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

Impact of Different Silymarin Dosages to Decrease Drug-induced Elevated Liver Enzymes Compared to Placebo in a Prospective Controlled Dose Finding Phase IIb Trial

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Drug-induced Liver Injury
• Intervention / Treatment: Drug: Placebo; Drug: 2x 140 mg per day; Drug: 3x 280 mg per day; Drug: 1x 1120 mg

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 Type: Interventional
• Enrollment (Anticipated): 156
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Hessia
    • Frankfurt, Hessia, Germany, 60590
      • Universtity Hospital - clinic for dermatology, venerology and allergology
    • Frankfurt, Hessia, Germany, 60596
      • CIRI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 1 capsule twice per day	Drug: Placebo; 1 capsule per day of placebo
Active Comparator: oral administration of 2x 140 mg per day; 1 capsule twice per day	Drug: 2x 140 mg per day; 2 capsule per day of silimarit
Active Comparator: oral administration of 3x 280 mg per day; 2 capsules three times a day	Drug: 3x 280 mg per day; 3 capsule per day of silimarit
Active Comparator: oral administration of 1x 1120 mg per day; 8 capsules once per day	Drug: 1x 1120 mg; 8 capsule per day of silimarit

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood ALT (Alanine-Aminotransferase) in IU/L	Change in blood ALT in IU/Lin all treatment groups	at day 35

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver enzyme blood parameter AST (Aspartate-Aminotransferase)	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups	Baseline (prior treatment)
Liver enzyme blood parameter AST	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups	Day 7
Liver enzyme blood parameter AST	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups	Day 14
Liver enzyme blood parameters: AST	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups	Day 21
Liver enzyme blood parameter AST	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups	Day 28
Change Liver enzyme blood parameter AST	Change of Liver enzyme blood parameter AST in IU/Lin all treatment groups	Day 35
Change Liver enzyme blood parameter ALT	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups	Baseline
Change Liver enzyme blood parameter ALT	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups	Day 7
Change Liver enzyme blood parameter ALT	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups	Day 14
Change Liver enzyme blood parameter ALT	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups	Day 21
Change Liver enzyme blood parameter ALT	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups	Day 28
Change Liver enzyme blood parameter ALT	Change of Liver enzyme blood parameter ALT in IU/Lin all treatment groups	Day 35
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups	Baseline
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups	Day 7
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups	Day 14
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups	Day 21
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups	Day 28
Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)	Change of Liver enzyme blood parameter GGT in IU/Lin all treatment groups	Day 35
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Change of Liver enzyme blood parameter AP in IU/Lin all treatment groups	Baseline
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Change of Liver enzyme blood parameter AP in IU/Lin all treatment groups	Day 7
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Change of Liver enzyme blood parameter AP in IU/Lin all treatment groups	Day 14
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Change of Liver enzyme blood parameter AP in IU/Lin all treatment groups	Day 21
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Change of Liver enzyme blood parameter AP in IU/L in all treatment groups	Day 28
Change Liver enzyme blood parameter AP (Alkaline phosphatase )	Change of Liver enzyme blood parameter AP in IU/L in all treatment groups	Day 35
Change Liver enzyme blood parameter bilirubin	Change of Liver enzyme blood parameter bilirubin in all treatment groups	Baseline
Change Liver enzyme blood parameter bilirubin	Change of Liver enzyme blood parameter bilirubin in all treatment groups	Day 7
Change Liver enzyme blood parameter bilirubin	Change of Liver enzyme blood parameter bilirubin in all treatment groups	Day 14
Change Liver enzyme blood parameter bilirubin	Change of Liver enzyme blood parameter bilirubin in all treatment groups	Day 21
Change Liver enzyme blood parameter bilirubin	Change of Liver enzyme blood parameter bilirubin in all treatment groups	Day 28
Change Liver enzyme blood parameter bilirubin	Change of Liver enzyme blood parameter bilirubin in all treatment groups	Day 35
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Change of Liver enzyme blood parameter INR in all treatment groups	baseline
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Change of Liver enzyme blood parameter INR in all treatment groups	Day 7
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Change of Liver enzyme blood parameter INR in all treatment groups	Day 14
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Change of Liver enzyme blood parameter INR in all treatment groups	Day 21
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Change of Liver enzyme blood parameter INR in all treatment groups	Day 28
Change Liver enzyme blood parameter INR (International Normalized Ratio)	Change of Liver enzyme blood parameter INR in all treatment groups	Day 35
Change Liver enzyme blood parameter Quick value	Change of Liver enzyme blood parameter Quick value in all treatment groups	baseline
Change Liver enzyme blood parameter Quick value	Change of Liver enzyme blood parameter Quick value in all treatment groups	Day 7
Change Liver enzyme blood parameter Quick value	Change of Liver enzyme blood parameter Quick value in all treatment groups	Day 14
Change Liver enzyme blood parameter Quick value	Change of Liver enzyme blood parameter Quick value in all treatment groups	Day 21
Change Liver enzyme blood parameter Quick value	Change of Liver enzyme blood parameter Quick value in all treatment groups	Day 28
Change Liver enzyme blood parameter Quick value	Change of Liver enzyme blood parameter Quick value in all treatment groups	Day 35
Change ALT/AP ratio	Change of ALT/AP ratio in all treatment groups	baseline
Change ALT/AP ratio	Change of ALT/AP ratio in all treatment groups	Day 7
Change ALT/AP ratio	Change of ALT/AP ratio in all treatment groups	Day 14
Change ALT/AP ratio	Change of ALT/AP ratio in all treatment groups	Day 21
Change ALT/AP ratio	Change of ALT/AP ratio in all treatment groups	Day 28
Change ALT/AP ratio	Change of ALT/AP ratio in all treatment groups	Day 35
Lipids analysis	LDL (Low Density Lipoproteins) in all treatment groups	Baseline
Lipids analysis LDL	LDL (Low Density Lipoproteins) in all treatment groups	Day 7
Lipids analysis LDL	LDL (Low Density Lipoproteins) in all treatment groups	Day 14
Lipids analysis LDL	LDL (Low Density Lipoproteins) in all treatment groups	Day 21
Lipids analysis LDL	LDL (Low Density Lipoproteins) in all treatment groups	Day 28
Lipids analysis LDL	LDL (Low Density Lipoproteins) in all treatment groups	Day 35
Lipids analysis	HDL (High Density Lipoproteins) in all treatment groups	baseline
Lipids analysis	HDL (High Density Lipoproteins) in all treatment groups	Day 7
Lipids analysis	HDL (High Density Lipoproteins) in all treatment groups	Day 14
Lipids analysis	HDL (High Density Lipoproteins) in all treatment groups	Day 21
Lipids analysis	HDL (High Density Lipoproteins) in all treatment groups	Day 28
Lipids analysis	HDL (High Density Lipoproteins) in all treatment groups	Day 35
Lipids analysis	VLDL (very low Density Lipoproteins) in all treatment groups	Day baseline
Lipids analysis VLDL	VLDL (very low Density Lipoproteins) in all treatment groups	Day 7
Lipids analysis VLDL	VLDL (very low Density Lipoproteins) in all treatment groups	Day 14
Lipids analysis VLDL	VLDL (very low Density Lipoproteins) in all treatment groups	Day 21
Lipids analysis VLDL	VLDL (very low Density Lipoproteins) in all treatment groups	Day 28
Lipids analysis VLDL	VLDL (very low Density Lipoproteins) in all treatment groups	Day 35
Lipids analysis triglycerides	triglycerides in all treatment groups	baseline
Lipids analysis triglycerides	triglycerides in all treatment groups	Day 7
Lipids analysis triglycerides	triglycerides in all treatment groups	Day 14
Lipids analysis triglycerides	triglycerides in all treatment groups	Day 21
Lipids analysis triglycerides	triglycerides in all treatment groups	Day 28
Lipids analysis triglycerides	triglycerides in all treatment groups	Day 35
Lipids analysis total cholesterol	total cholesterol in all treatment groups	baseline
Lipids analysis total cholesterol	total cholesterol in all treatment groups	Day 7
Lipids analysis total cholesterol	total cholesterol in all treatment groups	Day 14
Lipids analysis total cholesterol	total cholesterol in all treatment groups	Day 21
Lipids analysis total cholesterol	total cholesterol in all treatment groups	Day 28
Lipids analysis total cholesterol	total cholesterol in all treatment groups	Day 35
bloodparameter assessment	fasting glucose value in all treatment groups	baseline
bloodparameter assessment	fasting glucose value in all treatment groups	Day 7
blood parameter assessment	fasting glucose value in all treatment groups	Day 14
blood parameter assessment	fasting glucose value in all treatment groups	Day 21
blood parameter assessment	fasting glucose value in all treatment groups	Day 28
blood parameter assessment	fasting glucose value in all treatment groups	Day 35
Proportion of patients with normalization in liver enzyme blood parameters	normalisation of liver enzyme blood parameters such as AST (< 40 IU/L), ALT (< 40 IU/L), GGT, AP, bilirubin, INR, Quick	Day 35
Plasma silymarin dose concentration	concentration of silymarin	Base line
Plasma silymarin dose concentration	concentration of silymarin	day 7
Plasma silymarin dose concentration	concentration of silymarin	day 14
Plasma silymarin dose concentration	concentration of silymarin	day 21
Plasma silymarin dose concentration	concentration of silymarin	day 28
Plasma silymarin dose concentration	concentration of silymarin	day 35
Fibroscan value	measurement of Fibroscan	baseline
Fibroscan value	measurement of Fibroscan	day 14
Fibroscan value	measurement of Fibroscan	day 35
Fibrosis score	score F0 to F4	baseline
Fibrosis score	score F0 to F4	Day 14
Fibrosis score	score F0 to F4	Day 35
CAP score	score measured in dB/m	baseline
CAP score	score measured in dB/m	day 14
CAP score	score measured in dB/m	day 35
Body Mass Index (BMI)	index measured in weight and height	baseline
Silymarin concentration in blood plasma in pharmakokinetic substudy - AUC	assessement of area under the curve (AUC),	baseline
Silymarin concentration in blood plasma in pharmakokinetic substudy - tmax	assessement of time to maximal concentration (tmax)	baseline
Silymarin concentration in blood plasma in pharmakokinetic substudy - Cmax	assessement of maximal concentration (Cmax)	baseline
Treatment adherence	measured by patient diary	Baseline
Treatment adherence	measured by patient diary	Day 7
Treatment adherence	measured by patient diary	Day 14
Treatment adherence	measured by patient diary	Day 21
Treatment adherence	measured by patient diary	Day 28
Treatment adherence	measured by patient diary	Day 35
quality of life measurements	measured by short form survey (SF36) questionnaire	baseline
quality of life measurements	measured by short form survey (SF36) questionnaire	Day 7
quality of life measurements	measured by short form survey (SF36) questionnaire	Day 14
quality of life measurements	measured by short form survey (SF36) questionnaire	Day 21
quality of life measurements	measured by short form survey (SF36) questionnaire	Day 28
quality of life measurements	measured by short form survey (SF36) questionnaire	Day 35

Collaborators and Investigators

• Sponsor: Dr. Frank Behrens
• Collaborators: Bionorica SE
• Investigators: Study Chair: Stephan Schaefer, MD, Fraunhofer ITMP

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: November 21, 2021
• First Submitted That Met QC Criteria: November 21, 2021
• First Posted (Actual): December 3, 2021

Study Record Updates

• Last Update Posted (Actual): December 3, 2021
• Last Update Submitted That Met QC Criteria: November 21, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: silymarin
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Liver Diseases; Drug-Related Side Effects and Adverse Reactions; Poisoning; Chemical and Drug Induced Liver Injury
• Other Study ID Numbers: TMP-2501-2019-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No