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    Summary
    EudraCT Number:2014-005530-64
    Sponsor's Protocol Code Number:ACE-CL-006
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-18
    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 number2014-005530-64
    A.3Full title of the trial
    A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects with High Risk Chronic Lymphocytic Leukemia
    Studio di fase 3 randomizzato, multicentrico, in aperto, di non inferiorità con ACP-196 rispetto a ibrutinib in soggetti affetti da leucemia linfatica cronica ad alto rischio già precedentemente trattata.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase 3 Study of ACP-196 Versus Ibrutinib in Previously Treated Subjects with High Risk Chronic Lymphocytic Leukemia
    Studio di fase 3 randomizzato, multicentrico, in aperto, di non inferiorità con ACP-196 rispetto a ibrutinib in soggetti affetti da leucemia linfatica cronica ad alto rischio già precedentemente trattata.
    A.3.2Name or abbreviated title of the trial where available
    ACP-196
    ACP-196
    A.4.1Sponsor's protocol code numberACE-CL-006
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00000000
    A.5.4Other Identifiers
    Name:IND Number:118717
    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 SponsorACERTA PHARMA BV
    B.1.3.4CountryNetherlands
    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 supportAcerta Pharma BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointKellie Macleod
    B.5.3 Address:
    B.5.3.1Street AddressGranta Park
    B.5.3.2Town/ cityGreatr Abingdon
    B.5.3.3Post codeCB21 6GQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number004401309673279
    B.5.5Fax number0000000000000
    B.5.6E-mailKellie.Macleod@ppdi.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 No
    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/3/16/1624
    D.3 Description of the IMP
    D.3.1Product nameacalabrutinib
    D.3.2Product code [ACP-196]
    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 INNacalabrutinib
    D.3.9.1CAS number 1420477-60-6
    D.3.9.2Current sponsor codeACP-196
    D.3.9.3Other descriptive nameCML-1476 (CML)
    D.3.9.4EV Substance CodeSUB166233
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen Biotech
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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/3/12/984
    D.3 Description of the IMP
    D.3.1Product nameibrutinib
    D.3.2Product code [-]
    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.3.9.1CAS number 936563-96-1
    D.3.9.2Current sponsor codeN.A.
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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
    High Risk Chronic Lymphocytic Leukemia
    Leucemia linfatica cronica ad alto rischio
    E.1.1.1Medical condition in easily understood language
    Long term cancer of the blood
    Tumore del sangue a lungo termine
    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 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether ACP-196 is non-inferior to ibrutinib with respect to progression-free survival (PFS) based on independent review committee (IRC) assessment in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk prognostic markers
    Valutare se ACP-196 è non inferiore a ibrutinib per quanto riguarda la sopravvivenza libera da progressione (PFS) sulla base della valutazione del Comitato di revisione indipendente (IRC) in soggetti affetti da leucemia linfatica cronica (LLC) recidiva o refrattaria con marcatori prognostici di alto rischio.
    E.2.2Secondary objectives of the trial
    To evaluate the benefit:risk of ACP-196 versus ibrutinib in terms of:
    •Grade = 3 infections
    •Richter's transformation
    •Atrial fibrillation
    •Overall survival (OS)

    Safety Objectives:
    •Safety and tolerability including adverse events (AEs) of interest and laboratory assessments
    Exploratory Objectives:
    •IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria
    •Investigator-assessed PFS and ORR per IWCLL 2008 criteria
    •Improvement and/or resolution of disease-related symptoms
    •Improvement in incidence of diarrhea, major bleeding events, lymphocytosis, and second primary malignancy
    •Patient-reported outcome (PRO) by various scales
    •Medical resource utilization (MRU)
    •Pharmacokinetic (PK) characteristics of ACP-196 in subjects with CLL to determine which, if any, covariates (eg, age, sex, body size, race) influence exposure to ACP-196
    •Potential predictive biomarkers and mechanisms of resistance for the disease
    Valutare rapporto beneficio/rischio di ACP-196 rispetto a ibrutinib in termini di:
    •Infezioni di grado = 3
    •Trasformazione in sindrome di Richter
    •Fibrillazione atriale
    •OS
    Obiettivi di sicurezza
    •Sicurezza e tollerabilità, compresi gli eventi avversi (AEs) di interesse e valutazioni di laboratorio
    Obiettivi esplorativi:
    •Tasso risposta globale (ORR) valutato da IRC in base a criteri IWCLL2008
    •PFS e ORR valutati dallo sperimentatore in base a criteri IWCLL2008
    •Miglioramento e/o risoluzione di sintomi correlati alla malattia
    •Miglioramento incidenza di diarrea, eventi di sanguinamento maggiore, linfocitosi e secondo tumore maligno primario
    •Esiti riferiti dai pazienti (PRO) secondo diverse scale
    •Utilizzo di risorse mediche (MRU)
    •PK di ACP-196 in soggetti affetti da LLC per stabilire quali eventuali covariate (ad es. età, sesso, dimensioni corporee, razza) influiscono sull'esposizione ad ACP-196
    •Potenziali biomarcatori predittivi e meccanismi di resistenza relativi alla malattia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Men and women = 18 years of age.
    •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to2.
    •Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008): oMonoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing = 1 B-cell marker (CD19, CD20, or CD23) and CD5.
    oProlymphocytes may comprise = 55% of blood lymphocytes.
    oPresence of = 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any point since diagnosis).
    •Must have = 1 of the following high-risk prognostic factors:
    oPresence of 17p del by central laboratory oPresence of 11q del by central laboratory
    •Active disease meeting = 1 of the following IWCLL 2008 criteria for requiring treatment:
    Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/µL).
    oMassive (ie, = 6 cm below the left costal margin), progressive, or symptomatic splenomegaly
    oMassive nodes (ie, = 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
    oProgressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30 X 10^9/L (30,000/µL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
    oAutoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
    oConstitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as = 1 of the following disease-related symptoms or signs:
    Unintentional weight loss = 10% within the previous 6 months before Screening.
    Significant fatigue (ie, ECOG performance status 2 or worse; inability to work or perform usual activities)
    Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
    Night sweats for > 1 month before Screening without evidence of infection.
    •Measurable nodal disease by computed tomography (CT). Measurable nodal disease is defined as = 1 lymph node > 1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
    •Must have received = 1 prior therapies for CLL.
    •Meet the following laboratory parameters:
    oAbsolute neutrophil count (ANC) = 750 cells/µL (0.75 x 10^9/L) or =500 cells/µL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment.
    oPlatelet count = 30,000 cells/µL (30 x 10^9/L) without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.
    oSerum aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) =3.0 x upper limit of normal (ULN). oTotal bilirubin = 1.5 x ULN.
    oEstimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) = 30 mL/min.
    For a complete list of Inclusion Criteria please refer to the Study Protocol
    •Uomini e donne di età = 18 anni.
    •Stato di validità ECOG da 0 a 2.
    •Diagnosi di LLC che soddisfa i criteri diagnostici pubblicati (Hallek 2008): oCellule B monoclonali (con restrizione per la catena leggera kappa o lambda) che coesprimono clonalmente = 1 marcatore delle cellule B (CD19, CD20 o CD23) e CD5.
    I prolinfociti possono costituire = 55% dei linfociti del sangue.
    Presenza di = 5 x 109 linfociti B/l (5000 µl) nel sangue periferico (in qualsiasi momento dalla diagnosi), solo per CLL
    Devono presentare = 1 dei seguenti fattori prognostici di alto rischio:
    Presenza di delezione 17p rilevata da lab centrale
    oPresenza di delezione 11q rilevata da lab centrale
    Malattia attiva che soddisfa = 1 dei seguenti criteri IWCLL 2008 relativi alla necessità di trattamento:
    Evidenza di insufficienza progressiva del midollo osseo come dimostrato dallo sviluppo, o dal peggioramento, di anemia (emoglobina < 10 g/dL) e/o trombocitopenia (piastrine < 100.000/µL).
    Splenomegalia massiva (ovvero = 6 cm al di sotto del margine costale sinistro), progressiva o sintomatica
    Linfoadenopatia massiva (ovvero = 10 cm nel diametro più lungo), progressiva o sintomatica.
    Linfocitosi progressiva con un aumento di > 50% nell'arco di 2 mesi o un tempo di raddoppiamento dei linfociti (LDT) < 6 mesi. Il valore di LDT può essere ottenuto con estrapolazione mediante regressione lineare della conta linfocitaria assoluta (ALC) ottenuta a intervalli di 2 settimane nell'arco di un periodo di osservazione di 2-3 mesi. In soggetti con conte iniziali dei linfociti nel sangue di < 30 X 10^9/L (30.000/µL), il valore di LDT non deve essere utilizzato come unico parametro per definire l'indicazione al trattamento. Inoltre, i fattori che contribuiscono alla linfocitosi o alla linfoadenopatia diversi dalla LLC (ad es. infezioni) devono essere esclusi.
    Anemia autoimmune e/o trombocitopenia con scarsa risposta alla terapia standard.
    Sintomi costituzionali documentati nelle cartelle del soggetto con misurazioni oggettive di supporto, se del caso, definiti come = 1 dei seguenti segni o sintomi correlati alla malattia:
    Calo di peso involontario = 10% nei 6 mesi precedenti lo Screening.
    Affaticamento significativo (per es stato di performance ECOG pari a 2 o peggiore: incapacità di lavorare o svolgere attività abituali).
    Febbre superiore a 38,0°C per 2 o più settimane prima dello Screening senza evidenza di infezione.
    Sudorazione notturna per > 1 mese prima dello Screening senza evidenza di infezione.
    •Malattia linfonodale misurabile mediante TAC. La malattia linfonodale misurabile è definita come = 1 linfonodi > 1,5 cm nel diametro più lungo in una sede non sottoposta in precedenza a radiazioni. Una lesione sottoposta a radiazioni può essere valutata come malattia misurabile solo se vi è stata progressione documentata in quella lesione dalla fine della radioterapia.
    •Devono aver ricevuto = 1 precedenti terapie per LLC.
    •Soddisfano i seguenti parametri di laboratorio:
    Conta assoluta dei neutrofili (ANC) = 750 cellule/µL (0,75 x 10^9/L) o = 500 cellule/µL (0,50 x 10^9/L) in soggetti con coinvolgimento documentato del midollo osseo e a prescindere dal supporto del fattore di crescita 7 giorni prima della valutazione.
    Conta delle piastrine = 30.000 cellule/µL (30 x 10^9/L) senza supporto trasfusionale 7 giorni prima della valutazione. Sono esclusi i soggetti con trombocitopenia dipendente da trasfusioni.
    AST/SGOT e ALT/SGPT nel siero = 3,0 x limite superiore della norma (ULN). oBilirubina totale = 1,5 x ULN.
    Clearance della creatinina stimata (ovvero velocità di filtrazione glomerulare stimata [eGFR] utilizzando l'equazione di Cockcroft-Gault) = 30 mL/min.
    Per un elenco completo dei criteri di inclusione fare riferimento al Protocollo di studio
    E.4Principal exclusion criteria
    •Known central nervous system (CNS) lymphoma or leukemia.
    •Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
    •Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone daily or equivalent).
    •Prior exposure to ibrutinib or to a B-cell receptor (BCR) inhibitor (eg, Bruton tyrosine kinase [Btk] inhibitors or phosphoinositide-3 [PI3] kinase inhibitors or Syk inhibitors) or a BCL-2 inhibitor (eg, ABT-199).
    •Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
    •Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For examples, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded.
    •Prior radio- or toxin-conjugated antibody therapy.
    •Prior allogeneic stem cell transplant or autologous transplant.
    •Major surgery within 4 weeks before first dose of study drug.
    •History of prior malignancy except for the following:
    oMalignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician
    oAdequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
    oAdequately treated cervical carcinoma in situ without current evidence of disease
    •11. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening
    •Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
    •Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective treatment.
    •Known history of infection with human immunodeficiency virus (HIV).
    •Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
    •History of stroke or intracranial hemorrhage within 6 months before randomization.
    •History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
    For a complete list of exclusion criteria please refer to the Protocol
    Linfoma o leucemia del sistema nervoso centrale (SNC) noti.
    •Leucemia prolinfocitica nota o sindrome di Richter in anamnesi o attualmente sospetta.
    •Anemia emolitica autoimmune (AIHA) o porpora trombocitopenica idiopatica (ITP) non controllate definite come diminuzione dell'emoglobina o conta delle piastrine secondaria a distruzione autoimmune all'interno del periodo di Screening o necessità di alte dosi di steroidi (> 20 mg al giorno di prednisone o equivalente).
    •Precedente esposizione a ibrutinib o a un inibitore del recettore delle cellule B (BCR) (ad es. inibitori della tirosin-chinasi di Bruton [Btk] o inibitori della fosfoinositide-3-chinasi [PI3K] o inibitori della Syk) o a un inibitore di BCL-2 (ad es. ABT-199).
    •Qualunque chemioterapia, radioterapia esterna, anticorpo antitumorale o farmaco sperimentale nei 30 giorni precedenti la prima dose di farmaco in studio.
    •Uso di corticosteroidi > 20 mg nell'arco di 1 settimana prima della prima dose di farmaco in studio, salvo se indicato per altre patologie, ad esempio steroidi per via inalatoria per l'asma, uso di steroidi topici o come trattamento preparatorio per la somministrazione del farmaco in studio o del mezzo di contrasto. Per esempio, soggetti che richiedono steroidi a dosi giornaliere > 20 mg di esposizione sistemica giornaliera a equivalenti del prednisone o i soggetti che ricevono steroidi per il controllo della leucemia o la riduzione della conta dei globuli bianchi sono esclusi.
    •Precedente terapia con anticorpi radioconiugati o coniugati a tossina.
    •Precedente trapianto di cellule staminali allogenico o trapianto autologo.
    •Intervento chirurgico significativo nelle 4 settimane precedenti la prima dose di farmaco in studio.
    •Anamnesi di tumori maligni eccettuati i seguenti:
    Tumore maligno trattato con intento curativo e senza evidenza di malattia attiva presente per oltre 3 anni prima dello Screening e considerato a basso rischio di recidiva dal medico curante
    Melanoma lentigo maligna adeguatamente trattato senza attuale evidenza di malattia o tumore cutaneo non melanomatoso adeguatamente controllato
    Carcinoma in situ della cervice uterina adeguatamente trattato senza attuale evidenza di malattia
    •Malattia cardiovascolare clinicamente significativa attualmente attiva, ad esempio aritmia non controllata o sintomatica, insufficienza cardiaca congestizia, qualunque malattia cardiaca di classe 3 o 4 in base alla classificazione funzionale della New York Heart Association o QTc > 480 msec allo screening.
    •Incapacità di deglutire le capsule o sindrome da malassorbimento, malattia che colpisce significativamente la funzione gastrointestinale o resezione dello stomaco oppure dell'intestino tenue o bypass gastrico, malattia infiammatoria intestinale sintomatica oppure occlusione intestinale parziale o completa.
    •Infezione micotica, batterica, virale o altra infezione sistemica attiva non controllata (definita come presenza di segni/sintomi in corso correlati all'infezione e senza miglioramento nonostante adeguata terapia antibiotica e/o altro trattamento) o trattamento anti-infettivo endovenoso in corso.
    •Anamnesi nota di infezione da virus dell'immunodeficienza umana (HIV).
    •Stato sierologico che mostra infezione attiva da epatite B o C. I soggetti positivi all’anticorpo anti-core dell'epatite B e negativi all'antigene di superficie o positivi agli anticorpi dell'epatite C dovranno presentare un risultato negativo della reazione a catena della polimerasi (PCR) prima della randomizzazione. I soggetti positivi all'antigene di superficie dell'epatite B o con PCR positiva per epatite B e i soggetti con PCR positiva per epatite C saranno esclusi.
    •Anamnesi di ictus o emorragia intracranica nei 6 mesi precedenti la randomizzazione.
    •Anamnesi di diatesi emorragica (ad es. emofilia, malattia di von Willebrand).
    Per un elenco completo dei criteri di esclusione fare riferimento al Protocollo
    E.5 End points
    E.5.1Primary end point(s)
    To assess whether ACP-196 is non-inferior to ibrutinib with respect to
    progression-free survival (PFS) based on independent review committee (IRC) assessment in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk prognostic markers.
    Valutare se ACE-196 sia non inferiore a ibrutinib per quanto riguarda la sopravvivenza libera da progressione (PFS) sulla base della valutazione del comitato di revisione indipenddente (IRC) in soggetti affetti da leucemia linfatica cronica (LLC) recidiva o refrattaria con marcatori prognostici di alto rischio
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 months - estimated
    48 mesi stimati
    E.5.2Secondary end point(s)
    To compare between ACP-196 and ibrutinib in terms of:
    •Incidence of Grade = 3 infections
    •Incidence of Richter's transformation
    •Incidence of atrial fibrillation
    •OS
    Confrontare ACP-196 e ibrutinib in termini di:
    •Incidenza di infezioni di grado = 3
    •Incidenza della trasformazione in sindrome di Richter
    •Incidenza di fibrillazione atriale
    •OS
    E.5.2.1Timepoint(s) of evaluation of this end point
    estimated 48 months
    48 mesi stimati
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group 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) 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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA95
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Israel
    New Zealand
    Turkey
    United States
    Belgium
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 500
    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)
    Treatment to continue as per normal treatment for this condition
    Il trattamento deve proseguire secondo il normale trattamento per questa patologia
    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 Decision2015-08-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-08
    P. End of Trial
    P.End of Trial StatusCompleted
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