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)

Phase 2

Terminated

Conditions: Liver Diseases
Hypertension, Portal

Interventions: Drug: Avenciguat
Drug: Empagliflozin

Registration Number: NCT05282121

Lead Sponsor: Boehringer Ingelheim

Brief Summary: 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 Avenciguat (BI 685509) taken alone or in combination with a medicine called empagliflozin helps people with this condition.

Participants take Avenciguat (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 Avenciguat (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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 90

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patients with HBV - avenciguat	Avenciguat	Patients with Hepatitis B Virus (HBV) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment.
Patients with HCV - avenciguat	Avenciguat	Patients with Hepatitis C Virus (HCV) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment.
Patients with NASH with or without T2DM - avenciguat	Avenciguat	Patients with Non-Alcoholic Steatohepatitis (NASH) with or without type 2 Diabetes Mellitus (T2DM) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment.
Patients with NASH with T2DM - avenciguat + empagliflozin	Avenciguat	Patients with Non-Alcoholic Steatohepatitis (NASH) with type 2 Diabetes Mellitus (T2DM) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment. Patients were additionally administered one 10 mg film-coated tablet of empagliflozin orally once a day.
Patients with NASH with T2DM - avenciguat + empagliflozin	Empagliflozin	Patients with Non-Alcoholic Steatohepatitis (NASH) with type 2 Diabetes Mellitus (T2DM) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment. Patients were additionally administered one 10 mg film-coated tablet of empagliflozin orally once a day.

Primary Outcome Measures

Name	Time	Method
Percentage Change in HVPG From Baseline (Measured in mmHg) After 8 Weeks of Treatment	Before the first intake of trial medication (baseline), and after 8 weeks of treatment.	Percentage change in Hepatic Venous Pressure Gradient (HVPG) from baseline (measured in millimetre of mercury \[mmHg\]) after 8 weeks of treatment is reported. Adjusted mean (Least Square Mean) was calculated using an analysis of covariance (ANCOVA) model without imputing the missing data. The model included treatment as fixed classification effects, and baseline HVPG as a linear covariate. The random error was assumed to be normally distributed with mean 0 and variance σ².

Secondary Outcome Measures

Name	Time	Method
Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 8-week Treatment Period	From first intake of study medication, until last intake of study medication plus 7 days, up to approximately 10 weeks.	Occurrence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 (or higher) hypotension or syncope based on Investigator judgement, during the 8-week treatment period is reported. The CTCAE grades are: 1 (mild Adverse Event \[AE\]), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period	From first intake of study medication, until last intake of study medication plus 7 days, up to approximately 10 weeks.	Occurrence of discontinuation of treatment with avenciguat due to hypotension or syncope during the 8-week treatment period is reported.
Occurrence of a Response, Which is Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 8 Weeks of Treatment	Before the first intake of trial medication (baseline), and after 8 weeks of treatment.	Occurrence of a response, which is defined as \> 10% reduction from baseline HVPG (measured in mmHg) after 8 weeks of treatment is reported.
Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 8-week Treatment Period	From first intake of study medication, until last intake of study medication plus 7 days, up to approximately 10 weeks.	Occurrence of one or more decompensation events (i.e. ascites, Variceal Haemorrhage \[VH\], and / or overt Hepatic Encephalopathy \[HE\]) during the 8-week treatment period is reported.

Trial Locations

Locations (31): HOP Beaujon
🇫🇷
Clichy, France
HOP Rangueil
🇫🇷
Toulouse, France
Medizinische Hochschule Hannover
🇩🇪
Hannover, Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
🇩🇪
Mainz, Germany
Universitätsklinikum Münster
🇩🇪
Münster, Germany
Rambam Medical Center
🇮🇱
Haifa, Israel
Western Galilee Hospital
🇮🇱
Nahariya, Israel
Ospedale Civile di Baggiovara
🇮🇹
Baggiovara (MO), Italy
Azienda Ospedaliera Policlinico di Modena
🇮🇹
Modena, Italy
Policlinico "Paolo Giaccone"
🇮🇹
Palermo, Italy
National Hospital Organization Yokohama Medical Center
🇯🇵
Kanagawa, Yokohama, Japan
California Liver Research Institute
🇺🇸
Pasadena, California, United States
Inland Empire Clinical Trials, LLC
🇺🇸
Rialto, California, United States
Floridian Clinical Research-Miami Lakes-68368
🇺🇸
Miami Lakes, Florida, United States
American Research Corporation
🇺🇸
San Antonio, Texas, United States
Hospital Britanico de Buenos Aires
🇦🇷
Caba, Argentina
Hospital Italiano de Buenos Aires
🇦🇷
Caba, Argentina
AKH - Medical University of Vienna
🇦🇹
Wien, Austria
Edegem - UNIV UZ Antwerpen
🇧🇪
Edegem, Belgium
Centre Hospitalier de l'Universite de Montreal (CHUM)
🇨🇦
Montreal, Quebec, Canada
Beijing Friendship Hospital
🇨🇳
Beijing, China
NanFang Hosptial
🇨🇳
Guangzhou, China
The Affiliated Hospital of Hangzhou Normal University
🇨🇳
Hangzhou, China
Zhongshan Hospital Affiliated to Fudan University
🇨🇳
Shanghai, China
Hvidovre Hospital
🇩🇰
Hvidovre, Denmark
Osaka Metropolitan University Hospital
🇯🇵
Osaka, Osaka, Japan
Amsterdam UMC, location VUMC
🇳🇱
Amsterdam, Netherlands
Regional Institute of Gastroenterology Hepatology "Prof. Dr. O. Fodor"
🇷🇴
Cluj-Napoca, Romania
Singapore General Hospital
🇸🇬
Singapore, Singapore
Hospital Vall d'Hebron
🇪🇸
Barcelona, Spain
Hospital Ramón y Cajal
🇪🇸
Madrid, Spain