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    Summary
    EudraCT Number:2018-002898-21
    Sponsor's Protocol Code Number:CAMN107AIT15
    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:2021-01-21
    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 number2018-002898-21
    A.3Full title of the trial
    A phase II, single-arm, multicenter study of full treatment-free remission in patients with chronic myeloid leukemia in chronic phase treated with nilotinib in first-line therapy who have achieved a sustained deep molecular response for at least 1 year: DANTE study
    Studio di fase II, multicentrico, con singolo braccio di trattamento, sulla remissione totale libera da trattamento in pazienti con leucemia mieloide cronica in fase cronica trattati con nilotinib in terapia di prima linea che hanno ottenuto una risposta molecolare profonda sostenuta per almeno un anno: studio DANTE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of full treatment-free remission in patients with chronic myeloid leukemia treated with nilotinib
    Studio sulla remissione totale libera da trattamento a dosaggio standard in pazienti con leucemia mieloide cronica trattati con nilotinib
    A.3.2Name or abbreviated title of the trial where available
    DANTE study
    Studio DANTE
    A.4.1Sponsor's protocol code numberCAMN107AIT15
    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 SponsorNOVARTIS FARMA S.P.A.
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Farma S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farma S.p.A.
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityOriggio
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number0296541
    B.5.5Fax number029659066
    B.5.6E-mailinfo.studiclinici@novartis.com
    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 TASIGNA - 150 MG - CAPSULA RIGIDA - USO ORALE - BLISTER(PVC/PVDC/AL) 112 CAPSULE
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/06/375
    D.3 Description of the IMP
    D.3.1Product namenilotinib
    D.3.2Product code [AMN107]
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.3Other descriptive nameTasigna
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Yes
    D.2.1.1.1Trade name TASIGNA - 200 MG CAPSULA RIGIDA - USO ORALE BLISTER (PVC/PVDC/AL) 112 CAPSULE
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/06/375
    D.3 Description of the IMP
    D.3.1Product namenilotinib
    D.3.2Product code [AMN107]
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.3Other descriptive nameTasigna
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Patients with chronic myeloid leukemia in chronic phase treated with nilotinib in first-line therapy who have achieved a sustained, deep molecular response for at least 1 year.
    Pazienti con leucemia mieloide cronica in fase cronica trattati con nilotinib in terapia di prima linea che hanno ottenuto una risposta molecolare profonda sostenuta per almeno un anno.
    E.1.1.1Medical condition in easily understood language
    Adult patients with CML in chronic phase treated with nilotinib (Tasigna) who achieved a certain level of molecular response for at least 1 year before entering the study.
    Pazienti adulti con LMC in fase cronica trattati con nilotinib (Tasigna) che hanno raggiunto un certo livello di risposta molecolare per almeno 1 anno prima di entrare nello studio.
    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 10054352
    E.1.2Term Chronic phase chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase.
    Determinare la percentuale di pazienti in remissione libera dal trattamento a dosaggio standard Full Treatment –Free Remission a 96 settimane dopo l’inizio della fase di consolidamento.
    E.2.2Secondary objectives of the trial
    • To determine the percentage of patients who remain in sustained DMR at the end of the consolidation phase (week 48).
    • To determine the percentage of patients who remain in DMR at the end of the consolidation phase (week 48), at 96 weeks and at 144 weeks after the start of the study.
    • To determine the percentage of patients in full treatment-free remission at 144 weeks after the start of the consolidation phase.
    • To determine the percentage of patients with Major Molecular Response (MMR) or better at 48, 96 and 144 weeks after starting the consolidation phase regardless of whether they required reinitiation of treatment.
    • To characterize the kinetics of BCR-ABL transcript after restart of nilotinib therapy in patients who failed the TFR phase.
    For further secondary objectives please refer to the protocol.
    • Determinare la percentuale di pazienti che rimangono in DMR sostenuta al termine della fase di consolidamento (settimana 48).
    • Determinare la percentuale di pazienti che rimane in DMR al termine della fase di consolidamento (settimana 48), a 96 settimane e a 144 settimane dopo l’inizio dello studio.
    • Determinare la percentuale di pazienti in remissione libera dal trattamento a dosaggio standard (full treatment - free remission) a 144 settimane dopo l’inizio della fase di consolidamento.
    • Determinare la percentuale di pazienti con risposta molecolare maggiore (Major Molecular Response – MMR) o migliore a 48, 96 e 144 settimane dopo l’inizio della fase di consolidamento indipendentemente dal fatto che abbiano avuto o meno necessità di ricominciare il trattamento.
    • Caratterizzare la cinetica del trascritto BCR-ABL dopo la ripresa della terapia con nilotinib in pazienti per cui la fase TFR è fallita.
    Per ulteriori obiettivi secondari fare riferimento al protocollo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female patients 18 years or older.
    2. Diagnosis of CML-CP according to the World Health Organization.
    3. Patients with CML-CP under treatment with nilotinib at the approved daily dose of 300 mg BID mg for at least 3 calendar years.
    4. Sustained DMR for at least one year at screening, defined as MR4.5 (BCR-ABL level = 0.0032% IS) or undetectable MR4.0 (undetectable BCR-ABL level (IS) with assay sensitivity of 4.0 log in 3 of the last 4 quarterly BCR-ABL RQ-PCR assessments, and with the last assessment also in MR4.5 or undetectable MR4.0.
    5. Patient must meet the following laboratory values at the screening visit:
    • Absolute Neutrophil Count =1.5 x 109/L
    • Platelets =75 x 109/L
    • Hemoglobin (Hgb) = 9 g/dL
    • Serum creatinine < 1.5 mg/dL
    • Total bilirubin = 1.5 x ULN
    • Aspartate transaminase (AST) = 3.0 x ULN
    • Alanine transaminase (ALT) = 3.0 x ULN
    • Serum lipase = 2 x ULN
    6. Eastern Cooperative Oncology Group performance status 0-2.
    7. Study subjects must be able to comply with study procedures and follow-up examinations.
    1. Pazienti di sesso maschile e femminile di età uguale o superiore a 18 anni.
    2. Diagnosi di CML-CP secondo l’Organizzazione Mondiale della Sanità (World Health Organization – WHO).
    3. Pazienti con CML-CP in trattamento con nilotinib alla dose giornaliera approvata di 300 mg BID da almeno 3 anni di calendario.
    4. DMR sostenuta da almeno un anno allo screening, definita come MR4.5 (livello di BCR-ABL = 0.0032% IS) o MR4.0 non rilevabile (livello di BCR-ABL non rilevabile IS) con saggio di sensibilità di 4.0 log in 3 delle ultime 4 valutazioni trimestrali di BCR-ABL RQ-PCR, e con anche l’ultima valutazione MR4.5 o MR4.0 non rilevabile.
    5. I pazienti devono soddisfare i seguenti valori di laboratorio alle visite di screening:
    • Conta assoluta dei neutrofili 1.5 x 109/L
    • Piastrine =75 x 109/L
    • Emoglobina (Hgb) = 9 g/dL
    • Creatinina sierica < 1.5 mg/dL
    • Bilirubina totale = 1.5 x ULN
    • Aspartato transaminasi (AST) = 3.0 x ULN
    • Alanina transaminasi (ALT) = 3.0 x ULN
    • Lipasi sierica = 2 x ULN
    6. Eastern Cooperative Oncology Group performance status 0-2.
    7. I soggetti in studio devono essere in grado di aderire alle procedure di studio e alle valutazioni di follow-up.
    E.4Principal exclusion criteria
    1. Patients with known atypical transcript.
    2. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past).
    3. Dose reductions due to neutropenia or thrombocytopenia in the past 6 months.
    4. Patient ever attempted to permanently discontinue imatinib or nilotinib treatment.
    5. Known impaired cardiac function including any one of the following:
    • Inability to determine QT interval on ECG
    • Complete left bundle branch block
    • Long QT syndrome or a known family history of long QT syndrome
    • History of or presence of clinically significant ventricular or atrial tachyarrhythmias
    • Clinically significant resting bradycardia
    • QTcF > 480 msec
    • History or clinical signs of myocardial infarction within 1 year prior to study entry
    • History of unstable angina within 1 year prior to study entry
    • Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or uncontrolled hypertension)
    6. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol.
    7. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
    8. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
    9. History of other active malignancy within 5 years prior to study entry except for previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively.
    10. Patients who have not recovered from prior surgery.
    11. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1.
    12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
    13. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry.
    14. Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.
    15. Pregnant or nursing (lactating) women.
    16. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 14 days after stopping medication. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate treatment with nilotinib during pregnancy.
    For further exclusion criteria please refer to the protocol.
    1. Pazienti con trascritto atipico noto.
    2. Mutazioni resistenti al trattamento per CML (T315I, E255K/V, Y253H, F359C/V) rilevate se il test è stato effettuato in passato (non è richiesta l’effettuazione del test mutazionale al momento dell’ingresso nello studio se non è stato effettuato in passato).
    3. Riduzioni di dosaggio dovute a neutropenia o trombocitopenia nei 6 mesi precedenti.
    4. Pazienti che non hanno mai provato a interrompere in modo permanente il trattamento con imatinib o nilotinib.
    5. Noto deterioramento della funzionalità cardiaca, compreso uno qualsiasi dei seguenti:
    • Impossibilità di determinare l’intervallo QT all’ECG
    • Blocco di branca sinistra completo
    • Sindrome del QT lungo o anamnesi familiare nota di sindrome del QT lungo
    • Anamnesi o presenza di tachiaritmie atriali o ventricolari clinicamente significative
    • Bradicardia a riposto clinicamente significativa
    • QTcF > 480 msec
    • Anamnesi o segni clinici di infarto miocardico nell’anno precedente l’ingresso in studio
    • Anamnesi di angina instabile nell’anno precedente l’ingresso in studio
    • Altre patologie cardiache clinicamente significative (ad esempio scompenso cardiaco congestizio o ipertensione non controllata)
    6. Malattia concomitante severa e/o non controllata che, a giudizio dello sperimentatore, potrebbe causare rischi di sicurezza inaccettabile o compromettere l’aderenza al protocollo.
    7. Anamnesi di pancreatite acuta nell’anno precedente l’ingresso in studio o anamnesi pregressa di pancreatite cronica.
    8. Nota presenza di disturbo emorragico congenito o acquisito significativo non correlato al cancro.
    9. Anamnesi di altra patologia maligna attiva nei 5 anni precedenti l’ingresso in studio, ad eccezione di carcinoma cutaneo basocellulare pregresso o concomitante, carcinoma cervicale in sito pregresso trattato in modo curativo.
    10. Pazienti ancora in fase di convalescenza per un intervento chirurgico precedente.
    11. Trattamento con altri agenti sperimentali (definiti come non utilizzati in accordo all’indicazione approvata) nelle 4 settimane precedenti il Giorno 1.
    12. Deterioramento della funzionalità gastrointestinale (GI) o malattia GI che potrebbe alterare in modo significativo l’assorbimento del farmaco in studio (ad es. patologia ulcerativa, nausea non controllata, vomito, sindrome da malassorbimento, resezione dell’intestino tenue o intervento chirurgico per bypass gastrico).
    13. Pazienti che ricevono attivamente una terapia con forti inibitori e/o induttori di CYP3A4, e il trattamento non può essere interrotto o non possono essere fatti passare ad un diverso trattamento prima dell’ingresso in studio.
    14. Pazienti che ricevono attivamente una terapia con trattamenti erboristici che sono forti inibitori e/o induttori di CYP3A4, e il trattamento non può essere interrotto o non possono essere fatti passare ad un diverso trattamento prima dell’ingresso in studio. Tali trattamenti erboristici possono comprendere Echinacea (comprese E. purpurea, E. angustifolia e E. pallida), Piperina, Artemisinina, Iperico (erba di San Giovanni) e Ginkgo.
    15. Donne in gravidanza o allattamento.
    16. Donne potenzialmente fertili, definite come tutte le donne fisiologicamente in grado di iniziare una gravidanza, a meno che non utilizzino metodi contraccettivi di elevata efficacia durante la somministrazione e per almeno 14 giorni dopo aver interrotto il trattamento. Sono disponibili dati limitati sulle gravidanze in pazienti che cercano di ottenere la remissione libera da trattamento (TFR). Se la gravidanza viene pianificata durante la fase TFR, la paziente deve essere informata della potenziale necessità di riprendere il trattamento con nilotinib durante la gravidanza.
    Per ulteriori criteri di esclusione fare riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    BCR-ABL = 0.1% (IS) 96 weeks after the start of the consolidation phase.
    The proportion of patients in full treatment-free remission 96 weeks after the start of the consolidation phase is calculated by dividing the number of patients with no loss of MMR after 96 weeks by the number of patients who entered the consolidation phase.
    Patients who require re-initiation of standard dosage during TFR or during the consolidation phase for loss of MMR, and those discontinued from the study before week 96 will be considered failures.
    Determinare la percentuale di pazienti in remissione totale libera da trattamento (FTFR).
    La proporzione di pazienti in FTFR 96 settimane dopo l’inizio della fase di consolidamento è calcolata dividendo il numero di pazienti senza perdita di MMR dopo 96 settimane per il numero di pazienti che sono entrati nella fase di consolidamento.
    I pazienti che necessitano di riprendere la dose standard durante la TFR o durante la fase di consolidamento per perdita di MMR, e i pazienti che hanno interrotto lo studio prima della settimana 96 saranno considerati insuccessi.
    E.5.1.1Timepoint(s) of evaluation of this end point
    96 weeks after the start of the consolidation phase.
    96 settimane dopo l’inizio della fase di consolidamento.
    E.5.2Secondary end point(s)
    Sustained DMR: Molecular Response (MR) 4.5 (IS) or undetectable MR4.0 with assay sensitivity of 4.0 log in 3 of the 4 BCR-ABL qPCR monthly assessments performed.
    The proportion of patients in sustained DMR at the end of the consolidation phase (week 48) is calculated by dividing the number of patients in sustained DMR at week 48 by the number of patients who entered the consolidation phase.; DMR: MR4.5 or undetectable MR4.0.
    The proportion of patients in deep molecular response is calculated by dividing the number of patients in DMR 48, 96 and 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.; BCR-ABL = 0.1% (IS).
    The proportion of patients in full treatment-free remission at week 144 is calculated by dividing the number of patients with no loss of MMR 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.; BCR-ABL = 0.1% (IS).
    The proportion of patients with MMR at week 48, 96 and 144 is calculated by dividing the number of patients with MMR at week 48, 96 and 144, regardless of whether they required re-initiation of treatment after the start the study, by the number of patients who entered the consolidation phase.; BCR-ABL transcript levels (IS) in patients who failed TFR phase.; BCR-ABL transcript levels (IS) in patients in TFR phase.; BCR-ABL transcript levels (IS).; FTFS.; TFS.; PFS.; PFS.; OS.; Type, frequency and severity of adverse events, laboratory values that fall outside of the pre-determined ranges and clinically notable ECG and other safety data.; Successful FTFR and TFR - no loss of MMR and no reinitiation of nilotinib therapy.
    DMR sostenuta: risposta molecolare (MR) 4,5 (IS) o MR4.0 non rilevabile con sensibilità del test di 4,0 log in 3 delle 4 valutazioni mensili del qPCR BCR-ABL eseguite.
    La proporzione di pazienti in DMR sostenuta alla fine della fase di consolidamento (settimana 48) viene calcolata dividendo il numero di pazienti in DMR sostenuta alla settimana 48 dal numero di pazienti che sono entrati nella fase di consolidamento.; DMR: MR4.5 o MR4.0 non rilevabile.
    La proporzione di pazienti in risposta molecolare profonda è calcolata dividendo il numero di pazienti in DMR 48, 96 e 144 settimane dopo l'inizio della fase di consolidamento per il numero di pazienti che sono entrati nella fase di consolidamento.; BCR-ABL = 0,1% (IS).
    La proporzione di pazienti in completa remissione senza trattamento alla settimana 144 viene calcolata dividendo il numero di pazienti senza perdita di MMR 144 settimane dopo l'inizio della fase di consolidamento per il numero di pazienti che sono entrati nella fase di consolidamento.; BCR-ABL = 0,1% (IS) 48, 96, 144 settimane dopo l'inizio della fase di consolidamento.
    La proporzione di pazienti con MMR alla settimana 48, 96 e 144 viene calcolata dividendo il numero di pazienti con MMR alla settimana 48, 96 e 144, indipendentemente dal fatto che richiesero la ripresa del trattamento dopo l'inizio dello studio, per il numero di pazienti che sono entrati nella fase di consolidamento.; Livelli di trascrizione BCR-ABL (IS) in pazienti che hanno fallito la fase di TFR.; Livelli di trascrizione BCR-ABL (IS) in pazienti in fase di TFR.; Livelli di trascrizione BCR-ABL (IS).; FTFS.; TFS.; PFS.; PFS.; OS.; Tipo, frequenza e gravità degli eventi avversi, valori di laboratorio che non rientrano negli intervalli predeterminati e ECG clinicamente rilevante e altri dati sulla sicurezza.; Tasso di FTFR e TFR di successo - nessuna perdita di MMR e nessuna reiniziazione della terapia con nilotinib.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 4 months, and with the last assessment in MR4.5 or undetectable MR4 before entering the TFR phase.; At week 48, 96 and 144 after the start of the consolidation phase.; 144 weeks after the consolidation phase.; 48, 96, 144 weeks after the start of the consolidation phase.; After restart of nilotinib therapy.; After discontinuation of nilotinib therapy.; During the consolidation period.; From the start of the consolidation phase to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to accelerated phase (AP)/blast crisis (BC), or death due to any cause.; From the start of the TFR phase to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to
    Ogni 4 mesi e con l'ultima valutazione in MR4.5 o non rilevabile MR4 prima di entrare nella fase TFR.; Alla settimana 48, 96 e 144 dopo l'inizio della fase di consolidamento.; 144 settimane dopo l'inizio della fase di consolidamento.; Alla settimana 48, 96, 144 settimane dopo l'inizio della fase di consolidamento.; Dopo il riavvio della terapia con nilotinib.; Dopo interruzione della terapia con nilotinib.; Durante il periodo di consolidamento.; Dall'inizio della fase di consolidamento alla prima occorrenza di uno qualsiasi dei seguenti eventi: perdita di MMR, reiniziazione del trattamento a causa di qualsiasi causa, passaggio alla fase accelerata (AP) / crisi blastica (BC), o morte dovuta per qualsiasi causa.; Dall'inizio della fase di TFR alla prima occorrenza di uno dei seguenti eventi:
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 No
    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 years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 56
    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 state136
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 136
    F.4.2.2In the whole clinical trial 136
    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 still in study treatment with nilotinib will return to treatment with commercial nilotinib at the end of the study.
    I pazienti ancora in trattamento con nilotinib alla fine studio ritorneranno al trattamento con nilotinib presente in commercio.
    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 Decision2018-10-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-14
    P. End of Trial
    P.End of Trial StatusOngoing
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