A Study to Test Whether Two Different Doses of Avenciguat Help People With Liver Cirrhosis and High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver)

Phase 2TerminatedNCT05161481

Boehringer Ingelheim80 enrolled

Overview

This study is open to adults with liver cirrhosis and 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 helps people with this condition. Participants are put into 3 groups randomly, which means by chance. Participants in 2 groups take different doses of Avenciguat as tablets twice a day. Participants in the placebo group take placebo as tablets twice a day. Placebo tablets look like Avenciguat tablets but do not contain any medicine. Participants are in the study for about 8 months. During this time, they visit the study site about 14 times. At 3 of the visits, the doctors check the pressure in a liver vein. This is done with a catheter (a long thin tube) and gives information about the pressure in the portal vein. The change in blood pressure is then compared between the groups to see whether the treatment works. The doctors also regularly check participants' health and take note of any unwanted effects.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Hypertension, Portal

Interventions

Participants received Avenciguat twice daily (BID) throughout the study. Up-titration depended on the assigned dose group. At Visit 2 (Week 1), each dose included one 1 mg Avenciguat tablet. At Visit 3 (Week 2), the dose was increased to one 2 mg Avenciguat tablet per dose. From Visit 4 onward (Week 3+), participants received one 3 mg Avenciguat tablet per dose. This regimen continued for 24 weeks, with all doses taken with water, with or without food.

Placebo matching Avenciguat (BI 685509)DRUG

Participants received matching placebo twice daily (BID) throughout the study. At Visit 2 (Week 1), each dose included one 1 mg and one 2 mg placebo tablet (four tablets daily). A pseudo up-titration was applied at Visit 3 (Week 2), maintaining the same tablet composition to preserve blinding. From Visit 4 (Week 3) onward, a second pseudo up-titration adjusted each dose to one 2 mg and one 3 mg placebo tablet (four tablets daily). All doses were taken with water, with or without food.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Signed and dated written informed consent in accordance with International Council on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial 2. 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 3. 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 or within 6 months prior to screening. * documented endoscopic proof of oesophageal varices and / or gastric varices at screening or within 6 months prior to screening * documented endoscopic-treated oesophageal varices as preventative treatment 4. CSPH defined as baseline Hepatic Venous Pressure Gradient (HVPG) ≥ 10 mmHg, based on a local interpretation of the pressure tracing 5. Diagnosis of compensated alcohol-related cirrhosis. Diagnosis must be based on histology (historical data is acceptable) or on clinical evidence of cirrhosis (e.g. platelet count \< 150 x 10\^9/L \[150 x 10\^3/µL\], nodular liver surface on imaging or splenomegaly) 6. Abstinence from significant alcohol misuse / abuse for a minimum of 2 months prior to screening, and the ability to abstain from alcohol throughout the trial (both evaluated based on Investigator judgement) 7. Willing and able to undergo HVPG measurements per protocol (based on Investigator judgement) 8. If receiving statins must be on a stable dose for at least 3 months prior to screening, with no planned dose change throughout the trial Further inclusion criteria apply. Exclusion Criteria: 1. Previous clinically significant decompensation events (e.g. ascites \[more than perihepatic ascites\], Variceal Haemorrhage (VH) and / or apparent Hepatic Encephalopathy (HE)) 2. History of other forms of chronic liver disease (e.g. non-alcoholic steatohepatitis (NASH), Hepatitis B virus (HBV), untreated Hepatitis C Virus (HCV), autoimmune liver disease, primary biliary cholangitis, primary sclerosing cholangitis, Wilson's disease, haemachromatosis, alpha-1 antitrypsin (A1At) deficiency) 3. Has received curative anti-viral therapy with direct-acting anti-virals within the last 2 years for HCV, or, if such treatment was \> 2 years ago and there is no sustained virological response (SVR) at screening, or, must take curative anti-viral therapy with direct-acting anti-virals throughout the trial 4. Alcohol-Related Liver Disease (ARLD) without adequate treatment (e.g. lifestyle modification) or with ongoing pathological drinking behaviour (misuse / abuse based on Investigator judgement) 5. 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 6. Systolic Blood Pressure (SBP) \< 100 mmHg and Diastolic Blood Pressure (DBP) \< 70 mmHg at screening 7. Model of End-stage Liver Disease (MELD) score of \> 15 at screening, calculated by the central laboratory 8. Hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 at screening, calculated by the site, using central laboratory results Further exclusion criteria apply.

Locations (45)

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

Northwell Health Center for Liver Disease

Manhasset, New York, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Outcomes

Primary Outcomes

Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment

HVPG was calculated as the difference between the average wedged hepatic venous pressure (WHVP) and either: Proximal Free Hepatic Venous Pressure (PFHVP), if judged more reliable, or Average Free Hepatic Venous Pressure (FHVP), if considered more reliable. Based on the central reader's judgment: If PFHVP was more reliable: HVPG(mmHg)= Average WHVP (mmHg) - PFHVP (mmHg) If FHVP was more reliable: HVPG(mmHg)=Average WHVP (mmHg)-Average FHVP (mmHg) Percentage Change = (HVPG at 24 weeks- Baseline HVPG/Baseline HVPG) × 100 A restricted maximum likelihood (REML) approach using a mixed model with repeated measurements (MMRM) was used to estimate adjusted treatment means. The analysis included fixed categorical effects for treatment at each visit, use of non-selective beta-blockers (NSBBs) or carvedilol at baseline (yes/no), and fixed continuous effects for baseline hepatic venous pressure gradient (HVPG) at each visit.

Time frame: From first administration of trial medication up to 24 weeks.

Secondary Outcomes

Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline, Measured in Millimeters of Mercury (mmHg), After 8 Weeks of Treatment

HVPG was calculated as the difference between the average wedged hepatic venous pressure (WHVP) and either: Proximal Free Hepatic Venous Pressure (PFHVP), if judged more reliable. Average Free Hepatic Venous Pressure (FHVP), if considered more reliable. Based on the central reader's judgment: If PFHVP was more reliable: HVPG(mmHg)= Average WHVP (mmHg) - PFHVP (mmHg) If FHVP was more reliable: HVPG(mmHg)=Average WHVP (mmHg)-Average FHVP (mmHg) Percentage Change = (HVPG at 8 weeks- Baseline HVPG/Baseline HVPG) × 100 This endpoint was analyzed using the Treatment Policy Estimand and an ANCOVA model. The model included baseline HVPG as a linear covariate, and treatment and use of non-selective beta-blockers (NSBBs) or carvedilol as fixed effects.

Time frame: From first administration of trial medication up to 8 weeks.

Response Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 8 Weeks of Treatment

Response is defined as greater than 10% reduction from baseline HVPG (measured in mmHg) after 8 weeks of treatment. The number of participants with, or without response after 8 weeks of treatment with Avenciguat is reported.

Time frame: From first administration of trial medication up to 8 weeks.

Response Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 24 Weeks of Treatment

Response is defined as greater than 10% reduction from baseline HVPG (measured in mmHg) after 24 weeks of treatment.

Time frame: From first administration of trial medication up to 24 weeks.

Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 24 Week Treatment Period

A decompensation event is characterized by the occurrence of any of the following: * Ascites, * Variceal hemorrhage, * Overt hepatic encephalopathy.

Time frame: From first administration of trial medication up to 24 weeks.

Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the First 8 Weeks of the Treatment Period

The occurrence of CTCAE grade 3 (or higher) hypotension or syncope, based on the investigator's judgment, during the first 8 weeks of the treatment period is reported.

Time frame: From first administration of trial medication up to 8 weeks.

Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 24 Week Treatment Period

The occurrence of CTCAE grade 3 (or higher) hypotension or syncope, based on the investigator's judgment, during the 24 weeks of the treatment period is reported.

Time frame: From first administration of trial medication up to 24 weeks.

Occurrence of Discontinuation Due to Hypotension or Syncope During the First 8 Weeks of the Treatment Period

The occurrence of hypotension or syncope during the first 8 weeks of the treatment period leading to the participant's discontinuation is reported.

Time frame: From first administration of trial medication up to 8 weeks.

Occurrence of Discontinuation Due to Hypotension or Syncope During the 24 Week Treatment Period

The occurrence of hypotension or syncope during the first 24 weeks of the treatment period leading to the participant's discontinuation is reported.

Time frame: From first administration of trial medication up to 24 weeks.