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)

Randomised, Double-blind, Placebo-controlled and Parallel Group Trial to Investigate the Effects of Two Doses (Up-titration to a Fixed Dose Regimen) of Oral BI 685509 on Portal Hypertension After 24 Weeks Treatment in Patients With Clinically Significant Portal Hypertension (CSPH) in Compensated Cirrhosis

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05161481

Enrollment

Registered

2021-12-17

Start date

2022-04-27

Completion date

2024-06-12

Last updated

2025-09-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension, Portal

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.

Interventions

DRUGAvenciguat (BI 685509)

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.

DRUGPlacebo matching Avenciguat (BI 685509)

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment	From first administration of trial medication up to 24 weeks.	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.

Secondary

Measure	Time frame	Description
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 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.
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.	Response is defined as greater than 10% reduction from baseline HVPG (measured in mmHg) after 24 weeks of treatment.
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.	A decompensation event is characterized by the occurrence of any of the following: * Ascites, * Variceal hemorrhage, * Overt hepatic encephalopathy.
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.	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.
Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 24 Week Treatment Period	From first administration of trial medication up to 24 weeks.	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.
Occurrence of Discontinuation Due to Hypotension or Syncope During the First 8 Weeks of the Treatment Period	From first administration of trial medication up to 8 weeks.	The occurrence of hypotension or syncope during the first 8 weeks of the treatment period leading to the participant's discontinuation is reported.
Occurrence of Discontinuation Due to Hypotension or Syncope During the 24 Week Treatment Period	From first administration of trial medication up to 24 weeks.	The occurrence of hypotension or syncope during the first 24 weeks of the treatment period leading to the participant's discontinuation is reported.
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.	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.

Countries

Argentina, Austria, Belgium, Canada, China, Croatia, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Portugal, Romania, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States

Participant flow

Recruitment details

This randomized, double-blind, placebo-controlled, parallel-group, multicenter trial included three treatment groups: two doses of avenciguat and a placebo, alongside standard care, in patients with clinically significant portal hypertension (CSPH) due to compensated alcohol-related cirrhosis. The primary objective was to estimate the mean difference in the percentage change in hepatic venous pressure gradient (HVPG) from baseline after 24 weeks. Safety and tolerability were also assessed.

Pre-assignment details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Participants by arm

Arm	Count
Placebo 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.	26
Avenciguat 2 mg BID 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.	27
Avenciguat 3 mg BID 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.	27
Total	80

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	3	0	6
Overall Study	Randomised in error and was not treated	1	0	0
Overall Study	Study terminated by sponsor	3	3	2
Overall Study	Subject decision	0	0	1
Overall Study	Withdrawal of consent	0	1	1

Baseline characteristics

Characteristic	Placebo	Avenciguat 2 mg BID	Avenciguat 3 mg BID	Total
Age, Continuous	57.8 Years STANDARD_DEVIATION 8.1	56.6 Years STANDARD_DEVIATION 9.2	57.1 Years STANDARD_DEVIATION 10.9	57.2 Years STANDARD_DEVIATION 9.4
Baseline hepatic venous pressure gradient (HVPG)	15.11 Millimeter mercury (mmHg) STANDARD_DEVIATION 4.1	14.95 Millimeter mercury (mmHg) STANDARD_DEVIATION 4.27	14.61 Millimeter mercury (mmHg) STANDARD_DEVIATION 4.07	14.88 Millimeter mercury (mmHg) STANDARD_DEVIATION 4.1
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	9 Participants	3 Participants	16 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants	18 Participants	24 Participants	64 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	6 Participants	6 Participants	6 Participants	18 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	20 Participants	21 Participants	21 Participants	62 Participants
Sex: Female, Male Female	9 Participants	9 Participants	4 Participants	22 Participants
Sex: Female, Male Male	17 Participants	18 Participants	23 Participants	58 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 25	0 / 27	0 / 27
other Total, other adverse events	9 / 25	10 / 27	11 / 27
serious Total, serious adverse events	4 / 25	1 / 27	3 / 27

Outcome results

Primary

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.

Population: Full analysis set (FAS) - this analysis set includes all randomised patients who received at least one dose of trial medication and have a baseline measurement for the primary endpoint recorded.~The hypothetical strategy was used for handling intercurrent events for the primary objective as a main analysis as if all the intercurrent events had not happened.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo	Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment	7.07 Percentage of change
Avenciguat 2 mg BID	Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment	-1.33 Percentage of change
Avenciguat 3 mg BID	Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment	-7.11 Percentage of change

Comparison: Model includes baseline HVPG as linear covariate and treatment and use of NSBBs or carvedilol as fixed effects, treatment by visit interaction and baseline HVPG by visit interaction. The following covariance structure has been used to fit the mixed model: Unstructured.95% CI: [-26.25, 9.45]

Secondary

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.