Table 1 Summary of recommendations

1

Alcohol use should be quantified based on the number of standard drinks and converted to grams of ethanol to provide global uniformity and comparability of research studies. Frequency and duration of drinking should be assessed, including change over time to capture remote and recent use (Table 2)

2

For clinical trial design, we recommend using DSM-5 criteria to diagnose AUD¹⁷ or ICD-11 criteria for alcohol dependence¹⁸

3

Considering the high prevalence of cardiometabolic risk factors in patients with ALD, for the purposes of clinical trials, populations with ALD should include both patients with and without these known cardiometabolic risk factors, recognizing that the relative contribution of metabolic risk factors versus alcohol intake to SLD might vary from individual to individual. These cardiometabolic risk factors should be carefully assessed in clinical trials

4

For clinical trial design focusing on the effect of alcohol use on progression of SLD, we recommend a threshold of drinking for women as 140 g or more per week and for men as 210 g or more per week over an extended period. These amounts are above the WHO low-risk level of drinking for female individuals and above the NIAAA level of heavy drinking for male individuals²³ and correspond to the threshold for MetALD. MetALD refers to individuals with SLD who have cardiometabolic risk factor (factors) and consume greater amounts of alcohol per week (threshold of drinking for women as 140–350 g per week and for men as 210–420 g per week)²⁶ (Fig. 1)

5

For the purposes of clinical trial design, we recommend utilizing the term ‘advanced chronic liver disease (ACLD)’ to include patients with MetALD and ALD with stage 3–4 fibrosis

6

For clinical trial design, patients with MetALD and ALD must be classified into distinct subpopulations that can be linked to indications for regulatory approval of drugs: early-stage ALD without advanced fibrosis; compensated advanced chronic liver disease (cACLD); decompensated ALD and alcohol-associated hepatitis

7

When conducting clinical trials in AUD and/or ALD, we recommend measuring stigma and discussing ways to reduce stigma with all team members (e.g., using person first language, recognizing that both AUD and ALD are treatable conditions)^44,45

8

Demographic data such as age, biological sex, gender identity, race, family history of AUD and ALD and ethnicity should be included

9

Metabolic comorbidities such as weight, height, body mass index, waist–hip ratio, systolic blood pressure, diastolic blood pressure, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and HbA1c should be included

10

Biomarkers as noted in Box 1 should be used for identifying stage of disease, safety and response considerations for therapeutic interventions, and trial end points in terms of liver function trajectory in response to treatment, as these are crucial components for a clinical trial

11

Given the influence of genetic factors that modify risk of fibrosis, inflammation and steatosis in patients with ALD, future clinical trials in patients with early-stage ALD and cACLD should consider stratifying patients to balance the study populations according to known genetic risk factors

12

Inclusion and exclusion criteria for clinical trials should be tailored to the subpopulation of ALD as detailed in Box 2

13

End points for clinical trials should be clinically meaningful in the context of the stage of disease and the phase of clinical development (as detailed in Table 4)

14

Any drug trial that involves participants with ALD, irrespective of the drug target, should account for potential alterations in pharmacodynamics and pharmacokinetics owing to the potential effects of both alcohol consumption and ACLD

15

Trials for ALD should acknowledge explicitly the benefits of abstinence and reduction in drinking and the potential need for alcohol treatment. Brief motivational interviewing for reducing heavy drinking should be offered with few exceptions

16

AUD treatment strategies should be tailored to the severity of AUD: brief interventions and motivational enhancement are generally best for those with at-risk drinking or mild AUD, whereas more intensive treatments are best for those with moderate-to-severe AUD

17

For clinical trials in ALD, particularly those testing distinct AUD treatment (treatments) or those that will provide standardized intervention for alcohol use as part of the protocol, any such treatments including pharmacological, behavioural or cognitive therapies should be pre-specified in the protocol with stratified results if more than one treatment modality for AUD is pre-specified

18

Non-normal data are common in AUD and ALD clinical trials, and appropriate transformations or non-parametric approaches should be applied. Robust statistical models should be used to assess outcomes over time. Modern missing data methods are recommended for sensitivity analyses

19

In AUD and ALD research, innovative trial designs should be considered, including group sequential designs include predetermined interim analyses that allow the trial to stop early for efficacy, futility or safety, and enrichment designs may start with broad eligibility criteria, but modify eligibility criteria to enrich the sample for the group in which the intervention seems most promising

20

Early-phase clinical trials for new drug development should exclude individuals with alcohol-associated hepatitis and decompensated ACLD

21

Standardized reporting of adverse events that include seriousness, expectedness and relatedness should be required while avoiding the conclusion that ‘any event is possibly related’ when determining whether an event is related to the investigational product or intervention

22

Adverse events are of special concern in individuals with conditions that are associated with a high complication rate — the investigator must distinguish between events that are most likely caused by the underlying condition (e.g., ALD), and those that are related to the investigational product

23

Oversight by a DSMB whose members are knowledgeable about the natural history of ALD is essential

24

A separate hepatic safety adjudication committee that conducts adjudication in a blinded manner and reports to the DSMB should be utilized in adjudicating the diagnosis of DILI or drug-induced kidney injury in the presence of severe alcohol-associated hepatitis or decompensated ACLD when there is baseline elevation in the liver tests and serum creatinine concentrations

25

Inclusion of study stopping rules might enhance study safety and efficacy by allowing early termination for either positive (primary end point reached) or negative (likely futility or excessive harm) outcomes

26

Individual stopping rules should be in place to hold and/or discontinue investigational drug treatment in patients with evidence of infections refractory to treatment, an increase in level of AST >500 or ALT >400 without alternative explanation, development of liver failure characterized by rising bilirubin, worsening coagulopathy or the development of AKI with hepatorenal physiology during further evaluation and adjudication

27

Strategies should be developed for both recruitment and retention (Table 5) to improve the validity, reproducibility and applicability of clinical trials for AUD and ALD

28

Future studies designed to address heavy drinking and AUD in patients with ALD should include addiction medicine experts as well as hepatologists to assist in selecting key measures for alcohol use and incorporating methods and outcomes from both AUD and ALD research arenas to achieve the highest quality studies