Impact of Different Silymarin Dosages to Decrease Drug-induced Elevated Liver Enzymes Compared to Placebo in a Prospective Controlled Dose Finding Phase IIb Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 19
- 试验地点
- 2
- 主要终点
- Change in blood ALT (Alanine-Aminotransferase) in IU/L
研究概览
简要总结
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.
详细描述
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?
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
盲法说明
study medication and placebo are provided in identical blister
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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)
- •BMI ≥ 18 and ≤ 30
- •Liver enzyme elevation inducing medication stable for ≥ 8 weeks before screening in the discretion of the treating physician
- •Written informed consent, after having been informed about potential benefit and potential risks of the clinical trial
- •Willing and capable to understand informed consent and follow the protocol
排除标准
- •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
研究组 & 干预措施
Placebo
1 capsule twice per day
干预措施: Placebo (Drug)
oral administration of 2x 140 mg per day
1 capsule twice per day
干预措施: 2x 140 mg per day (Drug)
oral administration of 3x 280 mg per day
2 capsules three times a day
干预措施: 3x 280 mg per day (Drug)
oral administration of 1x 1120 mg per day
8 capsules once per day
干预措施: 1x 1120 mg (Drug)
结局指标
主要结局
Change in blood ALT (Alanine-Aminotransferase) in IU/L
时间窗: at day 35
Change in blood ALT in IU/Lin all treatment groups
次要结局
- quality of life measurements(Day 35)
- Body Mass Index (BMI)(baseline)
- Change Liver enzyme blood parameter INR (International Normalized Ratio)(Day 35)
- Lipids analysis LDL(Day 35)
- Lipids analysis VLDL(Day 35)
- Lipids analysis triglycerides(Day 35)
- Lipids analysis total cholesterol(Day 35)
- bloodparameter assessment(Day 7)
- blood parameter assessment(Day 35)
- Proportion of patients with normalization in liver enzyme blood parameters(Day 35)
- Plasma silymarin dose concentration(day 35)
- Fibroscan value(day 35)
- Fibrosis score(Day 35)
- CAP score(day 35)
- Change Liver enzyme blood parameter Quick value(Day 35)
- Liver enzyme blood parameters: AST(Day 21)
- Change Liver enzyme blood parameter AP (Alkaline phosphatase )(Day 35)
- Change Liver enzyme blood parameter AST(Day 35)
- Change Liver enzyme blood parameter bilirubin(Day 35)
- Change ALT/AP ratio(Day 35)
- Lipids analysis(Day baseline)
- Liver enzyme blood parameter AST (Aspartate-Aminotransferase)(Baseline (prior treatment))
- Liver enzyme blood parameter AST(Day 28)
- Change Liver enzyme blood parameter ALT(Day 35)
- Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)(Day 35)
- Silymarin concentration in blood plasma in pharmakokinetic substudy - AUC(baseline)
- Silymarin concentration in blood plasma in pharmakokinetic substudy - tmax(baseline)
- Silymarin concentration in blood plasma in pharmakokinetic substudy - Cmax(baseline)
- Treatment adherence(Day 35)
- Liver enzyme blood parameter AST(Day 7)
- Liver enzyme blood parameter AST(Day 14)
- Change Liver enzyme blood parameter ALT(Baseline)
- Change Liver enzyme blood parameter ALT(Day 7)
- Change Liver enzyme blood parameter ALT(Day 14)
- Change Liver enzyme blood parameter ALT(Day 21)
- Change Liver enzyme blood parameter ALT(Day 28)
- Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)(Baseline)
- Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)(Day 7)
- Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)(Day 14)
- Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)(Day 21)
- Change Liver enzyme blood parameter GGT (Gamma-Glutamyl-Transferase)(Day 28)
- Change Liver enzyme blood parameter AP (Alkaline phosphatase )(Baseline)
- Change Liver enzyme blood parameter AP (Alkaline phosphatase )(Day 7)
- Change Liver enzyme blood parameter AP (Alkaline phosphatase )(Day 14)
- Change Liver enzyme blood parameter AP (Alkaline phosphatase )(Day 21)
- Change Liver enzyme blood parameter AP (Alkaline phosphatase )(Day 28)
- Change Liver enzyme blood parameter bilirubin(Baseline)
- Change Liver enzyme blood parameter bilirubin(Day 7)
- Change Liver enzyme blood parameter bilirubin(Day 14)
- Change Liver enzyme blood parameter bilirubin(Day 21)
- Change Liver enzyme blood parameter bilirubin(Day 28)
- Change Liver enzyme blood parameter INR (International Normalized Ratio)(baseline)
- Change Liver enzyme blood parameter INR (International Normalized Ratio)(Day 7)
- Change Liver enzyme blood parameter INR (International Normalized Ratio)(Day 14)
- Change Liver enzyme blood parameter INR (International Normalized Ratio)(Day 21)
- Change Liver enzyme blood parameter INR (International Normalized Ratio)(Day 28)
- Change Liver enzyme blood parameter Quick value(baseline)
- Change Liver enzyme blood parameter Quick value(Day 7)
- Change Liver enzyme blood parameter Quick value(Day 14)
- Change Liver enzyme blood parameter Quick value(Day 21)
- Change Liver enzyme blood parameter Quick value(Day 28)
- Change ALT/AP ratio(baseline)
- Change ALT/AP ratio(Day 7)
- Change ALT/AP ratio(Day 14)
- Change ALT/AP ratio(Day 21)
- Change ALT/AP ratio(Day 28)
- Lipids analysis(Baseline)
- Lipids analysis LDL(Day 7)
- Lipids analysis LDL(Day 14)
- Lipids analysis LDL(Day 21)
- Lipids analysis LDL(Day 28)
- Lipids analysis(baseline)
- Lipids analysis(Day 7)
- Lipids analysis(Day 14)
- Lipids analysis(Day 21)
- Lipids analysis(Day 28)
- Lipids analysis(Day 35)
- Lipids analysis VLDL(Day 7)
- Lipids analysis VLDL(Day 14)
- Lipids analysis VLDL(Day 21)
- Lipids analysis VLDL(Day 28)
- Lipids analysis triglycerides(baseline)
- Lipids analysis triglycerides(Day 7)
- Lipids analysis triglycerides(Day 14)
- Lipids analysis triglycerides(Day 21)
- Lipids analysis triglycerides(Day 28)
- Lipids analysis total cholesterol(baseline)
- Lipids analysis total cholesterol(Day 7)
- Lipids analysis total cholesterol(Day 14)
- Lipids analysis total cholesterol(Day 21)
- Lipids analysis total cholesterol(Day 28)
- bloodparameter assessment(baseline)
- blood parameter assessment(Day 14)
- blood parameter assessment(Day 21)
- blood parameter assessment(Day 28)
- Plasma silymarin dose concentration(Base line)
- Plasma silymarin dose concentration(day 7)
- Plasma silymarin dose concentration(day 14)
- Plasma silymarin dose concentration(day 21)
- Plasma silymarin dose concentration(day 28)
- Fibroscan value(baseline)
- Fibroscan value(day 14)
- Fibrosis score(baseline)
- Fibrosis score(Day 14)
- CAP score(baseline)
- CAP score(day 14)
- Treatment adherence(Baseline)
- Treatment adherence(Day 7)
- Treatment adherence(Day 14)
- Treatment adherence(Day 21)
- Treatment adherence(Day 28)
- quality of life measurements(baseline)
- quality of life measurements(Day 7)
- quality of life measurements(Day 14)
- quality of life measurements(Day 21)
- quality of life measurements(Day 28)
研究者
Prof. Dr. Frank Behrens
Sponsor representative
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP