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    Summary
    EudraCT Number:2020-000894-26
    Sponsor's Protocol Code Number:BN42083
    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:2021-01-25
    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 number2020-000894-26
    A.3Full title of the trial
    A PHASE IIIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY AND PHARMACOKINETICS OF A HIGHER DOSE OF OCRELIZUMAB IN ADULTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
    STUDIO DI FASE IIIB, MULTICENTRICO, RANDOMIZZATO, IN DOPPIO CIECO E CONTROLLATO VOLTO A VALUTARE L’EFFICACIA, LA SICUREZZA E LA FARMACOCINETICA DI UNA DOSE DI OCRELIZUMAB PIÙ ELEVATA IN 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, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis
    Questo studio valuterà l’efficacia, la sicurezza e la farmacocinetica di una dose di ocrelizumab più elevata rispetto alla dose di ocrelizumab approvata in adulti con sclerosi multipla primariamente progressiva.
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberBN42083
    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. Hoffmann-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 number0000000
    B.5.5Fax number0000000
    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 Yes
    D.2.1.1.1Trade name Ocrevus
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH - n° 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/F07-01]
    D.3.4Pharmaceutical form Concentrate for solution for 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.3.9.1CAS number 637334-45-3
    D.3.9.2Current sponsor codeRO4964913
    D.3.9.3Other descriptive nameOCRELIZUMAB
    D.3.9.4EV Substance CodeSUB121707
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Progressive Multiple Sclerosis (MS)
    SCLEROSI MULTIPLA PRIMARIAMENTE PROGRESSIVA
    E.1.1.1Medical condition in easily understood language
    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 condiz. che può colpire il cervello e il MS, causando una vasta gamma di potenziali sintomi, tra cui problemi di vista, di movimento delle braccia o delle gambe, sensazione o equilibrio
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10039720
    E.1.2Term Sclerosis multiple
    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 demonstrate the superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab as assessed by risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks
    • Dimostrare la superiorità di una dose di ocrelizumab più elevata rispetto alla dose di ocrelizumab approvata in base alla riduzione del rischio di progressione confermata della disabilità in funzione dell’indice composito (cCDP) mantenuta per almeno 12 settimane
    E.2.2Secondary objectives of the trial
    • To demonstrate superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab on the basis of time to onset of 24 week cCDP (cCDP24), CDP12, CDP24, time to >= 20% increase in 12 and 24 week confirmed timed 25 foot walk test (T25FWT) and 9 hole peg test (9 HPT), change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29), percent change in total brain volume, Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT)
    • To evaluate the safety profile of a higher dose of ocrelizumab compared with the approved dose of ocrelizumab as well as the overall safety profile and safety profile by treatment arm over time
    • To assess the exposure to ocrelizumab in serum in all patients in both study arms
    • To characterize the ocrelizumab PD profile
    • To evaluate the immune response to ocrelizumab
    • To identify biomarkers that are predictive of response to a higher dose of ocrelizumab
    • Dimostrare la superiorità di una dose di ocrelizumab più elevata rispetto alla dose di ocrelizumab approvata sulla base del tempo alla comparsa di cCDP a 24 settimane (cCDP24), CDP12, CDP24; tempo a un aumento del risultato confermato a 12 e 24 sett >= 20% ottenuto nel T25FWT e nel 9 HPT; variazione dal basale sulla scala fisica MSIS 29; variazione % del volume cerebrale totale; tempo a un peggioramento confermato del punteggio ottenuto nel SDMT pari a 4 punti a 12 sett
    • Valutare il profilo di sicurezza di una dose più elevata di ocrelizumab rispetto alla dose approvata di ocrelizumab, nonché il profilo globale di sicurezza e il profilo di sicurezza per braccio di trattamento nel tempo
    • Valutare l'esposizione a ocrelizumab nel siero in tutti i pazienti in entrambi i bracci di studio
    • Caratterizzare il profilo PD di ocrelizumab
    • Valutare la risposta immunitaria a ocrelizumab
    • Identificare biomarcatori che sono predittivi della risposta a una dose più elevata di ocrelizumab
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: A CSF Biomarker Substudy within BN42083 (PPMS) Trials, Phase IIIb Multicenter, Randomized, Double-Blind, Controlled Studies to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis
    Primary objective
    • To compare a higher dose of ocrelizumab versus the approved dose of ocrelizumab
    Secondary objective
    • To assess the correlation between changes in CSF biomarkers with those in blood and to compare higher dose of ocrelizumab versus the approved dose of ocrelizumab
    • To characterize the ocrelizumab concentration in CSF and to investigate the relationship between changes in biomarkers in CSF/blood and ocrelizumab concentration in CSF

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio relativo ai biomarcatori nel CSF nel contesto dello studio BN42083 (PPMS) di fase III, multicentrico, randomizzato, in doppio cieco e controllato volto a valutare l'efficacia, la sicurezza e la farmacocinetica di dosi di ocrelizumab più elevate in adulti con sclerosi multipla primariamente progressiva
    Obbiettivo primario
    • Confrontare gli effetti di dosi di ocrelizumab più elevate rispetto ad una normale dose approvata di ocrelizumab
    Obiettivo secondario
    • Valutare la correlazione tra le variazioni dei biomarcatori presenti nel CSF rispetto al sangue e confrontare gli effetti di dosi di ocrelizumab più elevate rispetto ad una normale dose approvata di ocrelizumab
    • Misurare i livelli di ocrelizumab nel CSF e valutare la correlazione tra le variazioni dei biomarcatori presenti nel CSF/sangue e la concentrazione di ocrelizumab nel CSF
    E.3Principal inclusion criteria
    • Ages 18-55 years at time of signing ICF
    • Ability to comply with the study protocol
    • Diagnosis of PPMS in accordance with the revised McDonald Criteria 2017
    • Expanded disability status scale (EDSS) score at screening and baseline >=3- 6.5, inclusive
    • Score of >=2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings
    • Patients requiring symptomatic treatment for MS (e.g., fampridine, cannabis) and/or physiotherapy must be treated at a stable dose during the screening period prior to the initiation of study drug on Day 1 and must have a plan to remain at a stable dose for the duration of study treatment
    • Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments
    • Disease duration from the onset of MS symptoms:
    o Less than 15 years in patients with an EDSS score at screening >5.0
    o Less than 10 years in patients with an EDSS score at screening >5.0
    • Documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands
    • For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months (as applicable by the ocrelizumab [Ocrevus] local label) after the final dose of ocrelizumab.
    • For female patients without reproductive potential: Females may be enrolled if post menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy).
    • Età compresa tra 18 e 55 anni al momento dello screening.
    • Capacità di rispettare il protocollo dello studio.
    • Diagnosi di SMPP secondo i criteri rivisti di McDonald del 2017 (Thompson et al. 2018).
    • Punteggio EDSS, allo screening e al basale, compreso tra 3 e 6,5.
    • Punteggio >= 2,0 nella scala Functional Systems (FS) relativa al sistema piramidale per via dei risultati riguardanti gli arti inferiori.
    • I pazienti necessitanti di trattamento sintomatico per la SM (per es. fampridina, cannabis) e/o fisioterapia dovranno essere trattati a dose stabile durante il periodo di screening prima dell’inizio del trattamento con il farmaco in studio il Giorno 1 e dovrà essere previsto il mantenimento di una dose stabile per l’intera durata del trattamento in studio.
    • I pazienti dovranno essere neurologicamente stabili per almeno 30 giorni prima della randomizzazione e delle valutazioni basali.
    • Durata della malattia dall'insorgenza dei sintomi di SM:
    o Meno di 15 anni nei pazienti con punteggio EDSS allo screening > 5,0.
    o Meno di 10 anni nei pazienti con punteggio EDSS allo screening <= 5,0.
    • Evidenza documentata della presenza di bande oligoclonali specifiche del liquido cefalorachidiano.
    • Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o a far uso di metodi contraccettivi adeguati durante il periodo di trattamento e per 6 o 12 mesi (secondo quanto applicabile in base alle indicazioni prescrittive locali di ocrelizumab [Ocrevus]) dopo l’ultima dose di ocrelizumab
    • Per le donne non in età fertile: a meno che la paziente non sia in trattamento con una terapia ormonale per la menopausa o non sia stata sottoposta a sterilizzazione chirurgica (isterectomia, ovariectomia bilaterale integrale), le donne in stato postmenopausale potranno essere arruolate.
    E.4Principal exclusion criteria
    • History of relapsing remitting or secondary progressive MS at screening
    • Any known or suspected active infection at screening or baseline, or any major episode of infection requiring hospitalization or treatment with IV anti microbials within 8 weeks prior to and during screening or treatment with oral anti microbials within 2 weeks prior to and during screening
    • History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)
    • History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
    • Immunocompromised state
    • Receipt of a live or live attenuated vaccine within 6 weeks prior to randomization
    • Inability to complete an MRI (contraindications for MRI, including but not restricted to, pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, etc.) or contraindication to gadolinium administration
    • Contraindications to mandatory pre medications (i.e., corticosteroids and antihistamines) for IRRs, including uncontrolled psychosis for corticosteroids or closed angle glaucoma for antihistamines
    • Known presence of other neurologic disorders
    • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
    • Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
    • History of or currently active primary or secondary (non-drug related) immunodeficiency
    • Pregnant or breastfeeding or intending to become pregnant during the study or 6 or 12 months (as applicable from the local label for ocrelizumab) after final dose of the study drug
    • Lack of peripheral venous access
    • History of alcohol or other drug abuse within 12 months prior to screening
    • Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or five half lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
    • Previous use of anti-CD20s is allowed if the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy.
    • Previous use of mitoxantrone, cladribine, atacicept, and alemtuzumab
    • Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label
    • If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication. The PD effects of the previous medication must also be considered when determining the required time for washout.
    • Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
    • Any previous history of transplantation or anti-rejection therapy
    • Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
    • Systemic corticosteroid therapy within 4 weeks prior to screening
    • Positive screening tests for active, latent, or inadequately treated hepatitis B
    • Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab
    • Any additional exclusionary criterion as per ocrelizumab (Ocrevus) local label, if more stringent than the above
    • Anamnesi positiva per SM recidivante-remittente o secondariamente progressiva allo screening
    • Infezione attiva nota o sospetta allo screening o al basale (eccetto infezioni del letto ungueale) o episodio maggiore di infezione necessitante di ricovero in ospedale o trattamento con antimicrobici e.v. nelle 8 sett precedenti e durante lo screening o trattamento con antimicrobici orali nelle 2 sett precedenti e durante lo screening
    • Anamnesi positiva per PML confermata o sospetta
    • Anamnesi positiva per tumore, compresi neoplasia maligna ematologica e tumori solidi, entro 10 anni dallo screening
    • Stato immunocompromesso
    • Somministraz. di un vaccino vivo o vivo attenuato nelle 6 sett precedenti la randomizzazione
    • Impossibilità di sottoporsi alla RM o controindicazione alla somministrazione di gadolinio
    • Controindicazioni alle premedicazioni obbligatorie (corticosteroidi e antistaminici) per IRR, tra cui psicosi non controllata per i corticosteroidi o glaucoma ad angolo chiuso per gli antistaminici
    • Presenza nota di altre patologie neurologiche
    • Qualsiasi malattia concomitante che potrebbe necessitare di un trattamento cronico con immunosoppressori o corticosteroidi sistemici durante lo studio
    • Malattia significativa non controllata, per es. cardiovascolare (compresa aritmia cardiaca), polmonare (compresa broncopneumopatia cronica ostruttiva), renale, epatica, endocrina o gastrointestinale, o qualsiasi altra malattia significativa che potrebbe precludere la partecipazione del paziente allo studio
    • Immunodeficienza primaria o secondaria (non farmaco-correlata) pregressa o attualmente attiva
    • Gravidanza o allattamento o intenzione di iniziare una gravidanza durante lo studio oppure nei 6 o 12 mesi (secondo quanto applicabile in base alle indicazioni prescrittive locali di ocrelizumab) successivi l’ultima dose del farmaco in studio
    • Assenza di accesso venoso periferico
    • Abuso pregresso di alcol o altre sostanze nei 12 mesi precedenti lo screening
    • Trattamento con qualsiasi agente sperimentale nelle 24 sett precedenti lo screening (Visita 1) o entro cinque emivite del farmaco sperimentale (qualora queste ultime abbiano durata superiore), oppure trattamento con qualsiasi procedura sperimentale per la SM
    • L’uso pregresso di anticorpi anti-CD20 è ammesso se l’ultima infusione risale a più di 2 anni prima dello screening, la conta dei linfociti B è nella norma e l’interruzione del trattamento non è stata motivata da ragioni di sicurezza o mancanza di efficacia
    • Uso pregresso di mitoxantrone, cladribina, atacicept e alemtuzumab
    • Precedente trattamento con qualsiasi altro immunomodulatore o immunosoppressore non già riportato in precedenza senza washout adeguato secondo quanto illustrato nelle informazioni prescrittive locali applicabili
    • Se nelle informazioni prescrittive locali applicabili non sono indicati i requisiti di washout, il periodo di washout dovrà essere uguale a cinque volte l’emivita del medicinale. Nel momento in cui si stabilisce la durata necessaria del washout occorre prendere in considerazione anche gli effetti PD del medicinale precedente
    • Qualsiasi trattamento precedente con trapianto di midollo osseo e di cellule staminali ematopoietiche
    • Qualsiasi trapianto o terapia antirigetto precedente
    • Trattamento con Ig e.v. o plasmaferesi nelle 12 sett precedenti la randomizzazione
    • Terapia a base di corticosteroidi sistemici nelle 4 sett precedenti lo screening
    • Test di screening positivi per epatite B attiva, latente o inadeguatamente trattata
    • Sensibilità o intolleranza a qualsiasi ingrediente (eccipienti compresi) di ocrelizumab
    • Qualsiasi altro criterio di esclusione in conformità alle indicazioni prescrittive locali di ocrelizumab, se più rigorose di quanto precede
    E.5 End points
    E.5.1Primary end point(s)
    1. Reduction in cCDP sustained for at least 12 weeks
    1. riduzione del rischio di progressione confermata della disabilità in funzione dell’indice composito (cCDP) mantenuta per almeno 12 settimane.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to Week 120 (Double blind treatment [DBT]) and Week 96 (Open label extension [OLE])
    1. Fino alla settimana 120 (trattamento in doppio cieco [DBT]) e alla settimana 96 (estensione in aperto [OLE])
    E.5.2Secondary end point(s)
    1.Time to onset of 24 week cCDP (cCDP24)
    2.Time to onset of 12-week CDP (CDP12)
    3.Time to onset of 24-week CDP (CDP24)
    4.Time to >= 20% increase in 12 week confirmed T25FWT
    5.Time to >= 20% increase in 24 week confirmed T25FWT
    6.Time to >= 20% increase in 12 week confirmed 9 HPT
    7.Time to >= 20% increase in 24 week confirmed 9 HPT
    8.Change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29) physical scale at Week 120
    9.Percent change in total brain volume from Week 24 to Week 120
    10.Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT)
    11.Presence, frequency, timing, outcome and severity of AEs, serious adverse events (SAE) and AEs leading to study treatment withdrawal
    12.Proportion of patients with AEs and SAEs
    13.Incidence and severity of adverse events, with severity determined according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
    14.Change from baseline in clinical laboratory test results (including hematology, chemistry, Ig levels)
    15.Change from baseline in vital signs (including systolic and diastolic blood pressure, pulse rate) following study treatment administration
    16.Serum concentration of ocrelizumab at specified timepoints
    17.B cell levels in blood as the pharmacodynamic marker of ocrelizumab (including comparing the degree of B-cell depletion between the doses)
    18.Proportion of patients achieving 5 or less B-cells per microliter of blood
    19.Proportion of patients achieving 5 or less B-cells per microliter of blood in patients with the high versus low affinity Fcgamma Receptor 3A (FcgR3A) genotype per arm
    20.Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study
    21.Levels of soluble biomarkers
    22.Levels of blood B-cells based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
    23.Levels of B or T cell subsets in blood
    24.DNA genotype of patients; 1.Tempo alla comparsa di cCDP a 24 settimane (cCDP24).
    2.Tempo alla comparsa di progressione confermata della disabilità (CDP) a 12 settimane (CDP12).
    3.Tempo alla comparsa di CDP a 24 settimane (CDP24)
    4.Tempo a un aumento del risultato ottenuto nel Timed 25-Foot Walk Test (T25FWT) confermato a 12 settimane >= 20%
    5.Tempo a un aumento del risultato T25FWT confermato a 24 settimane >= 20%
    6.Tempo a un aumento del risultato ottenuto nel 9-Hole Peg Test (9 HPT) confermato a 12 settimane >=20%
    7.Tempo a un aumento del risultato 9 HPT confermato a 24 settimane >=20%
    8.Variazione sulla scala fisica della Multiple Sclerosis Impact Scale (MSIS 29) dal basale alla Settimana 120
    9.Variazione percentuale del volume cerebrale totale dalla Settimana 24 alla Settimana 120
    10.Tempo a un peggioramento confermato del punteggio ottenuto nel Symbol Digit Modality Test (SDMT) pari a 4 punti a 12 settimane
    11.Presenza, frequenza, tempistica, esito e gravità degli eventi avversi (AE), degli eventi avversi seri (SAE) e degli AE che portano alla sospensione del trattamento
    12.Proporzione di pazienti con AE e SAE
    13.Incidenza e severità degli eventi avversi, con severità stabilita in funzione dei Common Terminology Criteria for Adverse Events del National Cancer Institute (NCI CTCAE) v5.0
    14.Variazione dei risultati degli esami clinici di laboratorio (compresi esami ematologici,di chimica clinica e livelli di Ig) rispetto al basale
    15.Variazione dei parametri vitali (comprese pressione arteriosa sistolica e diastolica e frequenza cardiaca) dopo la somministrazione del trattamento in studio rispetto al basale
    16.Concentrazione sierica di ocrelizumab a specifici timepoint
    17.Livelli ematici di linfociti B (compreso il confronto del grado di deplezione dei linfociti B tra le dosi)
    18.Percentuale di pazienti con 5 o meno linfociti B per microlitro di sangue
    19.Percentuale di pazienti con 5 o meno linfociti B per microlitro di sangue tra i soggetti con genotipo 3A dei recettori Fcgamma (FcgammaR3A) ad alta versus bassa affinità per braccio
    20.Prevalenza di anticorpi anti-farmaco (ADA) al basale e incidenza degli ADA durante lo studio
    21.Identificare livelli di biomarcatori predittivi
    22.Livelli ematici di linfociti B sulla base di un dosaggio altamente sensibile che può misurare accuratamente al di sotto di 5 linfociti B per microlitro di sangue
    23.Livelli di sottogruppi di cellule B o T nel sangue
    24.Genotipo del DNA dei pazienti
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-7. Up to Week 120 (DBT) and Week 96 (OLE)
    8. Baseline to Week 120
    9. Week 24 to Week 120
    10. Up to Week 120 (DBT) and Week 96 (OLE)
    11-13. Up to Week 120 (DBT) and Week 96 (OLE)
    14-15. Baseline to Week 120 (DBT) and Week 96 (OLE)
    16-19. Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96
    20. Week 0, 24, 48, 72, 96
    21-24. DBT: Week 0, 2, 12, 24, 48, 72, 96; OLE: Week 0, 48, 96
    1-7. fino alla settimana 120 (DBT) e settimana 96 (OLE)
    8. dal basale alla settimana 120
    9. dalla settimana 24 alla 120
    10. sino alla settimana 120 (DBT) e settimana 96 (OLE)
    11-13. sino alla settimana 120 (DBT) e settimana 96 (OLE)
    14-15. dal basale alla settimana 120 (DBT) e settimana 96 (OLE)
    16-19. settimana 0, 2, 12, 24, 36, 48, 60, 72, 84, 96
    20. settimana 0, 24, 48, 72, 96
    21-24. DBT: settimana 0, 2, 12, 24, 48, 72, 96; OLE: settimana 0, 48, 96
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3.1Comparator description
    Ocrelizumab approved dose compared to higher dose
    Ocrelizumab approved dose compared to higher dose
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA67
    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
    Brazil
    Canada
    Mexico
    New Zealand
    Peru
    Russian Federation
    Turkey
    Ukraine
    United States
    Belgium
    Czechia
    Denmark
    France
    Germany
    Greece
    Hungary
    Italy
    Poland
    Portugal
    Spain
    Switzerland
    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
    The end of the study will occur when all patients, who are not being treated with an alternative B-cell depleting therapy, have repleted their B-cells (i.e., B-cell level of the patient has returned to the baseline value or the lower limit of normal, whichever is lower).
    La fine dello studio coinciderà con il momento in cui tutti i pazienti non trattati con una terapia di deplezione dei linfociti B alternativa avranno registrato un ripopolamento dei linfociti B (ossia i livelli di linfociti B del paziente saranno tornati al valore basale o, se minore, al limite inferiore della norma).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    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 years8
    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: 699
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 362
    F.4.2.2In the whole clinical trial 699
    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 may be eligible to receive ocrelizumab as part of an open label extension of this study, as described in Section 3.1. The Roche Global Policy on Continued Access to Investigational Medicinal Product is available at the following website:
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    I pazienti potrebbero essere idonei a ricevere ocrelizumab nella fase di estensione in aperto di questo studio, come descritto nella Sezione 3.1. Le linee di condotta globali di Roche sull'accesso continuato ai medicinali sperimentali sono disponibili sul seguente sito Web:
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    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 Decision2020-11-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-11
    P. End of Trial
    P.End of Trial StatusOngoing
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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