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    Summary
    EudraCT Number:2020-001205-23
    Sponsor's Protocol Code Number:OVERLORD-MS
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-06-02
    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 ConcernedNorway - NOMA
    A.2EudraCT number2020-001205-23
    A.3Full title of the trial
    Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing
    MS Disease (OVERLORD-MS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing MS Disease
    A.3.2Name or abbreviated title of the trial where available
    OVERLORD-MS
    A.4.1Sponsor's protocol code numberOVERLORD-MS
    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 SponsorHelse Bergen HF, Haukeland University Hospital
    B.1.3.4CountryNorway
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportProgram for klinisk behandlingsforskning i spesialisthelsetjenesten (KLINBEFORSK)
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHelse Bergen HF, Haukeland University Hospital
    B.5.2Functional name of contact pointØivind Fredvik Grytten Torkildsen
    B.5.3 Address:
    B.5.3.1Street AddressHaukelandsveien 22
    B.5.3.2Town/ cityBergen
    B.5.3.3Post code5021
    B.5.3.4CountryNorway
    B.5.6E-mailoivind.fredvik.grytten.torkildsen@helse-bergen.no
    D. IMP Identification
    D.IMP: 1
    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.2.5The 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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 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 No
    D.IMP: 2
    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 Rituximab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameRituximab
    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.3.11 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 No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Remitting Relapsing Multiple Sclerosis
    E.1.1.1Medical condition in easily understood language
    Relapsing Remitting Multiple Sclerosis
    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 10063399
    E.1.2Term Relapsing-remitting 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 non-inferiority of rituximab compared to ocrelizumab with regards to efficacy and safety in treatment of naïve RRMS patients, diagnosed within the last 12 months.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Biomarker research;
    1) Serum levels of neurofilament light chain (NFL), serum levels of vitamin D, the level of CD27+ B memory cells and heterogeneity in immunoglobulin receptors (FcR), will be analysed to evaluate their association with the observed clinical responses to the primary and secondary outcome measures to rituximab and ocrelizumab.
    2) Analyses may be performed on biomarker variants thought to play a role in MS-immunology including, but not limited to, cytokine profiles, protein patterns, EBV antibodies, T-cell receptor sequencing, B-cell receptor sequencing, various immunological analyses, immunophenotyping, functional markers, mass/flow cytometry, gene expression, sequencing, sorting, proteomics, immunohistochemistry, somatic mutations, DNA methylation and DNA modification.

    Immunogenicity assessments;
    Serum samples will be screened for antibodies binding to rituximab and ocrelizumab. Analyses may be performed to verify the stability of antibodies to rituximab. Samples will also be evaluated for rituximab and ocrelizumab serum concentration to enable interpretation of the antibody data. Antibodies may be further characterized and/or evaluated for their ability to neutralize the activity of the study intervention(s).


    E.3Principal inclusion criteria
    1.Male and female patients, treatment naïve, and aged between 18 and 60 years included
    2.Women of childbearing potential1 (WOCBP) able and willing to use highly effective methods of birth control2 per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly for the duration of the study OR until 3 months after last dose administered.
    3.A diagnosis of RRMS according to the 2017 revised diagnostic criteria of McDonald (Thompson, Banwell et al. 2018) within the last 12 months.
    4.Disease activity defined as ≥ 1 relapse3 or ≥ 1 new MRI lesion4 during the last 12 months
    5.EDSS score ≤ 4.0
    6.Absence of comorbidity or drug abuse that preclude study participation
    7.Able to complete treatment or follow-up visits in the study (e.g. no contraindications for MRI or plans of moving)
    E.4Principal exclusion criteria
    1.Known hypersensitivity or other known side effects for any of the study medications, including co-medications such as high glucocorticosteroids
    2.A diagnosis of primary progressive MS according to the revised diagnostic criteria of McDonald (Thompson, Banwell et al. 2018)
    3.A disease course of secondary progressive MS (Lublin, Reingold et al. 2014)
    4.EDSS score > 4.0
    5.Any ongoing infection, including tuberculosis, VZV, hepatitis virus or HIV, as well as hepatitis B surface antigen positivity and/or hepatitis C PCR positivity verified at screening visit.
    6.Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol.
    7.Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmia, unstable or advanced ischemic heart disease (NYHA III or IV)
    8.Active malignancy or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
    9.WBC < 1.5 x 109/L if not caused by a reversible effect of documented ongoing medication. If WBC < 1.5 x 109/L is caused by a reversible effect of documented ongoing medication the WBC count must be > 1,5 x 109/L before start of study treatment.
    10.Platelet (thrombocyte) count < 100 x 109/L
    11.ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)
    12.Serum creatinine > 200 µmol/L
    13.Serum bilirubin > ULN
    14.Pregnancy or lactating female patients
    15.Any disease that can influence the patient safety and compliance, or the evaluation of disability
    16.History of life-threatening infusion reaction to ocrelizumab or rituximab, if previously treated with these medications for other diseases than MS
    17.Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
    18.Previous use of MS-therapies such as natalizumab, fingolimod, interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, cladribine, rituximab, alemtuzumab, ocrelizumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression therapies with long lasting effects, or any other disease modifying therapy (DMT) for MS.
    19.Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study (s), or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded.
    20.Presence of metallic objects implanted in the body, or allergy to MRI contrast that would preclude the ability of the patient to safely have MRI exams
    21.Current alcohol or drug dependencies
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is to determine the difference in efficacy and safety between rituximab and ocrelizumab according to the following criteria:
    •Proportion of patients with no new or enlarging T2-weighted brain MRI lesions from month 6 (re-baseline) to month 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    From re-baseline at 6 months to 24 months.
    E.5.2Secondary end point(s)
    •Proportion of patients with 6-months confirmed disability progression (6M-CDP) as measured by the Expanded disability status scale (EDSS) from baseline to month 24. CDP-EDSS defined as an increase of one point in the EDSS score confirmed after 6 months, with an absence of relapse at the time of assessment.
    •Proportion of patients with 6-months confirmed disability improvement (6M-CDI) as measured by the Expanded disability status scale (EDSS) from baseline to month 24. CDI-EDSS is defined as a decrease of one point in the EDSS score, confirmed after 6 months, with an absence of relapse at the time of assessment.
    •The annual relapse rate from baseline to month 24
    •Proportion of patients without relapses from baseline to month 24
    •Proportion of patients with 6M-CDP in T25FW from baseline to month 24. 6M-CDP in T25FW is defined as patients experiencing an increase of ≥20% from baseline which is confirmed after 6 months
    •Proportion of patients with 6M-CDP in 9-HPT from baseline to month 24. 6M-CDP in 9HPT is defined as patients experiencing an increase of ≥20% from baseline which is confirmed after 6 months
    •Proportion of patients with 6M-CDP in SDMT from baseline to month 24. 6-month CDP in SDMT is defined as patients experiencing a reduction of 15% from baseline which is confirmed after 6 months
    •Proportion of patients with no new or enlarging T2-weighted brain MRI lesions from baseline to month 6, and from baseline to month 24
    •Proportion of patients without new gadolinium enhancing T1-weighted brain MRI lesions at month 6, month 12 and month 24
    •Change in brain volumes from baseline to month 24 and from month 6 to month 24
    •Overall safety during 24 months of treatment
    •The frequency of immediate and delayed infusion reactions during 24 months of treatment
    •The frequency of infections during 24 months of treatment
    •The frequency any malignancies during 24 months of treatment
    •Change in the quality of life as measured by MS impact scale 29 (MSIS-29) from baseline to month 24
    •Change in Health related Anxiety and Depression as measured by HADS from baseline to month 24
    •Change in the fatigue as measured by fatigue scale for motor and cognitive functions (FSMC)
    •Change in EQ-5D score from baseline to month 24
    •Change in employment status from baseline to month 24
    •The frequency of anti-drug-antibodies during 24 months of treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline (month 0) or re-baseline (month 6) to month 12 and/or month 24.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 211
    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 state211
    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 in both treatment arms will be offered information about alternative treatment options and will together with the treating neurologist decide on the best option for them as individual patients.

    If rituximab is determined to be non-inferior to rituxiamb, all patients will be offered to switch to treatment with rituximab, and a planned observational extension switch-study will be performed to determine safety and efficacy.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-03
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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