Controversies in Clinical Trials for Alcoholic Hepatitis 08-Nov-2017.pdf · Abbreviations:...
Transcript of Controversies in Clinical Trials for Alcoholic Hepatitis 08-Nov-2017.pdf · Abbreviations:...
Accepted Manuscript
Controversies in Hepatology
Controversies in Clinical Trials for Alcoholic Hepatitis
Sarah R. Lieber, John P. Rice, Michael R. Lucey, Ramon Bataller
PII: S0168-8278(17)32325-5DOI: https://doi.org/10.1016/j.jhep.2017.09.013Reference: JHEPAT 6684
To appear in: Journal of Hepatology
Received Date: 20 January 2017Revised Date: 18 August 2017Accepted Date: 20 September 2017
Please cite this article as: Lieber, S.R., Rice, J.P., Lucey, M.R., Bataller, R., Controversies in Clinical Trials forAlcoholic Hepatitis, Journal of Hepatology (2017), doi: https://doi.org/10.1016/j.jhep.2017.09.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, andreview of the resulting proof before it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Controversies in Clinical Trials for Alcoholic Hepatitis
Sarah R. Lieber M.D.1, John P. Rice M.D.2, Michael R. Lucey M.D.2, Ramon Bataller
M.D.3
1 Division of Gastroenterology and Hepatology and 3Biochemistry Departments of
Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC,
USA.
2 Division of Gastroenterology and Hepatology, Departments of Medicine and Public
Health, University of Wisconsin, WI, USA.
3Division of Gastroenterology, Hepatology and Nutririon, Pittsburgh Liver Research
Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Corresponding Authors: Dr. Michael Lucey, Division of Gastroenterology and
Hepatology, University of Wisconsin, WI, USA ([email protected]) and Dr. Ramon
Bataller, Division of Gastroenterology, Hepatology and Nutririon, Pittsburgh Liver
Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Keywords: alcoholic liver disease, alcohol use disorder, ethics of placebo-controlled
trials, prednisolone.
Manuscript qInformation: 3298 words, 3 Tables
Abbreviations: alcoholic hepatitis (AH), alcoholic liver disease (ALD), Maddrey
Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD)
Conflict of interest
The authors declare that they do not have anything to disclose regarding conflict of
interest with respect to this manuscript.
2
Author Contributions
All authors were involved in the manuscript conception, design, drafting
and revising, and final approval of the submitted version.
3
Abstract:
Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease, contributing to
significant morbidity and mortality. Yet, the only available therapies that improve survival
are corticosteroids and liver transplantation with no new drugs successfully developed
for decades. This article describes briefly the current state of affairs in AH therapy and
examines the practical and ethical challenges to conducting controlled trials in patients
with severe AH. While prednisolone is considered to be standard of care in severe AH,
this recommendation remains controversial given the marginal benefits and
questionable longterm safety of steroids. Placebo controlled trials without steroids may
be necessary and ethically justified in certain populations of AH who have not been
adequately investigated. Ultimately, we suggest the field will advance with the
development of a plausible animal model of true AH, a consensus on a composite
clinical end-point that does not rely solely on mortality for use in future RCTs, and the
adoption of the recommendations of the NIAAA Alcoholic Hepatitis Consortia regarding
standard definitions and when to require a liver biopsy prior to study entry.
4
I. Introduction
Alcoholic hepatitis (AH) represents one of the deadliest diseases in clinical hepatology
contributing to significant morbidity and mortality among patients with alcoholic liver
disease (ALD) [1]. Patients with severe AH often show signs of systemic inflammation
and are prone to infections, kidney injury, and ultimately multiorgan dysfunction.
Mortality rates range from 20 to 50% at 3 months [2,3]. Few advances have been made
in the management of patients with AH [4,5]. To date, the only therapies that improve
survival in AH are corticosteroids alone and liver transplantation [6–8]. The landscape
for treatment of severe AH has remained relatively static since the early 1970s, at which
time the use of corticosteroids was proposed to treat severe AH, which is in sharp
contrast to the landmark developments in treatment of chronic viral hepatitis [9].
The lack of advances in the field of AH have been due to intrinsic difficulties in
performing randomized clinical trials (RCTs) in patients with active addiction and
advanced clinical illness as is the case in patients with severe AH. Furthermore, the lack
of experimental models of advanced ALD has held back the discovery of treatments
based on basic mechanisms, and hampered proof of concept therapeutic interventions
[1,5,9,10]. Undoubtedly, there is an urgent need to develop novel therapies to treat AH.
There is a burgeoning list of potential therapies, and an optimistic assessment would be
that we are on the crest of a new wave of therapies for AH. The challenge remains,
however, how to conduct phase 2 and phase 3 studies using new AH therapies wherein
the studies are both practically and ethically sound.
In this review article, we will discuss RCTs to study novel therapies for AH. We will
review the evidence surrounding the use of corticosteroids, the current “mainstay” or
standard of care therapy. With this as our backdrop, we will focus on practical and
ethical challenges to advancing therapy for patients with severe AH.
II. Current State of AH Treatment
5
All studies of AH treatment start with the notion that research subjects should abstain
from all alcohol. Although this is a concept that could be studied, there have been no
well-conducted studies aimed at enhancing sobriety in severe AH, either with
motivational interventions or by pharmacologic interventions to reduce craving or
enhancement after drinking has begun.
Corticosteroid therapy in AH has been studied in numerous RCTs spanning several
decades (see Table 1). These studies have been limited by small sample sizes,
heterogeneity in study design and patient population, variability in steroid dosing and
duration, and a high risk of bias [11]. Furthermore, the definition of severe alcoholic
hepatitis, and thus the population at risk, has changed over time encompassing the
presence of hepatic encephalopathy and the widely adopted Maddrey’s discriminant
function. Regardless, prednisolone is widely considered the first line therapy for severe
AH. Both the American Association for the Study of Liver Disease (AASLD) and
European Association for the Study of Liver (EASL) practice guidelines recommend the
use of corticosteroids (i.e. prednisolone 40 mg daily for 4 weeks) for patients with
severe AH, defined by Maddrey’s discriminant function (MDF) ≥ 32 [12], or the
presence of hepatic encephalopathy [3,13,14].
The basis of these recommendations comes from the 2011 meta-analysis by Mathurin
et al. of five previously published randomized controlled trials, with a combined
recruitment of more than 400 patients with severe AH on the basis of the MDF >32, all
of whom had biopsy-confirmed alcoholic steatohepatitis [15]. This reanalysis
demonstrated a significant 28-day survival benefit of 79.97+2.8% in the corticosteroid-
treated subjects compared to 65.7+3.4% (p=0.0005) in the control subjects. In addition,
while a 2008 Cochrane meta-analysis of 15 trials (over 700 patients) by Rambaldi et al.
showed no statistically significant reduction in mortality in the corticosteroid group
compared with placebo or no intervention in the entire population, there was a
significant reduction in mortality in patients with a discriminant function greater than 32
or hepatic encephalopathy [16]. Another recent French RCT in severe AH compared
corticosteroids to corticosteroids plus intravenous n-acetyl cysteine (NAC) [17]. The
6
primary end-point, which was survival at 6-months, was not improved by the
combination of prednisolone and NAC. However, post hoc analysis showed a significant
survival benefit for prednisolone and NAC at 28 days. Unfortunately, the majority of the
trials were at high risk of bias owing to significant heterogeneity.
A more recent randomized trial published by Thursz et al. investigated steroids or
pentoxyfilline for AH (given the acronym ‘STOPAH’) and concluded that corticosteroids
had a beneficial survival effect in only the first 28 days [8]. This multicenter, double-
blind, factorial (2x2) trial randomized 1103 AH patients with MDF >32 into one of four
arms: placebo/placebo (i.e., the natural history of the disease), prednisolone/placebo,
pentoxyfilline (PTX)/placebo, or prednisolone/PTX [8]. All diagnoses were made on
clinical criteria and liver biopsies were not required. Furthermore, subjects were
randomized based on a risk stratification, with high risk defined as recent
gastrointestinal hemorrhage, renal insufficiency, or sepsis. Exclusionary criteria included
severe renal failure (renal replacement therapy or a serum creatinine > 5.7 mg/dL or
500 µmoles/L), gastrointestinal hemorrhage, sepsis, or inotropic support after 7 days of
therapy. There was a non-significant survival advantage during the first four weeks
among recipients of prednisolone (OR 0.72; 95% CI 0.52-1.01, p=0.06). On cross-
sectional analysis of 28-day survival, prednisolone was not associated with a survival
benefit. However, on a post-hoc multivariable analysis, prednisolone was associated
with improved 28-day survival, with an odds ratio of survival of 0.609 (p = 0.015), while
having no effect on 90-day or 1-year mortality. Interestingly, the mortality rate from
severe alcoholic hepatitis was lower in all treatment arms than was projected in the
power analysis and lower than the mortality rate in the alcoholic hepatitis literature
overall. Nevertheless, the STOPAH trial lends further evidence to the efficacy of
corticosteroids in the treatment of severe alcoholic hepatitis.
On the basis of this short review, we conclude that the design of an RCT of AH
treatment requires careful consideration of several design issues, and an awareness of
the ethical challenges when studying this population. In the remainder of this paper we
will discuss these challenges in further detail.
7
III. Controversies in Designing AH Trials
Inclusionary Criteria
Since AH is a clinical entity, diagnosis will be made with specified clinical parameters.
The MDF has become the ubiquitous minimal measure of severity to ensure that
patients with a good chance of spontaneous recovery are excluded. However, the range
of mortality risk of patients with an MDF above 32 is very broad, and several authorities
have recommended restricting entry into RTCs for a specific strata of patients within this
general criterion of MDF >32. This could require a second prognostic score such as
ABIC [18], MELD [19–21], Lille [22,23] or the Glasgow score [24,25]. A consequence of
restricting recruitment in this way will be to limit recruitment.
A second area of controversy is whether or not to require liver biopsy confirmation of
AH. The benefit of this policy is to avoid inclusion of subjects with conditions that mimic
clinical AH while lacking alcoholic steatohepatitis. Examples are alcoholic cirrhosis with
sepsis, or alcoholic foamy cell hepatitis [26,27]. Furthermore, immunohistochemistry
data, in conjunction with laboratory and clinical data, can provide important diagnostic
and prognostic information including risk for infection and mortality [28–30]. Once again
the unwanted consequence is that of limiting recruitment. Indeed the unavailability of
transjugular biopsy in many community hospitals would preclude their participation were
a biopsy required. Even if biopsy is available, the histologic diagnosis of AH is not
standardized across all pathologists and is subject to variable interpretation.
Furthermore, requiring biopsy confirmation of histologic alcoholic steatohepatitis may
limit the “real-world” application of clinical trial results in these same community
hospitals where histologic confirmation of AH may not be possible. Recently, the NIAAA
study consortia have proposed a partial way around this conundrum by characterizing
severe AH as definite, probable and possible (Table 2) [31]. In clinical studies, biopsy
would be required in order to include patients in the possible category, but not in
probably or definite categories.
8
Exclusionary Criteria
As we discussed above, the authors of future studies will have to decide the severity of
liver injury needed to be included. Since AH is a dynamic condition, it makes sense, as
in STOPAH, to avoid patients who are very likely to die irrespective of treatment.
However, the converse is also true. Patients in the ICU, with severe renal failure, or with
very high MDF and MELD scores are important populations to investigate. Determining
whether these patients should be excluded or stratified into subgroups is important for
the design of future studies. The principal benefit of using MDF > 32 as an entry
requirement is to avoid including patients who would likely recover in any case. On foot
of the salutary effect of alcohol withdrawal, some studies introduce a short waiting
period before commencement of the RCT, in order to avoid diluting the cohorts with
patients who would recover with simple medical management. However, as more
restrictions to recruitment are applied, the harder it becomes to fulfil power
requirements. The inclusion and exclusion criteria recently proposed by the NIAAA-
funded consortia on alcoholic hepatitis are depicted in Table 3.
Power Calculations and End Points
A common limitation to performing successful RCTs in the field of AH is the need for
large subject numbers in each therapeutic arm. The issues surrounding power
calculations are well demonstrated by STOPAH. The power analysis was based on a
predicted 28-day survival in the placebo/placebo group similar to that reported by
Mathurin et al. of 70%, with an expected improvement to 79% in the treated groups. In
fact, the 28-day survival in the placebo/placebo group was 83% compared to 86% in
subjects who received prednisolone. These findings pose several questions. Does the
STOPAH outcome constitute a new normal? Should future studies be based on this
estimated survival at 28 days? If this is the case, it will further complicate studies using
mortality as the primary end-point and necessitate very large cohorts.
The selection of end-points is linked to the choice of duration of observation, and the
power calculation. Even in very large studies, such as STOPAH, when power
9
calculation expectations are not met, the end-point of mortality may not yield a clear
result. The field would be advanced by the development of a consensus endpoint that
included survival but also clinical markers of recovery or deterioration. In fact, there is a
current effort to define new primary end points other than survival in order to reduce the
number of patients needed for such studies [31].
Observation Interval and Monitoring Abstinence
We have already drawn attention to the studies of the AH treatment which have shown
a survival benefit at 28 days, but not at 3 or 6 months. This is not surprising, since the
events arising in the shorter time period are directly related to severity of liver injury, the
capacity of the liver to recover, and the influence of related events such as infection and
multiorgan failure. In this short interval, many patients are hospitalized or admitted to
nursing home care, thereby restricting their access to alcohol. Furthermore, ill-health
itself may act as a restraint on drinking. In contrast, as the interval from the onset of
treatment of AH admission is extended out to 3 or 6 months, the contribution of alcohol
use disorder tends to increase, as the patient recovers from the immediate effects of the
AH episode. It seems reasonable to make two suggestions in light of the two separate
pathways of AH and alcohol use disorder: first, that the interval of observation of AH
treatment closely mirrored the expected natural history of the disease. Given that most
of the clinical improvment from alcoholic hepatitis occurs within the first three months of
alcohol abstinence, 90 days seems to be a reasonable duration of observation.
Second, studies adopting end-points after 28 days should include some structured
treatment of alcohol use disorder.
Since the greater the duration of study, the greater the risk of relapse, alcohol relapse is
a potential powerful confounder in those studies that are continued beyond 28 days.
Consequently these studies would be greatly enhanced by formal plans to monitor
alcohol use. There is no consensus on how best to do this, but we would recommend a
mixed approach involving asking questions about drinking and use of biomarkers [32].
10
IV. Ethics of Placebo Controlled Trials in AH
Placebo-controlled trials are scientifically necessary and important in advancing the
therapy of deadly diseases such as AH. However, the question remains whether such
studies are ethical when an established therapy exists. For a RTC to be ethical, it is
essential that investigators have no preference for any particular intervention, a concept
known as equipoise [33,34]. In circumstances where there is no established treatment,
placebo-controlled trials provide the greatest methodologic rigor and robust data.
However, it is usually unethical to include a placebo arm in an RCT when it deprives a
subject from receiving an established therapy that is available and effective [35,36]. We
discuss the ethical controversy of conducting placebo-controlled trials in the setting of
AH and arguments for and against conducting such studies.
Argument For Placebo Controlled Trials in AH
There are compelling methodologic reasons to conduct placebo-controlled trials.
Research in AH is limited by small sample sizes and placebo arms of RTCs ensure
internal validity and provide stronger evidence of the effectiveness of novel therapies
[37]. A well-designed study that shows superiority of a treatment to a control provides
strong evidence of its effectiveness. On the contrary, a noninferiority trial that shows
“equivalence” (i.e. little difference between a new drug and known active treatment)
does not itself demonstrate that the new treatment is effective [35,38].
Additionally, proven therapies for AH (e.g. prednisolone) may not have long-term
benefits and committing patients to potentially ineffective therapies just because it is
“standard of care” in itself may be unethical and harmful. When the effectiveness of an
available treatment is modest or inconsistent, placebo arms can shed light on the
benefits of new treatments or different dosing of current therapies. In the setting of AH,
the STOPAH trial demonstrated that prednisolone did not improve long-term health and
potentially harmed individuals after one month given increased infectious risks. Based
on this evidence, it is reasonable to believe that omitting steroids would pose no
significantly greater harm to individuals than that experienced in the natural course of
11
AH. That being said, the placebo arm should not be substantially more likely than those
receiving active-treatment to die, to experience severe discomfort, or to suffer serious
harm [37].
Furthermore, we acknowledge that placebo alone trials may be ethical in certain patient
populations which have not been traditionally studied, and in which there are limited
data regarding whether regional differences or patient characteristics might influence
steroid efficacy. Examples of such special populations would be patients in countries in
the developing world, or patients with severe renal disease, encephalopathy, or recent
variceal hemorrhage that were excluded from the studies reviewed above.
In order for placebo-controlled trials in AH to be ethical, there must be robust informed
consent. Individuals must be informed of the rationale for using a placebo arm, must be
aware of the existence of any effective therapy, and understand the consequences of
not receiving such therapy. If an individual believes that foregoing known therapy poses
unacceptable risks and that receiving placebo is unreasonable, then he/she can choose
not to participate in such a trial.
Argument Against Placebo Controlled Trials in AH
In the setting of a known therapy for AH, placebo-controlled trials violate the therapeutic
obligation of clinicians to offer optimal medical care and pose unnecessary harm and
risk to individuals [34,39]. According to the original Declaration of Helsinki: “In any
medical study, every patient—including those of a control group, if any—should be
assured of the best proven diagnostic and therapeutic method” [40],[41]. As discussed
in the review above, prednisolone is currently considered the standard of care for
severe AH with MDF >32 [11,15,42,43]. In high stakes situations in which morbidity and
mortality are veritable risks, it is unethical to deprive individuals of a proven beneficial
therapy (even if the benefit is marginal). If we consider steroids to have any benefit in
terms of reducing morbidity and mortality, then it is unethical to use untreated controls
or placebos in the setting of AH [39,44].
12
The benefits of prednisolone may have been marginalized given the divergent results
between small clinical trials and the STOPAH study. First, these smaller studies were
subject to Type II errors. Second, differences in mortality from AH varied significantly
based on the study country and socioeconomic factors (i.e. in Mexico and India 3-month
mortality averaged 50-60%) [45]. Lastly, these studies varied due to different exclusion
criteria (i.e. presence of sepsis, acute kidney injury (AKI), severe encephalopathy as in
STOPAH) and so did not have comparable study populations. Based on these
considerations, it is conceivable that disease severity and local socioeconomic factors
masked the efficacy of prednisolone. Although findings varied, controlling for these
variables including locoregional differences may have revealed more consistent benefits
of steroids among AH patients.
Lastly, individuals with AH comprise a critically ill patient population in which it may be
difficult to obtain robust informed consent. For informed consent to be valid, however,
comprehension and voluntariness are required. Individuals with substance abuse
problems and hepatic encephalopathy may have impaired decision-making capacity
and comprehension, limiting their ability to provide truly informed consent [46,47]. It is
problematic to rely on these individuals to determine for themselves whether forgoing
standard of care or known effective therapy is reasonable. Developing standardized
methods for assessing and grading hepatic encephalopathy prior to research enrollment
may help to ensure an ethical balance between protecting research participants with
encephalopathy from undue influences and promoting their research participation.
Current state of clinical trials in alcoholic hepatitis
The current state of clinical trials in severe alcoholic hepatitis reflect the ethical dilemma
outlined above. Frequently, novel investigational agents are used in combination with
corticosteroids and outcomes compared to subjects treated with corticosteroids alone.
Clinical trials investigating ASK-1 inhibitors, N-acetylcysteine, metadoxine, and
granulocyte-colony stimulating factor (G-CSF) are examples of trials using novel agents
in conjunction with corticosteroids. In a similar vein, true placebo controlled trials of
13
investigational agents are frequently reserved for patients that fail corticosteroids.
Current trials utilizing mycophenolate mofetil and G-CSF have inclusion criteria
requiring corticosteroid failure prior to enrollment. Thus, true placebo controlled trials in
severe alcoholic hepatitis are presently uncommon.
V. Conclusion
There are formidable barriers to developing high-quality, well-powered RCTs of therapy
for severe AH. We have outlined several practical barriers and ethical challenges
related to designing such trials. All call for a balance between clarity of purpose, and the
inherent danger that greater stringency in regards to entry criteria, selection of end-
points and the like, will damage recruitment. We specifically address the issue of
placebo inclusion and ethical challenges to testing novel therapies using placebo control
arms. We suggest the field will advanced by the development of a plausible animal
model of AH, by the framing of a consensus on a composite clinical end-point that does
not solely rely on mortality, and the adoption of the recommendations of the NIAAA
Alcoholic Hepatitis Consortia regarding standard definitions, and when to require a liver
biopsy prior to study entry. While the AASLD and EASL consider prednisolone to be
standard of care in severe AH, this recommendation remains controversial given the
marginal benefits and questionable longterm safety of steroids in severe AH. Placebo
controlled trials without steroids may be necessary and ethically justified in certain
populations of AH who have not been adequately investigated. Future trials will have to
determine whether omitting corticosteroids is an ethical and pragmatic way to test novel
therapies in AH.
14
Table 1. Summary of placebo controlled trials of corticosteroids in alcoholic hepatitis
* While the primary endpoint did not reach statistical significance, prednisolone was associated with a decreased odds ratio of 28 day mortality on a multivariable regression analysis adjusted for predictors of mortality
AUTHOR (YEAR)
TOTAL SUBJECTS
(N)
THERAPEUTIC INTERVENTION
CONTROL GROUP
BIOPSY
MDF USED AS THRESHOLD
FOR STEROID THERAPY
ENDPOINT
MORTALITY BENEFIT OF
STEROID THERAPY
Porter (1971)[48]
20 Prednisolone IV tapered over 15
days Placebo No No Mortality No
Helman (1971)[9]
37 Prednisolone 40
mg daily x 4 weeks then tapered
Placebo Yes No Mortality Yes
Campra (1973)[49]
45
Prednisone 0.5 mg/kg/day for 3 weeks then 0.25 mg/kg/day for 3
weeks
Placebo No No Mortality No
Blitzer (1977)[50]
33
Prednisolone 10 mg QID x 14 days then tapered over
12 days
Placebo No No Mortality No
Shumaker (1978)[51]
27
Prednisolone 80 mg daily for 4-7
days then tapered over 4 weeks
Placebo No No Mortality No
Maddrey (1978)[12]
55 Prednisolone 40
mg/day x 30 days Placebo
No
No Mortality
Yes, for patients with
high discriminant
function
Depew (1980)[52]
28
Prednisolone 40 mg/day x 28 days then tapered over
two weeks
Placebo No Yes Mortality No
Theodossi (1982)[53]
55 Methylprednisolone
1 g/day x 3 days Placebo No No Mortality No
Mendenhall (1984)[54]
178
Prednisolone 60 mg/day x 4 days and tapered over
30 days
Placebo No No
30 day mortality and
overall survival
No
Carithers (1989)[55]
66 Prednisolone 32
mg/day x 28 days then tapered
Placebo No Yes 28 day
mortality Yes
Ramond (1992)[56]
61 Prednisolone 40
mg x 28 days Placebo Yes Yes
66 day mortality
Yes
Thursz (2015)[8]
1103
Prednisolone 40 mg/day x 28 days (with or without pentoxifylline
Placebo and Placebo+PTX
No Yes 28 day
mortality No*
15
Table 2. NIAAA Study Consortium Definitions of alcoholic hepatitis (AH)*
CERTAINTY OF AH DIAGNOSIS
DEFINITION
DEFINITE � Clinically diagnosed � Biopsy proven
PROBABLE
� Clinically diagnosed without confounding factors (e.g. possible ischemic hepatitis from multiorgan failure, uncontrolled gastrointestinal bleeding, hypotension, cocaine use, etc.)
� Heavy alcohol use and typical liver tests � Negative markers for immune and metabolic liver disease � Absence of sepsis, shock, cocaine use, or recent drug use
making DILI unlikely
POSSIBLE
� Clinically diagnosed � Potential confounding factors (e.g. ischemic hepatitis from
GI bleeding, septic shock, cocaine use, DILI, uncertain alcohol use)
� Atypical laboratory tests (e.g. AST < 50 IU/mL or > 400 IU/mL, AST/ALT ratio < 1.5, ANA Ab > 1:160, SMA > 1:80)
*Permission granted to represent this adaptation of the definitions outlined by Crabb et al. Gastroenterology 2016; 150;4:785-90.
Abbreviations: ALT = alanine aminotransferase, ANA = antinuclear antibody, AST = aspartate aminotransferase, DILI = drug-induced liver injury, SMA = smooth muscle antibody.
16
Table 3. NIAAA Study Consortium Proposed Inclusion and Exclusion Criteria for Clinical Trials in alcoholic hepatitis (AH)*
RECOMMENDATIONS
INCLUSION CRITERIA
� Onset of jaundice within prior 8 weeks � Alcohol Consumption:
o Females: > 40 g per day for at least 6 months o Males: > 60 g per day for at least 6 months
� Less than 60 days of abstinence before onset of jaundice � AST > 50 IU / L � AST and ALT < 400 IU / L � ALT / ALT > 1.5 � Serum total bilirubin > 3.0 mg/dL � Liver biopsy confirmation in patients with confounding factors
(e.g. potential ischemic hepatitis, DILI, immune or metabolic liver disease, viral hepatitis, etc.)
EXCLUSION CRITERIA
� Patients with very severe disease (MDF > 60 or MELD > 30) � Uncontrolled infections � Multiorgan failure � Uncontrolled upper gastrointestinal bleeding � Preexisting kidney injury with severe creatinine > 2.5 mg/dL � Other underlying liver diseases including HBV, autoimmune
liver diseases, Wilson disease, suspected DILI � HCC or other active malignancies except skin cancer � Pregnancy � Underlying diseases that might be exacerbated by proposed
treatments (e.g. HCV, hemocromathosis, latent TB) � Uncontrolled drug addiction
STRATIFICATION BASED ON SEVERITY
� MDF > 32 assuming a control prothrombin of 12 seconds � MELD > 20 � Less ill patients may be appropriate for early phases or
mechanistic studies *Permission granted to represent this adaptation of the definitions outlined by Crabb et al. Gastroenterology 2016; 150;4:785-90. Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, DILI = drug-induced liver injury, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, HCV = hepatitis C virus, MDF = Maddrey’s discriminant function test, MELD = Model for End-Stage Liver Disease, TB = tuberculosis.
17
References
[1] Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: Translational approaches to develop targeted therapies. Hepatology 2016;64:1343–55. doi:10.1002/hep.28530.
[2] Mathurin P, Bataller R. Trends in the management and burden of alcoholic liver disease. J Hepatol 2015;62:S38-46.
[3] Arsene D, Farooq O, Bataller R. New therapeutic targets in alcoholic hepatitis. Hepatol Int 2016;10:538–52.
[4] Tome S, Lucey MR. Review article: current management of alcoholic liver disease. Aliment Pharmacol Ther 2004;19:707–14.
[5] Cheong J, Stein E, Bataller R. Diagnostic Approaches and Clinical End Points of Treatment in Alcoholic Liver Disease. Alcohol. Non-Alcoholic Fat. Liver Dis., Cham: Springer International Publishing; 2016, p. 195–209. doi:10.1007/978-3-319-20538-0_10.
[6] Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011;365:1790–800.
[7] Im GY, Kim-Schluger L, Shenoy A, Schubert E, Goel A, Friedman SL, et al. Early Liver Transplantation for Severe Alcoholic Hepatitis in the United States--A Single-Center Experience. Am J Transplant 2016;16:841–9.
[8] Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015;372:1619–28.
[9] Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med 1971;74:311–21.
[10] Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572–85.
[11] Singh S, Murad MH, Chandar AK, Bongiorno CM, Singal AK, Atkinson SR, et al. Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis. Gastroenterology 2015;149:958–70.e12.
[12] Maddrey WC, Boitnott JK, Bedine MS, Weber FL, Mezey E, White RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75:193–9.
[13] O’Shea RS, Dasarathy S, McCullough AJ, Practice Guideline Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010;51:307–28.
[14] European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012;57:399–420.
[15] Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011;60:255–60.
[16] Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther 2008;27:1167–78.
18
doi:10.1111/j.1365-2036.2008.03685.x. [17] Nguyen-Khac E, Thevenot T, Piquet M-A, Benferhat S, Goria O, Chatelain D, et
al. Glucocorticoids plus N-Acetylcysteine in Severe Alcoholic Hepatitis. N Engl J Med 2011;365:1781–9. doi:10.1056/NEJMoa1101214.
[18] Dominguez M, Rincón D, Abraldes JG, Miquel R, Colmenero J, Bellot P, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol 2008;103:2747–56.
[19] Cholongitas E, Marelli L, Shusang V, Senzolo M, Rolles K, Patch D, et al. A systematic review of the performance of the model for end-stage liver disease (MELD) in the setting of liver transplantation. Liver Transplant 2006;12:1049–61. doi:10.1002/lt.20824.
[20] Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PCJ. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864–71. doi:10.1053/he.2000.5852.
[21] Kamath P, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464–70. doi:10.1053/jhep.2001.22172.
[22] Kamath PS, Therneau T, Shah VH. MELDing the Lille Score to More Accurately Predict Mortality in Alcoholic Hepatitis. Gastroenterology 2015;149:281–3. doi:10.1053/j.gastro.2015.06.020.
[23] Louvet A, Labreuche J, Artru F, Boursier J, Kim DJ, O’Grady J, et al. Combining Data From Liver Disease Scoring Systems Better Predicts Outcomes of Patients With Alcoholic Hepatitis. Gastroenterology 2015;149:398–406.e8. doi:10.1053/j.gastro.2015.04.044.
[24] Abe T, Tashiro H, Hattori M, Kuroda S, Tahara H, Ohira M, et al. Prediction of long-term survival by using the Glasgow Prognostic Score in patients with hepatocellular carcinoma after liver transplantation. Hepatol Res 2016;46:622–33. doi:10.1111/hepr.12597.
[25] Kaltenborn A, Schrem H, Reichert B, Braun F, Emmanouilidis N, Klempnauer J, et al. The Glasgow Prognostic Score and its variants predict mortality in living donor but not in deceased donor liver transplantation for hepatocellular carcinoma: A double-center validation study. Hepatol Res 2016. doi:10.1111/hepr.12818.
[26] Roth N, Kanel G, Kaplowitz N. Alcoholic foamy degeneration and alcoholic fatty liver with jaundice: Often overlooked causes of jaundice and hepatic decompensation that can mimic alcoholic hepatitis. Clin Liver Dis 2015;6:145–8. doi:10.1002/cld.520.
[27] Ruiz P, Michelena J, Altamirano J, Miquel R, Moreira L, Cárdenas A, et al. Hepatic hemodynamics and transient elastography in alcoholic foamy degeneration: report of 2 cases 2012;11:399–403.
[28] Hardy T, Wells C, Kendrick S, Hudson M, Day CP, Burt AD, et al. White cell count and platelet count associate with histological alcoholic hepatitis in jaundiced harmful drinkers. BMC Gastroenterol 2013;13:55. doi:10.1186/1471-230X-13-55.
[29] Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146:1231-9-6.
[30] Mookerjee RP, Lackner C, Stauber R, Stadlbauer V, Deheragoda M, Aigelsreiter
19
A, et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011;55:1103–11. doi:10.1016/j.jhep.2011.02.021.
[31] Crabb DW, Bataller R, Chalasani NP, Kamath PS, Lucey M, Mathurin P, et al. Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia. Gastroenterology 2016;150:785–90. doi:10.1053/j.gastro.2016.02.042.
[32] Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis 2016;8:59–63. doi:10.1002/cld.571.
[33] Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141–5.
[34] Miller FG, Brody H. What makes placebo-controlled trials unethical? Am J Bioeth 2002;2:3–9.
[35] Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med 2000;133:455–63.
[36] Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and specific cases. Ann Intern Med 2000;133:464–70.
[37] Emanuel EJ, Miller FG. The ethics of placebo-controlled trials--a middle ground. N Engl J Med 2001;345:915–9.
[38] Simon R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists? Ann Intern Med 2000;133:474–5.
[39] Michels KB, Rothman KJ. Update on unethical use of placebos in randomised trials. Bioethics 2003;17:188–204.
[40] World Medical Association Declaration of Helsinki. JAMA 1997;277:925. doi:10.1001/jama.1997.03540350075038.
[41] WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects 2013.
[42] McPherson S, Lucey MR, Moriarty KJ. Decompensated alcohol related liver disease: acute management. BMJ 2016:i124. doi:10.1136/bmj.i124.
[43] Thursz M, Louvet A, Kim D, Labreuche J, Atkinson S, Sidhu S, et al. Corticosteroids are the only remaining pharmacological option for severe alcoholic hepatitis: a meta-analysis of individual data on 1974 patients. 67th Annu. Meet. Am. Assoc. Study Liver Dis., WILEY-BLACKWELL; 2016.
[44] Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med 1994;331:394–8.
[45] Altamirano J, Higuera-de laTijera F, Duarte-Rojo A, Martínez-Vázquez MA, Abraldes JG, Herrera-Jiménez LE, et al. The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis. Am J Gastroenterol 2011;106:1472–80.
[46] Walker R, Logan TK, Clark JJ, Leukefeld C. Informed consent to undergo treatment for substance abuse: a recommended approach. J Subst Abuse Treat 2005;29:241–51.
[47] Anderson EE, DuBois JM. The need for evidence-based research ethics: a review of the substance abuse literature. Drug Alcohol Depend 2007;86:95–105.
20
[48] Porter HP, Simon FR, Pope CE, Volwiler W, Fenster LF. Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial. N Engl J Med 1971;284:1350–5. doi:10.1056/NEJM197106172842404.
[49] Campra JL, Hamlin EM, Kirshbaum RJ, Olivier M, Redeker AG, Reynolds TB. Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial. Ann Intern Med 1973;79:625–31.
[50] Blitzer BL, Mutchnick MG, Joshi PH, Phillips MM, Fessel JM, Conn HO. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double-blind randomized study. Am J Dig Dis 1977;22:477–84.
[51] Shumaker JB, Resnick RH, Galambos JT, Makopour H, Iber FL. A controlled trial of 6-methylprednisolone in acute alcoholic hepatitis. With a note on published results in encephalopathic patients. Am J Gastroenterol 1978;69:443–9.
[52] Depew W, Boyer T, Omata M, Redeker A, Reynolds T. Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy. Gastroenterology 1980;78:524–9.
[53] Theodossi A, Eddleston AL, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut 1982;23:75–9.
[54] Mendenhall CL, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T, Seeff LB, et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984;311:1464–70. doi:10.1056/NEJM198412063112302.
[55] Carithers RL, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, et al. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med 1989;110:685–90.
[56] Ramond MJ, Poynard T, Rueff B, Mathurin P, Théodore C, Chaput JC, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992;326:507–12. doi:10.1056/NEJM199202203260802.