A Multi-Center Trial to Study Acute Liver Failure in Adults
Conditions: Acute Liver Failure, Fulminant Hepatic Failure, Acute Liver Injury
Sponsor: William Lee

 
 
 
 
 
 
 
 
 
 
 
 
A Multi-Center Group to Study Acute Liver Failure 
 
 
 
 
Version 7.0 
 
 
April 1, 2016 
 
 
 
 
Principal Investigator: William M. Lee, M.D. 
 
Clinical Coordinating Center:  UT Southwestern Medical Center at Dallas 
 
5959 Harry Hines Blvd. 
POB1, Suite 420 
Dallas TX 75390-8887 
(214) 645-6110 
fax: (214) 645-6198 
 
email: William.Lee@UTSouthwestern.edu 
 
 
 
 
Data Coordination Unit: Medical University of South Carolina 
 
Director: 
Valerie Durkalski, PhD 
135 Cannon St, Ste 303 
MSC 815 
Charleston, SC 29425-8150 
(843) 876-1911 
fax: (843) 876-1923 
email: durkalsv@musc.edu 
 
 
 
 
National Clinical Trial Identified Number:  NCT00518440 
NCT # added to cover sheet on 13Jan2022 
 

ALF Protocol 7.0, p.  2 
 
 
 
 
A.  SPECIFIC AIMS ................................................................................................................................ 3 
B. BACKGROUND AND SIGNIFICANCE........................................................................................... 4 
C. STUDY MECHANICS ....................................................................................................................... 6 
D. INSTITUTIONAL REVIEW BOARD ............................................................................................. 10 
E. CONFIDENTIALITY........................................................................................................................ 11 
F. INCLUSION OF WOMEN AND MINORITIES .............................................................................. 12 
G. STATISTICAL ANALYSIS ............................................................................................................. 12 
G. REIMBURSEMENT ......................................................................................................................... 12 
H. REFERENCES .................................................................................................................................. 12 

ALF Protocol 7.0, p.  3 
 
 
 
A.  SPECIFIC AIMS 
 
 
 
Acute liver failure (ALF) is a dramatic syndrome in which previously healthy 
individuals rapidly lose hepatic function due to a variety of causes, develop 
hepatic encephalopathy, and become critically ill within days.  The mortality is 
high, up to 94%.   Even in the era of liver transplantation, more than 40% die, 
either due to complications of this devastating disease or because donor organs 
are not available.  Since ALF occurs relatively infrequently, no one center in the 
US has a large enough experience to conduct important studies of this condition. 
The Acute Liver Failure Study Group had received funding from the National 
Institutes of Health (NIH) from September 1997 through August 31, 2005 under 
grants R03 DK52827 and R01 DK58369. In September of 2005, the study 
received funding through August 31, 2010 under a cooperative U01 agreement. 
ALFSG is currently funded by a continuation of this same U-01 cooperative 
research agreement through 2020, and currently involves 12 sites in the 
United States and Canada.  Our initial goals were to develop a multi-center ALF 
study group initially at liver transplant centers around the United States, with the 
broad aims of 1) gathering data and serum on ALF patients, and 2) developing a 
pilot therapy trial of N-acetylcysteine (NAC) for ALF  and  these  have  largely  
been  accomplished.  Clinical  data  and  serum collected since January 1, 1998 
on over 2,500 carefully defined patients have yielded new insights into the natural 
history and outcomes of ALF.  One important trend has been an apparent 
increase in the number of patients with drug-induced acute liver failure, which 
currently represents >50% of all cases. The unique availability of blood and 
tissue samples from a large number of patients with ALF has triggered more 
than 140 ancillary studies, generated over 70 original articles on all aspects of 
ALF. An addition in 2009 was the Acute Liver Injury (ALI) study, capturing earlier 
stage disease, prior to the onset of encephalopathy and advanced liver failure. 
 
 
 
The specific aims of the study listed are below: 
 
Specific Aim 1: To continue and extend the current highly successful registry 
tracking secular trends in ALF, with several added features: a tighter study group, 
continuation of the ALI study, more detailed data and specimen gathering on each 
case, electronic data capture, and use of detailed check lists for ICU management,. 
Emphasis will be placed on gathering tissue samples for mechanistic studies and 
detailed intensive care unit (ICU) data while improving prognostic scoring systems. 
 
Specific Aim 2: To further elucidate the pathogenesis of liver injury and multi- 
organ failure. We continue to undertake studies of basic mechanisms of the innate 
and adaptive immune responses, the role of genetic predisposition, cytokines, 
coagulation, endothelial dysfunction and hepatic regeneration that initiate, sustain 
and resolve ALF. 
 
Specific Aim 3: To evaluate the safety and efficacy of new prognostic and 
therapeutic agents in the management of ALF and ALI. 
 
B. BACKGROUND AND SIGNIFICANCE 
 

ALF Protocol 7.0, p.  4 
 
B.1. Introduction: Historical perspective. Acute liver failure (ALF) was first 
recognized as a specific and unique entity in the early 1950’s. Defined as including 
coagulopathy and encephalopathy, cerebral edema is a unique feature of acute 
liver failure that frequently leads to death.1,2 Survival has improved in recent years 
from <10% to ~60% due in part to the use of liver transplantation and an evolution 
to more benign etiologies. Even now this catastrophic illness can progress within 
hours to coma and death due to multi-organ dysfunction.3,4 We estimate that 24% 
of those listed for transplantation die because a liver graft cannot be found in time. 
Although ALF is truly an orphan disease affecting only about 2,000 persons per 
year,5 its severity, its frequency among young adults, and its high resource 
utilization justifies the attention paid to it. In addition, ALF has captured the interest 
and attention of researchers because of its unique pathogenesis and extreme 
severity, encouraging us to understand the processes underlying all forms of liver 
injury, by focusing on this most lethal manifestation. 
 
Acute Liver Injury (ALI), a milder form of ALF: Patients with ALF represent the most 
severe end of a spectrum of advanced liver injury. A second group of patients 
worthy of study are those with acute liver injury who have coagulopathy but do not 
reach the threshold of encephalopathy. Few studies have been performed on this 
less severe group; however, their morbidity and mortality may approach that of 
conventionally defined ALF.6  It would be of value to study patients destined to 
possibly have ALF earlier in their illness for several reasons: first, we might be able 
to better predict who will progress to full liver failure; second, the current definition 
requiring encephalopathy limits the number of patients available for study at any 
site; finally, therapeutic trials might have greater efficacy if begun at earlier disease 
stages.  
 
B.2. Prior studies in ALF: Specific Etiologies. Early reports of acute liver failure 
were limited to small series from individual centers over many years. The lack of 
specific serologic tests led to most cases being attributed on clinical grounds to 
viral hepatitis,2,5 with hepatitis B as the most common cause. Early on, no 
hepatitis A or acetaminophen toxicity cases were recognized.  In the 60’s through 
the 1980’s, the etiologic makeup of ALF was unclear, in part because of lack of 
accurate diagnoses, but also because there was no central ALF registry. Our 

ALF Protocol 7.0, p.  5 
 
 
 
initial report of 295 patients seen between 1994 and 1996 at the 14 initial Acute 
Liver Failure Study Group (ALFSG) centers was the first systematic multi-center 
review of etiologies and outcomes. That study identified acetaminophen toxicity 
as present in 20% of ALF patients.7 The etiologies associated with ALF have 
continued to change further over the years with an apparent decline in viral 
hepatitis, and a remarkable increase in acetaminophen toxicity to its current level 
of ~44-50% of cases.8,9   A further problem in studying ALF is that the number of 
cases of a specific etiology observed at any one institution are vanishingly small. 
The earliest goals of the ALF Study then were to more carefully define the 
etiologies of ALF on a national scale, and to finally allow in-depth study of 
specific ALF causes such as autoimmune ALF, viral hepatitis and Wilson disease 
(WD). 
 
B.3. Outcome in Acute Liver Failure and the Role of Transplantation: Despite the 
diverse etiologies recognized, the final clinical common pathway of acute liver 
failure is remarkably similar across all patient groups. Coagulopathy, 
encephalopathy and cerebral edema constitute a hallmark triad, but hypotension 
and renal insufficiency, susceptibility to infection and other multi-organ system 
failure are typically observed as well. Causes of death include cerebral edema, 
multi-organ failure, sepsis, cardiac arrhythmia or respiratory failure. Factors 
associated with prognosis, scoring systems and analysis of intensive care prior 
to transplant—all these features of ALF have been exceedingly difficult to study 
at a single institution. The short-term survival of patients after transplantation is 
said to be less than that of patients with cirrhosis, presumably due to the severity 
of illness and the emergent nature of the surgery performed, but specific studies 
of post-transplant outcomes have not been available previously. In the US, under 
the authority of the United Network of Organ Sharing (UNOS) criteria, acute liver 
failure remains the only criterion for the most urgent listing category, status 1. 
However, data regarding ALF provided by the UNOS registry have been limited 
since UNOS’ focus is directed toward transplantation and not to the underlying 
diseases prior to transplantation. We have recently published an analysis of the 
outcomes of patients with ALF listed for transplantation, indicating that etiology of 
ALF governs outcomes both with and without transplantation.10 
 
B.4. Therapeutic Trials: Prior to 1998, therapeutic trials in ALF were limited to 
those performed at a single center, Kings College Hospital in the United Kingdom 
(UK). Only one multi-center US therapy trial in ALF had taken place: steroid 
therapy was tested for fulminant hepatitis B in the 1970’s and its negative results 
finally reported in 1991.11 A multi-center trial using a bio-artificial assist machine 
(BAL) sponsored by the manufacturer was published in 2004.12  While the BAL 
study yielded negative results and has flaws, the authors encountered many of 
the difficulties inherent in the design and execution of a controlled trial for this 
rare condition. 
 
B.5. Summary of the Past: Research in acute liver failure in the US prior to the 
ALFSG remained limited due to lack of a coordinated effort.  Much of the data 
concerning ALF came either from London or from single US sites over many 

ALF Protocol 7.0, p.  6 
 
 
 
years time, were not necessarily representative of the overall United States’ 
experience and few therapy trials were performed. 
 
 
 
C. STUDY MECHANICS 
 
The virtue (and difficulty) in studying acute liver failure is that the syndrome 
evolves rapidly and the outcome is known quickly (either death, survival, or 
transplantation occur within one to three weeks in most cases).  Most study 
patients will be cared for in an intensive care unit setting.  The key to accurate 
and complete data collection is rapid accession of all eligible patients into the 
study. Both for data and bio-sample collection purposes, and particularly for 
therapeutic trials, late study entry will skew results, and may preclude inclusion of 
patients. 
 
C.1.   Study monitors/site visits/marketing. Monitoring visits to the sites are 
undertaken by the Clinical Coordinating Center PI and coordinator at intervals of 
about one and a half years, providing support for the investigators and 
coordinators and quality control with regard to data collection and the therapeutic 
trial. Source documents are reviewed for accuracy and further data queries 
submitted. The study has a Website, acuteliverfailure.org, as well as providing 
patient information brochures in lay language.  
 
C.2.   Governance. The Clinical Coordinating Center PI provides overall 
supervision with a multiple PI leadership team, an Executive Committee, 
Ancillary Studies and Publications committees actively participating. We have 
face-to-face meetings at AASLD, DDW and, most important, a 1-1/2 day fly-in 
meeting each year to review study progress, and aspects of ALF. We have 
monthly teleconferences to update coordinators and site investigators and 
encourage enrollment. 
 
C.3.  Eligibility Criteria: Our present system provides that when a patient with 
suspected acute liver failure arrives at a study site, the local site investigator or 
his coordinator is promptly notified. The patient is evaluated and a determination 
is made as to whether he or she qualifies for the data and serum collection 
portion of the study. Criteria for ALF to enter a patient to the study must include 
altered mentation of any degree, evidence of moderately severe coagulopathy 
(INR ≥ 1.5) and a presumed acute illness onset of less than 26 weeks.  No 
patients with cirrhosis should be included in the study. 
 
C.4.  A separate category of patients may also be enrolled that have Acute Liver 
Injury (ALI) and meet the following criteria: 
1) Hospitalized patient 
2) If presumed acetaminophen etiology: acute hepatic illness < 2 weeks, with 
INR ≥ 2.0, alanine aminotransferase (ALT) of ≥ 10X ULN. 

ALF Protocol 7.0, p.  7 
 
 
 
3) If presumed non-acetaminophen etiology: acute hepatic illness of < 26 
weeks, with INR ≥ 2.0, ALT of ≥ 10X ULN, total bilirubin of ≥ 3.0 mg/dL. 
 
C.5.  Screening. A screen failure log is entered monthly into WebDCUTM  at each 
enrolling site, documenting demographic information and the reasons for failure to 
enroll. These are principally related to inability to  obtain informed consent (or 
refusal presence of liver failure without evident encephalopathy lack of available 
next of kin or ‘other’—transplanted before patient could be enrolled, for example. 
 
C.6.   Informed Consent:    When a patient is identified at a study site, the site 
Principal Investigator (PI) obtains separate informed consents for the data/blood 
and urine/tissue registry and DNA (up to 2 consents total).  Informed written 
consent from the patient's next of kin (since by definition, patients enrolled in the 
study will not have normal mental functioning) is required for data and specimen 
collection (7 days of serum, first day urine and plasma samples and liver tissue 
where available). A separate consent is required for collection of a DNA 
specimen.   A copy of the consent(s) shall be given to the person signing the 
form. The consent form must embody the legally required elements of informed 
consent. The site investigator shall give the patient’s representative adequate 
time to read the form prior to signature. The subject or the next of kin can 
withdraw the subject from the study at any time, and this decision will not 
influence  the  treatment  otherwise  offered.  A  copy  of  the  data  and  serum 
collection consent must be placed in the medical chart and the original securely 
kept in the study files. The DNA consent should not be filed in the medical chart 
but stored securely in the study files. 
 
C.6.a. Patients meeting criteria for ALI, by definition, do not have encephalopathy 
and can therefore sign their own consent forms. If any doubt exists about mental 
status, then they are considered to have ALF and require consent by next of kin. 
Patients that meet criteria for ALI and subsequently become encephalopathic are 
considered to have consented for the entire study.  If this occurs, the subject 
becomes enrolled in the ALF study. The first day that ALF criteria are reached 
becomes day 1 for ALF enrollment. 
 
It is not anticipated that any special groups will be enrolled in the study in any 
proportion other than those representative of the US population. However, 
vulnerable   groups   such   as   prisoners   may   be   enrolled   under   special 
circumstances if approval has been sought and obtained by the site and its 
Institutional Review Board (IRB). In the case of cognitively impaired individuals, 
the next of kin or guardian will serve as the responsible party for consent 
purposes. The NIH guidelines on the inclusion of women and minorities as 
patients in clinical research will be observed. Emergency consent procedures will 
be invoked, if prior approval for such is obtained from the site’s IRB. 
 
C.7.  Overall  Subject  Management:  A  detailed  standardized  management 
protocol is available at each site (see reference 13). This protocol has been 

ALF Protocol 7.0, p.  8 
 
 
 
approved by the principal investigators at each site as representing best current 
practice for patients with ALF. Several additional articles have outlined 
established 
expert 
opinion 
in 
this 
orphan 
disease 
area 
regarding 
management.14,15  In addition, ALFSG has performed clinical trials of the use of 
N-acetylcysteine for non-acetaminophen acute liver failure,16 and is currently 
undertaking a trial of OCR-002, ornithine phenylacetate, for the treatment of 
elevated ammonia levels in the ALF setting. 
 
C.8. Data collection:  Every effort has been made to streamline data accession and 
entry.  Data is entered electronically into the study database at the enrolling sites. 
The study database, called WebDCUTM, is developed and maintained by the Data 
Coordination Unit at the Medical University of South Carolina (MUSC). As data is 
submitted, the principal investigator or designee and data managers review the 
data, and generate queries to resolve discrepancies. 
 
After informed consent, the site investigator must detail all aspects of study 
admission, history, physical exam, lab data and clinical course, including the 
presumed diagnosis, applying standard criteria. The details of patient history are 
often lacking in these very ill referral patients where, by definition, mental changes 
must have occurred to be included in the study. 
 
A defined set of clinical measurements will be available to the site investigator 
largely done as standard of care for acute liver failure: complete blood count, 
chemistry profile including aminotransferases, alkaline phosphatase and bilirubin; 
coagulation studies including prothrombin time and activated partial thromboplastin 
time, electrolytes, calcium, magnesium, phosphorus and acetaminophen levels. 
Serologic studies for acute hepatitis A, B, C and HIV, ceruloplasmin levels, and a 
drug screen to include cocaine, opiates and barbiturates will be performed. 
Demographic data, medical history and data influencing etiology including drug and 
alcohol intake, all pharmaceutical agents, herbals and other xenobiotics ingested in 
the prior six months will be recorded. 
 
Data  collection  for  cases  of  ALF  or  ALI  related  to  acetaminophen  poisoning 
includes a two-part questionnaire that the subject may be asked to respond to, 
once they begin to recover. Once medically stable, these patients may be 
approached by study personnel and asked to provide informed consent to answer a 
detailed questionnaire regarding use of acetaminophen prior to hospitalization, a 
diagnostic screen for psychiatric illnesses, symptom severity score for depression, 
and a short impulsivity scale. There will be no additional collection of bio-samples 
for these patients. 
 
Data will be collected through Day 7 unless the patient undergoes transplantation, 
dies or is discharged from the hospital. At Day 21, patients will be contacted by 
study personnel to determine vital status. 
 
 
 
 
 
C.9.  Bio-sample collection: 
 
C.9.a.  Serum:  Daily serum samples (two 10 ml serum separating tubes) are 

ALF Protocol 7.0, p.  9 
 
collected starting on the first day of study for up to 7 days, aliquoted in 500 µL 
aliquots and stored at –800  for later shipment to the central repository. If there is 
difficulty collecting samples, existing serum that has been refrigerated for clinical 
purposes can be used.   The serum is aliquoted to provide multiple samples for 
each time point. If an ALI subject develops encephalopathy (qualifies as having 
ALF) then collection begins again as study day 1 of ALF study, continuing for a 
total of no more than 14 days.  
 
C.9.b.  Plasma:  A single 10 ml blood sample will be obtained on study admission 
in EDTA and / or citrated tubes, and the plasma separated, aliquotted in similar 
fashion to serum, marked clearly as plasma, and stored at –80o prior to shipment 
to the Repository.  However, if an ALI subject develops encephalopathy (qualifies 
as having ALF) a second plasma sample will be collected. 
 
C.9.c.  Urine:  Ten ml of urine is to be collected on the day of study admission or 
the following day, to be aliquotted in 1 ml aliquots stored at –80o and shipped with 
other  samples  to  the  Repository. 
However,  if  an  ALI  subject  develops 
encephalopathy (qualifies as having ALF) a second urine sample will be collected. 
These samples (serum, plasma and urine) are labeled with sample specific pre- 
printed labels containing: the NIDDK site number, the ALF site number, subject 
EDC ID number (generated by WEBDCU upon enrollment), and collection date. 
They are stored at -80º and batch shipped Monday thru Wednesday to the NIDDK 
Repository  at  approximately  3-month  intervals  depending  on  the  quantities 
involved. 
 
C.9.d.  Tissue:  Liver tissue samples in the form of stained /unstained slides, frozen 
tissue, and blocks are to be sent to the NIDDK Repository from all patients who 
have  a  liver  biopsy,  liver  transplant  or  autopsy.  Frozen  tissue  should  be 
accessioned where possible at the time of explantation. 
 
In the case of an explant, we suggest that 10-20 g of liver tissue be collected for 
storage at -80º and sectioned in special 10 ml cryovials provided by the NIDDK 
repository. The liver tissue should be shipped frozen with other bio-samples or 
separately as needed on dry ice to the NIDDK Repository. 

ALF Protocol 7.0, p.  10 
 
 
 
 
C.4.f.  DNA:  Samples are to be collected only after the special separate DNA 
consent has been signed.   The separate consent is necessary because of the 
more complex issues surrounding archiving DNA.  Only a single time point draw is 
necessary to collect the blood for extraction of DNA that can be archived for future 
DNA tests.  This should be collected on all patients when possible; however, those 
of particular interest include suspected drug toxicity, indeterminate cases and 
acetaminophen toxicity cases.  Archiving DNA samples provides a unique source 
of information regarding ALF that can only be obtained from DNA - many of the 
tests for this aspect of the study are only now being developed, but should provide 
totally different body of knowledge in the future. 
 
The logistics for obtaining the DNA sample necessitate drawing the blood at only 
one time point, on a Monday, Tuesday or Wednesday, using at least two 10 ml 
lavender top (EDTA) tubes which must be shipped overnight at ambient 
temperature, by Fed Ex to UTSW ALFSG DNA processing core.  A shipment 
notification email must be sent to:  ALFDNA@UTSouthwestern.edu 
on the day  of  shipment to notify UTSW.  DNA samples can be collected at any 
time and need not be drawn on the first hospital day. The extracted DNA will be 
shipped from UTSW to the central NIDDK repository in batch shipments. 
 
C.10.  Subject Withdrawal:  It is the right of the subject’s family or next of kin or 
the physicians caring for each subject to discontinue from the study at any time. 
Data and samples collected before discontinuation should be maintained if there 
is no objection.   Progression to liver transplantation, intubation, placement of 
intra-cerebral pressure monitoring devices or other standard of care procedures 
should be unaffected by study participation. 
 
 
 
 
D. INSTITUTIONAL REVIEW BOARD 
 
The Institutional Review Board (IRB) at the Clinical Coordinating Center and at 
each study site must provide a current approval for the study to proceed.   No 
subject enrollment can occur before IRB approval has been obtained at that site. 
The Clinical Coordinating Center and the Principal or Site Investigator will assure 
that an appropriately constituted IRB, that complies with the requirements of 21 
CFR 56, will be responsible for the initial and continuing review approval of the 
clinical study at each individual site.  A photocopy of the site's IRB approval and 
consent form must be forwarded to the Clinical Coordinating Center. 
 
The Clinical Coordinating Center will also assure that the sites will promptly 
report  to  the  IRBs  concerned  all  changes  in  the  research  activity,  all 
unanticipated problems involving risks to human subjects or others, and that 
he/she will not make any changes in the research without IRB approval except 
where  necessary  to  eliminate  apparent  immediate  hazards  to  the  human 

ALF Protocol 7.0, p.  11 
 
 
 
subjects.  For minor changes to previously approved research, it may be possible 
for the site investigator to obtain an expedited review by IRBs as allowed for 
under 21 CFR 56.110. 
 
As part of the IRB requirements for continuing review of approved research, the 
Clinical Coordinating Center and Site Investigator will be responsible for 
submitting periodic progress reports to the IRBs at intervals appropriate to the 
degree of patient risks involved but no less than once per year.  Copies of all 
correspondence between the site investigator and the site IRB indicating its 
continued approval of this study or the withdrawal of such approval must be 
forwarded immediately to the Clinical Coordinating Center. 
 
E. CONFIDENTIALITY 
E.1. Each subject is automatically assigned a unique subject ID number by 
WebDCUTM at the time of enrollment.     All electronic CRF data is housed on 
secure servers at the Data Coordinating Center located at the Medical University 
of South Carolina in Charleston, SC. Every effort is made to protect the identity 
of the subject and his samples. 
 
 
E.2. The ALFSG has obtained a Certificate of Confidentiality to provide special 
privacy protection for each subject enrolled.  A copy of the certificate should be 
on file at your site.   This privacy protection means that the subject will not be 
identified as participating in the study, unless he or she consents, or if it is 
necessary to reveal the information in order to protect the subject or another from 
serious harm, as in cases of child abuse. 
 
Data that are protected by a Certificate of Confidentiality may be disclosed under 
the following circumstances: 
 
• Voluntary   disclosure   of   information   by   study   participants   themselves   to 
physicians or other third parties, or authorization by study participants of release 
of information to insurers, employers, or other third parties. 
 
• Voluntary reporting by the investigator of information, such as child abuse or 
threat of other potential violence by the study participant to the participant or 
others, provided such intention is specified in the informed consent document. 
 
• Voluntary compliance by the researcher with reporting requirements of other 
state laws such as knowledge of a communicable disease, provided such 
intention is specified in the informed consent document. 
 
• Release  of  information  by  investigators  to  Department  of  Health  &  Human 
Services (DHHS) as required for audits of research records or to the Food and 
Drug Administration (FDA) as required under the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. § 301 et seq.). 

ALF Protocol 7.0, p.  12 
 
 
 
F. INCLUSION OF WOMEN AND MINORITIES 
 
Acutely ill ALF patients are not amenable to conventional recruitment methods. 
They are evaluated on admission in the ICU setting without consideration of race 
or gender.   In our retrospective study, patients were nearly equally divided 
between the sexes, although there are more women (74%) than men in the 
current prospective study.  There is no preponderance of any racial group, other 
than that represented by specific hospital populations.   No exclusion will be 
made on the basis of race, ethnic group or gender.  Criteria for inclusion of 
women and minorities will be those established in the NIH guidelines. 
 
G. DATA ANALYSIS 
 
The collected registry data is analyzed for various study-wide papers as well as 
ancillary studies.   Each study/paper proposal goes through a formal review 
process by the ancillary studies committee that includes a detailed plan of the 
objectives, necessary registry data, analysis plans and timeline. All publications 
are approved by the ALFSG publication committees prior to submission. 
 
G. SITE REIMBURSEMENT 
 
Site reimbursement is a flat yearly rate based on past performance and will be 
disbursed quarterly throughout the year dependent on time worked on study for that 
quarter and after invoicing by the sites to the central site. 
 
H. REFERENCES 
 
1)  Trey C, Davidson CS. The management of fulminant hepatic failure. In: 
Popper H, Schaffner F, eds. Progress in liver diseases. New York: 
Grune & Stratton; 1970: 282-98. 
2)  Ritt DJ, Whelan G, Werner DJ, Eigenbrodt EH, Schenker S, Combes B. 
Acute hepatic necrosis with stupor or coma. An analysis of thirty-one 
patients. Medicine. 1969;48:151-72. 
3)  Lee WM, Schiødt FV. Fulminant hepatic failure. In: Schiff ER, Sorrell 
MF, Maddrey WC, eds. Schiff's Diseases of the Liver. 8th ed. 
Philadelphia: Lippincott-Raven Publishers; 1999: 879-95. 
4)  Benhamou J-P. Fulminant and subfulminant liver failure: definition and 
causes. In: Williams R, Hughes RD, eds. Acute liver failure. Improved 
understanding and better therapy. London: SmithKline Beecham 
Pharmaceuticals;1991:6-10. 
5) Hoofnagle JH, Carithers RL, Shapiro C, Ascher N. Fulminant hepatic 
failure: summary of a workshop. Hepatology. 1995;21:240-252. 
6)  Elinav E, Ben-Dov I, Hai-Am E, Ackerman Z, Ofran Y. Predictive value 
of admission and follow-up Factor V and VII levels in patients with acute 
hepatitis and coagulopathy. J Hepatol 2005;42:82-6. 

ALF Protocol 7.0, p.  13 
 
 
 
7)  Schiødt FV, Atillasoy E, Shakil O, Lee WM, et al. Etiology and outcome 
for 295 patients with acute liver failure in the United States.  Liver 
Transplant Surg, 5:29-34, 1999. 
8) Ostapowicz GA, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han 
SBH, Lee WM, et al., Results of a prospective study of acute liver 
failure at 17 tertiary care centers in the United States. Ann Intern Med 
2002;137:945-54. 
9)  Larson AM, Fontana RJ, Davern TJ, Polson J,  Lalani EK, Hynan LS, 
Reisch JS, Shakil OA, Schiødt FV, Ostapowicz GA, Lee WM and the 
ALFSG. Acetaminophen-induced acute liver failure: Results of a United 
States multicenter, prospective study. Hepatology 2005:42:1367-72. 
10) Reddy KR, Ellerbe C, Schilsky M, Stravitz RT, Fontana RJ, 
Durkalski V, Lee WM, Acute Liver Failure Study Group. 
Determinants of Outcome Among Patients with Acute Liver 
Failure Listed for Liver Transplantation in the US. Liver Transpl 
2015 Sep 30. [Epub head of print]. 
11)Rakela J, Mosley JW, Edwards VM, and the Acute Hepatic Failure 
Study Group. A double-blinded, randomized trial of hydrocortisone in 
acute hepatic failure. Dig Dis Sci. 1991;36:1223-8. 
12)Demetriou AA, Brown RS Jr, Busuttil RW, Fair J, McGuire BM, 
Rosenthal P, et al. Prospective, randomized, multicenter, controlled trial 
of   a   bioartificial   liver   in   treating   acute   liver   failure.   Ann   Surg 
2004;239:660-7. 
13)Stravitz RT, Kramer AH, Davern T, Shaikh AOS, Caldwell SH, Mehta 
RL, Blei AT, Fontana RJ, McGuire BM, Rossaro L, Smith AD, Lee WM 
and the Acute Liver Failure Study Group. Intensive care of patients with 
acute liver failure: Recommendations of the U.S. Acute Liver Failure 
Study Group. Crit Care Med. 2007;35:2498-2508. 
14)Polson J, Lee WM. AASLD Position Paper: Acute Liver Failure. 
Hepatology 2005,41:1179-97. 
15)Lee WM, Stravitz RT, Larson AM. Introduction to the revised American 
Association for the Study of Liver Diseases Position Paper on acute liver 
failure 2011. Hepatology 2012;55:965-7. 
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