Soluble guanylate cyclase activators for treating clinically significant portal hypertension and decompensated cirrhosis

Abstract

The present invention relates to methods for using soluble guanylate cyclase (sGC) activators for preventing, slowing the progression of, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis due to non-cholestatic liver disease.

Description

[0001] SOLUBLE GUANYLATE CYCLASE ACTIVATORS FOR TREATING CLINICALLY SIGNIFICANT PORTAL HYPERTENSION AND DECOMPENSATED CIRRHOSIS

[0002] FIELD OF THE INVENTION

[0003] The invention relates to the use of certain soluble guanylate cyclase activators for treating patients with clinically significant portal hypertension (CSPH) and decompensated cirrhosis due to non-cholestatic liver disease.

[0004] BACKGROUND

[0005] Cirrhosis is the end-stage liver condition caused by multiple chronic diseases, like hepatitis C virus infection (HCV), chronic alcohol abuse, or metabolic syndrome with non-alcoholic fatty liver disease (NAFLD). Cirrhosis by itself is a chronic condition with a high mortality. It is a heterogenous disease that is classified into two main prognostic stages: compensated and decompensated cirrhosis. This classification depends on the presence or absence of clinically evident decompensating events (specifically ascites [more than perihepatic ascites], variceal haemorrhage (VH) and I or apparent 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 for cirrhosis for reduction of fibrotic tissue or regeneration of hepatocytes. The main treatment goal is to delay decompensation, improve quality of life, and treat the symptoms of cirrhosis and especially decompensation.

[0006] Portal hypertension (PH) is the initial and main consequence of cirrhosis and is responsible for 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 currently recommended clinical approaches to prevent PH-related decompensating events in patients are endoscopic variceal ligations or off-label use of non-selective beta-blockers (NSBBs) or carvedilol for primary and secondary prophylaxis of variceal bleeding. However, not all patients with PH achieve a hemodynamic response with these current treatment options. NSBBs and carvedilol are currently used to prevent complications of cirrhosis and improve survival in patients, but these benefits only occur in less than half of patients treated, and mostly in those who achieve a significant decrease in portal pressure. An unmet need remains for a substantial number of patients who cannot tolerate treatment with NSBBs or carvedilol due to decreased systemic blood pressure (BP) and heart rate (HR), and who have a higher risk for further progression and decompensation.

[0007] Therefore, there is an existing unmet medical need to reduce portal pressure and improve liver perfusion in this population of patients with PH and especially clinically significant portal hypertension (CSPH). CSPH is associated with an increased risk of developing varices, overt clinical decompensation (ascites, VH, and HE), postsurgical decompensation, and hepatocellular carcinoma. (See 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. 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.)

[0008] BRIEF SUMMARY OF THE INVENTION

[0009] The present invention relates to methods for preventing, slowing the progression of, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis, comprising administering to a patient in need thereof a pharmaceutically effective amount of a soluble guanylate cyclase (sGC) activator of the invention, or a pharmaceutically acceptable salt thereof.

[0010] In another embodiment, the present invention relates to methods for preventing, slowing the progression of, delaying or treating of CSPH in decompensated cirrhosis due to non-cholestatic liver diseases, comprising administering to a patient in need thereof a pharmaceutically effective amount of a soluble guanylate cyclase (sGC) activator of the invention, or a pharmaceutically acceptable salt thereof.

[0011] The invention also relates to a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, for use in preventing, slowing the progression of, delaying or treating CSPH and decompensated cirrhosis due to non-cholestatic liver disease.

[0012] In another embodiment, the invention relates to methods for preventing, slowing the progression of, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis due to non-cholestatic liver disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effect amount of a sGC activator of the invention, or a pharmaceutically acceptable salt thereof, wherein

[0013] (i) the method provides a reduction of hepatic venous pressure gradient (HVPG) from baseline in the patient,

[0014] (ii) the method provides a reduction in liver stiffness from baseline in the patient, and / or

[0015] (iii) the method provides a reduction in spleen stiffness from baseline in the patient.

[0016] In another embodiment, the invention relates to a soluble guanylate cyclase (sGC) activator for use in preventing, slowing the progression of, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis due to non-cholestatic liver disease in a patient, wherein

[0017] (i) the use provides a reduction of hepatic venous pressure gradient (HVPG) from baseline in the patient,

[0018] (ii) the use provides a reduction in liver stiffness from baseline in the patient, and / or

[0019] (iii) the use provides a reduction in spleen stiffness from baseline in the patient.

[0020] In one embodiment, the method or use provides at least a 10% reduction of HVPG from baseline in the patient after 8 weeks of treatment.

[0021] In another embodiment, method or use provides at least a 10% reduction in liver stiffness from baseline in the patient after 8 weeks of treatment.

[0022] In another embodiment, method or use provides at least a 10% reduction in spleen stiffness from baseline in the patient after 8 weeks of treatment.

[0023] In another embodiment, the reduction in liver stiffness and / or spleen stiffness is measured using transient elastography.

[0024] In one embodiment of the invention, the sGC activator used in the methods or uses of the invention is a compound is selected from the group consisting of compound number 18, 27, 84, 114, 133, 134, 136, 148, 154, 165, and 167 (“the sGC activators of the invention” or “the compounds of the invention”):

[0025]

[0026] 133, 134,

[0027] and the pharmaceutically acceptable salts thereof. In one embodiment, the sCG activator used in the methods or uses of the invention is compound number 114.

[0028] BRIEF DESCRIPTION OF THE SEVERAL VIEW OF THE DRAWINGS

[0029] Figure 1 shows the design schematic of the clinical trial described herein.

[0030] Figures 2A-2D show a Flow Chart summarizing the screening, treatment of follow-up of patients according to the clinical trial described herein.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] Table 1. Abbreviations.

[0033]

[0034] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts 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 the like. For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides / hydrobromides, edetates, camsylates, carbonates, chlorides / hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methylbromides, methylnitrates, methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates / diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

[0035] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0036] Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g., trifluoro acetate salts) also comprise a part of the invention.

[0037] For all compounds disclosed herein above in this application, in the event the nomenclature is in conflict with the structure, it shall be understood that the compound is defined by the structure.

[0038] GENERAL SYNTHETIC METHODS

[0039] The compounds of formula (I) used in the methods or uses of the invention may be prepared by the methods and examples described in WO 2014 / 039434.

[0040] METHODS OF THERAPEUTIC USE

[0041] For therapeutic use, the compounds of formula (I) may be administered via a pharmaceutical composition in any conventional pharmaceutical dosage form in any conventional manner. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable to the particular dosage form selected. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred modes of administration are oral, intravenous, and subcutaneous.

[0042] The compounds of the invention may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. In one embodiment, for example, multiple compounds of the present invention can be administered. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds of the invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of the invention (w / w) or a combination thereof. The optimum percentage (w / w) of a compound of the invention may vary and is within the purview of those skilled in the art. Alternatively, the compounds of the present invention and the conventional therapeutics or other adjuvants may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regimen.

[0043] As mentioned above, dosage forms of the compounds of the invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable to the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician.

[0044] In this context, “combination” or “combined” within the meaning of this invention may include, without being limited, fixed and non-fixed (e.g. free) forms (including kits, or other administration, application or dosage forms) and uses, such as e.g. the simultaneous, sequential or separate use of the sGC activator and a further therapeutic agent or concomitant therapies as described herein.

[0045] The combined administration or application of this invention may take place by administering the therapeutic components together, such as e.g. by administering them simultaneously in one single or in two separate formulations. Alternatively, the administration may take place by administering the therapeutic components sequentially, such as e.g. successively in two separate formulations.

[0046] For the combination therapy of this invention the therapeutic components may be administered separately (which implies that they are formulated separately) or formulated altogether (which implies that they are formulated in the same preparation). Hence, the administration of one element of the combination of the present invention may be prior to, concurrent to, or subsequent to the administration of the other element of the combination.

[0047] In one embodiment, the methods of the invention comprise administering to the patient a daily amount of from 0.1 mg to about 50 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment, the methods of the invention comprise administering to the patient a daily amount of from 1 mg to about 30 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the sGC activator of the invention, or a pharmaceutically acceptable salt thereof, is administered to the patient in a daily amount of from 0.1 to 100 mg; or 1 to 25 mg; or 1 to 10 mg; or 2 to 5 mg, or a pharmaceutically acceptable salt thereof.

[0050] In another embodiment, the sGC activator of the invention, or a pharmaceutically acceptable salt thereof, is administered to the 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.

[0051] In another embodiment, the SGC activator of the invention, or a pharmaceutically acceptable salt thereof, is administered to the patient in an amount selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg.

[0052] In another embodiment, the methods of the invention comprise administering to the patient up to 3 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0053] In another embodiment, the methods of the invention comprise administering to the patient 1 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0054] In another embodiment, the methods of the invention comprise administering to the patient 2 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof. In another embodiment, the methods of the invention comprise administering to the patient 3 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0055] The vasodilatation of the sGC activator may lead to orthostatic dysregulation and hypotensive episodes. Titration of the sGC activator may allow the total daily exposure of sGC activator to be further increased while high peak concentrations are avoided.

[0056] In one embodiment, the invention relates to a method for preventing or reducing the severity of orthostatic dysregulation caused by, due to, or related to administration of a sGC activator, or a pharmaceutically acceptable salt thereof, the method comprising administering the daily dose of the sGC activator to the patient QD, BID, or TID.

[0057] In another embodiment, the sGC activator is administered to the patient QD.

[0058] In another embodiment, the sGC activator is administered to the patient BID.

[0059] In another embodiment, the sGC activator is administered to the patient TID.

[0060] In another embodiment, the methods of the invention comprise a twice daily administration to a patient of up to 3 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0061] In another embodiment, the methods of the invention comprise a twice daily administration to a patient of 3 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, to provide a total daily amount of 6 mg of sGC activator.

[0062] In another embodiment, the methods of the invention comprise a twice daily administration to a patient of 2 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, to provide a total daily amount of 4 mg of sGC activator.

[0063] In another embodiment, the methods of the invention comprise a twice daily administration to a patient of 1 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, to provide a total daily amount of 2 mg of sGC activator.

[0064] In another embodiment, the methods of the invention comprise a TID dosing to a patient of up to 3 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof.

[0065] In another embodiment, the methods of the invention comprise TID dosing to a patient of 3 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, to provide a total daily amount of 9 mg of sGC activator. In another embodiment, the methods of the invention comprise TID dosing to a patient of 2 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, to provide a total daily amount of 6 mg of sGC activator.

[0066] In another embodiment, the methods of the invention comprise TID dosing to a patient of 1 mg of a SGC activator of the invention, or a pharmaceutically acceptable salt thereof, to provide a total daily amount of 3 mg of sGC activator.

[0067] In another embodiment, the invention relates to methods for initiating treatment of the patients with an sGC activator. A nonlimiting example of initial treatment comprising uptitrating the patients from a small dose to the target dose.

[0068] In one embodiment, the initial treatment of the patient comprises: administering the sGC activator of the invention for two weeks (weeks one and two of treatment) at a dose of 1 mg TID, administering the sGC activator for two weeks (weeks three and four) at a dose of 2 mg TID, and administering the sGC activator after week four at a dose of 3 mg TID.

[0069] Patients being treated with the sCG activator of the invention may be treated with one or more additional therapeutic agents including SGLT2 inhibitors (e.g., empagliflozin), GLP-1 agonists, nintedanib, and betablockers.

[0070] Clinical Trial Protocol

[0071] The below describes a randomised, double-blind, placebo-controlled and parallel group trial to investigate the effects of one dose (up-titration to a fixed dose regimen) of Compound 114, administered orally, on portal hypertension after 8 weeks treatment in patients with clinically significant portal hypertension (CSPH) and decompensated cirrhosis after their first decompensation event, who are stabilized. The study to test whether an sGC activator of the invention helps people with liver cirrhosis and high blood pressure in the portal vein (main vessel going to the liver) who had bleeding in the esophagus or fluid accumulation in the belly

[0072] 1.1 MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS

[0073] 1.1.1 Main objectives

[0074] The trial will investigate the safety and tolerability of Compound 114 in patients with CSPH in decompensated cirrhosis due to non-cholestatic liver diseases on top of standard of care. The primary objective is to estimate the percentage change in HVPG from baseline measured after 8 weeks in comparison to placebo. The primary analysis will be made for treated patients with baseline HVPG measurements (Full Analysis Set, FAS) as if all trial participants took treatment for the duration of the trial.

[0075] 1.1.2 Primary endpoint

[0076] The primary endpoint is the percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of treatment.

[0077] 1.1.3 Secondary endpoints

[0078] Secondary endpoints include:

[0079] • occurrence of a response, which is defined as >10% reduction from baseline HVPG (measured in mmHg) after 8 weeks of treatment

[0080] • occurrence of further decompensation events (i.e. ascites, VH, and I or overt HE) during the 8-week treatment period

[0081] • occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator judgement, during the 8-week treatment period

[0082] • occurrence of discontinuation due to hypotension or syncope during the 8-week treatment period

[0083] 1.2 FURTHER OBJECTIVES AND FURTHER ENDPOINTS

[0084] 1.2.1 Further objectives

[0085] In addition to the main objectives defined above, further objectives of this trial include an evaluation of general safety, PK, PD, disease activity biomarkers, and to gain further insight into the use of non-invasive methods to investigate liver function and portal pressure.

[0086] 1.2.2 Further endpoints

[0087] • change from baseline in spleen stiffness (kPa), by Fibroscan® Expert 630, after 8 weeks of treatment

[0088] • change from baseline in liver stiffness (kPa) by FibroScan® Expert 630 LSM, after 8 weeks of treatment, for example, a reduction of liver stiffness <10% or <15%

[0089] • change from baseline in body weight after 8 weeks of treatment

[0090] • change from baseline in hepatic function after 8 weeks of treatment measured by: o PT / INR, aPTT o bilirubin (direct and indirect) o liver enzymes (ALT, AST, y-GT and alkaline phosphatase) o albumin

[0091] • change from baseline in renal function after 8 weeks of treatment, measured by eGFR

[0092] • change from baseline across disease-specific and mode of action exploratory biomarkers after 8 weeks of treatment and at EoS o Fibrosis markers (e.g. PRO-C3, ELF score) o Inflammation markers (e.g. hs-CRP) o Cardiac and renal biomarkers (e.g. Brain Natriuretic Peptide (BNP), Troponin I, eGFR, creatinine)

[0093] • PK endpoints of Compound 114 will be determined if feasible: o Cmax (maximum measured concentration of the analyte in plasma) o tmax (time from dosing to maximum measured concentration of the analyte in plasma) o AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2 after single dose administration) o Cmax.ss (maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval T) o tmax.ss (time from last dosing to maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval T) o AUCt1-t2,ss (area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2 at steady state)

[0094] DESCRIPTION OF DESIGN AND TRIAL POPULATION

[0095] 2.1 OVERALL TRIAL DESIGN

[0096] This phase 2 multi-national, randomised, placebo-controlled and parallel group trial to investigate the effects of oral Compound 114 on portal hypertension after 8 weeks treatment in patients with clinically significant portal hypertension (CSPH) and decompensated cirrhosis after the first decompensation event, who are stabilized.

[0097] Trial participants will be enrolled in the trial and screened for eligibility once they have signed the informed consent. The screening period consists of up to 2 visits (Visits 1a and b) and will last a maximum of 4 weeks. Trial participants will be able to progress from one visit to the next when eligibility of the previous visit is confirmed. Assessments will include ultrasound of the liver and spleen, FibroScan® of the liver and spleen, and measurement of HVPG. T rial participants who remain eligible and who successfully complete this period will proceed to the 8- week randomised, placebo-controlled treatment period.

[0098] In total, 40 trial participants will be randomized in a 1 :1 ratio, with 20 trial participants in the active treatment arm, and 20 trial participants in the placebo arm. The randomization will be stratified by use (or not) of NSBBs I carvedilol and type of first decompensation event (ascites or variceal haemorrhage).

[0099] Following randomization at visit 2, trial participants will begin the intake of trial medication(s) and will enter a dose-titration period of Compound 114 or matching placebo. If the dose is tolerated, one week later (at Visit 3, day 8), the dose for all will be up-titrated to 2 mg BID of Compound 114 or matching placebo. If this dose is tolerated, a second up-titration to 3 mg BID of Compound 114 or matching placebo will occur after another week (at Visit 4, day 15). Following the dose-titration period, and if the dose is tolerated, trial participants will remain on the highest dose of Compound 114 for the remainder of the treatment period until they reach the End of Treatment (EoT) visit and 8 weeks of treatment. If the dose is not tolerated, trial medication may be interrupted or the dose can be reduced I down -titrated.

[0100] The ultrasound and FibroScan® of the liver and spleen, and the HVPG measurement will be repeated during the treatment period (refer to Figure 1 .

[0101] After the 8 week treatment period all trial participants will enter a 2 week follow-up period without trial medication. The trial participant’s participation in the trial will be complete when they have performed the last planned visit (i.e. End of Study [EoS], 2 weeks after EoT). See Figure 1.

[0102] 2.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUP(S)

[0103] A randomised, double-blind, placebo-controlled and parallel group design has been chosen for this trial, on top of standard of care. The randomised double-blind design will control for assignment bias. Placebo as control was chosen to show the efficacy of Compound 114 compared to placebo plus standard of care.

[0104] A treatment duration of 8 weeks has been chosen to allow an evaluation of short-term efficacy and indirect comparison to the week 8 results from trials 1366-0021 and 1366-0029.

[0105] The trial participant population of this trial has been chosen as it represents the intended patient population to be treated with for Compound 114 (patients with clinically significant portal hypertension in decompensated cirrhosis due to non-cholestatic liver diseases).

[0106] The measurement of HVPG was chosen as the primary endpoint as it is the gold standard to estimate portal venous pressure in trial participants with cirrhosis, i.e. assessing the severity of sinusoidal PH. (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.). It is used as an established surrogate marker for improvement and I or worsening of liver fibrosis I function, since a decrease in HVPG translates into a clinically meaningful benefit. (See 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. Hepatology 2020;71 (3); 1023-1036.) The prognostic value of HVPG has been underlined by several landmark studies, showing that an HVPG > 10 mmHg (i.e. CSPH) is predictive of the formation of varices (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), while a (pharmacologically-induced) decrease of HVPG modulates the respective risk of variceal growth and decompensation. (See Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, et al, Gruppo Triveneto per I'lpertensione 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.) Hence, this also explains the choice of the secondary endpoint relating 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 chosen as they are relevant based on the mechanism of action of Compound 114.

[0107] Trial participants will be screened for the trial based on the eligibility. At Visit 1 b (the final visit within the screening period) trial participants who remain eligible following Visits 1a will undergo their first HVPG measurement. Non-invasive assessments (i.e. ultrasound and FibroScan® of the liver and spleen and functional liver testing) have been chosen as part of the screening procedures to further investigate the trial participants’ status, to establish baseline values for comparison with treatment, and to gain further insight into the use of non-invasive methods to investigate liver function and portal pressure. These assessments will be repeated (refer to Figure 1 and the Flow Chart shown in Figures 2A-2D) to assess a time-dependency of the treatment.

[0108] Following randomisation, the trial design includes a dose-titration period. The mechanism related vasodilatation of Compound 114 can lead to orthostatic dysregulation and hypotensive episodes. The orthostatic dysregulation is dose-limiting and clinical tolerability is improved if the dose is titrated. A BID administration also allows the total daily exposure of Compound 114 to be further increased while high peak concentrations are avoided. Hence, in this trial, a dosetitration regimen of 1 mg BID to 2 mg BID to 3mg BID will be followed.

[0109] Trial participants selected for this trial have a risk for further decompensation. A DMC, independent from the Sponsor, will therefore be established to review safety data at intervals to identify any potential risks and I or the need for implementation of further safety measures. The tasks and responsibilities of the DMC members will be detailed in the DMC charter.

[0110] An independent AC will also be established for adjudication of hepatic injury. The tasks and responsibilities of the AC members will be detailed in the AC charter.

[0111] 2.3 SELECTION OF TRIAL POPULATION

[0112] 40 trial participants with CSPH and decompensated cirrhosis due to non-cholestatic liver disease will be randomized into the trial. Approximately 20 sites are planned across multiple countries. It is anticipated that 2 trial participants will be randomised at each site. If enrolment is delayed, additional sites may be recruited.

[0113] Screening of trial participants for this trial is competitive, i.e. screening for the trial will stop at all sites at the same time once a sufficient number of trial participants have been screened to deliver the required number of randomised trial participants. Investigators will be notified about the screening completion and will then not be allowed to screen additional trial participants for this trial. Trial participants already in screening at this time will be allowed to continue to randomisation if eligible.

[0114] Re-testing during the screening period is allowed once (e.g. if the Investigator believes an ineligible laboratory test is the result of an error or extenuating circumstances, the test can be repeated once without the trial participant having to be re-screened). Re-screening is also allowed once provided that the reasons for screen failure were reversible and have been resolved, based on Investigator judgement. A trial participant is considered a “re-screener” if he I she was not eligible for the trial initially and is subsequently re-screened, going through the informed consent process for a second time, receiving a new unique trial participant number and repeating the screening period assessments.

[0115] A log of all trial participants enrolled into the trial (i.e. who have signed the informed consent) will be maintained in the Investigator Site File (ISF) irrespective of whether they have been treated with investigational drug or not.

[0116] If retrospectively it is found that a patient has been randomized in error (=did not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be contacted immediately. Based on an individual benefit-risk assessment a decision will be made whether continued trial participation is possible or not.

[0117] This trial will include an option for participants to complete anonymized questionnaires to provide feedback on their clinical trial experience. Providing this feedback is not required for trial participation, and information collected from these questionnaires will not be analysed as part of the clinical data for the trial.

[0118] 2.3.1 Main diagnosis for trial entry

[0119] The trial will include trial participants with decompensated cirrhosis due to non-cholestatic liver disease after the first decompensation event, who are stabilized.

[0120] 2.3.2 Inclusion criteria

[0121] 1 . Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial

[0122] 2. Male or female who is >18 (or who is of legal age in countries where that is greater than 18) and <75 years old at screening (Visit 1a)

[0123] 3. Diagnosis of cirrhosis due to non-cholestatic liver disease (including HCV, HBV, NASH, alcohol-related liver disease, autoimmune hepatitis, Wilson’s disease, haemachromatosis, alpha-1 antitrypsin [A1At] deficiency)

[0124] 4. One previous clinically significant decompensation event with clinical resolution at least 4 weeks prior start of screening (visit 1a): a. First variceal haemorrhage b. First episode of clinically significant ascites (requiring intervention in lifestyle [fluid and salt restriction] or medical treatment) Willing and able to undergo HVPG measurements per protocol (based on Investigator judgement) If receiving statins must be on a stable dose for at least 3 months prior to screening (Visit 1b), with no planned dose change throughout the trial If receiving treatment with NSBBs or carvedilol must be on a stable dose for at least 1 month prior to screening (Visit 1b), with no planned dose change throughout the trial For patient with alcohol-related cirrhosis, abstinence from significant alcohol misuse I abuse for a minimum of 2 months prior to screening (Visit 1 a), and the ability to abstain from alcohol throughout the trial (both evaluated based on Investigator judgement) WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1 % per year when used consistently and correctly from the randomisation visit (Visit 2) until 7 days after the last treatment in this trial. The patient must agree to periodic pregnancy testing during participation in the trial. (A woman is considered of child-bearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause Men able to father a child and who have a female sexual partner of CBP, must use a condom with or without spermicide, or adopt complete sexual abstinence, or be vasectomised (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate), from the randomisation visit (Visit 2) until 7 days after the last treatment in this trial. Exclusion criteria History of cholestatic chronic liver disease (e.g. primary biliary sclerosis, primary sclerosing cholangitis) Trial participants without adequate treatment for HBV, HCV or NASH as per local guidance (e.g. antiviral therapy for chronic HBV or HCV infection or lifestyle modification in NASH) If received curative anti-viral therapy for HCV, SVR sustained for less than 1 years prior to screening If receiving anti-viral therapy for HBV, less than 6 months on a stable dose prior to screening, with planned dose change during the trial or HBV DNA detectable Weight change >5% within 6 months prior screening in patients with NASH Must take, or wishes to continue the intake of, restricted concomitant therapy or any concomitant therapy considered likely (based on Investigator judgement) to interfere with the safe conduct of the trial SBP <100 mmHg or DBP <70 mmHg at screening (Visit 1a) Hepatic impairment defined as a Child-Turcotte-Pugh score >8 at screening Model of End-stage Liver Disease (MELD) score of >15 at screening (Visit 1a), calculated by the central laboratory ALT or AST >5 times upper limit of normal (ULN) at screening (Visit 1a), measured by the central laboratory eGFR (CKD-EPI formula) < 20 mL / min / 1.73 m2at screening (Visit 1 a), measured by the central laboratory Platelet count <50x109 / L Alpha-fetoprotein >50 ng / mL (>50 pg / L) at screening (Visit 1a), measured by the central laboratory Prior orthotopic liver transplantation Prior or planned TIPS or other porto-systemic bypass procedure during the trial conduct Known portal vein thrombosis History of clinically relevant orthostatic hypotension, fainting spells or blackouts due to hypotension or of unknown origin (based on Investigator judgement) QTcF-interval >450 ms in men or >470 ms in women at screening (Visit 1a), a family history of long QT syndrome, or concomitant use of therapies with a known risk of Torsade de Pointes or planned initiation of such therapies during the trial Contraindication to any of the trial assessments (e.g. poor patient co-operation for HVPG, cardiac pacemakers for FibroScan® [if contraindicated based on local market approval] Major surgery (major according to the investigator’s assessment) performed within

[0125] 12 weeks prior to randomisation (Visit 2) or planned during the trial, e.g. hip replacement.

[0126] 21 . Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening (Visit 1a), except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix

[0127] 22. History of (in the 6 months prior to randomisation [Visit 2]), or ongoing, chronic drug abuse, or not expected to comply with the protocol requirements for any other reason that, based on Investigator judgement, makes the patient an unreliable trial recruit or unlikely to complete the trial as scheduled

[0128] 23. Previous randomisation in this trial, previous exposure to Compound 114, or an allergy I contraindication to Compound 114 and matching placebo I or any of their excipients

[0129] 24. Currently enrolled in another investigational device or drug trial, or less than 30 days or 5 half-lives (whichever is longer) prior to randomisation (Visit 2) since ending another investigational device or drug trial, or receiving other investigational treatment(s)

[0130] 25. Women who are pregnant, nursing, or who plan to become pregnant while in the trial

[0131] 26. Any other medical condition that, based on Investigator judgement, poses a safety risk for the patient or may interfere with the objectives of the trial 4 Discontinuation of trial participants from treatment or assessments

[0132] Trial participants may discontinue trial treatment or withdraw consent to trial participation as a whole (“withdrawal of consent”) with very different implications.

[0133] However, if the trial participants agree, they should stay in the trial. Even if continued trial treatment is not possible, they should attend further trial visits to ensure their safety and to collect important trial data.

[0134] Measures to control the withdrawal rate include careful trial participant selection, appropriate explanation of the trial requirements and procedures prior to trial enrolment, as well as the explanation of the consequences of withdrawal.

[0135] The decision to discontinue trial treatment or withdraw consent to trial participation and the reason must be documented in the trial participant files and CRF. If applicable, consider the requirements for AE collection reporting.

[0136] Trial participants who discontinue after randomisation will not be replaced and may not be re-enrolled later. However, the Sponsor may decide to randomise more trial participants than originally planned, to account for a reduced sample size, if trial participants terminate early due to e.g. trial disruption (such as measures to control a global pandemic).

[0137] 2.3.4.1 Discontinuation of trial treatment

[0138] Ideally, the trial participant should attend all remaining visits. Should the trial participant not agree, at least phone contacts should occur at the scheduled visit time points, should that not be acceptable, a phone contact once or at the end of the planned observation period should occur to collect the most relevant information: vital status, outcome events, adverse events, or last contact date in case of lost to follow-up.

[0139] An individual trial participant will discontinue trial medication if:

[0140] • the trial participant wants to discontinue trial treatment. The trial participant will be asked to explain the reasons but has the right to refuse to answer.

[0141] • the trial participant has repeatedly shown to be non-compliant with important trial procedures and, in the opinion of both the investigator and sponsor representative, the safety of the trial participant cannot be guaranteed as he I she is not willing or able to adhere to the trial requirements in the future.

[0142] • the trial participant needs to take concomitant medication that interferes with the safety / efficacy of the investigational medicinal product or other trial treatment. If shortterm, acute use of a restricted concomitant therapy is required (e.g. 5-7 days of antibiotic treatment for an infection), this will not automatically require discontinuation of Compound 114. Similarly, if a trial participant needs to modify a dose, where only a stable dose is permitted (e.g. NSBBs I carvedilol, statins, anti-viral therapy for HBV), this also will not automatically require discontinuation. In both cases, the Sponsor should be consulted.

[0143] • the trial participant meets the criteria for hepatic injury

[0144] • the trial participant has an acute liver decompensation event such as VH, therapyrefractory ascites, overt encephalopathy, or other decompensation event based on Investigator judgement

[0145] • trial participants with worsening of their liver function (e.g. increase of Child Turcotte Pugh score of more than 2 points with clinical evidence of deteriorating liver function in the opinion of the Investigator). • trial participants with a QT or QTcF interval > 500 ms, or an increase of QT or QTcF of > 60 ms from the pre-dose value at Visit 2 I randomization (baseline). Such cases must be reported as AEs

[0146] • the trial participant can no longer receive trial medication for other medical reasons such as surgery, AEs, other diseases

[0147] • the trial participant's treatment assignment has been unblended due to an emergency situation

[0148] • the trial participant has not successfully completed the dose titration period (i.e. Visit 4), but has persistent AEs or severe effects requiring down-titration of the trial medication

[0149] • a female trial participant becomes pregnant. The trial participant will be followed up until birth or otherwise termination of the pregnancy. The data of the trial participant will be collected and reported in the Clinical Trial Report (CTR) until last trial participant last visit and any events thereafter will be reported in the Bl Pharmacovigilance (PV) database

[0150] Trial-specific procedures have also been defined for Investigators to follow in case of increased liver enzymes (AST, ALT, and total bilirubin) after randomisation.

[0151] In the event of intolerance to Compound 114 after successful completion of the dose titration period at Visit 4 (e.g. persistent AEs despite two down-titrations, or severe effects at any dose), permanent treatment discontinuation should also be considered, based on Investigator judgement.

[0152] In addition to these criteria, the Investigator may discontinue trial participants at any time based on clinical judgement.

[0153] If a trial participant permanently discontinues the trial medication before the last allocated dose, an Early Discontinuation (ED) visit is required ideally within 7 days of discontinuing the medication. An EoS visit should be performed 2 weeks after the ED visit.

[0154] In case of a temporary discontinuation, trial medication (Compound 114) should be restarted if medically justified.

[0155] If new efficacy I safety information becomes available, Boehringer Ingelheim will review the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all trial participants or take any other appropriate actions to guarantee the safety of the trial participants. 2.3.4.2 Withdrawal of consent to trial participation

[0156] Trial participants may withdraw their consent to trial participation at any time without the need to justify the decision.

[0157] If a trial participant wants to withdraw consent, the investigator should be involved in the discussion with the trial participant and explain the difference between trial treatment discontinuation and withdrawal of consent to trial participation, as well as explain the options for continued follow-up after trial treatment discontinuation.

[0158] If a patient withdraws consent for further trial participation, no further data will be collected from the respective patient.

[0159] 2.3.4.3 Discontinuation of the trial by the sponsor

[0160] Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site at any time for the following reasons:

[0161] • Failure to meet expected enrolment goals overall or at a particular trial site

[0162] • New efficacy or safety information invalidating the earlier positive benefit-risk assessment

[0163] • Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct of the trial

[0164] • The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of trial termination (except in case of the third reason).

[0165] 3. TREATMENTS

[0166] 3.1 INVESTIGATIONAL TREATMENTS

[0167] The investigational medicinal products in the trial is Compound 114 and placebo to match Compound 114. Bl will supply all products.

[0168] 3.1.1 Identity of the Investigational Medicinal Products

[0169] The characteristics of the investigational medicinal products are described in Tables 2.1_to 2.6 below.

[0170] Table 2.1. Compound 114: 1 mg

[0171]

[0172] Table 2.2. Compound 114: 2 mg

[0173] Table 2.3. Compound 114: 3 mg

[0174] Table 2.4. Placebo to match Compound 114: 2 mg

[0175] Table 2.5. Placebo to match Compound 114: 1 mg

[0176] Table 2.6. Placebo to match Compound 114: 3 mg

[0177] 3.1.2 Selection of doses in the trial and dose modifications

[0178] Compound 114 has been tested in a single rising dose trial, a food effect and DDI trial and two MRD trials in male healthy volunteers. Single doses ranged from 0.5 mg to 5.0 mg and multiple doses up to 12.0 mg daily were tested. Overall, Compound 114 was well tolerated except for dose-limiting orthostatic dysregulation. Up-titration and 3 times daily dosing markedly improved the cardiovascular tolerability.

[0179] One phase 1 multiple oral rising dose trial and one phase 2 trial in trial participants with DN have also been completed. Multiple oral doses up to 3 mg TID were found to be safe and well tolerated. The highest total daily dose of 9 mg was achieved following up-titration in 2 steps over 14 days. An estimated human dose of 2.3 mg BID is predicted to achieve pharmacologically relevant exposure in trial participants with hepatic impairment. As 3 mg is the maximum tolerated single dose, 2 doses (2 mg BID and 3 mg BID) is being evaluated in the phase 2 trial 1366-0021 currently, that is conducted in trial participants with CSPH and compensated alcohol-related cirrhosis. These doses have been selected based on safety and PK results from the Phase I MRD hepatic impairment trial (1366-0020). In addition, 3 mg of Compound 114 BID maintenance dose is also being evaluated in 3 trial participants groups (HBV, HCV and NASH) in trial 1366-0029.

[0180] In this trial, 3 mg of Compound 114 BID maintenance dose will be evaluated in trial participants with CSPH and decompensated cirrhosis due to non-cholestatic liver diseases, with the potential to down-titrate, if not tolerated just as in trials 1366-0021 and 1366-0029

[0181] 3.1.3 Method of assigning trial participants to treatment groups

[0182] After the assessment of all in- and exclusion criteria, each eligible trial participant will be randomised in a blinded fashion to treatment groups according to a randomisation plan in a 1 :1 ratio at Visit 2 via an Interactive Response Technology (IRT) system.

[0183] Note that the medication numbers, assigned via the IRT system at each dispensing visit, are different from the trial participant number (which is generated via the IRT system when a new trial participant is registered [screened] in the system).

[0184] The Investigator (and relevant designated site personnel) will be provided with instructions to access the IRT system.

[0185] 3.1.4 Drug assignment and administration of doses for each trial participant

[0186] Trial medication will be dispensed at the investigational sites in accordance with the Flow Chart (Figures 2A-2D). At dispensing visits trial participants will be given the appropriate number of medication kits for Compound 114 (range 1-2) depending on the interval between the visits. The last dose of Compound 114 will be administered in the evening of the day before the EoT visit.

[0187] All trial participants, regardless of the treatment group they are assigned to, will start at Visit 2 on a dose of 1 mg of Compound 114 BID or matching placebo. At Visit 3, 7 days later, and again at Visit 4, a further 7 days after Visit 3, all trial participants will be up-titrated first to a dose of 2 mg of Compound 114 BID or matching placebo, and then to a dose of 3 mg of Compound 114 BID or matching placebo. In this way the blind across treatment groups will be maintained (refer to Table 3). Trial participants will be informed about the dose titration period and will be made aware that up-titration for Compound 114 is being used. From Visit 4 onwards, trial participants will continue to receive the maximum dose of 3mg Compound 114 BID (unless a down-titration is required), until reaching the EoT visit 8 weeks after starting the trial medication.

[0188] If a trial participant has an AE that, based on Investigator judgement, may be related to Compound 114, the trial medication can either be:

[0189] • interrupted (i.e. the trial medication is stopped, and subsequently re-started. The up- titration approach described above is followed.)

[0190] OR

[0191] • the dose can be reduced (down-titrated) for Compound 114 if the trial participant has successfully completed the dose titration period (i.e. Visit 4).

[0192] All trial medication assignments, including up I down-titrations for Compound 114 and provision of replacement kits, will be managed through the IRT system. Down-titrations of Compound 114 must not be performed by instructing the trial participant to take less than the two daily doses.

[0193] Table 3. Drug assignment and dosage by treatment group.

[0194] From the start of the treatment period (i.e. from Visit 2), and until reaching the EoT visit 8 weeks later, trial participants will be instructed to take Compound 114 orally twice a day (BID).

[0195] Each dose of Compound 114 will consist of one film-coated tablet. It is recommended that the first daily dose is taken in the morning, and the second dose in the evening. Ideally there should be at least 10 hours in between the intake of each dose. Compound 114 should be taken at approximately the same time every day. If a dose is missed this must not be rectified by taking two doses (i.e. double doses) at the next time point; if a dose is missed by more than 6 hours, that dose should be skipped altogether and the next dose taken as scheduled. Trial medication should be taken with a glass of water and can be taken with or without food.

[0196] In the morning of a visit, the trial medication will be administered as part of the visit. Therefore, on these days, trial participants should be instructed not to take their morning dose in advance of the visits. This is of particular importance for visits when PK I biomarker I pharmacogenomic (PG) sampling is required (refer to the Flow Chart (Figures 2A-2D)). Trial participants who fail to follow these instructions should have the visit re-scheduled as soon as possible, ideally on the following day. On days with no scheduled visit the trial participant will self-administer their medication at home. Trial participants should be instructed to bring all unused trial medication and empty wallets I packaging with them when they return for clinic visits to the investigational site.

[0197] For visits with PK sampling, the trial participant should also record the time of dosing with trial medication on the 3 days that precede each visit. A reminder card will be provided for this purpose.

[0198] In the event of force majeure or other disrupting circumstances physical trial participant visits to sites may not be feasible or may need to be restricted to ensure trial participant safety. Based on a thorough assessment of the benefits and risks, the Investigator may still decide to continue trial medication, and, if acceptable according to local law and regulations, trial medication may be shipped from the site to the trial participant’s home.

[0199] 3.1 .4.1 Rules for down-titration in case of intolerance to Compound 114

[0200] If a trial participant has an AE that, based on Investigator judgement, may be related to trial medication, the down-titration rules below must be followed. These rules apply if the trial participant has successfully completed the dose titration period (i.e. Visit 4) and is either still taking their final assigned dose of trial medication, or if they have missed <3 consecutive doses. If the trial participant has not successfully completed the dose titration period (i.e. Visit 4), downtitration is not permitted; in case of persistent AEs or severe effects, the trial participant must permanently discontinue treatment.

[0201] • if the trial participant is receiving 3 mg BID of Compound 114 the dose will be down- titrated one level to 2 mg BID of Compound 114

[0202] Once down-titration has taken place, no further up-titration will be permitted.

[0203] If a trial participant continues to have an AE, or a new AE develops, that based on Investigator judgement, may be related to trial medication, a second down-titration will be permitted:

[0204] • if the trial participant is receiving 2 mg BID of Compound 114 the dose will be downtitrated to 1 mg BID of Compound 114

[0205] Down-titration must not be performed by taking less than the two daily doses or by splitting tablets so that a whole tablet is not taken. Down-titration will be managed through the IRT system. After the successful completion of the dose titration period (i.e. Visit 4), in case of persistent AEs despite down-titration, or severe effects at any dose, permanent treatment discontinuation should be considered. Trial participants who are down-titrated will need to return to the investigational site to receive their continuing supply of trial medication, either at the next scheduled visit or via an unscheduled visit.

[0206] 3.1 .4.2 Rules for re-starting up-titration in case of interruption of Compound 114

[0207] An interruption of Compound 114 may have an influence on the tolerability. Hence, if a trial participant has missed > 3 consecutive doses of trial medication for any reason (e.g. due to an AE, or for compliance reasons), the rules below will apply for the safety of the trial participant. (One dose refers to an individual time point e.g. morning dose or evening dose.) If < 3 consecutive doses of trial medication have been missed and there is no related AE, then the next dose of trial medication should be taken as scheduled.

[0208] • after an interruption of trial medication of >3 consecutive doses, the trial participant should re-start the dose titration period at 1 mg BID of Compound 114 / matching placebo

[0209] • before any further up-titration occurs the trial participant must have taken the preceding dose for at least 7 consecutive days. This applies throughout the treatment period o this may mean that a trial participant due to be up-titrated at Visit 3 or 4 (as per Table 3) is held at their current dose until their next scheduled visit. They could also be up- titrated at an unscheduled visit once this requirement is met

[0210] • if interruption occurs after Visit 4, subsequent up-titration will be allowed either at a scheduled visit or at an unscheduled visit Trial participants with an interruption of trial medication will need to return to the investigational site to receive their continuing supply of trial medication, either at the next scheduled visit or via an unscheduled visit.

[0211] 3.1.5 Blinding and procedures for unblinding

[0212] 3.1.5.1 Blinding

[0213] Trial participants, investigators, central reviewers, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial will remain blinded regarding the randomised treatment assignments until the database is declared ready for analysis according to the sponsor’s SOPs. Further details regarding the timepoint of unblinding the database for analysis are documented in the TSAP.

[0214] The access to the randomisation code will be kept restricted until its documented release per sponsor SOP.

[0215] The randomisation codes will be provided to bioanalytics before the last trial participant completes the trial to allow for the exclusion from the analyses of PK samples taken from trial participants receiving placebo. Bioanalytics will not disclose the randomisation code or the results of their measurements until the trial is officially unblinded after the database lock (DBL).

[0216] In order to expedite the population PK and PK-PD analyses and ensure timely delivery of PK / PD results after DBL, specific data must be unblinded and the treatment information must be made available to selected individuals (e.g. pharmacometric and programming personnel). The unblinding procedure and logistics specific to this purpose will be provided in a separate document. It should be noted no PK / PD results will be communicated to the project and trial team prior to DBL.

[0217] A DMC, independent from the Sponsor, will perform an unblinded safety evaluation at intervals specified in the DMC charter in order to ensure that trial participants are protected from potential harm. A trial independent statistician (iSTAT) will be assigned to prepare tables and listings as well as the summary reports for the DMC based on the agreed upon format and layout. Randomisation codes will be provided to the iSTAT. All information, including AEs, mortality, laboratory parameters, and decisions from hepatic injury adjudication will be provided in an unblinded fashion. This will be accomplished by using coded labels and by providing the DMC members with the decoding information separately, if needed. 3.1 .5.2 Emergency unblinding and breaking the code

[0218] Emergency unblinding will be available to the Investigator via IRT. It must only be used in an emergency situation when the identity of the trial medication must be known to the Investigator in order to provide appropriate medical treatment or otherwise assure safety of trial participants. The reason for unblinding must be documented in the source documents and I or appropriate eCRF page. If a trial participant is unblinded by the Investigator, the trial participant has to be discontinued from the trial.

[0219] Due to the requirements to report Suspected Unexpected Serious Adverse Reactions (SUSARs), it may be necessary for a representative from Bl’s PV group to access the randomisation code for individual trial participants during trial conduct. The access to the code will only be given to authorised PV representatives for processing in the PV database system and not be shared further.

[0220] 3.1.6 Packaging, labelling, and re-supply

[0221] The investigational medicinal products will be provided by Bl or a designated Clinical Research Organisation (CRO). They will be packaged and labelled in accordance with the principles of Good Manufacturing Practice. Re-supply to the sites will be managed via an IRT system, which will also monitor expiry dates of supplies available at the sites.

[0222] In this trial, each medication kit with BID of Compound 114 will contain one wallet and each wallet will hold 20 film-coated tablets (i.e. seven days treatment plus three days reserve). The number of kits dispensed at each dispensing visit, will be sufficient to cover both the planned number of weeks of treatment between visits, and the use of any permitted visit windows.

[0223] For details of packaging and the description of the label, refer to the ISF.

[0224] 3.1.7 Storage conditions

[0225] Drug supplies will be kept in their original packaging and in a secure limited access storage area according to the recommended storage conditions on the medication label. A temperature log must be maintained for documentation.

[0226] If the storage conditions are found to be outside the specified range, the Clinical Research Associate (CRA), as provided in the list of contacts in the ISF, must be contacted immediately. 3.1.8 Drug accountability

[0227] The Investigator or designee will receive the trial medication delivered by the Sponsor or delegate when the following requirements are fulfilled:

[0228] • approval of the CTP by the Institutional Review Board (IRB) I Independent Ethics Committee (I EC)

[0229] • availability of a signed and dated clinical trial contract between the Sponsor or delegate and the investigational site

[0230] • approval I notification of the regulatory authority, e.g. competent authority (CA)

[0231] • availability of the curriculum vitae of the Principal Investigator

[0232] • availability of a signed and dated CTP

[0233] • availability of the proof of a medical license for the Principal Investigator (if applicable)

[0234] • availability of FDA Form 1572 (if applicable)

[0235] Trial medication is not allowed to be used outside the context of this CTP. It must not be forwarded to other Investigators or clinics. Trial participants should be instructed to return unused trial medication.

[0236] The Investigator or designee must maintain records of the medication’s delivery to the trial site, the inventory at the site, the use by each trial participant, and the return to the Sponsor or warehouse I drug distribution center or alternative disposal of unused medication. If applicable, the Sponsor or warehouse I drug distribution center will maintain records of the disposal.

[0237] These records will include dates, quantities, batch I serial numbers, expiry (‘use-by’) dates, and the unique code numbers assigned to the trial medication and trial participants. The Investigator or designee will maintain records that document adequately that the trial participants were provided the doses specified by the CTP and reconcile all trial medication received from the Sponsor. At the time of return to the Sponsor and I or appointed CRO, the Investigator or designee must verify that all unused or partially used trial medication has been returned by the clinical trial participant and that no remaining supplies are in the Investigator’s possession.

[0238] 3.2 OTHER TREATMENTS, EMERGENCY PROCEDURES, RESTRICTIONS

[0239] 3.2.1 Other treatments and emergency procedures

[0240] There are no special emergency procedures to be followed. Stable doses of concomitant therapies for chronic conditions, for which neither the condition nor the treatment are judged to exclude the trial participant from participation are permissible throughout the duration of the trial. All concomitant therapy should be carefully evaluated by the Investigator and the Sponsor should be contacted when there are questions.

[0241] In case of AEs in need of treatment, any concomitant therapy, based on Investigator’s judgement, will be permitted. Diagnostics and treatment should be initiated according to local standard of care.

[0242] All concomitant therapies will be recorded on the appropriate pages of the eCRF.

[0243] Endoscopic variceal ligation (performed according to local guidelines) is permitted during the trial as required. The procedure should be recorded on the appropriate page of the eCRF.

[0244] 3.2.2 Restrictions

[0245] 3.2.2.1 Restrictions regarding concomitant treatment

[0246] The concomitant therapies mentioned below must not be co-administered with Compound 114.

[0247] • NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl trinitrate, isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g. sildenafil, tadalafil, and vardenafil), non-specific PDE inhibitors such as dipyridamole and theophylline, or sGC-stimulators (e.g. riociguat): These restrictions apply from within 5 half-lives after the concomitant therapy has been stopped prior to enrolment (visit 2), until the EoS visit.

[0248] • Concomitant therapies with a known risk of Torsade de Pointes: These restrictions apply from screening Visit 1a, until the EoS visit. In the event of temporary concomitant use of such a therapy, the trial medication must be temporarily stopped and can then be restarted at least 5 half-lives after the concomitant therapy with the known risk of Torsade de Pointes has been stopped.

[0249] • clinically relevant OATP1 B1 / 3 inhibitors

[0250] • clinically relevant concomitant therapies known to inhibit or induce UGT enzymes

[0251] In the event of temporary concomitant use of medication that is not permitted, Compound 114 must be temporarily stopped and can be re-started after a period of at least 5 half-lives after the concomitant therapy has been stopped.

[0252] A list to support the identification of the above-mentioned concomitant therapies will be provided in the ISF. The list will not claim completeness. Furthermore, trial participants who are receiving statins, must be on a stable dose for at least 3 months prior to screening (Visit 1b), with no planned dose change throughout the trial, and trial participants who are receiving NSBBs I carvedilol, must be on a stable dose for at least 1 month prior to screening (Visit 1b), with no planned dose change throughout the trial. In addition, these concomitant therapies should not be initiated during the trial as they will interfere with the efficacy of the trial medication.

[0253] If receiving anti-viral therapy for HBV, trial participants must be on a stable dose for at least 6 months prior to screening, with no planned dose change throughout the trial .

[0254] 3.2.2.1.1 Close monitoring for AEs based on concomitant therapy

[0255] If a trial participant is taking concomitant therapy that is metabolised by CYP3A4 and / or CYP2C8, which has a narrow therapeutic index and / or is a sensitive substrate, close monitoring for AEs is recommended in this trial. A list to support the identification of the above- mentioned concomitant therapies will also be provided in the ISF. The list will not claim completeness.

[0256] 3.2.2.2 Restrictions on diet and lifestyle

[0257] Drastic changes of diet and lifestyle in the course of the trial should be avoided. This includes unusual and strenuous exercise for the trial participant (e.g. taking up exercises that put pressure on the abdomen, such as weightlifting).

[0258] Alcohol consumption should be avoided throughout the trial; excessive alcohol consumption could lead to hypotension when taken concomitantly with Compound 114.

[0259] During the treatment period, trial participants will be asked if they have consumed any alcohol, and where necessary, reminders should be issued to abstain from alcohol consumption.

[0260] The requirement for a fasting status upon arrival at clinic visits is as defined in the Flow Chart (Figures 2A-2D). Once all visit assessments are complete that require this status, the trial participant may eat as normal.

[0261] 3.2.2.3 Contraception requirements

[0262] Women of childbearing potential (WOCBP) and men able to father a child must use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1 % per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the trial participant information. WOCBP must be ready and able to use a highly effective method of birth control from the randomisation visit (Visit 2) until 7 days after the last trial medication intake, if their partner is a male able to father a child. No contraceptive is required for the partner of the WOCBP.

[0263] Highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1 % per year when used consistently and correctly include (if local regulations permit):

[0264] • combined (oestrogen and progestogen containing) hormonal birth control that prevents ovulation (oral, intravaginal, transdermal)

[0265] • progestogen-only hormonal birth control that prevents ovulation (oral, injectable, implantable)

[0266] • intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

[0267] • bilateral tubal occlusion

[0268] A male trial participant must use a condom with or without spermicide until at least 7 days after last trial medication intake if their sexual partner is a WOCBP, or, be vasectomised with documented absence of sperm in the ejaculate. No contraceptive is required for the male trial participant’s partner.

[0269] Alternatively WOCBP and male trial participants able to father a child must abstain from malefemale sex. This is defined as being in line with the preferred and usual lifestyle of the trial participant. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods; declaration of abstinence for the duration of exposure to trial medication; and withdrawal are not acceptable.

[0270] 3.3 TREATMENT COMPLIANCE

[0271] Trial participants are requested to bring all remaining trial medication including empty package material with them when attending visits.

[0272] Based on tablet counts, treatment compliance will be calculated as shown in the formula below. Compliance will be verified by the CRA authorised by the sponsor or delegate.

[0273] Number of actually taken X 100 Treatment compliance (%) = >

[0274] Number of which should have been taken as directed by the investigator

[0275] If the number of doses taken is not between 80-120%, site staff will explain to the trial participant the importance of treatment compliance.

[0276] 4. ASSESSMENTS

[0277] 4.1 ASSESSMENT OF EFFICACY

[0278] 4.1.1 Hepatic venous pressure gradient

[0279] HVPG measurement will be performed at the time points specified in the Flow Chart (Figures 2A-2D). Sites must have access to the necessary infrastructure and equipment to measure HVPG (e.g. a hepatic hemodynamic laboratory at their site, or at a nearby institution). Site staff performing the procedure must have sufficient expertise (e.g. performing in the region of 25 or more HVPG measurements per year) with interventional skills and expertise in the reading of pressure tracings, since a local interpretation of the tracing from Visit 1 b and EoT visit will be recorded in the trial participant source documents and the eCRF.

[0280] The HVPG procedure within the trial will be conducted in a standardised fashion at all sites (for details refer to the HVPG manual in the ISF); training will be provided. Each trial site will be asked to provide acceptable sample HVPG tracing(s) prior to commencing trial participant recruitment if not already provided for Trials 1366-0021 or 1366-0029. Measurements of wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) will be performed in triplicate; tracings will be provided to an external Supplier and read centrally by independent expert(s) in PH; the central read will include a subjective assessment of the overall trace quality as well as a read of the relevant pressures. The independent expert(s) will be blinded to the timepoint that the trace relates to. The central read will include the traces from Visit 1b that have also been interpreted locally. The results of the central read will be transferred to the Sponsor and will be considered the official evaluation of the trial. In case of discrepancies between a local interpretation and the central evaluation (e.g. of the Visit 1b tracing), the central evaluation will remain valid.

[0281] HVPG measurements should be performed using the same hepatic vein, prior to intake of the trial medication, after an overnight fast, and ideally in the morning. If it is not possible to perform the measurement at Visit 1 b in the morning an alternative time of day can be chosen; in this case, a fast of at least four hours is required. The subsequent HVPG measurement must then be performed at approximately the same time of day as the Visit 1 b measurement for a single trial participant. At the EoT visit, the HVPG measurement should be performed on the day of the scheduled visit, or within seven days (if this latter approach is taken, the measurement should still be performed after an overnight fast I after a fast of at least four hours). If this scenario is chosen for an HVPG performed during the treatment period, the morning dose of trial medication can be taken prior to the procedure.

[0282] A summary of the HVPG procedure is as follows (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).

[0283] Under local anaesthesia and ultrasound guidance, a catheter introducer sheath is placed in the right internal jugular vein. Using fluoroscopic guidance, a balloon catheter is advanced into the inferior vena cava (IVC) and inserted into a large hepatic vein. Correct and sufficient wedge position of the catheter is ensured by injecting contrast media while the balloon is blocking the outflow of the cannulated hepatic vein. After calibrating the external pressure transducer, continuous pressure recordings are obtained with triplicate recordings of the WHVP and FHVP. The difference between FHVP and WHVP is referred to as HVPG, with values > 10 mmHg indicating CSPH. Before removing the catheter, pressure readings obtained in the IVC at the same level, as well as the right atrial pressure, are recorded.

[0284] 4.1.2 FibroScan measurements

[0285] The liver and spleen will be evaluated using the FibroScan® Expert 630 device, a non-invasive advanced technique using vibration controlled transient elastography (VCTETM) technology. FibroScan® of the liver has been available for a number of years, and is a standard procedure used for screening and management of trial participants with liver disease. The ability to assess spleen stiffness using FibroScan® has only recently become possible following the introduction of the FibroScan® Expert 630 model; hence, spleen stiffness measurements are not yet a standard part of clinical practice in the trial participant population planned for this trial.

[0286] Evaluations will be performed at the time points specified in the Flow Chart (Figures 2A-2D), after an overnight fast and in accordance with the FibroScan® manual in the ISF. FibroScan® assessments should ideally be performed on the same day as the ultrasound examination.

[0287] During the treatment period, following randomisation, assessments should be performed on the day of the scheduled visit, or within seven days (if this latter approach is taken, the measurement must still be performed after an overnight fast). The following assessments will be performed:

[0288] • liver stiffness measurement (LSM) using VCTE

[0289] • spleen stiffness measurement using VCTE

[0290] Data from the FibroScan® measurements will be sent to an external Supplier, who will transfer the results to the Sponsor or delegate.

[0291] Site personnel using the FibroScan® Expert 630 device must be appropriately trained and certified. Site personnel are expected to have prior experience with the use of FibroScan® for LSM. Training will be provided as necessary; each trial site will also go through a qualification process prior to commencing trial participant recruitment, if not already performed for Trials 1366-0021 or 1366-0029 (for further details refer to the FibroScan® manual in the ISF). If the FibroScan® Expert 630 device is not available at the site, it will be provided by the Sponsor for the duration of the trial.

[0292] If possible, the same operator should perform the assessments for a single trial participant.

[0293] 4.2 ASSESSMENT OF SAFETY

[0294] 4.2.1 Physical examination

[0295] A complete physical examination must be performed at the two time points specified in the Flow Chart (Figures 2A-2D); further physical examinations are only required if the trial participant reports symptoms. A complete physical examination includes, as a minimum, general appearance, neck, lungs, cardiovascular system, abdomen, extremities and skin.

[0296] 4.2.1.1 Anthropometric measurements (height, weight, waist and hip circumference)

[0297] Measurement of height, body weight, waist and hip circumference will be performed at the time points specified in the Flow Chart (Figures 2A-2D). Height will be measured at Visit 1a only. The results of anthropometric measurements must be included in the source documents available at the site.

[0298] Whenever possible, weight measurements should always be performed on the same weighing scales for one trial participant. In order to get comparable body weight values, the assessment should be performed in the following way:

[0299] • shoes, coat / jackets and any headgear should be taken off

[0300] • pockets should be emptied of heavy objects (i.e. keys, coins)

[0301] • after bladder voiding The measuring tape used for waist and hip circumference should be made of a material that is not easily stretched, such as fiberglass. Waist circumference measurements should be made around a trial participant’s bare midriff, after the trial participant exhales while standing without shoes and with both feet touching and arms hanging freely. Waist circumference should be determined by measuring the midpoint between the lowest rib and the iliac crest. The tape should be placed perpendicular to the long axis of the body and horizontal to the floor and applied with sufficient tension to conform to the measurement surface.

[0302] Hip circumference measurements should start at one hip, wrapping the measuring tape around the widest part of the buttocks, and around the other hip to the front. Coats I jackets should be taken off and pockets emptied to ensure a close measurement and with both feet touching and arms hanging freely.

[0303] 4.2.2 Vital signs / home blood pressure and heart rate monitoring

[0304] Vital signs (SBP, DBP, as well as HR [pulse rate]) will be evaluated at trial visits at the time points specified in the Flow Chart (Figures 2A-2D), prior to blood sampling and prior to the 12- lead ECG. BP measurements should be recorded in the eCRF to the nearest 1 mmHg. BP measurements should be performed on the non-dominant arm. HR should be measured electronically or by palpation and counted for one minute. BP and HR measurements should be taken after trial participants have rested quietly, in the seated I supine position, for at least 5 minutes. The measurements recorded at the trial visit must be included in the source documents available at the site.

[0305] At screening (Visit 1a), the site should use their preferred method to measure vital signs. From Visit 2 onwards, vital signs should be measured using the trial participants home BP monitoring equipment in order to have a consistent method for the duration of the trial. This includes the pre- and post-dose vital signs measurements during the dose-titration period and at the subsequent visit (refer to the Flow Chart (Figures 2A-2D)).

[0306] 4.2.2.1 Home blood pressure and heart rate monitoring

[0307] Home BP and HR monitoring will be performed by the trial participant as specified in the Flow Chart (Figures 2A-2D). Electronic BP and HR monitoring equipment will be provided for this purpose. Site staff will train the trial participant in the correct use of the equipment at Visit 2, explaining that it must be used only to record BP and HR measurements belonging to the trial participant. Subsequent refresher training should be provided at subsequent visits if required. Trial participants will be asked to measure their BP and HR every day in the morning, soon after waking up prior to much physical activity, and after resting seated for approximately 5 minutes. Measurements must be taken before administration of the morning dose of trial medication.

[0308] The electronic readings will be stored in the memory of the home BP and HR monitoring equipment.

[0309] If, at any time after trial medication intake, a trial participant experiences symptoms suggestive of hypotension (e.g. he I she feels light-headed I dizzy, sees black spots, suffers from weakness), particularly if the symptoms occur whilst standing up, or if he I she has any other symptoms in between trial visits, additional BP and HR reading(s) can be taken and the trial participant should report these symptoms at the next trial visit. The trial participant should bring the home BP and HR monitoring equipment with them to each trial visit (refer to the Flow Chart shown in Figures 2A-2D) for the site staff to review the electronic readings, and to use for the measurement of BP and HR during trial visits from Visit 2 onwards. Any BP I HR measurements which, following review, are evaluated as AEs, must be included in the source documents available at the site.

[0310] 4.2.3 Safety laboratory parameters

[0311] Safety laboratory parameters that will be assessed are listed in Table 4. Sampling time points will be as indicated in the Flow Chart (Figures 2A-2D). All analyses will be performed by a central laboratory; the respective reference ranges will be provided in the ISF. Refer to Table 5 for a list of “minimum required safety laboratory parameters” in the event of force majeure or other disruptive circumstances.

[0312] Trial participants should be fasted for blood sampling for the safety laboratory where that visit is defined as a fasting visit in the Flow Chart (Figures 2A-2D); where a non-fasting status is defined, the safety laboratory sample can be collected in a non-fasting status. The fasting status will be recorded for e.g. PK sampling purposes. Blood samples for safety laboratory parameters should be drawn prior to administration of trial medication.

[0313] Instructions regarding sample collection, sample handling I processing and sample shipping will be provided in the central laboratory manual in the ISF.

[0314] The central laboratory will provide laboratory reports to the Investigator. It is the responsibility of the Investigator to evaluate these reports. Clinically relevant abnormal findings, as judged by the Investigator, must be reported as AEs. Laboratory tests may need to be repeated in case of required medical follow-up due to an AE or if a test was not successful due to incorrect specimen handling or storage. Should a trial participant not fulfil all laboratory requirements to take part in the trial due to a transitional medical condition, the trial participant may continue in the screening period but cannot be randomised until the re-test of the laboratory result is available to determine the eligibility of the trial participant.

[0315] In case that the criteria for hepatic injury are fulfilled, a number of additional measures will be performed. The amount of blood taken from the trial participant concerned will be increased due to this additional sampling.

[0316] The CKD-EPI formula (isotope dilution mass spectrometry standardised) will be used for reporting eGFR based on serum creatinine.

[0317] The central laboratory will transfer the results of the analysis to the Sponsor or delegate.

[0318] In case that the qualitative parameters are abnormal, a quantitative analysis will be performed by the central laboratory.

[0319] Table 4. Safety laboratory tests.

[0320] 1 . If initial CK is elevated, re-test CK with CK-MB and troponin I

[0321] 2. Not performed at screening (Visit 1a)

[0322] 3. Not performed at screening (Visit 1a) or EoS; collect seated after patient seated for at least 5 to 15 minutes, and once patient has been out of bed for at least 2 hours

[0323] 4. Only performed at screening (Visit 1a)

[0324] 5. Reflex in case of abnormal TSH 6. WOCBP only; only at Visit 1a, and as a reflex if urine testing is positive

[0325] 7. WOCBP only, Visit 2 onwards. Measured locally at the site every 4 weeks using a pregnancy test kit provided by the central laboratory. Serum pregnancy testing will be done as a reflex if urine testing is positive (see above). More frequent pregnancy testing should be done if required by local regulation and / or authority or per investigator judgement. Pregnancy testing at dosing visits should be completed prior to administration of the trial medication

[0326] 8. Reflex in case of positive HCV antibody

[0327] 9. Reflex in case of positive HBV core antibody

[0328] Table 5. Minimum required safety laboratory tests (force majeure I other disruptive circumstances).

[0329] 4.2.4 Electrocardiogram

[0330] The 12-lead ECGs will be recorded at the time points specified in the Flow Chart (Figures 2A- 2D); the ECGs should be performed prior to blood sampling and intake of trial medication (at visits where only a one ECG is required), and recorded after the trial participant has rested for at least 5 minutes in a supine position.

[0331] During the dose-titration period (i.e. when up-titration is occurring) and at the subsequent visit, 12-lead ECGs will also be performed approximately 1 hour and 2 hours after intake of trial medication. These ECGs should precede the 1 hour and 2 hour post-dose PK samples.

[0332] ECGs must be administered by a qualified physician, nurse or technologist. The Investigator or delegate will evaluate whether the ECG is normal or abnormal and assess clinical relevance. An ECG may be repeated for quality reasons and the repeated recording used for analysis. If necessary, additional ECGs may be recorded for safety reasons.

[0333] Dated and signed print-outs of the ECG, with findings, should be documented in the trial participant’s medical record. Clinically relevant abnormal findings will be reported either as a baseline condition (if identified at the screening visit [Visit 1a]) or otherwise as AEs and will be followed up and I or treated as medically appropriate. ECG abnormalities will be carefully assessed by the Investigator or delegate, and if trial discontinuation criteria are met, the trial participant will be discontinued from the trial.

[0334] Copies of ECGs will be sent to a central ECG Supplier for storage purposes. This will enable a subsequent centralised and independent re-evaluation if necessary.

[0335] 4.2.5 Other safety parameters

[0336] 4.2.5.1 Ultrasound (liver and spleen)

[0337] Ultrasound imaging of the liver and spleen will be performed after an overnight fast, using local site equipment, and at the time points specified in the Flow Chart (Figures 2A-2D). Ultrasound assessments should ideally be performed on the same day as the FibroScan® examination.

[0338] During the treatment period, following randomisation, ultrasound assessments should be performed on the day of the scheduled visit, or within seven days (if this latter approach is taken, the assessment must still be performed after an overnight fast).

[0339] Ultrasound is used as a safety measure to assess the condition of the liver and spleen, organ size and the presence of ascites. The skin-to-liver capsule distance (i.e. the subcutaneous thickness), portal vein diameter, the skin-to-spleen capsule distance, and spleen height, length and width will also be measured, since large distances can affect the ability to sufficiently measure liver and spleen stiffness with the Fibroscan® Expert 630 device.

[0340] Sites will be expected to follow local standard processes prior to and during the procedure.

[0341] 4.2.5.2 Hepatic injury adjudication

[0342] An independent AC will be used to adjudicate certain hepatic events for severity and causal relationship with the trial medication. 4.2.6 Assessment of adverse events

[0343] Data and information necessary for the thorough assessment of AEs, SAEs, and AESIs will be reported to the sponsor via eCRF. This may include specific data and information not prospectively specified in this protocol.

[0344] 4.2.6.1 Definitions of AEs

[0345] 4.2.6.1.1 Adverse event

[0346] An AE is defined as any untoward medical occurrence in a trial participant or clinical investigation subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment.

[0347] An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether considered related or not.

[0348] The following should also be recorded as an appropriate eCRF :

[0349] • Worsening of the underlying disease or of other pre-existing conditions

[0350] • Changes in vital signs, ECG, physical examination and laboratory test results, if they are judged clinically relevant by the Investigator

[0351] If such abnormalities already exist prior to trial inclusion, they will be considered as baseline conditions and should be collected in the eCRF only.

[0352] 4.2.6.1 .2 Serious adverse event

[0353] A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the following criteria:

[0354] • Results in death,

[0355] • Is life-threatening, which refers to an event in which the trial participant was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if more severe,

[0356] • Requires intrial participant hospitalisation or prolongation of existing hospitalisation

[0357] • Results in persistent or significant disability or incapacity,

[0358] • Is a congenital anomaly I birth defect,

[0359] • Is deemed serious for any other reason if it is an important medical event when based on appropriate medical judgement which may jeopardise the trial participant and may require medial or surgical intervention to prevent one of the other outcomes listed in the above definitions. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or development of dependency or abuse.

[0360] For Japan only: An event that possibly leads to disability will be handled as ‘deemed serious for any other reason’ and, therefore, reported as an SAE.

[0361] 4.2.6.1 .3 AEs considered “Always Serious”

[0362] In accordance with the European Medicines Agency initiative on Important Medical Events, Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be considered to be “serious” even though they may not have met the criteria of an SAE as defined above. The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest list of “Always Serious AEs” will be provided upon request. These events should always be reported as SAEs. Cancers of new histology and exacerbations of existing cancer must be classified as a serious event regardless of the time since discontinuation of the drug and must be reported as described in subsections “AE Collection” and “AE reporting to sponsor and timelines”.

[0363] 4.2.6.1 .4 Adverse events of special interest

[0364] The term adverse events of special interest (AESI) relates to any specific AE that has been identified at the project level as being of particular concern for prospective safety monitoring and safety assessment within this trial, e.g. the potential for AEs based on knowledge from other compounds in the same class. AESIs need to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe that applies to SAEs.

[0365] The following are considered as AESIs:

[0366] • Hepatic injury

[0367] A hepatic injury is defined by alterations of the hepatic laboratory and clinical parameters after randomisation as detailed by the removal and stopping criteria.

[0368] These laboratory findings constitute a hepatic injury alert and patients showing these abnormalities need to be followed up according to the “DILI checklist” which can be downloaded from the eDC system. In case of clinical symptoms of hepatic injury (e.g. encephalopathy, nausea, vomiting, pruritus, severe fatigue, icterus) without laboratory results (ALT, AST, total bilirubin, INR) available, the Investigator should make sure these parameters are analysed, if necessary, in an unscheduled blood test. Should the results meet the criteria of the hepatic injury alert, the procedures described in the DILI checklist should be followed.

[0369] 4.2.6.1 .5 Intensity (severity) of adverse events

[0370] The intensity (severity) of AEs should be classified and recorded in the eCRF according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 dated 27 November 2017.

[0371] 4.2.6.1 .6 Causal relationship of adverse events

[0372] Medical judgement should be used to determine the relationship between the AE and the Bl investigational compound, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant therapy, concomitant diseases and relevant history.

[0373] Arguments that may suggest that there is no reasonable possibility of a causal relationship could be:

[0374] • No plausible time to onset of the event relative to the time of drug exposure is evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days I weeks of drug administration; an allergic reaction weeks after discontinuation of the trial drug concerned).

[0375] • Continuation of the event despite the withdrawal of the medication, considering the pharmacological properties of the compound (e.g. after 5 half-lives).

[0376] Of note, this criterion may not be applicable to events whose time course is prolonged despite removing the original trigger.

[0377] • There is an alternative explanation, e.g. situations where other drugs or underlying diseases appear to provide a more likely explanation for the observed event than the drug concerned.

[0378] • Disappearance of the event even though the trial drug treatment continues or remains unchanged.

[0379] Arguments that may suggest that there is a reasonable possibility of a causal relationship could be:

[0380] • The event is consistent with the known pharmacology of the trial drug.

[0381] • The event is known to be caused by or attributed to the drug class.

[0382] • A plausible time to onset of the event relative to the time of drug exposure.

[0383] • Evidence that the event is reproducible when the drug is re-introduced. • No medically sound alternative aetiologies that could explain the event (e.g. pre-existing or concomitant diseases, or co-medications).

[0384] • The event is typically drug-related and infrequent in the general population not exposed to drugs (e.g. Stevens-Johnson syndrome).

[0385] • An indication of dose-response (i.e. greater effect size if the dose is increased, smaller effect size if dose is reduced).

[0386] 4.2.6.2 Adverse event collection and reporting

[0387] 4.2.6.2.1 AE Collection

[0388] The investigator shall maintain and keep detailed records of all AEs in the participant files .

[0389] Per default SAEs / AESIs should be reported via the eCRF in the EDC system. If the EDC system is not or no longer available (e.g. after database lock), the Bl paper SAE form should be used. The following must be collected and documented:

[0390] • From signing the informed consent onwards until the individual participant’s end of trial (= the End of Study [EoS] visit): all AEs (serious and non-serious) and all AESIs.

[0391] • After the individual participant’s end of trial:

[0392] The investigator does not need to actively monitor the participant for new AEs but should only report any occurrence of cancer of new histology and trial drug related SAEs and trial drug related AESIs of which the investigator may become aware of by any means of communication, e.g. phone call.

[0393] 4.2.6.2.2 AE reporting to the sponsor and timelines

[0394] The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the reported SAE or AESI , on the AE or SAE eCRF pages to the sponsor’s unique entry point within 24 hours of becoming aware of the event, the country specific process will be specified in the ISF. The same timeline applies if follow-up information becomes available. In specific occasions, the investigator could inform the sponsor upfront via telephone in addition.

[0395] With receipt of any further information to these events, follow-up reports have to be provided. For follow-up information the same rules and timeline apply as for initial information. All (S)AEs, including those persisting after individual participant send of trial must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no further information can be obtained. Should the EDC system not be available for more than 24 hours, reporting must occur via the Bl paper SAE forms.

[0396] 4.2.6.2.3 Pregnancy

[0397] In rare cases, pregnancy might occur in a clinical trial. Once a trial participant has been enrolled in the clinical trial and has taken trial medication, the investigator must report any drug exposure during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.

[0398] Similarly, potential drug exposure during pregnancy must be reported if a partner of a male trial participant becomes pregnant. This requires written consent of the pregnant partner. Reporting and consenting must be in line with local regulations. The ISF will contain the trial specific information and consent for the pregnant partner.

[0399] The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring Form for Studies (Part B).

[0400] The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and B).

[0401] As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE and / or AESI, only the Pregnancy Monitoring Form for Studies is to be completed. However, a SAE and / or AESI associated with the pregnancy it must be reported.

[0402] 4.3 DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS

[0403] 4.3.1 Assessment of pharmacokinetics

[0404] PK sampling times and periods are as indicated in the Flow Chart (Figures 2A-2D). Date and clock time of trial medication administration(s) and PK sampling will be recorded in the eCRF, as well as the fasting status of the trial participant for each PK sampling time. Additional PK parameters may be calculated as appropriate. Noncompartmental PK parameters will be calculated based on actual sampling times using a validated PK software (Phoenix® WinNonlin® 8.1).

[0405] Individual plasma concentration data and the PK parameters calculated thereof will be tabulated and graphically displayed. A trial participant’s PK data will be flagged and excluded from the PK analyses in case of protocol deviations relevant to the evaluation of PK or in case of PK non-evaluability (as revealed during data analysis, based on the criteria specified below). Reasons for exclusion of a trial participant’s data will be documented in the CTR.

[0406] Protocol deviations relevant to the evaluation of PK may be:

[0407] • incorrect trial medication taken, i.e. trial participant received at least one dose of trial medication the trial participant was not assigned to

[0408] • incorrect dose of trial medication taken

[0409] • actual trial medication taken considerably deviated from the planned up-titration

[0410] • use of restricted concomitant therapy

[0411] • treatment compliance differs considerably from 100%

[0412] PK non-evaluability applies, if for example:

[0413] • the trial participant experienced emesis that occurred in the time window of two times median tmax (median tmax is to be determined excluding the trial participant(s) experiencing emesis)

[0414] • the trial participant has missing samples I concentration data at important phases of the PK disposition curve

[0415] 4.3.2 Methods of sample collection

[0416] For quantification of analyte plasma concentrations of Compound 114 blood will be taken from an antecubital or forearm vein. Blood will be drawn by means of either an indwelling venous catheter or by venepuncture with a metal needle. Further details of sample processing for plasma generation will be described in the central laboratory manual in the ISF.

[0417] After analysis, the samples may be used for further methodological investigations (e.g. for stability testing or assessment of metabolites) or to address Health Authority questions regarding the results I methodology. However, only data related to the analyte and I or its metabolite(s) will be generated by these additional investigations.

[0418] The trial samples will be discarded after completion of the additional investigations but not later than 5 years after the final CTR has been signed.

[0419] 4.3.3 Analytical determinations

[0420] Compound 114 concentrations in plasma will be determined by a validated liquid chromatography tandem mass spectrometry (LC-MS / MS) assay each. All details of the analytical method will be available prior to the start of sample analysis. 4.3.4 Pharmacokinetic - pharmacodynamic relationship

[0421] The PK and PD data from this trial may be used for an exploratory investigation of the PKPD relationship of Compound 114. A population PK-PD analysis may be performed at the project level using a non-linear mixed effects modelling approach. This analysis will not be part of the CTR but will be reported separately.

[0422] 4.4 ASSESSMENT OF BIOMARKER(S)

[0423] This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety are described and discussed herein

[0424] In order to characterise the effects of Compound 114 in trial participants with CSPH in decompensated cirrhosis due to non-cholestatic liver disease, a number of additional biomarkers will be analysed that represent the key mechanisms of liver pathophysiology (e.g. markers of inflammation, fibrosis and endothelial dysfunction) and I or which are associated with the mechanisms of action of an sGC activator. The biomarkers are summarised in Table 6.

[0425] Table 6. Summary of exploratory biomarkers.

[0426] Additional biomarkers deemed relevant to elucidate mechanism of action, disease activity and I or safety may be evaluated to address the objectives of this trial.

[0427] For timing of sampling for biomarkers refer to the Flow Chart (Figures 2A-2D). For China, the collection of exploratory biomarkers will be optional due to regulatory restrictions. Biomarker sampling requires a consistent status from one sample to another in terms of fasting vs nonfasting; a fasting status has been chosen for this trial. Biomarker samples should be drawn prior to administration of trial medication. Details on sampling procedures and handling will be described in the central laboratory manual in the ISF.

[0428] The trial samples will be discarded after completion of the additional investigations but not later than 5 years after the final CTR has been signed.

[0429] Exploratory biomarkers may be reported in a separate biomarker report.

[0430] 4.4.1 Predictive biomarkers

[0431] Pharmacogenomics (PG) investigates genetic variations to explain and to predict an individual’s response to drugs. Therefore, a blood sample for PG testing will be taken from each trial participant. For China, the collection of the PG sample will be optional due to regulatory restrictions. In case of unexplainable variability of PK or PD parameters, DNA may be extracted from these samples and used for exploratory analysis of variants of the sGC gene and other genes in pathway, and genes involved in ADME of drugs.

[0432] Multiple gene variants have been associated with liver fibrosis and I or a degree of liver fibrosis. For example, the rs58542926 polymorphism in transmembrane 6 superfamily member 2 (TM6SF2) is a genetic factor predisposing to NAFLD. It needs to be explored whether carriers of specific polymorphisms respond differently to treatment with Compound 114 .

[0433] It is not intended to include these data in the final CTR. However, the data may be part of the CTR if necessary.

[0434] Detailed instructions for PG sampling, including handling and shipment of samples, will be described in the central laboratory manual in the ISF.

[0435] 4.4.2 Pharmacodynamics, safety, and trial participant selection biomarkers

[0436] Some laboratory measurements from the safety laboratory (e.g. liver enzymes [ALT, AST, y-GT and alkaline phosphatase]) are relevant for the assessment of effects of Compound 114 on liver pathophysiology and will be analysed along with the above-mentioned exploratory biomarkers. For example, the inflammatory marker hs-CRP, the cardiac biomarkers BNP, and Troponin I as well as the renal safety parameters eGFR and creatinine. Additional established liver fibrosis and cirrhosis biomarkers will be investigated such as Caspase-cleaved cytokeratin 18 (M30), total cytokeratin 18 (M65), Pro-C3, Pro-C6, HA (hyaluronic acid), PIIINP (procollagen III amino terminal peptide), TIMP 1 (tissue inhibitor of metalloproteinase 1), ferritin, alpha-2 macroglobulin, and apolipoprotein A1 (separately from the safety laboratory parameters).

[0437] The following composite scores indicative of disease activity will be determined:

[0438] • Fibrosis-4 (Fib-4) index indicative of the level of liver fibrosis (age, AST, ALT, platelets)

[0439] • FibroScan®-AST (FAST™) score

[0440] • FibroScan® based scores for advanced fibrosis agile 3+ (Liver stiffness, AST / ALT ratio, platelets, gender, age and presence of diabetes mellitus) and indicative of liver cirrhosis agile 4 (Liver stiffness, AST / ALT ratio, platelets, gender, age and presence of diabetes mellitus)

[0441] • MELD utilising total bilirubin, INR, creatinine • MELD-Na (total bilirubin, INR, creatinine, sodium)

[0442] • Enhanced Liver Fibrosis (ELF) score (HA, PHI NP, TIMP 1)

[0443] Pathological changes in liver fibrosis have been reported to be reflected in an altered micro RNA (miR) profile in the circulation. miRNA profiling will be conducted to characterise disease activity and response to treatment.

[0444] Alterations in faecal and circulating bile acid levels have been reported in trial participants suffering from liver cirrhosis. An increase in taurine- and glycine-conjugated bile acids as well as an increased amount of secondary bile acids have been described. Investigating a panel of plasma bile acids (e.g. by utilising the AbsolutelDQ® Bile Acids kit from Biocrates) should aid in characterising the effects of Compound 114 on bile acid homeostasis.

[0445] The biomarkers will be evaluated for monitoring of treatment (i.e. change from baseline assessment) but also for their potential to predict treatment response I non-response (i.e. correlation of baseline data with treatment outcome for relevant endpoints). Selected evaluations may be conducted in serial order (selected time points, conditional) or not conducted at all, depending on clinical trial outcome.

[0446] 4.5 BIOBANKING

[0447] Participation in biobanking is voluntary and not a prerequisite for participation in the trial. Biobanking will only occur after a separate biobanking informed consent has been given in accordance with local ethical and regulatory requirements. For China, samples for biobanking will not be collected, due to regulatory restrictions.

[0448] 4.5.1 Methods and timing of sample collection

[0449] For all biospecimens collected, detailed instructions on sampling, preparation, processing, shipment and storage will be provided in the central laboratory manual in the ISF. Plasma and serum for biobanking will be collected at the timepoints specified in the Flow Chart (Figures 2A- 2D). Biobanking sampling requires a consistent status from one sample to another in terms of the fasting vs non-fasting; a fasting status has been chosen for this trial. 4.6 OTHER ASSESSMENTS

[0450] 4.6.1 Trial participant reminder cardAt Visit 2, trial participants will be provided with a paper reminder card to record the time of dosing with trial medication on the three days that precede each visit where PK samples are taken (refer to the Flow Chart shown in Figures 2A-2D). Following initial training of the trial participant at Visit 2 with respect to completion of the reminder card, subsequent refresher training should be provided if required. The trial participant should be asked to bring the reminder card to the relevant trial visits for site staff to review and check for compliance with the above-mentioned instructions.

[0451] 4.7 APPROPRIATENESS OF MEASUREMENTS

[0452] This trial includes standard efficacy and safety measurements routinely performed in clinical practice in the chosen trial populations, as well as non-standard measurements.

[0453] 5. INVESTIGATIONAL PLAN

[0454] In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the execution of the investigational plan as per this clinical trial protocol may not be feasible. With the consent of the participant, the sponsor and investigator may agree on alternative, back-up or rescue methodology which may include but will not be limited to virtual trial participant visits and assessments, home healthcare nurse visits, direct-to-participant / direct-from-participant shipments of trial treatment or bio-sample pick up from the participant’s home. The implementation of these measures will depend on participant’s consent, operational feasibility, local law and regulations. If alternative methodology is implemented, the deviations from the original plan will be precisely documented.

[0455] 5.1 VISIT SCHEDULE

[0456] All visits should be scheduled according to the Flow Chart (Figures 2A-2D). Each visit date (with its permitted time window) should be calculated in relation to the day of randomization (i.e. Day 1). During the dose titration period of the trial (i.e. from Visit 2 to Visit 4), scheduled trial visits must be at least 7 days apart, since a trial participant must have taken the preceding dose of Compound 114 for at least 7 consecutive days before up-titration occurs. For this reason, if the permitted time window (+2 days) is applied to Visit 3, the permitted time window must also be applied to Visit 4 (+2 days). Missed visits should be re-scheduled as soon as possible ideally within the permitted time window for that visit. If any visit has to be rescheduled, subsequent visits should follow the original visit schedule. Unscheduled visits can be performed at the discretion of the Investigator at any time for safety reasons or, for instance, to provide trial medication (e.g. a re-start of Compound 114 following treatment interruption).

[0457] All visits will take place at the investigational site, and ideally they should be performed in the morning. In the randomised treatment period, on the morning of a visit, the trial medication will be administered as part of the visit. Therefore, on these days, trial participants should be instructed not to take their morning dose in advance of their clinic visit. This is of particular importance for visits when PK I biomarker I PG sampling is required; as far as possible, PK samples should also be drawn at approximately the same time of day from one PK visit to the next (refer to the Flow Chart shown in Figures 2A-2D). The fasting status of a trial participant should be in accordance with the Flow Chart (Figures 2A-2D) and will be recorded in the eCRF. Trial participants who fail to follow the afore-mentioned instructions should have the visit rescheduled as soon as possible, ideally on the following day.

[0458] In the event of force majeure or other disrupting circumstances, physical trial participant visits to the sites may not be feasible or may need to be restricted to ensure trial participant safety. Based on a thorough assessment of the benefits and risks, the following visit may be performed at the trial participant’s home, remotely (by phone) or as a combination of home and remote visit:

[0459] • Visit 6

[0460] When scheduling such visit every effort should be made to ensure a continuous supply of trial medication for the trial participant, whilst also taking into account that the next kit(s) of trial medication may need to be shipped from the site to the trial participant’s home and, that medical pre-requisites should be performed and confirmed prior to shipment of new supplies.

[0461] All deviations from the original schedule of visits will be documented and the implications considered for the analysis of the trial data.

[0462] 5.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS

[0463] At each visit, assessments should be performed as indicated in the Flow Chart (Figures 2A-2D).

[0464] In the treatment period, all assessments should be performed before the trial medication is taken. Exceptions to this are post-dose vital signs and ECGs and post-dose PK samples (see below). Once the trial medication is administered / once all visit assessments are complete that require a fasting status, trial participants may eat as normal (hence, post-dose PK samples do not require a fasting status).

[0465] Vital signs measurements should always precede the ECG, and the ECG should always be measured before any blood samples are taken (refer to the Flow Chart shown in Figures 2A- 2D).

[0466] In the event of force majeure or other disrupting circumstances the visit may have to be performed at the trial participant’s home, remotely (by phone) or as a combination of home and remote visit. At this visit, the following assessments can be performed at the trial participant’s home or remotely:

[0467] • concomitant therapy

[0468] • IRT call

[0469] • dispense trial medication

[0470] • train trial participant I provide refresher training I dispense I review results (home BP and HR monitoring; trial participant reminder card)

[0471] • all AEs / SAEs / AESIs

[0472] • compliance check

[0473] Trial medication will not be collected at the visit performed remotely. Instead, the medication should be collected when the trial participant next visits the site, or when a visit is performed at the trial participant’s home (see below).

[0474] The following assessments can be performed at the trial participant’s home:

[0475] • anthropometric measures

[0476] • vital signs

[0477] • physical examination

[0478] • resting 12-lead ECG (using a portable ECG machine)

[0479] • collect trial medication

[0480] If safety laboratory sampling via the central laboratory is not possible from the investigational site in the event of force majeure or other disrupting circumstances (and is instead performed at the trial participant’s home), analyses can be performed at a local laboratory. The results of the safety laboratory tests must be transferred to the Investigator who must ensure a medical review and document any clinically relevant safety issues as AEs. For a list of “minimum required safety laboratory parameters” refer to Table 5. All deviations from the original schedule of assessments as defined in the Flow Chart (Figures 2A-2D) will be documented and the implications considered for the analysis of the trial data.

[0481] 5.2.1 Screening period (Visit 1a and 1b)

[0482] No trial procedures should be performed unless the trial participant has consented to take part in the trial. Once a trial participant has consented, he I she is considered to be enrolled in the trial and to have started screening. The trial participant should be recorded on the enrolment log and be registered in the IRT system as a screened trial participant. Trial participants who are not eligible to proceed to Visit 2 (i.e. they fail screening at either Visit 1a or 1 b) should be registered as a screen failure in the IRT system and the eCRF and no further follow-up is required.

[0483] The screening period is defined as the period prior to randomisation and the first administration of trial medication. It consists of 2 visits (refer to Flow Chart shown in Figures 2A-2D), namely Visit 1a and Visit 1 b; these visits should ideally be completed within a period of 4 weeks, (i.e. Day 1 , Visit 2). There is no minimum duration for the screening period. A trial participant can proceed from one visit to the next within the screening period as soon as all results from the previous visit are available and if he I she remains eligible for the trial.

[0484] At Visit 1a demographic information will be collected. This includes the following:

[0485] • age on the day of informed consent (in years)

[0486] • sex (male I female in order to describe the trial participant's sex at birth)

[0487] • for female trial participants: of childbearing potential yes I no in order to characterise the trial participant population and as a basis for contraception requirements

[0488] • ethnicity and race in order to sufficiently characterise the trial participant population, to support possible subgroup analyses if needed, and to support the calculation of the kidney function via the CKD EPI formula which requires a trial participant to be classified as black or non-black (unless not acceptable according to local regulations)

[0489] Baseline Conditions and Medical History

[0490] Information with respect to medical history I baseline conditions will also be collected at Visit 1a (e.g. relevant chronic diseases, current observable conditions and other relevant conditions, based on Investigator judgement, which may not be observable on the day of the examination [e.g. because the trial participant is receiving concomitant therapy to treat the condition]). This includes any new clinically relevant findings identified during the screening period. 5.2.2 Treatment period(s)

[0491] If a trial participant is deemed eligible for the trial following Visits 1a and 1 b, the trial participant will be randomised at Visit 2 (Day 1) by using the IRT system. All Visit 2 assessments (refer to the Flow chart shown in Figures 2A-2D) should have been completed prior to administration of the first dose of trial medication; exceptions are the post-dose vital signs and ECGs and postdose PK samples. Each trial participant can be randomised only once into the trial. The randomised treatment period starts with Visit 2 and ends when a trial participant reaches the EoT visit (refer to the Flow Chart shown in Figures 2A-2D). The last dose of Compound 114 will be administered in the evening of the day before the EoT visit.

[0492] Trial participants will be assessed regularly at scheduled visits as specified in the Flow Chart (Figures 2A-2D). During the dose titration phase of the treatment period, scheduled visits are more frequent. It is of particular importance that the time window for these visits is adhered to since the trial participant must have taken the preceding dose of Compound 114 for at least seven consecutive days before any up-titration occurs. Unscheduled visits may also be arranged where necessary; assessments completed during an unscheduled visit will depend on the circumstances under which the visit was planned, and should be based on Investigator judgement.

[0493] Blood samples for PK will also be collected at some of the visits within the treatment period (refer to the Flow Chart shown in Figures 2A-2D). On the 3 days that precede each of these visits, the trial participant should record the time of dosing with trial medication in a paper reminder card. The entries will be checked and documented in the eCRF by site staff during the relevant clinic visit. Where possible, the site should remind trial participants (e.g. by telephone) to start completing the paper reminder card on the relevant day. Trial participants should also be reminded to bring the reminder card and the electronic BP and HR monitoring device with them to each trial visit. Refresher training should be provided as required.

[0494] At every dispensing visit in the trial (refer to Flow Chart shown in Figures 2A-2D), an IRT call should be made.

[0495] 5.2.2.1 End of treatment I Early discontinuation visit

[0496] Patients who successfully complete the entire 8 week treatment period should have the assessments for the EoT visit performed as indicated in the Flow Chart (Figures 2A-2D). Such patients should be registered as completed in the IRT system. End of trial medication must also be recorded on the corresponding eCRF. For patients who discontinue trial medication prematurely (for whatever reason), an ED visit (refer to the Flow Chart shown in Figures 2A-2D) should be completed instead of the planned treatment period visit. Ideally the ED visit should be performed within seven days of discontinuing the trial medication. The assessments performed at the ED visit should be in accordance with the Flow Chart (Figures 2A-2D), with the following exceptions:

[0497] HVPG: not required biomarkers not required

[0498] PK sampling: not required biobanking sampling: not required

[0499] Patients who discontinue treatment early should be registered as discontinued in the IRT system. End of trial medication must also be recorded on the corresponding eCRF.

[0500] At the EoT and I or ED visit, patients should be reminded about restrictions that still need to be observed up until the EoS visit. Home BP and HR monitoring should continue between the EoT

[0501] I ED visit and the EoS visit.

[0502] 5.2.3 Follow-up period and trial completion

[0503] An EoS visit should be scheduled 2 weeks after an EoT and I or ED visit (refer to the Flow Chart shown in Figures 2A-2D); participation in the trial is over once this visit has been completed; completion must be recorded on the corresponding eCRF.

[0504] When an EoS visit is performed after an ED visit, the assessments performed at the EoS visit should be in accordance with the Flow Chart (Figures 2A-2D), with the following exceptions:

[0505] For an individual patient, trial completion is defined as completion of the EoS visit within the specified time window and who has not discontinued trial medication prematurely. Following an EoS visit, the patient will return to standard medical care.

[0506] 6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE

[0507] In this trial, the primary endpoint is the percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of treatment. The purpose of this trial is to demonstrate the short-time clinical activity of Compound 114 on trial participants with CSPH in decompensated cirrhosis after the first decompensation event.

[0508] 6.1 NULL AND ALTERNATIVE HYPOTHESES

[0509] Statistical testing is not planned for this trial. All analyses will be descriptive in nature. The endpoints will be investigated. However, it is not planned to test a statistical hypothesis with regards to these variables in a confirmatory matter. Instead, they will be described and evaluated by descriptive statistical methods.

[0510] 6.2 PLANNED ANALYSES

[0511] 6.2.1 General considerations

[0512] The analyses will be performed based on the following analysis sets:

[0513] • Enrolled set (ES) - this analysis set includes all trial participants having signed informed consent and who were eligible for inclusion into the trial. The ES will be used for analyses of trial participant disposition

[0514] • Randomised set (RS) - this analysis set includes all enrolled trial participants that were entered or randomised to the trial medication. The RS will be used for demographic and baseline disease characteristics presentation

[0515] • Treated set (TS) - the treated set includes all trial participants who were enrolled or randomised to the trial medication and were treated with at least one dose. The TS will be used for all safety analyses

[0516] • Full analysis set (FAS) - this analysis set includes all enrolled or randomised trial participants who received at least one dose of trial medication and have a baseline measurement for the primary endpoint recorded. The FAS will be used for the efficacy analyses

[0517] Further analysis sets will be defined in the TSAP, if needed.

[0518] Efficacy analyses will be performed based on the planned treatment (i.e. the treatment assignment at randomisation). Safety analyses will be based on the actual treatment received at the enrolment / randomisation visit.

[0519] Unless otherwise stated, baseline is defined as the latest measurement before the first trial medication intake.

[0520] Pharmacokinetics

[0521] The PK parameters for Compound 114 will be calculated according to the relevant Standard Operating Procedure (SOP) of the Sponsor. The non-compartmental analysis will be performed using a validated software program such as Phoenix WinNonlin™ software (version 8.1 or higher, Certara USA Inc., Princeton, NJ, USA) or SAS® Version 9.4 (or later version). Plasma concentration data and parameters of a trial participant will be included in descriptive statistics if they are not flagged for exclusion due to a protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning Meeting [RPM]) or due to PK non-evaluability (as revealed during data analysis).

[0522] Biomarkers

[0523] Statistical biomarker analyses will include exploratory biomarker endpoints. These endpoints will be included in the analysis if not flagged for exclusion due to a protocol deviation relevant to the evaluation of biomarkers (to be decided no later than in the RPM). Exclusion of trial participant’s data will be documented in the CTR.

[0524] Relevant protocol deviations affecting biomarker analyses may be, for example:

[0525] • incorrect trial medication taken, i.e. trial participant received at least one dose of the trial medication the trial participant was not assigned to

[0526] • actual trial medication taken considerably deviated from the planned up-titration of Compound 114

[0527] • use of restricted concomitant therapy

[0528] • treatment compliance differs considerably from 100%

[0529] • biomarker assessment was not performed in fasting status as appropriate for the respective assessment

[0530] 6.2.2 Handling of Intercurrent Events

[0531] The expected intercurrent events of interest in this trial are:

[0532] • use of the following restricted concomitant therapy: o NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl trinitrate, isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g. sildenafil, tadalafil, and vardenafil), non-specific PDE inhibitors such as dipyridamole and theophylline, or sGC-stimulators (e.g. riociguat)

[0533] • new onset of / dose change in existing NSBB I carvedilolconcomitant therapy

[0534] • occurrence of a decompensation event

[0535] • Premature discontinuation of assigned trial medication

[0536] The strategies for handling intercurrent events in this trial are as follows:

[0537] Treatment Policy: This is the effect of randomizing trial participants to a treatment arm regardless of treatment actually being taken. All intercurrent events will be handled according to the treatment policy approach as defined in ICH E9(R1). Each analysis will reference the strategy for handling intercurrent events that it will be estimating. The estimand for each main analysis in this protocol is the combination of the relevant detailed clinical objective described herein and this strategy.

[0538] Handling of the intercurrent events that are not listed above will be decided by the review and will be documented in the TSAP.

[0539] 6.2.3 Primary objective analyses

[0540] The primary endpoint will be analyzed using an ANCOVA model in the FAS without imputing the missing data.

[0541] The model is as follows:

[0542] Percentage change of HVPG from baseline at Week 8 = overall mean

[0543] + HVPG baseline

[0544] + treatment + use of NSBBs or carvedilol

[0545] + type of first decompensation event

[0546] + random error

[0547] This model includes effects accounting for the following sources of variation: ‘treatment’, ‘use of NSBBs or carvedilol’ and ‘type of first decompensation event’ are a fixed classification effects, and ‘HVPG at baseline’ is a linear covariate. The random error is assumed to be normally distributed with mean 0 and unknown variance a2.

[0548] The analysis will only be used for estimation of treatment effects without hypothesis testing. Trial participants will be analysed according to the stratum to which they belong (regardless of any mis-assignment to treatment based on identification of the wrong stratum), as such an error occurs before randomisation and is therefore consistent with regulatory guidance. Procedures to follow if the analysis fails to converge will be described in the TSAP.

[0549] 6.2.3.1 Sensitivity Analyses

[0550] Sensitivity analyses may be performed and will be described in more detail in the TSAP, if applicable.

[0551] 6.2.3.2 Subgroup Analyses

[0552] Any subgroup analyses planned for this trial will be described in the TSAP, if applicable. 6.2.4 Secondary objective analyses

[0553] Unless otherwise stated, only descriptive statistics will be presented for the secondary endpoints defined herein. The percentage of trial participants who have experienced the events of interest for secondary endpoints will be presented.

[0554] 6.2.5 Further objective analyses

[0555] Only descriptive statistics will be presented for further endpoints. The analyses of PK and biomarker parameters are described herein.

[0556] 6.2.6 Safety analyses

[0557] Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). Standard Bl summary tables and listings will be produced. All adverse events with an onset between start of treatment and end of the REP, a period of 7 days after the last dose of trial medication, will be assigned to the on-treatment period for evaluation.

[0558] Safety analyses will be done by “treatment at onset” principle. All treated trial participants will be included in the safety analysis. In general, safety analyses will be descriptive in nature and will be based on Bl standards. No hypothesis testing is planned.

[0559] Statistical analysis and reporting of adverse events will concentrate on treatment-emergent adverse events, i.e. all adverse events occurring between start of treatment and end of the REP. Adverse events that start before first drug intake and deteriorate under treatment will also be considered as ‘treatment-emergent’.

[0560] Frequency, severity, and causal relationship of adverse events will be tabulated by system organ class and preferred term after coding according to the current version of the Medical Dictionary for Drug Regulatory Activities (MedDRA) at database lock.

[0561] Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be done via comparison of laboratory data to their reference ranges. Values outside the reference range as well as values defined as clinically relevant will be summarised. Treatment groups will be compared descriptively with regard to distribution parameters as well as with regard to frequency and percentage of trial participants with abnormal values or clinically relevant abnormal values.

[0562] Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with regard to possible changes compared to findings before start of treatment. 6.2.7 Other Analyses

[0563] PK and biomarker parameters will be analysed descriptively. Correlation analyses of exploratory biomarkers at baseline and response to treatment with key endpoints will be performed.

[0564] 6.2.8 Interim Analyses

[0565] No interim analysis is planned but a Data Monitoring Committee (DMC) will be in place with tasks as described herein. Full details will be specified in the DMC charter. The primary role of the DMC is the ongoing evaluation of safety.

[0566] 6.3 HANDLING OF MISSING DATA

[0567] Handling of missing PK data will be performed according to the relevant Bl internal procedures.

[0568] No imputation of missing data is planned for the remaining endpoints. If a trial participant misses a visit, the missing data will not be imputed.

[0569] 6.4 RANDOMISATION

[0570] Bl will arrange for the randomisation and the packaging and labelling of trial medication. The trial will be performed as a double-blind design with respect to placebo and active Compound 114. Trial participants will be randomised in blocks to one of the two treatment groups in a 1 :1 ratio. The randomisation will be stratified by use (or not) of NSBBs or carvedilol and type of first decompensation event (ascites or variceal haemorrhage).

[0571] The randomisation list will be generated using a validated system, which involves a pseudorandom number generator so that the assigned treatment will be reproducible but at the same time non-predictable. The block size will be documented in the CTR. Access to the codes will be controlled and documented.

[0572] 6.5 DETERMINATION OF SAMPLE SIZE

[0573] It is planned to enroll 40 trial participants in total in this trial: 20 trial participants per treatment group (active vs. placebo).

[0574] It will be considered as a positive signal if a mean percentage reduction of HVPG from baseline after 8 weeks of treatment of at least 15% is observed, it was assumed that the mean percentage reduction of HVPG from baseline at week 8 would be: 0% and 20% for placebo and Compound 114, respectively(with a standard deviation of 25% in each group) based on previous studies. (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, Shiftman 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 the sample size of 40 (20 trial participants per treatment group), the probability to observe a mean percentage reduction of HVPG> 10% in Compound 114 is 89.3%. This probability would be only 26.5% in case that the mean percentage reduction of HVPG from baseline is 5%. Probabilities of achieving an assumed treatment effect within different scenarios are presented in Table 7.

[0575] Table 7. Scenarios of probabilities of achieving the assumed treatment effect.

[0576] SD = 25%

[0577] N=20 per treatment group.

[0578] 7. INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, PUBLICATION

[0579] POLICY, AND ADMINISTRATIVE STRUCTURE

[0580] The trial will be carried out in compliance with the CTP, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for GCP, relevant Bl SOPs, the EU directive 2001 / 20 / EC, EU regulation 536 / 2014, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations. Investigators and site staff must adhere to these principles. Deviation from the CTP, the principles of ICH-GCP or applicable regulations as will be treated as “protocol deviation”.

[0581] Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the responsibility of the treating physician of the patient. The Investigator will inform the Sponsor or delegate immediately of any urgent safety measures taken to protect the trial patients against any immediate hazard, as well as of any serious breaches of the CTP or of ICH-GCP.

[0582] The Bl transparency and publication policy can be found on the following web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the Sponsor with regard to publication of the results of this trial will be described in the Investigator contract. As a rule, no trial results should be published prior to finalisation of the CTR.

[0583] The certificate of insurance cover will be made available to the Investigator and the patients, and will be stored in the ISF.

[0584] 7.1 TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT

[0585] This trial will be initiated only after all required legal documentation has been reviewed and approved by the respective Institutional Review Board (IRB I Independent Ethics Committee (I EC and competent authority (CA) according to national and international regulations. The same applies for the implementation of changes introduced by amendments.

[0586] Prior to patient participation in the trial, written informed consent must be obtained from each patient (or the patient’s legally accepted representative) according to ICH-GCP and to the regulatory and legal requirements of the participating country. Each signature must be personally dated by each signatory and the informed consent and any additional patientinformation form retained by the investigator as part of the trial records. A signed copy of the informed consent and any additional patient information must be given to each patient or the patient’s legally accepted representative.

[0587] The investigator or delegate must give a full explanation to trial patients based on the patient information form. A language understandable to the patient should be chosen, technical terms and expressions avoided, if possible.

[0588] The patient must be given sufficient time to consider participation in the trial. The investigator or delegate obtains written consent of the patient’s own free will with the informed consent form after confirming that the patient understands the contents. The investigator or his delegate must sign (or place a seal on) and date the informed consent form. If a trial collaborator has given a supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the informed consent.

[0589] Re-consenting may become necessary when new relevant information becomes available and should be conducted according to the sponsor’s instructions.

[0590] The consent and re-consenting process should be properly documented in the source documentation.

[0591] 7.2 DATA QUALITY ASSURANCE

[0592] A risk-based approach is used for trial quality management. It is initiated by the assessment of critical data and processes for trial participant protection and reliability of the results as well as identification and assessment of associated risks. An Integrated Quality and Risk Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and ICH-GCP E6, documents the rationale and strategies for risk management during trial conduct including monitoring approaches, vendor management and other processes focusing on areas of greatest risk.

[0593] Continuous risk review and assessment may lead to adjustments in trial conduct, trial design or monitoring approaches.

[0594] A quality assurance audit / inspection of this trial may be conducted by the sponsor, sponsor’s designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will have access to all medical records, the investigator’s trial-related files and correspondence, and the informed consent documentation of this clinical trial.

[0595] 7.3 RECORDS

[0596] CRFs for individual trial participants will be provided by the sponsor.

[0597] 7.3.1 Source documents

[0598] In accordance with regulatory requirements, the Investigator should prepare and maintain adequate and accurate source documents and trial records that include all observations and other data pertinent to the investigation on each trial patient. Source data, as well as reported data, should follow the “ALCOA principles” and be attributable, legible, contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).

[0599] Data reported on the eCRF must be consistent with the source data or the discrepancies must be explained. The current medical history of the patient may not be sufficient to confirm eligibility for the trial and the Investigator may need to request previous medical histories and evidence of any diagnostic tests. In this case, the Investigator must make at least one documented attempt to retrieve previous medical records. If this fails, a verbal history from the patient, documented in their medical records, would be acceptable. Copies of source documents necessary for e.g. HVPG central evaluation and hepatic injury adjudication will be provided to external Suppliers. Before sending or uploading those copies, the Investigator must ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social security number) have been properly removed or redacted from any copy of the patients’ source documents.

[0600] If the patient is not compliant with the CTP, any corrective action e.g. re-training must be documented in the patient file.

[0601] For the eCRF, data must be derived from source documents, for example:

[0602] • patient identification: sex, year of birth (in accordance with local laws and regulations)

[0603] • patient participation in the trial (substance, trial number, patient number, date patient was informed)

[0604] • dates of patient’s visits, including dispensing of trial medication

[0605] • medical history (including trial indication and concomitant diseases, if applicable)

[0606] • medication history

[0607] • AEs and AESIs (onset date [mandatory], and end date [if available]), including those identified from measurements within the home BP and HR monitoring equipment

[0608] • SAEs (onset date [mandatory], and end date [if available])

[0609] • concomitant therapy (start date [where required], dose I frequency [where required], changes)

[0610] • originals or copies of laboratory results and other imaging or testing results (e.g. HVPG, ultrasound and FibroScan® results), with proper documented medical evaluation (in validated electronic format, if available)

[0611] • ECG results

[0612] • patient reminder card (the paper record is the source document)

[0613] • completion of patient’s participation in the trial (end date; in case of early discontinuation, the reason for it should be documented if available)

[0614] • prior to allocation of a patient to a treatment into 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 records (either medical records, verbal documented feedback of the patient or testing conducted specific for a CTP) to support inclusion I exclusion criteria does not make the patient eligible for the clinical trial 7.3.2 Direct access to source data and documents

[0615] The investigator / institution will allow site trial-related monitoring, audits, IRB / IEC review and regulatory inspections. Direct access must be provided to the CRF and all source documents / data, including progress notes, copies of laboratory and medical test results, which must always be available for review by the CRA, auditor and regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will be verified by direct comparison with the source documents described herein. The sponsor or delegate will also monitor compliance with the protocol and GCP.

[0616] In the event of force majeure or other disrupting circumstances, site access may be restricted, thus limiting the ability to perform standard site monitoring activities on site such as on-site source data review and source data verification. Therefore, some of these activities may be performed remotely or replaced by centralized monitoring to the extent possible, based on a documented risk assessment and in alignment with local regulations.

[0617] 7.3.3 Storage period of records

[0618] Trial sites:

[0619] The trial sites must retain the source and essential documents (including ISF) according to contract or the local requirements valid at the time of the end of the trial (whatever is longer).

[0620] Sponsor:

[0621] The sponsor must retain the essential documents according to the sponsor’s SOPs.

[0622] 7.4 EXPEDITED REPORTING OF ADVERSE EVENTS

[0623] Bl is responsible to fulfil their legal and regulatory reporting obligation in accordance with regulatory requirements.

[0624] 7.5 STATEMENT OF CONFIDENTIALITY AND TRIAL PARTICIPANT PRIVACY

[0625] Data protection and data security measures are implemented for the collection, storage and processing of trial participant data in accordance with the principles 7 and 12 of the WHO GCP handbook.

[0626] To ensure confidentiality of records and personal data, only pseudonymised data will be transferred to the sponsor by using a participant identification number instead of the trial participant’s name. The code is only available at the site and must not be forwarded to the sponsor. In case participant’s records will be forwarded e.g. for SAE processing or adjudication committees, personal data that can identify the trial participant will be redacted by the site prior to forwarding. Access to the participant files and clinical data is strictly limited: personalised treatment data may be given to the trial participant’s personal physician or to other appropriate medical personnel responsible for the trial participant’s welfare. Data generated at the site as a result of the trial need to be available for inspection on request by the participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.

[0627] A potential data security breach will be assessed regarding the implications for rights and privacy of the affected person(s). Immediate actions as well as corrective and preventive actions will be implemented. Respective regulatory authorities, IRBs / IECs and trial participants will be informed as appropriate.

[0628] 7.5.1 Collection, storage and future use of biological samples and corresponding data

[0629] Measures are in place to comply with the applicable rules for the collection, biobanking and future use of biological samples and clinical data, in particular

[0630] • Sample and data usage have to be in accordance with the separate biobanking informed consent

[0631] • The Bl-internal facilities storing biological samples from clinical trial participants as well as the external banking facility are qualified for the storage of biological samples collected in clinical trials

[0632] • An appropriate sample and data management system, incl. audit trail for clinical data and samples to identify and destroy such samples according to IGF is in place

[0633] • A fit for the purpose documentation (biomarker proposal, analysis plan and report) ensures compliant usage

[0634] • A fit for purpose approach will be used for assay / equipment validation depending on the intended use of the biomarker data

[0635] • Samples and / or data may be transferred to third parties and other countries as specified in the biobanking IGF

[0636] 7.6 TRIAL MILESTONES

[0637] The first act of recruitment represents the start of the trial and is defined as the date when the first trial participant in the whole trial signs informed consent.

[0638] The end of the trial is defined as the date of the last visit of the last trial participant in the whole trial (“Last Participant Completed”).

[0639] The “Last Participant Last Treatment” (LPLT) date is defined as the date on which the last trial participant in the whole trial is administered the last dose of trial treatment (as scheduled per protocol or prematurely). Individual investigators will be notified of SUSARs occurring with the trial medication until 30 days after LPLT at their site.

[0640] Early termination of the trial is defined as the premature termination of the trial due to any reason before the end of the trial as specified in this protocol.

[0641] Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor with the intention to resume it.

[0642] Suspension of the trial is defined as an interruption of the trial based on a Health Authority request.

[0643] The lEC / competent authority in each participating EU member state will be notified about the trial milestones according to the respective laws.

[0644] A final report of the clinical trial data will be written only after all trial participants have completed the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.

[0645] The sponsor will submit to the EU database a summary of the final trial results within one year from the end of a clinical trial as a whole, regardless of the country of the last trial participant (EU or non-EU).

[0646] 7.7 ADMINISTRATIVE STRUCTURE OF THE TRIAL

[0647] The trial is sponsored by Boehringer Ingelheim (Bl).

[0648] A Coordinating Investigator is responsible to coordinate investigators at the different sites participating in this trial. Tasks and responsibilities are defined in a contract.

[0649] Data Monitoring Committee:

[0650] A DMC will be established. Members of the DMC will be independent of Bl, and will include physicians experienced in the treatment of the disease under investigation, and a statistician. The DMC will evaluate safety data, and receive efficacy data, significant safety concerns, and decisions from hepatic injury adjudication for evaluation. While DMC members may be unblinded, measures are in place to ensure the blinding for everyone else involved in the trial Regular DMC meetings will be held at specified intervals. The DMC will recommend continuation, modification or termination of the trial as detailed in the DMC charter. DMC recommendations, as well as the final Bl decision, will be reported to the appropriate regulatory authorities I Health Authorities, IRBs I ECs, and to Investigators as requested by local law. The tasks and responsibilities of the DMC will be specified in the charter.

[0651] Hepatic injury Adjudication Committee:

[0652] An independent AC will be used to adjudicate certain hepatic injury events for severity and causal relationship with the trial medication. Events may either be defined by abnormal laboratory values and I or relevant AEs. They will be defined in the hepatic injury AC charter. For qualifying events, relevant source documents generated from any medical evaluations of these events will be requested. Relevant source documents might include laboratory values, histological analysis, reports from ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), hospital discharge letters and medical reports from other physicians.

[0653] Relevant documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF. The Investigators will have access to the Bl web portal Clinergize to access documents provided by the Sponsor.

[0654] Bl has appointed a Clinical Trial Leader responsible for coordinating all required activities, in order to:

[0655] • manage the trial in accordance with applicable regulations and internal SOPs

[0656] • direct the clinical trial team in the preparation, conduct and reporting of the trial

[0657] • ensure appropriate training and information of Clinical Trial Managers, CRAs and Investigators of participating countries

[0658] In the participating countries the trial will be performed by the respective local or regional Bl- organisation (Operating Unit) in accordance with applicable regulations and Bl SOPs, or by a CRO based on a contract. The CRO will perform project management, clinical field monitoring, medical monitoring, and reporting.

[0659] Data Management and statistical evaluation will be done by Bl according to Bl SOPs.

[0660] Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined according to Bl SOPs. A list of responsible persons and relevant local information can be found in the ISF.

[0661] A central laboratory service, a central reading service for HVPG, an IRT supplier and other central services I equipment will be used I provided in this trial. Details will be provided in the respective manuals and will be available in the ISF.

Claims

ClaimsWhat is claimed is:1 . A method for preventing, slowing the progression of, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis due to non-cholestatic liver disease in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a soluble guanylate cyclase (sGC) activator selected from the group consisting of compound number 18, 27, 84, 114, 133, 134, 136, 148, 154, 165, and 167:84, 114,, 165, and167, and the pharmaceutically acceptable salts thereof, wherein(i) the method provides a reduction of hepatic venous pressure gradient (HVPG) from baseline in the patient,(ii) the method provides a reduction in liver stiffness from baseline in the patient, and / or(iii) the method provides a reduction in spleen stiffness from baseline in the patient.

2. A soluble guanylate cyclase (sGC) activator for use in preventing, slowing the progression of, delaying or treating clinically significant portal hypertension (CSPH) and decompensated cirrhosis due to non-cholestatic liver disease in a patient, wherein the sGC activator is selected from the group consisting of compound number 18, 27, 84, 114, 133, 134, 136, 148, 154, 165, and 167:27,18,167, and the pharmaceutically acceptable salts thereof, wherein(i) the use provides a reduction of hepatic venous pressure gradient (HVPG) from baseline in the patient,(ii) the use provides a reduction in liver stiffness from baseline in the patient, and / or(iii) the use provides a reduction in spleen stiffness from baseline in the patient.

3. The method according to claim 1 or 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 the preceding claims, wherein the sGC activator is administered to the patient three times a day (TID).

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

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

7. The method according to claim 1 or use according to claim 2, wherein the treatment comprises an initiation treatment comprising administering the sGC activator in an amount of 1 mg TID for weeks one and two; followed by 2 mg TID for weeks 3 and 4 weeks, followed by 3 mg for week 5 until the end of treatment.

8. The method or use according to any one of the preceding claims, wherein the amount of the sGC activator is decreased if the patient develops symptomatic orthostatic hypotension.

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

12. The method or use according to any one of the preceding claims, wherein the sGC activator is Compound 114.

Images