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

Drug-induced Liver Injury Clinical Trial

— SILVER  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05144217
• Other study ID #: TMP-2501-2019-2
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: June 23, 2021
• Est. completion date: December 31, 2022

Study information

• Verified date: November 2021
• Source: Fraunhofer Institute for Molecular Biology and Applied Ecology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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?

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 156
• Est. completion date: December 31, 2022
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chemical and Drug Induced Liver Injury
• Drug-induced Liver Injury

Intervention

Drug:
• Placebo
1 capsule per day of placebo
• 2x 140 mg per day
2 capsule per day of silimarit
• 3x 280 mg per day
3 capsule per day of silimarit
• 1x 1120 mg
8 capsule per day of silimarit

Locations

Country	Name	City	State
Germany	CIRI	Frankfurt	Hessia
Germany	Universtity Hospital - clinic for dermatology, venerology and allergology	Frankfurt	Hessia

Sponsors (2)

Lead Sponsor	Collaborator
Dr. Frank Behrens	Bionorica SE

Country where clinical trial is conducted

Germany, 

Outcome

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