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    Summary
    EudraCT Number:2020-000637-41
    Sponsor's Protocol Code Number:EFC16033
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-07-15
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2020-000637-41
    A.3Full title of the trial
    A Phase 3, randomized, double-blind efficacy and safety study comparing SAR442168 to teriflunomide (Aubagio®) in participants with relapsing forms of multiple sclerosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Relapsing Forms of multiple sclerosis (RMS) study of Bruton's Tyrosine Kinase (BTK) inhibitor Tolebrutinib (SAR442168) (GEMINI 1)
    A.3.2Name or abbreviated title of the trial where available
    GEMINI 1
    A.4.1Sponsor's protocol code numberEFC16033
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1238-1418
    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 SponsorGenzyme Corporation
    B.1.3.4CountryUnited States
    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 supportGenzyme Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.3.2Product code SAR442168
    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 INNNot available
    D.3.9.1CAS number 1971920-73-6
    D.3.9.2Current sponsor codeSAR442168
    D.3.9.3Other descriptive namePRN2246
    D.3.9.4EV Substance CodeSUB195428
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Aubagio
    D.2.1.1.2Name of the Marketing Authorisation holdersanofi-aventis groupe
    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 nameTeriflunomide
    D.3.2Product code HMR1726
    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 INNTERIFLUNOMIDE
    D.3.9.1CAS number 108605-62-5
    D.3.9.2Current sponsor codeHMR1726
    D.3.9.4EV Substance CodeSUB25218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number14
    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 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 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
    Relapsing Multiple Sclerosis
    E.1.1.1Medical condition in easily understood language
    Relapsing 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 21.0
    E.1.2Level PT
    E.1.2Classification code 10080700
    E.1.2Term Relapsing 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 assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS
    E.2.2Secondary objectives of the trial
    - To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life
    - To evaluate the safety and tolerability of daily SAR442168
    - To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety
    - To evaluate pharmacodynamics (PD) of SAR442168
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent
    - The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria
    - The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first Screening Visit
    - The participant must have at least 1 of the following prior to screening:
    -- ≥1 documented relapse within the previous year OR
    -- ≥2 documented relapses within the previous 2 years, OR
    -- ≥1 documented Gd enhancing lesion on an MRI scan within the previous year
    - Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    - Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure:
    Refrain from donating sperm
    Plus either:
    Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
    OR
    Must agree to use contraception/barrier as detailed below
    Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
    - A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply:
    Is not a Woman of child-bearing potential (WOCBP)
    OR
    Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user
    dependency, during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last
    dose of SAR442168, if the case was unblinded
    - A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24 hours before the first dose of study intervention
    - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    - The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    - The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant’s legally authorized representative
    E.4Principal exclusion criteria
    - The participant has been diagnosed with primary progressive multiplesclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiplesclerosis (SPMS)
    - The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, hepatitis B or C, any persistent chronic or active recurring infection
    -Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening
    - Confirmed screening ALT >2 × ULN
    - The participant has conditions or situations that would adversely affect participation in this study, including but not limited to:
    -- A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist
    -- Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator
    -- A requirement for concomitant treatment that could bias the primary evaluation
    - The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study
    The participant has any of the following:
    -- A bleeding disorder or known platelet dysfunction at any time prior to the screening visit
    -- A platelet count <150 000/μL at the screening visit
    - The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit
    - The presence of psychiatric disturbance or substance abuse
    Prior/concomitant therapy
    - The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes
    - The participant is receiving anticoagulant/antiplatelet therapies

    The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial
    E.5 End points
    E.5.1Primary end point(s)
    Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined relapses ; Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 36 months
    E.5.2Secondary end point(s)
    1 - Time to onset of confirmed disability worsening confirmed over at least 6 months ; Time to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows:
    -- increase of ≥1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0
    OR
    -- increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5
    OR
    -- increase of ≥0.5 point from the baseline EDSS score when the baseline score is >5.5
    2 - Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 month
    3 - Total number of new and/or enlarging T2 hyperintense lesions as detected by MRI from Month 6 through the end of study
    4 - Total of Gd-enhancing T1 hyperintense lesions as detected by MRI from 6 months through the EOS
    5 - Change in cognitive function ; Change in cognitive function from baseline to the EOS as assessed by SDMTand by CVLT-II where available
    6 - Time to confirmed disability improvement ; Time to confirmed disability improvement (CDI), defined as a ≥1.0 point decrease on the EDSS from the baseline EDSS score confirmed over at least 6 months
    7 - Percent Change in Brain volume loss (BVL) ; Brain volume loss (BVL) rate as detected by brain MRI from Month 6 to the EOS
    8 - Change in Multiple Sclerosis Quality of Life ; Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
    9 - Number of participants with adverse events (AEs) leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
    10 - Population Pharmacokinetics ;
    Plasma concentration of SAR442168 (population PK assessment) at 6 Months
    Plasma concentration of SAR442168 (population PK assessment) at 9 Months
    Plasma concentration of SAR442168 (population PK assessment) at 12 Months
    11 - Change in plasma NfL ; Change in plasma neurofilament light chain (NfL) levels at the EOS compared to baseline
    12 - Change in lymphocyte Phenotype ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of
    participants
    13 - Changes in plasma Immunoglobulin levels ; Changes in serum immunoglobulin level at the EOS compared to baseline
    14 - Change in CHI3L1 levels ; Change in serum Chi3L1 levels at the EOS compared to baseline
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2 - Up to approximately 36 months
    3, 4, 5, 6, 7, 8 - From 6 months up to approximately 36 months
    9 - From screening until end of study approximately 36 months
    10 - 6 Months
    9 Months
    12 Months
    11, 12, 13, 14 - From Baseline until end of study (up to 36 months)
    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 Yes
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    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
    Ukraine
    Hong Kong
    Taiwan
    Belarus
    Canada
    China
    Japan
    Mexico
    Russian Federation
    United States
    Austria
    Bulgaria
    Czechia
    Denmark
    Estonia
    Finland
    Germany
    Italy
    Lithuania
    Poland
    Romania
    Spain
    Sweden
    Türkiye
    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
    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 months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 1200
    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 state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 367
    F.4.2.2In the whole clinical trial 1200
    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)
    Participants completing the study will be offered to participate in a long term safety study.
    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 Decision2020-08-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-17
    P. End of Trial
    P.End of Trial StatusOngoing
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