A Study to Test Whether BI 685509 Alone or in Combination With Empagliflozin Helps People With Liver Cirrhosis Caused by Viral Hepatitis or Non-alcoholic Steatohepatitis (NASH) Who Have High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver)

Study Overview
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Brief Summary
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This study is open to adults with liver cirrhosis caused by hepatitis B, hepatitis C or nonalcoholic steatohepatitis (NASH). People can join this study if they have high blood pressure in the portal vein (main vessel going to the liver). The purpose of this study is to find out whether a medicine called BI 685509 taken alone or in combination with a medicine called empagliflozin helps people with this condition. Participants take BI 685509 as tablets twice a day for 8 weeks. Half of the participants with NASH who also have type 2 diabetes take empagliflozin as tablets once a day in addition to BI 685509. Participants are in the study for about 3 months. During this time, they visit the study site about 10 times. At 2 of the visits, the doctors check the pressure in a liver vein to see whether the treatment works. This is done with a catheter (a long thin tube) and gives information about the pressure in the portal vein. The doctors also regularly check participants' health and take note of any unwanted effects.

Official Title
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Randomised, Open-label and Parallel Group Trial to Investigate the Effects of Oral BI 685509 Alone or in Combination With Empagliflozin on Portal Hypertension After 8 Weeks Treatment in Patients With Clinically Significant Portal Hypertension (CSPH) in Compensated Cirrhosis

Conditions
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Liver Diseases, Hypertension, Portal

Intervention / Treatment
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* Drug: BI 685509
* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial Male or female who is ≥ 18 (or who is of legal age in countries where that is greater than 18) and ≤ 75 years old at screening (Visit 1a) Clinical signs of Clinically Significant Portal Hypertension (CSPH) as described by either one of the points below. Each trial patient must have a gastroscopy during the screening period (Visit 1b) or within 6 months prior to screening (Visit 1b). documented endoscopic proof of oesophageal varices and / or gastric varices at screening (Visit 1b) or within 6 months prior to screening (Visit 1b) documented endoscopic-treated oesophageal varices as preventative treatment CSPH defined as baseline Hepatic Venous Pressure Gradient (HVPG) ≥ 10 mmHg (measured at Visit 1c), based on a local interpretation of the pressure tracing Diagnosis of compensated cirrhosis due to Hepatitis C virus (HCV), Hepatitis B virus (HBV), or Non-Alcoholic Steatohepatitis (NASH) with or without Type 2 Diabetes Melitus (T2DM). Diagnosis of cirrhosis must be based on histology (historical data is acceptable) or on clinical evidence of cirrhosis (e.g. platelet count < 150 x 109/L [150 x 103/microlitre (μL)], nodular liver surface on imaging or splenomegaly etc.) Diagnosis of NASH based on either i. Current or historic histological diagnosis of NASH OR steatosis OR ii. Clinical diagnosis of NASH based on historic or current imaging diagnosis of fatty liver (Fibroscan, Ultrasound (US), Magnetic Resonance Imaging (MRI), Computed Tomography (CT)) AND at least 2 current or historic comorbidities of the metabolic syndrome (overweight/obesity, T2DM, hypertension, hyperlipidemia) Willing and able to undergo HVPG measurements per protocol (based on Investigator judgement) If receiving statins must be on a stable dose for at least 3 months prior to screening (Visit 1b), with no planned dose change throughout the trial If receiving treatment with Non-Selective Beta-Blocker (NSBBs) or carvedilol must be on a stable dose for at least 1 months prior to screening (Visit 1b), with no planned dose change throughout the trial Further inclusion criteria apply Exclusion Criteria: Previous clinically significant decompensation events (e.g. ascites [more than perihepatic ascites], Variceal Haemorrhage (VH) and / or overt / apparent Hepatic Encephalopathy (HE)) History of other forms of chronic liver disease (e.g. alcohol-related liver disease (ARLD), autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease, haemachromatosis, alpha-1 antitrypsin [A1At] deficiency) Patients without adequate treatment for HBV, HCV or NASH as per local guidance (e.g. antiviral therapy for chronic HBV or HCV infection or lifestyle modification in NASH) if received curative anti-viral therapy for HCV, no sustained virological response (SVR) or SVR sustained for less than 2 years prior to screening or if HCV Ribonucleic Acid (RNA) detectable If receiving anti-viral therapy for HBV, less than 6 months on a stable dose prior to screening, with planned dose change during the trial or HBV deoxyribonucleic acid (DNA) detectable Weight change ≥ 5% within 6 months prior screening Must take, or wishes to continue the intake of, restricted concomitant therapy or any concomitant therapy considered likely (based on Investigator judgement) to interfere with the safe conduct of the trial Systolic Blood Pressure (SBP) < 100 mmHg and Diastolic Blood Pressure (DBP) < 70 mmHg at screening (Visit 1a) Model of End-stage Liver Disease (MELD) score of > 15 at screening (Visit 1a), calculated by the central laboratory Hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 at screening (Visit 1a), calculated by the site, using central laboratory results Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) > 5 times upper limit of normal (ULN) at screening (Visit 1a), measured by the central laboratory Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 685509 HBV treatment group<br>Hepatitis B Virus (HBV) | Drug: BI 685509<br>* BI 685509<br>|
| Experimental: BI 685509 HCV treatment group<br>Hepatitis C Virus (HCV) | Drug: BI 685509<br>* BI 685509<br>|
| Experimental: BI 685509 NASH treatment group<br>Non-Alcoholic Steatohepatitis (NASH) | Drug: BI 685509<br>* BI 685509<br>|
| Experimental: BI 685509 + empagliflozin NASH treatment group<br> | Drug: BI 685509<br>* BI 685509<br>Drug: Empagliflozin<br>* Empagliflozin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in Hepatic Venous Pressure Gradient (HVPG) from baseline |  | At baseline and at week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a response | defined as > 10 percent (%) reduction from baseline HVPG | At baseline and at week 8 | 
| Occurrence of one or more decompensation events | i. e. ascites, Variceal Haemorrhage (VH), and / or overt Hepatic Encephalopathy (HE) | Up to 8 weeks | 
| Occurrence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 (or higher) hypotension or syncope based on Investigator judgement |  | Up to 8 weeks | 
| Occurrence of discontinuation due to hypotension or syncope |  | Up to 8 weeks |