A dose-finding clinical study investigating the effects of different doses of silymarin compared to placebo on elevated liver enzymes due to drug-induced liver enzyme elevation.

Phase 1

• Conditions: Drug-induced elevated liver enzymes; MedDRA version: 20.0Level: LLTClassification code 10024668Term: Liver damageSystem Organ Class: 100000004871; Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

• Registration Number: EUCTR2020-004645-36-DE
• Lead Sponsor: Fraunhofer Gesellschaft for its Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-03-10
• Last Update Posted: 30 January 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 156

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.Documentation (within the last 4 weeks before BL) of exclusion of 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 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 56

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.Any malignancy 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, in particular regarding the risks and inconveniences they will be exposed

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified