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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 80
- 试验地点
- 45
- 主要终点
- Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
- •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.
排除标准
- •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
- •Hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 at screening, calculated by the site, using central laboratory results Further exclusion criteria apply.
研究组 & 干预措施
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.
干预措施: Avenciguat (BI 685509) (Drug)
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.
干预措施: Avenciguat (BI 685509) (Drug)
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.
干预措施: Placebo matching Avenciguat (BI 685509) (Drug)
结局指标
主要结局
Percentage Change in Hepatic Venous Pressure Gradient (HVPG) From Baseline After 24 Weeks of Treatment
时间窗: 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.
次要结局
- 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.)
- 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.)
- 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.)
- Occurrence of Discontinuation Due to Hypotension or Syncope During the 24 Week Treatment Period(From first administration of trial medication up to 24 weeks.)