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    Summary
    EudraCT Number:2020-002981-15
    Sponsor's Protocol Code Number:DanNORMS
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-07-13
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2020-002981-15
    A.3Full title of the trial
    Danish non-inferiority study of ocrelizumab and rituximab in MS (DanNORMS): A randomized study comparing the efficacy of ocrelizumab and rituximab in active multiple sclerosis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Non-inferiority study of ocrelizumab and rituximab in active multiple sclerosis.
    A.3.2Name or abbreviated title of the trial where available
    DanNORMS
    A.4.1Sponsor's protocol code numberDanNORMS
    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 SponsorDanish Multiple Sclerosis Center, Rigshospitalet
    B.1.3.4CountryDenmark
    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 supportDanish Regions
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDanish Multiple Sclerosis Center, Rigshospitalet
    B.5.2Functional name of contact pointDanish Multiple Sclerosis Center
    B.5.3 Address:
    B.5.3.1Street AddressValdemar Hansens Vej 1- 23
    B.5.3.2Town/ cityGlostrup
    B.5.3.3Post code2600
    B.5.3.4CountryDenmark
    B.5.4Telephone number4538633045
    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
    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.3.4Pharmaceutical 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.3.9.3Other 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 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 Ruxience
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    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.3.4Pharmaceutical 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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: 3
    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 Rixathon
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz
    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.3.4Pharmaceutical 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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
    Multiple sclerosis.
    E.1.1.1Medical condition in easily understood language
    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 10063400
    E.1.2Term Secondary progressive 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 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
    The primary aim of the study is to test whether rituximab treatment is non-inferior to ocrelizumab treatment in active forms of multiple sclerosis, which will be evaluated with the primary endpoint percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24.

    Patients completing the core-study of 24 months treatment, will be asked to continue in the extension study of additional 36 months duration.
    The extension long-term phase of the study (month 24 to month 60) will evaluate the long term efficacy and safety of rituximab and ocrelizumab therapy given as either standard dosing or extended interval dosing.
    The long-term phase of the study will examine whether extended interval dosing may be a preferable dosing strategy for patients who have been stable on well-established CD20-depleting therapy.
    E.2.2Secondary objectives of the trial
    Secondary aims include evaluation of other standard efficacy and safety endpoints and tertiary, explorative endpoints related to assessment of efficacy and safety (blood flow cytometry, whole blood gene expression, genotyping of Fcγ-receptor or complement genes, serum NFL, IgG concentrations) in the 24-month core study period.

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudies at local sites include additional MRI, clinical, optical coherence and cerebrospinal fluid biomarker endpoints.
    E.3Principal inclusion criteria
    • Age ≥18 and ≤65 years
    • MS diagnosis and definition of disease course according to the 2017 McDonald criteria
    • Expanded disability status scale (EDSS) ≤6.5
    • Fulfilling criteria for active MS:

    o Treatment naïve RRMS patients (never treated, or no DMT the previous 3 months):
    ▪ ≥2 relapse previous 12 months
    OR ▪ ≥1 relapse previous 12 months AND ≥9 T2 lesions on brain and/or spinal MRI AND ≥1 contrast-enhancing lesion or ≥1 new or enlarging T2 lesion on brain and/or spinal MRI previous 12 month

    o Previously treated RRMS patients:
    ▪ ≥1 relapse previous 12 months
    OR ▪ ≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain MRI previous 12 months

    o Progressive MS patients:
    ▪ ≥1 relapse previous 12 months
    OR ▪ ≥1 contrast-enhancing lesion previous 12 months or ≥1 new/enlarging T2 lesions on brain MRI previous 12 months or ≥2 new or enlarging T2 lesion on brain MRI previous 24 months
    OR ▪ Increased levels of neurofilament light chain in serum or cerebrospinal on sample collected previous 12 months
    Progressive MS patients not fulfilling the clinical/MRI criteria for active disease, may qualify for inclusion in the study if:

     CSF NFL level (measured with NF-Light® ELISA assay from Uman Diagnostics or Simoa):
    o 18 to 40 years >560 ng/l
    o 41 to 60 years >890 ng/l
    o 61 to 65 years >1850 ng/l

     sNFL level (measured with Simoa™ NF-light® Advantage Kit)
    o 18 to 20 years >7.4 ng/l
    o 21 to 30 years >9.9 ng/l
    o 31 to 40 years >13.1 ng/l
    o 41 to 50 years >17.5 ng/l
    o 51 to 60 years >23.3 ng/l
    o 61 to 75 years >30.9 ng/l


    • Signed written informed consent

    long-term follow-up phase of the study:

    Standard dosing:
    • Completed the first 24 months of the study
    • No signs of active disease the previous 18 months

    Inclusion criteria for extended interval dosing sub-study though randomisation
    • Completed the first 24 months of the study
    • No signs of active disease the previous 18 months
    • Signed written informed consent

    Inclusion criteria for extended interval dosing outside the randomisation process

    • Completed the first 24 months of the study
    • Recommended by physician to switch to extended interval dosing due to Low IgG (<6,1 g/L) or Frequent infections
    • No signs of active disease the previous 18 months
    • Signed written informed consent
    E.4Principal exclusion criteria
    • Pregnancy or breast feeding
    • Lack of effective contraception for women of child-bearing potential
    Effective contraception includes:
     Oral contraception (combined and progestogen-only)
     Intrauterine devices and intrauterine hormone-releasing system
     Bilateral tubal occlusion
     Vasectomised partner (provided that partner is the sole sexual partner)
     Sexual abstinence (refraining from heterosexual intercourse during the study period; sexual abstinence should be evaluated in relation to the participants preferred and usual lifestyle)
     Other forms of contraception with failure rate <1%
    • Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization
    • Active malignant disease in the previous 5 years
    • Positive test for HIV, hepatitis B or C, or tuberculosis
    • Negative test for varicella zoster
    • Lymphopenia grade 2 (0.5 to 0.8 × 109/L) or higher grades of lymphopenia (in case of switching from fingolimod, siponimod or ozanimod lymphopenia is accepted at screening visit (note that treatment with interferon-beta can induce transient lymphopenia)
    • Neutropenia grade 2 (1.0 to 1.5 × 109/L) or higher grades
    • Thrombocytopenia grade 2 (50 to 75 × 109/L) or higher grades
    • Previous treatment with alemtuzumab or hematopoietic stem-cell transplantation
    • Previous treatment with cladribine, CD20-depleting antibodies, daclizumab or other immune suppressive treatment which is judged to still exert immune suppressive effect by treating physician
    • Methylprednisolone treatment 4 weeks within baseline visit and baseline MRI scan
    • Findings on the screening MRI (for patients without MRI scan of the brain the previous 12 months the baseline MRI scan is also used as screening MRI) judged to preclude participation by the treating physician
    • Other diseases judged to be relevant by the treating physician
    • Contraindication to MRI
    • Known allergy or hypersensitivity to rituximab or ocrelizumab
    E.5 End points
    E.5.1Primary end point(s)
    • Percentage of patients with no new or enlarging T2 white matter lesions
    E.5.1.1Timepoint(s) of evaluation of this end point
    From month 6 to month 24
    E.5.2Secondary end point(s)
    • Percentage of patients with 6-month confirmed disease worsening (CDW) in EDSS from baseline to month 24
    • ARR based on cumulative number of confirmed relapses from baseline to months 24
    • Percentage of patients with 6-months CDW in T25FW from baseline to month 24
    • Percentage of patients with 6-months CDW in 9HPT from baseline to month 24
    • Percentage of patients with 6-months CDW in SDMT from baseline to month 24
    • Change in MSIS-29 from baseline to month 24
    • Change in FSMC from baseline to month 24
    • EQ-5D (5-level version) from baseline to month 24
    • Percentage of patients without GdEL on month 6 and month 24 scans
    • Change in T2 white matter lesion volume from month 6 to month 24
    • Change in T1 white matter lesion volume from month 6 to month 24
    • PBVC from month 6 to month 24
    • Difference in serum NFL level from baseline to month 24
    • Blood levels of CD19+ B cells at month 6 and month 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    See definition above for each endpoint.
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Primary endpoint with blinded evaluation
    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 concerned11
    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 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
    31st of may 2029
    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 months0
    E.8.9.1In the Member State concerned days0
    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: 584
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state594
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 594
    F.4.2.2In the whole clinical trial 594
    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)
    When the subject leaves the study, further treatment will be accordingto local MS centre practice.
    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 Decision2020-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-15
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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