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`Published in final edited form as:
`. 2009 September ; 137(3): 856–864.e1. doi:10.1053/j.gastro.2009.06.006.
`Gastroenterology
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`INTRAVENOUS N-ACETYLCYSTEINE IMPROVES TRANSPLANT(cid:173)
`FREE SURVIVAL IN EARLY STAGE NON-ACETAMINOPHEN
`ACUTE LIVER FAILURE
`
`AM Larson
`5, TL Davern 116,
`WM Lee 1, LS Hynan 1, L Rossaro2, RJ Fontana3, RT Stravitz4,
`PR Robuck
`NG Murray7, T McCashland8, JS Reisch 1,
`9, and the Acute Liver Failure Study
`Group
`1 University of Texas Southwestern Medical Center, Dallas
`
`2 University of California Davis, Sacramento
`
`3 University of Michigan, Ann Arbor
`
`4 Virginia Commonwealth University, Richmond
`
`5 University of Washington, Seattle
`
`6 University of California, San Francisco
`
`7 Baylor University Medical Center, Dallas
`
`8 University of Nebraska, Omaha, and the National Institutes of Diabetes and Digestive and
`Kidney Diseases
`
`9 National Institutes of Health
`
`• Acute Liver Failure Study Group Investigators
`
`Abstract
`Background—
`N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit
`patients with non-acetaminophen related acute liver failure.
`
`Methods-In a prospective, double-blind trial, acute liver failure patients without clinical or
`historical evidence of acetaminophen overdose were stratified by site and coma grade and
`randomly assigned to groups that were given NAC or placebo (dextrose) infusion for 72 hours.
`
`Corresponding author: William M. Lee, MD, Division of Digestive and Liver Diseases, The University of Texas Southwestern
`Medical Center at Dallas, 5959 Harry Hines Boulevard, HP.4.420, Dallas, Texas 75390-8887, (214) 645 6111; Fax (214) 645 6114,
`William.Lee@utsouthwestern.edu.
`There are no conflicts of interest to disclose. The statistical analysis of the entire data sets pertaining to efficacy ( specifically primary
`and major secondary efficacy endpoints) and safety (specifically, serious adverse events as defined in federal guidelines) have been
`independently confirmed by a biostatistician who is not employed by the corporate entity. The corresponding author had full access to
`all of the data and takes full responsibility for the veracity of the data and analysis. This is a randomized clinical trial
`(ClinicalTrials.gov number NCT00004467)
`The Data and Safety Monitoring Board for the trial included Michael W. Fried, Chair, University of North Carolina, Chapel Hill;
`Edward Geehan, Georgetown University, Washington, DC: Lewis Tepperman, New York University; Caroline Riely, University of
`Tennessee, Memphis; Patrick Northup, University of Virginia, Charlottesville; Prashant Pandya, VA Medical Center, Kansas City,
`MO; Aynar Unalp-Arida, Johns Hopkins University, Baltimore, MD:
`Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
`customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
`the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
`discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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`Lee et al.
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`Page 2
`
`The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant(cid:173)
`free survival and rate of transplantation.
`
`Results-A total of 173 patients received NAC (n=8 l) or placebo (n=92). Overall survival at 3
`weeks was 70% for patients given NAC and 66% for patients given placebo ( one-sided p=0.283).
`Transplant-free survival was significantly better for NAC patients ( 40%) than for those given
`placebo (27%; one-sided p=0.043). The benefits of transplant-free survival appeared to be
`confined to the 114 patients with coma grade 1-11 who received NAC (52% compared with 30%
`for placebo; one-sided p=0.010); transplant-free survival for the 59 patients with coma grade III(cid:173)
`IV was 9% in those given NAC and 22% in those given placebo (one-sided p=0.912). The
`transplantation rate was lower in the NAC group but not significantly different between groups
`(32% vs. 45%; p=0.093). Intravenous NAC was generally well tolerated; only nausea and
`vomiting occurred significantly more frequently in the NAC group (14% vs. 4%; p=0.031).
`
`Conclusions-Intravenous NAC improves transplant-free survival in patients with early stage
`non-acetaminophen related acute liver failure. Patients with advanced coma grades do not benefit
`from NAC and typically require emergency liver transplantation. (ClinicalTrials.gov number
`NCT00004467) -~ - - - - - - - - - - - - - - - - - - - - - - - - - -
`Acute liver failure is a relatively rare syndrome associated with a high mortality and
`frequent need for liver transplantation. Since the 1950s, trials of therapies to limit further
`–
`damage or improve hepatic regeneration have failed to show evidence of benefit. I 6 In
`recent years, acetaminophen poisoning, either intentional or unintentional, has become the
`most common etiology of acute liver failure identified both in Europe and in the United
`States. 7 When given within the first 24 hours after ingestion, N-acetylcysteine (NAC) can
`effectively prevent or minimize liver damage due to acetaminophen, even after massive
`–10
`overdoses,.8
`
`Treatment with NAC may benefit patients with other forms of acute liver failure,11 either by
`–
`improving systemic hemodynamics, tissue oxygen delivery,12 16 or via other favorable
`,
`effects on the acutely injured liver.17 18 No clinical trials using NAC for patients with non(cid:173)
`acetaminophen acute liver failure have been performed.19 In 1998, the Acute Liver Failure
`Study Group, funded by the National Institute of Diabetes and Digestive and Kidney
`Diseases (NIDDK) of the National Institutes of Health (NIH), began a registry at 24
`participating sites around the United States to better characterize and understand
`mechanisms of acute liver failure. A prospective, randomized, double blind placebo
`controlled trial ofNAC for cases of acute liver failure not due to acetaminophen was
`initiated in late 1998, ending in 2006. This paper summarizes the outcomes of this trial.
`
`METHODS
`Objective
`
`The primary outcome measure for this trial was the overall number of patients surviving at 3
`weeks following study admission; our research hypothesis was that patients receiving NAC
`would have a significantly higher overall survival than those receiving the placebo. The
`secondary outcome measures were the number of patients surviving without transplantation
`and the number of patients undergoing transplantation at three weeks following study
`admission. Our research hypothesis for transplant-free survival was that patients receiving
`NAC would demonstrate higher rates of transplant-free survival. The research hypothesis for
`transplantation did not specify a direction. Because of the extensive experience with NAC
`for acetaminophen-related liver failure, our original protocol specified the use of one-sided
`tests for overall survival and transplant-free survival, since it seemed very unlikely that
`NAC would harm patients in this setting.
`
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`Lee et al.
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`Page 3
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`Study Population
`Detailed prospective data as well as serum, tissue and DNA were collected on all cases of
`acute liver failure meeting study criteria beginning in January 1998. Eligibility for the
`registry included age 18 years old or greater, evidence of acute liver failure (any degree of
`encephalopathy and coagulopathy: international normalized ratio [INR] ~1.5) due to an
`illness of less than 24 weeks duration. Medical histories, clinical and laboratory findings
`were recorded on case report forms through death, transplantation or three weeks following
`study admission and at long-term follow-up visits one and two years following study entry.
`
`Eligibility requirements were the same for both the NAC trial and registry with the
`following exceptions. Patients were excluded from the NAC trial for known or suspected
`acetaminophen overdose, if they had previously received NAC or if they were determined to
`have hepatic ischemia (shock liver), liver failure due to pregnancy or cancer. Patients with
`refractory hypotension, septic shock, and those expected to undergo transplantation
`imminently (i.e., in less than 8 hours), or those >70 years old were also excluded. Since all
`participants were, by defmition, encephalopathic, informed consent was obtained from next
`of kin. The study was approved by the institutional review boards at all participating centers.
`
`Study Design
`Randomization was stratified by the standard hepatic encephalopathy (coma) categories (I(cid:173)
`II versus III-IV),20 and by site with a blocking factor of 4. The site pharmacist received the
`randomization list prepared by the biostatistician (JSR); all study personnel (except the two
`biostatisticians, LSH and JSR) remained blinded throughout the study. After consent was
`obtained, patients were weighed and coma grade was determined so that the site pharmacist
`could randomize the patient and prepare the medication.
`
`Response to treatment was carefully recorded, including vital signs, progression of coma
`grade and use of other supportive measures such as mannitol, need for intubation, rise in
`intracranial pressure in patients with an intra-cranial monitor inserted, and assessment of
`adverse events. All other aspects of care conformed to standard of care at each study site, all
`of which were liver transplant centers during the study except for one site, which had ready
`transplantation access nearby.
`
`Study Medication
`Following randomization, infusion of either 5% dextrose (placebo) or 5% dextrose with N(cid:173)
`acetylcysteine (Acetadote®, Cumberland Pharmaceuticals, Nashville, TN) was begun, with
`an initial loading dose of 150 mg/kg/hr ofNAC over one hour, followed by 12.5 mg/kg/hour
`for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours.
`
`Study Outcomes
`The primary outcome of the trial was overall survival at three weeks after randomization. To
`obtain long-term outcomes, we used information gathered by the sites, in addition to the
`original study data set, censored 365 days after study admission. Secondary outcomes
`specified in the protocol were transplant-free survival and transplant rate. Two additional
`secondary outcomes also listed in the original protocol were length of hospital stay and a
`composite of the number of organ systems failing, utilizing specific definitions for hepatic
`encephalopathy, evidence for cerebral edema, use ofvasopressor or ventilatory support,
`300
`serum creatinine level(~
`µMIL) or bacteremia. Data were reviewed twice yearly by a
`Data and Safety Monitoring Board and three interim analyses were performed, after 57, 113
`and 170 patients had been enrolled.
`
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`Page4
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`Sample Size
`Based on our own pre-study data, overall survival for non-acetaminophen related ALF in the
`United States at the start of the trial was estimated at 57%.1 Assuming overall survival
`(combining transplant-free plus transplanted and alive) of 57% (25%+32%) in the placebo
`arm and a predicted improvement in overall survival to 75% in the treated arm (45%+30%),
`170 patients were targeted for enrollment to achieve 80% power (likelihood of rejecting the
`hypothesis of equal response rates) with a one-sided test of proportions at the 0.05
`significance level.
`
`Statistical analyses were based on the intention-to-treat principle and involved all
`randomized patients except for nine who represented protocol violations (see below).
`
`Statistical Analysis
`Univariate analyses were performed for patient demographic and illness characteristics at
`baseline for descriptive purposes and to determine their possible influences on the primary
`2
`and secondary outcomes using x or Fisher's Exact test, and independent group Student's t(cid:173)
`test or Mann-Whitney U test as indicated. Additional analyses were performed on the
`baseline measures to separately compare the entire consented group, the placebo group and
`the group of eligible patients who were not consented.
`
`The primary outcome, patients who survived (with or without transplant) versus those who
`died, and two of the secondary outcomes, patients (a) who survived without transplantation
`versus those dead or transplanted and (b) those transplanted versus not transplanted, were
`2
`compared for the two treatment groups using x analysis, Breslow-Day homogeneity of odds
`ratio test and the Mantel-Hanszel Common Odds Ratio tests. Results are presented using
`percentages and 95 percent confidence intervals (95% CI). As stated in the protocol, both
`overall survival and transplant-free survival were one-sided tests with the research
`hypothesis stated as the NAC group is expected to have higher or equal proportions of
`survival and transplant-free survival than the placebo group.
`
`Three separate Kaplan-Meier models were developed for the primary/secondary measures
`censored at one year testing for group differences using the log rank test. A single measure
`was defined to combine treatment group and coma category into one variable: NAC 1-11,
`NAC III-IV, placebo 1-11, and placebo III-IV.
`
`The statistical packages used to analyze the data were SPSS V16 and SAS V 9.1.
`Assumptions of all statistical tests were examined (normality, homogeneity of variance,
`etc.); since most variables were non-normally distributed, non-parametric analyses were
`used to analyze the data. Unless otherwise noted, all statistical tests were two-sided and p <
`0.05 was considered significant. No corrections to the p-values were made for multiple
`comparisons.
`
`RESULTS
`Study Population
`Among 820 eligible patients at sites with IRB approval, 558 (68%) met exclusion criteria
`(Figure 1 ). Of the remaining 262 patients, 89 were excluded either because consent was
`refused (46), was unobtainable (34) or, after randomization, because of protocol violations
`(9). The 9 protocol violations included inadvertent enrollment of two prisoners who were
`removed from consideration once their status was recognized, one patient for whom all
`hospital records were lost, 4 who met exclusion criteria but were mistakenly offered
`participation in the study, one patient who underwent transplantation before the first dose of
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`Page 5
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`NAC was administered and one patient who was withdrawn because the trial solution turned
`pink in the intravenous bottle. This harmless dye reaction was considered by the site
`investigator at the time as evidence of possible bacterial contamination; the patient was
`withdrawn and given open label medication. Data on the first 3 protocol violations were not
`available. For the latter group, 2 of the 6 were slated to, or did, receive NAC.
`
`Thus, 173 patients comprised the final study group (Table 1 ), 92 randomized to receive
`placebo and 81 to receive NAC. The imbalance in size of study groups was related to the
`randomization process whereby patients were stratified by site and coma grade (1-11 vs. III(cid:173)
`IV); not all sites reached a balance point on the randomization lists. During the course of the
`trial, the project biostatisticians verified the accurate use of the randomization scheme with
`the site pharmacist before each DSMB meeting. The majority of patients enrolled comprised
`four etiologies: drug-induced liver injury (DILi, n=45), autoimmune hepatitis (AIH, n=26),
`hepatitis B (HBV, n=37) and indeterminate (n=41). Patient numbers were reasonably well
`balanced between the placebo and treatment group within each etiology. The characteristics
`of the patients in the two groups were similar at enrollment (Table 1), except that the
`placebo group had longer median duration between jaundice and encephalopathy than the
`treated group (12 vs. 7 days, p=0.026) and a higher percentage of females (p=0.004). The 80
`unconsented patients did not differ from the enrolled group (n=l 73) or the placebo group
`(n=92), except for lower median alanine aminotransferase (ALT) values than either
`comparison group (both p < 0.001, results not shown). Patients were enrolled at 22 sites over
`the period of the study, with 12 sites enrolling 8 or more patients (overall range 1-19). Five
`sites enrolled ~3 patients.
`
`Overall, 58 (63%) in the placebo and 48 (59%) in the NAC arm completed 72 hours of
`therapy (Figure 1), and the majority (138/173, 80%) of patients received at least 24 hours of
`treatment. Reasons for early discontinuation included death or withdrawal of support (n= 17),
`transplantation (n=36) or side effects possibly due to the drug (5 total, 4 thought to be due to
`NAC).
`
`Study outcomes
`Overall survival at 3 weeks was 70% (95% CI=60%, 81 %, n=81) for NAC and 66% (95%
`CI=56%, 77%, n=92) for placebo (one-sided p=0.283; Table 2). However, transplant-free
`survival was significantly higher at 40% (95% CI=28%, 51 %, n=81) in the treatment group
`as compared to 27% for placebo (95% CI=18%, 37%, n=92, one-sided p=0.043). When
`examining transplant-free survival by coma category at randomization (1-11 vs. III-IV), the
`largest difference was observed in patients with coma grade 1-11: 52% (95% CI=38%, 65%,
`n=58) survived in the NAC group as compared to 30% (95% CI=l 7%, 43%, n=56) in the
`placebo group (one-sided p=0.010). This was not the case for coma III-IV patients where
`transplant-free survival was only 9% (95% CI=0%, 22%, n=23) with NAC vs. 22% (95%
`CI=7%, 37%, n=36) with placebo (one-sided p=0.912). The odds ratios comparing the
`treatment groups for transplant-free survival were 2.46 (95% CI= 1.14, 5.30) for coma
`category 1-11 and 0.33 (95% CI=0.06, 1.74) for coma category III-IV; that is, patients in
`coma category 1-11 receiving NAC were 2.46 times more likely to survive than those in the
`placebo group, while those with advanced coma (III-IV) receiving NAC were only 0.33
`(95% CI=0.06, 1.74) times as likely to survive as those in the placebo group (Breslow-Day
`2
`x (1)=5.11, p=0.012). Overall transplantation rates were 32% (95% CI= 21%, 43%, n=81)
`for NAC vs. 45% (95% CI= 34%, 55%, n=92) for placebo, p=0.093.
`
`Survival Analysis
`Treatment group/coma category was found to have significantly different survival times
`using the Log Rank Test (p=0.007; Figure 2). Patients in the NAC 1-11 group were found to
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`have significantly longer survival than Placebo III-IV (p = 0.012) and NAC III-IV (p =
`0.002), but not Placebo 1-11 (p =0.350). For the secondary outcome of survival without
`transplant, treatment group/coma category was significantly different (p=0.001 ; Figure 3).
`Patients in the NAC coma category 1-11 group were found to have significantly longer
`transplant-free survival time than the other three groups (largest p = 0.017). For the other
`secondary outcome, transplantation, treatment group/coma category was found to be
`significant (p = 0.025). Patients in the NAC coma category 1-11 group were found to have a
`significantly longer time to transplantation than the other three groups (largest p = 0.032). In
`a sub-analysis of the primary and secondary outcomes for patients receiving ~ 4 hours or ~
`24 hours infusion, the results were similar to those reported (results not shown).
`
`When overall and transplant-free survival were considered within each of the four largest
`etiologic groups, patients with DILi or hepatitis B showed improved outcomes compared to
`those with AIH or indeterminate etiologies (Table 4). For example, transplant-free survival
`for DILi patients was 58% (95% CI=33%, 83%) for those receiving NAC compared to 27%
`(95% CI=8%, 46%) for those receiving placebo, and was 40% (95% CI=19%, 61 %) for
`NAC vs. 17% (95% CI=0%, 42%) for placebo for HBV patients. Since the numbers in each
`group were small, we did not draw conclusions or calculate significance, based on these
`analyses.
`
`Use of acetaminophen
`To determine if unrecognized acetaminophen toxicity might have caused some of the
`indeterminate cases, sera from 113 patients (those with available samples) were analyzed
`after the conclusion of the trial using a highly sensitive and specific assay for acetaminophen
`,
`adducts in serum.21 22 Three patients in each treatment group had adduct levels strongly
`implicating high-dose acetaminophen ingestions. A re-analysis excluding these 6 cases
`showed no difference in outcomes or percentage survival for the two treatment groups.
`
`Length of hospital stay, number of organ systems failing
`In comparing length of hospital stay among survivors, a trend was observed for NAC-treated
`patients to have shorter hospital stays (median 9 vs. 13 days (p=0.056). Comparison of organ
`system failure(s) between the two treatment groups failed to demonstrate individual (or total
`group) significant differences (Supplemental Table 1). This appears to relate to the small
`number of defined organ failure events occurring during the immediate study period.
`Progression or regression of encephalopathy between the two treatment groups appeared to
`be similar.
`
`Adverse Events
`Adverse events were equal between the groups (Supplemental Table 2); side effects were
`minimal with no differences in incidence except for nausea and vomiting, present in 14%
`(95% CI= 6%, 22%, n=81) ofNAC treated patients and 4% (95% CI=0%, 9%, n=92) of
`placebo patients (p=0.031). Although bronchospasm has been reported with NAC, only one
`patient in each treatment group experienced this symptom.
`
`DISCUSSION
`
`There is no established treatment for non-acetaminophen acute liver failure other than liver
`transplantation. Our study suggests that transplant-free survival was improved by N(cid:173)
`acetylcysteine. However, this improvement in survival was primarily observed in those with
`early stage hepatic encephalopathy: among those with coma grade 1-11 at admission, 52%
`receiving NAC survived without transplantation vs. 30% survival for those who received
`placebo. This finding was supported by the survival analyses (Figures 2 and 3).
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`Page 7
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`Advanced coma grade patients showed no benefit from NAC but represented a smaller
`patient group, half the size of the early coma grade group. Within the advanced coma group,
`10% died or were withdrawn from care while still on study medication, 50% died or
`underwent transplantation by 4 days and nearly 90% achieved these outcomes by 3 weeks.
`Among the 100 study patients of all grades listed for transplantation, 67 received a graft, 30
`( 45%) within 48 hours of study initiation. Twenty one of 59 advanced coma grade patients
`(36% overall, 57% of those listed) received a transplant by day 4, compared to 23/114 (20%
`overall, 37% of those listed) with early coma grades, confirming that coma grade at
`admission determines outcome, and, more specifically, whether a transplant will be obtained
`and utilized in rapid fashion. Only 4 additional patients in the advanced coma group were
`transplanted after day 4, vs. 19 additional grafts for those with early grade encephalopathy.
`The majority of patients recovered after transplantation, although short-term survival was
`slightly decreased when compared to patients with chronic liver disease.23 Thus, high early
`mortality, rapid transplantation and excellent early post-transplant survival rates appeared
`more likely than any possible medical therapy to affect overall survival for those with
`advanced coma grades. By contrast, patients with early hepatic encephalopathy only reached
`the 50% outcome point by 10 days. There appeared to be additional benefit beyond three
`weeks in that the differences between the treatment/coma categories observed during the
`initial 21 days were more significantly different at 365 days. The apparent benefit for those
`with early encephalopathy suggests that NAC treatment, to affect outcome, must be
`instituted early in the course of disease.
`
`The overall survival of 66% for the placebo group was 9% higher than the 57% we had
`predicted. Although the overall registry includes equal numbers of patients in coma grade I(cid:173)
`II vs. III-IV, and we had predicted equal emollment of early and late coma grade patients, as
`noted above, twice as many patients with early coma grades were emolled in the study (66%
`(114) with coma grade 1-11 vs. 35% (59) with coma grade III-IV). We did not specifically
`target the early coma grades for emollment; however, we excluded those considered pre(cid:173)
`terminal or about to undergo liver transplantation. Although the apparent improved overall
`survival for placebo subjects in all coma grades is likely related to the over-representation of
`early coma grades, improvement in overall survival during the trial period for other reasons,
`such as improved intensive care, might also play a role.
`
`Establishing prognosis in non-acetaminophen acute liver failure has proven difficult and is
`confounded by transplantation, since this 'rescue' intervention, which affected 40% of our
`patients, does not allow the true outcome (death or recovery) to occur. We predicted that
`NAC therapy might benefit patients undergoing transplantation but could not demonstrate
`this. Since short-term outcomes of transplantation hinge on many other factors, such as
`organ quality and availability, it seems unlikely, in retrospect, that a short-term pre(cid:173)
`transplant medical therapy would make much difference. The main prognostic factors in 3-
`week survival for the overall group using multivariate analyses were coma grade and INR at
`admission to study; these important variables have been previously noted and used by
`others.24
`
`The study groups were well balanced in terms of age, gender, weight and etiology. While
`the placebo patients had a longer apparent duration of illness, the groups were well matched
`–27
`in all other parameters including Model for End-stage Liver Disease (MELD) scores.25
`The imbalance in numbers emolled in the two groups reflected the randomization scheme
`which took into account site as well as coma grade using a blocking factor of 4, and did not
`appear to affect the balance in each group.
`
`Of note, there were relatively similar numbers of patients (26 to 45) among the four main
`etiologies: DILi, autoimmune hepatitis, hepatitis B and indeterminate. There was a trend for
`
`Gastroenterology. Author manuscript; available in PMC 2011 October 9.
`
`Eton Ex. 1103
`7 of 18
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`Lee et al.
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`Page 8
`
`improved overall and transplant-free outcomes among the DILi and hepatitis B patients and
`for less favorable overall outcomes among those with AIH or indeterminate etiology.
`
`The study occurred over nearly 8 years despite the large number of study sites because of
`the difficulties encountered with enrollment in this already-rare condition: it was necessary
`to choose only the subgroup that were unrelated to acetaminophen which represents less
`than half of all ALF in the United States7, then to identify next of kin in a timely fashion,
`help them understand both the data registry and the nature of the trial so that informed
`consent could be obtained. The urgent nature of the study setting and the simultaneous
`consideration of transplantation often distracted attention from the study. In the early years,
`competing trials ofliver assist devices and, later, availability of intravenous NAC
`(Acetadote®; FDA approved for acetaminophen poisoning in 2003) also confounded
`enrollment. Among our registry, 58 non-acetaminophen patients received NAC prior to
`consideration for study enrollment despite the lack of evidence regarding its efficacy.
`
`Examining the evolution to secondary end points disclosed a trend toward shorter hospital
`stays but no other differences between the two treatment groups, possibly reflecting that few
`of our specified outcomes (such as use ofmannitol, intubation) were reached during
`treatment. There were no changes in mean arterial pressure or urine output during NAC
`infusion; however, pulmonary artery catheters or other hemodynamic measurements were
`not mandated by the study and were rarely used. A recent retrospective study using
`historical controls in pediatric acute liver failure not due to acetaminophen showed
`improved transplant-free survival and shorter hospital stays with NAC.28
`
`Nausea and vomiting were the only symptoms more frequent in the treatment than the
`placebo group. Along with its excellent safety profile, NAC is easy to administer, does not
`require intensive care and can be given in community hospitals.
`
`In summary, a significantly improved transplant-free survival at 3 weeks and at one year
`was observed with the use of N-acetylcysteine for the treatment of non-acetaminophen
`related acute liver failure, the benefit being confined to those with early hepatic
`encephalopathy. Extrapolating NAC efficacy to patients with less severe liver injury (e.g.,
`coagulopathy without encephalopathy) cannot be made from our study since all study
`patients were required to exhibit some degree of encephalopathy at enrollment. Use ofNAC
`should not be a substitute for early referral to a transplant center for any patient
`demonstrating evidence of coagulopathy (prolonged INR), regardless of whether
`encephalopathy is present, since referral ensures that these critically ill patients can undergo
`urgent transplantation, should it be needed. Based on the present study and its generally
`favorable safety profile, intravenous NAC should be considered for patients with early stage
`non-acetaminophen acute liver failure. Additional studies are needed to determine the
`optimal dose and duration ofNAC therapy, predictors ofresponse and the physiologic basis
`for these improved outcomes.
`
`Supplementary Material
`
`Refer to W eh version on PubMed Central for supplementary material.
`
`Acknowledgments
`
`*Members and institutions participating in the Acute Liver Failure Study Group 1998- 2006: W.M. Lee, MD
`(Principal Investigator), George A. Ostapowicz, MD, Frank V. Schi0dt, MD, Julie Polson, MD, University of Texas
`Southwestern, Dallas, TX; Anne M. La