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    Summary
    EudraCT Number:2020-000647-30
    Sponsor's Protocol Code Number:EFC16645
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-09-14
    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 ConcernedLithuania - SMCA
    A.2EudraCT number2020-000647-30
    A.3Full title of the trial
    A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton tyrosine kinase (BTK) inhibitor tolebrutinib SAR442168 (HERCULES)
    A.3.2Name or abbreviated title of the trial where available
    HERCULES
    A.4.1Sponsor's protocol code numberEFC16645
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1246-7768
    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 organisationSanofi AB
    B.5.2Functional name of contact pointClinical Study Unit
    B.5.3 Address:
    B.5.3.1Street AddressBox 30052
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code10425
    B.5.3.4CountrySweden
    B.5.4Telephone number+46 86345000
    B.5.6E-mailclinicaltrials.sweden@sanofi.com
    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.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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-relapsing Secondary Progressive Multiple Sclerosis
    E.1.1.1Medical condition in easily understood language
    Non-relapsing Secondary Progressive 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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in
    NRSPMS
    E.2.2Secondary objectives of the trial
    - To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonsnce
    imaging (MRI) lesions, cognitive performance, physical function, and quality of life
    - To evaluate safety and tolerability of SAR442168
    - To evaluate population pharmacokinetics (PK) of SAR442168 in NRSPMS 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
    - 18 to 60 years of age inclusive
    - Diagnosis of nonrelapsing secondary progressive multiple sclerosis according to the 2017 McDonald criteria
    - Expanded disability status scale (EDSS) between 3.0 to 6.5 points inclusive, at screening
    - The participant must have documented evidence of disability progression observed during the 12 months before screening
    - Absence of clinical relapses for at least 24 months
    - Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    - Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a woman of child bearing potential (WOCBP)
    OR
    - Is a WOCBP and agrees to use an acceptable contraceptive method
    E.4Principal exclusion criteria
    - The participant has conditions that would adversely affect study participation such as short life expectancy.
    - History of organ transplant.
    - Evidence of infection with human immuodeficiency virus (HIV), transplantation, progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infections that would adversely affect study participation.
    - Persistent chronic or active or recurring system infection, that may adversely affect participation or IMP administration in this study, as judged by the Investigator.
    - History of malignancy within 5 years prior to screening.
    - History of alchohol or drug abuse within 1 year prior to screening.
    - Hospitalized for psychiatric disease within 2 years prior to screening.
    - Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at screening
    - 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.
    -A history of significant bleeding event within 6 months prior to screening, according to the Investigator’s judgment such as, but not limited to cerebral or gastrointestinal bleeding.
    - Lymphocyte count below the lower limit of normal at screening.
    - Recent live (attenuated) vaccine within 2 months before the first treatment visit.
    - Recent major surgery (within 4 weeks of Screening) or planned major surgery during the study.
    - The participant has received medications/treatments for MS within a specified time frame.
    - Receiving potent and moderate inducers of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes
    - Receiving anticoagulant or antiplatelet therapy (such as aspirin >81mg/day, clopidogrel, warfarin).
    - Contraindications to magnetic resonance imaging (MRI).
    NOTE: Other Inclusion/Exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    6-month confirmed disability progression (CDP) ; Time to onset of 6 months CDP defined as follows:
    -Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.0, or
    -Increase of ≥0.5 point when the baseline EDSS score is >5.0
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 48 months
    E.5.2Secondary end point(s)
    1 - 3-months change in T25-FW and 9-HPT ; Time to onset of sustained 20% increase in the timed 25 foot walk (T25-FW) and the 9-hole peg test (9-HPT) for at least 3 months
    2 - 3-month CDP ; Time to onset of 3-month CDP as assessed by EDSS score
    3 - T2 hyperintense lesion by MRI ; Total number of new or enlarging T2 hyperintense lesions as detected by MRI
    4 - Time to confirmed disability improvement (CDI) ; Time to onset of CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months
    5 - Brain volume loss (BVL) ; Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6
    6 - Change in cognitive function ; Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II)
    7 - Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) ; Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
    8 - Safety and Tolerability ; Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
    9 - Population pharmacokinetics ; Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12
    10 - Change in plasma neurofilament light chain (NfL) ; Change in NfL levels at the EOS compared to baseline
    11 - Changes in serum Immunoglobulin level ; Changes in serum Immunoglobulin level at the EOS compared to baseline
    12 - Change in lymphocyte phenotype subsets ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants
    13 - Change in serum chitinase-3 like protein 1 (Chi3L1) ; Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2 : Up to approximately 48 months
    3, 4, 5, 6, 7, 10, 11, 12, 13 : From Baseline up to approximately 48 months
    8 : From Screening until end of study up to approximately 48 months
    9 : Months 6, 9 and 12
    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) No
    E.8.2.2Placebo Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA163
    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
    Argentina
    Chile
    Ukraine
    Australia
    Belarus
    Canada
    China
    India
    Israel
    Japan
    Russian Federation
    United Kingdom
    United States
    Austria
    Belgium
    Bulgaria
    Czechia
    Denmark
    Finland
    France
    Germany
    Greece
    Hungary
    Italy
    Lithuania
    Netherlands
    Norway
    Poland
    Portugal
    Romania
    Spain
    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
    This study will end when approximately 288 primary endpoint events of 6-month CDP have been observed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 1700
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 800
    F.4.2.2In the whole clinical trial 1700
    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 treatment period will be proposed to enroll in a separate 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 Decision2020-10-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-15
    P. End of Trial
    P.End of Trial StatusOngoing
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