A study to test the effect of different doses of BI 456906 in people with a liver disease called non-alcoholic steatohepatitis (NASH) and liver fibrosis

Exclusion Criteria33

• Current or history of significant alcohol consumption (defined as intake of greater than 210 g/ week in males and greater than 140 g/ week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on Investigator judgement within the last 5 years.
• Intake of medications historically associated with liver injury, hepatic steatosis or steatohepatitis within 12 weeks prior to screening visit. Intake of restricted medications or any medications considered likely to interfere with the safe conduct of the trial.
• History of other forms of chronic liver disease (e.g. viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson’s disease, hemochromatosis, A1 At deficiency, history of liver transplantation). Hepatitis B and C testing will be done at screening visit.
• Suspicion, diagnosis or history of hepatocellular carcinoma (HCC), or any documented active or suspected malignancy or history of malignancy with in 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.
• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at screening visit.
• History of chronic or acute pancreatitis or elevation of serum lipase/amylase > 2x ULN, or fasting serum triglyceride levels of > 500 mg/dL at screening visit.
• Known history of HIV (Human Immunodeficiency Virus) infection and/or tuberculosis and/or acute SARS-CoV-2 infection at screening visit
• Abnormal laboratory values as listed below:
• a) Estimated Glomerular Filtration Rate (eGFR) < 30 ml/min/1.73 m2 at screening visit (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula);
• b) Platelet count < 150.000/ µL at screening visit;
• c) Bilirubin level > 1.5x ULN at screening visit (except for known Gilbert’s disease with a conjugated bilirubin of < 0.3 mg/dL;
• d) ALT and/or AST > 5x ULN at screening visit;
• e) Glycosylated haemoglobin (HbA1c) greater to or equal than 9.5% at screening visit;
• f) Calcitonin greater to or equal then 20pg/mL at screening visit.
• Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease),
• endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease and other conditions that, in the clinical judgment of the Investigator, are likely to interfere with the analyses of safety and efficacy in this trial. Patients with an expected life expectancy of less than 2 years are also excluded.
• Any suicidal behavior or history of major depressive disorder in the past 2 years before randomization, any suicidal ideation of type 4 or 5 in the C -SSRS in the past 3
• months prior to screening visit.
• Bariatric surgery, prior to or planned during trial conduct; except gastric-band surgery more than 2 years prior to screening (including adjustments) with a stable body
• weight within the last 12 months. Any other major surgery (major according to Investigator’s assessment) performed within 12 weeks prior to randomization or planned during trial conduct.
• Resting heart rate > 100 beats per minute (bpm) and/or blood pressure greater than or equal to 160/ 95 mmHg at screening visit.
• A marked baseline prolongation of QT/ QTc interval (such as QTc intervals greater than 450 ms at screening visit) or any other abnormal clinically significant ECG finding at screening visit (e.g., type 2 second-degree AV block (Type Mobitz II) or third-degree AV block).
• History of ventricular tachycardia, type 2 second-degree AV block (Type Mobitz II) or third-degree AV block.
• Heart rhythm disturbances (e.g., bradycardia with baseline heart rate < 50 bpm, in the absence of heart rate lowering medications), tachycardia or tachyarrhythmia (e.g.,
• atrial fibrillation, atrial flutter or ventricular tachycardia), considered by the Investigator indicative of relevant cardiac disease or with abnormalities that may
• interfere with the interpretation of changes in ECG intervals at screening visit. Family history of long QT syndrome, use of prescription or over-the-counter medications
• known to significantly prolong the QT/ QTc interval at screening visit.
• Any of the following conditions or procedures within the last six months prior to screening visit: myocardial infarction, unstable angina (e.g. Canadian Cardiovascular Society (CCS) grading of Angina pectoris grade III and IV), artery bypass (e.g. coronary artery bypass graft, carotid bypass, peripheral artery bypass), percutaneous coronary intervention (diagnostic angiograms are permitted), transient ischaemic attack, cerebrovascular accident (stroke) or decompensated congestive heart failure.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
• Contraindication to magnetic resonance imaging including, but not limited to: severe claustrophobia, extensive tattoos, inner ear implant, pacemakers or other implanted cardiac rhythm management devices, intracranial aneurism clips incompatible with MRI, any other metallic, non-MR compatible implanted
• devices (e.g. insulin pump, hip joint replacement), a history of intra-orbital metal fragments that have not been removed, and weight or girth that exceeds scanner capabilities.
• Prior participation in an interventional trial during the previous 6 months or 5 times the half-life of the investigational drug, whichever is longer, before screening visit.
• Any other clinical condition that, in the opinion of the Investigator, would jeopardize patient safety while participating in the trial.