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

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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 (mrl@medicine.wisc.edu) and Dr. Ramon

Bataller, Division of Gastroenterology, Hepatology and Nutririon, Pittsburgh Liver

Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

(Bataller@pitt.edu).

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.