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    Summary
    EudraCT Number:2019-003919-53
    Sponsor's Protocol Code Number:GN41791
    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:2022-02-11
    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 number2019-003919-53
    A.3Full title of the trial
    A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED WITH OCRELIZUMAB IN ADULT PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
    STUDIO DI FASE III, MULTICENTRICO, RANDOMIZZATO, IN DOPPIO CIECO, DOUBLE-DUMMY E A GRUPPI PARALLELI VOLTO A VALUTARE L’EFFICACIA E LA SICUREZZA DI FENEBRUTINIB RISPETTO A OCRELIZUMAB IN PAZIENTI ADULTI CON SCLEROSI MULTIPLA PRIMARIAMENTE PROGRESSIVA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared with Ocrelizumab in Adult Patients with Primary Progressive Multiple Sclerosis
    Uno studio per valutare l’efficacia di Fenebrutinib rispetto a Ocrelizumab in pazienti con sclerosi multipla primariamente progressiva
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberGN41791
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04544449
    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 SponsorF. HOFFMANN - LA ROCHE LTD.
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffman-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number000000
    B.5.5Fax number000000
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFENEBRUTINIB
    D.3.2Product code [RO7010939]
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNFENEBRUTINIB
    D.3.9.2Current sponsor codeRO7010939
    D.3.9.3Other descriptive nameGDC-0853 RO7010939
    D.3.9.4EV Substance CodeSUB190378
    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 OCREVUS
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH - n. di AIC: EU/1/17/1231/001 and EU/1/17/1231/002
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOCRELIZUMAB
    D.3.2Product code [RO4964913]
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOCRELIZUMAB
    D.3.9.2Current sponsor codeRO4964913
    D.3.9.4EV Substance CodeSUB121707
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typehumanized monoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple sclerosis
    Sclerosi multipla
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis (MS) is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance
    La SM è una condizione che può colpire il cervello e il midollo spinale causando una vasta gamma di potenziali sintomi tra cui problemi di vista di movimento di braccia o gambe,sensazione o equilibrio
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063401
    E.1.2Term Primary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the efficacy of fenebrutinib compared with ocrelizumab in patients with primary progressive multiple sclerosis (PPMS) regardless of adherence to randomized treatment based on time to onset of composite 12-week confirmed disability progression (cCDP12)
    • valutare l’efficacia di fenebrutinib rispetto a ocrelizumab in pazienti con sclerosi multipla primariamente progressiva (SMPP) indipendentemente dall’aderenza al trattamento randomizzato sulla base del tempo alla comparsa di progressione confermata della disabilità a 12 settimane in funzione dell’indice composito (cCDP12).
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of fenebrutinib compared with ocrelizumab in patients with PPMS regardless of adherence to randomized treatment based on time to onset of composite 24-week CDP (cCDP24), time to onset of 12-week CDP (CDP12) and time to onset of 24-week CDP (CDP24)
    • To evaluate the efficacy of fenebrutinib had patients not switched to post-CDP24 open-label ocrelizumab (PC-OCR)
    • To evaluate the safety of fenebrutinib compared with ocrelizumab
    • To characterize the fenebrutinib pharmacokinetic (PK) profile

    • valutare l’efficacia del trattamento con fenebrutinib rispetto a ocrelizumab, indipendentemente dall’aderenza al trattamento randomizzato, in pazienti con SMPP in base al tempo alla comparsa di CDP a 24 settimane in funzione dell’indice composito (cCDP24) al tempo alla comparsa di CDP a 12 settimane (CDP12), tempo alla comparsa di CDP a 24 settimane (CDP24)
    • valutare l’efficacia di fenebrutinib in caso di mancato passaggio dei pazienti al trattamento con ocrelizumab in aperto post-CDP24 (PC-OCR)
    • valutare la sicurezza di fenebrutinib rispetto a ocrelizumab
    • caratterizzare il profilo PK di fenebrutinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age 46-65 years
    • A diagnosis of PPMS in accordance to revised 2017 McDonald Criteria
    • Disability progression in the 12 months prior to screening, as assessed by the Pre-Baseline Disability Progression Questionnaire
    • Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 inclusive at screening
    • Pyramidal functional subscore >=2 at screening
    • For patients currently receiving proton pump inhibitors (PPIs) or H2-receptor antagonists (H2RAs): treatment at a stable dose during the screening period prior to the initiation of study treatment and plans to remain at a stable dose for the duration of study treatment
    • For patients requiring symptomatic treatment for MS and/or physiotherapy: treatment at a stable dose/regimen during the screening period prior to the initiation of study drug and plans to remain at a stable dose/regimen for the duration of study treatment
    • Neurologically stable for at least 30 days prior to randomization and baseline assessments
    • Ability to complete the 9-Hole Peg Test (9-HPT) for each hand in <240 seconds
    • Ability to perform Timed 25-Foot Walk Test (T25FWT) in <150 seconds
    • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 6 or 12 months after the final dose of study medication
    • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm during the treatment period and for 28 days after the final dose of study medication to avoid exposing the embryo
    • Età compresa tra 46 e 65 anni
    • Diagnosi di SMPP secondo i criteri rivisti di McDonald del 2017
    • Progressione della disabilità nei 12 mesi precedenti lo screening in base al Pre Baseline Disability Progression Questionnaire
    • Punteggio EDSS compreso tra 3,0 e 6,5 allo screening
    • Sottopunteggio relativo al sistema funzionale piramidale ¿ 2 allo screening
    • Per i pazienti attualmente trattati con inibitori della pompa protonica (PPI) o antagonisti dei recettori H2 (H2RA): trattamento a una dose stabile durante il periodo di screening prima dell’inizio del trattamento in studio e che si prevede rimarrà a una dose stabile per l’intera durata del trattamento in studio
    • Per i pazienti che necessitano di trattamento sintomatico per la SM e/o fisioterapia: trattamento a una dose/un regime stabile durante il periodo di screening prima dell’inizio del trattamento con il farmaco studio e che si prevede rimarrà a una dose/un regime stabile per l’intera durata del trattamento in studio
    • Pazienti neurologicamente stabili per almeno 30 giorni prima della randomizzazione e delle valutazioni basali
    • Capacità di effettuare il test 9 HPT con ciascuna mano in ¿ 240 secondi
    • Capacità di effettuare il test T25FWT in ¿ 150 secondi
    • Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o ad adottare metodi contraccettivi durante il periodo di trattamento e per 6 o 12 mesi dopo l’ultima dose del farmaco in studio
    • Per gli uomini: consenso a praticare l’astinenza dai rapporti eterosessuali o a usare il preservativo e consenso ad astenersi dalla donazione del seme durante il periodo di trattamento e per 28 giorni dopo l’ultima dose del farmaco in studio, al fine di evitare l’esposizione dell’embrione
    E.4Principal exclusion criteria
    • Gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (T1Gd+) lesion present on the screen MRI
    • Any known or suspected active infection at screen or baseline,or any major episode of infection requiring hospitaliz or tx with IV anti-microbials
    • Hx of confirmed or suspected progressive multifocal leukoencephalopathy
    • Pt with a previous Hx of a serious IRR(CTCAE Grade >=4) and/or any hypersensitivity reaction to ocrelizumab
    • Hx of cancer,including hematologic malignancy and solid tumors,within 10 years of screen
    • Immunocompromised state
    • Known presence of other neuro disorders
    • Evidence of clinic signif cardiov,psychiatric,pulmonary,renal, hepatic,endocrine,metabolic,gastrointestinal (GI) disease that, in the PI opinion,would preclude pt participation
    • Pt meeting the New York Heart Association Class III and Class IV criteria for congestive heart failure
    • Screen 12-lead ECG that demonstrates clinic relevant abnormalities
    • Current tx with medications that are well known to prolong the QT interval at doses that have a clinic meaningful effect on QT, as determined by the PI
    • Hx of ventricular dysrhythmias or risk factors for ventricular dysrhythmias
    • Any concomitant disease that may require chronic tx with systemic corticosteroids or immunosuppressants during the study
    • Hx of alcohol or other drug abuse within 12 months prior to screen
    • Pregnant or breastfeeding,or intending to become pregnant during the study or 6 or 12 months after final dose of study drug
    • Men intending to father a child during the study or for 28 days after final dose of study drug
    • + screen tests for active,latent,or inadequately treated hepatitis B
    • + screen tests for hepatitis C
    • Evidence of active or latent or inadequately treated infection with tuberculosis
    • Hx of hospital or transfusion for a GI bleed
    • Known bleeding diathesis
    • Any condition possibly affecting oral drug absorption
    • Hx of or currently active primary or secondary immunodeficiency
    • Contraindications to mandatory pre-medications for IPRs
    • Inability to complete an MRI scan
    • Lack of peripheral venous access
    • Any prev tx with bone marrow transplantation and hematopoietic stem cell transplantation
    • Any prev Hx of transplantation or anti-rejection therapy
    • Systemic corticosteroid therapy within 4 weeks prior to screen or during the screen period
    • Tx with IV Ig or plasmapheresis within 12 weeks prior to RDM
    • Sensitivity or intolerance to any ingredient of fenebrutinib or ocrelizumab
    • Receipt of a live or live-attenuated vaccine within 6 weeks prior to RDM
    • Need for systemic anti-coagulation (oral or injectable) or anti-platelet agent
    • Prev tx with fenebrutinib or another Bruton's tyrosine kinase (BTK) inhibitor for any indication
    • Tx with any investigational agent within 24 weeks prior to screen (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or tx with any experimental procedure for MS
    • Requirement for any prohibited concomitant medications
    • Tx with strong CYP3A4 inhibitors,strong or moderate CYP3A4 inducers,within 7 days or 5 drug elimination half-lives(whichever is longer)prior to RDM
    • Tx with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug elimination half-lives(whichever is longer)prior to RDM
    • Prev use of an anti-CD20 therapy within 6 months of RDM
    • Prev use of fingolimod, siponimod, or ozanimod within 8 weeks of RDM or ponesimod within 4 weeks of RDM
    • Prev use of natalizumab within 6 months of RDM
    • Prev tx with dimethyl fumarate, interferons or glatiramer acetate within 4 weeks of RDM
    • Prev tx with mycophenolate mofetil, methotrexate or azathioprine within 12 weeks of RDM
    • Prev use of teriflunomide, unless >=24 months from screen or teriflunomide plasma concentrations are <0.02 mg/L at screen
    • Any prev tx with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide
    • Prev tx with any other immunomodulatory or immunosuppressive medication
    • Abnor lab results
    •Lesioni T1Gd+ alla MRI di screen
    •Infez attiva nota o sospetta allo screen o al basale o qls episodio maggiore di infez che richieda ospedalizz o il tratt con antimicrobici EV
    •Storia di leucoencefalopatia multifocale progressiva confermata o sospetta
    •Storia di IRR grave[CTCAE] Grado >=4)e/o qls reazione di ipersensibilità a ocrelizumab
    •Storia di tumore,compresi neoplasia maligna ematologica e tumori solidi,entro 10 anni dallo screen
    •Stato immunocompromesso
    •Presenza nota di disturbi neurologici
    •Evidenza di malattie cardiovascolari,psichiatriche,polmonari,renali,epatiche, endocrine,metaboliche o gastrointestinali(GI)clinic significative che,secondo lo sperimentatore,precluderebbero la partecipazione del pz
    •Pz con insuff cardiaca congestizia di classe III o IV secondo New York Heart Association
    •ECG a 12 derivazioni allo screen dal quale emergano anomalie clinic rilevanti
    •Tratt con medicinali notoriamente associati a prolungamento dell’intervallo QT a dosi che hanno un effetto clinic significativo sul QT,secondo lo sperimentatore
    •Storia di disaritmie ventricolari o fattori di rischio per disaritmie ventricolari
    •Qls malattia concomitante che richiede un tratt cronico con corticosteroidi sistemici o immunosoppressori
    •Abuso di alcool o droghe nei 12mesi precedenti lo screen
    • Gravidanza o allattamento,o intenzione di iniziare una gravidanza durante lo studio o 6 o 12mesi successivi l’ultima dose del farmaco
    •Uomini che intendono procreare durante lo studio o nei 28gg succ l’ultima dose del farmaco
    •Test di screen + per l'epatite B attiva,latente o nn trattata
    •Test di screen + per l'epatite C
    •Evidenza di infezione TBC attiva,latente o nn trattata
    •Storia di ricoveri in ospedale o trasfusioni per un’emorragia GI
    •Diatesi emorragica
    •Qls condiz che influenza l'assorbimento orale del farmaco
    •Immunodeficienza primaria o secondaria pregressa o attualmente attiva
    •Controindicaz alle premedicazioni obbligatorie per reazioni correlate all’infusione
    •Impossibilità di sottoporsi alla RM
    •Assenza di accesso venoso periferico
    •Qls prec tratt con trapianto di midollo osseo e trapianto di cellule staminali ematopoietiche
    •Qls trapianto o terapia antirigetto precedente
    •Terapia sistemica a base di corticosteroidi nelle 4sett precedenti o allo screen
    •Tratt con Ig IV o plasmaferesi nelle 12sett prec la randomiz
    •Sensibilità o intolleranza a qls ingrediente di fenebrutinib o ocrelizumab
    •Somministraz di vaccino vivo/attenuato entro 6sett dalla randomiz
    •Necessità di anticoagulanti sistemici(orali o iniettabili)o agenti antipiastrinici
    •Tratt prec con fenebrutinib o altro inibitore della tirosin-chinasi di Bruton(BTK)per qls indicaz
    •Tratt con qls agente sperimentale entro 24sett dallo screen(visita 1)o 5 emivite del farmaco(a seconda di quale sia più lungo)o tratt con qls procedura sperimentale per la SM
    •Necessità di medicinali concomitanti nn ammessi
    •Tratt con inibitori del CYP3A4 o potenti/moderati induttori del CYP3A4 nei 7gg o 5 emivite del farmaco(qualora queste ultime abbiano durata superiore) precedenti la randomiz
    •Tratt con substrati del CYP3A4 aventi finestra terapeutica ristretta nei 7gg o 5 emivite del farmaco(qualora queste ultime abbiano durata superiore)precedenti la randomiz
    •Uso pregresso di terapia anti-CD20 entro 6mesi dalla randomiz
    •Uso pregresso di fingolimod,siponimod o ozanimod entro 8sett dalla randomiz o ponesimod entro 4sett dalla randomiz
    •Uso pregresso di natalizumab entro 6mesi dalla randomiz
    •Prec tratt con dimetilfumarato,interferoni o glatiramer acetato entro 4sett dalla randomiz
    •Prec tratt con micofenolato mofetile,metotrexato o azatioprina entro 12sett dalla randomiz
    •Uso precedente di teriflunomide,tranne se risalente a >=24mesi prima dello screen o in caso di concentraz plasmatiche di teriflunomide ¿ 0,02 mg/l allo screen
    •Prec tratt con cladribina,mitoxantrone,daclizumab,alemtuzumab o ciclofosfamide
    •Tratt prec con qls farmaco immunomodulatore o immunosoppressore
    •Risultati di lab anormali
    E.5 End points
    E.5.1Primary end point(s)
    1. Time to onset of composite 12-week confirmed disability progression (cCDP12)
    1. Tempo alla comparsa di progressione confermata della disabilità a 12 settimane in funzione dell’indice composito (cCDP12)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to 4.7 years [estimated duration of Double-Blind Treatment (DBT)]
    1. Fino a 4,7 anni [durata stimata del trattamento in doppio cieco (DBT)]
    E.5.2Secondary end point(s)
    1. Time to onset of composite 24 week CDP (cCDP24)
    2. Time to onset of 12-week CDP (CDP12)
    3. Time to onset of 24 week CDP (CDP24)
    4. Percent change in total brain volume from Week 24 as assessed by MRI scan
    5. Change from baseline in patient-reported physical impacts of MS (as measured by Multiple Sclerosis Impact Scale, 29-Item [MSIS-29] physical scale
    6. Time to onset of 12 week confirmed 4 point worsening in Symbol Digit Modality Test (SDMT) score
    7. The nature, frequency, timing, and severity of adverse events; serious adverse events; and adverse events leading to study treatment withdrawal
    8. Change from baseline in targeted vital signs
    9. Change from baseline in targeted ECG parameters
    10. Change from baseline in clinical laboratory results following study treatment administration
    11. Proportion of patients with suicidal ideation or behavior, as assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
    12. Plasma concentration of fenebrutinib at specified timepoints
    1. Tempo alla comparsa della CDP composita a 24 settimane (cCDP24)
    2. Tempo alla comparsa della CDP a 12 settimane (CDP12)
    3. Tempo alla comparsa della CDP a 24 settimane (CDP24)
    4. Variazione % del volume cerebrale tot alla Settimana 24 in base alla risonanza magnetica (RM).
    5. Variazione dell’impatto fisico della sclerosi multipla (SM) riferito dai pazienti (in funzione della scala fisica della Multiple Sclerosis Impact Scale, 29 Item)
    6. Tempo alla comparsa di un peggioramento confermato del punteggio ottenuto nel Symbol Digit Modality Test (SDMT) pari a 4 punti a 12 settimane
    7. La natura, frequenza, tempistica e gravità degli eventi avversi; eventi avversi gravi ed eventi avversi che portano all’interruzione del trattamento in studio
    8. Variazione dei parametri vitali di interesse rispetto al basale.
    9. Variazione dei parametri dell’elettrocardiogramma (ECG) rispetto al basale.
    10. Variazione dei risultati clinici di laboratorio rispetto al basale dopo la somministrazione del trattamento in studio.
    11. Percentuale di pazienti con ideazione o comportamento suicidario in base alla Columbia Suicide Severity Rating Scale.
    12. Concentrazione plasmatica di fenebrutinib a specifici timepoint
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-3. Up to 4.7 years (estimated duration of DBT)
    4-5. At Week 120
    6-11. Up to 4.7 years (estimated duration of DBT)
    12. Week 0, 2, 12, 24, 48, 72, 96, 120, at treatment discontinuation or unscheduled visit
    1-3. Fino a 4,7 anni (durata stimata del DBT)
    4-5. Alla settimana 120
    6-11. Fino a 4,7 anni (durata stimata del DBT)
    12. Settimana 0, 2, 12, 24, 48, 72, 96, 120, all'interruzione del trattamento o visita non programmata
    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 Yes
    E.6.7Pharmacodynamic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Denmark
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Latvia
    Lithuania
    Mexico
    New Zealand
    Peru
    Poland
    Portugal
    Romania
    Russian Federation
    South Africa
    Spain
    Switzerland
    Turkey
    Ukraine
    United Kingdom
    United States
    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
    The end of this study is defined as the date when the last patient, last visit occurs in the OLE or the last patient last visit in the SFU, whichever occurs later. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 369 weeks or approximately 7 years.
    In addition, the Sponsor may decide to terminate the study at any time.
    La fine dello studio coinciderà con la data in cui avrà luogo l’ultima visita dell’ultimo paziente (LPLV) nella fase OLE o la LPLV nella fase OLE SFU, a seconda della circostanza che si verifichi per ultima.Si prevede che la durata massima dello studio, dallo screening del primo paziente alla conclusione della ricerca, sarà di circa 370 settimane o 7 anni. Inoltre, lo Sponsor può decidere di interrompere lo studio in qualsiasi momento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 946
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 303
    F.4.2.2In the whole clinical trial 946
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Sponsor will offer continued access to Roche IMP fenebrutinib and ocrelizumab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined in Section 4.3.4 of the protocol.
    Lo Sponsor continuerà a fornire fenebrutinib e ocrelizumab gratuitamente ai pazienti idonei in conformità con la Roche Global Policy on Continued Access to Investigational Medicinal Product, come delineato nella Sezione 4.3.4 del protocollo.
    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 Decision2022-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-10
    P. End of Trial
    P.End of Trial StatusOngoing
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