Hypertension, Portal, Liver Cirrhosis
Conditions
Brief summary
This study is open to adults with advanced liver cirrhosis caused by hepatitis B, hepatitis C, alcohol-related liver disease, non-alcoholic steatohepatitis or other causes. People can join the study if they have high blood pressure in the portal vein (main vessel going to the liver) and bleeding in the esophagus or fluid accumulation in the belly. The purpose of this study is to find out whether a medicine called avenciguat helps people with this condition. Participants are put into 2 groups by chance. One group takes avenciguat tablets and the other group takes placebo tablets. Placebo tablets look like avenciguat tablets but do not contain any medicine. Participants take a tablet twice a day for 8 weeks. Participants are in the study for 2 to 3 months. During this time, they visit the study site regularly. At 2 of the visits, the doctors check the pressure in the liver vein by inserting a catheter (a long thin tube) that gives information about pressure in the portal vein. The change in blood pressure is then compared between the 2 groups to see whether the treatment works. The doctors also regularly check participants' health and take note of any unwanted effects.
Interventions
DRUGAvenciguat
1 millligram (mg), 2 mg, or 3 mg film-coated tablet
DRUGPlacebo
Placebo-matching Avenciguat
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed and dated written informed consent in accordance with International Council for 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 (Visit 1a) * Diagnosis of cirrhosis due to non-cholestatic liver disease (including Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Non-Alcoholic Steatohepatitis (NASH), alcohol-related liver disease, autoimmune hepatitis, Wilson's disease, haemachromatosis, alpha-1 antitrypsin (A1At) deficiency) * One previous clinically significant decompensation event with clinical resolution at least 4 weeks prior start of screening (visit 1a): * First variceal haemorrhage * First episode of clinically significant ascites (requiring intervention in lifestyle \[fluid and salt restriction\] or medical treatment) * Willing and able to undergo Hepatic Venous Pressure Gradient (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 month prior to screening (Visit 1b), with no planned dose change throughout the trial * For patient with alcohol-related cirrhosis, abstinence from significant alcohol misuse / abuse for a minimum of 2 months prior to screening (Visit 1a), and the ability to abstain from alcohol throughout the trial (both evaluated based on Investigator judgement) Further inclusion criteria apply
Exclusion criteria
* History of cholestatic chronic liver disease (e.g. primary biliary cholangitis, primary sclerosing cholangitis) * Trial participants 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 Hepatitis C Virus (HCV), Sustained Virological Response (SVR) sustained for less than 1 years prior to screening * 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 DNA detectable * Weight change ≥5% within 6 months prior screening in patients with NASH * 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 or Diastolic Blood Pressure (DBP) \<70 mmHg at screening (Visit 1a) * Hepatic impairment defined as a Child-Turcotte-Pugh score ≥8 at screening Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline (Measured in mmHg) After 8 Weeks of Treatment | At baseline and at Week 8. | Percentage change in hepatic venous pressure gradient (HVPG) from baseline to Week 8. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of a Response, Defined as >10% Reduction From Baseline Hepatic Venous Pressure Gradient (HVPG) (Measured in mmHg) After 8 Weeks of Treatment | At baseline and at Week 8. | Occurrence of a response, defined as at least a 10% reduction in the hepatic venous pressure gradient (HVPG) (measured in mmHg) after 8 weeks of treatment. |
| Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Up to 46 days. | Number of participants with at least one decompensation events. Ascites, variceal hemorrhage (VH), and hepatic encephalopathy were defined as further decompensations events. As the trial was discontinued prematurely and no patient completed the 8-week treatment period, the data presented reflects the actual on-treatment period. |
| Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement During the 8-week Treatment Period | Up to 46 days. | Number of participants with grade 3 or higher common terminology criteria for adverse events (CTCAE) hypotension or syncope base on the investigator judgment. As the trial was discontinued prematurely and no patient completed the 8-week treatment period, the data presented reflects the actual on-treatment period. |
| Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | Up to 46 days. | Number of participants that discontinued avenciguat due to hypotension or syncope. As the trial was discontinued prematurely and no patient completed the 8-week treatment period, the data presented reflects the actual on-treatment period. |
Countries
Austria, Canada, China, France, Germany, Japan, Romania, South Korea, Spain, United States
Participant flow
Recruitment details
Multi-national, randomised, double-blind, parallel group, placebo-controlled trial to investigate the safety and tolerability of avenciguat on top of standard of care on portal hypertension. The trial was prematurely discontinued due to the sponsor's decision.
Pre-assignment details
All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they (the participants) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants with stabilized decompensated cirrhosis due to non-cholestatic liver disease, following their first decompensation event, received 1 milligram (mg), 2 mg, or 3 mg film-coated tablets of placebo-matching avenciguat (BI 685509) orally twice daily (bid). Participants started the treatment with a 1 mg film-coated tablet of placebo-matching avenciguat administered bid. One week later (Visit 3), the dosage was increased to 2 mg film-coated tablets bid, and after another week, participants started on 3 mg film-coated tablet bid (Visit 4), which was maintained for the rest of the treatment. | 12 |
| Avenciguat Participants with stabilized decompensated cirrhosis due to non-cholestatic liver disease, following their first decompensation event, received 1 milligram (mg), 2 mg, or 3 mg film-coated tablets of avenciguat (BI 685509) orally twice daily (bid), up to a total dose of 6 milligrams (mg). The treatment period began (Visit 2) with a 1 mg film-coated tablet of avenciguat administered bid. If the dose was well-tolerated, it was increased to 2 mg film-coated tablets bid after one week (Visit 3), followed by an increase to the maintenance dose of 3 mg film-coated tablet one week later (Visit 4). If the maintenance dose of avenciguat was not well-tolerated, it was reduced, with the participants remaining on the highest tolerated dose for the rest of the treatment period. | 10 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study terminated by sponsor | 12 | 8 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Avenciguat | Total |
|---|---|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 10.6 | 59.2 Years STANDARD_DEVIATION 10.1 | 59.8 Years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 8 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hepatic Venous Pressure Gradient (HVPG) | 14.19 mmHg STANDARD_DEVIATION 4.49 | 11.55 mmHg STANDARD_DEVIATION 3.94 | 12.99 mmHg STANDARD_DEVIATION 4.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 10 |
| other Total, other adverse events | 1 / 12 | 3 / 10 |
| serious Total, serious adverse events | 0 / 12 | 2 / 10 |
Outcome results
Primary
Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline (Measured in mmHg) After 8 Weeks of Treatment
Percentage change in hepatic venous pressure gradient (HVPG) from baseline to Week 8.
Time frame: At baseline and at Week 8.
Population: As the trial was discontinued prematurely and no patient completed the 8-week treatment period, no data were available to assess the endpoint.
Secondary
Occurrence of a Response, Defined as >10% Reduction From Baseline Hepatic Venous Pressure Gradient (HVPG) (Measured in mmHg) After 8 Weeks of Treatment
Occurrence of a response, defined as at least a 10% reduction in the hepatic venous pressure gradient (HVPG) (measured in mmHg) after 8 weeks of treatment.
Time frame: At baseline and at Week 8.
Population: As the trial was discontinued prematurely and no patient completed the 8-week treatment period, no data were available to assess the endpoint.
Secondary
Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement During the 8-week Treatment Period
Number of participants with grade 3 or higher common terminology criteria for adverse events (CTCAE) hypotension or syncope base on the investigator judgment. As the trial was discontinued prematurely and no patient completed the 8-week treatment period, the data presented reflects the actual on-treatment period.
Time frame: Up to 46 days.
Population: Treated set (TS): all trial participants who were randomized to the trial medication and were treated with at least one dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement During the 8-week Treatment Period | 0 Participants |
| Avenciguat | Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement During the 8-week Treatment Period | 0 Participants |
Secondary
Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period
Number of participants that discontinued avenciguat due to hypotension or syncope. As the trial was discontinued prematurely and no patient completed the 8-week treatment period, the data presented reflects the actual on-treatment period.
Time frame: Up to 46 days.
Population: Treated set (TS): all trial participants who were randomized to the trial medication and were treated with at least one dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | 0 Participants |
| Avenciguat | Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | 0 Participants |
Secondary
Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period
Number of participants with at least one decompensation events. Ascites, variceal hemorrhage (VH), and hepatic encephalopathy were defined as further decompensations events. As the trial was discontinued prematurely and no patient completed the 8-week treatment period, the data presented reflects the actual on-treatment period.
Time frame: Up to 46 days.
Population: Treated set (TS): all trial participants who were randomized to the trial medication and were treated with at least one dose.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Ascites | 0 Participants |
| Placebo | Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Variceal Hemorrhage | 0 Participants |
| Placebo | Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Hepatic encephalopathy | 0 Participants |
| Avenciguat | Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Ascites | 0 Participants |
| Avenciguat | Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Variceal Hemorrhage | 0 Participants |
| Avenciguat | Occurrence of Further Decompensation Events (Ascites, Variceal Hemorrhage (VH), and / or Overt Hepatic Encephalopathy (HE)) During the 8-week Treatment Period | Hepatic encephalopathy | 0 Participants |