Evaluation of BI 685509 on Portal Hypertension in Patients with Decompensated Cirrhosis Post-First Decompensation Event

The primary objective of this trial is to evaluate the **safety** and **tolerability** of BI 685509 in patients with clinically significant portal hypertension (CSPH) in decompensated cirrhosis due to non-cholestatic liver diseases, in addition to standard care. The primary endpoint is the estimation of the percentage change in hepatic venous pressure gradient (HVPG) from baseline after 8 weeks of treatment, compared to placebo. This is clinically relevant as it aims to assess the potential of BI 685509 to reduce portal hypertension, which is a critical factor in the management of decompensated cirrhosis and its complications.

The clinical trial involves a total of **20 participants** diagnosed with **clinically significant portal hypertension (CSPH)** in decompensated cirrhosis due to non-cholestatic liver disease. The study population includes both male and female subjects aged between 18 and 75 years. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of cirrhosis due to non-cholestatic liver disease, such as hepatitis C virus (HCV), hepatitis B virus (HBV), non-alcoholic steatohepatitis (NASH), alcohol-related liver disease, autoimmune hepatitis, Wilson’s disease, haemochromatosis, or alpha-1 antitrypsin deficiency. The trial population is required to have experienced at least one previous clinically significant decompensation event with clinical resolution at least four weeks prior to the start of screening. Lifestyle considerations include the requirement for patients with alcohol-related cirrhosis to abstain from significant alcohol misuse for a minimum of two months prior to screening and throughout the trial. Participants receiving statins or non-selective beta-blockers (NSBBs) or carvedilol must be on a stable dose for a specified period before screening. The trial includes a vulnerable population, and all participants must provide signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, and parallel group** study to evaluate the effects of the investigational drug **BI 685509** on **clinically significant portal hypertension (CSPH)** in patients with decompensated cirrhosis. The trial aims to assess the safety and tolerability of BI 685509, with the primary objective being the estimation of the percentage change in hepatic venous pressure gradient (HVPG) from baseline after 8 weeks of treatment compared to placebo. The study will involve an up-titration to a fixed dose regimen of oral BI 685509, administered in the form of film-coated tablets.

The trial is expected to last approximately 8 weeks, with participant involvement beginning from the screening visit and concluding with the end-of-study visit. The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis of cirrhosis due to non-cholestatic liver disease, and previous decompensation events. Following successful screening, participants will be randomized and commence treatment, with follow-up visits scheduled to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the 8-week treatment period, where final assessments will be conducted.

Participants are expected to be involved in the study for the entire 8-week duration unless conditions arise that necessitate early termination. Such conditions include the occurrence of CTCAE grade 3 or higher hypotension or syncope, or discontinuation due to these adverse events. The trial will also monitor secondary endpoints, including the occurrence of further decompensation events and the response rate defined as a greater than 10% reduction in HVPG from baseline. The trial is conducted in accordance with ICH-GCP guidelines, ensuring the integrity and scientific validity of the study.

The clinical trial involves the administration of **BI 685509**, an experimental medication developed by Boehringer Ingelheim International. BI 685509 is provided in the form of a **film-coated tablet** and is of chemical origin. The active substance, also named BI 685509, is administered orally. The trial includes three different dosing regimens: a maximum daily dose of 2 mg with a total dose of 14 mg over a 1-week period, a maximum daily dose of 4 mg with a total dose of 28 mg over a 1-week period, and a maximum daily dose of 6 mg with a total dose of 252 mg over a 6-week period. The dosing schedule is designed to assess the safety and efficacy of BI 685509 in patients with clinically significant portal hypertension (CSPH) in decompensated cirrhosis.

In addition to the experimental medication, the trial employs a **placebo** control to ensure the validity of the results. The placebo is designed to match the BI 685509 film-coated tablet in appearance but contains no active substance. The placebo is used to compare the effects of the experimental treatment against a non-active control, allowing for a more accurate assessment of the medication's efficacy. The placebo is administered in a similar manner to the active treatment, ensuring that the study remains double-blind and that neither the participants nor the investigators are aware of the treatment assignments.

The efficacy of the investigational product, **BI 685509**, in the clinical trial will be assessed primarily by measuring the percentage change in hepatic venous pressure gradient (HVPG) from baseline after 8 weeks of treatment. HVPG is a critical parameter in evaluating **portal hypertension** in patients with decompensated cirrhosis. The primary endpoint is the percentage change in HVPG, measured in mmHg, after the treatment period compared to placebo.

Secondary endpoints include the occurrence of a response, defined as a greater than 10% reduction from baseline HVPG after 8 weeks, and the occurrence of further decompensation events such as ascites, variceal hemorrhage (VH), or overt hepatic encephalopathy (HE) during the treatment period. Additionally, the trial will monitor for the occurrence of CTCAE grade 3 or higher hypotension or syncope, as well as any discontinuation due to these adverse events during the 8-week period.

Data collection will involve HVPG measurements, which are to be conducted per protocol, based on the investigator's judgment. The trial is designed as a randomized, double-blind, placebo-controlled, and parallel-group study, ensuring rigorous assessment of the investigational product's efficacy in the target patient population. The trial will also ensure that patients are stabilized on any concomitant medications, such as statins or non-selective beta-blockers (NSBBs), to maintain consistent treatment conditions throughout the study.