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    Summary
    EudraCT Number:2020-000893-69
    Sponsor's Protocol Code Number:BN42082
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-08-11
    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 ConcernedFrance - ANSM
    A.2EudraCT number2020-000893-69
    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 RELAPSING MULTIPLE SCLEROSIS
    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 Relapsing Multiple Sclerosis
    A.4.1Sponsor's protocol code numberBN42082
    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.5.6E-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
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    Relapsing Multiple Sclerosis (MS)
    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
    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 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 21.1
    E.1.2Level PT
    E.1.2Classification code 10063399
    E.1.2Term Relapsing-remitting multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10048393
    E.1.2Term Multiple sclerosis relapse
    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
    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), 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
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A CSF Biomarker Substudy within BN42082 (RMS) 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 Relapsing 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
    E.3Principal inclusion criteria
    • Ages 18-55 years at time of signing ICF
    • Ability to comply with the study protocol
    • Diagnosis of RMS in accordance with the revised McDonald Criteria 2017
    • At least two documented clinical attacks within the last 2 years prior to screening, or one clinical attack in the year prior to screening (with no relapse 30 days prior to screening and at baseline)
    • Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments
    • Expanded disability status scale (EDSS), at screening and baseline, from 0 to 5.5 inclusive
    • Documented MRI of brain with abnormalities consistent with MS prior to screening
    • 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
    • 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).
    E.4Principal exclusion criteria
    • History of primary 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 of previous history 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
    E.5 End points
    E.5.1Primary end point(s)
    1. Reduction in cCDP sustained for at least 12 weeks
    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])
    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. Change from baseline in the Multiple Sclerosis Impact Scale (MSIS 29) physical scale at Week 120
    7. Percent change in total brain volume from Week 24 to Week 120
    8. Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT)
    9. Presence, frequency, timing, outcome and severity of AEs, serious adverse events (SAE) and AEs leading to study treatment withdrawal
    10. Proportion of patients with AEs and SAEs
    11. 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
    12. Change from baseline in clinical laboratory test results (including hematology, chemistry, Ig levels)
    13. Change from baseline in vital signs (including systolic and diastolic blood pressure, pulse rate) following study treatment administration
    14. Serum concentration of ocrelizumab at specified timepoints
    15. B cell levels in blood (including comparing the degree of B-cell depletion between the doses)
    16. Proportion of patients achieving 5 or less B-cells per microliter of blood
    17. 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
    18. Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study
    19. Levels of soluble biomarkers
    20. Levels of blood B-cells based on a highly sensitive assay that can accurately measure below 5 B-cells per microliter in blood
    21. Levels of B or T cell subsets in blood
    22. DNA genotype of patients
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-5. Up to Week 120 (DBT) and Week 96 (OLE)
    6. Baseline to Week 120
    7. Week 24 to Week 120
    8. Up to Week 120 (DBT) and Week 96 (OLE)
    9-11. Up to Week 120 (DBT) and Week 96 (OLE)
    12-13. Baseline to Week 120 (DBT) and Week 96 (OLE)
    14-17. Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96
    18. Week 0, 24, 48, 72, 96
    19-22. DBT: Week 0, 2, 12, 24, 48, 72, 96; OLE: Week 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
    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 No
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA111
    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 No
    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
    Belgium
    Brazil
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Mexico
    Netherlands
    New Zealand
    Peru
    Poland
    Portugal
    Russian Federation
    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 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).
    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 months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months4
    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: 786
    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 state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 592
    F.4.2.2In the whole clinical trial 786
    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
    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 Decision2020-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-04
    P. End of Trial
    P.End of Trial StatusOngoing
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