Soluble guanylate cyclase activator for the treatment of clinically significant portal hypertension and decompensated cirrhosis.

Abstract

The present invention relates to a method for using a soluble guanylate cyclase (sGC) activator for the prevention, slowing, delaying, or treatment of clinically significant portal hypertension (CSPH) and decompensated cirrhosis resulting from non-cholestasis liver disease.

Description

Technical Field

[0001] The present invention relates to the use of certain soluble guanylate cyclase activators for treating patients with clinically significant portal hypertension (CSPH) and decompensated cirrhosis resulting from non-cholestatic liver disease.

Background Art

[0002] Cirrhosis is an end-stage liver condition caused by various chronic diseases such as hepatitis C virus infection (HCV), chronic alcohol abuse, or metabolic syndrome associated with non-alcoholic fatty liver disease (NAFLD). Cirrhosis is itself a chronic disease with a high mortality rate. Cirrhosis is a heterogeneous disease classified into two major prognostic stages: compensated cirrhosis and decompensated cirrhosis. This classification is determined by the presence or absence of clinically evident decompensating events (specifically, ascites [ascites that does not remain only around the liver], variceal hemorrhage (VH), and / or overt hepatic encephalopathy (HE)). (See Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65(1):310-335). Currently, there is no treatment available to reduce fibrotic tissue or regenerate hepatocytes in cirrhosis. The main treatment goals are to delay decompensation, improve quality of life, and treat the symptoms of cirrhosis, especially decompensation.

[0003] Portal hypertension (PH) is a major early consequence of cirrhosis and the cause of the majority of its complications. (See GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385(9963):117-171; and Garcia-Tsao, 2017). The only clinical approaches currently recommended to prevent PH-related decompensatory events in patients are endoscopic variceal ligation or off-label use of non-selective beta-blockers (NSBBs) or carvedilol for primary and secondary prevention of variceal bleeding. However, not all patients with PH achieve a hemodynamic response to these current treatment options. While NSBBs and carvedilol are currently used to prevent complications of cirrhosis and improve patient survival rates, these benefits are realized in less than half of treated patients, many of whom achieve a significant reduction in portal pressure. A considerable number of patients remain unmet needs, as they cannot tolerate treatment with NSBBs or carvedilol due to the resulting decrease in systemic blood pressure (BP) and heart rate (HR), and are at higher risk of further progression and decompensation.

[0004] Therefore, there is an unmet medical need to lower portal pressure and improve hepatic perfusion in this patient population, particularly those with clinically significant portal hypertension (CSPH). CSPH is associated with the development of varices, obvious clinical decompensation (ascites, VH, and HE), postoperative decompensation, and an increased risk of hepatocellular carcinoma. (Villanueva C, Albillos A, Genesca J, Abraldes JG, Calleja JL, Aracil C, et al. Development of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with portal hypertension. Hepatology 2016;63(1):197-206;D'Amico G, Pasta L, Morabito A, D'Amico M, Caltagirone M, Malizia G, et al. al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014;39(10):1180-1193; and Garcia-Tsao G 2017) [Overview of the project]

[0005] The present invention relates to a method for the prevention, slowing, delaying, or treatment of clinically significant portal hypertension (CSPH) and decompensated cirrhosis, comprising administering a pharmaceutically effective amount of the soluble guanylate cyclase (sGC) activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need. In another embodiment, the present invention relates to a method for preventing, slowing, delaying, or treating CSPH in decompensated cirrhosis resulting from non-cholestasis liver disease, comprising administering a pharmaceutically effective amount of the soluble guanylate cyclase (sGC) activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need. The present invention also relates to the SGC activator of the present invention, or pharmaceutically acceptable salts thereof, for use in the prevention, slowing, delaying, or treatment of CSPH and decompensated cirrhosis resulting from non-cholestasis hepatic disease.

[0006] In another embodiment, the present invention provides a method for preventing, slowing, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis resulting from non-cholestasis liver disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the sGC activator of the present invention or a pharmaceutically acceptable salt thereof. (i) The method results in a decrease in the hepatic venous pressure gradient (HVPG) from baseline in the patient, (ii) The method results in a reduction of liver stiffness from baseline in the patient, and / or (iii) Methods that result in a reduction of splenic stiffness from baseline in patients.

[0007] In yet another embodiment, the present invention relates to a soluble guanylate cyclase (sGC) activator for use in the prevention, slowing, delaying, or treatment of clinically significant portal hypertension (CSPH) and decompensated cirrhosis resulting from non-cholestasis liver disease in patients. (i) Use results in a decrease in the hepatic venous pressure gradient (HVPG) from baseline in the patient, (ii) Use results in a reduction of liver stiffness from baseline in the patient, and / or (iii) relating to sGC activators whose use results in a reduction of splenic stiffness from baseline in patients. In one embodiment, the method or use results in at least a 10% reduction in HVPG levels from baseline in a patient after 8 weeks of treatment.

[0008] In another embodiment, the method or use results in a reduction of at least 10% from baseline in the patient after 8 weeks of treatment. In yet another embodiment, the method or use results in a reduction of at least 10% from baseline in the patient after 8 weeks of treatment. In another embodiment, the reduction in liver stiffness and / or spleen stiffness is measured using transient elastography. In one embodiment of the present invention, the sGC activators used in the method or use of the present invention are compound numbers 18, 27, 84, 114, 133, 134, 136, 148, 154, 165, and 167 ("sGC activators of the present invention" or "compounds of the present invention"): [ka] [ka] The compound is selected from the group consisting of these pharmaceutically acceptable salts.

[0009] In one embodiment, the sCG activator used in the method or use of the present invention is compound number 114. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows a schematic design of the clinical trial described herein. [Figure 2A] Figure 2A shows a flowchart summarizing the screening, treatment, and follow-up of patients in accordance with the clinical trials described herein. [Figure 2B]Figure 2B shows a flowchart summarizing the screening, treatment, and follow-up of patients according to the clinical trials described in this specification. [Figure 2C] Figure 2C shows a flowchart summarizing the screening, treatment, and follow-up of patients according to the clinical trials described in this specification. [Figure 2D] Figure 2D shows a flowchart summarizing the screening, treatment, and follow-up of patients according to the clinical trials described in this specification.

Mode for Carrying Out the Invention

[0011]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0012] As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound is modified by forming an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and so on. For example, such salts include acetates, ascorbic acid salts, benzenesulfonates, benzoates, besilates, bicarbonates, acidic tartrates, bromides / hydrobromides, edetates, cansilates, carbonates, chlorides / hydrochlorides, citrates, edisylates, ethanedisulfonates, and esterates. Esilate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsnilate, hexylresorcinate, hydravamin, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, methyl sulfate This includes salts, mucinates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates / diphosphates, polygalacturonates, propions, salicylates, stearates, basic acetates, succinates, sulfamides, sulfates, tannates, tartrates, theoclates, toluenesulfonates, triethiozides, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Further pharmaceutically acceptable salts can be formed with metal-derived cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. (See also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 66, 1-19).

[0013] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Generally, such salts can be prepared by reacting these compounds in free acidic or basic forms with a sufficient amount of a suitable base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. For example, salts of other acids other than those mentioned above (e.g., trifluoroacetates) that are useful for purifying or isolating the compounds of the present invention also constitute part of the present invention. In this application, if the naming of any compound disclosed above in this specification is inconsistent with its structure, the compound shall be understood to be defined by its structure.

[0014] General synthesis methods Compounds of formula (I) used in the method or use of the present invention can be prepared by the method and examples described in International Publication No. 2014 / 039434. Method of therapeutic use For therapeutic use, the compound of formula (I) may be administered in any conventional manner as a pharmaceutical composition in any conventional form of drug administration. Conventional forms of administration typically include a pharmaceutically acceptable carrier suitable for the individual forms of administration selected. Routes of administration are not limited to, but include, intravenous, intramuscular, subcutaneous, bursal, drip infusion, sublingual, transdermal, oral, topical, or inhalation. Preferred methods of administration are oral, intravenous, and subcutaneous.

[0015] The compounds of the present invention may be administered alone or in combination with other active ingredients, in combination with adjuvants that enhance the stability of inhibitors, facilitate the administration of pharmaceutical compositions containing them in certain embodiments, result in increased solubility or dispersion, enhance inhibitory activity, and provide adjuvant therapy. For example, in one embodiment, multiple compounds of the present invention may be administered. Advantageously, such combination therapy utilizes lower doses of conventional therapeutic agents and thus avoids the toxicity and adverse side effects that may occur when those agents are used as monotherapy. The compounds of the present invention may be physically combined with conventional therapeutic agents or other adjuvants to form a single pharmaceutical composition. Advantageously, the compounds may then be administered together as a single dosage form. In some embodiments, a pharmaceutical composition containing such a combination of compounds contains at least about 5%, more preferably at least about 20%, of the compounds of the present invention (w / w) or their combinations. The optimal proportion (w / w) of the compounds of the present invention may vary and is within the knowledge of those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants may be administered separately (sequentially or simultaneously). Separate dosing allows for greater flexibility in the administration plan.

[0016] As described above, the dosage forms of the compounds of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for such dosage forms. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffers, water, salts or electrolytes, and cellulosic substances. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstituteable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, for example, HC Ansel and NG Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Individual dosages and treatment plans depend on factors such as the patient's overall health profile, the severity and course of the patient's disorder or aversion to it, and the judgment of the treating physician.

[0017] In connection therewith, “combination” or “combined” within the meaning of this invention may include, without limitation, fixed and non-fixed (e.g., free) forms (including kits or other forms of administration, application or drug delivery) and uses, such as the simultaneous, sequential or separate use of sGC activators and further therapeutic agents or combination therapies as described herein. The combined administration or application of this invention may occur by administering the therapeutic components together, for example, by administering them simultaneously as one single or two separate formulations. Alternatively, administration may occur by administering the therapeutic components sequentially, for example, as two separate formulations in succession. In the combination therapy of this invention, the therapeutic components may be administered separately (implying that they are formulated separately) or formulated together (implying that they are formulated in the same preparation). Thus, the administration of one component of the combination of this invention may occur before, at the same time as, or after the administration of the other components of the combination.

[0018] In one embodiment, the method of the present invention involves administering to a patient a daily dose of 0.1 mg to about 50 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof. In another embodiment, the method of the present invention involves administering to a patient a daily dose of 1 mg to about 30 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the sGC activator of the present invention, or a pharmaceutically acceptable salt thereof, is administered to a patient in a daily dose of 0.1 to 100 mg; or 1 to 25 mg; or 1 to 10 mg; or 2 to 5 mg, or as a pharmaceutically acceptable salt thereof. In another embodiment, the sGC activator of the present invention, or a pharmaceutically acceptable salt thereof, is administered to a patient in an amount selected from the group consisting of 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and 10 mg.

[0019] In yet another embodiment, the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, is administered to a patient in an amount selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg. In another embodiment, the method of the present invention comprises administering to a patient 3 mg or less of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the method of the present invention comprises administering 1 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient.

[0020] In another embodiment, the method of the present invention comprises administering 2 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient. In yet another embodiment, the method of the present invention comprises administering 3 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient. Vasodilation caused by sGC activators can lead to orthostatic dysregulation and hypotensive episodes. Gradual increases in sGC activator doses may allow for further increases in total daily exposure to sGC activators while avoiding high peak concentrations. In one embodiment, the present invention relates to a method for preventing or reducing the severity of orthostatic dysregulation caused by or in connection with the administration of an sGC activator or a pharmaceutically acceptable salt thereof, the method comprising administering a daily dose of the sGC activator to a patient via QD, BID, or TID.

[0021] In another embodiment, the sGC activator is administered to the patient via QD. In yet another embodiment, the sGC activator is administered to the patient via BID. In another embodiment, the sGC activator is administered to the patient via TID. In yet another embodiment, the method of the present invention comprises administering to a patient 3 mg or less of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, twice daily. In another embodiment, the method of the present invention comprises administering 3 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient twice daily, resulting in a total daily dose of 6 mg of the sGC activator. In yet another embodiment, the method of the present invention comprises administering 2 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient twice daily, resulting in a total daily dose of 4 mg of the sGC activator.

[0022] In another embodiment, the method of the present invention comprises administering 1 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient twice daily, resulting in a total daily dose of 2 mg of the sGC activator. In yet another embodiment, the method of the present invention comprises administering a TID to a patient in a dose of 3 mg or less of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof. In another embodiment, the method of the present invention comprises administering 3 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient with TID, resulting in a total daily dose of 9 mg of the sGC activator. In yet another embodiment, the method of the present invention comprises administering 2 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient with TID, resulting in a total daily dose of 6 mg of the sGC activator.

[0023] In another embodiment, the method of the present invention comprises administering 1 mg of the SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient with TID, resulting in a total daily dose of 3 mg of the sGC activator. In yet another embodiment, the present invention relates to a method for initiating treatment of a patient with an sGC activator. An unspecified example of the initial treatment includes gradually increasing the patient's dose from a low dose to a target dose. In one embodiment, the initial treatment of the patient is: The sGC activator of the present invention is administered as a TID at a dose of 1 mg for 2 weeks (weeks 1 and 2 of treatment). The sGC activator was administered as a TID at a dose of 2 mg for 2 weeks (3 and 4 times per week). This includes administering a 3 mg dose of sGC activator as a TID four times a week. Patients treated with the sCG activator of the present invention may be treated with one or more additional therapeutic agents, including SGLT2 inhibitors (e.g., empagliflozin), GLP-1 agonists, nintedanib, and beta-blockers.

[0024] Clinical trial protocol Below is a randomized, double-blind, placebo-controlled, parallel-group trial to investigate the effect of one dose (from escalating to fixed-dose regimen) of orally administered compound 114 on portal hypertension after 8 weeks of treatment in patients with clinically significant portal hypertension (CSPH) and decompensated cirrhosis who had stabilized after an initial decompensation event. A study to test whether the sGC activator of the present invention helps people with high portal vein (major vessel leading to the liver) blood pressure who have had esophageal bleeding or abdominal fluid accumulation.

[0025] 1.1 Primary Objectives, Primary and Secondary Endpoints 1.1.1 Main Objectives The trial investigates the safety and tolerability of compound 114 in patients with CSPH in decompensated cirrhosis resulting from non-cholestasis liver disease, in addition to standard treatment. The primary objective is to estimate the percentage change in HVPG from baseline measured at 8 weeks compared to placebo. The primary analysis will be performed on treated patients with HVPG measurements (full analysis set, FAS) at baseline, and it will be assumed that all trial participants were treated throughout the trial period. 1.1.2 Primary Endpoint The primary endpoint is the percentage change in HVPG (measured in mmHg) from baseline after 8 weeks of treatment. 1.1.3 Secondary Endpoints The secondary endpoint is, • Occurrence of a reaction defined as a decrease of more than 10% from baseline HVPG (measured in mmHg) after 8 weeks of treatment. • During the 8-week treatment period, the occurrence of further decompensatory events (i.e., ascites, VH, and / or obvious HE) • During the 8-week treatment period, the occurrence of hypotension or syncope of CTCAE grade 3 (or higher) as determined by the investigator. • During the 8-week treatment period, discontinuation due to hypotension or syncope occurred. Includes.

[0026] 1.2 Further Objectives and Further Endpoints 1.2.1 Further Objectives In addition to the primary objectives defined above, further objectives of this study include gaining further insights into the use of non-invasive methods to assess overall safety, PK, PD, disease activity biomarkers, and liver function and portal pressure. 1.2.2 Further Endpoints • Change from baseline in spleen stiffness (kPa) measured with Fibroscan® Expert 630 after 8 weeks of treatment. • Change from baseline in liver stiffness (kPa) measured by FibroScan® Expert 630 LSM after 8 weeks of treatment, e.g., a <10% or <15% reduction in liver stiffness. • Change in weight from baseline after 8 weeks of treatment • After the procedure at 8 weeks oPT / INR, aPTT o Bilirubin (direct and indirect) o Liver enzymes (ALT, AST, γ-GT, and alkaline phosphatase) o Albumin Changes in liver function from baseline as measured by • Change from baseline in renal function as measured by eGFR after 8 weeks of treatment. • Changes from baseline across disease-specific and mechanism-exploratory biomarkers up to 8 weeks post-treatment end-of-situation (EoS). o Fibrosis markers (e.g., PRO-C3, ELF score) o Inflammatory markers (e.g., hs-CRP) o Cardiac and renal biomarkers (e.g., brain natriuretic peptide (BNP), troponin I, eGFR, creatinine) • The PK endpoint of compound 114 is, if possible, oCmax (maximum measurable concentration in plasma sample) otmax (time from drug administration to the peak concentration of the sample in plasma) oAUCt1-t2 (area under the concentration-time curve of the plasma sample over the time interval t1-t2 after a single dose) oCmax,ss (Maximum measurable concentration of the sample in plasma at steady state over a uniform dosing interval τ) otmax,ss (time from the last dose to the peak measurable concentration of the sample in plasma at steady state over a uniform dosing interval τ) oAUCt1-t2,ss (area under the concentration-time curve of the plasma sample over a steady-state time interval t1 to t2) It will be determined by [the method used].

[0027] Description of design and test group 2.1 Overall Study Design This Phase 2 international, collaborative, randomized, placebo-controlled, parallel-group trial will investigate the effect of oral compound 114 after 8 weeks of treatment on portal hypertension in patients with clinically significant portal hypertension (CSPH) and decompensated cirrhosis who have stabilized after an initial decompensation event.

[0028] Trial participants are enrolled in the study after signing informed consent, and their eligibility is screened. The screening period consists of up to two visits (visits 1a and 1b) and lasts up to four weeks. If eligibility is confirmed at the previous visit, trial participants can proceed to the next visit. Assessments include liver and spleen ultrasound, liver and spleen FibroScan®, and HVPG measurement. Trial participants who maintain eligibility and complete this period without complications proceed to an eight-week randomized, placebo-controlled treatment period.

[0029] A total of 40 participants will be randomized in a 1:1 ratio, with 20 participants assigned to the active treatment arm and 20 to the placebo arm. Randomization will be stratified by the use (or non-use) of NSBB / carvedilol and the type of the first decompensation event (ascites or variceal bleeding).

[0030] Following randomization at visit 2, participants will begin taking the study medication and enter a dose escalation period of compound 114 or placebo. If the dose is tolerated, after one week (visit 3, day 8), the dose for all participants will be escalated to 2 mg BID of compound 114 or placebo. If this dose is tolerated, a second escalation will be performed after another week (visit 4, day 15) to 3 mg BID of compound 114 or placebo. After the dose escalation period, if the dose is tolerated, participants will remain on the highest dose of compound 114 for the remainder of the treatment period, until the end-of-treatment (EoT) visit and the 8-week treatment. If the dose is not tolerated, the study medication may be discontinued or the dose may be reduced / tasked. Liver and spleen ultrasound and FibroScan®, as well as HVPG measurement, will be repeated throughout the treatment period (see Figure 1). After an 8-week treatment period, all participants enter a 2-week follow-up period without receiving the study medication. Participants' participation in the study ends upon their final scheduled visit (i.e., study end [EoS], 2 weeks after EoT). See Figure 1.

[0031] 2.2 Consideration of the study design, including the selection of the control group A randomized, double-blind, placebo-controlled, parallel-group design was selected for this trial in addition to standard care. The randomized, double-blind design controls for allocation bias. Placebo as a control was selected to demonstrate the efficacy of compound 114 compared to placebo plus standard care. The 8-week treatment duration was chosen to allow for the evaluation of short-term efficacy and to enable indirect comparison with the results of 8 weeks in trials 1366-0021 and 1366-0029. The trial participant population for this study was selected because it represents the intended patient population to be treated with compound 114 (patients with clinically significant portal hypertension in decompensated cirrhosis resulting from non-cholestasis liver disease).

[0032] HVPG measurement was selected as the primary endpoint because it is the absolute criterion for assessing portal pressure, i.e., the severity of sinusoidal hypertension, in trial participants with cirrhosis. (See Reiberger T, Puespoek A, Schoder M, Baumann-Durchschein F, Bucsics T, Datz C, et al. Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III). Wien Klin Wochenschr 2017;129(Suppl 3):S135-158). This is because a decrease in HVPG results in a clinically meaningful benefit, and is therefore used as an established surrogate marker for improvement and / or deterioration of liver fibrosis / function. (Mandorfer M, Kozbial K, Schwabl P, Chromy D, Semmler G, Staettermay AF, et al. Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy. See Hepatology 2020;71(3);1023-1036.The prognostic value of HVPG has been highlighted by several groundbreaking studies showing that HVPG ≥ 10 mmHg (i.e., CSPH) predicts varicose vein formation (Groszmann RJ, Garcia-Tsao G, Bosch J, Grace D, Burroughs AK, Planas R, et al, Portal Hypertension Collaborative Group. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353(21);2254-2261), but (pharmacologically induced) reduction of HVPG modulates the risk of varicose vein growth and decompensation, respectively. (See Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, et al, Gruppo Triveneto per l'Ipertensione Portale. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004;127(2);476-484; and Mandorfer M, Hernandez-Gea V, Reiberger T, Garcia-Pagan JC. Hepatic venous pressure gradient response in non-selective beta-blocker treatment - is it worth measuring? Curr Hepatol Rep 2019;18;174-186.) Thus, this also explains the selection of secondary endpoints related to the occurrence of further decompensation events. Other secondary endpoints (occurrence of significant hypotension or syncope, and occurrence of discontinuation due to hypotension or syncope) were selected because they are relevant based on the mechanism of action of compound 114.

[0033] Trial participants are screened for the trial based on their eligibility. At visit 1b (the last visit during the screening period), trial participants who remain eligible after visit 1a receive their first HVPG measurement. Non-invasive assessments (i.e., ultrasound and FibroScan® of the liver and spleen, and functional liver tests) were selected as part of the screening method to further investigate the status of study participants, to establish baseline values ​​for comparison with the procedure, and to gain further insights into the use of non-invasive methods to assess liver function and portal pressure. These assessments were repeated to evaluate the time dependence of the procedure (see flowcharts shown in Figures 1 and 2A-2D).

[0034] After randomization, the study design includes a dose escalation period. Vasodilation associated with the mechanism of action of compound 114 may cause orthostatic dysregulation and hypotensive episodes. Orthostatic dysregulation is dose-limiting, and clinical tolerability improves with dose escalation. BID administration also allows for further increases in total daily exposure to compound 114 while avoiding high peak concentrations. Therefore, this study will follow a dose escalation regimen of 1 mg BID to 2 mg BID to 3 mg BID. Participants selected for this trial are at risk of further decompensation. Therefore, a DMC (Data Management Committee), independent of the sponsor, has been established to regularly review safety data and identify any potential risks and / or the need for further safety measures. The duties and responsibilities of DMC members are detailed in the DMC Charter. An independent AC (Advisory Council) will also be established to adjudicate liver injury cases. The duties and responsibilities of AC members will be detailed in the AC Charter.

[0035] 2.3 Selection of the test population Forty participants with CSPH and decompensated cirrhosis resulting from non-cholestasis liver disease will be randomized to the trial. Approximately 20 sites are planned across multiple countries. Two participants are expected to be randomized at each site. Additional sites may be added if enrollment is delayed. Screening for trial participants for this trial will be competitive; that is, screening for the trial will stop simultaneously at all sites once a sufficient number of participants have been screened to supply the required number of randomized trial participants. Investigators will be notified of the completion of screening and will not be permitted to screen any additional trial participants for this trial thereafter. At this point, trial participants who have already been screened and are eligible will be permitted to continue with randomization.

[0036] A re-test during the screening period is permitted once (for example, if the investigator believes that an ineligible laboratory test was the result of an error or extenuating circumstances, the trial participant may be repeated without being rescreened). Re-screening is also permitted once, provided that, in the investigator's judgment, the reason for the screening failure was reversible and has already been resolved. A trial participant who was initially ineligible for the trial, was subsequently rescreened, is undergoing a second informed consent procedure, has received a new unique trial participant number, and has had their screening period evaluation repeated is considered a "re-screener". Logs of all trial participants who are enrolled in the trial (i.e., who have signed informed consent) are maintained in the Site Essential Document (ISF), regardless of whether or not they are treated with the investigational drug.

[0037] If it is subsequently discovered that a patient was mistakenly randomized (i.e., did not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or agent must contact the patient immediately. A decision on whether the patient can continue participating in the trial will be made based on an individual benefit-risk assessment. This trial includes participant choices on fully anonymous questionnaires to provide feedback on the clinical trial experience. Providing this feedback is not required to participate in the trial, and the information collected from these questionnaires will not be analyzed as part of the clinical data for the trial.

[0038] 2.3.1 Primary diagnostic criteria for participation in the study The trial includes participants with stabilized decompensated cirrhosis resulting from non-cholestasis hepatic disease following an initial decompensation event.

[0039] 2.3.2 Inclusion Criteria 1. Informed consent in writing, signed in accordance with ICH-GCP and local laws, prior to registration for the examination. 2. Male or female who is 18 years of age or older (or the legal age in that country if it is higher than 18) and 75 years of age or younger at the time of screening (visit 1a). 3. Diagnosis of cirrhosis caused by non-cholestasis liver disease (including HCV, HBV, NASH, alcohol-related liver disease, autoimmune hepatitis, Wilson's disease, hemochromatosis, and alpha-antitrypsin [A1At] deficiency) 4. One prior clinically significant decompensation event that clinically resolved at least 4 weeks prior to the start of screening (visit 1a): a. Initial varicose bleeding b. First clinically significant onset of ascites (requiring lifestyle intervention [fluid and salt restriction] or medical treatment) 5. The participant is willing and able to undergo HVPG measurement for each protocol (based on the judgment of the clinical trial physician). 6. If you choose to receive statins, the dosage must be stable for at least three months prior to screening (visit 1b), and there are no plans for dose changes throughout the trial. 7. If treatment is to be administered, the NSBB or carvedilol treatment must be at a stable dose for at least one month prior to screening (visit 1b), and there are no plans for dose changes during the trial. 8. In the case of patients with alcohol-related cirrhosis, they must have not had any serious alcohol misuse / abuse for at least two months prior to screening (visit 1a), and be able to abstain from alcohol throughout the trial (both will be assessed at the discretion of the investigating physician). 9. WOCBP must be willing and able to use a highly effective method of contraception by ICH M3 (R2), which, if used steadily and correctly from the randomization visit (visit 2) until 7 days after the final treatment in this trial, has a low failure rate of less than 1% per year. Patients must consent to periodic pregnancy testing during participation in the trial. (Women are considered fertile, i.e., capable of bearing children from menarche until postmenopause unless permanently infertile. Methods of permanent sterilization include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is not a method of permanent sterilization. Postmenopausal status is defined as the absence of menstruation for 12 months without other medical cause.) 10. Men who are capable of fathering a child and have sexual partners with women with CBP must use condoms containing or not containing spermicide, practice complete sexual abstinence, or have a vasectomy (with appropriate post-vasectomy evidence of sperm absence in semen) from the randomization visit (visit 2) until 7 days after the final treatment of this trial.

[0040] 2.3.3 Exclusion criteria 1. History of cholestatic chronic liver disease (e.g., primary biliary cholangitis, primary sclerosing cholangitis) 2. Trial participants without appropriate treatment for HBV, HCV, or NASH as per local guidance (e.g., antiviral therapy for chronic HBV or HCV infection or lifestyle changes for NASH) 3. If you have received treatment, antiviral therapy for HCV or SVR that lasted for less than one year prior to screening. 4. If you are going to receive it, you should have received a stable dose of antiviral therapy for HBV for less than 6 months prior to screening, or have planned dose changes based on experimental or detectable HBV DNA. 5. Weight change ≥ 5% within 6 months prior to screening in NASH patients. 6. You wish to take or continue taking any restricted combination therapy or any combination therapy that is likely to interfere with the safe conduct of the trial (as determined by the investigator). 7. SBP < 100 mmHg or DBP < 70 mmHg at screening (visit 1a) 8. Liver impairment defined as a Child-Turcotte-Pugh score of ≥ 8 at screening. 9. A model of end-stage liver disease (MELD) score > 15 at screening (visit 1a) calculated by the central laboratory. 10. ALT or AST levels measured by the central laboratory at screening (visit 1a) are more than 5 times the upper limit of normal (ULN). 11. eGFR (CKD-EPI formula) <20 mL / min / 1.73 m² measured by the central laboratory at screening (visit 1a). 2 12. Platelet count<50x10 9 / L 13. Alpha-fetoprotein >50 ng / mL (>50 μg / L) measured by the central laboratory during screening (visit 1a) 14. Prior orthotopic liver transplantation 15. Pre- or planned TIPS or other portal vein bypass procedures during the trial. 16. Known portal vein thrombosis 17. A history of clinically relevant orthostatic hypotension, syncope, or transient memory loss (as determined by the investigator) due to or of unknown cause. 18. QTcF interval >450ms in males or >470ms in females at screening (visit 1a), family history of long QT syndrome, or combination therapy with known risk of Torsade de Pointes, or planned initiation of such treatment during the trial. 19. Contraindications for any of the trial evaluations (e.g., insufficient patient cooperation with HVPG, cardiac pacemakers with FibroScan® [if contraindicated based on local market approvals]). 20. Major surgery performed within 12 weeks prior to randomization (visit 2) or scheduled during the trial (as assessed by the investigator), such as total hip replacement. 21. Any confirmed active or suspected cancer or a history of cancer within five years prior to screening (visit 1a), excluding appropriately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix. 22. Patients who have a history of chronic substance abuse (within 6 months prior to randomization [visit 2]) or are currently experiencing such abuse, or who, based on the investigator's judgment, are unreliable for trial inclusion or are not expected to meet protocol requirements for any other reason that would make it unlikely the trial will be completed as planned. 23. Prior randomization in this study, prior exposure to compound 114, or allergies / contraindications to compound 114 and / or any of the placebo excipients. 24. Currently enrolled in another test device or drug trial, or less than 30 days or 5 half-lives (whichever is longer) have passed since the completion of another test device or drug trial or the receipt of another test procedure prior to randomization (visit 2). 25. Pregnant, breastfeeding women, or women who plan to become pregnant during the trial. 26. Any other medical condition that, at the discretion of the investigating physician, would impose a safety risk on the patient or would interfere with the objectives of the study.

[0041] 2.3.4 Treatment of or discontinuation of evaluation of trial participants Participants in the study can either discontinue the study treatment or withdraw their consent to participate in the study entirely ("withdrawal of consent"), but these have significantly different implications. However, the trial should be continued if the trial participant consents. Even if it is not possible to continue the trial procedure, they should still participate in subsequent trial visits to ensure their safety and to collect important trial data. Measures to control the withdrawal rate include careful selection of trial participants, adequate explanation of trial conditions and procedures prior to trial registration, and explanation of the consequences of withdrawal. The decision to discontinue the trial procedure or to withdraw consent to participate in the trial, and the reasons for such decision, must be recorded in the participant file and CRF. Where applicable, the requirements for AE collection and reporting should be considered. Trial participants who drop out after randomization will not be replaced and cannot be re-enrolled later. However, if a trial participant terminates early due to, for example, a trial interruption (e.g., measures to contain a global pandemic), the sponsor may decide to randomize more trial participants than originally planned to compensate for the reduction in sample size.

[0042] 2.3.4.1 Discontinuation of experimental treatment Ideally, trial participants should attend all remaining visits. If a trial participant does not consent, they must be contacted by phone at least at the scheduled visit, and if that is not permissible, they must be contacted by phone once or at the end of the scheduled observation period to collect the most important information: life status, outcome events, adverse events, or, if follow-up was not possible, the date of the last contact.

[0043] Individual trial participants should discontinue the trial medication if any of the following conditions apply: • A test participant wants to stop the test procedure. The test participant will be asked to explain their reasons, but has the right to refuse to answer. • The trial participant repeatedly failed to follow important trial procedures, and in the opinion of the clinical trial investigator and sponsor representative, the participant lacked the intention or ability to faithfully follow trial requirements in the future, making it impossible to guarantee safety. • If a trial participant needs to take a concomitant medication that may interfere with the safety / efficacy of the study drug or other study treatment, and if short-term emergency use of a restricted concomitant therapy is required (e.g., a 5-7 day antibiotic treatment for an infection), discontinuation of compound 114 is not automatically required. Similarly, if only stable doses are acceptable (e.g., NSBB / carvedilol, statins, antiviral therapy for HBV), if a trial participant needs to change their dose, this also does not automatically require discontinuation. In either case, the sponsor must be consulted. • The trial participants meet the criteria for liver injury. Based on the judgment of the investigator, if a trial participant has an acute hepatic decompensation event, such as VH, treatment-resistant ascites, overt brain injury, or other decompensation event • Trial participants with worsening liver function (e.g., an increase of more than 2 points in the Child Turcotte Pugh score accompanied by clinical evidence of worsening liver function in the opinion of the clinical trial physician). Trial participants with a QT or QTcF interval >500ms, or an increase of >60ms from the baseline value at visit 2 / pre-randomization administration. Such cases must be reported as adverse events (AEs). • A trial participant is unable to receive the study medication for other medical reasons, such as surgery, adverse events, or other illnesses. • The treatment assignments of the trial participants were not mixed due to the emergency situation. • The trial participant did not successfully complete the dose escalation period (i.e., visit 4), but had a persistent adverse event or serious effect requiring tapering of the study medication. • When a female trial participant becomes pregnant, the participant will be followed up until delivery or the end of the pregnancy. Participant data will be collected and reported to the Clinical Trial Report (CTR) until the last visit of the last trial participant, and all subsequent events will be reported to the BI Drug Safety Surveillance (PV) database.

[0044] Trial-specific procedures are also prescribed for the investigator to follow in the event of elevated liver enzymes (AST, ALT, and total bilirubin) after randomization. If, at visit 4, after the successful completion of the dose escalation period, intolerance to compound 114 occurs (e.g., persistent adverse events regardless of two dose escalations, or serious effects at any dose), permanent discontinuation of treatment should be considered at the discretion of the investigating physician. In addition to these criteria, the clinical trial physician may discontinue a trial participant's participation based on clinical judgment. If a trial participant permanently discontinues the study medication before the final assigned dose, an early discontinuation (ED) visit is ideally required within 7 days of discontinuation. The end-of-severance (EoS) visit should take place two weeks after the ED visit.

[0045] In the event of a temporary discontinuation, the test drug (compound 114) must be resumed if medically justifiable. Once new efficacy / safety information becomes available, Boehringer Ingelheim will review its benefit-risk assessment and, if necessary, suspend or discontinue the study procedure for all study participants or take any other appropriate action to ensure the safety of the study participants. 2.3.4.2 Withdrawal of consent to participate in the study Participants in the study can withdraw their consent to participate in the study at any time without needing to justify their decision. If a trial participant wishes to withdraw their consent, the clinical trial physician must discuss the matter with the participant, explain the difference between discontinuing the trial procedure and withdrawing consent to participate in the trial, and explain the option of continuing follow-up after discontinuing the trial procedure. If a patient withdraws their consent to participate in further trials, no further data will be collected from that patient.

[0046] 2.3.4.3 Cancellation of the exam by the sponsor Boehringer Ingelheim reserves the right to discontinue the trial as a whole or at any individual trial site at any time for the following reasons: • The expected registration targets cannot be met overall or at individual testing sites. • New efficacy or safety information that overrides the previous positive benefit-risk assessment • Deviations from GCP, test protocols, or contracts that impair the proper conduct of the test. • The clinical trial physician / study site will be reimbursed for reasonable costs incurred if the trial is terminated (except in the third case).

[0047] 3. Treatment 3.1 Test Procedure The test drugs in the trial are compound 114 and a placebo (dummy drug) that matches compound 114. BI will supply all products. 3.1.1 Contents of the test drug The characteristics of the test drug are described in Tables 2.1 to 2.6 below. [Table 2]

[0048] [Table 3] [Table 4]

[0049] [Table 5] [Table 6] [Table 7]

[0050] 3.1.2 Dosage selection in trials and dose changes Compound 114 was tested in healthy male volunteers in a single dose-escalation study, a food effect and DDI study, and two MRD studies. Single doses ranging from 0.5 mg to 5.0 mg and multiple doses up to 12.0 mg per day were tested. Overall, compound 114 was well tolerated except for orthostatic dysregulation that limited the dose. Dose escalation and dosing three times daily significantly improved cardiovascular tolerability. One Phase 1 multiple oral dose escalation study and one Phase 2 study have also been completed in DN trial participants. Multiple oral doses of 3 mg or less (TID) were found to be safe and well-tolerated. The highest total daily dose of 9 mg was achieved after a two-stage dose escalation over 14 days.

[0051] The estimated human dose of 2.3 mg BID is predicted to achieve pharmacologically significant exposure in trial participants with liver impairment. Since 3 mg is the maximum acceptable single dose, two doses (2 mg BID and 3 mg BID) are currently being evaluated in Phase 2 trial 1366-0021, which is being conducted in trial participants with CSPH and compensated alcohol-related cirrhosis. These doses were selected based on safety and PK results from the Phase I MRD liver impairment trial (1366-0020). In addition, the BID maintenance dose of 3 mg of compound 114 is also being evaluated in three trial participant groups (HBV, HCV, and NASH) in trial 1366-0029. In this study, if the BID maintenance dose of 3 mg of compound 114 is not tolerated in study participants with CSPH and decompensated cirrhosis due to non-cholestasis liver disease, as in studies 1366-0021 and 1366-0029, the dose will be reduced and evaluated.

[0052] 3.1.3 Method for assigning trial participants to treatment groups After evaluation of all eligible patients and exclusion criteria, each eligible trial participant will be randomized to a treatment group in a blinded manner at visit 2 using an interactive response technology (IRT) system according to a 1:1 randomization plan. Note that the medication number assigned by the IRT system at each dispensing visit is different from the trial participant number (which is generated by the IRT system when a new trial participant is registered in the system [screened]). The clinical trial physician (and other designated on-site personnel) will be instructed to access the IRT system.

[0053] 3.1.4 Drug allocation and dosage administration to each study participant The investigational drug will be distributed to the trial sites according to the flowchart (Figures 2A-2D). Upon arrival for dispensing, trial participants will be given a dosage kit (range 1-2) for compound 114 with an appropriate number, depending on the interval between visits. The final dose of compound 114 will be administered the evening before the end-of-treatment (EoT) visit. All participants, regardless of their assigned treatment group, begin at visit 2 with a dose of either compound 114 BID or placebo. At visit 3, 7 days later, and again at visit 4, 7 days after visit 3, all participants are first increased to a dose of either compound 114 BID or placebo, and then to a dose of either compound 114 BID or placebo. Blindness is maintained across treatment groups in this manner (see Table 3). Participants are informed about the dose escalation period and that increasing doses of compound 114 are being used. From visit 4 onward, participants continue to receive the maximum dose of compound 114 BID at 3 mg (unless tapering is required) until they reach their EoT visit, 8 weeks after the start of the study dose.

[0054] If a trial participant has an adverse event (AE) that appears to be related to compound 114, based on the investigator's judgment, the study drug may be administered: Can it be interrupted (i.e., the trial dose is stopped and then restarted, using the gradual increase method described above)? or If the trial participants successfully completed the dose escalation period (i.e., visit 4), the dose of compound 114 can be reduced (tasked). All investigational drug allocations, including the provision of dose escalation / decrease and substitution kits for compound 114, will be managed by the IRT system. Decrease of compound 114 must not be performed by instructing study participants to take fewer than two daily doses.

[0055] [Table 8]

[0056] From the start of the treatment period (i.e., from visit 2) until reaching the 8-week EoT visit, study participants are instructed to take compound 114 orally twice daily (BID). Each dose of compound 114 consists of one film-coated tablet. The first daily dose is recommended to be taken in the morning, and the second dose in the evening. Ideally, there should be at least 10 hours between doses. Compound 114 should be taken at approximately the same time each day. If a dose is missed, it should not be corrected by taking two doses (i.e., double the dose) at the next time; if a dose is missed by more than 6 hours, that dose should be completely skipped and the next dose should be taken as scheduled. The test drug should be taken with a glass of water, and food may or may not be consumed.

[0057] On the morning of their visit, the study drug will be administered as part of the visit. Therefore, participants on these days are instructed not to take their morning dose before their visit. This is especially important if the visit requires PK / biomarker / pharmacogenomic (PG) sample collection (see flowchart (Figures 2A-2D)). Participants who cannot follow these instructions should reschedule their visit as soon as possible, ideally to the following day. Participants on days without scheduled visits will administer the drug themselves at home. Participants are instructed to bring all unused study drug and an empty wallet / package with them when returning to the study site for their visit. For visits involving PK sample collection, trial participants should also record the time of administration of the study drug three days prior to each visit. A reminder card will be provided for this purpose. In the event of force majeure or other interruption, it may not be possible for trial participants to physically visit the site, or it may need to be restricted to protect the safety of the trial participants. Based on a thorough assessment of the benefits and risks, the investigator may still decide to continue administering the study drug, and if permitted by local laws and regulations, the study drug may be transported from the site to the trial participant's home.

[0058] 3.1.4.1 Rules for gradual reduction in cases of intolerance to compound 114 If a study participant experiences an adverse event (AE) that is considered to be related to the study drug, based on the judgment of the investigator, the following tapering rules must be followed. These rules apply if the study participant has successfully completed the dose escalation period (i.e., visit 4) and is still taking the last assigned dose of the study drug or has missed three or fewer consecutive doses. If the study participant has not successfully completed the dose escalation period (i.e., visit 4), tapering is not permitted; in cases of persistent AE or serious adverse effects, the study participant must permanently discontinue treatment. If a trial participant is receiving compound 114 at 3 mg BID, the dose will be reduced by one level to 2 mg BID of compound 114. Once a gradual reduction has been implemented, further dose increases are not permitted.

[0059] A second tapering is permitted if the trial participant continues to have an adverse event (AE), or if a new AE develops that the investigator believes to be related to the investigational drug. • If a trial participant is receiving compound 114 at a 2 mg BID, the dose will be reduced to 1 mg BID. Tapering should not be performed by taking fewer than two daily doses or by splitting tablets so that the entire tablet is not taken. Tapering is managed by an IRT system. After successful completion of the dose escalation period (i.e., visit 4), permanent discontinuation of treatment should be considered in the event of persistent adverse events despite tapering, or serious effects at any dose. Participants undergoing dose reduction must return to the study site to receive a continuous supply of the study drug at their next scheduled visit or in the event of an unscheduled visit.

[0060] 3.1.4.2 Rules for resuming dose escalation in case of discontinuation of compound 114 Interruption of compound 114 may affect tolerability. Therefore, if a study participant misses taking more than three consecutive doses of the study drug for any reason (e.g., due to adverse events or compliance issues), the following rules apply for the safety of the study participant: (One dose means an individual dose at a specific time, e.g., morning dose or evening dose.) If a participant misses three or fewer consecutive doses of the study drug and there are no associated adverse events, the next dose of the study drug should be taken as scheduled. • After discontinuing more than three consecutive doses of the investigational drug, participants should restart the dose escalation period with 1 mg BID of compound 114 / corresponding placebo. • Before any further dose escalation occurs, study participants must have taken the preceding dose for at least 7 consecutive days. This applies throughout the treatment period. This could mean that trial participants who are scheduled to have their dose escalated at visit 3 or 4 (according to Table 3) will remain at their current dose until their next scheduled visit. Alternatively, if this requirement is met, the dose may be escalated at an unscheduled visit. If the interruption occurs after visit 4, subsequent dose escalations are permitted during scheduled or unscheduled visits. Trial participants whose treatment with the investigational drug is interrupted will need to return to the trial site to receive a continuous supply of the investigational drug at their next scheduled or unscheduled visit.

[0061] 3.1.5 Procedures for blinding and deblinding 3.1.5.1 Blinding In this double-blind trial, trial participants, investigators, central reviewers, and any other person involved in or interested in the execution or analysis of the trial remain unaware of their randomized treatment assignments until the database is declared ready for analysis according to the sponsor's SOP. Further details regarding when the database will be deblinded for analysis are documented in the TSAP. Access to the randomized codes will be restricted until they are publicly released as per the sponsor's SOP.

[0062] The randomization code will be provided to bioanalytics before the final trial participants can complete the trial and exclude PK samples taken from trial participants receiving a placebo from the analysis. Bioanalytics will not disclose the randomization code or the results of the measurement until the post-database-locked (DBL) trial is officially unblinded. To facilitate population PK and PK-PD analyses and ensure timely delivery of post-DBL PK / PD results, specific data must be deblinded, and treatment information must be made available to selected individuals (e.g., pharmacometrics and programming staff). Specific deblinding procedures and logistics for this purpose are provided in a separate document. It should be noted that PK / PD results will not be communicated to the project and trial teams prior to DBL. The DMC, independent of the sponsor, will conduct open-label safety assessments at intervals specified in the DMC Charter to ensure that trial participants are protected from potential harm. A trial-independent statistician (iSTAT) will be appointed to prepare tables, catalogs, and summary reports for the DMC based on an agreed-upon format and layout. The randomization code will be provided to iSTAT. All information, including decisions from adverse events (AEs), mortality, laboratory parameters, and liver injury adjudication, will be provided in an open-label format. This will be achieved by using coded labels and, if necessary, providing decoded information separately to the DMC members.

[0063] 3.1.5.2 Deblinding of Emergency Situations and Deactivation of Codes Emergency deblinding is available to the investigator via the IRT. This should only be used in emergency situations where the investigator must be informed of the contents of the investigational drug in order to provide appropriate medical treatment or otherwise ensure the safety of the trial participant. The reason for deblinding must be documented in the source document and / or the appropriate eCRF page. If a trial participant is deblinded by the investigator, the trial participant must discontinue the trial. Due to the requirement to report unpredictable serious adverse events (SUSARs), it may be necessary for a representative of the PV group in the BI during the trial to access the randomization code of an individual trial participant. Access to the code is granted only to authorized PV representatives who process the information in the PV database system and is not shared further.

[0064] 3.1.6 Packaging, labeling, and resupply Investigational drugs are supplied by BI or a designated Clinical Research Organization (CRO). They are packaged and labeled according to the principles of Good Manufacturing Practice. Resupply to facilities is managed through the IRT system, which also monitors the expiration date of supplies available at the facility. In this study, each medication kit containing compound 114 of BID contains one wallet, each wallet holding 20 film-coated tablets (i.e., 7 days of treatment plus 3 days of reserve). The number of kits distributed at each dispensing visit is sufficient to cover both the number of weeks of scheduled treatment between visits and the use of any acceptable visit window. For details on packaging and labeling, please refer to ISF.

[0065] 3.1.7 Storage conditions Drug supplies are placed in their original packaging and stored in a restricted, fixed storage area according to the recommended storage conditions on the drug label. Temperature logs must be maintained for documentary purposes. If it is discovered that the storage conditions are outside the specified range, you must immediately contact a Clinical Research Associate (CRA) listed on the ISF's contact list.

[0066] 3.1.8 Drug Accountability The investigator or designated person will receive the investigational drug delivered by the sponsor or agent when the following conditions are met: • Approval of CTP by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) • Validity of the signed and dated clinical trial agreement between the sponsor or agent and the trial site. • Approval / notification from regulatory authorities, e.g., the competent authority (CA) • Validity of the principal investigator's resume • Validity of the signed and dated CTP • Validity of evidence of the principal investigator's medical license (if applicable) • Validity of FDA Form 1572 (if applicable)

[0067] The investigational drug is not permitted to be used outside of this CTP (Computer-to-Trial) situation. Furthermore, it must not be transferred to other investigators or clinicians. Participants will be instructed to return any unused investigational drug. The clinical trial physician or designated investigator must maintain records of the delivery of medication to the trial site, all products at the site, use by each trial participant, and return to the sponsor or warehouse / medicine distribution center, or disposal of unused medication. Where applicable, the sponsor or warehouse / medicine distribution center must maintain records of disposal.

[0068] These records include the date, quantity, batch / serial number, expiration date ("use-by date"), and a unique code number assigned to the investigational drug and the study participant. The investigator or designated investigator shall maintain records that adequately indicate that the study participant was provided with the dose specified by the CTP and shall verify all investigational drugs received from the sponsor. Upon return to the sponsor and / or designated CRO, the investigator or designated investigator shall certify that all unused or partially used investigational drugs have been returned by the clinical trial participant and that no supplies remain in the investigator's possession.

[0069] 3.2 Other measures, emergency procedures, and restrictions 3.2.1 Other Procedures and Emergency Procedures There are no special emergency procedures to follow. Stable doses of combination therapy for chronic conditions that do not warrant exclusion from the trial are permitted throughout the trial period. All combination therapies should be carefully evaluated by the investigator, and any questions should be directed to the sponsor. In cases of adverse events (AEs) requiring treatment, any combination therapy is permitted at the discretion of the investigating physician. Diagnosis and treatment must be initiated in accordance with local standard care. All combination therapies are recorded on the appropriate page of the eCRF. Endoscopic variceal ligation (performed according to local guidelines) is permitted during the trial if necessary. The procedure must be recorded on an appropriate page of the eCRF.

[0070] 3.2.2 Restrictions 3.2.2.1 Restrictions on incidental measures The combination therapies described below should not be administered concurrently with compound 114. • The NO-sGC-cGMP pathway that activates therapy, such as NO-donors (e.g., glycerin trinitrate, isosorbide dinitrate or mononitrate, morcidomin), PDE-5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil), nonspecific PDE inhibitors (e.g., dipyridamole and theophylline), or sGC-stimulants (e.g., riociguat): These restrictions apply within 5 half-lives after discontinuation of combination therapy prior to enrollment (visit 2) until the end-of-service (EoS) visit. • Combination therapies with known Torsades de Pointes risks: These restrictions apply from screening visit 1a to End of Service (EoS) visit. In the case of transient combination therapy with such therapies, the study drug must be temporarily discontinued and can then be resumed at least 5 half-lives after the combination therapy with known Torsades de Pointes risks has been discontinued. • Clinically relevant OATP1B1 / 3 inhibitors • Clinically relevant combination therapies known to inhibit or induce UGT enzymes

[0071] In the case of an unacceptable temporary combination of drugs, compound 114 must be temporarily discontinued and can be restarted at least 5 half-lives after the combination therapy has been discontinued. A list to assist in confirming the aforementioned combination therapies is provided to the ISF. The list is not exhaustive. Furthermore, participants receiving statins must have been at a stable dose for at least three months prior to screening (visit 1b), and no dose changes should be planned throughout the trial. Similarly, participants receiving NSBB / carvedilol must have been at a stable dose for at least one month prior to screening (visit 1b), and no dose changes should be planned throughout the trial. In addition, these combination therapies should not be initiated during the trial as they may interfere with the efficacy of the investigational drug. If a patient is receiving antiviral therapy for HBV, they should be on a stable dose for at least six months prior to screening, and no dose changes should be planned throughout the trial.

[0072] 3.2.2.1.1 Close monitoring of adverse events based on combination therapy Close monitoring of adverse events (AEs) is recommended in this trial if trial participants are receiving combination therapy metabolized by CYP3A4 and / or CYP2C8, which have a narrow therapeutic index and / or are sensitive substrates. A list to assist in identifying the aforementioned combination therapies has also been provided to the ISF. The list is not exhaustive. 3.2.2.2 Restrictions on diet and lifestyle Extreme changes in diet and lifestyle should be avoided during the study. This includes unusually strenuous exercise for study participants (e.g., exercises that put pressure on the abdomen, such as starting weightlifting).

[0073] Alcohol consumption should be avoided throughout the test; excessive alcohol intake, when combined with compound 114, may cause hypotension. During the treatment period, participants should be asked if they have consumed alcohol and, if necessary, advised to refrain from alcohol consumption. The conditions for fasting upon arrival at the hospital are as specified in the flowchart (Figures 2A-2D). Once all necessary hospital visit assessments have been completed, participants may eat normally.

[0074] 3.2.2.3 Contraception Requirements Women of childbearing potential (WOCBP) and men capable of fathering must use highly effective contraceptives such as ICH M3(R2), which have a low failure rate of less than 1% per year when used consistently and correctly. A list of contraceptives that meet these criteria will be provided in the study participant information. WOCBPs must have a partner who is capable of fathering and must be willing and able to use highly effective contraception from the randomized visit (visit 2) until 7 days after the last dose of the study medication. WOCBP partners do not require contraception. ICH M3(R2) is an extremely effective method of contraception with a low failure rate of less than 1% per year when used consistently and correctly (if permitted by local regulations): • Hormone contraception (oral, vaginal, transdermal) containing combinations that suppress ovulation (estrogen and progestogen) • Hormone contraception using only progestogens to stop ovulation (oral, injectable, implantable) • Intrauterine contraceptive device (IUD) / Intrauterine hormone-releasing system (IUS) • Bilateral fallopian tube obstruction

[0075] Male participants in the study must use condoms containing or without spermicide, or undergo a vasectomy with documented proof of sperm-free semen, for at least 7 days after their last dose of the study drug, if their sexual partner is a WOCBP. Partners of male participants are not required to use contraception. Alternatively, male study participants who are WOCBP or capable of fathering must refrain from sexual intercourse with women. This will be determined in accordance with the participant's preferred normal lifestyle. Periodic abstinence, e.g., using a calendar, ovulation, symptomatic body temperature, or post-ovulation methods; a declaration of abstinence during the period of exposure to the study drug; withdrawal will not be permitted.

[0076] 3.3 Adherence to Procedures Participants in the trial will be asked to bring all remaining test medication, including empty packaging materials, when they come to the clinic. Based on the total number of tablets, compliance with the treatment is calculated as shown in the formula below. Compliance is verified by a sponsor-approved CRA.

number

[0077] 4. Evaluation 4.1 Evaluation of effectiveness 4.1.1 Hepatic venous pressure gradient HVPG measurements will be performed at the times specified in the flowchart (Figures 2A-2D). The facility must have the necessary infrastructure and equipment for measuring HVPG (e.g., a liver hemodynamic laboratory at the facility or a nearby facility) available. Facility staff performing the procedure must have sufficient expertise (e.g., performing in 25 or more HVPG measurement activity areas per year), along with interventional skills and expertise in interpreting pressure curves, as local interpretations of the output from visit 1b and EoT visits will be recorded in the study participant source document and eCRF.

[0078] HVPG procedures within the trial will be performed in a standardized manner at all sites (see the ISF HVPG manual for details); training will be provided. Each trial site will be asked to provide acceptable sample HVPG outputs for trial 1366-0021 or 1366-0029 if they have not already been provided before the start of participant recruitment. Occlusive hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) will be measured three times each (in triplicate); outputs will be provided to an external supplier and read centrally by an independent expert at PH; the central reading will include a subjective assessment of the overall trace quality as well as relevant pressure readings. The independent expert will not be informed of the point in time to which the trace is relevant. The central reading will include traces from visit 1b, which have also been interpreted locally. The results of the central reading will be communicated to the sponsor and will be considered the official assessment of the trial. If there is a discrepancy between the local interpretation (e.g., visit 1b output) and the central assessment, the central assessment will remain valid. HVPG measurement should ideally be performed in the morning, prior to ingestion of the study drug, and after an overnight fast, using the same hepatic vein. If measurement cannot be performed on the morning of visit 1b, another time may be chosen; in this case, at least 4 hours of fasting is required. Subsequent HVPG measurements for single-dose trial participants should then be performed at approximately the same time as the visit 1b measurement.

[0079] At the end-of-treatment (EoT) visit, HVPG measurement should be performed on the scheduled visit or within 7 days (if the latter approach is taken, the measurement should still be performed after an overnight fast / at least 4 hours of fasting). If this method is chosen for HVPG administered during the treatment period, the morning dose of the investigational drug can be taken before this procedure. The HVPG procedure is outlined below (Reiberger T, Schwabl P, Trauner M, Peck-Radosavljevic M, Mandorfer M. Measurement of the hepatic venous pressure gradient and transjugular liver biopsy. J Vis Exp 2020 (160); e58819). Under local anesthesia and ultrasound guidance, the catheter introducer sheath is positioned in the right internal jugular vein. Using fluoroscopy, the balloon catheter is advanced into the inferior vena cava (IVC) and inserted into the great hepatic vein. The accurate and sufficient wedge position of the catheter is ensured by injecting contrast agent, while the balloon occludes the outflow of the hepatic vein into which the cannula was inserted. After checking the external pressure transducer, a continuous pressure record is obtained along with three records of WHVP and FHVP. The difference between FHVP and WHVP is called HVPG, and a value of ≥10 mmHg indicates CSPH. Before removing the catheter, the pressure reading obtained in the same level IVC and the right atrial pressure are recorded.

[0080] 4.1.2 FibroScan Measurement The liver and spleen undergo vibration-controlled transient elastography (VCTE). TM The assessment will be performed using the FibroScan® Expert 630 instrument, a non-invasive, advanced technology. FibroScan® for the liver has been used for many years and is a standard procedure for screening and managing trial participants with liver disease. The ability to assess splenic stiffness using FibroScan® has only recently become possible with the introduction of the FibroScan® Expert 630 model; therefore, splenic stiffness measurement is not a standard part of clinical practice in the trial participant population planned for this study. The evaluation should be performed at the time specified in the flowchart (Figures 2A-2D), after an overnight fast, in accordance with the ISF FibroScan® instruction manual. Ideally, the FibroScan® evaluation should be performed on the same day as the ultrasound examination.

[0081] During the treatment period, after randomization, evaluation should be performed on the scheduled visit day or within 7 days (if the latter approach is taken, measurements must be taken after an overnight fast). The next evaluation will be conducted: • Liver stiffness measurement using VCTE (LSM) • Spleen stiffness measurement using VCTE Data from FibroScan® measurements is sent to an external supplier, who then communicates the results to the sponsor or agent.

[0082] Field personnel using the FibroScan® Expert 630 instrument must be adequately trained and certified. Field personnel are expected to have prior experience using FibroScan® on LSMs. Training will be provided as needed; each test site will also undergo an eligibility process before commencing test participant recruitment if it has not already been conducted for test 1366-0021 or 1366-0029 (see the ISF FibroScan® Instruction Manual for further details). If the FibroScan® Expert 630 instrument is not available at the site, it will be provided by the sponsor for the duration of the test. If possible, the same operator should perform the evaluation for single-trial participants.

[0083] 4.2 Safety Assessment 4.2.1 Physical Examination A complete physical examination must be performed at two points in time as specified in the flowchart (Figures 2A-2D); further physical examinations are only required if the test participant reports symptoms. The complete physical examination should include a minimum of a full external view, neck, lungs, cardiovascular system, abdomen, limbs, and skin. 4.2.1.1 Body measurements (height, weight, waist circumference, and hip circumference) Height, weight, waist circumference, and hip circumference measurements are performed at the times specified in the flowchart (Figures 2A-2D). Height is measured only during the initial visit (1a). The results of the physical measurements must be included in the source documentation available at the facility.

[0084] Whenever possible, weight measurements should always be taken using the same scale for each study participant. To obtain comparable weight values, the assessment should be carried out as follows: Shoes, jackets, and all head coverings must be removed. • You have to take heavy things (i.e., keys, coins) out of your pockets. · After urinating The measuring tape used for waist and hip circumference should be made of a material that does not stretch easily, such as fiberglass. Waist circumference should be measured around the bare upper abdomen of the participant while they are standing with their shoes off, feet together, and arms hanging freely, after they have exhaled. Waist circumference should be determined by measuring the midpoint between the lowest rib and the iliac crest. The measuring tape should be perpendicular to the long axis of the body, horizontal to the floor, and taut enough to conform to the measurement surface. When measuring your waist circumference, start with one waist, wrap the measuring tape around the widest part of the buttocks, and then wrap it around the other waist to the front. Remove your jacket / coat, empty your pockets to ensure a precise measurement, stand with your feet together, and let your arms hang freely.

[0085] 4.2.2 Monitoring of vital signs / home blood pressure and heart rate Vital signs (SBP, DBP, and HR [heart rate]) are assessed at the time specified in the flowchart (Figures 2A-2D), prior to blood sample collection and 12-lead ECG, upon arrival at the study. BP measurements should be recorded at 1 mmHg, closest to the eCRF. BP should be measured in the non-dominant arm. HR is measured electronically or palpating and counted for 1 minute. BP and HR measurements should be taken after the study participant has rested in a seated / supine position for at least 5 minutes. Measurements recorded upon arrival at the study must be included in the source documentation available at the facility. During screening (visit 1a), the facility should measure vital signs using a preferred method. From visit 2 onward, vital signs should be measured using the participant's home BP monitoring device to ensure consistency throughout the study. This includes pre- and post-administration vital sign measurements during dose escalation periods and subsequent visits (see flowchart (Figures 2A-2D)).

[0086] 4.2.2.1 Home blood pressure and heart rate monitoring Home-use BP and HR monitoring will be performed by the study participant as specified in the flowchart (Figures 2A-2D). An electronic BP and HR monitoring device will be provided for this purpose. Facility staff will educate the study participant on the correct use of the device during visit 2 and explain that it should only be used to record BP and HR measurements belonging to the study participant. If necessary, follow-up training will be provided at the next visit. Study participants are asked to measure their blood pressure (BP) and heart rate (HR) each morning immediately after waking up, before engaging in significant physical activity, and after sitting and resting for approximately 5 minutes. Measurements must be taken before administration of the morning dose of the study drug. Electronic readings are stored in the memory of a home BP and HR monitoring device.

[0087] If a participant experiences any symptoms suggestive of hypotension at any time after taking the study drug (e.g., dizziness / lightheadedness, seeing black spots, weakness), especially if the symptoms occur while standing or if any other symptoms are experienced between study visits, additional BP and HR readings may be taken, and participants should report these symptoms at their next study visit. Participants should bring a home BP and HR monitoring device to each study visit (see flowcharts shown in Figures 2A-2D), and site staff will review the electronic readings and use them to measure BP and HR during study visits from visit 2 onward. Any BP / HR measurements deemed to be adverse events (AEs) after review must be included in the source documentation available at the site.

[0088] 4.2.3 Safety Laboratory Parameters The safety laboratory parameters to be evaluated are shown in Table 4. The sample collection times are as shown in the flowchart (Figures 2A-2D). All analyses are performed in the central laboratory; the respective reference ranges are provided to the ISF. See Table 5 for a list of "minimum required safety laboratory parameters" in the event of force majeure or other destructive circumstances. Trial participants must fast for blood sample collection for safety laboratories, as specified in the flowchart (Figures 2A-2D) for hospital visits; if non-fasting conditions are specified, safety laboratory samples may be collected under non-fasting conditions. Fasting conditions are recorded, for example, for PK sample collection purposes. Blood samples for safety laboratory parameters should be collected prior to administration of the investigational drug.

[0089] Instructions regarding sample collection, sample handling / processing, and sample transportation are provided in the ISF Central Laboratory Manual. The central laboratory provides laboratory reports to the clinical trial physician. It is the clinical trial physician's responsibility to evaluate these reports. Any clinically relevant abnormal findings, as determined by the clinical trial physician, must be reported as adverse events (AEs). Laboratory tests may need to be repeated if medical follow-up is required due to an adverse event (AE) or if the test is unsuccessful due to improper handling or storage of the sample. If a participant fails to meet all laboratory requirements for participation in the study due to a transitional medical condition, the participant may continue through the screening period but cannot be randomized until the retesting of the laboratory results is available to determine the participant's eligibility.

[0090] If the criteria for liver damage are met, several additional measures will be implemented. The amount of blood drawn from the affected trial participants will increase to accommodate these additional samples. The CKD-EPI formula (standardized by isotope dilution mass spectrometry) is used to report eGFR based on serum creatinine. The central laboratory communicates the analysis results to the sponsor or their representative. If qualitative parameters are abnormal, quantitative analysis will be performed by the central laboratory. [Table 9-1] [Table 9-2]

[0091] [Table 10]

[0092] 4.2.4 Electrocardiogram A 12-lead ECG is recorded at the times specified in the flowchart (Figures 2A-2D); the ECG is performed prior to blood sample collection and administration of the study drug (at the time of arrival when only one ECG is required), and after the study participant has rested in a supine position for at least 5 minutes. During the dose escalation period (i.e., while dose escalation is occurring) and at subsequent visits, a 12-lead ECG should be performed approximately 1 and 2 hours after administration of the study drug. These ECGs should be taken 1 and 2 hours before the PK sample is taken post-administration.

[0093] ECGs must be administered by a qualified physician, nurse, or technician. The investigator or agent will evaluate whether the ECG is normal or abnormal and assess its clinical relevance. ECGs may be repeated for quality reasons, and repeated records will be used for analysis. Additional ECGs may be recorded for safety reasons if necessary. ECG dated and signed printouts, along with findings, will be documented in the participant's medical record. Clinically relevant abnormal findings will be reported as baseline status (if confirmed at screening visit [visit 1a]) or as an AE otherwise, monitored, and / or treated if medically appropriate. ECG abnormalities will be carefully evaluated by the investigator or their representative, and if the criteria for discontinuation are met, the participant will be discontinued from the study. A copy of the ECG is sent to a central ECG supplier for archival purposes. This allows for subsequent centralized and independent reassessment if necessary.

[0094] 4.2.5 Other Safety Parameters 4.2.5.1 Ultrasound (Liver and Spleen) Ultrasound imaging of the liver and spleen is performed after an overnight fast, using local facility equipment, at the times specified in the flowchart (Figures 2A-2D). Ideally, the ultrasound evaluation should be performed on the same day as the FibroScan® examination. During the treatment period, after randomization, ultrasound evaluation will be performed within 7 days of the scheduled visit (if this latter approach is taken, the evaluation must still be performed after an overnight fast). Ultrasound is used as a safety measure to assess the condition of the liver and spleen, organ size, and the presence of ascites. The capsule distance between the skin and the liver (i.e., subcutaneous thickness), portal vein diameter, capsule distance between the skin and the spleen, and the height, length, and width of the spleen are also measured. This is because large gaps can affect the ability of the FibroScan® Expert 630 instrument to adequately measure liver and spleen stiffness. The facility is expected to follow local standard procedures before and during the process. 4.2.5.2 Liver injury adjudication An independent AC (Acquisition Criteria) is used to determine the severity of certain liver events and their causal relationship with the investigational drug.

[0095] 4.2.6 Evaluation of Adverse Events Data and information necessary for a complete assessment of AE, SAE, and AESI will be reported to the sponsor via eCRF. This may include specific data and information not specified in this protocol, in anticipation of future needs. 4.2.6.1 Definition of AE 4.2.6.1.1 Adverse Events An adverse event (AE) is defined as any medical event that causes an adverse reaction in a trial participant or clinical trial subject receiving a drug, and does not necessarily have to be causally related to the treatment. Therefore, an adverse event (AE) can be any undesirable or unintended sign (including unusual laboratory findings), symptom, or disease that is temporally related to the use of a drug, whether or not it is considered related.

[0096] The following are also recorded as appropriate eCRFs: • Worsening of an underlying disease or a pre-existing condition • Changes in vital signs, ECG, physical examination, and laboratory test results, if deemed clinically relevant by the investigator. If such an abnormality already existed prior to participation in the trial, it is considered the baseline condition and collected only in the eCRF.

[0097] 4.2.6.1.2 Serious Adverse Events A serious adverse event (SAE) is defined as any AE that meets at least one of the following criteria: • Causes death, This refers to events that are life-threatening and in which the test participant was at risk of death at the time of the event; it does not refer to events that, if more serious, could have caused death. • Participants in the study require hospitalization or extension of their current hospitalization. • Causes persistent or significant physical disability or helplessness • It is a congenital abnormality / congenital defect. A serious medical event is considered serious for any other reason if, based on appropriate medical judgment, it could endanger a trial participant and require central or surgical intervention to prevent one of the other outcomes defined above. Examples of such events include intensive emergency room or home treatment for allergic bronchospasm, blood cachexia, or seizures that do not result in hospitalization or the onset of dependence or abuse.

[0098] In Japan only: Events that could potentially cause physical injury are treated as "appearing serious for some other reason" and are therefore reported as SAEs (Serious Events). 4.2.6.1.3 AEs considered "always serious" In accordance with the European Medicines Agency's initiative on Important Medical Events, Boehringer Ingelheim has established a list of AEs that may not meet the criteria for SAEs as defined above, but which can always be considered “serious” by their nature. The latest list of “always serious AEs” can be found in the eDC system. Copies of the latest list of “always serious AEs” are available upon request. These events are always reported as SAEs. Cancer and the worsening of existing cancer must be classified as serious events regardless of the time elapsed since discontinuation of the drug and must be reported as described in the subsections “AE Collection” and “AE Reporting and Planning to the Sponsor.”

[0099] 4.2.6.1.4 Particularly noteworthy adverse events The term "Analytical Adverse Event of Particular Interest (AESI)" refers to any specific adverse event that was identified at the planning level as of future safety monitoring and safety assessment within this trial, such as a potential AE based on knowledge from other compounds in the same class. AESIs must be reported to the sponsor's Pharmacovigilance Department within the same timeframe as those applied to SAEs.

[0100] The following are considered to be AESI: · Liver damage Liver injury is defined by changes in laboratory and clinical parameters of the liver after randomization, as detailed in the elimination and cessation criteria. These laboratory findings constitute a warning of liver injury, and patients exhibiting these abnormalities should be monitored according to the "DILI Checklist," which can be downloaded from the eDC system. In cases of clinical symptoms of liver injury (e.g., brain damage, nausea, vomiting, itching, severe fatigue, jaundice) without available laboratory results (ALT, AST, total bilirubin, INR), the investigator should ensure that these parameters are analyzed in unscheduled blood tests if necessary. If the criteria for a liver injury warning are met, the procedures outlined in the DILI Checklist should be followed.

[0101] 4.2.6.1.5 Severity of adverse events The severity of an adverse event (AE) should be classified according to version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE) dated November 27, 2017, and recorded in the eCRF. 4.2.6.1.6 Causal relationship of adverse events Using medical judgment, the association between the adverse event (AE) and the biosecurity (BI) test compound is determined by considering all relevant factors, including the pattern of response, temporary relationship, discontinuation or retesting of administration, confounding factors such as concomitant therapy, complications, and relevant medical history. The following arguments may suggest that there is no rational possibility of a causal relationship: • The plausible time interval between drug exposure and the onset of an event is unclear (e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of drug administration; allergic reactions several weeks after discontinuation of the investigational drug). • The persistence of the effect (e.g., after 5 half-lives) despite the withdrawal of the drug, taking into account the pharmacological properties of the compound. Notably, this criterion cannot be applied to events that persist over time despite the removal of the initial trigger. • There are situations where an alternative explanation, such as another drug or an underlying disease, appears more plausible than the drug in question for the observed event. • Disappearance of the event despite continued or unchanged treatment with the test drug.

[0102] The following arguments may suggest a reasonable possibility of causality: • The observed phenomena are consistent with the known pharmacology of the test drug. • The event is known to be caused by or attributed to that drug class. • The most likely time from the time of drug exposure to the onset of the event. • Evidence that the event is reproducible when the drug is reintroduced. • There is no other medically sound causal explanation for the event (e.g., pre-existing factors, complications, or concomitant use of other medications). • The event is typically drug-related and rarely occurs in the general population that is not exposed to the drug (e.g., Stevens-Johnson syndrome). • Signs of dose-response (i.e., the effect becomes greater as the dose increases, and the effect becomes smaller as the dose decreases).

[0103] 4.2.6.2 Collection and Reporting of Adverse Events 4.2.6.2.1 AE Collection The clinical trial physician will maintain and retain detailed records of all adverse events (AEs) in the participant file. By default, SAE / AESI reports are submitted via the eCRF of the EDC system. If the EDC system is unavailable or becomes unavailable (e.g., after a database lock), the BI paper SAE format is used. The following must be collected and documented: From the signing of informed consent until the end of the study for each participant (=end of study [EoS] visit): all AEs (serious and non-serious) and all AESIs. • After each participant completes their exam: While the investigator is not required to proactively monitor participants for new adverse events (AEs), they are only required to report any new histological cancers, as well as any SAEs and AESIs related to the study drug that they become aware of through any means of communication, such as a phone call.

[0104] 4.2.6.2.2 Reporting to AE's Sponsors and Planned Procedures Investigators must report SAEs, AESIs, and any non-serious AEs associated with a reported SAE or AESI to the sponsor's sole entry point on the AE or SAE eCRF page within 24 hours of becoming aware of the event. Country-specific procedures are specified in the ISF. The same timeline applies once follow-up information becomes available. In addition, in special cases, investigators may contact the sponsor by telephone in advance.

[0105] Further information regarding these events must be received and a follow-up report submitted. The same rules and timelines apply to follow-up information as to the initial information. All (S)AEs, including those that persist after the end of the trial for individual participants, must be followed up until they are resolved and assessed as “chronic” or “stable,” or until no further information is available. If the EDC system is unavailable for more than 24 hours, reporting must be done using the SAE format on BI paper. 4.2.6.2.3 Pregnancy In rare cases, pregnancy may occur during clinical trials. Once a trial participant is enrolled in a clinical trial and has taken the investigational drug, the investigator must immediately (within 24 hours) report any drug exposure in a pregnant trial participant to the sponsor's sole entry point using Part A of the Pregnancy Monitoring Form.

[0106] Similarly, if a male trial participant's partner becomes pregnant, potential drug exposure during pregnancy must be reported. This requires the pregnant partner's written consent. Reporting and consent must comply with local regulations. The ISF includes trial-specific information and consent for the pregnant partner. Pregnancy outcomes related to drug exposure during pregnancy must be tracked and reported to the sponsor's sole entry point via the Pregnancy Monitoring Form (Part B) for the study. The ISF includes pregnancy monitoring forms (Parts A and B) for the study. Since pregnancy itself is not reported as an AE, only the pregnancy monitoring form for the study is completed if there are no associated SAEs and / or AESIs. However, pregnancy-related SAEs and / or AESIs must be reported.

[0107] 4.3 Drug concentration measurement and pharmacokinetics 4.3.1 Pharmacokinetic evaluation The PK sample collection time and period are as shown in the flowchart (Figures 2A-2D). The date and time of investigational drug administration and PK sample collection are recorded in the eCRF along with the fasting status of the study participants at each PK sample collection time. Additional PK parameters are calculated as needed. Unseptal PK parameters are calculated based on the actual sample collection time using valid PK software (Phoenix® WinNonlin® 8.1). Individual plasma concentration data and the PK parameters calculated therefrom are listed in a table and displayed using graphs. Participant PK data are flagged and excluded from the PK analysis in cases of protocol deviations relevant to PK assessment or in cases of unassessable PK (as revealed during data analysis based on the criteria specified below). The reasons for excluding data from trial participants will be documented in the CTR.

[0108] Protocol deviations relevant to PK evaluation may include the following: • Incorrect intake of the test drug, i.e., a participant receiving at least one dose of the test drug that was not assigned to the participant. • Ingestion of the wrong dosage of test medication • Actual intake of the test drug deviated significantly from the planned dose escalation. • Restricted use of combination therapies • Adherence to procedures is significantly different from 100%. Examples of PK unevaluability include: • Participants experienced vomiting within a time frame twice the median tmax (the median tmax is determined by excluding participants who experienced vomiting). • Study participants missed sample / concentration data at key phases of the PK configuration curve.

[0109] 4.3.2 Method of sample collection To quantify the plasma concentration of compound 114, blood is collected from the midline cubital or forearm vein. Blood is withdrawn via an indwelling intravenous catheter or by venipuncture with a metal needle. Further details of sample preparation for plasma preparation are described in the ISF Central Laboratory Manual. After analysis, the samples may be used for further methodological investigations (e.g., stability testing or metabolite evaluation) or to address questions from health authorities regarding the results / methodology. However, only data related to the specimen and / or its metabolites will be generated by these additional investigations. Test samples will be discarded after the completion of any further investigations, but within five years after the final CTR is signed.

[0110] 4.3.3 Analysis and Decision The plasma concentrations of compound 114 are determined by a valid liquid chromatography-tandem mass spectrometry (LC-MS / MS) assay. All details of the analytical method are available before the start of sample analysis.

[0111] 4.3.4 Pharmacokinetic-Pharmacodynamic Relationship PK and PD data from this study can be used for PKPD-related investigations of compound 114. Population PK-PD analysis can be performed at the project level using a nonlinear mixed-effects modeling method. This analysis is not part of the CTR but will be reported separately.

[0112] 4.4 Evaluation of Biomarkers This section concerns diagnostic biomarkers. Biomarkers with established efficacy and safety are described and discussed herein. To characterize the effects of compound 114 in trial participants with CSPH in decompensated cirrhosis resulting from non-cholestasis liver disease, several additional biomarkers representing key mechanisms of hepatic pathophysiology (e.g., markers of inflammation, fibrosis, and intradermal dysfunction) and / or related to the mechanism of action of the sGC activator will be analyzed. The biomarkers are summarized in Table 6. [Table 11]

[0113] Additional biomarkers that appear relevant to elucidating the mechanism of action, disease activity, and / or safety may be evaluated to address the objectives of this study. Refer to the flowchart (Figures 2A-2D) for the timing of sample collection for biomarkers. In China, collection of diagnostic biomarkers is optional due to regulatory restrictions. Biomarker sample collection requires consistent conditions for one sample and another, regarding fasting versus non-fasting; in this study, the fasting condition is chosen. Biomarker samples should be collected before administration of the investigational drug. Detailed sample collection procedures and handling instructions are described in the ISF Central Laboratory Manual. The test samples will be discarded after the completion of additional investigations, but within 5 years after the final CTR is signed. Diagnostic biomarkers may be reported in a separate biomarker report.

[0114] 4.4.1 Predictive biomarkers Pharmacogenomics (PG) investigates genetic variations to explain and predict an individual's response to drugs. Therefore, blood samples for PG studies are collected from each study participant. In China, the collection of PG samples is optional due to regulatory restrictions. In cases of unexplained variability in PK or PD parameters, DNA is extracted from these samples and used for diagnostic analysis of variants in the sGC gene and other genes in the pathway, as well as genes involved in drug-aided mesenteric metabolism (ADME). Numerous gene variants were associated with hepatic fibrosis and / or the degree of hepatic fibrosis. For example, the rs58542926 polymorphism in transmembrane 6 superfamily member 2 (TM6SF2) is a predisposing genetic factor for NAFLD. It is necessary to investigate whether carriers of specific polymorphisms respond differently to treatment with compound 114. These data are not intended to be included in the final CTR. However, the data may be part of the CTR if necessary. Detailed instructions for PG sample collection, including sample handling and transportation, are described in the ISF Central Laboratory Manual.

[0115] 4.4.2 Pharmacodynamics, safety, and participant selection biomarkers Several laboratory measurements from the safety laboratory (e.g., liver enzymes [ALT, AST, γ-GT, and alkaline phosphatase]) are relevant to evaluating the effects of compound 114 on hepatic pathophysiology and will be analyzed along with the diagnostic biomarkers mentioned above. For example, the inflammatory marker hs-CRP, the cardiac biomarker BNP, and troponin I, as well as the renal safety parameters eGFR and creatinine. Additional established hepatic fibrosis and cirrhosis biomarkers, such as caspase-cleaved cytokeratin 18 (M30), total cytokeratin 18 (M65), Pro-C3, Pro-C6, HA (hyaluronic acid), PIIINP (type III procollagen amino-terminal peptide), TIMP1 (tissue metalloproteinase inhibitor 1), ferritin, alpha-2 macroglobulin, and apolipoprotein A1 will be investigated (separate from safety laboratory parameters).

[0116] The following composite score indicating disease activity is determined: • Fibrosis-4 (Fib-4) index (age, AST, ALT, platelet count) indicating the level of liver fibrosis. • FibroScan (registered trademark) - AST (FAST (trademark)) score • FibroScan®-based scores for advanced fibrosis Agile 3+ (liver stiffness, AST / ALT ratio, platelet count, gender, age, and presence of diabetes) and cirrhosis Agile 4 (liver stiffness, AST / ALT ratio, platelet count, gender, age, and presence of diabetes) • Total bilirubin, INR, and creatinine using MELD • MELD-Na (Total bilirubin, INR, creatinine, sodium) • Enhanced liver fibrosis (ELF) score (HA, PIIINP, TIMP 1)

[0117] Pathological changes in liver fibrosis have been reported to be reflected in altered microRNA (miR) profiles in the blood circulation. miRNA profiling is performed to characterize disease activity and response to treatment. Changes in fecal and circulating bile acid levels have been reported in study participants with cirrhosis. Increases in taurine and glycine-conjugated bile acids, as well as increased amounts of secondary bile acids, have been described. Investigating a panel of plasma bile acids (e.g., using Biocrates' AbsoluteIDQ® bile acid kit) should help characterize the effect of compound 114 on bile acid homeostasis. Biomarkers are evaluated for monitoring treatment (i.e., changes from baseline assessment), but also for their potential to predict treatment response / non-response (i.e., correlation with treatment outcomes to endpoints associated with baseline data). The selected evaluations may be performed in numerical order (depending on the time and conditions of selection) or not at all, depending on the results of the clinical trial.

[0118] 4.5 Biobanking Participation in biobanking is voluntary and not a prerequisite for trial participation. Biobanking will only occur after separate biobanking informed consent has been given in accordance with local ethical and regulatory requirements. In China, due to regulatory restrictions, no samples will be collected for biobanking. 4.5.1 Method and timing of sample collection Detailed instructions regarding sample collection, preparation, processing, transport, and storage for all biological samples collected are provided in the ISF Central Laboratory Manual. Plasma and serum for biobanking are collected at the times specified in the flowchart (Figures 2A-2D). Biobanking sample collection requires consistent conditions for one sample and another, regarding fasting versus non-fasting; in this test, the fasting condition is selected.

[0119] 4.6 Other ratings 4.6.1 Participant Warning Card At visit 2, participants are given a paper reminder card to record the administration time of the investigational drug three days prior to each visit in which a PK sample is collected (see flowcharts shown in Figures 2A-2D). Following the participant's initial training on completing the reminder card at visit 2, further retraining will be provided if necessary. Participants are asked to bring their reminder cards to relevant trial visits so that facility staff can review and check their adherence to the instructions described above. 4.7 Validity of Measurement This trial will include standard efficacy and safety measurements, as well as non-standard measurements, that are performed in accordance with the clinical practice standards in the selected trial population.

[0120] 5. Test Implementation Plan In the event of force majeure or other disruptive circumstances (e.g., pandemic, war), implementation of the study plan under this clinical trial protocol may not be feasible. With the participant's consent, the sponsor and the investigator may agree to alternative, backup, or remedy methodologies, which may include, but are not limited to, the actual visit and evaluation of the trial participant, visits by a home care nurse, transportation of study procedures that involve direct interaction with the participant, or collection of biosamples from the participant's home. Implementation of these measures will depend on the participant's consent, operational feasibility, and local laws and regulations. If alternative methodologies are implemented, the deviation from the original plan will be precisely documented.

[0121] 5.1 Scheduled visit All visits are scheduled according to the flowchart (Figures 2A-2D). Each visit day (including its allowable time frame) is calculated in relation to the randomization day (i.e., Day 1). During the dose escalation period of the study (i.e., visits 2-4), scheduled study visits must be spaced at least 7 days apart. This is because there must be at least 7 consecutive days between the intake of a prior dose of compound 114 by the study participant and the occurrence of the dose escalation. For this reason, if an allowable time frame (+2 days) applies to visit 3, that allowable time frame (+2 days) must also apply to visit 4. If a visit is missed, it should be rescheduled as soon as possible, ideally within the allowable time frame for that visit. If any visit needs to be rescheduled, subsequent visits should follow the original scheduled visit. Unscheduled visits may be made at any time at the discretion of the investigator for safety reasons or, for example, to provide the investigational drug (e.g., to restart compound 114 after treatment interruption).

[0122] All visits will take place at the study site, ideally in the morning. During the randomized treatment period, the study drug will be administered as part of the visit on the morning of the visit. Therefore, on these days, participants should be instructed not to take their morning dose prior to the visit. This is especially important for visits where PK / biomarker / PG sample collection is required; whenever possible, PK samples should be collected at approximately the same time during subsequent PK visits (see flowcharts shown in Figures 2A-2D). Participant fasting status will be recorded in the eCRF according to the flowchart (Figures 2A-2D). Participants who fail to follow the above instructions should have their visit rescheduled as soon as possible, ideally to the following day. In the event of force majeure or other interruption, a participant's physical visit to the facility may not be feasible or may need to be restricted to ensure the participant's safety. Based on a thorough assessment of benefits and risks, the following visits may be conducted remotely from the participant's home (by telephone) or as a combination of home and remote visits: • 6th visit When scheduling such visits, every effort should be made to ensure a continuous supply of the investigational drug for the trial participant, taking into account that the next kit of the investigational drug may need to be transported from the facility to the participant's home, and that medical requirements must be met and confirmed prior to the transport of new supplies. Any deviations from the initial scheduled visit will be documented, and their implications will be considered for the analysis of the test data.

[0123] 5.2 Details of the selected in-visit examination procedure At each visit, the evaluation will be performed as shown in the flowchart (Figures 2A-2D). During the treatment period, all evaluations are performed before the study drug is ingested. Exceptions to this are post-dose vital signs and ECG as well as post-dose PK samples (see below). Once the study drug has been administered / once all in-clinic evaluations that require fasting have been completed, the study participants can eat as normal (thus, post-dose PK samples do not require a fasting situation).

[0124] Vital signs are always measured before the ECG, and the ECG is always measured before any blood samples are taken (see the flowcharts shown in Figures 2A - 2D). In case of force majeure or other interruption situations, the in-clinic visit may have to be done remotely (by phone) far from the study participants' homes or as a combination of home and remote in-clinic visits. During this in-clinic visit, the following evaluations can be done at the study participants' homes or remotely: · Concomitant therapy · IRT call · Administer the study drug · Provide / administer / review the results of the study participants' training / re-education sessions (home BP and HR monitoring; study participant reminder cards) · All AEs / SAEs / AESIs · Compliance check

[0125] The study drug is not collected during in-clinic visits that are done remotely. Instead, the drug is collected when the study participant next visits the facility or when the in-clinic visit is done at the study participant's home (see below). The following evaluations can be done at the study participants' homes: · Physical measurements · Vital signs · Physical examination · 12-lead resting ECG (using a portable ECG device) · Collection of the study drug

[0126] In the event of force majeure or other interruption, if safety laboratory sample collection via the central laboratory is not possible from the study site (and is instead performed at the participant's home), the analysis may be performed in a local laboratory. The results of the safety laboratory study must be communicated to the investigator, who must ensure medical review and document any clinically relevant safety issues as adverse events (AEs). See Table 5 for a list of "minimum required safety laboratory parameters." Any deviations from the initial evaluation schedule defined in the flowchart (Figures 2A-2D) are documented, and their implications are considered for the analysis of the test data.

[0127] 5.2.1 Screening period (visit 1a and 1b) The study procedure must not be performed unless the study participant consents to participate in the study. Once the study participant consents, they are considered enrolled in the study and screening has begun. The study participant is recorded in the enrollment log and registered in the IRT system as a screened study participant. Study participants who are not eligible to proceed to visit 2 (i.e., who fail screening at visit 1a or 1b) are registered as screening failures in the IRT system and eCRF and no further follow-up is required. The screening period is defined as the period prior to randomization and the administration of the first investigational drug. The screening period consists of two visits (see flowcharts shown in Figures 2A-2D), namely visit 1a and visit 1b; these visits are ideally completed within a 4-week period (i.e., day 1, visit 2). There is no minimum duration for the screening period. Trial participants may proceed from one visit to the next within the screening period as soon as all results from the previous visit become available, provided they remain eligible for the trial.

[0128] Demographic information is collected during the first visit (1a). This includes: • Age (years) on the day of informed consent • Gender (male / female, to record the gender at birth of the test participant) • For female trial participants: the presence or absence of the possibility of childbirth, and as a basis for contraception requirements in order to characterize the trial participant population. • To adequately characterize ethnic and racial groups of study participants, to support subgroup analyses where necessary, and to support the calculation of renal function using the CKD EPI formula, which requires that study participants be classified as Black or non-Black (where permitted by local regulations). Baseline condition and medical history Information regarding medical history / baseline status will also be gathered at visit 1a (e.g., relevant chronic diseases, current observable diseases, and other relevant conditions, at the discretion of the investigator, which may not be observable on the day of the examination [e.g., because the study participant is receiving combination therapy to treat the disease]). This includes any new clinically relevant findings confirmed during the screening period.

[0129] 5.2.2 Treatment period If a participant is deemed eligible for the study after visits 1a and 1b, they will be randomized to visit 2 (day 1) using the IRT system. All visit 2 assessments (see flowcharts shown in Figures 2A-2D) should be completed before the administration of the first dose of the investigational drug; the exceptions are post-administration vital signs and ECG, and post-administration PK samples. Each participant can only be randomized after entering the study. The randomized treatment period begins at visit 2 and ends when the participant reaches the end-of-tour (EoT) visit (see flowcharts shown in Figures 2A-2D). The final dose of compound 114 is administered on the evening before the EoT visit. Trial participants will be evaluated at regularly scheduled visits as specified in the flowchart (Figures 2A-2D). During the dose escalation phase of the treatment period, scheduled visits will be more frequent. It is especially important that the time slots for these visits are strictly adhered to, because trial participants must have at least seven consecutive days between the ingestion of a preceding dose of compound 114 and any dose escalation. Unscheduled visits may be arranged if necessary; evaluations completed during unscheduled visits will depend on the circumstances under which the visit was scheduled and will be at the discretion of the investigator.

[0130] Blood samples for PK are also collected at several visits during the treatment period (see flowcharts shown in Figures 2A-2D). Three days prior to each of these visits, participants record the administration time of the study drug on a paper reminder card. The recorded information is checked by facility staff during the relevant visit and documented in the eCRF. Where possible, the facility reminds participants (e.g., by phone) to begin completing the paper reminder card on the relevant day. Participants are also reminded to bring the reminder card, as well as electronic BP and HR monitoring devices, to each trial visit. Retraining is provided as needed. An IRT call is made each time the patient visits the pharmacy for dispensing medication during the trial (see the flowcharts shown in Figures 2A-2D).

[0131] 5.2.2.1 Completion of treatment / early discontinuation of treatment: Visit the hospital Patients who successfully complete the entire 8-week treatment period should have an evaluation for their EoT visit, as shown in the flowchart (Figures 2A-2D). Such patients will be registered in the IRT system as completed. The completion of the trial medication must also be recorded in the corresponding eCRF. In patients who discontinue the trial medication prematurely (regardless of the reason), an ED visit (see flowchart shown in Figures 2A-2D) should be completed instead of the scheduled treatment period visit. Ideally, the ED visit should take place within 7 days of discontinuing the trial medication. The evaluation performed at the ED visit should follow the flowchart (Figures 2A-2D), with the following exceptions: • HVPG: Not required • Biomarkers are not required. • PK sample collection: Not required • Biobanking sample collection: Not required

[0132] Patients who discontinue treatment early will be registered in the IRT system as having discontinued treatment. The termination of the trial medication must also be recorded in the corresponding eCRF. At the end-of-time (EoT) and / or end-of-day (ED) visit, patients will be reminded of the limitations that require continued observation until the end-of-situ (EoS) visit. Home-based blood pressure and heart rate monitoring should continue between the EoT / ED visit and the EoS visit.

[0133] 5.2.3 Observation period and end of the trial The End-of-Site (EoS) visit is scheduled two weeks after the End-of-T (EoT) and / or End-of-Day (ED) visits (see flowcharts shown in Figures 2A-2D); participation in the study ends upon completion of this visit, and the termination must be recorded in the corresponding eCRF. When the End of Service (EoS) visit takes place after the End of Service (ED) visit, the evaluation performed at the EoS visit should follow the flowchart (Figures 2A-2D), with the following exceptions: For individual patients, the end of the trial was defined as the completion of the End of Service (EoS) visit within the specified time frame, and the trial medication was not discontinued prematurely. After the EoS visit, patients returned to standard medical care.

[0134] 6. Determination of statistical methods and sample size In this trial, the primary endpoint is the percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of treatment. The objective of this trial is to demonstrate the short-term clinical activity of compound 114 in trial participants with CSPH in decompensated cirrhosis following the first decompensated event.

[0135] 6.1 Zero and Alternative Hypothesis Statistical testing is not planned for this study. All analyses are descriptive in effect. The endpoints are investigated. It will be. However, testing the statistical hypothesis regarding the variables in the items to be confirmed is not planned. Instead, it will be described and evaluated by descriptive statistical methods. 6.2 Planned Analyses 6.2.1 General Considerations The analysis will be performed based on the following analysis target populations: · Enrolled set (ES) - This analysis target population includes all trial participants who had a signed informed consent and were eligible as trial subjects. ES is used for the analysis of the qualifications of trial participants. · Randomised set (RS) - This analysis target population includes all enrolled trial participants who participated and were randomised to the trial medication. RS is used for the presentation of demographics and baseline disease characteristics. · Treated set (TS) - The treated population includes all trial participants who were enrolled or randomised to the trial medication and were treated with at least one dose. TS is used for all safety analyses. · Full analysis set (FAS) - This analysis target population includes all enrolled or randomised trial participants who received at least one dose of the trial drug and had a baseline measurement of the recorded primary endpoint. FAS is used for efficacy analysis.

[0136] Additional analysis target populations will be defined in the TSAP if necessary. The efficacy analysis will be performed based on the planned treatment (i.e., treatment assignment at randomisation). The safety analysis is based on the actual treatment received at the registration / randomisation visit. Unless otherwise specified, the baseline is defined as the most recent measurement before the first intake of the trial drug.

[0137] Pharmacokinetics The PK parameters for compound 114 are calculated according to the sponsor's relevant standard operating procedures (SOPs). Non-compartmental analysis is performed using a valid software program, such as Phoenix WinNonlin® software (version 8.1 or later, Certara USA Inc., Princeton, NJ, USA) or SAS® Version 9.4 (or later). Participant plasma concentration data and parameters are included in the descriptive statistics unless flagged for exclusion due to protocol deviations related to PK assessment (which should be determined before the Report Planning Meeting [RPM]) or due to inability to assess PK (which will be revealed during data analysis).

[0138] biomarkers Statistical biomarker analysis includes diagnostic biomarker endpoints. These endpoints are included in the analysis unless they are flagged for exclusion due to protocol deviations (which should be determined prior to the RPM) related to the evaluation of biomarkers. Exclusion of trial participant data is documented in the CTR. Relevant protocol deviations that may affect biomarker analysis may include, for example: • Incorrect intake of the test drug, i.e., a participant receiving at least one dose of the test drug that was not assigned to the participant. • Actual intake of the test drug deviated considerably from the planned dose escalation of compound 114. • Restricted use of combination therapies • Adherence to procedures varies considerably from 100%. • Biomarker evaluations were not performed under the fasting conditions required for each evaluation.

[0139] 6.2.2 Handling of Intercurrent Events The following are the expected intermediate events of interest in this trial: • Restricted use of combination therapies: NO-sGC-cGMP pathway activation therapy such as NO-donors (e.g., glycerin trinitrate, isosorbide dinitrate or mononitrate, morcidomin), PDE-5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil), nonspecific PDE inhibitors (e.g., dipyridamole and theophylline), or sGC-stimulants (e.g., riociguat). • New initiation / dose changes in existing NSBB / carvedilol combination therapies • Occurrence of decompensated events • Premature discontinuation of assigned trial doses The strategy for handling intermediate events in this test is as follows: Treatment strategy: This is the effect of randomizing trial participants to a treatment arm regardless of the treatment actually taken. All intermediate events will be handled according to the treatment strategy methodology specified in ICH E9(R1). Each analysis refers to a strategy for handling the intermediate events being evaluated. The estimand for each major analysis in this protocol is a combination of the relevant detailed clinical objectives and this strategy described herein. The handling of intermediate events not listed above will be determined through reconsideration and documented in TSAP.

[0140] 6.2.3 Primary objective analysis The primary endpoint is analyzed in FAS using the ANCOVA model without imputing any missed data. The models are as follows: Percentage change in HVPG from baseline in week 8 = overall mean +HVPG baseline +Treatment+ Use of NSBB or carvedilol +Type of initial decompensation event + Random error

[0141] This model includes the following primary causative effects of the mutagen: “Treatment,” “Use of NSBB or carvedilol,” and “Type of first decompensation event” are fixed classification effects, and “HVPG at baseline” is a linear covariate. Random errors typically have a mean of 0 and an unknown variance Σ. 2 It is assumed that they are distributed as follows: The analysis is used solely to evaluate the effect of the treatment without hypothesis testing. Trial participants are analyzed according to their assigned tier (regardless of any incorrect assignment of treatment based on incorrect tier confirmation). This is because such errors occur before randomization and are therefore consistent with regulatory guidance. Procedures to follow if the analysis is unsuccessful are described in the TSAP. 6.2.3.1 Sensitivity analysis Susceptibility analysis may be performed, and if applicable, it will be described in detail by TSAP. 6.2.3.2 Subgroup Analysis Any subgroup analyses planned for this study will be documented in the TSAP, where applicable.

[0142] 6.2.4 Secondary objective analysis Unless otherwise specified, only descriptive statistics will be presented for the secondary endpoints defined herein. The percentage of trial participants who experienced an event of interest related to the secondary endpoint will be presented. 6.2.5 Further Objective Analysis Descriptive statistics are presented only for further endpoints. Analysis of PK and biomarker parameters is described herein. 6.2.6 Safety analysis Adverse events are coded using the International Medical Terminology Dictionary (MedDRA). A standard BI summary table and catalog are created. All adverse events that commence between the start of treatment and the end of the REP (7 days after the last dose of the study drug) are assigned to the on-treatment period for evaluation.

[0143] Safety analyses will be conducted according to the "initial treatment" principle. All treated trial participants will be included in the safety analysis. Generally, safety analyses will be descriptive and based on the BI standard. Hypothesis testing will not be conducted. Statistical analysis and reporting of adverse events will focus on adverse events that occurred as a result of the treatment, i.e., all adverse events that occurred between the start of the treatment and the end of the REP. Adverse events that began before the first drug intake and worsened under the treatment will also be considered "responsible for the treatment." The frequency, severity, and causal relationship of adverse events are coded according to the latest version of the International Medical Terminology (MedDRA) database at the time of database locking, and then listed in a table using organ-specific major classifications and preferred terminology.

[0144] Laboratory data are analyzed both quantitatively and qualitatively. The latter is performed by comparing the laboratory data to a reference range. Values ​​outside the reference range and values ​​defined as clinically relevant are summarized. Treatment groups are descriptively compared with respect to distribution parameters, as well as the frequency and proportion of study participants with abnormal or clinically relevant abnormal values. At screening, baseline, during the trial, and at the end of the trial, vital signs, physical examination, or other safety-related data observed will be evaluated for any possible changes compared to pre-procedure findings.

[0145] 6.2.7 Other Analysis PK and biomarker parameters are descriptively analyzed. Correlation analyses are performed between baseline diagnostic biomarkers and key endpoints of response to treatment. 6.2.8 Interim Analysis While no interim analysis is planned, the Data Monitoring Committee (DMC) is undertaking the tasks outlined herein. Further details are provided in the DMC Charter. The DMC's primary role is the sustained assessment of safety. 6.3 Handling of Missed Data The handling of missed primary key data will be carried out according to the relevant BI internal procedures. Data recovery for missed endpoints is not planned. If a trial participant fails to attend a clinic visit, the data will not be recovered.

[0146] 6.4 Randomization BI will be responsible for randomization and arranging the packaging and labeling of the investigational drug. The trial will be conducted in a double-blind design with placebo and 114 active compounds. Participants will be randomized in a 1:1 ratio to one of two treatment groups in block units. Randomization will be stratified by the use (or absence) of NSBB or carvedilol and the type of the first decompensation event (ascites or variceal bleeding). The randomized list is generated using a valid system that includes a pseudo-random number generator, ensuring that the assigned treatment is reproducible but simultaneously unpredictable. The block size is documented in the CTR. Access to the code is controlled and documented.

[0147] 6.5 Determining the Sample Size This trial is planned to enroll a total of 40 participants: 20 participants per treatment group (active drug vs. placebo). A mean reduction of at least 15% of HVPG levels from baseline after 8 weeks of treatment is considered a positive signal. Based on previous studies, the mean percentage reduction in HVPG from baseline at week 8 was assumed to be 0% for placebo and 20% for compound 114 (standard deviation of 25% in each group) (see Gupta V, Rawat R, Shalimar, Saraya A. Carvedilol versus propranolol effect on hepatic venous pressure gradient at 1 month in patients with index variceal bleed: RCT. Hepatol Int 2017;11:181-187; and Garcia-Tsao G, Fuchs M, Shiffman M, Borg BB, Pyrsopoulos N, Shetty K, et al. Emricasan (IND-6556) lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatology 2019;69(2);717-728). With a sample size of 40 people (20 participants per treatment group), the probability of observing a mean reduction of HVPG ≥ 10% with compound 114 is 89.3%. This probability would be only 26.5% if the mean reduction in HVPG from baseline was 5%. Table 7 shows the probabilities of achieving the assumed treatment effect under various scenarios.

[0148] [Table 12]

[0149] 7. Informed consent, test records, data protection, publication policy, and operating structure The trial will be conducted in accordance with the ethical principles set forth in the CTP and the Declaration of Helsinki, the ICH Harmonized Guideline for GCP, relevant BI SOPs, EU Directive 2001 / 20 / EC, EU Regulation 536 / 2014, the Japanese GCP Regulations (Ministry of Health, Labour and Welfare Notification No. 28, March 27, 1997), and other relevant regulations. The investigators and site staff must adhere to these principles. Any deviation from the CTP, ICH-GCP principles, or applicable regulations will be treated as a "protocol deviation." Standard medical care (prevention, diagnosis, and treatment methods) is the responsibility of the physician treating the patient. The investigator will immediately notify the sponsor or agent of any immediate dangers, any urgent safety measures that should be taken to protect the patient in the study, and any material violations of CTP or ICH-GCP. The BI transparency and publication policy can be found on the following webpage: trials.boehringer-ingelheim.com. The rights of the investigators and sponsors regarding the publication of the results of this trial are set forth in the investigator agreement. As a general rule, trial results should not be published before the completion of the CTR. Certificates of insurance coverage will be provided to the clinical trial physician and the patient, and will be stored at the ISF.

[0150] 7.1 Trial approval, patient information, and informed consent This trial will only commence after all required legal documentation has been reviewed and approved by the respective Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs) and competent authorities (CAs) in accordance with national and international regulations. The same applies to the implementation of any changes introduced by the amendments. Prior to a patient's participation in the trial, written informed consent must be obtained from each patient (or their legally authorized representative) in accordance with ICH-GCP and the regulatory and legal requirements of the participating country. Each signature must be dated directly by the signatory, and the informed consent and any additional patient information forms must be retained by the investigator as part of the trial record. A signed copy of the informed consent and any additional patient information must be provided to each patient or their legally authorized representative.

[0151] The clinical trial physician or their representative must provide the trial patient with a thorough explanation based on the patient information form. The language should be understandable to the patient, and technical terms and expressions should be avoided whenever possible. Patients must be given sufficient time to consider participating in the trial. The investigator or their representative must obtain the patient's voluntary written consent using an informed consent form after confirming that the patient understands the contents. The investigator or their representative must sign (or affix a seal) and date the informed consent form. If a study collaborator has provided supplementary information, the collaborator must also sign (or affix a seal) and date the informed consent form. Re-consent may be required when new relevant information becomes available, and this should be done in accordance with the sponsor's instructions. The consent and re-consent procedures should be properly documented in the source documents.

[0152] 7.2 Data Quality Assurance Risk-based approaches are used in trial quality control. This begins with the assessment of significant data and processes for participant protection and the reliability of results, as well as the identification and assessment of associated risks. An Integrated Quality and Risk Management Plan (IPC) or alternative plan, consistent with the guidance provided by ICH Q9 and ICH-GCP E6, documents the rationale and strategy for risk management during trial execution, including monitoring methods, vendor control, and processes focusing on other areas of greatest risk. Continuous risk analysis and assessment may lead to adjustments in the execution of the study, the study design, or the monitoring methods. Quality assurance audits / inspections for this trial may be conducted by the sponsor, a sponsor's designated representative, or the IRB / IEC or regulatory authority. The quality assurance auditor will have access to all medical records, the investigator's trial-related files and communications, and the informed consent documentation for this clinical trial.

[0153] 7.3 Record CRFs for individual trial participants are provided by the sponsor. 7.3.1 Source Document In accordance with regulatory requirements, the investigator should prepare and maintain appropriate and accurate source documentation and study records, including all findings and other data relevant to the study of each patient. Source data, as well as reported data, should adhere to the "ALCOA principle" and be attributable, legible, synchronous, original, and accurate. Changes to the data should be traceable (audit trail).

[0154] Data reported in the eCRF must match the source data, or any discrepancies must be explained. A patient's most recent medical history may not be sufficient to confirm their eligibility for the trial, and the investigator may need to request evidence of previous medical history and any diagnostic tests. In this case, the investigator should at least attempt to search previous medical records. If this is not possible, an oral medical history documented in those records from the patient may be acceptable. For example, copies of source documents necessary for central evaluation of HVPG and adjudication of liver injury are provided to external suppliers. Before sending or uploading such copies, the investigator must ensure that all patient identifiers (e.g., patient's name, initials, address, telephone number, social security number) have been appropriately removed or deleted from all copies of the patient's source documents. If a patient does not comply with the CTP, any corrective action, such as retraining, must be documented in the patient file.

[0155] For eCRF, data must be extracted from the source document, for example: • Patient identification: Sex, year of birth (in accordance with local laws and regulations) • Patient participation in the trial (substance, trial number, patient number, date the patient was notified) • Includes the date of the patient's visit and the dispensing of the investigational drug. • Medical history (including test symptoms and complications, if applicable) • Medical history • Includes AE and AESI (start date [required] and end date [if possible]), and those confirmed from measurements in home BP and HR monitoring devices. • SAE (Start date [required] and end date [if possible]) • Combination therapy (start date [if necessary], dosage / frequency [if necessary], change) • Original or copy of laboratory results and other imaging or test results (e.g., HVPG, ultrasound, and FibroScan® results), accompanied by appropriate documented medical evaluations (in a valid electronic format where possible). · ECG results • Patient warning card (the source document is a paper record) • Termination of patient participation in the trial (termination date; if early termination occurs, the reason should be documented if possible) Prior to allocating patients to a procedure in a clinical trial, there must be documented evidence in the source data (e.g., medical records) that the trial participant meets all inclusion criteria and does not meet any exclusion criteria. The absence of supporting records for trial inclusion / exclusion criteria (medical records, documented oral feedback from the patient, or trials conducted specifically for the CTP) will disqualify the patient from the clinical trial.

[0156] 7.3.2 Direct Access to Source Data and Documents The investigator / site will enable site-based trial-related monitoring, audits, IRB / IEC inspections, and regulatory checks. Direct access must be provided to the CRF, and copies of all source documents / data, e.g., progress records, laboratory and medical trial results, must always be available for review by the CRA, auditors, and regulatory inspectors (e.g., the FDA). They can review all CRFs and informed consents. Data accuracy will be verified by direct comparison with the source documents described herein. The sponsor or agent will also monitor compliance with protocols and GCPs. In the event of force majeure or other interruptions, facility access may be restricted, thus limiting the ability to perform standard facility monitoring activities, such as on-site source data inspection and source data verification. Therefore, some of these activities may be performed remotely or replaced with centralized monitoring to the extent possible, based on documented risk assessments and in accordance with local regulations.

[0157] 7.3.3 Record retention period Testing facilities: The testing facility must retain sources and essential documents (including ISF) in accordance with local requirements in effect at the time of contract or termination of the test (whichever is longer). sponsor: Sponsors must maintain required documents in accordance with their SOPs. 7.4 Rapid reporting of adverse events BI is responsible for fulfilling its legal and regulatory reporting obligations in accordance with regulatory requirements. 7.5 Confidentiality Statement and Participant Privacy Data protection and data security measures will be implemented for the collection, storage, and processing of study participant data in accordance with Principles 7 and 12 of the WHO GCP Handbook.

[0158] To ensure the confidentiality of records and personal data, only pseudonymized data is transmitted to the sponsor using a participant identification number instead of the participant's name. The code is for site use only and must not be transferred to the sponsor. If participant records are transferred, for example, for SAE processing or for review by a review committee, any personal data that could identify the participant is deleted by the site before transfer. Access to participant files and clinical data is strictly restricted: named treatment data may be given to the participant's attending physician or other appropriate healthcare professional responsible for the participant's well-being. Data generated at the site as a result of the trial must be available for review at the request of participating physicians, sponsor representatives, IRB / IEC, and regulatory authorities. Potential data security breaches will be assessed in relation to the rights and privacy of those affected. Immediate and accurate preventative measures will be taken. Relevant regulatory authorities, IRBs / IECs, and trial participants will be contacted as necessary.

[0159] 7.5.1 Collection, storage, and future use of biological samples and corresponding data Measures are being taken to comply with applicable regulations regarding the collection of biological samples and clinical data, biobanking, and future use, in particular • Sample and data use must be subject to separate biobanking informed consent. • BI's internal and external banking facilities for storing biological samples from clinical trial participants are authorized to store biological samples collected in clinical trials. • Appropriate sample and data management systems are in place for clinical data and samples, including audit trails that verify and destroy such samples in accordance with the ICF. • Compliance with the purpose documents (biomarker proposals, analysis plans, and reports) ensures compliant use. • The suitability for the target method is used for assay / equipment validation depending on the intended use of the biomarker data. • Samples and / or data may be shared with third parties and other countries as defined by the Biobanking ICF.

[0160] 7.6 Exam Milestones Act 1 of the recruitment process represents the start of the examination, defined as the day when the first test participants in the entire examination sign informed consent. The end of the trial is defined as the last day of the final visit by the last participant in the entire trial ("the last participant has finished"). The "Last Treatment for the Last Participant" (LPLT) day is defined as the day when the last participant in the entire trial receives their final dose of the study treatment (as scheduled or prematurely, according to the protocol). Individual investigators are notified of any SUSARs (Sustainable Sustained Actions) that occurred with the study drug within 30 days of the LPLT at their site. Early termination of a test is defined as the premature termination of a test due to any reason prior to the completion of the test as defined in this protocol.

[0161] A temporary suspension of an exam is defined as any unplanned interruption of an exam by a sponsor who intends to resume it. A suspension of the trial is defined as a suspension of the trial at the request of health authorities. Each participating EU member state's IEC / competent authority will be notified of the examination milestones in accordance with its respective legislation. The final report of clinical trial data is written only after all trial participants have completed the trial in all countries (EU or non-EU) in order to incorporate and consider all data from the report. Within one year of the completion of the entire clinical trial, the sponsor will submit a summary of the final trial results to the EU database, regardless of the country (EU or non-EU) of the last trial participant.

[0162] 7.7 Examination Administration The trial is sponsored by Boehringer Ingelheim (BI). The clinical trial coordinator is responsible for coordinating the clinical trial physicians at the various sites participating in this trial. Their duties and responsibilities are defined in the contract.

[0163] Data Monitoring Committee: A DMC is established. DMC members are independent of the BI and include physicians and statisticians with experience in treating the disease under investigation. The DMC evaluates safety data and receives decisions from efficacy data, significant safety concerns, and liver injury rulings on the evaluation. DMC members may be open-label, and measures are taken to ensure blinding for all individuals involved in regular trial DMC meetings held at prescribed intervals. The DMC recommends the continuation, modification, or termination of the trial as detailed in the DMC Charter. DMC recommendations, as well as final BI decisions, are reported to the appropriate regulatory / health authority, IRB / EC, and investigators as required by local legislation. The DMC's duties and responsibilities are defined in the Charter.

[0164] Liver damage assessment committee: An independent AC is used to determine the severity of certain liver injury events and their causal relationship with the investigational drug. Events may be defined by abnormal laboratory values ​​and / or related AEs, which are defined in the Liver Injury AC Charter. To qualify an event, relevant source documentation arising from all medical evaluations of these events is required. Relevant source documentation may include laboratory values, histological analysis, computed tomography (CT) and magnetic resonance imaging (MRI) reports, hospital discharge letters, and medical reports from other physicians.

[0165] Important supporting documents (e.g., CVs) regarding the participating (principal) investigator are filed with the ISF. Investigators access the BI web portal Clinergize to access documents provided by the sponsor. BI is, • Conduct testing in accordance with applicable rules and internal SOPs. • Lead the clinical trial team in the preparation, execution, and reporting of the trial. • Ensure appropriate training and information for Clinical Trial Managers, CRAs, and clinical investigators in participating countries. Therefore, a Clinical Trial Leader was appointed to be responsible for coordinating all necessary activities.

[0166] In participating countries, the trials will be conducted by local or regional BI organizations (Operating Units) in accordance with applicable rules and BI SOPs, or by CROs under contract. The CROs will perform project management, clinical site monitoring, medical monitoring, and reporting. Data management and statistical evaluation are performed using BI in accordance with BI SOPs. The tasks and functions assigned to organize, manage, and evaluate the examinations are defined in accordance with the BI SOP. A list of responsible persons and relevant local information can be found at the ISF. Central laboratory services, central reading services for HVPG, IRT suppliers, and other central services / facilities will be used / provided in this test. Details are provided in the respective manuals and are available at ISF.

Claims

1. A method for the prevention, slowing, delaying, or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis resulting from non-cholestasis liver disease in patients requiring it, comprising, to patients requiring it, a therapeutically effective amount of compound numbers 18, 27, 84, 114, 133, 134, 136, 148, 154, 165, and 167: 【Chemistry 1-1】 [Chemistry 1-2] The method also includes administering a soluble guanylate cyclase (sGC) activator selected from the group consisting of these pharmaceutically acceptable salts. (i) The method results in a decrease in the hepatic venous pressure gradient (HVPG) from baseline in the patient. (ii) The method results in a reduction of liver stiffness from baseline in the patient, and / or (iii) The method results in a reduction of splenic stiffness from baseline in the patient. method.

2. A soluble guanylate cyclase (sGC) activator for use in the prevention, slowing, delaying, or treatment of clinically significant portal hypertension (CSPH) and decompensated cirrhosis resulting from non-cholestasis liver disease in patients, wherein the sGC activator is compound number 18, 27, 84, 114, 133, 134, 136, 148, 154, 165, and 167: 【Chemistry 2-1】 【Chemistry 2-2】 Furthermore, selected from the group consisting of these pharmaceutically acceptable salts, (i) Use results in a decrease in the hepatic venous pressure gradient (HVPG) from baseline in the patient, (ii) Use results in a reduction of liver stiffness from baseline in the patient, and / or (iii) Use results in a reduction of splenic stiffness from baseline in patients. sGC activator.

3. The method according to claim 1 or the use according to claim 2, wherein the sGC activator is administered to the patient in an amount selected from the group consisting of 0.25 mg, 0.50 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and 10 mg.

4. The method or use according to any one of claims 1 to 3, wherein the sGC activator is administered to the patient three times a day (TID).

5. The method or use according to any one of claims 1 to 4, wherein the sGC activator is administered to the patient in an amount selected from the group consisting of 1 mg, 2 mg, and 3 mg.

6. The method according to claim 1 or the use according to claim 2, wherein the sGC activator is administered to a patient with TID in an amount of 1 mg, or in an amount of TID in an amount of 2 mg, or in an amount of TID in an amount of 3 mg.

7. The method according to claim 1 or the use according to claim 2, wherein the treatment includes an initiation treatment in which an sGC activator is administered at a dose of 1 mg TID in the first and second weeks; then at a dose of 2 mg TID in the third and fourth weeks; and then at a dose of 3 mg from the fifth week until the end of treatment.

8. The method or use according to any one of claims 1 to 7, wherein the amount of sGC activator is reduced when the patient develops symptomatic orthostatic hypotension.

9. The method or use according to any one of claims 1 to 8, wherein the administration results in at least a 10% reduction in the hepatic venous pressure gradient (HVPG) from baseline in the patient after 8 weeks of treatment.

10. The method or use according to any one of claims 1 to 8, wherein the administration results in at least a 10% reduction in liver stiffness from baseline in the patient after 8 weeks of treatment.

11. The method or use according to any one of claims 1 to 8, wherein the administration results in at least a 10% reduction in splenic stiffness from baseline in the patient after 8 weeks of treatment.

12. The method or use according to any one of claims 1 to 11, wherein the sGC activator is compound 114.

Images