Hypertension, Portal, Liver Diseases
Conditions
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.
Interventions
DRUGAvenciguat
one film-coated tablet orally twice a day, at least 10 hours apart. The starting dose (1 mg) was up-titrated up to 3 mg
DRUGEmpagliflozin
one 10 mg film-coated tablet of orally once a day
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Argentina, Austria, Belgium, Canada, China, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Romania, Singapore, Spain, United States
Participant flow
Recruitment details
This randomised, open-label, parallel-group multinational phase II trial was conducted to investigate the effects of oral avenciguat (BI 685509) alone and in combination with empagliflozin on portal hypertension after 8 weeks treatment in patients with clinically significant portal hypertension (CSPH) in compensated cirrhosis.
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 entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Patients With HBV - 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. | 14 |
| Patients With HCV - 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. | 13 |
| Patients With NASH With or Without T2DM - 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. | 38 |
| Patients With NASH With T2DM - Avenciguat + 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. | 25 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 4 | 1 |
| Overall Study | No reason available | 0 | 0 | 1 | 0 |
| Overall Study | Other than listed | 0 | 0 | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 1 | 2 | 2 | 2 |
Baseline characteristics
| Characteristic | Patients With HBV - Avenciguat | Patients With HCV - Avenciguat | Patients With NASH With or Without T2DM - Avenciguat | Patients With NASH With T2DM - Avenciguat + Empagliflozin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 49.9 Years STANDARD_DEVIATION 12 | 60.3 Years STANDARD_DEVIATION 7.2 | 62.6 Years STANDARD_DEVIATION 7.5 | 64.1 Years STANDARD_DEVIATION 5.6 | 60.7 Years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 14 Participants | 14 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 9 Participants | 24 Participants | 11 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hepatic Venous Pressure Gradient (HVPG) | 13.68 millimetre of mercury (mmHg) STANDARD_DEVIATION 3.94 | 12.10 millimetre of mercury (mmHg) STANDARD_DEVIATION 2.51 | 15.46 millimetre of mercury (mmHg) STANDARD_DEVIATION 4.53 | 15.28 millimetre of mercury (mmHg) STANDARD_DEVIATION 3.7 | 14.63 millimetre of mercury (mmHg) STANDARD_DEVIATION 4.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 0 Participants | 2 Participants | 2 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 13 Participants | 35 Participants | 23 Participants | 75 Participants |
| Sex: Female, Male Female | 0 Participants | 6 Participants | 23 Participants | 16 Participants | 45 Participants |
| Sex: Female, Male Male | 14 Participants | 7 Participants | 15 Participants | 9 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 | 0 / 38 | 0 / 25 |
| other Total, other adverse events | 12 / 14 | 5 / 13 | 16 / 38 | 13 / 25 |
| serious Total, serious adverse events | 1 / 14 | 2 / 13 | 6 / 38 | 0 / 25 |
Outcome results
Primary
Percentage Change in HVPG From Baseline (Measured in mmHg) 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.
Time frame: Before the first intake of trial medication (baseline), and after 8 weeks of treatment.
Population: Full analysis set (FAS): this analysis set includes all enrolled or randomised patients who received at least one dose of trial medication and have a baseline measurement for the primary endpoint recorded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patients With HBV - Avenciguat | Percentage Change in HVPG From Baseline (Measured in mmHg) After 8 Weeks of Treatment | -16.06 Percentage of change in HVPG | Standard Error 6.66 |
| Patients With HCV - Avenciguat | Percentage Change in HVPG From Baseline (Measured in mmHg) After 8 Weeks of Treatment | -5.81 Percentage of change in HVPG | Standard Error 7.09 |
| Patients With NASH With or Without T2DM - Avenciguat | Percentage Change in HVPG From Baseline (Measured in mmHg) After 8 Weeks of Treatment | 3.83 Percentage of change in HVPG | Standard Error 4.25 |
| Patients With NASH With T2DM - Avenciguat + Empagliflozin | Percentage Change in HVPG From Baseline (Measured in mmHg) After 8 Weeks of Treatment | 3.27 Percentage of change in HVPG | Standard Error 5.08 |
Secondary
Occurrence of a Response, Which is Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) 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.
Time frame: Before the first intake of trial medication (baseline), and after 8 weeks of treatment.
Population: Full analysis set (FAS): this analysis set includes all enrolled or randomised patients who received at least one dose of trial medication and have a baseline measurement for the primary endpoint recorded. Only patients with a HVPG measurement at week 8 are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With HBV - Avenciguat | Occurrence of a Response, Which is Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 8 Weeks of Treatment | 9 Count of participants |
| Patients With HCV - Avenciguat | Occurrence of a Response, Which is Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 8 Weeks of Treatment | 2 Count of participants |
| Patients With NASH With or Without T2DM - Avenciguat | Occurrence of a Response, Which is Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 8 Weeks of Treatment | 9 Count of participants |
| Patients With NASH With T2DM - Avenciguat + Empagliflozin | Occurrence of a Response, Which is Defined as > 10% Reduction From Baseline HVPG (Measured in mmHg) After 8 Weeks of Treatment | 4 Count of participants |
Secondary
Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 8-week Treatment Period
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).
Time frame: From first intake of study medication, until last intake of study medication plus 7 days, up to approximately 10 weeks.
Population: Treated set (TS): all patients who were enrolled or randomised to the trial medication and were treated with at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With HBV - Avenciguat | Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 8-week Treatment Period | 0 Count of participants |
| Patients With HCV - Avenciguat | Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 8-week Treatment Period | 0 Count of participants |
| Patients With NASH With or Without T2DM - Avenciguat | Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 8-week Treatment Period | 0 Count of participants |
| Patients With NASH With T2DM - Avenciguat + Empagliflozin | Occurrence of CTCAE Grade 3 (or Higher) Hypotension or Syncope Based on Investigator Judgement, During the 8-week Treatment Period | 1 Count of participants |
Secondary
Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period
Occurrence of discontinuation of treatment with avenciguat due to hypotension or syncope during the 8-week treatment period is reported.
Time frame: From first intake of study medication, until last intake of study medication plus 7 days, up to approximately 10 weeks.
Population: Treated set (TS): all patients who were enrolled or randomised to the trial medication and were treated with at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With HBV - Avenciguat | Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | 0 Count of participants |
| Patients With HCV - Avenciguat | Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | 0 Count of participants |
| Patients With NASH With or Without T2DM - Avenciguat | Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | 0 Count of participants |
| Patients With NASH With T2DM - Avenciguat + Empagliflozin | Occurrence of Discontinuation Due to Hypotension or Syncope During the 8-week Treatment Period | 1 Count of participants |
Secondary
Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 8-week Treatment Period
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.
Time frame: From first intake of study medication, until last intake of study medication plus 7 days, up to approximately 10 weeks.
Population: Treated set (TS): all patients who were enrolled or randomised to the trial medication and were treated with at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With HBV - Avenciguat | Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 8-week Treatment Period | 1 Count of participants |
| Patients With HCV - Avenciguat | Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 8-week Treatment Period | 0 Count of participants |
| Patients With NASH With or Without T2DM - Avenciguat | Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 8-week Treatment Period | 4 Count of participants |
| Patients With NASH With T2DM - Avenciguat + Empagliflozin | Occurrence of One or More Decompensation Events (i.e. Ascites, VH, and / or Overt HE) During the 8-week Treatment Period | 1 Count of participants |