A home-based, multidisciplinary liver optimisation programme for the first 28 days after an admission for acute-on-chronic liver failure (LivR well): a study protocol for a randomised controlled trial.

BACKGROUND: Acute-on-chronic liver failure (ACLF) represents a rising global healthcare burden, characterised by increasing prevalence among patients with decompensated cirrhosis who have a 28-day transplantation-free mortality of 33.9%. Due to disease complexity and a high prevalence of socio-economic disadvantage, there are deficits in quality of care and adherence to guideline-based treatment in this cohort. Compared to other chronic conditions such as heart failure, those with liver disease have reduced access to integrated ambulatory care services. The LivR Well programme is a multidisciplinary intervention aimed at improving 28-day mortality and reducing 30-day readmission through a home-based, liver optimisation programme implemented in the first 28 days after an admission with either ACLF or hepatic decompensation. Outcomes from our feasibility study suggest that the intervention is safe and acceptable to patients and carers. METHODS: We will recruit adult patients with chronic liver disease from the emergency departments, in-patient admissions, and an ambulatory liver clinic of a multi-site quaternary health service in Melbourne, Australia. A total of 120 patients meeting EF-Clif criteria will be recruited to the ACLF arm, and 320 patients to the hepatic decompensation arm. Participants in each cohort will be randomised to the intervention arm, a 28-day multidisciplinary programme or to standard ambulatory care in a 1:1 ratio. The intervention arm includes access to nursing, pharmacy, physiotherapy, dietetics, social work, and neuropsychiatry clinicians. For the ACLF cohort, the primary outcome is 28-day mortality. For the hepatic decompensation cohort, the primary outcome is 30-day re-admission. Secondary outcomes assess changes in liver disease severity and quality of life. An interim analysis will be performed at 50% recruitment to consider early cessation of the trial if the intervention is superior to the control, as suggested in our feasibility study. A cost-effectiveness analysis will be performed. Patients will be followed up for 12 weeks from randomisation. Three exploratory subgroup analyses will be conducted by (a) source of referral, (b) unplanned hospitalisation, and (c) concurrent COVID-19. The trial has been registered with the Australian New Zealand Clinical Trials Registry. DISCUSSION: This study implements a multidisciplinary intervention for ACLF patients with proven benefits in other chronic diseases with the addition of novel digital health tools to enable remote patient monitoring during the COVID-19 pandemic. Our feasibility study demonstrates safety and acceptability and suggests clinical improvement in a small sample size. An RCT is required to generate robust outcomes in this frail, high healthcare resource utilisation cohort with high readmission and mortality risk. Interventions such as LivR Well are urgently required but also need to be evaluated to ensure feasibility, replicability, and scalability across different healthcare systems. The implications of this trial include the generalisability of the programme for implementation across regional and urban centres. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621001703897 . Registered on 13 December 2021. WHO Trial Registration Data Set. See Appendix 1.

Opaganib in Coronavirus Disease 2019 Pneumonia: Results of a Randomized, Placebo-Controlled Phase 2a Trial.

Background: Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe coronavirus disease 2019 (COVID-19) pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods: This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in 8 sites in the United States. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo. Results: There were no safety concerns arising in this study. The incidence of ≥Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this nonpowered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge. Conclusions: In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population.

Short-term intraperitoneal catheters: An ambulatory care intervention for refractory ascites secondary to cirrhosis during COVID-19.

BACKGROUND AND AIM: Patients with refractory ascites have frequent hospital admissions, which pose exposure risks in the context of the COVID-19 pandemic. The aim of this study was to investigate the safety and efficacy of a novel 12-week, multidisciplinary ambulatory care program allowing frequent low-volume ascitic drainage through a tunneled, intraperitoneal catheter (IPC). METHODS: Adult patients with cirrhosis complicated by refractory ascites were recruited through a liver clinic in a tertiary health service in Melbourne, Australia from April to December 2020. All patients were enrolled in a 12-week multidisciplinary program including medical, nursing, dietetics, and pharmacy support. A Rocket Medical IPC was inserted on day 1 with 1-2 L of ascitic fluid drained over 1-3 sessions per week either at the patients' homes or at the hospital day ward. Patients' demographics, death, complications, and self-reported outcomes were recorded. RESULTS: Twelve patients were enrolled with a median of 65-day (interquartile range [IQR]: 16.5-93) IPC duration between April and December 2020 across two periods of COVID-related lockdown in Melbourne, Australia. There were no IPC-related deaths. Early removal was necessitated in three patients due to leakage, nonadherence, and bacteremia. On day 30, the median self-reported health score increased from 50 (IQR: 50-70) to 78 (IQR: 50-85), attributable to a reduction in symptom burden. CONCLUSION: A multidisciplinary IPC program including the use of short-term IPC was safe and associated with a self-reported improvement in perceptions of health. In the context of the COVID-19 pandemic, the program aimed to reduce patient and clinician exposure, which is maintaining engagement and management of decompensated cirrhosis.