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    Summary
    EudraCT Number:2020-000894-26
    Sponsor's Protocol Code Number:BN42083
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-01-29
    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 ConcernedBulgarian Drug 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
    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
    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.5.6E-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
    Primary Progressive 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 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 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) and 9-hole peg test
    (9-HPT), change from baseline in the Multiple Sclerosis
    Impact Scale 29 (MSIS 29) at week 120, annual rate of percent change from baseline in
    total brain volume, Time to 12 week confirmed 4 point worsening in
    Symbol Digit Modalities 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 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
    E.3Principal inclusion criteria
    ● Ages 18−55 years at time of screening
    ● 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
    ● Average T25FWT score over two trials at screening and over two trials
    at baseline respectively, up to 150 (inclusive) seconds
    ● Average 9HPT score over four trials (two trials with each hand) at screening and over four trials at
    baseline (two trials with each hand) respectively, up to 250 (inclusive) seconds
    ● Score of >=2.0 on the Functional Systems (FS) scale for the pyramidal
    system that was due to lower extremity findings at screening and
    baseline
    ● Documented MRI of brain with abnormalities consistent with MS
    ● Participants requiring symptomatic treatment for MS and/or
    physiotherapy must be treated at a stable dose. No initiation of
    symptomatic treatment for MS or physiotherapy within 4 weeks of
    randomization
    ● Patients must be neurologically stable for at least 30 days prior to
    randomization and baseline assessments
    ● Disease duration from the onset of MS symptoms: 1] If EDSS score at
    screening is <=5.0, disease duration from the onset of MS symptoms
    must be less than 10 years , 2] If EDSS score at screening is >5.0,
    disease duration from the onset of MS symptoms must be less than 15
    years Documented evidence of the presence at least one of cerebrospinal fluidspecific
    oligoclonal bands
    ● For females of childbearing potential, agreement to remain abstinent
    or use adequate contraceptive method
    ● 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
    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 or contraindication to gadolinium
    administration
    ● Contraindications to mandatory pre medications for IRRs
    ● Known presence of other neurologic disorders that could interfere with
    the diagnosis of MS or assessments of efficacy and/or safety during the
    study
    ● Any concomitant disease that may require chronic treatment with
    systemic corticosteroids or immunosuppressants during the course of
    the study
    ● Significant, uncontrolled 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
    ● 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 or five half-lives of the investigational drug (whichever is
    longer) or treatment with any experimental procedure for MS Previous
    use of anti-CD20s (including ocrelizumab), unless the last infusion was
    more than 2 years before screening, or if B-cell count is normal, and if
    the stop of the treatment was not motivated by safety reasons or lack of
    efficacy
    ● Any previous treatment with mitoxantrone, cladribine, atacicept,
    alemtuzumab and daclizumab
    ● Previous treatment with fingolimod, siponimod, or ozanimod within 6
    weeks of baseline
    ● Previous treatment with natalizumab within 4.5 months of baseline
    ● Previous treatment with interferons beta (1a or 1b), or glatiramer
    acetate within 2 weeks of baseline
    ● 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
    E.5 End points
    E.5.1Primary end point(s)
    1. Reduction in cCDP sustained for at least 12 weeks, measured by time
    to onset of cCDP sustained for at least 12 weeks. Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression
    even measured by EDSS, T25FWT or 9-HPT
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. From Baseline up to 4.3 years (Double blind treatment [DBT])
    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 29 (MSIS 29) physical scale at Week 120
    9. Annual rate of percent change from baseline in total brain volume
    10. Time to 12 week confirmed 4 point worsening in Symbol Digit
    Modality test (SDMT)
    11. Serum concentration of ocrelizumab at specified timepoints
    12. Change in B cell levels in blood
    13. Proportion of participants achieving 5 or less B-cells per microliter of
    blood
    14. Proportion of participants achieving 5 or less B-cells per microliter of
    blood in participants with the high versus low affinity Fc gamma
    Receptor 3A (FcgR3A) genotype per arm
    15. Change from Baseline in the anti-drug antibodies (ADAs) levels
    16. Levels of Neurofilament Light Chain (NfL) in blood
    17. Levels of Interleukin-6 (IL-6) in blood18. Levels of blood B-cells
    19 Levels of Lymphocytes in blood
    20. Proportion of participants with different DNA genotypes
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-7. Baseline up to approximately 4.3 years
    8 Baseline to Week 120
    9-10 Baseline to approximately 4.3 years
    11. Weeks 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
    12-13. Baseline up to approximately 4.3 years
    14 Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
    15 Week 0, 24, 48, 72, 96, 120
    16-19 Baseline up to approximately 4.3 years
    20 Week 0, 2, 12, 24, 48, 72, 96, 120
    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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA118
    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
    Belgium
    Brazil
    Canada
    Czechia
    Denmark
    France
    Germany
    Greece
    Hungary
    Italy
    Mexico
    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 years8
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months5
    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 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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 488
    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
    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 Decision2021-02-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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