Non-alcoholic fatty liver disease (NAFLD) MedDRA version: 16.1 Level: PT Classification code 10024670 Term: Liver disorder System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Code: Px-104
Pharmaceutical Form: Capsule
Sponsors
Phenex Pharmaceuticals AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Male or females • Age 18-70 years • Diagnosis of NAFLD as defined as (all of the following 5 points must apply): 1. NAFLD on liver biopsy within 2 years prior to study participation OR liver steatosis on any imaging (ultrasound, MRI, CT) 2. Disturbed metabolic homeostasis based on impaired HOMA-IR > 1 3. ALT within or above the upper tertial of the ULN (ALT 15% at CAP Fibroscan at screening 5. Steatosis > 10% equivalent to histology at 1H-MRS at baseline • Weight > 65 kg • BMI > 25 and =65 years) no F.1.3.1 Number of subjects for this age range 2
Exclusion criteria
Exclusion criteria: • Evidence of excessive alcohol, drug or substance abuse • History or other evidence of a medical condition associated with chronic liver disease other than NAFLD • History or other evidence of decompensated liver disease (Child-Pugh Grade B or higher), coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites, hepatic encephalopathy, and bleeding from esophageal varices are conditions consistent with decompensated liver disease. • Concomitant intake of fibrates or statins I. History of any structural cardiac disease requiring treatment: • Any signs or symptoms of heart failure (NYHA II-IV) • History of ventricular tachyarrhythmia requiring ongoing treatment • History of bradyarrhythmia requiring Pacemaker treatment • Relevant coronary artery disease o History of myocardial infarction o stable or unstable angina II. Any clinically relevant findings in ECG at screening: • Conduction abnormalities o AV-Block 2nd (Type II) or 3rd degree o Pauses > 3seconds • Ventricular arrhythmia o Monomorphic or polymorphic ventricular ectopic beats = 30 beats/ hours calculated as mean over the continuous ECG recording period. o Non-sustained ventricular tachycardia (three or more consecutive ventricular beats at a rate of greater than 100 beats/min) • Atrial arrhythmia o Atrial ectopic beats = 30 beats/ hours calculated as mean over the continuous ECG recording period. o Re-entrant supraventricular tachycardia • Any type of tachycardia at rest (frequency >120/min at rest) in 12-lead ECG • Sinus bradycardia 440 ms for male subjects or > 480 ms for female subjects) of >10% over 24 hours using the Fridericia method for QTc analysis. IIII. Poorly controlled hypertension, OR (2) screening or baseline blood pressure = 160 mmHg for systolic OR (3) screening or baseline blood pressure = 100 mmHg for diastolic blood pressure. IV. History of cerebrovascular disease: • History of any stroke or transient ischemic attack • Type I or II diabetes with HbA1C > 6.5% at screening and/or fasting plasma glucose > 7mmol/L (> 126 mg/dl). • History or other evidence of a clinically relevant ophthalmologic disorder due to diabetes mellitus or hypertension or history or other evidence of severe retinopathy • Known sensibility to any ingredients contained in the IMP • All conditions that do not allow MR assessments • History of having received any investigational drug = 3 months and/or 6 x half-life prior to the first dose of study drug or the expectation that such drugs will be used during the study. Patients enrolled in this study cannot be enrolled in another study for either research, diagnostic or treatment purposes. • Woman with childbearing potential unless using adequate contraception; females who are pregnant or breast feeding. • History of severe allergic or immunologically mediated disease [(e.g., vasculitis, cryoglobulinemia, inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis (defined as affecting > 10% of the body, where the palm of one hand equals 1%, or if the hands and feet are affected), rheumatoid arthritis requiring more than intermittent nonsteroidal anti-inflammatory medications for management, etc.] • Evidence of an active or suspected cancer, or a history of malignancy within the last 2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Safety and tolerability assessment will be made by monitoring the subjects for adverse events and by interpreting the results of the ECGs, various laboratory tests (changes in ALT/AST) and the subjects’ diaries.;Secondary Objective: • Measurements of the hepatocellular lipid content (HCL)/composition and phosphorus metabolites by 3.0 and 7.0 Tesla Magnetic Resonance Spectroscopy (MRS) at 1H-MRS and 31P-MRS to investigate a lowering effect on HCL and possible changes in the liver cell metabolism. Comparison day 28 to baseline. • Changes in oral glucose tolerance test (oGTT) using levels of glucose, insulin and c-peptide, FGF-19, GLP-1, DPP-4 as well as different measures of whole body insulin resistance (e.g. CLIX: serum creatinine, Gluc, C-Peptide) will be investigated prior and after administration of the study drug. • Decrease of transaminases and parameters of cholestasis (ALT, AST, GGT, AP, Bilirubin) • Potentially lowering of free serum cholesterol and triglycerols • Reduction of body weight, BMI, waist-to-hip-ratio (WHR), ABSI (A body shape index) • Plasma cholesterol lowering; • FGF-19, Total bile acids reduction, ;Primary end point(s): Safety Endpoints: • Number of AEs, SAEs, TEAE • Changes in vital signs from baseline • ECG-related safety endpoints: o Occurrence of VES (determined by Holter-ECG) o Change of QTc (derived from 12-lead ECG) from baseline • Hepatological safety endpoints: o Change of ALT, AST from baseline o Change of Bilirubin from baseline • Changes in other laboratory values (e.g. serum creatinine) from baseline • Changes in concomitant medication ;Timepoint(s) of evaluation of this end point: 28 days post-baseline | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Change in of hepatocellular lipid content (HCL; derived using MRS) from baseline to Day 28. • Changes in glucose, insulin and C-peptid concentrations (derived using oral glucose tolerance test (oGTT)) from baseline to Day 28. • Change in levels of transaminases and parameters of cholestasis (ALT, AST, GGT, AP, Bilirubin) from baseline • Lowering of free serum cholesterol and triglycerides from baseline • Changes in bile acid composition and lowering of total plasma bile acid pool from baseline • Reduction of body weight, BMI, waist-to-hip-ratio (WHR), ABSI (A body shape index) baseline • Changes in phagocytic function of Kupffer cells (KCs) and possible microcirculatory changes in the liver from baseline. Changes in other serum or plasma markers of liver inflammation and fibrotisation (CK-18, sCD163, Procollagen III peptide, Hyaluronic Acid, TIMP-1, alpha2-macroglobulin, haptoglobin, HRG-1 and others) from baseline • Changes in bacterial translocation as evidenced by SLM-S test from baseline ;Timepoint(s) of evaluation of this end point: 28 days post-baseline | — |
Countries
Austria
Contacts
Public ContactCRO
Koordinationszentrum für Klinische Studien
Outcome results
None listed