Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium

Abstract

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.

Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute‐on‐chronic liver failure

“…Recently, and due to increased scientific efforts in this area, pathophysiological mechanisms are increasingly understood 25–27 . However, prediction of ACLF development remains a challenge in clinical routine 13 and apart from treatment of triggering factors, there are no ACLF‐specific therapeutic options 28,29 . Therefore, studies evaluating the natural course of decompensated cirrhosis and ACLF are required.…”

“…Apart from albumin substitution in a particular subgroup of patients, up to date, there is no established disease-modifying therapy to prevent further progression or the development of complications neither in decompensated cirrhosis nor in ACLF. 29 Additionally, early detection of complications may be difficult in times of the COVID-19pandemic since routine clinical visits are commonly postponed or performed via telemedical contact. 3 Additionally, alcohol consumption likely increased during the pandemic.…”

Letter: real‐world use of terlipressin in patients with the hepatorenal syndrome—authors' reply

“…Again, we agree here, as this competing risk needs to be accounted for in liver clinical trial designs. 12 That said, we had no liver transplantations during terlipressin treatment in our cohort, and only 2% were transplanted by 90 days. Therefore, we do not believe it to be a significant confounder in our survival analyses.…”

Outcomes and potential surrogate markers for future clinical trials of non‐alcoholic steatohepatitis cirrhosis

“…Considering the poor prognosis in the decompensated stage, transplant‐free survival is recommended as the primary endpoint for Phase III trials. 25 , 45 Either surrogate or secondary endpoints for Phase III trials (such as development of multiorgan involvement as in acute‐on‐chronic liver failure), or primary endpoints for Phase II trials focusing on specific decompensating events (recurrence of variceal haemorrhage, hepatic encephalopathy, control of ascites, etc), should be chosen according to the mechanism of action of the drug under investigation and the specific targeted patient subpopulation. Inclusion of patient reported outcomes should become standard practice in this symptomatic, late stage of NASH cirrhosis.…”