Seven Day Versus Fourteen-day Corticosteroid in Patients With Severe Alcohol -Associated Hepatitis- A Double Blind Randomized Controlled Trail (STASH II)

Alcohol-associated hepatitis (AAH) is one of the most severe manifestations of the spectrum of alcohol-related liver disease (ARLD). Severe alcohol-associated hepatitis (AAH), defined by a Maddrey's Discriminant Function score (mDF) greater than 32, can be associated with a greater than 20-30% mortality rate within 3 months in patients.1 Several therapies have been evaluated for AAH, but only corticosteroids and pentoxifylline have shown some benefit in the treatment.2 Currently, corticosteroids (prednisolone 40 mg or equivalent dose) are the recommended standard of care for patients with AAH who have severe disease identified by NIAAA criteria as steroids short-term mortality benefits.3 However, the dosing schedule of corticosteroids is not clearly stated. American Association for the Study of Liver Disease (AASLD), the European Association for the Study of Liver (EASL), and the American College of Gastroenterology (ACG) recommend using a daily dose of 40mg of oral prednisolone for 28 days, followed by abrupt discontinuation.4-6 While EASL mentions tapering doses over 2 to 3 weeks after 40 mg of therapy for 4 weeks or abrupt withdrawal. (Table 1) The reason for this dosing schedule of 40 mg for 4 weeks has been derived from studies performed more than 4 decades ago.7,8 The investigators recently reported that tapering of prednisolone over 4 weeks reduces the risk of infection in these patients compared to those receiving fixed 40 mg dose of prednisolone. The average daily prednisolone dose was 40 mg/day in the fixed-dose group compared with only 28.4±6.1 mg/day in the tapered-dose group (P<0.001), although the duration of prednisolone therapy was similar in both groups (22.1±9.1 days in the fixed-dose arm vs. 23±8.8 days in the tapered-dose arm; P=0.44). The lower dose of prednisolone led to a reduction in the incidence of infections. To continue the research in this area, the investigators wanted to test whether reducing the duration of prednisolone reduces infections.

- All patients of AAH with MELD score >21 and/or mDF >32 visiting the hospital (OPD/IPD) in the study period who do not have any contraindications for oral prednisolone therapy will be included in the study.

This is a double-blinded RCT. The CTC will generate a random allocation sequence using computer-based random numbers. Treatment allocation will be performed using block randomization with a block size of 10. The CTC will randomly assign patients to either the prednisolone 7-day or 14-day prednisolone using the sealed opaque sequentially numbered envelopes (SNOSE) method. The patients and investigators will be blinded to the allocated treatment. The drugs will be administered by the CTC.

STUDY METHODS / STUDY PROCEDURE / METHODS OF ASSESSMENT - All patients with AAH will be screened for inclusion in the study. Investigations to exclude infections before initiation of corticosteroids, including complete blood counts, cultures (blood, ascitic and urine), serum procalcitonin levels and Chest radiographs, will be performed. Design of infection screening is based on previous studies (8,9,10). Randomisation will be done centrally through a computer-generated randomisation sequence. One arm will be started on a prednisolone dose of 40mg/day for 7 days, followed by a placebo from day 8 to day 14 if Lille on Day 7 is < 0.45. The second arm will be started on prednisolone - 40mg per day for 7 days, followed by same dose for next 7 days if Lille is less than < 0.45. Lille scores will be calculated on Day 7; non-responders will discontinue the treatment. Patients will be screened for infections till 90 days from the day of initiation of prednisolone. The three patient arms will be compared for severity scores of the disease, rate and severity of infections, diabetic control, post treatment outcomes, and mortality. Patients enrolled in the study should not receive pentoxifylline, NAC, omega 3 fatty acid lipid emulsions, prophylactic antibiotics, granulocyte colony-stimulating factor, faecal microbiota transplantation or any other experimental therapies.

Sample size-A recent study (STASH) reported that 33.1% of patients with 28 day fixed dose steroid develop infections, and the investigators believe that 7 day steroid therapy may reduce infections significantly by 20% (13.1%) and with a power of 80%, significance level of 5%, the current study will need to include 66 in each arm, i.e., 132 in total. Considering a 10% attrition rate, the number of participants needed to included are 146 participants, i.e., 73 in each arm. Randomization will be done centrally at the primary centre, i.e., AIG Hospitals, by the clinical trial coordinators with a block size of 10 and randomized equally in a 1:1 ratio to either a 7-day steroid or 14-day steroid. Each center shall provide the details of respective CTCs or an individual who will contact the primary center CTC (at least 12 hours prior to the planned prednisolone initiation) for the randomized group.