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    Summary
    EudraCT Number:2019-003936-21
    Sponsor's Protocol Code Number:AML1919
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-17
    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 number2019-003936-21
    A.3Full title of the trial
    A Phase 3, prospective, randomized multi-center intervention trial of early intensification in AML patients bearing FLT3 mutations based on peripheral blast clearance. A MYNERVA-GIMEMA study.
    AMELIORATE (AML Early IntensificatiOn based on peRipheral blAsT clEarance).
    Studio interventistico di fase III, prospettico, randomizzato, multicentrico sulla intensificazione precoce del trattamento basata sulla Clearance dei Blasti Periferici in pazienti affetti da AML con mutazione FLT3. Studio MYNERVA-GIMEMA. AMELIORATE (AML Early IntensificatiOn based on peRipheral blAsT clEarance)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to identify the most appropriate therapy for patients with Acute Myeloid Leukemia carrying FLT3 mutation, using the PBC biomarker to customize therapy.
    Studio volto ad identificare la terapia più indicata per pazienti affetti da Leucemia Mieloide Acuta portatori di mutazione FLT3,utilizzando il biomarcatore PBC per personalizzare la terapia.
    A.3.2Name or abbreviated title of the trial where available
    AMELIORATE
    AMELIORATE
    A.4.1Sponsor's protocol code numberAML1919
    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 SponsorFONDAZIONE GIMEMA (GRUPPO ITALIANO MALATTIE EMATOLOGICHE DELL' ADULTO) FRANCO MANDELLI ONLUS
    B.1.3.4CountryItaly
    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 supportMYNERVA (MYeloid Neoplasms Research Venture AIRC) programma speciale finanziato dall'AIRC - Associazione Italiana per la
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportFondazione GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Franco Mandelli Onlus
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Franco Mandelli ONLUS
    B.5.2Functional name of contact pointCentro Dati GIMEMA
    B.5.3 Address:
    B.5.3.1Street Addressvia Casilina, 5 Roma
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00182
    B.5.3.4CountryItaly
    B.5.4Telephone number0670390526
    B.5.5Fax number0670390540
    B.5.6E-mailgimema@gimema.it
    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 ARACYTIN 500 mg/10 ml Polvere e Solvente per Soluzione Iniettabile
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER ITALIA S.R.L.
    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.3.1Product nameCitarabina
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCITARABINA
    D.3.9.1CAS number 147-94-4
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameAracytin
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.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 Myeloid Leukemia (LMA) with FLT3 mutation
    Leucemia Mieloide Acuta (LMA) con mutazione FLT3
    E.1.1.1Medical condition in easily understood language
    LMA disease linked to the proliferation of hematopoietic stem cells that do not mature and replace healthy tissue in the marrow producing altered cells that infiltrate other organs.
    LMA malattia legata alla proliferazione di cellule staminali ematopoietiche che non maturano e sostituiscono il tessuto sano nel midollo producendo cellule alterate che infiltrano altri organi.
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10000880
    E.1.2Term Acute myeloid leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10000880
    E.1.2Term Acute myeloid 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
    The primary objective of the trial is the improvement of outcome measured as event-free survival (EFS) in patients with FLT3+ acute myeloid leukemia who are predicted to have low chemosensitivity, by the measurement of “peripheral blast clearance (PBC)”, following the application of an early intensification of treatment, both in induction (high-doses delivery) and in consolidation (allocation to allogeneic transplant) phase, compared with standard regimens.
    L’obiettivo primario dello studio è il miglioramento dell’outcome misurato come event-free survival (EFS) in pazienti con LMA FLT3+ con ipotesi di bassa chemiosensibilità, misurata tramite PBC, dopo intensificazione precoce del trattamento, sia in fase di induzione (alte-dosi) sia di consolidamento (decisione di trapianto allogenico) rispetto ai regimi standard.
    E.2.2Secondary objectives of the trial
    1.Feasibility and safety of PBC-driven treatment, as assessed by:
    1-adverse events rate according to CTCAE criteria,
    2-rate of death in aplasia,
    3-days to neutrophil recovery and
    4-days to platelet recovery after induction and consolidation cycles, according to treatment arm
    2.Efficacy, in low PBC-patients, of PBC-driven treatment as assessed by:
    1-CR rate after first induction cycle,
    2-CR rate after two cycles,
    3-DFS,
    4-OS,
    5-CIR and TRM,
    6-MRD status,
    7- Allogeneic transplant rate in first CR and with active disease

    3. Evaluation of outcome for PBC-high patients treated per protocol (standard) and in comparison, with PBC-low treated as per randomization (standard vs experimental), as assessed by:
    1-CR rate after first induction cycle,
    2-CR rate after two cycles,
    3-DFS,
    4-OS,
    5-Cumulative incidence of relapse (CIR) and Treatment-related mortality (TRM),
    6-MRD status,
    7- Allogeneic transplant rate in first CR and with active disease
    1 Fattibilità e sicurezza del trattamento PBC-driven:
    1 Tasso di eventi avversi in accordo con i criteri CTCAE
    2 Tasso di morte in aplasia
    3 Giorni necessari per il recupero della conta neutrofila
    4 Giorni necessari per il recupero della conta piastrinica dopo i cicli di induzione e di consolidamento, a seconda del braccio di trattamento
    2 Efficacia in Pt PBC ridotta:
    1 CR dopo il primo ciclo di induzione
    2 CR dopo due cicli
    3 Sopravvivenza libera da malattia (DFS)
    4 Sopravvivenza globale (OS)
    5 Incidenza cumulativa di recidiva (CIR) e mortalità trattamento-correlata (TRM)
    6 Status della Malattia Minima Residua
    7 Trapianto allogenico in prima CR e con malattia attiva
    3.Valutazione dell’outcome per i Pt con elevata PBC trattati con terapia standard vs Pt con ridotta PBC trattati in maniera standard o sperimentale
    1 CR dopo il primo ciclo di induzione
    2 CR dopo due cicli
    3 DFS
    4 OS
    5 CIR e TRM
    6 Livelli di Malattia Minima Residua
    7 Trapianto allogenico in prima CR e con malattia attiva
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenetics
    Version: 1.0
    Date: 11/11/2019
    Title: Translational research
    Objectives: 1. To evaluate the prognostic impact of somatic mutations assessed at diagnosis on CR achievement and outcome (EFS, DFS, and OS) according to PBC and treatment arm 2. To evaluate changes in the somatic mutational pattern from diagnosis to relapse 3. To evaluate the prognostic value of genetic abnormalities assessed by nanopore sequencing at baseline 4. To compare MRD by RT-PCR and MFC on paired BM and PB samples at scheduled time-points and their prognostic impact on outcome 3.5. To evaluate the kinetics of MRD in high-risk patients based on ELN and at non-decisional time-points according to treatment protocol.

    Farmacogenetica
    Versione: 1.0
    Data: 11/11/2019
    Titolo: Ricerca Traslazionale
    Obiettivi: 1. Valutare l'impatto prognostico delle mutazioni somatiche valutate al momento della diagnosi sul raggiungimento e sull'esito della CR (EFS, DFS e OS) in base alla PBC e al braccio di trattamento 2. Valutare i cambiamenti nel modello mutazionale somatico dalla diagnosi alla ricaduta 3. Valutare il valore prognostico delle anomalie genetiche valutate mediante sequenziamento di nanopori al basale 4. Confrontare MRD mediante RT-PCR e MFC su campioni BM e PB accoppiati in punti temporali programmati e il loro impatto prognostico sull'esito 3.5. Valutare la cinetica della MRD nei pazienti ad alto rischio in base all'ELN e ai punti temporali non decisionali secondo il protocollo di trattamento.
    E.3Principal inclusion criteria
    1. Patients with de novo AML, untreated, newly diagnosed, according to WHO 2016 criteria
    2. Presence of a mutation of FLT3 gene, either ITD and/or TKD
    3. Adequate availability of diagnostic biologic material for full cytological, cytogenetic, genetic and immunophenotypic disease characterization according to ELN criteria.
    4. Presence of morphologically identifiable blasts on peripheral blood at diagnosis
    5. Presence of a Leukemia-associated aberrant immune-phenotype (LAIP) as assessed by MFC (multiparametric flow cytometry) at diagnosis
    6. Age between 18 and 65 years, included
    7. ECOG performance status 0-2 or disease-related reversible ECOG 3 score following adequate supportive care.
    8. Signed written informed consent according to ICH/EU/GCP and national local laws.
    1. Pazienti affetti da LMA di nuova diagnosi all’esordio, non precedentemente trattata, secondo i criteri diagnostici WHO 2016
    2. Presenza di mutazione del gene FLT3, o ITD e/o TKD
    3. Disponibilità adeguata del materiale biologico diagnostico per l’intera caratterizzazione citologica, citogenetica, genetica e immunofenotipica della malattia secondo i criteri ELN
    4. Presenza di blasti morfologicamente identificabili nel sangue periferico alla diagnosi
    5. Presenza di un profilo LAIP (Leukemia-associated aberrant immune-phenotype) come indicato da citometria a flusso multiparametrico (MFC) alla diagnosi
    6. Età compresa tra 18 e 65 anni, inclusi
    7. Performance status ECOG 0-2 o ECOG 3 correlato alla patologia, reversibile a seguito dell’adeguato trattamento di supporto.
    8. Firma del consenso informato scritto in accordo con le normative ICH/EU/GCP e le leggi nazionali.
    E.4Principal exclusion criteria
    1. Diagnosis of acute promyelocytic leukemia
    2. Diagnosis of AML with t(8;21)(q22:q22)/RUNX1-RUNX1T1 and t(16;16)(p13:q22) or inversion of chromosome 16 (16)(p13q22)/CBFB-MYH11; in case of suspicion of CBF-related AML due to morphological and/or immunophenotypic features, specific FISH or molecular testing is strongly recommended in accordance with WHO criteria3,157
    3. Patients with LVEF less than 45% (by echocardiogram or MUGA)
    4. Pre-existing, uncontrolled pathology such as heart failure (congestive/ischaemic, acute myocardial infarction within the post 3 months, untreatable arrhythmias, NYHA classes III and IV), sever liver disease with total bilirubin =2,5 x ULN and/or ALT>3 ULN (unless attributable to AML), acute or chronic pancreatitis, kidney function impairment with serum creatinine =2,5 (unless attributable to AML) and severe neuropsychiatric disorder that impairs the patient’s ability to understand and sign the informed consent or to cope with the intended treatment plan. For altered liver, pancreas and kidney function tests, eligibility criteria can be reassessed at 24-96 hours, following the institution of adequate supportive measures.
    4.5. Pre-existing HIV positive serology (i.e. already known before enrolment). The participation to the study will require serology testing for HIV positivity at baseline: in case of HIV positivity or refusal to perform HIV testing, the patient will be considered not eligible.
    5.6. Uncontrolled bacterial or fungal infections
    6.7. QTc >470 msec on screening ECG (Fridericia’s formula)
    7.8. A history of cancer that is not in remission phase following surgery and/or chemotherapy and/or radiotherapy with life expectancy < 1 year.
    8.9. Pregnancy declared by the patient herself. A pregnancy test is performed at diagnosis and, if applicable, before allogeneic HSCT. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 4 months after the end of treatment.
    1. Diagnosi di leucemia promielocitica acuta.
    2. Diagnosi di AML con t(8;21)(q22:q22)/RUNX1-RUNX1T1 e t(16;16)(p13:q22) o inversione del cromosoma 16 (16)(p13q22)/CBFB-MYH11; nel caso di sospetta AML CBF-correlata per caratteristiche morfologiche e/o immunofenotipiche, sono fortemente raccomandati il test FISH o l’analisi molecolare.
    3. Frazione di eiezione ventricolare sinistra < 45% (tramite ecocardiogramma o MUGA).
    4. Patologie pre-esistenti e non controllate, come insufficienza cardiaca (congestizia/ischemica, infarto acuto del miocardio negli ultimi 3 mesi, aritmia non controllata con terapia, classe III e IV del NYHA), grave patologia epatica con bilirubina sierica =2,5 x ULN e/o ALT >3 x ULN (a meno che non sia attribuibile alla AML) e grave disordine neuropsichiatrico che compromette la capacità del paziente di comprendere e firmare il consenso informato o l’aderenza al trattamento pianificato dallo studio. Per esami epatici, pancreatici e renali alterati i criteri per l’arruolamento possono essere valutati nuovamente a 24-96 ore, dopo aver adottato adeguate misure di supporto.
    5. Sierologia HIV positiva preesistente (ovvero già nota prima dell'arruolamento). La partecipazione allo studio richiederà test HIV sierologico al baseline: in caso di sieropositività o rifiuto di eseguire il test, il paziente sarà considerato non idoneo.
    6. Infezioni batteriche o fungine non controllate.
    7. QTc > 470 msec su ECG (formula di Fridericia).
    8. Una storia di cancro non in fase di remissione dopo chirurgia e/o chemioterapia e/o radioterapia con aspettativa di vita <1 anno.
    9. Gravidanza confermata dalla paziente stessa. Un test di gravidanza viene effettuato alla diagnosi e, se applicabile, prima del trapianto allogenico. Pazienti maschi e femmine potenzialmente fertili devono acconsentire all’utilizzo di un efficace metodo anticoncezionale dall’arruolamento fino ai 4 mesi successivi la fine del trattamento.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is to evaluate the event-free survival (EFS) at 2 years of an experimental intensified PBC-driven arm in comparison to a standard therapeutic regimen in patients with FLT3+ AML and low peripheral blood clearance (PBC) measured at day 4.
    L’endpoint primario è la valutazione dell’event-free survival a due anni in un braccio sperimentale PBC-driven a dosi intensificate in confronto a un regime terapeutico standard in pazienti con Leucemia Mieloide Acuta FLT3+ e ridotta peripheral blood clearance (PBC) misurata al giorno 4.
    E.5.1.1Timepoint(s) of evaluation of this end point
    EFS 2 years after treatment in the experimental arm;
    PBC measured on day 4 compared to day 1.
    EFS a 2 anni dal trattamento nel braccio sperimentale;
    PBC misurata al giorno 4 rispetto al giorno 1.
    E.5.2Secondary end point(s)
    1. Feasibility and safety of PBC-driven treatment:
    1. Adverse events rate according to CTCAE criteria according to PBC and treatment arm
    2. Rate of deaths in aplasia as per ELN 2017 definition according to PBC and treatment arm
    3. Days to neutrophils recovery after induction and consolidation cycles according to PBC and treatment arm
    4. Days to platelets recovery after induction and consolidation cycles according to PBC and treatment arm
    2. Efficacy, in low PBC-patients, of PBC-driven treatment:
    1. CR rate as per ELN 2017 definition after first induction cycle according to treatment arm
    2. CR rate as per ELN 2017 definition after two cycles according to treatment arm
    3. Disease-free survival (DFS) as per ELN 2017 definition according to treatment arm
    4. Overall survival (OS) as per ELN 2017 definition according to treatment arm
    5. Cumulative incidence of relapse (CIR) and Treatment-related mortality (TRM) according to treatment arm
    6. MRD status at pre-defined time-points as per ELN 2017 definition according to treatment arm
    7. Actual rate of patients receiving allogeneic transplant in first CR and with active disease according to treatment arm
    3. Evaluation of outcome for PBC-high patients treated per protocol (standard) and in comparison, with PBC-low treated as per randomization (standard vs experimental):
    1. CR rate as per ELN 2017 definition after first induction cycle according to PBC and treatment arm
    2. CR rate as per ELN 2017 definition after two cycles according to PBC and treatment arm
    3. Disease-free survival (DFS) as per ELN 2017 definition according to PBC and treatment arm
    4. Overall survival (OS) as per ELN 2017 definition according to PBC and treatment arm
    5. Cumulative incidence of relapse (CIR) and Treatment-related mortality (TRM) according to PBC and treatment arm
    6. MRD status at pre-defined time-points as per ELN 2017 definition according to PBC and treatment arm
    7. Actual rate of patients receiving allogeneic transplant in first CR and with active disease according to PBC and treatment arm
    1. Fattibilità e sicurezza del trattamento PBC- driven:
    1. Tasso di eventi avversi in accordo con i criteri CTCAE in base ai livelli PBC e al braccio di trattamento
    2. Tasso di decessi in aplasia secondo la definizione di ELN 2017 in base ai livelli PBC e al braccio di trattamento
    3. Giorni necessari per il recupero della conta neurofila dopo cicli di induzione e consolidamento in base ai livelli PBC e al braccio di trattamento
    4. Giorni necessari per il recupero della conta dopo i cicli di induzione e consolidamento in base ai livelli PBC e al braccio di trattamento
    2. Efficacia del trattamento PBC-driven nei pazienti con ridotta PBC, valutata tramite:
    1. Remissione Completa secondo la definizione di ELN 2017 dopo il primo ciclo di induzione e in base al braccio di trattamento
    2. Remissione Completa come da definizione ELN 2017 dopo due cicli in base al braccio di trattamento
    3. Sopravvivenza libera da malattia (DFS) secondo la definizione ELN 2017 secondo il braccio di trattamento
    4. Sopravvivenza globale (OS) secondo la definizione di ELN 2017 in base al braccio di trattamento
    5. Incidenza cumulativa di recidiva (CIR) e mortalità correlata al trattamento (TRM) in base al braccio di trattamento
    6. Status della Malattia Minima Residua in punti temporali predefiniti secondo la definizione ELN 2017 in base al braccio di trattamento
    7. Tasso effettivo di pazienti sottoposti a trapianto allogenico in prima CR e con malattia attiva in base al braccio di trattamento
    3. Valutazione dell’outcome per i pazienti con elevata PBC trattati con terapia standard comparato con pazienti con ridotta PBC trattati in maniera standard o sperimentale secondo randomizzazione, in termini di:
    1. Tasso di CR secondo la definizione di ELN 2017 dopo il primo ciclo di induzione in base ai livelli PBC e al braccio di trattamento
    2. Tasso di CR secondo la definizione di ELN 2017 dopo due cicli in base ai livelli PBC e al braccio di trattamento
    3. Sopravvivenza libera da malattia (DFS) secondo la definizione di ELN 2017 secondo PBC e braccio di trattamento
    4. Sopravvivenza globale (OS) secondo la definizione di ELN 2017 in base ai livelli PBC e al braccio di trattamento
    5. Incidenza cumulativa di recidiva (CIR) e mortalità correlata al trattamento (TRM) in base ai livelli PBC e al braccio di trattamento
    6. Stato MRD a punti temporali predefiniti secondo la definizione di ELN 2017 in base ai livelli PBC e al braccio di trattamento
    7. Tasso effettivo di pazienti sottoposti a trapianto allogenico in prima CR e con malattia attiva in base ai livelli PBC e al braccio di trattamento
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Feasibility and Safety:
    1. Throughout the course of the study;
    2. Throughout the course of the study;
    3. After the induction and consolidation cycles;
    4. After the induction and consolidation cycles.
    2. Effectiveness:
    1.After the first induction cycle;
    2. After 2 cycles depending on the treatment arm;
    3.During the entire course of the study;
    4.During the entire course of the study;
    5. Throughout the course of the study;
    6. Throughout the course of the study;
    7. Throughout the course of the study;
    3. Evaluation results comparing patients with high PBC (standard) and low PBC according to randomization (standard vs experimental):
    As for the Endpoint 2 - Effectiveness
    1. Fattibilità e Sicurezza:
    1. Durante tutto il corso dello studio;
    2. Durante tutto il corso dello studio;
    3. Dopo i cicli di induzione e consolidamento;
    4. Dopo i cicli di induzione e consolidamento.
    2. Efficacia:
    1.Dopo il primo ciclo di induzione;
    2. Dopo 2 cicli a seconda del braccio di trattamento;
    3.Durante tutto il corso dello studio;
    4.Durante tutto il corso dello studio;
    5. Durante tutto il corso dello studio;
    6. Durante tutto il corso dello studio;
    7. Durante tutto il corso dello studio;
    3. Valutazione risultati confronto pazienti con PBC alto (standard) e PBC basso secondo randomizzazione (standard vs sperimentale):
    Come per l'Endpoint 2 - Efficacia
    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 No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Comparazione terapia standard vs approccio terapeutico sperimentale
    Comparison of standard therapy vs. experimental therapeutic approach
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned25
    E.8.5The trial involves multiple Member States No
    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
    Last Visit Last Subject
    Ultima Visita dell'Ultimo Paziente
    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.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state172
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 172
    F.4.2.2In the whole clinical trial 172
    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)
    Patients will continue to be followed according to normal care provided by good clinical practice.
    I pazienti continueranno ad essere seguiti secondo la normale attività assistenziale prevista dalla buona pratica clinica.
    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 GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Franco Mandelli Onlus
    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 Decision2020-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-14
    P. End of Trial
    P.End of Trial StatusOngoing
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