Evaluation of BI 685509 and Empagliflozin on Portal Hypertension in Compensated Cirrhosis Patients with CSPH: A Randomized, Open-Label, Parallel Group Study

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 compensated cirrhosis due to hepatitis B virus (HBV), hepatitis C virus (HCV), and non-alcoholic steatohepatitis (NASH), with or without type 2 diabetes mellitus (T2DM). Additionally, the trial aims to assess the combination of BI 685509 and empagliflozin in patients with CSPH in compensated cirrhosis due to NASH with T2DM, alongside 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. This is clinically relevant as it may provide insights into the potential therapeutic benefits of these treatments in managing portal hypertension, a significant complication of liver cirrhosis.

The clinical trial involves a total of **38 participants** diagnosed with **portal hypertension** in the context of compensated cirrhosis due to HBV, HCV, or NASH, with or without Type 2 Diabetes Mellitus (T2DM). The study population includes both male and female subjects aged between 18 and 75 years. Participants were selected based on specific clinical criteria, including documented clinical signs of clinically significant portal hypertension (CSPH) and a diagnosis of compensated cirrhosis. The trial population is characterized by a stable health status, with requirements for stable doses of statins and non-selective beta-blockers (NSBBs) or carvedilol if applicable. Lifestyle considerations such as diet and physical activity are not explicitly detailed, but the presence of metabolic syndrome comorbidities like overweight/obesity, hypertension, and hyperlipidemia is noted. The trial does include a vulnerable population, ensuring comprehensive representation of the affected demographic.

The clinical trial is designed to evaluate the **safety** and tolerability of the investigational drug BI 685509, both as a monotherapy and in combination with **empagliflozin**, in patients with clinically significant **portal hypertension** (CSPH) in compensated cirrhosis. This is a randomized, open-label, parallel-group trial with a primary objective to estimate the percentage change in hepatic venous pressure gradient (HVPG) from baseline after an 8-week treatment period. The trial is categorized as a Phase 4 study, focusing on patients with CSPH due to hepatitis B virus (HBV), hepatitis C virus (HCV), or non-alcoholic steatohepatitis (NASH), with or without type 2 diabetes mellitus (T2DM).

The trial will involve a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, clinical signs of CSPH, and a diagnosis of compensated cirrhosis. Participants must provide written informed consent and meet specific clinical criteria, including a baseline HVPG of at least 10 mmHg. The screening period will include a gastroscopy to document esophageal or gastric varices. Following the screening, eligible participants will be randomized to receive either BI 685509 alone or in combination with empagliflozin, administered orally in the form of film-coated tablets.

Participants will be involved in the trial for a total of 8 weeks, during which they will attend regular follow-up visits to monitor safety and efficacy outcomes. The primary endpoint is the percentage change in HVPG from baseline, while secondary endpoints include the occurrence of a response defined as a greater than 10% reduction in HVPG, and the incidence of decompensation events such as ascites, variceal hemorrhage, or overt hepatic encephalopathy. The trial will also monitor for adverse events, including hypotension or syncope, which may lead to early termination of participation if deemed necessary by the investigator.

The end-of-study visit will occur at the conclusion of the 8-week treatment period, where final assessments will be conducted to evaluate the overall impact of the treatment on portal hypertension. Participants may be withdrawn from the study early if they experience significant adverse events or if they do not adhere to the study protocol. The trial is expected to conclude by November 20, 2023, with recruitment having commenced on July 28, 2023.

The clinical trial involves the administration of **EMPAGLIFLOZIN**, a film-coated tablet, as part of the experimental treatment regimen. EMPAGLIFLOZIN is a chemical compound used in this study to assess its effects on portal hypertension in patients with compensated cirrhosis. The medication is administered orally with a maximum daily dose of 10 mg and a total maximum dose of 80 mg over the course of the trial. The treatment period is set for 8 weeks. EMPAGLIFLOZIN is provided as a bulk product (Jardiance, MA number EU/1/14/930/010-018) and is specifically packaged and labeled for clinical trial supply.

Another experimental medication used in the trial is **BI 685509**, also in the form of a film-coated tablet. This chemical compound is administered orally in varying dosages depending on the specific trial group. The maximum daily doses are 2 mg, 4 mg, and 6 mg, with corresponding total maximum doses of 110 mg, 192 mg, and 252 mg, respectively. The treatment duration for BI 685509 is also 8 weeks. The medication is manufactured by Boehringer Ingelheim International and is used to evaluate its safety and tolerability in patients with clinically significant portal hypertension (CSPH) in compensated cirrhosis.

In this trial, there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments explicitly mentioned. The focus is on the effects of the experimental medications, EMPAGLIFLOZIN and BI 685509, either alone or in combination, on portal hypertension. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

The efficacy of the clinical trial will be assessed primarily by evaluating the percentage change in **hepatic venous pressure gradient (HVPG)** from baseline after 8 weeks of treatment. This primary endpoint will be measured in millimeters of mercury (mmHg) and is crucial for determining the impact of the investigational products on portal hypertension in patients with clinically significant portal hypertension (CSPH) in compensated cirrhosis. The primary analysis will include treated patients with baseline HVPG measurements, forming the Full Analysis Set (FAS), assuming all patients complete the treatment duration.

Secondary endpoints will include the occurrence of a response, defined as a greater than 10% reduction from baseline HVPG after 8 weeks of treatment. Additionally, the trial will monitor the occurrence of decompensation events such as ascites, variceal hemorrhage (VH), and overt hepatic encephalopathy (HE) during the treatment period. The incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher hypotension or syncope, as well as discontinuation due to these conditions, will also be evaluated. These secondary endpoints will provide further insights into the efficacy and safety profile of the treatment regimen.