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)

NCT05161481 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 1366-00212021-001285-38
• Study Type: interventional
• Target: 80
• Locations: 22 countries
• Sites: 45

Brief Summary

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.

Conditions

Hypertension, Portal

Outcome Measures

Primary Outcomes (1)

• 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.

  From first administration of trial medication up to 24 weeks.

Secondary Outcomes (8)

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

  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

  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

  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

  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

  From first administration of trial medication up to 8 weeks.

Study Arms (3)

Avenciguat 2 mg BID

EXPERIMENTAL

Participants received Avenciguat combined with matching placebo tablets twice daily (BID). At Visit 2 (Week 1), each dose included one 1 mg Avenciguat tablet and one 2 mg placebo tablet (four tablets daily). At Visit 3 (Week 2), the dose was up titrated to 2 mg Avenciguat BID (one 1 mg placebo tablet and one 2 mg Avenciguat tablet (four tablets daily)). From Visit 4 onward (Week 3+), a pseudo up-titration was applied, with participants taking one 2 mg Avenciguat tablet and one 3 mg placebo tablet per dose (four tablets daily) to maintain blinding. This regimen continued for 24 weeks, with doses taken with water, with or without food.

Drug: Avenciguat (BI 685509)

Avenciguat 3 mg BID

EXPERIMENTAL

Participants received Avenciguat with matching placebo tablets twice daily (BID). At Visit 2 (Week 1), each dose contained one 1 mg Avenciguat tablet and one 2 mg placebo tablet (four tablets daily). At Visit 3 (Week 2), the dose was up titrated to 2 mg Avenciguat BID (one 1 mg placebo tablet and one 2 mg active tablet (four tablets daily)). From Visit 4 onward (Week 3+), the dose was further up titrated to 3 mg Avenciguat BID (one 2 mg placebo tablet and one 3 mg active tablet per dose (four tablets daily)). This regimen was maintained for 24 weeks, with doses taken with water, with or without food.

Drug: Avenciguat (BI 685509)

Placebo

PLACEBO COMPARATOR

Participants in this dose group received matching placebo twice daily (BID) throughout the study period. At Visit 2 (Week 1), each dose consisted of one 1 mg placebo tablet and one 2 mg placebo tablet (four tablets daily). At Visit 3 (Week 2), a pseudo up-titration was implemented, maintaining the same tablets (one 1 mg and one 2 mg placebo per dose) for blinding. From Visit 4 onward (Week 3+), a second pseudo up-titration adjusted the dose to one 2 mg placebo tablet and one 3 mg placebo tablet per dose (four tablets daily). All doses were taken with water, with or without food.

Drug: Placebo matching Avenciguat (BI 685509)

Interventions

Avenciguat (BI 685509) DRUG

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.

Avenciguat 2 mg BID; Avenciguat 3 mg BID

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• 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
• CSPH defined as baseline Hepatic Venous Pressure Gradient (HVPG) ≥ 10 mmHg, based on a local interpretation of the pressure tracing
• 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)
• 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)
• Willing and able to undergo HVPG measurements per protocol (based on Investigator judgement)

You may not qualify if:

• Previous clinically significant decompensation events (e.g. ascites \[more than perihepatic ascites\], Variceal Haemorrhage (VH) and / or apparent Hepatic Encephalopathy (HE))
• 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)
• 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
• Alcohol-Related Liver Disease (ARLD) without adequate treatment (e.g. lifestyle modification) or with ongoing pathological drinking behaviour (misuse / abuse based on Investigator judgement)
• 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
• Model of End-stage Liver Disease (MELD) score of \> 15 at screening, calculated by the central laboratory

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (45)

California Liver Research Institute

Pasadena, California, 91105, United States

Location

Inland Empire Clinical Trials, LLC

Rialto, California, 92377, United States

Location

Floridian Clinical Research-Miami Lakes-68368

Miami Lakes, Florida, 33016, United States

Location

Northwell Health Center for Liver Disease

Manhasset, New York, 11030, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

American Research Corporation at the Texas Liver Institute

San Antonio, Texas, 78215, United States

Location

Hospital Italiano de Buenos Aires

CABA, C1199ABB, Argentina

Location

Medical University of Innsbruck

Innsbruck, 6020, Austria

Location

AKH - Medical University of Vienna

Vienna, 1090, Austria

Location

Edegem - UNIV UZ Antwerpen

Edegem, 2650, Belgium

Location

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, H2X 0A9, Canada

Location

Beijing Friendship Hospital

Beijing, 100050, China

Location

Beijing Youan Hospital, Capital Medical University

Beijing, 100071, China

Location

NanFang Hosptial

Guangzhou, 510515, China

Location

The Affiliated Hospital of Hangzhou Normal University

Hangzhou, 310000, China

Location

University Hospital Dubrava

Zagreb, 10000, Croatia

Location

Hvidovre Hospital

Hvidovre, 2650, Denmark

Location

HOP d'Angers

Angers, 49933, France

Location

HOP Rangueil

Toulouse, 31059, France

Location

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

Location

Universitätsklinikum Münster

Münster, 48149, Germany

Location

St. Josefs-Hospital, Wiesbaden

Wiesbaden, 65189, Germany

Location

Western Galilee Hospital

Nahariya, 2210001, Israel

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Azienda Ospedaliera Policlinico di Modena

Modena, 41124, Italy

Location

Policlinico "Paolo Giaccone"

Palermo, 90127, Italy

Location

Fondazione Policlinico Universitario A. Gemelli IRCCS

Roma, 00195, Italy

Location

Shin-yurigaoka General Hospital

Kanagawa, Kawasaki, 215-0026, Japan

Location

Kitasato University Hospital

Kanagawa, Sagamihara, 252-0375, Japan

Location

Yokohama City University Hospital

Kanagawa, Yokohama, 236-0004, Japan

Location

National Hospital Organization Yokohama Medical Center

Kanagawa, Yokohama, 245-8575, Japan

Location

Osaka Metropolitan University Hospital

Osaka, Osaka, 545-8586, Japan

Location

Leids Universitair Medisch Centrum (LUMC)

Leiden, 2333 ZA, Netherlands

Location

ULS de Santa Maria, E.P.E

Lisbon, 1649-035, Portugal

Location

Regional Institute of Gastroenterology Hepatology "Prof. Dr. O. Fodor"

Cluj-Napoca, 400000, Romania

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

Soon Chun Hyang University Hospital Bucheon

Bucheon-si, Gyeonggi-do, 14584, South Korea

Location

Yonsei University Wonju Severance Christian Hospital

Wonju-si, Gangwon State, 26426, South Korea

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Puerta de Hierro

Majadahonda, 28222, Spain

Location

Ospedale Regionale di Lugano

Viganello, 6962, Switzerland

Location

Taipei Veterans General Hospital

Taipei, 11217, Taiwan

Location

Queen Elizabeth Hospital Birmingham

Birmingham, B15 2TH, United Kingdom

Location

St Mary's Hospital

London, W2 1NY, United Kingdom

Location

Related Publications (1)

• Reiberger T, Berzigotti A, Trebicka J, Ertle J, Gashaw I, Swallow R, Tomisser A. The rationale and study design of two phase II trials examining the effects of BI 685,509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis. Trials. 2023 Apr 24;24(1):293. doi: 10.1186/s13063-023-07291-3.

  PMID: 37095557 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Hypertension, Portal

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Limitations and Caveats

This trial was discontinued after Boehringer Ingelheim ended Avenciguat's clinical development for CSPH due to lack of efficacy, not safety concerns. Enrollment was complete, but some patients were still in treatment. These patients were asked to stop trial medication and attend an Early Discontinuation Visit, then entered the follow-up period per the clinical trial protocol.

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

018002430127

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2021
• First Posted: December 17, 2021
• Study Start: April 27, 2022
• Primary Completion: May 2, 2024
• Study Completion: June 12, 2024
• Last Updated: September 3, 2025
• Results First Posted: June 15, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: After structured results have been posted, all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
• Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.

Locations

BE (1); DE (3); CH (1); GB (2); AR (1); JP (5); IT (4); NL (1); AU (2); SG (1); FR (2); RO (1); TW (1); IL (1); CA (1); PT (1); ES (3); US (6); DK (1); CN (4); KR (2); CR (1)