorientation for time or place; Subtle personality 
change; Inappropriate behavior; Impaired performance of subtraction. 
Grade 3: Somnolence to semi-stupor, but responsive to verbal stimuli; Confusion; Gross 
disorientation. 
Grade 4: Coma (unresponsive to verbal or noxious stimuli).  

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
95 
Appendix B. Tool for Determining Capacity to Consent 
 
Evaluation of Capacity to Consent to Participate in Research 
Subject Number: 
 
Date: 
 
Study: 
Study: VTL-308 “A Randomized, Open-label, Multicenter, Controlled Pivotal 
Study to Assess Safety and Efficacy of ELAD® in Subjects with Alcohol-induced 
Liver Decompensation (AILD)” 
Is Subject able to understand the nature and purpose of the study? 
 Yes   
 No 
Is Subject able to understand the risks and benefits of the study? 
 Yes   
 No 
Subject understands all that is required of him/her in this study? 
 Yes   
 No 
Subject is able to make an informed and rational decision regarding 
Participation? 
 Yes   
 No 
 
Comments: 
 
 
 
 
 
Based on the evaluation performed by: 
 
 
 
 
Clinician’s Name 
 
Subject Number 
Is deemed to have / not have (circle one) the capacity to provide consent for participation in this 
study. 
 
 
 
Clinician’s Signature 
 
Date 
 
 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
96 
Appendix C. EQ-5D-5L Quality of Life Questionnaire 
 
Health Questionnaire 
English version for the US 
(Other language versions are available from VTI as needed) 
 
 
SCRIPT FOR TELEPHONE INTERVIEW 
GENERAL INTRODUCTION 
It is suggested that the telephone interviewer follows the script of the EQ-5D. Although 
allowance should be made for the interviewer’s particular style of speaking, the wording of the 
questionnaire instructions should be followed as closely as possible. In the case of the EQ-5D 
descriptive system on page 2, the exact wording must be followed. 
It is recommended that the interviewer and respondent have a copy of the EQ-5D in front of 
them as it is administered over the telephone. This enables the respondent’s answers to be 
entered directly on the EQ-5D by the interviewer on behalf of the respondent (i.e. the appropriate 
boxes on page 2 are marked and the scale on page 3 is marked at the point indicating the 
respondent’s ‘health today’). If the respondent asks for clarification, the interviewer can help by 
re-reading the question verbatim. The interviewer should not try to offer his or her own 
explanation but suggest that the respondent uses his or her own interpretation. 
If the respondent has difficulty regarding which box to mark, the interviewer should repeat the 
question verbatim and ask the respondent to answer in a way that most closely resembles his or 
her thoughts about his or her health today. 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
97 
INTRODUCTION TO EQ-5D 
(Note to interviewer: please read the following) 
We are trying to find out what you think about your health. I will first ask you some simple 
questions about your health TODAY. I will then ask you to rate your health on a measuring 
scale. I will explain what to do as I go along but please interrupt me if you do not understand 
something or if things are not clear to you. Please also remember that there are no right or wrong 
answers. We are interested here only in your personal view. 
 
EQ-5D DESCRIPTIVE SYSTEM - PAGE 2: INTRODUCTION 
First I am going to read out some questions. Each question has a choice of five answers. Please 
tell me which answer best describes your health TODAY. Do not choose more than one answer 
in each group of questions. 
(Note to interviewer: it may be necessary to remind the respondent regularly that the timeframe 
is TODAY. It may also be necessary to repeat the questions verbatim.) 
 
EQ-5D DESCRIPTIVE SYSTEM - PAGE 2: TASK 
MOBILITY 
First I'd like to ask you about mobility. Would you say that: 
1. You have no problems walking? 
2. You have slight problems walking? 
3. You have moderate problems walking? 
4. You have severe problems walking? 
5. You are unable to walk? 
 
(Note to interviewer: mark the appropriate box on the EQ-5D questionnaire) 
 
SELF-CARE 
Next I'd like to ask you about self-care. Would you say that: 
1. You have no problems washing or dressing yourself? 
2. You have slight problems washing or dressing yourself? 
3. You have moderate problems washing or dressing yourself? 
4. You have severe problems washing or dressing yourself? 
5. You are unable to wash or dress yourself? 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
98 
(Note to interviewer: mark the appropriate box on the EQ-5D questionnaire) 
 
USUAL ACTIVITIES 
Next I'd like to ask you about your usual activities, for example work, study, housework, family 
or leisure activities. Would you say that: 
1. You have no problems doing your usual activities? 
2. You have slight problems doing your usual activities? 
3. You have moderate problems doing your usual activities? 
4. You have severe problems doing your usual activities? 
5. You are unable to do your usual activities? 
 
(Note to interviewer: mark the appropriate box on the EQ-5D questionnaire) 
 
PAIN/DISCOMFORT 
Next I'd like to ask you about pain or discomfort.Would you say that: 
1. You have no pain or discomfort? 
2. You have slight pain or discomfort? 
3. You have moderate pain or discomfort? 
4. You have severe pain or discomfort?  
5. You have extreme pain or discomfort? 
 
(Note to interviewer: mark the appropriate box on the EQ-5D questionnaire) 
 
ANXIETY/DEPRESSION 
Finally I'd like to ask you about anxiety or depression. Would you say that: 
1. You are not anxious or depressed? 
2. You are slightly anxious or depressed? 
3. You are moderately anxious or depressed? 
4. You are severely anxious or depressed?  
5. You are extremely anxious or depressed?  
 
(Note to interviewer: mark the appropriate box on the EQ-5D questionnaire) 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
99 
EQ VAS - PAGE 3: INTRODUCTION 
(Note for administrator: If possible, it might be useful to send a visual 
aid (i.e. the EQ VAS) before the telephone call so that they can have 
this in front of them when completing the task). 
 
Now, I would like to ask yu to say how good or bad your health is  
TODAY. 
I'd like you to try to picture in your mind a scale that looks a bit like a 
thermometer. Can you do that? The best health you can imagine is 
marked 100 (one hundred) at the top of the scale and the worst health 
you can imagine is marked 0 (zero) at the bottom. 
 
 
EQ VAS - PAGE 3: TASK 
 
I would now like you to tell me the point on this scale where you 
would put your health today. 
 
(Note to interviewer: mark the point on the scale at the point 
indicating the respondent’s ‘health today’) 
 
 
 
Thank you for taking the time to answer these questions. 
 
 
 
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health       
 you can imagine 
The worst health     
 you can imagine 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
100 
Under each heading, please check the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems walking   
 
 
 
 
I have slight problems walking  
 
 
 
 
I have moderate problems walking 
  
 
 
 
I have severe problems walking 
  
 
 
 
I am unable to walk 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
I have slight problems washing or dressing myself   
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself   
 
I am unable to wash or dress myself   
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
I have slight problems doing my usual activities  
 
 
I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
I have moderate pain or discomfort   
 
 
 
I have severe pain or discomfort  
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
I am moderately anxious or depressed  
 
 
 
I am severely anxious or depressed   
 
 
 
I am extremely anxious or depressed  
 
 
 
 
 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
101 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The worst health    
 you can imagine 
 
Best health you can 
imagine       
We would like to know how good or bad your health is  
TODAY. 
 This scale is numbered from 0 to 100. 
 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 Mark an X on the scale to indicate how your health is TODAY. 
 Now, please write the number you marked on the scale in 
the box below.  
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
102 
Appendix D. Clinical Trial Pharmacovigilance Investigator Guide 
Introduction 
The purpose of this document is to provide relevant background information and proposed 
criteria to determine whether an adverse event (AE) or serious adverse event (SAE) should be 
attributed to the VTL C3A cells (biologic), the ELAD System (device), or to the ELAD 
Procedure.   
ELAD-Related Adverse Events 
VTL C3A Cells in ELAD Cartridges: Overview 
The active drug product within the ELAD C3A cell cartridge are the VTL C3A cells, which are 
derived from a subclone of the human hepatoblastoma cell line HepG2. VTL C3A cells are 
monitored during the manufacturing process for the production of liver-specific proteins (e.g., 
albumin and transferrin) and for cell viability (oxygen utilization and glucose consumption).  
Oxygen utilization and glucose consumption by the VTL C3A cells are monitored closely during 
the course of patient treatment.     
The 0.2-µm hollow-fiber membrane that physically separates the VTL C3A cells from the 
patient ultrafiltrate allows diffusion of inflammatory cytokines, toxins, system source oxygen 
and system source glucose towards the VTL C3A cells and the simultaneous delivery of secreted 
macromolecules and other cellular products into the patient’s ultrafiltrate. 
Hepatocyte functions used to assess VTL C3A cell function include:  α-fetoprotein, albumin, 
factor V, monoethylglycine-xyliide (surrogate marker of cytochrome P450 enzyme activity), 
transferrin, transforming growth factor-α, and urea production; galactose and glucose 
consumption; oxygen utilization rate; and lactate production to glucose consumption ratio are 
displayed in the Investigator’s Brochure. Post-treatment ELAD cartridges maintained viability, 
made liver specific proteins, and metabolized galactose and lidocaine at levels similar to pre-
treatment ELAD cartridges containing VTL C3A cells released from manufacturing (see 
Investigator’s Brochure).   
The in-line cell filter (0.2-µm hollow fiber filter) prevents any VTL C3A cells that may have 
escaped from the ELAD cartridges from passing into subjects.  Histological examination of a 
sample of ELAD cartridges revealed no broken fibers (>50,000 observations).  
Adverse Events: VTL C3A Cells (Biologic) 
Adverse events (AEs) or SAEs that may be attributed to VTL C3A cells should be considered 
when there appears to be clinically-significant changes in hepatic function (synthesis, 
conjugation, and secretion) or allergic reactions while a subject is undergoing ELAD treatment.   
The following point should be noted when assessing changes in hepatic function while subjects 
are on ELAD treatment: 
 Increased levels of α-fetoprotein have been observed in ELAD-treated subjects 
in prior studies and are considered to be a surrogate marker of exposure of the 
plasma ultrafiltrate to VTL C3A cells. Levels of up to approximately 
10 × 107 ng/dL have been reported while subjects are on ELAD. 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
103 
Expected Adverse Events: VTL C3A Cells1 (Biologic) 
Based on a review of safety data from past clinical studies and investigator assessments of AEs 
in the VTI-208 study, the following AEs could potentially be related to VTL C3A cell function:  
Acidosis 
Coagulopathy 
Hypersensitivity 
Lactic acidosis 
Alkalosis 
Device occlusion 
Hypoglycemia 
Metabolic acidosis 
Allergic reaction 
Fungal infection 
Hypotension 
Pyrexia 
Anaphylactic reaction 
Hemolysis 
Increased ammonia 
levels 
Rash maculopapular 
Cartridge malfunction 
Hepatic enzyme increased 
Increased AST, ALT, 
and LDH levels 
Thrombocytopenia 
1 Listed alphabetically 
ELAD System (Device) 
ELAD System: Overview 
The current ELAD System, depicted in the Investigator’s Brochure, first draws blood from the 
subject via a dual-lumen catheter placed in a large vein using an extracorporeal pumping unit, 
and then separates the plasma fluid (ultrafiltrate) from cellular components by using a 
specifically-designed ultrafiltrate generator cartridge. While the cellular components are returned 
to the subject via the venous access, the ultrafiltrate is circulated at a high-flow rate through four 
metabolically-active ELAD cartridges. 
The cartridge that houses the VTL C3A cells contains approximately eight thousand hollow 
fibers made up of a semi-permeable polysulfone material that has a nominal pore size of 0.2-μm 
(Brotherton 2007). During ELAD treatment, an extracorporeal pumping system pumps the 
subject’s ultrafiltrate through the hollow fibers of the cartridge wherein the semipermeable 
membrane permits a bidirectional flow between the cells (grown between the hollow fibers) and 
the ultrafiltrate (contained in the lumen of the hollow fibers). Toxins, nutrients and dissolved 
oxygen pass from the ultrafiltrate to the cells, while the potentially-beneficial macromolecules 
and other substances synthesized by the cells simultaneously pass into the patient’s ultrafiltrate.   
After circulation through the cartridges, the ultrafiltrate passes through a 0.2-µm pore size filter, 
is recombined with the cellular components of the subject’s blood, and is returned to the patient 
through the dual-lumen catheter. The toxins metabolized by the VTL C3A cells are thereby 
returned to the subject to be excreted by the renal or gastrointestinal system. This circulation is 
maintained continuously for the duration of ELAD treatment, typically between three and 
five days. 
Adverse Events: ELAD System (Device) 
Adverse events should be attributed to the ELAD System when malfunctions of the bedside unit 
or contamination of catheters, tubing sets or filter components arise while the subject is 
undergoing ELAD treatment.  

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
104 
Expected Adverse Events: ELAD System1 (Device) 
Based on a review of safety data from past clinical studies and investigator assessments of AEs 
in the VTI-208 study, the following AEs could potentially be related to the ELAD System:  
Abdominal infection 
Coagulopathy 
Hypocalcaemia 
Pyrexia 
Activated partial 
thromboplastin time 
prolonged 
Catheter site haemorrhage 
Hypofibrinogenaemia 
Rectal haemorrhage 
Air embolism 
Disseminated 
intravascular coagulation 
Hypotension 
Thrombocytopenia 
Allergic reaction 
Haemorrhage 
Hypothermia 
 
Anemia 
Hemolytic anaemia 
Infection  
 
Anaphylactic reaction 
Hypersensitivity 
Lung Infection 
 
1 Listed alphabetically 
Note: Infection (contaminated ultrafiltrate cultures):  In one subject in study VTI-206, ultrafiltrate cultures taken 
from the ultrafiltrate lines before and after passage through the ELAD cartridge (but prior to the cell filter) 
grew out Streptococcus viridans and indicated bacterial contamination introduced during ELAD cartridge 
or other component replacement.  An SAE of sepsis occurred three days after stopping ELAD treatment 
and was considered to be possibly related to ELAD treatment (positive ultrafiltrate cultures); however, the 
causal role of the positive cultures in the sepsis was confounded by an episode of gastrointestinal bleeding 
(frequently associated with bacteremia) just before the onset of sepsis, concurrent clinically significant 
ascites associated with spontaneous bacterial peritonitis, and a urinary tract infection.  While it is possible 
that an infection in the ultrafiltrate loop might lead to a septic response in the subject due to transmission of 
exotoxin/endotoxin through the cell filter, it is highly unlikely that bacteria in the ultrafiltrate loop would 
lead directly to a positive blood culture due to the nominal pore sizes of the cell filter.  Blood cultures taken 
on the third day of ELAD treatment were negative. 
ELAD Procedure 
ELAD Procedure: Overview 
The ELAD Procedure is considered to occur while the subject’s blood is circulating through the 
ELAD System and also includes the time the subject is on the System when interruptions during 
treatment take place (due to switch out of the ELAD cartridges, clotting of catheters, replacement 
of catheters, etc.). 
Adverse Events: ELAD Procedure 
Adverse events should be attributed to the ELAD procedure when systemic events occur in 
subjects while their blood is being circulated through the ELAD System. Since usage of heparin 
during the ELAD procedure is based on the investigators’ clinical judgment and varied across 
prior studies, there is no distinction between the expected adverse events related to the ELAD 
procedure for those subjects who do or do not receive heparin. 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
105 
Expected Adverse Events: ELAD Procedure1 
Based on a review of safety data from past clinical studies and investigator assessments of AEs 
in the VTI-208 study, the following AEs could potentially be related to the ELAD procedure: 
Abdominal pain 
Coagulopathy 
Hyperglycaemia 
Metabolic acidosis 
Abdominal discomfort 
Device related infection 
Hyperkalaemia 
Mouth haemorrhage 
Abdominal distension 
Device related sepsis 
Hypernatraemia 
Multi-organ failure 
Acute respiratory distress 
syndrome 
Disseminated 
intravascular coagulation 
Hypersensitivity 
Oedema peripheral 
Agitation 
Ecchymosis 
Hypertension 
Oliguria 
Allergic reacton 
Edema 
Hypocalcemia 
Pain  
Anaemia 
Edema peripheral 
Hypocoagulable state 
Pneumonia 
Anuria 
Electrolyte imbalance 
Hypofibrinogemaemia 
Pulmonary oedema 
Application site bleeding 
Enecphalopathy 
Hypokalaemia 
Renal failure acute 
Ascites 
Epistaxis 
Hypomagnesaemia 
Respiratory arrest 
Asthma 
Fever 
Hypophospataemia 
Tachycardia 
Atrial fibrillation 
Fluid overload 
Hypotension 
Thromboctyopenia 
Bacteremia 
Gastrointestinal 
haemorrhage 
Hyopthermia 
Vessel puncture site 
haematoma 
Blood lactate 
dehydrogenase (LDH) 
increased 
Gingival bleeding 
Hypovolemia 
Wound secretion 
Blood pressure decreased 
Haematemesis 
Ileus 
 
Catheter site hematoma 
Haematuria 
Infection 
 
Catheter site hemorrhage 
Hemoglobin decreased 
Injection site 
haemorrhage 
 
Catheter site pain 
Hemolysis 
Ischemic hepatitis 
 
Catheter site reaction 
Haemorrhage 
Leukocytosis 
 
Coagulation disorder 
Hepatic encephalopathy 
Melaena 
 
Coagulation prolonged 
Hepatic failure 
Mental status changes 
 
1 Listed alphabetically 
 
Expected Adverse Events: Extracorporeal Procedures 
Certain adverse events are typically observed in patients undergoing treatment with 
extracorporeal procedures. Anemia, coagulopathy, and thrombocytopenia tend to be the most 
common adverse events observed during treatment with extracorporeal procedures. Specific 
details about each of these adverse events are presented in the following sections. 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
106 
Anemia 
Data from prior ELAD clinical studies (PS-0698; CR-202, VTIC-301, VTI-201, VTI-206 and 
VTI-208) indicate that hemoglobin levels tend to decrease after ELAD treatment is started. The 
reduced hemoglobin levels may be related to mechanical hemolysis, which is occasionally 
observed in patients undergoing other extracorporeal procedures (Boehning 2014). Patients with 
chronic liver disease may be predisposed to mechanical hemolysis during ELAD treatment due 
to abnormal RBC membranes, RBC membrane strength and durability, maintenance of RBC cell 
volume, and intermediary metabolism affecting RBC homeostasis. Anemia in the prior studies 
may also have been related to dilution, clotting in the catheters or dual-lumen, and stress during 
generation of the plasma ultrafiltrate. Additional information regarding anemia with 
extracorporeal procedures is provided in the Investigator’s Brochure. 
Coagulopathy 
Extracorporeal circulation increases the risk of hemorrhagic and thrombotic complications 
because blood is exposed to foreign non-endothelialized surfaces; cellular and acellular systems 
are activated/induced by exposure to foreign non-endothelialized surfaces and cause release of 
various intermediate products into the systemic circulation that induce hemorrhagic or 
thrombotic complications (Shann 2008). Patients with chronic liver disease have defective 
synthesis of coagulation factors (pro- and anti-coagulation factors) that can confound 
assessments of hemorrhagic and thrombotic complications observed in subjects undergoing 
ELAD treatment with or without concurrent anticoagulation. Additional information regarding 
coagulopathy with extracorporeal procedures is provided in the Investigator’s Brochure. 
Thrombocytopenia 
Thrombocytopenia is a potential side effect with extracorporeal procedures; the blood and 
dialyzer membrane interaction can cause significant thrombocytopenia through the activation of 
the complement (Olafiranye 2011). Thrombocytopenia in chronic liver disease patients 
undergoing ELAD treatment is confounded by concurrent coagulopathy, concomitant heparin 
use, and ongoing hypersplenism. Additional information regarding thrombocytopenia with 
extracorporeal procedures is provided in the Investigator’s Brochure. 
Clinically-Significant Laboratory Changes While on ELAD Treatment 
In general, laboratory changes in these critically-ill subjects should not be recorded as AEs. 
However in certain cases abnormal laboratory changes should be reported as AEs. The suggested 
laboratory values for hematology, serum chemistry, and urinalysis parameters that occur while 
the subject is on ELAD treatment that should be reported as AEs are listed in the Investigator’s 
Brochure.  
If the subject develops a laboratory abnormality meeting these criteria, a clinical diagnosis 
should be provided with the reported laboratory abnormality, if applicable. For example, if the 
subject developed hematuria in the presence of >1.0 g/dL of hemoglobin, hematuria should be 
listed as the clinical event and include in the details of the AE that a decrease in hemoglobin was 
associated with the hematuria. 
If the laboratory abnormality was not associated with a clinical event, the laboratory abnormality 
should be listed as an AE and indicate that no clinical findings were present. For example, 
hyponatremia is not usually associated with any specific clinical diagnosis but is found in 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
107 
subjects with clinically significant decompensated liver disease, so the specific diagnosis would 
not be included. 
The specific notable laboratory changes for hematology, serum chemistry, and the urinalysis 
while on ELAD to be reported as AEs are as follows: 
Hematology 
 Hemoglobin >1.0 g/dL decrease from Baseline in the absence of gastrointestinal 
bleeding or other clinically overt sources of bleeding (e.g., hematuria, central 
line bleeding) or hemoglobin levels <7.0 g/dL 
 WBC counts <1.5 × 103/mL in the absence of sepsis or an uncontrolled 
infection 
 Platelet counts <20,000 x 103/mL and note if there is evidence of impaired 
clotting or clinical bleeding or oozing 
 
Serum Chemistry 
 Abrupt (within 48 hours) reduction in kidney function defined as an absolute 
increase in serum creatinine of 0.3 mg/dL [≥26.4 µmol/L or increase of serum 
creatinine of 50% or more (1.5-fold) from baseline] 
 Hyperglycemia (serum glucose >350 mg/dL) 
 Hyperkalemia (serum potassium >7.0 mEq/L) 
 Hypocalcemia (serum calcium <3.5 mmol/L) 
 Hypoglycemia (serum glucose <50 mg/dL)  
 Hypokalemia (serum potassium <2.0 mEq/L)  
 Hypomagnesemia (serum magnesium <1.0 mEq/L)  
 Hyponatremia (serum sodium <120 mEq/L)  
 Hypophosphatemia (serum phosphate <0.3 mmol/L)  
 Lactate >4 mmol/L  
 
Urinalysis 
 Presence of significant increase in RBCs in the urine not related to the subject’s 
renal disease, Foley catheters, etc.  
 Urine hemoglobin levels of 3+ or 4+, if not present at these levels at Baseline 
Expected Adverse Reactions for ELAD Treatment 
According to the literature and previous protocols using either artificial or bio-artificial liver 
support systems, AEs in the following five categories might be expected to be encountered 
during treatment. 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
108 
General Risks of Fractionated Plasma Filtration 
 Higher risk of bleeding due to anticoagulation and/or unfavorable effects on the 
coagulation system. Specifically, in liver failure subjects, where hemostasis is 
disturbed, the use of plasma filtration or dialysis can precipitate bleeding. 
 Hypotension 
 Acute transient complement activation, leukopenia, thrombocytopenia, 
eosinophilia 
 Hemolysis due to mechanical destruction of RBCs during whole blood 
perfusion through the ultrafiltrate generator  
 Clotting within the extracorporeal blood circuit and in the ultrafiltrate generator 
 Hypersensitivity: for example, an acute reaction may be observed similar to that 
known as first use syndrome reaction observed in patients undergoing dialysis 
 Loss of valuable substances, including proteins, hormones, nutrients, 
electrolytes due to either dilution or binding to components of the tubing set  
 Temperature disorders (e.g. hypothermia) (Biggers 1977; Chiu 2006; 
VitaGen, CR-202 CSR, 2004). 
General Risks Associated With Using Heparin-Based Anticoagulation  
 Heparin-induced thrombocytopenia 
 Bleeding due to heparin (Hirsch 2001) 
General Risks Associated With Using Central Venous Catheters 
The general risks associated with central venous catheters may occur during insertion, while they 
are indwelling, and during extraction (Kusminsky 2008). 
 Insertion complications (pneumothorax, malpositioning, vascular injuries, 
dysrhythmias, neurological complications, lymphatic complications, and guide 
wire loss) 
 Indwelling complications (infection, thrombosis, occlusion, vascular erosion 
and perforation, as well as catheter fracture and embolization  
 Extraction complications (air embolism, catheter breakage or separation from 
hub, and catheter knotting) 
General Risks Associated With Administration of Albumin  
 Rash/allergic reactions 
 Hypotensive episodes/shock 
 Fever 
 Risk of transfusion-associated infections 
 Disturbances of plasma protein pattern with associated consequences, such as 
hyper- or hypocoagulability, immunodysfunction, and renal tubular injury 
(Torchia 2000; Albumin (Human) 5%) 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
109 
Specific Risks Associated With Cellular Therapy 
In addition to the general risks of liver support systems described above, specific risks are 
theoretically possible in using biological systems containing cells (Tsiaoussis 2001): 
 Hypoglycemia 
 Changes in levels of substances either made by or metabolized by the cells  
 Metabolic acidosis/alkalosis 
 Theoretical risk of tumor formation 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
110 
References 
Albumin (Human) 5%, Product Information. Octapharma Pharmazeutika, 02 October 2006. 
(http://www.fda.gov/downloads/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/li
censedproductsblas/fractionatedplasmaproducts/ucm056844.pdf ; verified 19 March 2014). 
Biggers JA, Remmers AR, Glassford DM, Sarles HE, Lindley JD, and Fish JC. The risk of 
anticoagulation in hemodialysis patients. Nephron, 1977; 18(2), 109-113. 
Boehning F, Mejia T, Schmitz-Rode T, Steinseifer U. Hemolysis in a laminar flow-through 
Couette shearing device: an experimental study. Artif Organs, 2014 Sep;38(9):761-5. 
Brotherton J, He D, Asslani S, Millis JM. ELAD Cellular and System Performance 
Improvements. Hepatology, 2007; 46:4:615A. 
Chiu A and Fan ST. MARS in the treatment of liver failure: controversies and evidence. Int J 
Artif Organs, 2006; 29(7), 660-667. 
Hirsh J, Anand SS, Halperin JL, Fuster V, and American Heart Association. AHA Scientific 
Statement: Guide to anticoagulant therapy: heparin: a statement for healthcare professionals from 
the American Heart Association. Arterioscler Thromb Vasc Biol, 2001; 21(7), E9-9. 
Investigator’s Brochure (on File) 
Kusminsky RE. Complications of central venous catheterization. J Am Coll Surg 2007; 
2004:681-696. 
Olafiranye F, Kyaw W, Olafiranye O. Resolution of dialyzer membrane-associated 
thrombocytopenia with use of cellulose triacetate membrane: a case report. Case Rep Med. 2011; 
2011:134295. 
Rocha E, Llorens R, Paramo JA, Arcas R, Cuesta B, and Trenor AM. Does desmopressin acetate 
reduce blood loss after surgery in patients on cardiopulmonary bypass? Circulation, 1988; 77(6), 
1319-1323. 
Shann KG, Giacomuzzi CR, Harness L, Myers GJ, Paugh TA, et al. Complications relating to 
perfusion and extracorporeal circulation associated with the treatment of patients with congenital 
cardiac disease: consensus definitions from the Multi-Societal Database Committee for Pediatric 
and Congenital Heart Disease. Cardiol Young, 2008; 18 Suppl 2, 206-214. 
Torchia MG and Danzinger, RG. Perioperative blood transfusion and albumin administration are 
independent risk factors for the development of postoperative infections after colorectal surgery. 
Can J Surg, 2000; 43(3), 212-216. 
Tsiaoussis J, Newsome PN, Nelson LJ, Hayes PC, and Plevris JN. Which hepatocyte will it be? 
Hepatocyte choice for bioartificial liver support systems. Liver Transpl, 2001; 7(1), 2-10.  
VitaGen, Inc. CR 202 Phase 2 Clinical Study Report. Phase 2 Evaluation of the VitaGen 
Extracorporeal Liver Assist Device (ELAD) System in the Management of the Patients with 
FHF. May 2004. 
 

Vital Therapies, Inc. 
 
ELAD® 
VTL-308 Protocol Amendment 1 
D4010-308 
CONFIDENTIAL 
111 
Appendix E. Anticoagulation Guidelines for the VTL-308 Study 
Anticoagulation Guidelines During ELAD Treatment 
In general, standard anticoagulation protocols of the Investigational institution for the 
administration of extracorporeal procedures should be applied during the administration of 
ELAD treatment. However, there may be a requirement for more rigorous monitoring.  
As a general guideline, subjects who are administered ELAD that have a baseline PTT of <50 
seconds or an activated clotting time (ACT) of <150 seconds may require heparin in order to 
prevent rapid clotting in the ELAD extracorporeal blood circuit.  In such cases, the initial dose 
applied may be as small as 200-400 Units of non-fractionated heparin per hour into the arterial 
line of the blood circuit, and a control sample should be taken within 1 hour of initiation of 
heparin treatment in order assess the impact of the heparin dosing on coagulation status.  If the 
PTT is >80 seconds, or the ACT is >200 seconds, the dose should be reduced, e.g. by half and a 
control sample should be taken within 1 hour of the adjustment of the heparin dose. If the PTT is 
still <50 seconds and the ACT is still <150 seconds, the dose should be increased, e.g. doubled 
and a control sample should be taken within 1 hour of the adjustment of the heparin dose.  
The goal is to maintain PTT between 50 and 80 seconds or the ACT between 150 and 200 
seconds in the case of non-fractionated heparin use. 
For alternative anticoagulants, such as hirudin, or fractionated heparin, institutional protocols for 
CVVH therapy may be applied, but must be monitored rigorously.  
CITRATE MUST NOT BE USED as an anticoagulant during ELAD treatment. 
A formal heparin-based protocol for extracorporeal therapy of liver patients can be found in an 
article by Hillebrand et al1. 
 
 
                                                 
 
1. 
Hillebrand, et al. Formal heparin anticoagulation protocol improves safety of charcoal-based liver assist devices. ASAIO J. 
2006 May-Jun;52(3):334-42.