Impact of Silymarin Dosages to Decrease Drug-induced Elevated Liver Enzymes Compared to Placebo

Phase 2

• Conditions: Drug-induced Liver Injury
• Interventions: Drug: Placebo; Drug: 2x 140 mg per day; Drug: 3x 280 mg per day; Drug: 1x 1120 mg

• Registration Number: NCT05144217
• Lead Sponsor: Dr. Frank Behrens

Brief Summary

In this clinical study silymarin will be administered in different dosages and compared to placebo in order to address if the liver protecting features of silymarin, measured by changes of liver enzyme concentration, can be improved in patients with drug-induced elevated liver enzymes or drug-induced hepatocellular liver injury with higher systemic bioavailabilities due to administration of higher oral dosages or administration of higher administration frequency over a 35-day treatment period.

Detailed Description

In clinical routine care, drug-induced elevation of liver enzymes occurs often in parallel to new treatment initiation, possibly leading to interruption of treatment strategies if liver enzyme elevation does not normalize within 2 to 4 weeks.

Liver injury from medications usually occurs within 6 months of drug initiation and typically within the first 1-4 weeks1. In general, drug-induced liver injury (DILI) is related to the class of drug, the quantity of drug consumed, the patient's age and sex, and such concurrent factors as diabetes mellitus, excessive alcohol intake, e.g. high caloric diet, which can lead to NAFLD/steatosis, or the use of other medications. Drugs administered in higher doses are more likely to cause liver injury, especially drugs that require extensive hepatic metabolism1. Different forms of drug-induced elevation of liver enzymes can be differentiated according to localisation of the injury: hepatocellular or cholestatic liver injury or a mixture of both.Besides methotrexate and isozid, other medications have been reported to induce hepatocellular liver injury: acarbose, allopurinol, amiodarone, baclofen, bupropion, fluoxetine, ketoconazole, lisinopril, losartan, non-steroidal anti-inflammatory drugs (NSAIDs), omeprazole, paracetamol, paroxetine, pyrazinamide, rifampicin, risperidone, sertraline, statins, tetracyclines, trazodone, and valproic acid. Silymarin containing oral preparations are widely used for their liver protecting characteristics. The milk thistle ingredient silibinin is registered for continuous intravenous administration in the case of acute liver intoxications such as consumption of amanita mushrooms. Although its mode of action is still not clear, the clinical therapeutic benefits in patients with liver diseases are documented.

Pharmacokinetics of silymarin after oral administration are well understood. Due to its poor solubility in aqueous media, absorption from the intestinal tract is generally limited. Silymarin's systemic bioavailability of marketed products is therefore rather low, also because of predominant first pass biliary elimination. Exact PK/PD relations of the compound have not been assessed so far.

Hence, in this clinical study silymarin will be administered in different dosages and compared to placebo in order to address the following question: Can liver protecting features of silymarin, measured by changes of liver enzyme concentration, be improved in patients with drug-induced elevated liver enzymes or drug-induced hepatocellular liver injury with higher systemic bioavailabilities due to administration of higher oral dosages or administration of higher administration frequency over a 35-day treatment period?

Study Timeline

• Study Start: 2021-06-23
• Status Verified: 2021-11
• Study First Submitted: 2021-11-21
• Study First Submitted QC: 2021-11-21
• Last Update Submitted: 2021-11-21
• Study First Posted: 2021-12-03
• Last Update Posted: 2021-12-03
• Primary Completion: 2022-12-31
• Study Completion: 2022-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 156

Inclusion Criteria

Evidence of hepatocellular drug-induced injury due to treatment*

• ALT/AP ratio ≥ 5 ((ALT level/ALT upper limit of normal (ULN))/(AP level/AP ULN)) OR Evidence of drug-induced elevation of liver-enzymes
• ALT > 40 U/L and ≤ 2 x ULN
• ALT (> 40 U/L) ≥ 2 weeks and ≤ 3 months 3. Documentation (within the last 4 weeks before screening) of exclusion of liver tissue damage using either ultrasonography of the liver or Fibroscan with results ≤ 7 kPa (fibrosis score of F0 to F1) 4. BMI ≥ 18 and ≤ 30 5. Liver enzyme elevation inducing medication stable for ≥ 8 weeks before screening in the discretion of 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

Exclusion Criteria

1. Use of silymarin within the last 6 months
2. Current intake and intake within the last 4 weeks of drugs that have been shown to induce cholestatic or mixed hepatocellular/cholestatic liver injury (inducing cholestatic liver injury: amoxicilline and clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, erythromycin, irbesartan, mirtazapine, estrogen, terbinafine; inducing mixed liver injury: amitriptyline, azathioprine, captopril, carbamazepine, clindamycin, co-trimoxazole, cyproheptadine, enalapril, flutamide, nitrofurantoin, phenobarbital, phenytoin, sulphonamide, trazodone, verapamil)
3. Patients with chronic liver disease, existing fibrosis or cirrhosis
4. Patients with acute viral hepatitis, 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 diabetes types 1 or 2
7. Any malignancy within the past 5 years
8. 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)
9. 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
10. History of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders
11. Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations, e.g. milk thistle, soy oil, peanut (according to Summary of Product Characteristics (SmPc))
12. Contraindications to use the investigational medicinal product (IMP), e.g. hereditary galactose intolerance, genetic lactase deficiency or glucose-galactose malabsorption (according to SmPC)
13. Subjects with severe or moderate allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
14. 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
15. Positive anti-HIV-test, antiHBs- or anti-HCV-test at Screening
16. History of or current drug or alcohol dependence
17. Subjects with a positive drug test at screening (incl. alcohol)
18. Regular intake of alcoholic food or beverages of ≥ 40 g pure ethanol for male or ≥ 20 g pure ethanol for female per day
19. Participation in a clinical trial during the last two months prior to individual enrolment of the subject or current participation
20. Use of drugs during the last two weeks prior Baseline that can affect absorption (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists)
21. Subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial
22. Subjects who do not agree to apply adequate contraceptive methods as defined in Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (CPMP/ICH/286/95, modification), November 2000

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	1 capsule twice per day
oral administration of 2x 140 mg per day	2x 140 mg per day	1 capsule twice per day
oral administration of 3x 280 mg per day	3x 280 mg per day	2 capsules three times a day
oral administration of 1x 1120 mg per day	1x 1120 mg	8 capsules once per day

Primary Outcome Measures

Name	Time	Method
Change in blood ALT (Alanine-Aminotransferase) in IU/L	at day 35	Change in blood ALT in IU/Lin all treatment groups

Secondary Outcome Measures

Name	Time	Method
quality of life measurements	Day 35	measured by short form survey (SF36) questionnaire
Body Mass Index (BMI)	baseline	index measured in weight and height
Fibroscan value	day 35	measurement of Fibroscan
Fibrosis score	Day 35	score F0 to F4
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Day 35	Change of Liver enzyme blood parameter INR in all treatment groups
Lipids analysis LDL	Day 35	LDL (Low Density Lipoproteins) in all treatment groups
Lipids analysis VLDL	Day 35	VLDL (very low Density Lipoproteins) in all treatment groups
Lipids analysis triglycerides	Day 35	triglycerides in all treatment groups
Lipids analysis total cholesterol	Day 35	total cholesterol in all treatment groups
bloodparameter assessment	Day 7	fasting glucose value in all treatment groups
blood parameter assessment	Day 35	fasting glucose value in all treatment groups
Proportion of patients with normalization in liver enzyme blood parameters	Day 35	normalisation of liver enzyme blood parameters such as AST (\< 40 IU/L), ALT (\< 40 IU/L), GGT, AP, bilirubin, INR, Quick
Plasma silymarin dose concentration	day 35	concentration of silymarin
CAP score	day 35	score measured in dB/m
Liver enzyme blood parameters: AST	Day 21	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups
Change Liver enzyme blood parameter Quick value	Day 35	Change of Liver enzyme blood parameter Quick value in all treatment groups
Liver enzyme blood parameter AST (Aspartate-Aminotransferase)	Baseline (prior treatment)	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups
Change Liver enzyme blood parameter AST	Day 35	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Day 35	Change of Liver enzyme blood parameter AP in IU/L in all treatment groups
Change Liver enzyme blood parameter bilirubin	Day 35	Change of Liver enzyme blood parameter bilirubin in all treatment groups
Change ALT/AP ratio	Day 35	Change of ALT/AP ratio in all treatment groups
Lipids analysis	Day baseline	VLDL (very low Density Lipoproteins) in all treatment groups
Liver enzyme blood parameter AST	Day 28	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups
Change Liver enzyme blood parameter ALT	Day 35	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Day 35	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups
Silymarin concentration in blood plasma in pharmakokinetic substudy - AUC	baseline	assessement of area under the curve (AUC),
Silymarin concentration in blood plasma in pharmakokinetic substudy - tmax	baseline	assessement of time to maximal concentration (tmax)
Silymarin concentration in blood plasma in pharmakokinetic substudy - Cmax	baseline	assessement of maximal concentration (Cmax)
Treatment adherence	Day 35	measured by patient diary

Trial Locations

Locations (2)

Universtity Hospital - clinic for dermatology, venerology and allergology; 🇩🇪 Frankfurt, Hessia, Germany

CIRI; 🇩🇪 Frankfurt, Hessia, Germany