Randomized, open-label clinical study with parallel groups to investigate the effects of oral BI 685509 as monotherapy or in combination with empagliflozin on portal hypertension after 8 weeks of treatment in patients with clinically significant portal hypertension (CSPH) with compensated cirrhosis

Critères de participation
1. Signed and dated informed consent in accordance with ICH-GCP and local legal requirements prior to enrollment in the study 2. Men and women aged ≥ 18 (or of legal age in countries where legal age is reached after 18 years) and ≤ 75 years at the time of pre-screening (visit 1a) 3. Clinical signs of CSPH according to the description by one of the following points. Study participants must undergo gastroscopy during the pre-screening phase (visit 1b) or have had one within 3 months prior to the pre-screening (visit 1b). • Documented endoscopic evidence of esophageal varices and/or gastric varices at the pre-screening (visit 1b) or within 3 months prior to the pre-screening (visit 1b) • Documented endoscopically treated esophageal varices as preventive treatment 4. CSPH, defined as a baseline HVPG ≥ 10 mmHg (measured at visit 1c), based on local interpretation of pressure measurements 5. Diagnosis of compensated cirrhosis due to HCV, HBV, or NASH with or without T2DM. The diagnosis of cirrhosis must be based either on histological findings (historical data are 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, etc.). The diagnosis of NASH must be based on one of the following two scenarios: i. Current or previous histological diagnosis of NASH OR steatosis OR ii. Clinical diagnosis of NASH, based on previous or current diagnosis of fatty liver by imaging (Fibroscan, US, MRI, CT), AND at least 2 current or previous comorbidities of metabolic syndrome (overweight/obesity, T2DM, hypertension, hyperlipidemia) 6. Willingness and ability (as assessed by the investigator) to undergo HVPG measurements according to the study protocol 7. For patients on statins, the dose must have been stable for at least 3 months prior to the pre-screening (visit 1b) and no dose change is to be planned throughout the study 8. For patients on NSBB or carvedilol, the dose must have been stable for at least 3 months prior to the pre-screening (visit 1b) and no dose change is to be planned throughout the study 9. For patients on pioglitazone, GLP1 agonists, or vitamin E, the dose must have been stable for at least 3 months prior to the pre-screening (visit 1b) and no dose change is to be planned throughout the study 10. Women of childbearing potential must be willing and able to use highly reliable contraceptive methods in accordance with ICH M3 (R2) from the randomization date (visit 2) until 7 days after the last treatment in the study, which, with consistent and correct use, have a failure rate of less than 1%. The patient must agree to regular pregnancy tests during the study participation. A list of contraceptive methods that meet these criteria is provided in the patient information. 11. Fertile men with female partners who can conceive must use a condom with or without spermicide, practice complete sexual abstinence, or be vasectomized (with appropriate documentation of the absence of sperm in the ejaculate after vasectomy) from the randomization date (visit 2) until 7 days after the last treatment in the study. (BASEC)

Critères d'exclusion
1. Previous clinically significant decompensation events (e.g., ascites [more pronounced than perihepatic ascites], variceal bleeding [VB] and/or overt hepatic encephalopathy [HE]) 2. Anamnestically known other forms of chronic liver disease (e.g., non-alcoholic steatohepatitis [NASH], hepatitis B virus [HBV] infection, untreated hepatitis C virus [HCV] infection, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, alpha-1-antitrypsin [A1At] deficiency) 3. Receipt of curative antiviral therapy with direct-acting antivirals against HCV in the last 2 years or use of such treatments more than 2 years ago without sustained virological response (SVR) at the pre-screening (visit 1a) or requirement for curative antiviral therapy during the study 4. Alcohol-related liver disease (ARLD) without appropriate treatment (e.g., lifestyle change) or with persistent pathological drinking behavior 5. Required or desired continuation of prohibited concomitant medications or use of concomitant therapy that would likely compromise the safe conduct of the study (in the opinion of the investigator) 6. Systolic blood pressure (SBP) < 100 mmHg and diastolic blood pressure (DBP) < 70 mmHg at pre-screening (visit 1a) 7. MELD score (Model of End-stage Liver Disease) > 15 at pre-screening (visit 1a), calculated by the central laboratory 8. Liver dysfunction, defined as a Child-Turcotte-Pugh score ≥ B8 at pre-screening (visit 1a), calculated by the trial center based on results from the central laboratory (see appendix 10.3) 9. ALT or AST > 5 x upper limit of normal (ULN) at pre-screening (visit 1a), measured by the central laboratory 10. eGFR (CKD-EPI formula) < 20 ml/min/1.73 m² at pre-screening (visit 1a), measured by the central laboratory 11. Alpha-fetoprotein > 50 ng/ml (> 50 µg/l) at pre-screening (visit 1a), measured by the central laboratory 12. Active infection with SARS-CoV-2 (or known positive test between pre-screening [visit 1a] and randomization [visit 2]) 13. Previous orthotopic liver transplantation 14. Previous or planned TIPS or other porto-systemic bypass procedure 15. Known portal vein thrombosis 16. Anamnestically known clinically relevant orthostatic hypotension, syncope, or brief loss of consciousness due to hypotension or unknown cause (in the opinion of the investigator) 17. Any documented active or suspected malignant disease or previous malignant disease in the last 5 years prior to pre-screening (visit 1a), except for a appropriately treated basal cell carcinoma of the skin or a cervical carcinoma in situ 18. QTcF time > 450 ms in men or > 470 ms in women at pre-screening (visit 1a), long QT syndrome in family history or concomitant use of therapies with known risk of Torsade de Pointes at pre-screening (visit 1a) or planned initiation of such therapies during the study. 19. Major surgical procedure (in the opinion of the investigator) performed in the last 3 months prior to randomization (visit 2) or planned during the study, e.g., hip replacement 20. Contraindication to any of the study procedures (e.g., lack of patient cooperation for gastroscopy, pacemaker for FibroScan® [if contraindication according to local market authorization] etc.) 21. Anamnestically known (in the 6 months prior to randomization [visit 2]) or current chronic drug abuse or expectation that the protocol requirements will not be met for any other reason, rendering the subject in the opinion of the investigator an unreliable study participant or making it unlikely that the study will be completed as planned 22. Any other condition that, in the opinion of the investigator, poses a safety risk to the patient or may interfere with the objectives of the study 23. Previous randomization in this study, previous exposure to BI 685509, or an allergy/contraindication to BI 685509 and/or empagliflozin and matched placebo or their respective other components 24. Ongoing participation in another study of an investigational product or preparation or less than 30 days or 5 half-lives (whichever is longer) prior to randomization (visit 2) since completion of another study of an investigational product or preparation or treatment with another investigational product 25. Women who are pregnant, breastfeeding, or planning to become pregnant during the study (BASEC)