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    EudraCT Number:2018-001511-73
    Sponsor's Protocol Code Number:WA40404
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-05-08
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2018-001511-73
    A.3Full title of the trial
    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 Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis
    A.4.1Sponsor's protocol code numberWA40404
    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.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.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
    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. name Ocrevus
    D. 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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. 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 (PPMS)
    E.1.1.1Medical condition in easily understood language
    PPMS is a form of multiple sclerosis that is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions
    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 evaluate the efficacy of ocrelizumab treatment compared with placebo-in patients on progression of upper limb disability, measured based on the time to 20% worsening from baseline in the 9-Hole Peg Test (9-HPT) confirmed for at least 12 weeks in all randomized patients and in patients with magnetic resonance imaging (MRI) activity
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients by the time to 24 week confirmed 20% increase from baseline in 9-HPT, time to 12-week and 24-week confirmed disability progression (CDP) as measured by changes in expanded disability status scale (EDSS)
    •To evaluate the efficacy of ocrelizumab compared with placebo for all patients by the % change in total volume of T2 lesions and total brain volume as measured by magnetic resonance imaging
    •To evaluate the safety of ocrelizumab compared with placebo and over time for all patients by the proportion of patients with adverse events, laboratory abnormalities
    •To assess the immunogenicity, by the presence of anti-drug antibody to ocrelizumab during the study relative to baseline and the relationship to pharmacokinetics (PK), pharmacodynamics, efficacy and safety
    •To characterize the PK profile of the ocrelizumab and its PD, measured by blood B-cell levels
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Diagnosis of PPMS in accordance with the McDonald criteria (Thompson et al. 2017)
    - Age 18-65 years at time of signing Informed Consent Form
    - EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
    - Disease duration from the onset of multiple sclerosis (MS) symptoms relative to randomization date:
    o Less than 20 years in patients with an EDSS score at screening 7.0-8.0
    o Less than 15 years in patients with an EDSS at screening 5.5-6.5
    o Less than 10 years in patients with an EDSS at screening <= 5.0
    - Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen
    o Elevated IgG index
    o One or more IgG oligoclonal bands detected by isoelectric focusing
    - Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
    - Neurological stability for >= 30 days prior to baseline
    - Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
    - Patients previously treated with immunosuppressant, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
    - For women of childbearing potential: agreement to remain abstinent or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab (adherence to local requirements, if more stringent, is required)

    Eligibility Criteria for OLE Phase:
    - Completed the double-blind treatment phase of the trial and who, in the opinion of the investigator, may benefit from treatment with ocrelizumab
    E.4Principal exclusion criteria
    - History of relapsing-remitting or secondary progressive MS at screening
    - Confirmed serious opportunistic infection
    - Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy
    - Known active malignancy or are being actively monitored for recurrence of malignancy
    - Immunocompromised state defined as one or more of the following: CD4 count < 250/μL, absolute neutrophil count <1.5 x 103/μL, Serum IgG < 4.6 g/L
    - Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
    - Inability to complete an MRI or contraindication to gadolinium (Gd) administration
    - Patients requiring symptomatic treatment of multiple sclerosis (MS) and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization
    - Contraindications to mandatory premedication for infusion-related reactions
    - Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study, including, but not limited to: history of hemorrhagic or ischemic cerebrovascular disorders or hemorrhage or ischemia of the spinal cord, history or known presence of CNS or spinal cord tumor, history of metabolic myelopathy or known presence of untreated causes of myelopathy, history or known presence of infectious metabolic myelopathy, history of genetically inherited progressive CNS degenerative disorder, neuromyelitis optica, history or known presence of non-MS systemic autoimmune disorders potentially causing progressive neurologic disease, history or known presence of sarcoidosis, history of severe, clinically significant brain or spinal cord trauma
    - Pregnant or breastfeeding, or intending to become pregnant during the study and 6 or 12 months after last infusion of the study drug
    - Lack of peripheral venous access
    - Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or
    gastrointestinal, or any other significant disease that may preclude patient from participating in the study
    - Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressant during the course of the study
    - History of alcohol or other drug abuse
    - History of primary or secondary (non-drug-related) immunodeficiency
    - Treatment with any investigational agent within 24 weeks prior to screening or 5 half-lives of the investigational drug, or treatment with any experimental procedure for MS
    - Previous treatment with B-cell targeting therapies, bone marrow transplantation or 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 serum β-hCG measured at screening or positive urine β -hCG at baseline
    - Positive screening tests for hepatitis B
    - 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.Upper limb disability progression, measured based on time to 20% worsening from baseline in 9-HPT confirmed for at least 12 weeks and in all patients and patients with MRI activity
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Double-Blind Treatment (DBT): Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, treatment discontinuation (TD), Follow Up 1: Visits every 12 weeks, 144 being the last visit
    E.5.2Secondary end point(s)
    1. Upper limb disability progression, measured based on time to 20% increase from baseline in 9-HPT confirmed at least 24 weeks
    2. Time to 12-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 12 weeks
    3. Time to 24-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 24 weeks
    4. Differences in the percent change in total volume of T2 lesions on MRI from baseline up to Week 120 will be analyzed using analysis of covariance and mixed effect model repeat measurement (MMRM) analyses
    5. Differences in the mean percentage change in total brain volume on MRI scans from Week 24 to Week 120 will be analyzed using an MMRM analysis
    6. Incidence and nature of adverse events, serious adverse events, adverse events leading to study treatment withdrawal
    7. Change from baseline in laboratory test results for hematology and chemistry association of decrease in certain laboratory parameters, and serious infections
    8. Presence of ADA of ocrelizumab
    9. Total plasma clearances (CL) of ocrelizumab
    10. Volumes of distribution(Vd) of ocrelizumab
    11. Area under the concentration-time curve (AUC) of ocrelizumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. DBT: Week 0, 12, 24, 36, 48, 60, 72, 84, n, n+12, 144 being the last visit, TD
    2-3. DBT: Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 being the last visit, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, 12, n and TD; OLE: Week 0, 24, 48, n and TD
    4. From baseline up to Week 120
    5. From Week 24 to Week 120
    6. Up to 9.5 years
    7. From baseline to 9.5 years
    8. DBT: Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, n and TD; OLE: Week 0, 48, n, TD; Follow-Up 2: Visits every 24 weeks
    9-11. DBT: Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, 2, 12 and n, TD; OLE: Week 0, 48, n, TD; Follow-Up 2: Visits every 24 weeks
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity, Health Status Utility and Biomarker Objectives
    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. 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 Yes
    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 No
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA68
    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
    New Zealand
    United States
    Russian Federation
    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 his or her 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 years
    E.8.9.1In the Member State concerned months
    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 months6
    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: 812
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 285
    F.4.2.2In the whole clinical trial 812
    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 the OLE phase of this study, as described in Section of the protocol. The Sponsor will offer continued access to Roche IMP ocrelizumab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined below in Section 4.3.4 of the protocol.
    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 Decision2019-11-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-16
    P. End of Trial
    P.End of Trial StatusCompleted
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