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    The EU Clinical Trials Register currently displays   36603   clinical trials with a EudraCT protocol, of which   6045   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
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    EudraCT Number:2010-020480-21
    Sponsor's Protocol Code Number:pro-duct001
    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:2010-07-28
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2010-020480-21
    A.3Full title of the trial
    Feasibility and efficacy of adjuvant gemcitabine chemotherapy after liver transplantation for proximal bile duct cancer
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberpro-duct001
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversitätsmedizin Charite
    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 support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.2.5The 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 nameGemcitabine
    D.3.4Pharmaceutical form Powder for infusion*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number800 to 1000
    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) Information not present in EudraCT
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D. medicinal product type cytostatic drug
    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
    proximal bile duct cancer
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate, if adjuvant gemcitabine chemotherapy is feasible in ≥ 85 % of patients after liver transplantation.
    E.2.2Secondary objectives of the trial
    To obtain preleminary data on recurrence- and survival rates after liver transplantation for hilar cholangiocarcinoma using strict selection criteria and either adjuvant or no adjuvant chemotherapy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Listing for liver transplantation

    • diagnosis of hilar cholangiocarcinoma with or without primary sclerosing cholangitis (PSC): i.e. histological diagnosis of cholangiocarcinoma (obtained via ERC) or dominant stenosis plus cytological diagnosis of severe dysplasia or two subsequent cytological results of severe dysplasia or carcinoma whereby the second has been obtained after 2 weeks of antibiotic treatment to exclude inflammatory changes
    • tumor not curatively resectable as judged by one local experienced hepatobiliary surgeon (> 50 liver resections for hilar cholangiocarcinoma)
    • on-line review (protective website) of defined patient data and acceptance for priority listing by an Eurotransplant expert panel consisting of two experts recruited from the Eurotransplant Liver Allocation Committee; in case of split decision addition of a third expert for definite decision on priority listing with an respective matchMELD.
    • obligatory staging laparotomy before priority listing (see SOP staging laparotomy)
    • age between 18 and 65 years
    • negative pregnancy test
    • informed consent before study specific procedures are performed (i.e. at the time of randomization for chemotherapy, all other procedures are clinical routine procedures in the management of these patients)

    for randomization adj. chemotherapy vs. observation:

    • liver transplantation within three months after listing for liver transplantation
    • histologically proven proximal bile duct cancer
    • curative resection of the tumor (R0)
    • in case of previously unknown hilar lymph node metastases nearby the tumor region in the final pathological report: stratification in the treatment groups
    • no previous photodynamic therapy, radiation, chemotherapy, brachytherapy or combinations of these procedures
    • CT scan of the chest not older than 8 weeks before randomization showing no detectable distant metastases
    • possibility to start adjuvant chemotherapy between 4 and 8 weeks (but not later than 10 weeks) after liver transplantation
    • sufficient bone marrow function (WBC > 3.5/nl, platelets > 80/nl, hemoglobin > 8 g/dl)
    • sufficient renal function (creatinin clearance ≥ 30 ml/min)
    • sufficient liver function (bilirubin < 3 mg/dl)
    • if female either be postmenopausal, surgically sterile or have a negative pregnancy test as part of the screening investigations. Women of childbearing potential also must agree to use an acceptable highly effective contraception method of birth control (defined as pearl index < 1), if necessary also for partners of test persons or complete abstinence of intercourse (from the date of liver transplantation until 2 months after end of adjuvant chemotherapy).
    if male must agree to use an acceptable method of birth control, as determined by the investigator, from the date of liver transplantation until 2 months after end of adjuvant chemotherapy
    • all patients must be informed of the nature of the study and provide written informed consent before any study specific procedures are performed
    E.4Principal exclusion criteria
    Contraindications for liver transplantation:

    • locally very advanced, irresectable tumor infiltrating adjacent other organs, the main trunk of the hepatic artery
    • a visible tumor mass on CT or MRI scan larger than 3 cm in diameter
    • highly elevated CA 19-9 levels (> 1000 U/ml)
    • tumors suspicious for gallbladder cancer
    • known lymph node or distant metastasis (determined mandatory by CT scan and laparoscopy, further investigations if deemed necessary, PET scan is strongly recommended)
    • patients undergoing multi-organ transplantation or have undergone previous solid organ or bone marrow transplantation
    • previous or intended photodynamic therapy, radiation, chemotherapy, brachytherapy or combinations of these procedures
    • previous tumor biopsy (except via ERC) systematic lymphadenectomy (except SOP defined staging laparotomy), surgical preparation at the region of the hepatoduodenal ligament (except cholecystectomy for other reasons) or previous completed or attempted surgery for hilar cholangiocarcinoma
    • patients with known hypersensibility for gemcitabine
    • pregnancy or breastfeeding
    • patients unwilling to consent to saving and propagation of pseudonymized medical data for study reasons
    • general contraindications for liver transplantation
    • subjects who are legally detained in an official institute
    • HIV infection (based on testing performed during the transplant-evaluation or within 6 months before)

    for randomization (adj. chemotherapy vs. observation):

    • patients with biliary sepsis, intrahepatic abscesses or other complications (e.g. severe liver dysfunction) contraindicating adjuvant chemotherapy
    • contraindications against study medication (including auxiliary substances)
    • pregnancy or breastfeeding
    • induction therapy with antibodies as primary immunosuppression after liver transplantation (rejection treatment with antibodies is not a contraindication)
    • therapy with mTOR-inhibitors (sirolimus, everolimus)
    • any clinically significant medical or surgical condition, that in the investigator`s opinion would preclude adjuvant chemotherapy
    • participitation in other clinical trials

    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints:
    • percentage of patients completing the 24 weeks course of adjuvant chemotherapy

    Secondary endpoints:
    • recurrence free survival at 12 months
    • overall survival at 3 and 5 years
    • complication rate (protocol defined high grade toxicities grade 3/4)
    • number of patients, which could not be randomized (due to perioperative complications, no detectable bile duct cancer in the explanted liver or other reasons)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 No
    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. 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 No
    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. description
    no therapy
    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 concerned29
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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 Information not present in EudraCT
    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
    study duration and till year 5 follow-up
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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.1.3Elderly (>=65 years) No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 45
    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 Decision2010-09-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-11-18
    P. End of Trial
    P.End of Trial StatusOngoing
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