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    The EU Clinical Trials Register currently displays   38465   clinical trials with a EudraCT protocol, of which   6316   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2018-001795-38
    Sponsor's Protocol Code Number:ALLTogether1
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-11-12
    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 ConcernedFinland - Fimea
    A.2EudraCT number2018-001795-38
    A.3Full title of the trial
    ALLTogether1– A Treatment study protocol of the ALLTogether Consortium for children and young adults (1-45 years of age) with newly diagnosed acute lymphoblastic leukaemia (ALL)
    ALLTogether1- Akuuttia lymfoblastileukemiaa (ALL) sairastavien lasten ja
    nuorten aikuisten hoitotutkimus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study protocol for children and young adults 1-45 years of age with newly diagnosed acute lymphoblastic leukaemia (ALL)
    Akuuttia lymfoblastileukemiaa (ALL) sairastavien lasten ja nuorten aikuisten
    hoitotutkimus
    A.3.2Name or abbreviated title of the trial where available
    ALLTogether1
    ALLTogether1
    A.4.1Sponsor's protocol code numberALLTogether1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04307576
    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 SponsorKarolinska University Hospital
    B.1.3.4CountrySweden
    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 supportThe Swedish Cancer Foundation
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportPfizer
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportServier
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportAmgen
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportSwedish Research Council
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportNova LAboratories Ltd
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportNordForsk
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportDanish Childhood Cancer Foundation
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportDanish Cancer Society
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportNovo Nordic Foundation
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKarolinska Institutet
    B.5.2Functional name of contact pointKarin Flood
    B.5.3 Address:
    B.5.3.1Street AddressKarolinska Institutet, Dept for Women's and Childrens Health, Tomtebodavägen 18 A
    B.5.3.2Town/ cityStockholm
    B.5.3.4CountrySweden
    B.5.4Telephone number0046703214922
    B.5.6E-mailkarin.flood@ki.se
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 nameDoxorubicin
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    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.3.9.3Other descriptive nameDOXORUBICIN
    D.3.9.4EV Substance CodeSUB06391MIG
    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 RoleComparator
    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 nameDexamethasone
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDexamethasone
    D.3.9.3Other descriptive nameDEXAMETHASONE
    D.3.9.4EV Substance CodeSUB07017MIG
    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 RoleComparator
    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 nameVincristine
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVincristine
    D.3.9.3Other descriptive nameVINCRISTINE SULFATE
    D.3.9.4EV Substance CodeSUB05101MIG
    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.2.1.1.1Trade name Besponsa
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1127
    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.3.9.1CAS number 635715-01-4
    D.3.9.3Other descriptive nameINOTUZUMAB OZOGAMICIN
    D.3.9.4EV Substance CodeSUB33081
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 No
    D.3.11.9Recombinant medicinal product Yes
    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.3.1Product nameMethotrexate
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameMETHOTREXATE
    D.3.9.4EV Substance CodeSUB08856MIG
    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.3.1Product nameImatinib
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 152459-95-5
    D.3.9.3Other descriptive nameIMATINIB
    D.3.9.4EV Substance CodeSUB25387
    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.3.1Product name6-mercaptopurine (InO)
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMERCAPTOPURINE
    D.3.9.1CAS number 50-44-2
    D.3.9.4EV Substance CodeSUB12149MIG
    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.3.1Product nameMethotrexate
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameMETHOTREXATE
    D.3.9.4EV Substance CodeSUB08856MIG
    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.3.1Product nameCytarabine
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameCYTARABINE
    D.3.9.4EV Substance CodeSUB06880MIG
    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.3.1Product namePrednisolone sodium succinate
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1715-33-9
    D.3.9.3Other descriptive namePREDNISOLONE SODIUM SUCCINATE
    D.3.9.4EV Substance CodeSUB04019MIG
    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.3.1Product nameMethylprednisolone sodium succinate
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameMETHYLPREDNISOLONE SODIUM SUCCINATE
    D.3.9.4EV Substance CodeSUB14562MIG
    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.3.1Product nameHydrocortisone sodium succinate
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameHYDROCORTISONE SODIUM SUCCINATE
    D.3.9.4EV Substance CodeSUB02569MIG
    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: 13
    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 nameDexamethasone
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDexamethasone
    D.3.9.3Other descriptive nameDEXAMETHASONE
    D.3.9.4EV Substance CodeSUB07017MIG
    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: 14
    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 nameVincristine
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVincristine
    D.3.9.3Other descriptive nameVINCRISTINE SULFATE
    D.3.9.4EV Substance CodeSUB05101MIG
    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: 15
    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 Blincyto
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/650
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for concentrate and solution 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 INNBlinatumomab
    D.3.9.3Other descriptive nameBLINATUMOMAB
    D.3.9.4EV Substance CodeSUB35403
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38.5
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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: 16
    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 name6-mercaptopurine (TEAM)
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMERCAPTOPURINE
    D.3.9.1CAS number 50-44-2
    D.3.9.4EV Substance CodeSUB12149MIG
    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: 17
    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 No
    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 name6-tioguanine
    D.3.4Pharmaceutical form Oral suspension
    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.3.8INN - Proposed INNTIOGUANINE
    D.3.9.1CAS number 154-42-7
    D.3.9.4EV Substance CodeSUB11084MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Acute lymphoblastic leukaemia (ALL)
    Akuutti lymfoblastileukemia
    E.1.1.1Medical condition in easily understood language
    Blood cancer in children and young adults
    Lasten ja nuorten aikusiten verisyöpä
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000844
    E.1.2Term Acute lymphoblastic leukaemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of ALLTogether is to improve survival and quality of survival in children and young adults with acute lymphoblastic leukaemia by a number of interventions that will be tested in a randomised fashion, compared with well-defined control-populations within the Protocol or explored in a non-randomised fashion either to obtain baseline information regarding characteristics, leukaemia-specific outcomes and toxicity or to be compared with well defined historical controls. A sub-group of patients will be identified that may benefit from novel (CAR-T) immunotherapy.
    ALLTogetherin ensisijaisena tavoitteena on parantaa akuuttia lymfoblastileukemiaa sairastavien lasten ja nuorten aikuisten
    henkiinjäämistä ja elämänlaatua hoidon jälkeen. Tähän pyritään toimilla, joista osa on satunnaistettuja ja verrokkeina toimivat tällä samalla
    hoitoprotokollalla hoidetut tarkoin määritellyt potilasryhmät. Osa toimenpiteistä ei ole satunnaistettu, vaan niiden avulla pyritään
    keräämään tietoa leukemian ominaisuuksista, leukemiaan liittyvistä vastetapahtumista ja hoidon haittavaikutuksista historiallisiin kontrolleihin verrattuna. Hoitoprotokollan puitteissa tunnistetaan pieni potilasryhmä, joka saattaa hyötyä kohdennetusta immnoterapiasta (CART)
    E.2.2Secondary objectives of the trial
    •To investigate if SR-& IR-low patients can benefit from de-intensification of therapy. Overall survival(OS) and leukaemia outcomes are balanced against toxicity including relapse treatment. Quality of life(QoL) measurements will ascertain and compare the burden of therapy
    •To ascertain if addition of Inotuzumab(InO) or low-dose 6-thioguanine (TEAM) impacts OS or other adverse outcomes and to assess if the toxicity induced by InO/TEAM is significant & acceptable. QoL measurements will assess the burden of the experimental intensifications
    •For patients treated with TKI, baseline data regarding OS, adverse outcomes, toxicity and QoL will be collected for future reference
    •To ascertain if replacing conventional chemotherapy with blinatumomab can improve leukaemic outcomes and reduce toxicity in Down patients
    •For patients defined as eligible for CAR-T survival, specific leukaemic adverse events, toxicity & QoL resulting from conventional HR-therapy & CAR-T cell treatment is measured
    - Tutkia, onko hoidon keventämisestä hyötyä SR ja IR_pieni riskin potilaille. Vastemuuttujana arvioidaan kokonaishenkiinjäämisen (OS) ja leukemiaan liittyvien haittoja suhteessa hoidon aiheuttamiin haittavaikutuksiin. Elämänlaatumittauksin (QoL) arvioidaan hoidon aiheuttamaa taakkaa.
    -Tutkia vaikuttaako inotutsumabi (InO) tai matala-annoksinen tioguaniini (TEAM) henkiinjäämiseen tai leukemian
    aiheuttamiin haittoihin. QoL arvioi hoitotaakkaa
    - TKI-lääkitystä saavilla potilailla mitataan kokonaishenkiinjäämistä,leukemian ja hoidon aiheuttamia haittoja ja
    elämänlaatua
    -tutkia tavanomaisen solunsalpaajahoidon korvaamista blinatumomabilla ja vaikutuksia hoidon tehoon
    - CAR-T hoitoon soveltuvien potilaiden vastemuuttujina ovat henkiinjääminen, leukemiaan ja hoidon aiheuttamat haitat sekä elämänlaatu ottaen huomioon sekä korkeariski solunsalpaajahoidon että CAR-T hoidon vaikutukset.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    •CSF-FLOW sub-study protocol, v 1.0 05Aug2019. Related objectives:
    -To use CSF FCM to improve diagnostic tests for CNS leukaemia compared to conventional CSF cytology and to develop a recommended protocol for CSF flow cytometry with external quality assessment to ensure uniformity of measurement
    -To investigate whether negative FCM identifies a group of children at very low risk of CNS relapse, suitable for testing de-escalation of CNS-directed therapy
    -To investigate whether positive FCM can identify children at increased risk of CNS relapse (FCM positive at day 15 onwards) might benefit from escalated CNS-directed therapy or a switch to more intensive treatment arms
    -To collect matching CSF supernatant for studies comparing CSF FCM with soluble biomarkers (e.g. metabolic, cell-free DNA, proteomic and microRNA)

    •Efficacy of Imatinib in ABL-class fusion positive ALL, v 1.0 05Aug2019. Related Objectives:
    -To determine the efficacy of imatinib in the treatment of ABL-class leukemia
    -To find the best biomarkers for TKI response in ABL-class ALL
    -To determine the frequency of intrinsic (at diagnosis) and acquired TKI resistance (due to treatment)
    -To find causes of TKI resistance in ABL-class patients
    -To determine the percent of ABL-class patients who need to switch from IR-high to HR because of high MRD levels
    -To determine the effect of imatinib exposure on clinical outcome
    -To determine the molecular response to imatinib by monitoring fusion transcript levels and mutational spectrum at diagnosis and during follow-up
    -To determine whether the molecular response parameters reflect the Ig/TCR MRD or flow-MRD response or are a better predictor of therapy failure than Ig/TCR or flow-based MRD monitoring
    -To determine the phosphorylation status of ABL-class proteins and presence of TKI-resistance associated mutations in ABL genes prior to and following imatinib treatment
    -To determine the presence of mutations in regulatory /other genes before and during imatinib treatment and address the importance of these mutations in TKI resistance
    -To determine whether the efficacy of TKIs depends on the type of fusion gene

    •Biomarkers to Reform Approaches to therapy-Induced Neurotoxicity (BRAIN) sub-study, v. 1.0 05Aug2019. Related objectives:
    -To institute universal screening of all children for adverse neurocognitive outcomes at the end of treatment using a validated user-friendly computer software programme (CogState) and compare neurocognitive outcomes by treatment allocation
    -To identify risk factors for adverse outcomes including whether acute neurotoxic events are associated with poor performance on cognitive tests at end of therapy compared to patients without acute neurotoxicity

    •A2G maintenance therapy pharmacokinetics/-dynamics sub-study, v 1.0 05Aug2019. Related objectives:
    -To map pharmacokinetics of 6MP and MTX during maintenance therapy in all patients in the A2G protocol
    -To associate metabolite profiles with TPMT and NUDT15 variants, as routinely analysed in A2G
    -To explore within the association of event-free survival with DNA-TG and other 6MP/MTX metabolites
    -To explore the association between risk of second cancers with DNA-TG and other 6MP/MTX metabolites
    -To explore the association of risk of invasive infections with DNA-TG and other 6MP/MTX metabolites
    -To explore the association of risk of osteonecrosis with DNA-TG and other 6MP/MTX metabolites
    -To explore the association of sinusoidal obstruction syndrome with DNA-TG and other 6MP/MTX metabolites

    •Association between asparaginase activity levels and outcome, v 1.0 05Aug2019. Related objectives:
    -To study the association between asparaginase activity levels and outcome ( MRD, relapse, survival)
    -To evaluate the association between asparaginase activity levels and toxicities, such as pancreatitis, infections and deep venous thrombosis (DVT)
    -To evaluate the association between asparaginase activity levels and hepatotoxicity
    - CSF-FLOW osatutkimuksen (v 1.0, 5.8.2019) tavoitteet:
    - verrata selkäydinnesteen (likvor) virtaussytometriaa (VSM) perinteiseen likvorin solututkimukseen keskushermostoleukemian toteamisessa tavoitteena luoda likvorin virtaussytometrian suorittamiselle suositukset ja laatukriteerit tasalaatuisuuden saavuttamiseksi
    -Tutkia, ennakoiko likvorin negatiivinen VSM pienempää keskushermostoleukemian riskiä, jota voidaan käyttää hoidon
    keventämiseen.
    - Tutkia tunnistaako likvorin VSM positiivisuus suuressa keskushermoston leukemian uusiutumisriskissä olevat potilaat hoidon tehostamista varten
    - kerätä likvorista näytteitä verrattavaksi virtaussytometrian kanssa (metaoliset markkerit, soluton DNA, proteomiikka ja mikroRNA)
    Imatinibin teho ABL-luokan fuusiopositiivisen ALL:n hoidossa (v1.0, 5.8.2019) tavoitteet
    -määrittää imatinibin teho ABL-luokan ALL:n hoidossa
    -Löytää parhaat tutkimukset TKI vasteen arviointiin ABL-luokan ALL:ssa
    -Tutkia leukemian luontaisen (jo diagnoosivaiheessa) ja hankitun TKIresistenssin yleisyyttä
    - Löytää syitä ABL-luokan ALL:n TKI resistenssiin
    - Tutkia, kuinka suuri osuus ABL-luokan leukemiapotilaista joutuu
    vaihtamaan jäännöstaudin vuoksi IR_suuri hoidosta korkeariskihoitoon
    - Arvioida imatinibin vaikutusta tuloksiin
    - Arvioida imatinibin vastetta molekyylitason jäännöstautiin mittaamalla
    fuusiotranskriptien määrää ja mutaatiokirjoa diagnoosivaiheessa ja
    seurannan aikana
    - Verrata jäännöstautianlyysin menetelmiä keskenään (molekylaarinen ,
    virtaussytometrinen ja immunoglobuliini- tai T solureseptorigeenin
    uudelleen järjetymään perustuva jäännöstautimittaus) hoitovasteen
    arviossa
    - Arvioida ABL-luokan proteiinien fosforylaatiotasoa ja TKIresistenssimutaatioiden määrää ennen ja imatinibihoidon aikana
    - Tutkia sääntely/muiden geenimutaatioiden määrää ennne hoitoa ja imatinibihoidon aikana ja arvioida näiden mutaatioiden merkitystä TKI
    resistenssin syntyyn
    - Tutkia vaikuttaako fuusiogeenin tyyppi TKI-lääkityksen tehoon
    Biologiset merkkiaineet hoidon aiheuttamien keskushermostohaittojen tunnistamisessa (v 1.0 5.8.2019) tavoitteet
    - Luoda yleisseulonta keskushermoston haittavaikutusten selvittämiseksi lapsuusikäisten ALL- hoidon päättyessä käyttäen helppokäyttöistä tietokoneohjelmaa (CogState)
    - Tunnistaa keskushermostohaittojen riskitekijöitä, mm. hoidonaikaisten keskushermosto-oireiden vaikutusta testisuoritumiseen.
    A2G ylläpitohoidon farmakokinetiikka/-dynamiikka osatutkimus v 1.0 5.8.2019 tavoitteet ovat:
    - Tutkia ylläpitohoidon aikana 6MP (merkaptopuriini) ja MTX (metotreksaatti) farmakokinetiikkaa kaikilla hoidetuilla potilailla
    - Tutkia metaboliittien kirjoa metaboloivien entsyymien aktiivisuuksien mukaan (TPMT, NUP15)
    - Tutkia DNA-TG ja muiden 6MP/MTX metaboliittien vaikutusta tapahtuma-vapaaseen henkiinjäämiseen (EFS)
    - Tutkia DNA-TG ja muiden 6MP/MTX metaboliittien vaikutusta toisen syövän syntyyn
    -Tutkia DNA-TG ja muiden 6MP/MTX metaboliittien vaikutusta vaikeiden infektioiden syntyyn
    - Tutkia DNA-TG ja muiden 6MP/MTX metaboliittien vaikutusta luukuolion syntyyn
    - Tutkia DNA-TG ja muiden 6MP/MTX metaboliittien vaikutusta maksan hattavaikutusten syntyyn (SOS)
    Asparaginaasiaktiivisuuden vaikutus hoitotulokseen osatutkimus v 1.0 5.8.2019 tavoitteena on
    - Tutkia asparaginaasiaktiivisuuden vaikutusta hoitotulokseen (jäännöstauti, uusiutuminen, henkiinjääminen)
    - Tutkia asparaginaasiaktiivisuuden vaikutusta hoidon haittavaikutuksiin kuten haimatulehdus ja syvä laskimotukos
    - Tutkia asparaginaasiaktiivisuuden vaikutusta maksan haittavaikutuksiin
    E.3Principal inclusion criteria
    1. Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopetic and Lymphoid Tissues (Revised 4th edition 2017) and with a diagnosis confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.
    2. Age ≥ 365 days and < 46 years (one day before 46th birthday) at the time of diagnosis.
    3. Informed consent signed by the patient and/or parents/legal guardians according to country-specific age-related guidelines (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199234.pdf ).
    4. The ALL diagnosis should be confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.
    5. The patient should be diagnosed and treated at a participating paediatric oncology or adult haematology centre in the participating countries.
    6. The patient should be a resident in one of the participating countries on a permanent basis or should intend to settle in a participating country, for instance by an application for asylum. Patients who are visiting the country as tourists should not be included. However, returning expatriots with primary diagnosis abroad may be included if no treatment has been administered and the diagnostic procedures are repeated at a participating centre.
    7. All women of childbearing potential (WOCBP) have to have a negative pregnancy test within 2 weeks prior to the start of treatment.
    8. For each intervention/randomisation an additional set of inclusion-criteria is provided.
    1. Potilaat, joilla on diagnosoitu tuore T-soluinen tai B-soluesiaste
    akuutti lymfoblastileukemia (ALL) WHO-luokituksen mukaisesti
    (Vertamuodostavan tai lymfaattisen kudoksen pahanlaatuiset sairaudet,
    revidoitu 4. painos, 2017) akkreditoidussa laboratoriossa joko lasten
    syöpää tai aikuisten veritauteja hoitavissa keskuksissa.
    2. Ikä tasan tai yli 365 päivää ja alle 46 v (1 päivä ennen
    46.syntymäpäivää) diagnoosihetkellä
    3. Potilaan ja/tai vanhempien ja/tai laillisen huoltajan allekirjoittama
    tietoinen suostumus kunkin maan säännösten mukaisesti.
    4. ALL-diagnoosi on tehty joko hoitotutkimukseen osallistuvan lasten
    syöpätauteja tai aikuisten veritauteja hoitavan yksikön kanssa
    yhteistyössä olevassa akkreditoidussa laboratoriossa
    5. Potilaan hoito toteutetaan hoitotutkimukseen osallistuvassa lasten
    syöpätauteja tai aikuisten veritauteja hoitavassa yksikössä
    6. Potilaan pitää asua pysyvästi tai suunnitella asettuvansa asumaan
    pysyvästi jossakin hoitotutkimukseen osallsituvassa maassa. Maassa
    vierailevat henkilöitä tai turisteja ei voida ottaa mukaan tähän
    hoitotutkimukseen. Kuitenkin paluumuuttajat voidaan ottaa mukaan
    hoitotutkimuskeen edellyttäen, että vaikka diagnoosi on tehty
    ulkomailla, hoito ei ole vielä alkanut jollain muulla hoito-ohjelmalla ja
    että diagnostiset toimenpiteet toistetaan hoitotutkimukseen
    osallistuvassa keskuksessa
    7. Fertiilissä iässä olevan naisen tulee osoittaa negatiivinen
    raskaustestitulos viikon sisällä ennen hoidon aloittamista
    8. Kuhunkin interventioon/satunnaistamiseen on esitetty erilliset
    lisäkriteerit sisäänotolle
    E.4Principal exclusion criteria
    1. Age < 365 days at diagnosis (infant ALL) or >45 years at diagnosis.
    2. Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN).
    3. Relapse of ALL.
    4. Patients with mature B-ALL (as defined by Surface Ig positivity or documented presence of one of the t(8;14), t(2;8), t(8;22) translocations and breakpoint as in B-ALL).
    5. Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR/ABL fusion transcript). These patients will be transferred to an adequate trial for t(9;22) if available.
    6. ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for Down syndrome. Exploration for such ALL prone syndromes is not mandatory.
    7. Treatment with systemic corticosteroids (>10mg/m2/day) for more than one week and/or other chemotherapeutic agents in a 4-week interval prior to diagnosis (pre-treatment).
    8. Pre-existing contraindications to any treatment according to the ALLTogether protocol (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate treatment).
    9. Any other disease or condition, as determined by the investigator, which could interfere with the participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures.
    10. Women of childbearing potential who are pregnant at the time of diagnosis.
    11. Women of childbearing potential and fertile men who are sexually active and are unwilling to use adequate contraception during therapy. Efficient birth control is required, see section 17.7.
    12. Female patients, who are breast-feeding.
    13. Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).
    14. For each intervention/randomisation an additional set of exclusion-criteria is provided.
    1. Ikä alle 365 päivää tai yli 45 v diagnoosivaiheessa
    2. Potilaat, joilla on aiemmin ollut muu pahanlaatuinen sairaus (ALL on
    toinen syöpä)
    4. Uusiutunut eli relapsoitunut ALL
    5. Potilaat, joilla on kypsä B-soluinen ALL (määriteltynä leukemiasolun
    pinnalla olevan Ig positiivisuuden mukaan tai leukemiasolussa todetaan
    t(8;21, t(2;8), t(8;22) translokaatio ja katkospaikat kromosomissa
    sopivat B-ALL:aan)
    6. Potilaat, joilla on Ph-positiivinen ALL (todettu t(9;22)(q34;q11) ja/tai
    BCR/ABL fuusiotranskriptin osoitus). Nämä potilaat tulee ohjata
    soveltuvaan kliiniseen hoitotutkimukseen, joka on tarkoitettu t(9;22)
    potilaille, jos sellainen on tarjolla
    7. ALL:lle altistava oireyhtymät (esim. Li-Fraumeni, ituradan ETV6
    mutaatio), paitsi Down syndrooma potilaat. Näiden oireyhtymien
    etsiminen erikseen ennen ALL hoidon aloittamista potilaalta ei ole
    pakollista
    8. Potilaan hoitaminen kortikosteroideilla (>10 mg/m2/päivä)
    pitempään kuin viikon ajan ja/tai muilla solunsalpaajilla edeltävien
    neljän viikon aikana ennen diagnoosia
    9. Ennalta tiedossa oleva vasta-aihe, joka estää ALLTogetherin mukaisen
    hoidon antamisen (synnynnäinen tai hankittu sairaus ennen ALL
    diagnoosia, joka ehkäisee riittävän hoidon antamisen)
    10. Mikä tahansa muu sairaus tai tila, joka tutkijan mukaan voi vaikuttaa
    potilaan osallistumiseen protokollan mukaiseen hoitoon tai potilaan
    kykyyn kommunikoida tai noudattaa hoitoon liittyviä hoito-ohjeita tai
    osallistua toimenpiteisiin
    11. Raskaana olevat naiset
    12. Fertiilissä iässä olevat naiset, jotka ovat seksuaalisesti aktiiveja eivätkä halua käyttää ehkäisyä hoidon aikana. Tehokas ehkäisy on
    hoidon edellytys, ks osa 17.7
    13. Naiset, jotka imettävät
    14. Diagnoosivaiheen tiedoista puuttuu oleellisia leukemiaan liittyviä
    tietoja
    15. jokaiseen interventioon/satunnaistamiseen liittyy erilliset
    lisäkriteerit poissulun suhteen
    E.5 End points
    E.5.1Primary end point(s)
    - The primary endpoint for the whole protocol (compared with the legacy protocols of the participating study-groups forming the consortium) is event-free survival (EFS) – as defined in the protocol.
    - The primary endpoint for the randomised interventions is disease-free survival (DFS) – as defined in the protocol.
    - The primary endpoint for the replacement of conventional chemotherapy for patients with Down syndrome and detectable MRD at the end of induction (ALLTogether1 DS) is the fraction of patients with undetectable MRD after one cycle of blinatumomab. This fraction will be compared with a well defined historic control cohort from the UKALL2011 protocol.
    - Koko hoitotutkimuksen ensisijainen päätetapahtuma (verrrattuna korsortiumin muodostavien tutkimusryhmien edeltäviin
    hoitotutkimuksiin) on tapahtumavapaa elossasäilyminen (EFS), kuten protokollassa on määritelty
    - Satunnaistettujen hoitotoimenpiteiden ensisijainen päätetapahtuma on tautivapaa elossasäilyminen (DFS), kuten se on protokollassa määritelty
    Tavanomaisen solunsalpaajahoidon korvaaminen Downin syndroomapotililta, joilla on alkuhoidon päätteeksi mitattavaa jäännöstautia (ALLTogether1 DS) on niiden potilaiden osuus, joilla ei ole mitattavaa jäännöstautia yhden blinatumomabi-syklin jälkeen. Tätä osuutta verrataan historiallisiin kontrllipotilaisiin (UKALL2011 hoito-ohjelma)
    E.5.1.1Timepoint(s) of evaluation of this end point
    EFS/DFS: 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up for all interventions except Inotuzumab-randomisation (minimum 2-year follow-up).
    In the ALLTogether1 DS sub-protocol, the primary endpoint will be evaluable after inclusion of the recruitment target (50 patients) and the last recruited of those patients being evaluable for MRD after one cycle of blinatumomab (approximately three months from diagnosis of the last patient).
    EFS/DFS: päätetapahtuman mittapisteeksi on sovittu 5 v, mutta molemmille päätetapahtumalle taataan riittävä seuranta-aika: vähintään 5 v kaikkien interventioiden jälkeen paitsi inotutsumabin jälkeen vähintään 2 v seuranta-aika.
    ALLTogether1 DS hoito-ohjelman ensisijainen päätetapahtuma voidaan arvioida potilasmäärän täytyttyä (50), jolloin saadaan jäännöstautinegatiivisten potilaiden osuus yhden blinatumomabi-syklin jälkeen (n 3 kk viimeisen potilaan diagnoosista)
    E.5.2Secondary end point(s)
    Main study secondary end-points
    The most important secondary outcome is overall survival (OS).

    Additional secondary measures of antileukaemic efficacy are: rate of -death during induction, -resistant disease, cumulative incidence of: -relapse (ciR), -death in first complete remission (ciDCR1) and -second malignancy (ciSMN).

    Over- and under-treatment events will also be combined into resulting treatment-related mortality (TRM) and leukaemia specific mortality (LSM) rates.

    Since over-treatment also includes cured patients who suffer potentially permanent side-effects, data will be collected regarding the incidence of some adverse events of special interest.
    De-escalation of therapy may also result in relapses that have to be rescued with allogeneic stem-cell transplant (allo-SCT), which is associated with serious permanent side effects. Therefore, the incidence of allo-HSCT in CR1 and CR2 will also be measured.
    An important aspect of evaluation of the quality of survival is measurement of quality of life (QoL). The whole protocol, as well as each of the non-randomised and randomised interventions will also be evaluated by measurements of quality of life (QoL). QoL will be measured by EQ5D-based instruments before and after all the randomised phases in all randomisations as well as later in the therapy and after cessation of treatment.

    R1 and R2 secondary end-points
    Efficacy:
    • Overall survival (OS)
    • Cumulative incidence of relapse (ciR)
    • Cumulative incidence of Death in CR1 (ciDCR1)
    • Cumulative incidence of SMN (ciSMN)
    • Fraction of surviving patients treated with allogeneic stem-cell transplant in second remission
    • Cumulative incidence of HSCT in CR2

    Toxicity:
    The studies are powered to answer the primary end-point non-inferiority question with a certain safety-margin. Even if reduction of exposure to potentially toxic therapy is an objective in itself, it is also reasonable to show some immediately measurable benefit from the reduction of therapy if the study is successful and non-inferiority can be shown.

    Non-lethal toxicities for the DI-phase (R1 and R2):
    • Rate of febrile neutropenia (yes/no) and agent (if isolated from a sterile site/blood)
    • Rate of invasive fungal infection (yes/no) together with assessment of “possible”/"probable”/”proven” and agent (if isolated from sterile site/blood/BAL)
    • Rate of serious viral reactivation (EBV, VZV, HSV and CMV), mucositis with need for intravenous analgesics and/or nutritional support with parenteral nutrition
    • The incidence of SAEs (except AESI)
    • The time-interval between the start of DI and the start of the next treatment- phase in days.
    • Rate of cardiac failure or serious arrhythmia (CTCAE ≥ grade 3)

    Quantifiable measures of the toxicities listed above (measured at the same time-points):
    • days admitted to hospital during the randomised phase and until the
    start of the next treatment phase
    • days on iv antibiotics
    • days on advanced antifungals
    • days on iv analgesics and/or nutritional support with parenteral nutrition

    Non-lethal toxicity for the Maintenance-phase (R2)
    Measured at the beginning of Maintenance and every 4 months during the maintenance-phase:
    • Rate of VCR-neuropathy Grade ≥3 according to the PdL definition
    • The number of doses of VCR that had to be reduced or omitted
    • Cumulative incidence of symptomatic osteonecrosis + grade.

    Follow-up end-point of obesity
    Body-mass index at the time of cessation of therapy and 5 years after the end of therapy.

    Secondary end-points R3-InO & R3-TEAM
    Efficacy:
    • Overall survival (OS)
    • Cumulative incidence of relapse (ciR)
    • Occurrence of CD22 negative relapse (InO)
    • Relation of all adverse outcomes with DNA-TG (TEAM)

    Toxicity InO & TEAM:
    • Incidence and severity of SOS/VOD all grades
    • Incidence and severity of other liver toxicity (defined as AST/ALT elevations grade > 3 and bilirubin grade > 3)

    Toxicity InO
    • Incidence and severity of infections CTCAE grade > 3
    • Incidence and duration of B-cell depletion reflected by immunoglobulin levels/IV immunoglobulin supplementation

    Toxicity TEAM
    • Cumulative incidence of SMN (ciSMN; TEAM)
    • Cumulative Incidence of NRH
    • Cumulative Incidence of osteonecrosis
    • Cumulative Incidence of hypoglycaemia

    Exploratory end-point (InO):
    CD22 expression level of leukemic cells in bone marrow samples at diagnosis and at TP2 (day 71).

    Secondary end-points ALLTogether1 DS
    • Event-Free Survival (EFS)
    • Overall survival (OS)
    • Cumulative incidence of relapse (ciR) and CD19 negative relapse
    • Cumulative incidence of Death in CR1 (ciDCR1)
    • Cumulative incidence of SMN (ciSMN)
    • Cumulative incidence of blinatumomab refractory disease
    • Cumulative incidence of Protocol Therapy Failure

    Exploratory end-point ALLTogether1 DS
    • MRD response at any timepoint within 2 cycles of blinatumomab
    Päätutkimuksen toissijaiset/muut päätetapahtumat
    Tärkein toissijainen päätetapahtuma on kokonaishenkiinjääminen (OS)
    Muut leukemiahoidon tehon mittarit ovat: Alkuhoidon aikaisten kuolemien määrä, hoitoon vastaamattoman taudin määrä; uusiutuneen
    leukemian esiintyvyys (ciR); remissiokuoleman esiintyvyys (ciDCR1) ja toisen syövän esiintyvyys (SMN)
    Yli- ja alihoidon tapahtumia yhdistetään hoitoon liittyväksi haittavaikutussuureeksi (TRM) ja leukemiaan liittyväksi haitta-suureeksi (LSM)
    Haittavaikutukset
    - Tutkimusten voima on ensisijaisen päätetahtuman osalta ei-huonompi asetelmassa vastauksen saamisen turvamarginaalilla. Mitataan myös
    välitöntä hyötyä hoidon keventämisestä (elämänlaatu).
    Ylihoidon pysyviä haittavaikutuksia arvioidaan
    Hoidon keventäminen voi johtaa leukemian uusiutuessa allogeeniseen kantasolusiirtoon (allo-SCT), joiden lukumäärää arvioidaan
    Henkiinjäämisen laadun arvioinnissa tärkeä mittari on elämänlaatumittaus (QoL). Elämänlaatumittaus suoritetaan EQ5Dmukaisella
    testillä ennen ja jälkeen kunkin satunnaistamisen, kuten myös hoidon myöhemmissä vaiheissa ja hoidon päättymisen jälkeen.
    R1 ja R2 toissijaiset päätetapahtumat
    Teho:
    - Kokonaishenkiinjääminen (OS); relapsien (ciR), remissiokuolemien (ciDCR1) ja toisen syövän (ciSMN) kokonaisesiintyvyys)
    Haittavaikutukset
    - tutkimusten voima on laskettu siten,e ttä saadaan ei- huonompi asetelmalla vastattua tutkimuskysymyksiin.
    Ei-kuolemaa aiheuttavat haitat myöhäisessä tehostevaiheessa (DI, R1 ja R2)
    - kuumeisen neutropenian määrä (kyllä/ei) ja aiheuttajat (osoitettuna steriilistä ympäristöstä/verestä)
    - Vaikeiden sieni-infektioiden määrä (kyllä/ei) arvioituna tasolla "mahdollinen"/"todennäköinen"/"osoitettu" ja aiheuttaja (osoitettu
    steriilissä ympäristössä/verestä/BALssa)
    - Vaikeiden virusinfektioiden aktivoituminen (EBV, vesirokko, HSV, CMV), limakalvotulehdus joka vaatii suoneenannosteltuna kipulääkityksen ja tai ravitsemustuen suoneen annettuna
    - Vakavien haittavaikutusten esiintyvyys (SAE) paitsi ( erityisen mielenkiinnon kohteena olevat haittavaikutukset AESI)
    - Aika DI-vaiheen (myöhäinen tehostevaihe) aloituksesta seuraavan hoitovaiheen aloitukseen (päiviä)
    - Sydämen vajaatoiminnan tai vaikeiden rytmihäisiöiden määrä (CTAE vähintään luokka 3)
    Edellä mainittujen mitattavien haittavaikutusten lisäksi samoissa aikapisteissä mitataan:
    - sairaalaan hoitopäivien määrä satunnaistetun vaiheen aikana seuraavan hoitovaiheen alkuun mennessä
    - antibioottihoidon kesto
    - sienilääkityksen kesto
    - suoneen annettavan kipulääkityksen/tai ravitsemustuen kesto
    Ei kuolemaan johtavat haittavaikutukset Ylläpitovaiheessa (R2)
    Mitataan Ylläpitohoidon alussa ja 4 kk välein hoitovaiheessa
    - vinkristiiniin liittyvän neuropatian määrä (PdL kriteerit)
    - Vinkristiinin annoksen vähennysten tai poisjättämisten määrä
    - Oireisten luunektoosien esiintyvyys ja vaikeusaste
    Seurannan päätetapahtuma lihavuus
    - PAinoindeksi hoidon päättyessä ja 5 v hoidon päättymisen jälkeen
    Toissijaiset vastemuuttujat R3-InO
    Teho:
    - kokonaishenkiinjääminen (OS); yhteenlaskettu relapsien esiintyvyys; CD22 negatiivisten relapsien määrä (InO); Haitttavaikutusten yhteys DNA-TG tasoon (TEAM)
    Haittavaikutukset InO&TEAM
    - Maksan spesifisten haittavaikutusten esiintyvyys SOS/VOD esiintyvyys ja vakavuus; Muiden maksan haittojen esiintyvyys ja vakavuus (ALAT/ASAT/Bil nousu >=vaikeusaste 3
    InO: Vaikeusasteeltaan >=3 olevien infektioiden määrä (CTAE luokitus); B-soluaplasian esiintyvyys ja kesto
    TEAM: Toisen syövän, NRH, luukuolion ja hypoglykemian esiintyvyys

    Tutkimuksellinen päätetapahtuma
    - CD22 ilmentyminen leukemiasolujen pinnalla luuydinnäytteissä diagnoosivaiheessa ja ajankohtana TP2 (päivä 71)
    Toissijaiset päätetapahtumat ALLTogether1 DS: Tapahtumavapaa henkiinjääminen (EFS); Kokonaishenkiinjääminen (OS); relapsien (ciR), remissiokuolemien (ciDCR1) ja toisen syövän (ciSMN) esiintyvyys; blinatumomabi ressitenssin esiintyvyys, protokolla ressitenssin esiintyvyys
    Tutkimuksellinen päätetapahtuma: jäännöstautivaste toisen blinatumomabi-syklin jälkeen
    E.5.2.1Timepoint(s) of evaluation of this end point
    Most efficacy-measures will be ascertained as 5-year estimates. In the R3-InO sub-protocol, the minimum follow-up for these measures will be 2 years from last inclusion, for all other sub-protocols, the minimum follow-up will be 5 years from last inclusion.
    In the ALLTogether1 DS sub-protocol, the cumulative incidence of blinatumomab refractory disease and cumulative incidence of Protocol Therapy Failure will be evaluable earlier, at approximately six months after last inclusion.
    Incidence, rates and frequencies of the toxicity end-points will be assessed at the end of therapy for all toxicities except obesity in R2, which is assessed finally 5 years after cessation of therapy.
    Kaikki hoidon tehoa mittaavat päätetapahtumat esitetään 5 v estimaatteina.
    R3-Ino hoitotutkimuksessa vähimmäisseuranta-aika on 2v viimeisestä infuusiosta, muissa osatutkimuksissa vähimmäisseuranta-aika on 5v viimeisen potilaan mukaan otosta.
    ALLTogether1 DS hoito-ohjelman päätetapahtumat (blinatumomabi-resistenssi ja protokolla-ressitenssi) voidaan arvioida aikaisemmin, noin 6 kk kuluttua viimeisimmän potilaan mukaan otosta.
    Haittavaikutukset päätetapahtumana arvioidaan esiintyvyyden, haittavaikutusten määrän ja yleisyyden avulla hoidon lopussa kaikkien
    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 Yes
    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 trial10
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA108
    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
    Last visit of the last subject
    viimeisen potilaan viimeinen kontrollikäynti
    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 Yes
    F.1.1Number of subjects for this age range: 6109
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 526
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 4678
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 905
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 321
    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
    Subjects under age incapable of giving consent personally and subjects with intellectual disabilities precluding personal consent (for instance some adult individuals with Down syndrome)
    Henkilöt, jotka eivät nuoren ikänsä vuoksi pysty itse antamaan tietoista
    suostumusta ja henkilöt, joiden henkisen suorituskyvyn heikkous tekee
    mahdottomaksi tietoisen suostumuksen antamisen (kuten aikuiset
    joilla on Downin syndrooma)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state300
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6430
    F.4.2.2In the whole clinical trial 6430
    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
    Ei
    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 Decision2019-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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