| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10036201 |
| E.1.2 | Term | Portal hypertensions |
| E.1.2 | System Organ Class | 100000004866 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The trial will compare two doses of BI 685509 (2 mg and 3 mg BID) with placebo, on top of standard of care, in patients with CSPH in compensated alcohol-related cirrhosis. The primary objective is to estimate the mean difference between treatment groups with placebo in percentage change in HVPG from baseline measured after 24 weeks. The primary treatment comparison will be made for treated patients with baseline HVPG measurements (Full Analysis Set, FAS) as if all patients took randomised treatment for the duration of the trial. |
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| E.2.2 | Secondary objectives of the trial |
| Safety and tolerability will also be investigated. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
- Clinical signs of 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 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 109/L [150 x 103/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
- If receiving treatment with NSBBs or carvedilol must be on a stable dose for at least 1 months prior to screening, with no planned dose change throughout the trial
- WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly from the randomisation visit until 7 days after the last treatment in this trial. The patient must agree to periodic pregnancy testing during participation in the trial.
- Men able to father a child and who have a female sexual partner of CBP, must use a condom with or without spermicide, or adopt complete sexual abstinence, or be vasectomised (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate), from the randomisation visit until 7 days after the last treatment in this trial. |
|
| E.4 | Principal exclusion criteria |
- Previous clinically significant decompensation events (e.g. ascites [more than perihepatic ascites], VH and / or apparent HE)
- History of other forms of chronic liver disease (e.g. non-alcoholic steatohepatitis [NASH], Hepatitis B virus [HBV], untreated 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 a 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
- 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
- SBP < 100 mmHg and 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
- ALT or AST > 5 times upper limit of normal (ULN) at screening, measured by the central laboratory
- eGFR (CKD-EPI formula) < 20 mL/min/1.73 m2 at screening, measured by the central laboratory
- Alpha-fetoprotein > 50 ng/mL (> 50 µg/L) at screening, measured by the central laboratory
- An active infection with SARS-CoV-2 (or who is known to have a positive test from screening until randomisation)
- Prior orthotopic liver transplantation
- Prior or planned TIPS or other porto-systemic bypass procedure
- Known portal vein thrombosis
- History of clinically relevant orthostatic hypotension, fainting spells or blackouts due to hypotension or of unknown origin (based on Investigator judgement)
- QTcF-interval > 450 ms in men or > 470 ms in women at screening, a family history of long QT syndrome, or concomitant use of therapies with a known risk of Torsade de Pointes at screening or planned initiation of such therapies during the trial
- Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial
- Further criteria apply |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| percentage change in HVPG from baseline (measured in mmHg) after 24 weeks of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of treatment
2) response rate defined as > 10% reduction from baseline HVPG (measured in mmHg) after 8 weeks of treatment
3) response rate defined as > 10% reduction from baseline HVPG (measured in mmHg) after 24 weeks of treatment
4) occurrence of one or more decompensation events (i.e. ascites, VH, and / or overt HE) during the 24 week treatment period
5) occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator judgement, during the first 8 weeks of the treatment period
6) occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator judgement, during the 24 week treatment period
7) occurrence of discontinuation due to hypotension or syncope during the first 8 weeks of the treatment period
8) occurrence of discontinuation due to hypotension or syncope during the 24 week treatment period |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) week 8
2) week 8
3) week 24
4) week 24
5) week 8
6) week 24
7) week 8
8) week 24 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Singapore |
| Switzerland |
| Taiwan |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Croatia |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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