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

Study Overview
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Brief Summary
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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
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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?

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

Conditions
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Drug-induced Liver Injury

Intervention / Treatment
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* Drug: Placebo
* Drug: 2x 140 mg per day
* Drug: 3x 280 mg per day
* Drug: 1x 1120 mg


Participation Criteria
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Eligibility Criteria
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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: Use of silymarin within the last 6 months 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) Patients with chronic liver disease, existing fibrosis or cirrhosis 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 Cholestatic or mixed hepatocellular/mixed liver injury Patients with diabetes types 1 or 2 Any malignancy within the past 5 years 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) 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 History of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders 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)) Contraindications to use the investigational medicinal product (IMP), e.g. hereditary galactose intolerance, genetic lactase deficiency or glucose-galactose malabsorption (according to SmPC) Subjects with severe or moderate allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator 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 Positive anti-HIV-test, antiHBs- or anti-HCV-test at Screening History of or current drug or alcohol dependence Subjects with a positive drug test at screening (incl. alcohol) Regular intake of alcoholic food or beverages of ≥ 40 g pure ethanol for male or ≥ 20 g pure ethanol for female per day Participation in a clinical trial during the last two months prior to individual enrolment of the subject or current participation Use of drugs during the last two weeks prior Baseline that can affect absorption (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists) 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective placebo-controlled dose-finding study
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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silymarin