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    The EU Clinical Trials Register currently displays   42312   clinical trials with a EudraCT protocol, of which   6968   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2019-001068-31
    Sponsor's Protocol Code Number:2019/2894
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-06
    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 ConcernedGreece - EOF
    A.2EudraCT number2019-001068-31
    A.3Full title of the trial
    High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
    Μελέτη Νευροβλαστώματος Υψηλού Κινδύνου 2.0 της SIOP-Europe- Neuroblastoma (SIOPEN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomised, international and multicentric study that evaluates and compares 2 treatment strategies in 3 therapeutic phases (induction, high-dose chemotherapy and radiotherapy) for patients with high-risk neuroblastoma.
    Τυχαιποιημένη, διεθνής και πολυκεντρική μελέτη που αξιολογεί και συγκρίνει 2 στρατηγικές θεραπείας σε 3 θεραπευτικές φάσεις (επαγωγή, χημειοθεραπεία υψηλής δόσης και ακτινοθεραπεία) για ασθενείς με νευροβλάστωμα υψηλού κινδύνου.
    A.3.2Name or abbreviated title of the trial where available
    HR-NBL2
    HR-NBL2
    A.4.1Sponsor's protocol code number2019/2894
    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 SponsorGustave Roussy
    B.1.3.4CountryFrance
    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 supportPHRC
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGustave Roussy
    B.5.2Functional name of contact pointSponsor CRA
    B.5.3 Address:
    B.5.3.1Street Address114 rue Edouard Vaillant
    B.5.3.2Town/ cityVillejuif
    B.5.3.3Post code94800
    B.5.3.4CountryFrance
    B.5.4Telephone number0033142114211
    B.5.5Fax number0033142116290
    B.5.6E-mailkhadidja.berrouane@gustaveroussy.fr
    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.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNBUSULFAN
    D.3.9.3Other descriptive nameBUSULFAN
    D.3.9.4EV Substance CodeSUB05993MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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.IMP: 2
    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.3.4Pharmaceutical form 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 INNCARBOPLATIN
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.IMP: 3
    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.3.4Pharmaceutical form Powder for solution for injection
    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 INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 4
    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.3.4Pharmaceutical form Concentrate 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 INNCISPLATIN
    D.3.9.3Other descriptive nameCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.IMP: 5
    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.3.4Pharmaceutical form Powder for solution for injection
    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 INNDACARBAZINE
    D.3.9.1CAS number 4342-03-4
    D.3.9.4EV Substance CodeSUB06882MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.IMP: 6
    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.3.4Pharmaceutical form 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 INNDOXORUBICIN
    D.3.9.1CAS number 23214-92-8
    D.3.9.4EV Substance CodeSUB06391MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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.IMP: 7
    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.3.4Pharmaceutical form Concentrate 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 INNETOPOSIDE
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 8
    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.3.4Pharmaceutical form Powder for concentrate 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 INNIFOSFAMIDE
    D.3.9.1CAS number 3778-73-2
    D.3.9.4EV Substance CodeSUB08125MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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.IMP: 9
    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.3.4Pharmaceutical form Powder and solvent for solution for injection/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 INNMELPHALAN
    D.3.9.1CAS number 148-82-3
    D.3.9.4EV Substance CodeSUB08728MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.4
    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.IMP: 10
    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.3.4Pharmaceutical form Powder for solution for injection
    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 INNTHIOTEPA
    D.3.9.1CAS number 52-24-4
    D.3.9.4EV Substance CodeSUB10985MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1 to 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.IMP: 11
    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.3.4Pharmaceutical form Solution for injection
    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 INNVINCRISTINE
    D.3.9.1CAS number 57-22-7
    D.3.9.4EV Substance CodeSUB00059MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number2
    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.IMP: 12
    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.3.4Pharmaceutical form Powder for solution for injection
    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 INNVINDESINE
    D.3.9.1CAS number 53643-48-4
    D.3.9.4EV Substance CodeSUB00061MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number6
    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
    Very High Risk Neuroblastoma
    Νευροβλάστωμα πολύ υψηλού κινδύνου
    E.1.1.1Medical condition in easily understood language
    Neuroblastoma
    Νευροβλάστωμα
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029261
    E.1.2Term Neuroblastoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    R-I:
    Comparison of the EFS rate of 2 induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma.

    R-HDC:
    Comparison of the EFS rate of single HDC with busulphan and melphalan (Bu-Mel) versus tandem HDC with Thiotepa followed by Bu-Mel in patients with high-risk neuroblastoma.

    R-RTx:
    Comparison of the EFS rate of 21.6 Gy radiotherapy to the preoperative tumor bed versus 21.6 Gy radiotherapy and a sequential boost up to 36 Gy to the residual tumor in patients with macroscopic residual disease after HDC and surgery.
    R-I:
    Σύγκριση του ποσοστού EFS (Event Fre Survival) 2 θεραπειών εφόδου, των GPOH και RAPID COJEC, σε ασθενείς με νευροβλάστωμα υψηλού κινδύνου.

    R-HDC:
    Σύγκριση του ποσοστού EFS της μεμονωμένης HDC με βουσουλφάνη και μελφαλάνη (Bu-Mel) έναντι της διαδοχικής HDC με Θειοτέπα ακολουθούμενης από Bu-Mel σε ασθενείς με νευροβλάστωμα υψηλού κινδύνου.

    R-RTx:
    Σύγκριση του ποσοστού EFS της ακτινοθεραπείας 21,6 Gy στον προεγχειρητικό όγκο στόχο σε σύγκριση με ακτινοθεραπεία 21,6 Gy και διαδοχική αύξηση έως τα 36 Gy στον εναπομείνοντα ιστό σε ασθενείς με μακροσκοπική υπολειμματική νόσο μετά από HDC και χειρουργική επέμβαση.
    E.2.2Secondary objectives of the trial
    To describe the EFS and overall survival (OS) from date of randomization of the whole cohort, To describe the effect of RAPID COJEC and GPOH induction regimens on metastatic disease during and after the end of induction, To assess the correlation of the response of metastatic disease during and after induction with survival (EFS and OS), To describe the effect of HDC with Bu-Mel versus Thiotepa + Bu-Mel on progression-free survival (PFS) and OS, To describe and compare the toxicity associated with RAPID COJEC and GPOH induction therapy, To describe and compare the acute and long term toxicities of both HDC arms, To describe the long term toxicities of dinutuximab beta, To investigate the relationship between the quality of surgical resection of the primary tumor, local control and survival, To investigate the impact of the radiotherapy dose on local relapse rate etc.
    Να περιγράψει το EFS και τη συνολική επιβίωση (OS) από την ημερομηνία τυχαιοποίησης ολόκληρης της κοόρτης, να περιγράψει την επίδραση των θεραπευτικών αγωγών RAPID COJEC και GPOH στη μεταστατική νόσο κατά τη διάρκεια και μετά το τέλος της επαγωγής, να αξιολογήσει τη συσχέτιση της ανταπόκρισης της μεταστατικής ασθένειας κατά τη διάρκεια και μετά την επαγωγή με επιβίωση (EFS και OS), να περιγράψει την επίδραση του HDC με Bu-Mel έναντι Thiotepa + Bu-Mel στην επιβίωση χωρίς εξέλιξη (PFS) και OS, να περιγράψει και να συγκρίνει την τοξικότητα που σχετίζεται με το RAPID COJEC και την επαγωγική θεραπεία GPOH, να περιγράψει και να συγκρίνει τις οξείες και μακροπρόθεσμες τοξικότητες και των δύο βραχιόνων HDC, να περιγράψει τις μακροπρόθεσμες τοξικότητες του dinutuximab beta, να διερευνήσει τη σχέση μεταξύ της ποιότητας της χειρουργικής εκτομής του πρωτοπαθούς όγκου, του τοπικού ελέγχου και της επιβίωσης, να διερευνήσει τον αντίκτυπο της δόσης ακτινοθεραπείας στο τοπικό ποσοστό υποτροπών κ.λπ.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    R-I eligibility criteria:
    1) Established diagnosis of neuroblastoma according to the SIOPEN-modified International Neuroblastoma Risk Group (INRG) criteria,
    High-risk neuroblastoma defined as:
    -Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit) and Ms neuroblastoma 12-18 months old, any MYCN status*
    or
    -L2, M or Ms neuroblastoma with MYCN amplification, any age
    * In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in HR-NBL2 trial.
    2) No previous chemotherapy (except one cycle of Etoposide-Carboplatin or, in Germany and Nertherlands, one course of the current protocol for low/intermediate risk neuroblastoma)
    3) Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use acceptable and appropriate contraception while on study drug and for one year after stopping the study drug. Acceptable contraception is defined in CTFG Guidelines “Recommendations related to contraception and pregnancy testing in clinical trials” (Appendix 11). Female patients who are lactating must agree to stop breast-feeding.
    4) Written informed consent to enter the R-I randomization from patient or parents/legal representative, patient, and age-appropriate assent.
    5) Patient affiliated to a social security regimen or beneficiary of the same according to local requrements.
    6) Patients should be able and willing to comply with study visits and procedures as per protocol.

    R-HDC eligibility criteria:
    1) - Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN status, EXCEPT patients with stage M or Ms 12-18 months old with numerical chromosomal alterations only, and in complete metastatic response at the end of induction: in this case, patients will have surgery but will not be eligible for R-HDC and will not be able to pursue the trial.
    OR
    - L2, M or Ms neuroblastoma with MYCN amplification
    2) Age < 21 years
    3) Complete response (CR) or partial response (PR) at metastatic sites:
    -Bone disease: MIBG uptake (or FDG-PET uptake for MIBG-nonavid tumors) completely resolved or SIOPEN score ≤ 3 and at least 50% reduction in mIBG score (or ≤ 3 bone lesions and at least 50% reduction in number of FDG-PET-avid bone lesions for MIBG-nonavid tumors).
    -Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria [Park JR, JCO 2017; Burchill S, Cancer 2017].
    -Other metastatic sites: complete response after induction chemotherapy +/- surgery.
    4) Acceptable organ function and performance status
    -Performance status ≥ 50%.
    -Hematological status: ANC>0.5x109/L, platelets > 20x 109/L
    -Cardiac function: Shortening fraction ≥ 28% or ejection fraction ≥ 55% by echocardiogram, no clinical congestive heart failure. Normal pulmonary artery pressure.
    -Normal chest X-ray and oxygen saturation.
    -Absence of any toxicity ≥ grade 3.
    5) Sufficient collected stem cells available; minimum required: 6 x 106 CD34+ cells/kg body weight stored in 3 separate fractions.
    6) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomization.
    7) Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
    8) Patients should be able and willing to comply with study visits and procedures as per protocol.

    if the following criteria are met:
    1) No evidence of disease progression after HDC/ASCR.
    2) Interval between the last ASCR and radiotherapy start between 60 and 90 days.
    3) Performance status greater or equal 50%.
    4) Hematological status: ANC >0.5x109/L, platelets > 20x109/L.
    5) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomization.
    6) Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
    7) Patients should be able and willing to comply with study visits and procedures as per protocol.
    R-I κριτήρια επιλεξιμότητας:
    1) Επιβεβαιωμένη διάγνωση νευροβλαστώματος σύμφωνα με τα κριτήρια της Διεθνούς Ομάδας Κινδύνου Νευροβλαστώματος (INRG) τροποποιημένη από τη SIOPEN. Το νευροβλάστωμα υψηλού κινδύνου οριζόμενο ως εξής:
    -Σταδίου M νευροβλάστωμα ηλικίας άνω των 365 ημερών κατά τη διάγνωση (χωρίς ανώτερο όριο ηλικίας) και Ms νευροβλάστωμα ηλικίας 12-18 μηνών, με οποιαδήποτε κατάσταση του MYCN*
    ή
    -Νευροβλάστωμα L2, M ή Ms με ενίσχυση του MYCN, οποιασδήποτε ηλικίας
    *Στη Γερμανία, ασθενείς ηλικίας κάτω των 18 μηνών με στάδιο M και χωρίς ενίσχυση του MYCN δεν θα ενταχθούν στη δοκιμή HR-NBL2.
    2) Χωρίς προηγούμενη χημειοθεραπεία (εκτός από έναν κύκλο Ετοποσίδης-Καρβοπλατίνης ή, στη Γερμανία και στην Ολλανδία, ένα κύκλο του τρέχοντος πρωτοκόλλου για νευροβλάστωμα χαμηλού/ενδιάμεσου κινδύνου).
    3) Οι γυναίκες σε αναπαραγωγική ηλικία πρέπει να φέρουν αρνητικό τεστ εγκυμοσύνης στον ορό ή στα ούρα εντός 7 ημερών πριν από την έναρξη της θεραπείας. Οι σεξουαλικά ενεργοί ασθενείς πρέπει να συμφωνήσουν να χρησιμοποιούν αποδεκτή και κατάλληλη αντισύλληψη κατά τη διάρκεια χορήγησης του υπό μελέτη φαρμάκου και για ένα έτος μετά τη διακοπή του. Η αποδεκτή αντισύλληψη ορίζεται στις Οδηγίες CTFG «Συστάσεις σχετικά με την αντισύλληψη και τον έλεγχο της εγκυμοσύνης σε κλινικές δοκιμές» (Παράρτημα 11). Οι γυναίκες που θηλάζουν πρέπει να συμφωνήσουν να σταματήσουν το θηλασμό.
    4) Έγγραφη συναίνεση μετά από ενημέρωση για την ένταξη στο τυχαιοποιημένο σκέλος R-I από τον ασθενή ή τους γονείς/νόμιμο εκπρόσωπο, και την κατάλληλη ηλικιακή συναίνεση του ασθενούς.
    5) Σύνδεση με πρόγραμμα κοινωνικής ασφάλισης ή δικαιούχο αυτού σύμφωνα με τις τοπικές απαιτήσεις.
    6) Ασθενείς ικανοί και πρόθυμοι να συμμορφωθούν με τις επισκέψεις ης μελέτης και τις διαδικασίες σύμφωνα με το πρωτόκολλο.

    R-HDC κριτήρια επιλεξιμότητας:
    1) - Σταδίου M νευροβλάστωμα άνω των 365 ημερών κατά τη διάγνωση, οποιαδήποτε κατάσταση του MYCN, ΕΞΑΙΡΟΥΝΤΑΙ οι ασθενείς με στάδιο Μ ή Μs 12-18 μηνών με αποκλειστικά αριθμητικές χρωμοσωμικές ανωμαλίες και με πλήρη μεταστατική ανταπόκριση στο τέλος της θεραπείας εφόδου. Σε αυτήν την περίπτωση, οι ασθενείς θα υποβάλλονται σε χειρουργική επέμβαση αλλά δεν θα θεωρούνται επιλέξιμοι για R-HDC και δεν θα είναι σε θέση να συνεχίσουν στη μελέτη.
    Ή
    - L2, M ή Ms νευροβλάστωμα με ενίσχυση του MYCN
    2) Ηλικία <21 ετών
    3) Πλήρης ανταπόκριση (CR) ή μερική ανταπόκριση (PR) των μεταστατικών εστιών:
    -Οστική νόσος: η πρόληψη MIBG (ή η πρόσληψη της FDG-PET για MIBG-μη ενεργούς όγκους) να έχει υποχωρήσει πλή ρως ή το MIBG score να είναι ≤ 3 και να παρατηρείται τουλάχιστον 50% μείωση στο MIBG score (ή να υπάρχουν ≤ 3 οστικές βλάβες και τουλάχιστον 50% μείωση στον αριθμό των FDG- PET-ενεργών οστικών βλαβών για MIBG-μη ενεργείς όγκους).
    -Nόσος μυελού των οστών: CR και/ή υπολλειματική νόσος (MD) σύμφωνα με τα Διεθνή Κριτήρια Ανταπόκρισης Νευροβλαστώματος [Park JR, JCO 2017; Burchill S, Cancer 2017].
    -Άλλες μεταστατικές περιοχές: πλήρης ανταπόκριση μετά από χημειοθεραπεία εφόδου +/- χειρουργική επέμβαση.
    4) Αποδεκτή οργανική λειτουργία και κατάσταση λειτουργικότητας
    -Κατάσταση λειτουργικότητας ≥ 50%.
    -Αιματολογική κατάσταση: ANC>0.5x109/L, αιμοπετάλια > 20x 109/L
    -Καρδιακή λειτουργία: Κλάσμα βράχυνσης (shortening fracion) ≥ 28% ή κλάσμα εξώθησης≥55% στο ηχοκαρδιογράφημα, χωρίς κλινική συμφορητική καρδιακή ανεπάρκεια. Φυσιολογική πίεση της πνευμονικής αρτηρίας.
    -Φυσιολογική ακτινογραφία θώρακος και κορεσμός οξυγόνου.
    -Απουσία τοξικότητας ≥ βαθμού 3.
    5) Επαρκή συλλεγμένα αρχέγονα αιμοποιητικά κύτταρα. Ελάχιστο απαιτούμενο: 6x106 CD34+ κύτταρα/kg σωματικού βάρους αποθηκευμένο σε 3 ξεχωριστά κλάσματα.
    6) Έγγραφη συναίνεση μετά από ενημέρωση, συμπεριλαμβανομένης της συμφωνίας του ασθενούς ή των γονέων/νόμιμου κηδεμόνα για ανηλίκους, για την ένταξη στην τυχαιοποίηση R-HDC.
    7) Σύνδεση με πρόγραμμα κοινωνικής ασφάλισης ή δικαιούχο του ιδίου σύμφωνα με τις τοπικές απαιτήσεις.
    8) Ασθενείς ικανοί και πρόθυμοι να συμμορφωθούν με τις επισκέψεις της μελέτης και τις διαδικασίες σύμφωνα με το πρωτόκολλο.

    R-RTx εάν τα παρκάτω κριτήρια πληρούνται:
    1) Απουσία ενδείξεων εξέλιξης της νόσου μετά από HDC/ASCR.
    2) Διάστημα μεταξύ της τελευταίας ASCR και της έναρξης της ακτινοθεραπείας μεταξύ 60 και 90 ημερών.
    3) Κατάσταση λειτουργικότητας μεγαλύτερη ή ίση με 50%.
    4) Αιματολογική κατάσταση: ANC>0.5x109/L, αιμοπετάλια>20x109/L.
    5) Έγγραφη συναίνεση μετά από ενημέρωση, συμπεριλαμβανομένης της συμφωνίας του ασθενούς ή των γονέων/νόμιμου κηδεμόνα για ανηλίκους, για ένταξη στην τυχαιοποίηση R-RTx.
    6) Σύνδεση με πρόγραμμα κοινωνικής ασφάλισης ή δικαιούχο του ιδίου σύμφωνα με τις τοπικές απαιτήσεις.
    7) Ασθενείς ικανοί και πρόθυμοι να συμμορφωθούν με τις επισκέψεις μελέτης και τις διαδικασίες σύμφωνα με το πρωτόκολλο.
    E.4Principal exclusion criteria
    Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) :
    1) Urinary outflow obstruction
    2) severe arrhythmia, heart failure, previous cardiac infarct, acute inflammatory heart disease
    3) severe peripheral neuropathy
    4) demyelinating form of Charcot-Marie-Tooth syndrome
    5) hearing impairment
    6) Concurrent prophylactic use of phenytoin
    7) cardiorespiratory disease that contraindicates hyperhydration

    Non-inclusion criteria common to all randomizations (R-I, R-HDC and R-RTx) :
    1) Any negative answer concerning the inclusion criteria of R-I or R-HDC or R-RTx will render the patient ineligible for the corresponding therapy phase randomization. However, these patients may remain on study and be considered to receive standard treatment of the respective therapy phase, and may be potentially eligible for subsequent randomizations.
    2) Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood bilirubin > 1.5 x ULN (toxicity ≥ grade 2). In case of toxicity ≥ grade 2, call national principal investigator study coordinator to discuss the feasibility.
    3) Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m² (toxicity ≥ grade 2). If GFR < 60ml/min/1.73m², call national principal investigator to discuss.the feasibility.
    4) Dyspnea at rest and/or pulse oximetry <95% in air.
    5) Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
    6) Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.
    7) Participating in another clinical study with an IMP while on study treatment.
    8) Concomittant use with yellow fever vaccine and with live virus or bacterial vaccines.
    9) Patient allergic to peanut or soya.
    10) Chronic inflammatory bowel disease and/or bowel obstruction.
    11) Pregnant or breastfeeding women.
    12) Known hypersensitivity to the active substance or to any of the excipients of study drugs known
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    13) Concomitant use with St John’s Wort (Hypericum Perforatum).
    Κριτήρια μη-επιλογής ειδικά για την τυχαιοποίηση R-I (RAPID COJEC/GPOH) :
    1) Απόφραξη της ουροφόρου οδού
    2) Σοβαρή αρρυθμία, καρδιακή ανεπάρκεια, προηγούμενο καρδιακό έμφρακτο, οξεία φλεγμονώδης καρδιακή νόσος
    3) Σοβαρή περιφερική νευροπάθεια
    4) Απομυελινωτική μορφή του συνδρόμου Charcot-Marie-Tooth
    5) Προβλήματα ακοής
    6) Ταυτόχρονη προφυλακτική χρήση φαινυτοΐνης
    7) Καρδιοαναπνευστική νόσος όπου αντενδείκνυται η υπερενυδάτωση

    Κριτήρια μη-επιλογής κοινά για όλες τις τυχαιοποιήσεις (R-I, R-HDC και R-RTx):
    1) Οποιαδήποτε αρνητική απάντηση σχετικά με τα κριτήρια εισαγωγής των R-I ή R-HDC ή R-RTx θα καταστήσει τον ασθενή μη κατάλληλο για την θεραπεία της αντίστοιχης τυχαιοποίησης . Ωστόσο, αυτοί οι ασθενείς μπορεί να παραμείνουν στη μελέτη και να θεωρηθεί ότι λαμβάνουν την καθιερωμένη θεραπεία της αντίστοιχης φάσης θεραπείας και ενδεχομένως να καταστούν επιλέξιμοι για τις επόμενες τυχαιοποιήσεις.
    2) Ηπατική λειτουργία: Αμινοτρανσφεράση της αλανίνης (ALT) > 3.0 x ULN και χολερυθρίνη αίματος > 1.5 x ULN (τοξικότητα ≥ βαθμού 2). Σε περίπτωση τοξικότητας ≥ βαθμού 2, καλέστε τον εθνικό συντονιστή μελέτης και τον εθνικό ερευνητή για να συζητήσετε τη σκοπιμότητα.
    3) Νεφρική λειτουργία: κάθαρση κρεατινίνης και/ή GFR<60 ml/min/1.73m² (τοξικότητα ≥ βαθμού 2). Εάν GFR<60ml/min/1.73m², καλέστε τον κύριο εθνικό ερευνητή για να συζητήσετε τη σκοπιμότητα.
    4) Δύσπνοια σε ηρεμία ή/και παλμική οξυμετρία <95% στον αέρα.
    5) Οποιαδήποτε ανεξέλεγκτη συννοσηρότητα ή λοίμωξη που κατά τη γνώμη του ερευνητή θα επηρεάσει τη συμμετοχή στη μελέτη.
    6) Ασθενής υπό κηδεμονία ή στερούμενος της ελευθερίας του με δικαστική ή διοικητική απόφαση ή ανίκανος να δώσει τη συναίνεση του.
    7) Συμμετοχή σε άλλη κλινική μελέτη με IMP ενώ βρίσκεται σε θεραπεία μελέτης.
    8) Ταυτόχρονη χρήση εμβολίου κατά του κίτρινου πυρετού και εμβόλια ζωντανών ιών ή βακτηρίων.
    9) Ασθενής αλλεργικός στο φιστίκι ή στη σόγια.
    10) Χρόνια φλεγμονώδης νόσος του εντέρου και/ή απόφραξη του εντέρου.
    11) Έγκυες ή θηλάζουσες γυναίκες.
    12) Γνωστή υπερευαισθησία στη δραστική ουσία ή σε κάποιο από τα γνωστά έκδοχα των φαρμάκων υπό μελέτη.
    13) Ταυτόχρονη χρήση του St John’s Wort (Hypericum Perforatum, αλσαμόλαδο, υπερικό ή βαλσαμόχορτο, σπαθόχορτο).
    E.5 End points
    E.5.1Primary end point(s)
    R-I: 3-year EFS from date of R-I randomization
    R-HDC: 3-year EFS from date of R-HDC randomization
    R-RTx: 3-year EFS from date of RTx randomization
    R-I: 3-ετής EFS από την ημέρα της R-I τυχαιοποίησης
    R-HDC: 3-ετής EFS από την ημέρα της R-HDC τυχαιοποίησης
    R-RTx: 3-ετής EFS από την ημέρα της RTx τυχαιοποίησης
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 years
    3 έτη
    E.5.2Secondary end point(s)
    For the whole population of high-risk neuroblastoma:
     3- and 5-year EFS, PFS and OS calculated from date of randomization
    For each treatment phase:
     5-year EFS, 3- and 5-year PFS and OS calculated from date of randomization
     Cumulative incidence of relapse/progression
     Cumulative incidence of treatment related mortality and of disease related mortality
     Overall response as per the new INRG response criteria [Park JR, JCO 2017] (including primary tumor after induction), skeletal response on MIBG, bone marrow response, local control
     Therapy-related toxicity
    Για ολόκληρο τον πληθυσμό νευροβλαστώματος υψηλού κινδύνου:
    -3- και 5-ετής EFS, PFS και OS που υπολογίζονται από την ημερομηνία τυχαιοποίησης
    Για κάθε φάση θεραπείας:
    -5-ετής EFS, 3- και 5-ετής PFS και OS που υπολογίζονται από την ημερομηνία της τυχαιοποίησης.
    -Αθροιστική συχνότητα υποτροπής/εξέλιξης.
    -Αθροιστική συχνότητα θνητότητας που σχετίζεται με τη θεραπεία και θνητότητας που σχετίζεται με την νόσο.
    -Συνολική ανταπόκριση σύμφωνα με τα νέα κριτήρια ανταπόκρισης INRG [Park JR, JCO 2017] (συμπεριλαμβανομένου του πρωτοπαθούς όγκου μετά τη χημειοθεραπεία εφόδου), σκελετική ανταπόκριση σε MIBG, ανταπόκριση μυελού των οστών, τοπικός έλεγχος.
    -Τοξικότητα σχετιζόμενη με τη θεραπεία.
    E.5.2.1Timepoint(s) of evaluation of this end point
    5 years
    5 έτη
    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 No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Croatia
    Czechia
    Denmark
    Finland
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Lithuania
    Netherlands
    New Zealand
    Norway
    Poland
    Portugal
    Serbia
    Slovakia
    Slovenia
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years11
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years12
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 800
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 5
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 380
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 355
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 50
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Written informed consent will be obtained from the patient or any approved guardian prior to performing any trial related procedure
    Γραπτή συγκατάθεση μετά από ενημέρωση θα λαμβάνεται από τον ασθενή ή οποιονδήποτε εγκεκριμένο κηδεμόνα πριν από την εκτέλεση οποιασδήποτε διαδικασίας που σχετίζεται με τη δοκιμή
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 550
    F.4.2.2In the whole clinical trial 800
    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
    ΚΑΝΕΝΑ
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation SIOPEN
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-11-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-21
    P. End of Trial
    P.End of Trial StatusOngoing
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