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    Summary
    EudraCT Number:2020-004645-36
    Sponsor's Protocol Code Number:TMP-2501-2019-2
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2020-004645-36
    A.3Full title of the trial
    Impact of different silymarin dosages to decrease drug-induced elevated liver enzymes compared to placebo in a prospective controlled dose finding Phase IIb trial (SILVER)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A dose-finding clinical study investigating the effects of different doses of silymarin compared to placebo on elevated liver enzymes due to drug-induced liver enzyme elevation.
    A.4.1Sponsor's protocol code numberTMP-2501-2019-2
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFraunhofer Gesellschaft for its Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP)
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBIONORICA SE
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportFraunhofer Gesellschaft e.V.
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFraunhofer Institute for Molecular Biology and Applied Ecology IME
    B.5.2Functional name of contact pointTMP Clinical research
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Stern-Kai 7
    B.5.3.2Town/ cityFrankfurt am Main
    B.5.3.3Post code60596
    B.5.3.4CountryGermany
    B.5.4Telephone number+4969630180208
    B.5.5Fax number+496971047692
    B.5.6E-mailClinicalResearch@itmp.fraunhofer.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Silimarit
    D.2.1.1.2Name of the Marketing Authorisation holderBIONORICA SE
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 65666-07-1
    D.3.9.3Other descriptive nameSILYMARIN
    D.3.9.4EV Substance CodeSUB15253MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number140
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product Yes
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Yes
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Drug-induced elevated liver enzymes
    E.1.1.1Medical condition in easily understood language
    Liver cells injury due to use of liver damaging medications
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024668
    E.1.2Term Liver damage
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate superiority in change of blood ALT concentration at day 35 compared to BL in patients receiving silymarin 3x280 mg (most effective dose) compared to patients receiving placebo.
    E.2.2Secondary objectives of the trial
    • Superiority of change of blood ALT concentration at D35 compared to BL in pat. receiving silymarin dosages 1x1120 mg and 2x140mg compared to pat. receiving PL
    • comparison of treatment effect with regard to change of blood ALT concentration at D35 compared to BL
    • concentrations of liver enzymes (incl. AST, ALT, GGT, AP, Bilirubin, INR, Quick) and their change (absolute and %) to BL b over time
    • ALT/AP ratio and its change to BL
    • concentration of lipids
    • HbA1c at BL and day 35
    • proportion of patients achieving normalized liver enzymes and/or clinically relevant changes over time
    • changes in liver tissue characteristics using Fibroscan measurement over time
    • pharmacokinetic characteristics of silymarin considering the different dosage regimens
    • pharmacodynamic characteristics of silymarin using results from analysis of liver function
    • Treatment adherence
    • changes in quality of life (SF36)
    • Safety
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Silymarin concentration in blood plasma in PK substudy for the assessment of pharmacokinetic characteristics (e.g. AUC, Cmax, tmax) of
    silymarin in the different dosage regimens. PK will be evaluated for a subgroup of planned 36 patients (12 per silymarin group).
    E.3Principal inclusion criteria
    1. Patients ≥ 18 years
    2. Evidence of hepatocellular drug-induced injury due to treatment*1 as judged by the treating physician
    • ALT/AP ratio ≥ 5 ((ALT level/ALT ULN)/(AP level/AP ULN))
    OR
    Evidence of drug-induced elevation of liver-enzymes
    • ALT > 40 U/L or ULN ≤ 4ULN*2
    *2 acknowledgement of the gastroenterologist that there is no safety risk for the patient and that on base of the analysis of the collected data there is no evidence of a liver function disorder will be needed for inclusion of the patient
    3. Exclusion of severe liver tissue damage and hepatic steatosis grade 3 using either ultrasonography of the liver and/or Fibroscan with results ≤ 7 kPa (fibrosis score of F0 to F1)
    4. BMI ≥ 18 and ≤ 35
    5. Liver enzyme elevation inducing medication ongoing for at least 6 weeks before SCR. If it has not been administered with a stable dose, the liver enzyme elevation should have been stable within the last 2 weeks before SCR (as judged by 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
    *1drugs defined to cause hepatocellular injury for inclusion in this study: anti-TNF agents, lamotrigine, proton pump inhibitors (e.g., omeprazole), allopurinol, inhaled anesthetics, minocycline, mirtazapine, valproate/valproate acid, amiodarone, INFα, IFNβ, nitrofurantoine, linoleic acid, bupropion, isoniazid, NSAIDs (e.g., aspirin, diclofenac), ciprofloxacine, ketoconazole, methotrexate, paracetamol, pyrazinamide, paroxetine, losartan, nevirapine, protease inhibitors, rifampicin, risperidone, statins, trazodone, venlafaxine, sertraline, macrolides, acarbose, tetracyclines, baclofen, fluoxetine, paroxetine, lisinopril, leflunomide, sulfasalazine, mycophenolate mofetil, fluoroquinolones, flavocoxid, cloxacillin
    E.4Principal exclusion criteria
    1. Use of silymarin within the last 6 months
    2. Evidence, that the reported liver enzyme elevation is caused by intake, induction or dose modification of a treatment that induces cholestatic or mixed hepatocellular/cholestatic liver injury (e.g. amoxicilline and clavulanic acid, anabolic steroids, chlorpromazine, clopidogrel, erythromycin, irbesartan, estrogen, terbinafine; inducing mixed liver injury: amitriptyline, azathioprine, captopril, carbamazepine, clindamycine, co-trimoxazole, cyproheptadine, enalapril, flutamide, nitrofurantoin, phenobarbital, phenytoin, sulphonamide, trazodone, verapamil)2 as juged by the treating physician. Evidence can be assumed if the medication was started or dose was increased within the last three months before enzyme elevation was detected and/or pausing of the drug caused total normalization or by trend.
    3. Patients with chronic liver disease, e.g. hepatic steatosis grade 3, existing fibrosis (fibrosis score of ≥F2) or cirrhosis
    4. Patients with acute viral hepatitis, active 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 any currently treated malignancy or patients with chemotherapy treatment within the past 5 years
    7. 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)
    8. 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
    9. Patients who are unable to understand the nature, importance, risks and scopre of the clinical trial, e.g. due to CNS and/or psychiatric disorders
    10. Known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations, e.g. milk thistle, soy oil, peanut (according to SmPc)
    11. Contraindications to use the IMP, e.g. hereditary galactose intolerance, genetic lactase deficiency or glucose-galactose malabsorption (according to SmPC)
    12. Subjects with severe or moderate allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
    13. 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
    14. Positive anti-HIV-test, antiHBs- or anti-HCV-test at Screening, except if patients are stable for at least 6 months
    15. History of or current drug or alcohol dependence
    16. Subjects with a positive drug test at screening (incl. alcohol)
    17. Regular intake of alcoholic food or beverages of ≥ 40 g pure ethanol for male or ≥ 20 g pure ethanol for female per day
    18. Participation in a clinical trial during the last two months prior to individual enrolment of the subject or current participation
    19. For the group who will be part of the PK substudy only: Use of drugs during the last two weeks prior Baseline that can affect absorption (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists)
    20. 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
    21. 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

    For female subjects only:
    22. Positive pregnancy test at screening/baseline examination
    23. Pregnant or lactating women
    E.5 End points
    E.5.1Primary end point(s)
    Change of blood ALT concentration at day 35 compared to BL in patients receiving silymarin 3x280 mg (most effective dose) compared to patients receiving placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 35 compared to baseline
    E.5.2Secondary end point(s)
    The following variables will be assessed for all available visits and treatment groups.
    • Liver enzyme blood parameters: AST, ALT, GGT, AP, Bilirubin, INR, Quick and their changes compared to BL
    • ALT/AP ratio and change compared to BL
    • Lipids, such as LDL, HDL, VLDL, triglycerides, total cholesterol, and fasting glucose
    • Proportion of patients with normalization in liver enzyme blood parameters such as AST (< 40 IU/L), ALT (< 40 IU/L), GGT, AP, bilirubin, INR, Quick
    • Plasma silymarin dose concentration in each treatment group at all visits
    • Fibroscan value and its change over time (kPa)
    • Fibrosis score (F0-F4)
    • CAP score (dB/m)
    • BMI
    • Silymarin concentration in blood plasma in PK substudy for the assessment of pharmacokinetic characteristics (e.g. AUC, Cmax, tmax) of silymarin in the different dosage regimens (in the subgroup analysis)
    • Dose-response relationship (all listed liver enzyme parameters) for assessment of pharmacodynamic characteristics of silymarin in the different dosage regimens
    • Treatment adherence to the study drug
    • Calculation of quality of life measurements (SF36) and changes compared to baseline

    Safety:
    Frequency, type, severity and relatedness of adverse events

    E.5.2.1Timepoint(s) of evaluation of this end point
    At all time Points between Groups, with exception of HbA1c (only at BL and day 35)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    database hard lock after data cleaning process is completed
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 115
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 71
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state186
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care for the underlaying condition
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-05-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-15
    P. End of Trial
    P.End of Trial StatusOngoing
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