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    Summary
    EudraCT Number:2018-000721-31
    Sponsor's Protocol Code Number:RIDOSE-MS
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-04-24
    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 ConcernedSweden - MPA
    A.2EudraCT number2018-000721-31
    A.3Full title of the trial
    RItuximab Long-Term DOSE Trial in Multiple Sclerosis – RIDOSE-MS
    A randomized trial of long-term dosage of rituximab in multiple sclerosis

    The RIDOSE-MS trial is a multi-centre trial of long-term treatment with rituximab in MS, randomised between two different dosing regimens.
    Population: Patients with RRMS that has completed the RIFUND-MS trial in either the rituximab or DMF arm. In addition, patients will be recruited that has not participated in the RIFUND trial but has been treated with rituximab with the same protocol as in the RIFUND trial as part of clinical practice.
    Intervention: Treatment with rituximab (Mabthera®) 500 mg every six months. Both the previous rituximab and DMF arms from the RIFUND trial will be treated with rituximab in the RIDOSE trial.
    Control: After one year of treatment in RIDOSE-MS, patients will be randomised 1:1 to either continue with 500 mg every 6 months or 500 mg every 12 months and continue on this treatment schedule for another 3 years.
    Outcome: Primary outcome will be the proportion of patients remaining with no evidence of disease activity (NEDA) -3 over the randomised period of 3 years. As secondary endpoints progression of disability, brain atrophy, cognitive function and level of serum Neurofilament-Light will be evaluated. In addition, Patient-related outcome scales measuring fatigue, work ability and treatment satisfaction will be analysed.
    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 doses of the drug Rituximab during long-term treatment of the neurological disease Multiple Sclerosis.
    A.3.2Name or abbreviated title of the trial where available
    RIDOSE-MS
    A.4.1Sponsor's protocol code numberRIDOSE-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, Karolinska Institutet 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, Karolinska Institutet Danderyd Hospital
    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, Karolinska Institutet Danderyd Hospital
    B.5.2Functional name of contact pointDepartment of Clinical Sciences, KI
    B.5.3 Address:
    B.5.3.1Street AddressNeurologmottagningen, Danderyd Hospital
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code18288
    B.5.3.4CountrySweden
    B.5.4Telephone number46812355584
    B.5.5Fax number46812357137
    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.3.1Product nameMabthera
    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 typeequal
    D.3.10.3Concentration number500
    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 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.3.1Product nameMabthera
    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.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
    Patients with multiple sclerosis (MS), 20 - 52 years of age, that have completed the RIFUND-MS trial (EudraCT 2015-004116-38) will be offered to continue in this extension trial, RODOSE-MS. In addition, patients will be recruited that has not participated in the RIFUND trial but has been treated with rituximab with the same protocol as in the RIFUND trial as part of clinical practice.
    E.1.1.1Medical condition in easily understood language
    Patients with MS included in the trial RIFUND-MS will be offered to continue in this extension trial. Additional patients treated with rituximab as in the RIFUND trial will be recruited.
    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 assess long-term efficacy and safety of rituximab in RRMS while comparing two different dosing regimens.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are
    • To compare effects on brain atrophy measures via magnetic resonance imaging between treatment with two long-term dosing regimens of Rituximab in MS.
    • To compare effects on cerebrospinal fluid markers between axonal damage from treatment with two long-term dosing regimens of Rituximab in MS.
    • To compare effects on serum markers for axonal damage between treatment with two long-term dosing regimens of Rituximab in MS.
    • To compare the rate of disability progression between treatment with two long-term dosing regimens of Rituximab in MS.
    • To compare the occurrence of immunological side-effects such as hypogammag-lobulinaemia and late onset neutropenia between treatment with two long-term dosing regimens of Rituximab in MS.
    • To compare the occurrence of severe infections between treatment with two long-term dosing regimens of Rituximab in MS.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    To compare the two doses of rituximab 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
    • The patient has completed the RIFUND-MS trial and is treated with either of the study medications rituximab or DMF at the last visit of the RIFUND trial OR has been treated with rituximab with a dose regimen of 500 – 1000 mg followed by 500 mg every 6 months* for a total of up to two years as part of clinical practice
    • Age 20 – 52 years (inclusive)
    • EDSS 0 – 5,5 (inclusive)
    • The patient is willing and able to give written informed consent, according to the judgement of the investigator.
    • 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 without an alternative medical cause or, in case of ambiguities, an FSH level in the postmenopausal range.
    * Occasional extended dose interval for up to 12 months in conjunction with the COVID epidemic is allowed
    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
    • Previous treatment with any “second-line” immunomodulatory drug, eg natalizumab, alemtuzumab**, fingolimod, or other long-acting immunosuppressive agents.
    • Pregnant or lactating women
    s-HCG will be tested on all women at screening, before each study-related infu-sion and in any situation where there is a reason to suspect pregnancy during the trial, eg delayed menstrual period more than five days above expected time.
    • Patients having contraindication for or otherwise not compliant with MRI investi-gations
    • Simultaneous treatment with other immunosuppressive drugs
    • Active, severe infections
    Signs of infections are assessed before inclusion and each study-related infusion through clinical examination and further evaluated by laboratory and other rele-vant investigations in case of suspected ongoing infection. Hepatitis serology (HBsAg and anti-HBc) will be evaluated before treatment onset if not tested within the previous three years.
    • Severe cardiac disorder, eg signs of congestive heart failure or coronary artery disease. This will be evaluated through clinical assessment before inclusion.
    • Vaccination within 4 weeks of first dose of study medication.
    • Documented allergy or intolerance to any of the IP:s
    • Severe psychiatric condition
    ** Up to 6 months initial treatment with natalizumab in conjunction with the COVID epidemic or for completing vaccination before inclusion in the trial is allowed.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is
    • The proportion of patients maintaining No Evidence of Disease Activity-3 (NEDA-3) during year 2 – 4 of the trial: No relapse, no new T2 lesions (> 3 mm), no EDSS progression in either dose arm.
    E.5.1.1Timepoint(s) of evaluation of this end point
    When all included subjects have been followed for the full duration of 4 years in the trial
    E.5.2Secondary end point(s)
    The secondary endpoints are
    • The proportion of patients maintaining NEDA-3 comparing the previous rituximab arm with the previous DMF arm from the RIFUND trial
    • Time to first relapse for the two dosing regimens
    • Treatment effect evaluated by MRI
    o Proportion without new/enlarging T2 lesions
    o Evolution of brain atrophy measured as brain parenchymal fraction (BPF) and corpus callosum area or -volume
    • Treatment effect as confirmed worsening evaluated via EDSS
    o Proportion of patient with confirmed progression in EDSS according to pre-specified criteria
    o The mean change in EDSS over the trial period
    • Treatment effect evaluated via levels of Neurofilament-Light protein in serum
    o Serum will be stored from blood samples each six month during the study, in total nine occasions
    • Treatment effect evaluated via levels of Neurofilament-Light protein in the CSF
    o The patients will be asked to participate in this part as an optional study involving LP at three occasions.
    • Time to discontinuation of dosing regimen allocation, ie “dose survival” analysis.
    • The occurrence of hypogammaglobulinaemia in the two dose arms
    • The occurrence of neutropenia in the two dose arms
    • The occurrence of infections in the two dose arms
    E.5.2.1Timepoint(s) of evaluation of this end point
    When all included subjects have been followed for the full duration of 4 years in the trial
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.7.1Other trial design description
    Dose comparison
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Another dose of the same medicinal product
    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 concerned17
    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 years6
    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 years6
    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: 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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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)
    Further extension study may be performed. If not, treatment according to clinical routine.
    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 Decision2018-06-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-04
    P. End of Trial
    P.End of Trial StatusOngoing
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