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    Summary
    EudraCT Number:2015-004116-38
    Sponsor's Protocol Code Number:RIFUND-MS
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-10-20
    Trial results View 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 ConcernedSweden - MPA
    A.2EudraCT number2015-004116-38
    A.3Full title of the trial
    RItuximab versus FUmarate in Newly Diagnosed Multiple Sclerosis – RIFUND-MS
    A randomized phase 3 study comparing Rituximab with Dimethyl Fumarate in early Relapsing-Remitting Multiple Sclerosis

    Objective: To compare the efficacy of rituximab on the ability to prevent relapses in early RRMS and CIS compared with dimethyl fumarate (DMF), which is an approved first-line medication for RRMS today, using a phase 3 design.
    Population: Patients with newly diagnosed RRMS or CIS with no more than 10 years disease duration (since diagnosis), 18 – 50 years of age and previously not treated with immunomodulating drugs OR treated with first-line injectables. Patients should display protocol-defined clinical or radiological disease activity during the preceding year before screening for inclusion.
    Intervention: Treatment with rituximab (Mabthera®) with an initial dose of 1000 mg intravenously (iv) followed by 500 mg iv every six months.
    Control: Treatment with DMF (Tecfidera®) 240 mg twice daily. The two treatments are randomised in a 1:1 proportion.
    Outcome: Primary outcome is the relative risk of experiencing a relapse during the two–year period for either compound. As secondary endpoints worsening on neurological disability, magnetic-resonance imaging-defined disease activity and effect on cerebrospinal fluid biomarkers will be analysed. In addition, health-economic evaluations of using rituximab as first-line treatment for RRMS will be performed.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clincial study comparing the effectiveness of two drugs, named Rituximab and Dimethyl Fumarate (Tecfidera®), for the neurological disease Multiple Sclerosis.
    A.4.1Sponsor's protocol code numberRIFUND-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 SponsorDepartment of Clinical Sciences, Danderyd Hospital
    B.1.3.4CountrySweden
    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 supportDepartment of Clinical Sciences, Danderyd Hospital, Karolinska Institutet
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of Clinical Sciences, Danderyd Hospital, Karolinska Institutet
    B.5.2Functional name of contact pointDepartment of Clinical Sciences, KI
    B.5.3 Address:
    B.5.3.1Street AddressKarolinska Institutet
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code17177
    B.5.3.4CountrySweden
    B.5.4Telephone number468123 555 33
    B.5.5Fax number468123 571 37
    B.5.6E-mailanders.svenningsson@ki.se
    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 Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 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 typerange
    D.3.10.3Concentration number500 to 1000
    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 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 Tecfidera
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Limited
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 Capsule, hard
    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 INNDIMETHYL FUMARATE
    D.3.9.1CAS number 624-49-7
    D.3.9.3Other descriptive nameDIMETHYL FUMARATE
    D.3.9.4EV Substance CodeSUB13608MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number480
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    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
    Patients with multiple sclerosis (MS) or patients presenting with symptoms highly suspicious of MS while not completely fulfilling diagnostic criteria, 18 - 50 years of age and no more than 10 years of disease duration (from diagnosis). Patients treated with immunomodulatory drugs or treated with first-line injectable therapies (eg interferons or glatiramer acetate) may be included.
    E.1.1.1Medical condition in easily understood language
    Patients with newly diagnosed multiple sclerosis (MS) or with symptoms and signs giving rise to high suspicion of MS, either non-treated or treated with first-line injection therapies.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    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 objective of this study is
    • To compare clinical efficacy between rituximab administered according to a Swed-ish treatment schedule and dimethyl fumarate administered according to label
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are
    • To compare effects on magnetic resonance imaging from treatment with rituximab and dimethyl fumarate
    • To compare effects on cerebrospinal fluid markers for axonal damage from treat-ment with rituximab and dimethyl fumarate
    • To compare effects on serum levels of the axonal injury marker neurofilament light from treatment with rituximab and dimethyl fumarate
    • To compare the rate of disability progression during the trial
    • To make health economic assessments, including work capacity, and compare cost – effectiveness between Rituximab and dimethyl fumarate
    • To compare patient satisfaction and health related quality of life during long-term treatment of RRMS patients with Rituximab and dimethyl fumarate
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    In early multiple sclerosis, compare the two drugs rituximab and dimethyl fumarate in their ability to prevent nerve damage measured as release of the biomarker Neurofilament Light in the cerebrospinal fluid
    E.3Principal inclusion criteria
    A subject will be eligible for inclusion in this study if all of the following criteria apply:

    • Diagnosis of Relapsing Remitting MS according to the 2017 revised McDonald criteria OR one demyelinating episode in conjunction with at least one asymptomatic high intensity T2 lesion with size and location compatible with MS
    • Untreated OR treated with first line injectables (interferon or glatiramer acetate)
    • Between the age of 18 and 50 years (inclusive) of age
    • No more than 10 years of disease duration (since MS diagnosis)
    • During the previous year, clinical or radiological disease activity defined as at least one of the following:
    o ≥ 1 relapse
    o ≥ 2 T2 lesions
    o ≥ 1 Gd+ lesions
    • EDSS 0 – 5,5 (inclusive)
    In fertile females, willing to comply with effective contraceptive methods. These include birth control pills, surgical sterilization of patient or partner or intrauterine device. Non-fertile women is defined as more than 12 months of amenorrhea
    E.4Principal exclusion criteria
    A subject will not be eligible for inclusion in this study if any of the following criteria ap-plies:

    • Diagnosis of Progressive MS
    • Pregnant or lactating women
    • Patients having contraindication for or otherwise not compliant with MRI investigations
    • Simultaneous treatment with other immunosuppressive drugs
    • Documented allergy or intolerance to any of the IP:s
    • Severe psychiatric condition
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints of this study is
    • The relative risk of experiencing a relapse during the two–year period for either compound.
    E.5.1.1Timepoint(s) of evaluation of this end point
    While all subjects in the trial has received treatment with either of the IMP for two years
    E.5.2Secondary end point(s)
    The secondary endpoints are
    • Treatment effect evaluated via MRI
    - Numbers of Gd+ lesions and new/enlarging T2 lesions
    - Evolution of brain atrophy measured as brain parenchymal fraction (BPF)
    • Treatment effect evaluated via levels of Neurofilament-Light protein in the CSF
    - The patients will be asked to participate in this part as an optional study involving LP at four occasions.
    • Treatment effect evaluated via levels of Neurofilament-Light protein in the serum
    • Treatment effect as confirmed worsening evaluated via EDSS
    - Proportion of patient with confirmed progression in EDSS according to pre-specified criteria
    - The mean change in EDSS over the trial period
    • Proportion of patients with No Evidene of Disease Activity (NEDA) -3 (free of ex-acerbations, new/enlarged T2-lesions and occurrence of Gd+ lesions) as well as NEDA-4 (NEDA-3 plus no worsening of EDSS from baseline)
    • Proportion rescue treatments from insufficient treatment effect determined by MRI in the two treatment arms
    E.5.2.1Timepoint(s) of evaluation of this end point
    While all subjects in the trial has received treatment with either of the IMP for two years
    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 Yes
    E.8.1.4Double blind No
    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 concerned18
    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
    Last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 200
    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 state200
    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 will be offered to continue treatment with either of the investigational drugs after end of trial according to patient preference. Extension trial may be applied for
    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 Decision2015-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-04-21
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