Drug-induced elevated liver enzymes MedDRA version: 20.0 Level: LLT Classification code 10024668 Term: Liver damage System Organ Class: 100000004871
Conditions
Interventions
Trade Name: Silimarit
Pharmaceutical Form: Capsule, soft
CAS Number: 65666-07-1
Other descriptive name: SILYMARIN
Concentration unit: mg milligram(s)
Concentration number: 140-
Pharmaceutical form of
Sponsors
Fraunhofer Gesellschaft for its Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients = 18 years 2. Evidence of hepatocellular drug-induced injury due to treatment*1 as judged by the treating physician • ALT/AP ratio = 5 ((ALT level/ALT ULN)/(AP level/AP ULN)) OR Evidence of drug-induced elevation of liver-enzymes • ALT > 40 U/L or ULN = 4ULN*2 *2 acknowledgement of the gastroenterologist that there is no safety risk for the patient and that on base of the analysis of the collected data there is no evidence of a liver function disorder will be needed for inclusion of the patient 3. Exclusion of severe liver tissue damage and hepatic steatosis grade 3 using either ultrasonography of the liver and/or Fibroscan with results = 7 kPa (fibrosis score of F0 to F1) 4. BMI = 18 and = 35 5. Liver enzyme elevation inducing medication ongoing for at least 6 weeks before SCR. If it has not been administered with a stable dose, the liver enzyme elevation should have been stable within the last 2 weeks before SCR (as judged by the treating physician). 6. Written informed consent, after having been informed about potential benefit and potential risks of the clinical trial 7. Willing and capable to understand informed consent and follow the protocol *1drugs defined to cause hepatocellular injury for inclusion in this study: anti-TNF agents, lamotrigine, proton pump inhibitors (e.g., omeprazole), allopurinol, inhaled anesthetics, minocycline, mirtazapine, valproate/valproate acid, amiodarone, INFa, IFNß, nitrofurantoine, linoleic acid, bupropion, isoniazid, NSAIDs (e.g., aspirin, diclofenac), ciprofloxacine, ketoconazole, methotrexate, paracetamol, pyrazinamide, paroxetine, losartan, nevirapine, protease inhibitors, rifampicin, risperidone, statins, trazodone, venlafaxine, sertraline, macrolides, acarbose, tetracyclines, baclofen, fluoxetine, paroxetine, lisinopril, leflunomide, sulfasalazine, mycophenolate mofetil, fluoroquinolones, flavocoxid, cloxacillin Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 115 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 71
Exclusion criteria
Exclusion criteria: 1. Use of silymarin within the last 6 months 2. Evidence, that the reported liver enzyme elevation is caused by intake, induction or dose modification of a treatment that induces cholestatic or mixed hepatocellular/cholestatic liver injury (e.g. amoxicilline and clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, erythromycin, irbesartan, estrogen, terbinafine; inducing mixed liver injury: amitriptyline, azathioprine, captopril, carbamazepine, clindamycine, co-trimoxazole, cyproheptadine, enalapril, flutamide, nitrofurantoin, phenobarbital, phenytoin, sulphonamide, trazodone, verapamil)2 as juged by the treating physician. Evidence can be assumed if the medication was started or dose was increased within the last three months before enzyme elevation was detected and/or pausing of the drug caused total normalization or by trend. 3. Patients with chronic liver disease, e.g. hepatic steatosis grade 3, existing fibrosis (fibrosis score of =F2) or cirrhosis 4. Patients with acute viral hepatitis, active autoimmune hepatitis or immune-mediated hepatitis (e.g., with immune checkpoint inhibitor treatment), acute Budd-Chiari syndrome, Wilson disease, and ischemic liver injury 5. Cholestatic or mixed hepatocellular/mixed liver injury 6. Patients with any currently treated malignancy or patients with chemotherapy treatment within the past 5 years 7. Patients with chronic intestinal diseases (e.g., ulcerative colitis) and intestinal barrier dysfunction in the discretion of the treating physician (e.g., patient can be included if disease is judged as stable by the treating physician with no likely interference with the study outcomes and the safety of the patient) 8. Evidence of significant uncontrolled concomitant diseases or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient`s safety and of the study outcome 9. Patients who are unable to understand the nature, importance, risks and scopre of the clinical trial, e.g. due to CNS and/or psychiatric disorders 10. Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations, e.g. milk thistle, soy oil, peanut (according to SmPc) 11. Contraindications to use the IMP, e.g. hereditary galactose intolerance, genetic lactase deficiency or glucose-galactose malabsorption (according to SmPC) 12. Subjects with severe or moderate allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator 13. Laboratory values other than target parameters out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator 14. Positive anti-HIV-test, antiHBs- or anti-HCV-test at Screening, except if patients are stable for at least 6 months 15. History of or current drug or alcohol dependence 16. Subjects with a positive drug test at screening (incl. alcohol) 17. Regular intake of alcoholic food or beverages of = 40 g pure ethanol for male or = 20 g pure ethanol for female per day 18. Participation in a clinical trial during the last two months prior to individual enrolment of the subject or current participation 19. For the group who will be part of the PK substudy only: Use of drugs during the last two weeks prior Baseline that can affect absorption (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists) 20. Subjects who are unable to understand the written and verbal instructions, i
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate superiority in change of blood ALT concentration at day 35 compared to BL in patients receiving silymarin 3x280 mg (most effective dose) compared to patients receiving placebo.;Secondary Objective: •Superiority of change of blood ALT concentration at D35 compared to BL in pat. receiving silymarin dosages 1x1120 mg and 2x140mg compared to pat. receiving PL •comparison of treatment effect with regard to change of blood ALT concentration at D35 compared to BL •concentrations of liver enzymes (incl. AST, ALT, GGT, AP, Bilirubin, INR, Quick) and their change (absolute and %) to BL b over time •ALT/AP ratio and its change to BL •concentration of lipids •HbA1c at BL and day 35 •proportion of patients achieving normalized liver enzymes and/or clinically relevant changes over time •changes in liver tissue characteristics using Fibroscan measurement over time •pharmacokinetic characteristics of silymarin considering the different dosage regimens •pharmacodynamic characteristics of silymarin using results from analysis of liver function •Treatment adherence •changes in quality of life (SF36) •Safety ;Primary end point(s): Change of blood ALT concentration at day 35 compared to BL in patients receiving silymarin 3x280 mg (most effective dose) compared to patients receiving placebo;Timepoint(s) of evaluation of this end point: Day 35 compared to baseline | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The following variables will be assessed for all available visits and treatment groups. • Liver enzyme blood parameters: AST, ALT, GGT, AP, Bilirubin, INR, Quick and their changes compared to BL • ALT/AP ratio and change compared to BL • Lipids, such as LDL, HDL, VLDL, triglycerides, total cholesterol, and fasting glucose • Proportion of patients with normalization in liver enzyme blood parameters such as AST (< 40 IU/L), ALT (< 40 IU/L), GGT, AP, bilirubin, INR, Quick • Plasma silymarin dose concentration in each treatment group at all visits • Fibroscan value and its change over time (kPa) • Fibrosis score (F0-F4) • CAP score (dB/m) • BMI • Silymarin concentration in blood plasma in PK substudy for the assessment of pharmacokinetic characteristics (e.g. AUC, Cmax, tmax) of silymarin in the different dosage regimens (in the subgroup analysis) • Dose-response relationship (all listed liver enzyme parameters) for assessment of pharmacodynamic characteristics of silymarin in the different dosage regimens • Treatment adherence to the study drug • Calculation of quality of life measurements (SF36) and changes compared to baseline Safety: Frequency, type, severity and relatedness of adverse events ;Timepoint(s) of evaluation of this end point: At all time Points between Groups, with exception of HbA1c (only at BL and day 35) | — |
Countries
Germany
Contacts
Public ContactTMP Clinical research
Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Outcome results
None listed