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    Summary
    EudraCT Number:2015-001151-68
    Sponsor's Protocol Code Number:TUD-APOLLO-064
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2019-02-19
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-001151-68
    A.3Full title of the trial
    A randomized Phase III study to compare arsenic trioxide (ATO) combined to ATRA and idarubicin versus standard ATRA and anthracycLines-based chemotherapy (AIDA regimen) for patient with newLy diagnosed, high-risk acute prOmyelocytic leukemia
    A randomized Phase III study to compare arsenic trioxide (ATO) combined to ATRA and idarubicin versus standard ATRA and anthracycLines-based chemotherapy (AIDA regimen) for patient with newLy diagnosed, high-risk acute prOmyelocytic leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study in which the assignment of patients to treatment is done with random method to compare a combination of drugs given to arsenic trioxide , standard ATRA and idarubicin with anthracycline -based chemotherapy in patients with newly diagnosed high- risk patients with acute promyelocytic leukemia .
    Studio in cui l'assegnazione del trattamento ai pazienti avviene con metodo casuale per confrontare un'associazione di farmaci data da Triossido di Arsenico, ATRA e Idarubicina con chemioterapia standard basata su antracicline in pazienti di nuova diagnosi ad alto rischio affetti da leucemia promielocitica acuta.
    A.3.2Name or abbreviated title of the trial where available
    APOLLO-TRIAL
    APOLLO-TRIAL
    A.4.1Sponsor's protocol code numberTUD-APOLLO-064
    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 SponsorTECHNISCHE UNIVERSITäT DRESDEN
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTeva Pharmaceuticals Europe B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Dresden Medizinische Klinik und Poliklinik I
    B.5.2Functional name of contact pointCoordination Study
    B.5.3 Address:
    B.5.3.1Street AddressFetscherstraße 74
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number+493514582583
    B.5.5Fax number+493514584367
    B.5.6E-mailuwe.platzbecker@uniklinikum-dresden.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TRISENOX - 1 MG/ML CONCENTRATO PER INFUSIONE ENDOVENOSA 10 FIALE 10 ML USO ENDOVENOSO
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA PHARMA B.V.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTriossido di arsenico
    D.3.9.1CAS number 1327-53-3
    D.3.9.2Current sponsor codeATO
    D.3.9.3Other descriptive name1327-53-3
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 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.3.4Pharmaceutical form Solution for injection
    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 INNIDARUBICINA CLORIDRATO (PER USO INIETTABILE)
    D.3.9.2Current sponsor codeIDA
    D.3.9.3Other descriptive nameIDARUBICINA CLORIDRATO (PER USO INIETTABILE)
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 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.3.4Pharmaceutical form Capsule, soft
    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 INNTRETINOINA
    D.3.9.2Current sponsor codeATRA
    D.3.9.3Other descriptive nameTRETINOINA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 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.3.4Pharmaceutical form Solution for infusion
    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 INNCITARABINA
    D.3.9.1CAS number 147-94-4
    D.3.9.2Current sponsor codeAra-C
    D.3.9.3Other descriptive nameCITARABINA
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 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.3.4Pharmaceutical form Solution for infusion
    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 INNMitoxantrone
    D.3.9.1CAS number 65271-80-9
    D.3.9.2Current sponsor codeMTZ
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 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.3.4Pharmaceutical form Tablet
    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 INN6- mercaptopurina
    D.3.9.1CAS number 50-44-2
    D.3.9.2Current sponsor code6MP
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy 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 promyelocytic leukemia
    Leucemia promielocitica acuta
    E.1.1.1Medical condition in easily understood language
    Blood cancer characterized by rapid development in excess of a specific type of cells contained in the blood and bone marrow which do not accrue over and invade the bone .
    Tumore del sangue, caratterizzato da un rapido sviluppo per eccesso di uno specifico tipo di cellule contenute nel sangue e nel midollo osseo le quali non maturano oltre ed invadono il midollo.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10001019
    E.1.2Term Acute promyelocytic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare event-free survival (EFS) of the experimental treatment arm including ATO/ATRA and idarubicin with standard treatment based on ATRA plus chemotherapy (AIDA regimen) in newly diagnosed high-risk APL
    Comparare la sopravvivenza libera da eventi (EFS) nel braccio di trattamento sperimentale con ATO/ATRA e idarubicina con il trattamento standard basato su ATRA più chemioterapia (regime AIDA) in pazienti con LAP ad alto rischio di nuova diagnosi
    E.2.2Secondary objectives of the trial
    - To compare CR, OS and CIR rates in the two arms
    - To compare early death rate during induction
    - To compare cumulative incidence of secondary MDS or AML
    - To compare quality of life in the two arms
    - To compare the toxicity profile in the two arms
    - To compare the kinetics of MRD in the two arms
    - To compare the duration of patient hospitalization in the two arms
    - To compare health economics in the two arms
    - remissione completa (CR), sopravvivenza globale (OS), incidenza cumulata di recidiva (CIR)
    - incidenza cumulata di mielodisplasia o leucemie secondarie
    - mortalità precoce durante la terapia di induzione
    - qualità della vita
    - profilo di tossicità
    - cinetica della malattia minima residua
    - durata dei ricoveri durante il trattamento
    - impatto economico dei trattamenti
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1.0-Tue Jun 09 00:00:00 CEST 2015- -The broad goal of QoL evaluation in this phase III study is to examine possible differences in key QoL aspects of high-risk APL adult patients treated with ATRA-chemotherapy (standard arm) versus ATRA-ATO therapy (experimental arm). This information will help better understand the overall treatment effectiveness of the newer therapy (i.e., ATRA-ATO) being tested. Based on our previous report, key selected scales have been chosen for the primary objective. QoL results of this trial will be reported in accordance with high methodological quality criteria for documenting patient-reported outcomes in RCTs so recommended by the CONSORT PRO Extension.
    To investigate possible differences in the following a priori selected scales: physical and cognitive functioning as well as fatigue, nausea and vomiting, constipation and appetite loss (outcome measure: EORTC QLQ-C30).
    • To investigate possible differences between treatment arms over time in all other QoL parameters assessed with the EORTC QLQ-C30 not considered in the primary objective.
    • to evaluate the relationship between self-reported fatigue (outcome measure: FACIT-Fatigue scale) and the overall change over time in other QoL parameters measured by the EORTC QLQ-C30 (i.e., functional and other symptom aspects).
    • To investigate the prognostic value of QoL parameters for overall survival. Fatigue and physical functioning will be regarded as the primary outcomes for prognostic factor analysis.
    1.0-Tue Jun 09 00:00:00 CEST 2015-Quality of Life Assessment-The broad goal of QoL evaluation in this phase III study is to examine possible differences in key QoL aspects of high-risk APL adult patients treated with ATRA-chemotherapy (standard arm) versus ATRA-ATO therapy (experimental arm). This information will help better understand the overall treatment effectiveness of the newer therapy (i.e., ATRA-ATO) being tested. Based on our previous report, key selected scales have been chosen for the primary objective. QoL results of this trial will be reported in accordance with high methodological quality criteria for documenting patient-reported outcomes in RCTs so recommended by the CONSORT PRO Extension.
    To investigate possible differences in the following a priori selected scales: physical and cognitive functioning as well as fatigue, nausea and vomiting, constipation and appetite loss (outcome measure: EORTC QLQ-C30).
    • To investigate possible differences between treatment arms over time in all other QoL parameters assessed with the EORTC QLQ-C30 not considered in the primary objective.
    • to evaluate the relationship between self-reported fatigue (outcome measure: FACIT-Fatigue scale) and the overall change over time in other QoL parameters measured by the EORTC QLQ-C30 (i.e., functional and other symptom aspects).
    • To investigate the prognostic value of QoL parameters for overall survival. Fatigue and physical functioning will be regarded as the primary outcomes for prognostic factor analysis.
    E.3Principal inclusion criteria

    - Informed consent
    - newly diagnosed APL by cytomorphology, confirmed also by molecular analysis*
    - Age ≥18 and ≤ 65 years
    - ECOG performance status 0-2
    - WBC at diagnosis > 10 Gpt/l
    - serum total bilirubin ≤ 3.0 mg/dl (≤ 51 µmol/l)
    - serum creatinine ≤ 3.0 mg/dl (≤ 260 µmol/l)
    - women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:
    o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml)
    o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
    o Continuous and correct application of a contraception method with a Pearl Index of <1% (e.g. implants, depots, oral contraceptives, intrauterine device – IUD).
    o Sexual abstinence
    o Vasectomy of the sexual partner

    * The confirmation of diagnosis at genetic level (microspeckled PML nuclear distribution by PGM3 monoclonal antibody and/or PML/RARa fusion by RT-PCR or fluorescence in situ hybridization (FISH) and/or demonstration of t(15;17) at karyotyping) will be mandatory for patient eligibility. However, in order to avoid delay in treatment initiation, patients can be randomized on the basis of morphologic diagnosis only and before the results of genetic tests are available.
    Consenso informato
    - Nuova diagnosi di LAP citomorfologica, confermata anche dalla analisi
    molecolare*
    - Età ≥18 e ≤ 65 anni
    - Performance status ECOG 0-2
    - WBC alla diagnosi > 10 GPt/l
    - bilirubina sierica totale ≤ 3.0 mg/dl (≤ 51 µmol/l)
    - creatinina sierica ≤ 3.0 mg/dl (≤ 260 µmol/l)
    - le donne devono rispettare almeno uno dei seguenti criteri per risultare
    eleggibili per l’inclusione nello studio:
    o Post-menopausa (12 mesi di amenorrea fisiologica o 6 mesi di amenorrea con FSH sierico > 40 U/ml)
    o Postoperatoria (i.e. 6 settimane) dopo ovariectomia bilaterale con o senza isterectomia
    o Utilizzo continuo e corretto di un metodo contraccettivo con un indice di Pearl <1% (i.e impianti, depots, contraccettivi orali, dispositivi intrauterini).
    o Astinenza sessuale
    o Vasectomia del partner sessuale

    * La conferma della diagnosi a livello molecolare (distribuzione nucleare microspeckled di PML tramite l’anticorpo monoclonale PGM3 e/o il gene di fusione PML/RARa tramite RT-PCR o fluorescence in situ hybridization (FISH) e/o dimostrazione della traslocazione t(15;17) al cariotipo) sarà obbligatoria per la eleggibilità dei pazienti. Tuttavia, allo scopo di evitare ritardi nell’inizio del trattamento, I pazienti possono essere randomizzati sulla base della sola diagnosi morfologica e prima che I risultati dei test genetici siano disponibili.
    E.4Principal exclusion criteria

    - Patients who are not eligible for chemotherapy as per discretion of the treating physician
    - Age <18 and > 65 years
    - WBC at diagnosis ≤ 10 Gpt/l
    - APL secondary to previous radio- or chemotherapy for non-APL disease
    - ECOG performance status >2
    - other active malignancy at time of study entry
    - lack of diagnostic confirmation at genetic level
    - Significant arrhythmias, ECG abnormalities or neuropathy:
     Congenital long QT syndrome;
     History or presence of significant ventricular or atrial tachyarrhythmia;
     Clinically significant resting bradycardia (<50 beats per minute)
     QTc >500msec on screening ECG for both genders (using the QTcF formula detailed on page 43-44)
     Right bundle branch block plus left anterior hemiblock, bifascicular block
    - other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
    - uncontrolled, life-threatening infections
    - severe non controlled pulmonary or cardiac disease
    -severe hepatic or renal dysfunction
    - known HIV and/or hepatitis C infection
    - pregnant or breast-feeding patients
    - allergy to trial medication or excipients in study medication
    - substance abuse, medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results
    - use of other investigational drugs at the time of enrolment or within 30 days before study entry
    - Pazienti che non sono eliggibili per la chemioterapia a discrezione del medico
    curante
    - Età <18 e > 65 anni
    - WBC alla diagnosi ≤ 10 GPt/l
    - LAP secondaria a precedente radio o chemioterapia per patologia diversa
    dalla LAP
    - Performance status ECOG>2
    - altre forme tumorali attive al momento dell’entrata nello studio
    - mancata conferma diagnostica a livello genetico
    - Aritmie significative, anomalie all’ECG o neuropatia:
    - Sindrome congenita del QT lungo;
    - Storia di presenza di tachiaritmie ventricolari o atriali significative;
    - Bradicardia a riposo clinicamente significativa (<50 battiti per minuto)
    - QTc >500msec all’ECG di screening in ambo i sessi
    - Blocco di branca destro più emiblocco sinistro anteriore, blocco bifascicolare,
    - altre controindicazioni cardiache alle chemioterapia intensiva (FEV-S <50%)
    - infezioni incontrollate, che pongono a rischio di vita
    - gravi e non controllabili patologie polmonari e cardiache
    - insufficienza epatica o renale grave
    - infezioni da HIV ed epatite C note
    - pazienti in corso di gravidanza o allattamento
    - allergia ai principi attivi o ad eccipienti contenuti nei farmaci dello studio
    - abuso di sostanze, condizioni mediche, psicologiche o sociali che possano
    interferire con la partecipazione dei pazienti allo studio o alla valutazione dei ù
    risultati dello studio
    - utilizzo di altri farmaci sperimentali al tempo dell’arruolamento o entro 30 giorni prima dell’arruolamento nello studio
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is event-free survival at 2 years. This is a time to event endpoint. This cumulative endpoint includes the following events: no achievement of hematological complete remission after induction therapy; no achievement of molecular remission after the last consolidation course (Arm A after 4 courses; Arm B after 3 courses) (molecular resistance); relapse (hematological/molecular); death including early death (within 30 days after randomization) or development of secondary myelodysplasia or leukemia .
    L’endopoint primario è la sopravvivenza libera da eventi a 2 anni. Gli eventi inclusi sono: fallito raggiungimento della remissione completa ematologica dopo la terapia di induzione; fallito raggiungimento della remissione molecolare dopo l’ultimo ciclo di consolidamento (Braccio A dopo 4 cicli; braccio B dopo 3 cicli) (resistenza molecolare); recidiva (ematologica/molecolare); mortalità che include la mortalità precoce (entro 30 giorni successivi la randomizzazione) o sviluppo di mielodisplasia o leucemia secondarie.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 2.5 years from last patient's randomization
    A 2.5 anni dalla randomizzazione dell'ultimo paziente
    E.5.2Secondary end point(s)
    - Rate of hematological CR after induction
    - Rate of early death during induction
    - Rate of overall survival (OS) at 2 years
    - Rate of cumulative incidence of secondary myelodysplasia or leukemia
    - Rate of cumulative incidence of relapse (CIR) at 2 years
    - Incidence of hematological and non-hematological toxicity
    - Rate of molecular remission after 3 consolidation cycles
    - Assessment of PML/RARA transcript level reduction during treatment
    - To investigate differences in the following a priori Quality of Life selected scales: physical and cognitive functioning as well as fatigue, nausea and vomiting, constipation and appetite loss
    - Total hospitalization days during therapy and health economic impact
    Remissione completa (CR); mortalità precoce durante la terapia di induzione; sopravvivenza globale (OS) a 2 anni; incidenza cumulata di mielodisplasia o leucemia secondarie; incidenza cumulata di recidiva (CIR) a 2 anni; profilo di tossicità ematologica e non ematologica; incidenza di remissione molecolare dopo 3 cicli di consolidamento; analisi della riduzione del livello del trascritto PML/RARA durante il trattamento; analisi della qualità della vita tramite differenti scale di riferimento (funzioni fisiche e cognitive); cinetica della malattia minima residua; durata dei ricoveri durante il trattamento; impatto economico dei trattamenti.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 2.5 years from the last patient's randomization, if not otherwise specified
    A 2.5 anni dall'ultimo paziente arruolato, se non diversamente specificato.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life
    Qualità della vita
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Terapia standard con ATRA e chemioterapia basata su antracicline (regime AIDA)
    Standard ATRA and anthracycLine-based chemotherapy (AIDA regimen)
    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 concerned54
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 280
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state44
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 280
    F.4.2.2In the whole clinical trial 280
    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)
    The patients will continue to be treated according to current clinical practise
    I pazienti continueranno ad essere trattati secondo pratica clinica corrente.
    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 Fondazione G.I.M.EM. A. Gruppo Italiano Malattie Ematologiche dell'Adulto
    G.4.3.4Network Country Italy
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-08-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-27
    P. End of Trial
    P.End of Trial StatusRestarted
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