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    Summary
    EudraCT Number:2013-000245-39
    Sponsor's Protocol Code Number:LEG-SIL-2-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-06-10
    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 number2013-000245-39
    A.3Full title of the trial
    Rescue effect of daily infusions with Legalon® SIL in Hepatitis C Virus-infected patients who are incomplete responders to standard pegylated interferon/ribavirin (dual therapy) or pegylated interferon/ribavirin plus a protease inhibitor (triple therapy): a randomized, controlled, parallel-group, multicenter clinical trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rescue effect of daily infusions with Legalon® SIL in Hepatitis C Virus-infected patients who are incomplete responders to standard anti-HCV treatment.
    A.3.2Name or abbreviated title of the trial where available
    Silibinin as an ANtiviral Treatment Enhancement to a standard antiviral combination therapy (SANTÉ)
    A.4.1Sponsor's protocol code numberLEG-SIL-2-01
    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 SponsorRottapharm S.p.A
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRottapharm S.p.A
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRottapharm S.p.A
    B.5.2Functional name of contact pointClinical Research Department
    B.5.3 Address:
    B.5.3.1Street AddressValosa di Sopra 7/9
    B.5.3.2Town/ cityMonza
    B.5.3.3Post code20900
    B.5.3.4CountryItaly
    B.5.4Telephone number00390397390454
    B.5.5Fax number00390397390615
    B.5.6E-mailsara.cazzaniga@rottapharm.com
    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 Legalon SIL
    D.2.1.1.2Name of the Marketing Authorisation holderMadaus GmbH
    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.3.1Product nameLegalon SIL
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSILIBININ-C-2´, 3-DIHYDROGEN SUCCINATE, DISODIUM SALT
    D.3.9.1CAS number 55254-34-7
    D.3.9.3Other descriptive nameSILIBININ-C-2´, 3-DIHYDROGEN SUCCINATE, DISODIUM SALT
    D.3.9.4EV Substance CodeSUB33890
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number528.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HCV infected patients who are incomplete responders to standard pegylated interferon/ribavirin (dual therapy) or pegylated interferon/ribavirin plus a protease inhibitor (triple therapy)
    E.1.1.1Medical condition in easily understood language
    Chronic Hepatitis C virus (HCV) infection
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10066936
    E.1.2Term HCV viral load
    E.1.2System Organ Class 100000004848
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether a short course of Legalon® SIL added to antiviral standard treatment can induce a complete virological response in hepatitis C patients with incomplete response to dual or triple antiviral therapy
    E.2.2Secondary objectives of the trial
    -To determine the optimal dose (20 mg/kg vs. 30 mg/kg) and treatment duration (5 vs. 10 vs. 12 days) of Legalon® SIL for this treatment strategy;
    -To assess the efficacy of Legalon® SIL in a variety of clinically meaningful virological responses;
    -To assess the safety and tolerability of Legalon® SIL in the context of chronic hepatitis C and HCV antiviral treatment;
    -To assess potential resistance mutations selected before, at the end of, and after Legalon® SIL treatment and their influence on virological response.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients meeting all the following inclusion criteria will be eligible for enrollment in the study:
    1.Signed and dated informed consent obtained before undergoing any trial-specific procedure
    2.Male and female patients; age between 18 and 70 years inclusive
    3.Chronic hepatitis C infection with genotype confirmed by genotypic testing
    4.Meeting a predefined virologic stopping rule to an ongoing standard of care antiviral treatment regimen [containing pegylated interferon-α 2a/b and ribavirin either alone (dual therapy) or in combination with selective HCV protease inhibitors (triple therapy)]
    5.detectable HCVRNA levels at the time of screening as follows: - for the Group 1: GT1 patients with HCV-RNA ≤10.000 IU/mL; - for the Exploratory Group (Group 2): GT1 patients with HCV-RNA >10.000 IU/mL but ≤30.000 IU/mL and any non-GT1 patient ≤30.000 IU/mL.
    6.Ability to communicate, participate, and comply with the requirements of the entire study.
    E.4Principal exclusion criteria
    Disease related criteria:
    1.Co-Infection with HIV and/or HBV
    2.Evidence or history in the previous 5 years of deconpensated liver cirrhosis as signs of ascites, esophageal varices or laboratory abnormalities that indicate impaired liver function
    3.Evidence of liver disease due to causes other than chronic HCV infection
    4.Bilirubin levels > 2.0 mg/dL unless explained by Gilbert’s disease
    5.Platelet Count < 50.000/µL
    6.Absolute Neutrophil count < 750/µL (mm3)

    Patient related criteria:
    1.Active or suspected non-hepatic malignancy or history of malignancy within the last 5 years
    2.Clinically significant TSH and T4 level and not adequately controlled thyroid function
    3.Patients with any abnormality on laboratory value, unless these abnormalities are judged to be not clinically significant by the Investigator
    4.Patients with any abnormality on physical examination, and/or ECG, unless these abnormalities are judged to be not clinically significant by the Investigator
    5.Body Mass Index < 16 or > 35 kg/m2
    6.Females of childbearing potential:
    -Pregnancy (i.e. positive pregnancy test at screening) or lactation
    -Failure to agree to practice adequate contraception methods (e.g. oral contraceptives, intra-uterine device [IUD], transdermal contraceptive patch)
    7.Male patients not vasectomized, who do not agree to abstain from intercourse or who do not use a condom
    8.Use of concomitant medication that is not allowed and that cannot be discontinued for the entire study period
    9.Use of other investigational drugs/treatments, or enrolment in a clinical study within the previous 3 months or 5 half lives (whichever is longer), except for investigational drug/treatments for HCV
    10.Known hypersensitivity to any of the test materials or related compounds
    11.Use of illicit drugs or significant alcohol abuse within the past 12 months. Use of cannabis is not exclusionary
    12.Active autoimmune disease
    13.History of moderate, severe or uncontrolled psychiatric disease, especially severe depression and prior suicidal attempt
    14.Poor venous access
    15.Patients with Creatinin >1,5 ULN
    16.Any other condition that, in the opinion of the Investigator, may jeopardize the study conduct according to the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Study Part I: Complete Virological response at the End-of-treatment (EOT), defined as undetectable HCV-RNA levels at the end of the treatment period.

    Study Part II: Sustained Virological Response-12 (SVR-12), i.e. undetectable HCV-RNA levels lasting until 12 weeks after the completion of the SOC treatment course.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Study Part I: HCV-RNA levels collected on day 8 and HCV-RNA levels collected after treatment infusion on day 12.
    Study Part II:HCV-RNA levels collected on week 12 after the end of SOC treatment course.
    E.5.2Secondary end point(s)
    Study Part I:
    •Evaluation of the complete virological response (defined as undetectable HCV-RNA levels) according to the different dose regimens;
    •Evaluation of the complete virological response (defined as undetectable HCV-RNA levels) according to the different treatment durations;
    •Number of patients with virological breakthrough (during SOC maintenance therapy);
    •Evaluation of viral kinetics (area under the curve (AUC) and slope of serum HCV-RNA concentration over time);
    •Normalization of Serum Alanine Aminotransferase (ALT) values at the end of treatment phase;
    •Improvement of Serum Alanine Aminotransferase (ALT) values at the end of treatment phase;
    •Viral mutations (primarly in NS4B and/or NS3) associated with resistance to treatment.

    Study Part II:
    •Undetectable HCV-RNA levels at the completion of the SOC treatment course;
    •SVR-24, i.e. undetectable HCV-RNA levels lasting until 24 weeks after completion of the SOC treatment course [SVR-24] (end of follow-up phase);
    •Number of patients with virological breakthrough and/or relapse during the maintenance treatment follow-up phase;
    •Viral resistance associated with resistance to treatment;
    •Normalization of Serum Alanine Aminotransferase (ALT) values 2 weeks after the beginning of the study PART II;
    •Improvement of Serum Alanine Aminotransferase (ALT) values 2 weeks after the beginning of the study PART II;
    •Normalization of Serum Alanine Aminotransferase (ALT) values at the completion of the SOC treatment course;
    •Improvement of Serum Alanine Aminotransferase (ALT) values at the completion of the SOC treatment course;
    •Normalization of Serum Alanine Aminotransferase (ALT) values at the end of follow-up;
    •Improvement of Serum Alanine Aminotransferase (ALT) values at the end of follow-up;
    •Correlation between EOT, SVR and relapse and levels of HCV RNA at baseline of Study PART I and at week 2 of Study PART II;
    •Fibrosis stage.

    Safety endpoints:
    • Adverse Events (AEs)
    • Laboratory Determinations
    • Vital signs
    • Physical examination
    • ECG (only in Part I)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Study Part I: from the screening visit (day 0) to the end of study part I on day 15
    Study Part II: from the beginning of study Part II (week 2) to the end of study part II (week 24 after the end of SOC treatment)
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Yes
    E.8.1.3Single blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Pooled Control group - Patients attend the observational period without Legalon® SIL treatment
    observational period- no treatment
    E.8.2.4Number of treatment arms in the trial5
    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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    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 Yes
    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
    LVLS
    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: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 190
    F.4.2.2In the whole clinical trial 190
    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)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-07-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-11
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2014-03-14
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