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    Summary
    EudraCT Number:2019-003919-53
    Sponsor's Protocol Code Number:GN41791
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-07-08
    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 number2019-003919-53
    A.3Full title of the trial
    A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED WITH OCRELIZUMAB IN ADULT PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared with Ocrelizumab in Adult Patients with Primary Progressive Multiple Sclerosis
    A.4.1Sponsor's protocol code numberGN41791
    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 supportGenentech Inc. c/o F. Hoffman-La Roche Ltd.
    B.4.2CountryUnited States
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namefenebrutinib
    D.3.2Product code RO7010939
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFENEBRUTINIB
    D.3.9.3Other descriptive nameGDC-0853 RO7010939
    D.3.9.4EV Substance CodeSUB190378
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ocrevus
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameocrelizumab
    D.3.2Product code RO4964913
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOcrelizumab
    D.3.9.2Current sponsor codeRO4964913
    D.3.9.3Other descriptive nameOCRELIZUMAB
    D.3.9.4EV Substance CodeSUB121707
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Progressive multiple sclerosis
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis (MS) is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10063401
    E.1.2Term Primary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    ● To evaluate the efficacy of fenebrutinib compared with ocrelizumab in patients with PPMS regardless of adherence to randomized treatment
    E.2.2Secondary objectives of the trial
    ● to evaluate the efficacy effectiveness of fenebrutinib treatment compared with ocrelizumab
    ● to evaluate the safety of fenebrutinib compared with ocrelizumab
    ● to characterize the fenebrutinib PK profile
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Age 18-65 years inclusive at time of signing Informed Consent Form
    ● Ability to comply with the study protocol
    ● A diagnosis of PPMS in accordance to the revised 2017 McDonald Criteria
    ● EDSS score from 3.0 to 6.5 inclusive at screening
    ● For patients currently receiving proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs): treatment at a stable dose during the screening period prior to the initiation of study treatment and plans to remain at a stable dose for the duration of study treatment
    ● For patients requiring symptomatic treatment for MS (e.g., fampridine, cannabis) and/or physiotherapy: treatment at a stable dose/regimen during the screening period prior to the initiation of study drug and plans to remain at a stable dose/regimen for the duration of study treatment Neurologically stable for at least 30 days prior to randomization and baseline assessments
    ● Ability to complete the 9 HPT for each hand in < 240 seconds
    ● Ability to perform T25FWT
    ● For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 6 or 12 months (as applicable by the local label for ocrelizumab) after the final dose of study medication. Women must refrain from donating eggs during this same period.
    ● For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm as defined below:
    o With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of study medication to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
    E.4Principal exclusion criteria
    ● 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)
    ● Patients with a previous history of a serious IRR and/or any hypersensitivity reaction to ocrelizumab
    ● History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
    ● Immunocompromised state
    ● Known presence of other neurological disorders
    ● Evidence of clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, or gastrointestinal (GI) disease that, in the investigator’s opinion, would preclude patient participation
    ● Patients meeting the New York Heart Association Class III and Class IV criteria for congestive heart failure
    ● Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
    ● History of alcohol or other drug abuse within 12 months prior to screening
    ● Positive screening tests for active, latent, or inadequately treated hepatitis B and hepatitis C (positive hepatitis C antibodies)
    ● Evidence of active or latent or inadequately treated infection with tuberculosis (TB)
    ● Abnormalities in hepatic synthetic function tests (e.g., PT, INR, PTT, albumin) judged by the investigator to be clinically significant
    ● History of hospitalizations or transfusion for a GI bleed
    ● Known bleeding diathesis
    ● Any condition possibly affecting oral drug absorption
    ● History of or currently active primary or secondary (non-drug related) immunodeficiency, including known history of HIV infection or IgG < 500 mg/dL
    ● Contraindications to mandatory premedications
    ● Inability to complete an MRI scan or contraindication to gadolinium administration
    ● Lack of peripheral venous access
    ● Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
    ● Any previous history of transplantation or anti rejection therapy
    ● Systemic corticosteroid therapy within 4 weeks prior to screening
    ● Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
    ● Sensitivity or intolerance to any ingredient (including excipients) of fenebrutinib or ocrelizumab
    ● Receipt of a live or live attenuated vaccine within 6 weeks prior to randomization
    ● Need for systemic anticoagulation (oral or injectable) or anti platelet agent other than nonsteroidal anti inflammatory drugs, aspirin, and other salicylates (aspirin up to 162 mg once daily is allowed)
    ● Previous treatment with fenebrutinib or another BTK inhibitor for any indication
    ● Treatment with any investigational agent (including high dose biotin) within 24 weeks prior to screening (Visit 1) or 5 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)
    ● Treatment with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, within 7 days or 5 drug elimination half-lives (whichever is longer) prior to randomization
    ● Treatment with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug elimination half-lives (whichever is longer) prior to randomization
    ● Previous use of anti-CD20s, including ocrelizumab, unless the last infusion was more than 2 years prior to screening, B-cell count is normal at screening, and treatment discontinuation was not motivated by safety reasons or lack of efficacy
    ● Previous use of fingolimod, siponimod, or ozanimod within 8 weeks of randomization
    ● Previous use of natalizumab for more than 1 year and within 6 months of randomization
    ● Previous treatment with dimethyl fumarate, interferons, and glatiramer acetate within 4 weeks of randomization
    ● Previous treatment with mycophenolate mofetil, or methotrexate within 3 months12 weeks of randomization
    ● Patients previously treated with teriflunomide will require the appropriate elimination protocol
    ● Previous treatment of teriflunomide, unless teriflunomide plasma concentrations are < 0.02 mg/L at screening
    ● Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide
    ● Previous treatment with any other immunomodulatory or immunosuppressive medication
    E.5 End points
    E.5.1Primary end point(s)
    1. Time to onset of cCDP12
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to 4.7 years [estimated duration of Double-Blind Treatment (DBT)]
    E.5.2Secondary end point(s)
    1. Time to onset of composite 24 week CDP (cCDP24)
    2. Time to onset of 12-week CDP (CDP12)
    3. Time to onset of 24 week CDP (CDP24)
    4. Percent change in total brain volume from Week 24 as assessed by MRI scan
    5. Change from baseline in patient-reported physical impacts of MS (as measured by Multiple Sclerosis Impact Scale, 29-Item [MSIS-29] physical scale
    6. Time to onset of 12 week confirmed 4 point worsening in Symbol Digit Modality Test (SDMT) score
    7. The nature, frequency, timing, and severity of adverse events; serious adverse events; and adverse events leading to study treatment withdrawal
    8. Change from baseline in targeted vital signs
    9. Change from baseline in targeted ECG parameters
    10. Change from baseline in clinical laboratory results following study treatment administration
    11. Change from baseline in the Proportion of patients with suicidal ideation or behavior, as assessed by Columbia Suicide Severity Rating Scale (C SSRS)
    12. Plasma concentration of fenebrutinib at specified timepoints
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-3. Up to 4.7 years (estimated duration of DBT)
    4-5. At Week 120
    6-11. Up to 4.7 years (estimated duration of DBT)
    12. Week 0, 2, 12, 24, 48, 72, 96, 120, at treatment discontinuation or unscheduled visit
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA125
    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
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Mexico
    New Zealand
    Peru
    Poland
    Portugal
    Romania
    Russian Federation
    South Africa
    Spain
    Switzerland
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of this study is defined as the date when the last patient, last visit occurs in the OLE or the last patient last visit in the SFU, whichever occurs later. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 369 weeks or approximately 7 years.
    In addition, the Sponsor may decide to terminate the study at any time.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months2
    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 months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 946
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state43
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 946
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Sponsor will offer continued access to Roche IMP fenebrutinib and ocrelizumab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined in Section 4.3.4 of the protocol.
    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 Decision2020-09-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-08-27
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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