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    Summary
    EudraCT Number:2021-003898-59
    Sponsor's Protocol Code Number:EFC17262
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-12-04
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2021-003898-59
    A.3Full title of the trial
    A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of tolebrutinib (SAR442168) in adults with generalized myasthenia gravis (MG)
    III. fázisú, randomizált, kettős vak, placebo-kontrollos, párhuzamos csoportos vizsgálat a tolebrutinib (SAR442168) hatásosságának és biztonságosságának értékelésére generalizált miaszténia gráviszban szenvedő felnőttek körében
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of tolebrutinib (SAR442168) tablets in adult participants with generalized myasthenia gravis
    A tolebrutinib (SAR442168) tabletta hatásossága és biztonságossága generalizált miaszténia gráviszban szenvedő felnőttek körében
    A.3.2Name or abbreviated title of the trial where available
    URSA
    A.4.1Sponsor's protocol code numberEFC17262
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1265-6378
    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 SponsorSanofi-Aventis Recherche & Développement
    B.1.3.4CountryFrance
    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 supportSanofi-Aventis Recherche & Développement
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSanofi-Aventis Zrt.
    B.5.2Functional name of contact pointNA.
    B.5.3 Address:
    B.5.3.1Street AddressTó utca 1-5.
    B.5.3.2Town/ cityBudapest
    B.5.3.3Post code1045
    B.5.3.4CountryHungary
    B.5.6E-mailkapcsolat@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.3.1Product nameTolebrutininb
    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 INNTolebrutinib
    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
    Myasthenia gravis
    miaszténia grávisz
    E.1.1.1Medical condition in easily understood language
    Myasthenia gravis
    miaszténia grávisz
    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 10028417
    E.1.2Term Myasthenia gravis
    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
    DB period:
    • To evaluate the efficacy of tolebrutinib compared to placebo as measured by myasthenia gravis-activities of daily living (MG-ADL) score in participants with gMG who are receiving SoC
    OLE:
    • To evaluate the long-term safety and tolerability of tolebrutinib in participants with gMG who are receiving SoC
    Kettős vak kezelési időszak:
    • A tolebrutinib hatásosságának értékelése a placebóhoz képest az MG-ADL (a MG mindennapi élettevékenységre gyakorolt hatását felmérő) pontszám alapján, standard ellátásban részesülő, gMG-ben szenvedő betegeknél.

    Nyílt kiterjesztés
    • A tolebrutinib hosszú távú biztonságosságának és tolerálhatóságának értékelése a standard (szokásos) ellátásban részesülő, gMG-ben szenvedő betegeknél.
    E.2.2Secondary objectives of the trial
    DB period:
    • To evaluate the efficacy of tolebrutinib compared to placebo on additional efficacy measurements: Quantitative MG (QMG), MG Impairment Index (MGII), MG quality of life 15-item Scale (MG-QOL15), MG-ADL in participants with gMG who are receiving SoC
    • To evaluate the safety and tolerability of tolebrutinib compared to placebo in participants with gMG who are receiving SoC
    OLE:
    • To evaluate the long-term efficacy of tolebrutinib in participants with gMG who are receiving SoC
    Kettős vak kezelési időszak:

    - A tolebrutinib hatásosságának értékelése a placebóhoz képest további hatásossági mérések (QMG, MGII, MG-QoL15, MG-ADL) alapján standard ellátásban részesülő, gMG-ben szenvedő betegeknél.
    - A tolebrutinib biztonságosságának és tolerálhatóságának értékelése a placebóhoz képest standard ellátásban részesülő, gMG-ben szenvedő betegeknél

    Nyílt kiterjesztés:
    - A tolebrutinib hosszú távú hatásosságának értékelése standard ellátásban részesülő, gMG-ben szenvedő betegeknél.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Participants must be 18 years of age to 85 years of age inclusive, at the time of signing the informed consent
    - Participants with a diagnosis of gMG at screening with generalized muscle weakness meeting the clinical criteria for diagnosis of MG, as defined by the MGFA Clinical Classification Class II, III, or IV, and likely not in need of a respirator for the duration of the study, as judged by the Investigator
    - Positive serologic testing for anti-AChR or anti-MuSK autoantibody at screening OR
    - Seronegative for both anti-AChR and anti-MuSK autoantibodies and with prior diagnosis supported by ≥1 of the following 3 tests:
    a) History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation
    b) History of positive edrophonium chloride test
    c) Participant has demonstrated improvement in gMG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.
    - The participant must have a total score ≥6 on MG-ADL scale at screening and D1 with greater than half of the score attributed to non-ocular items
    - A résztvevő életkora 18-85 év (a szélső értékeket is beleértve) a beleegyező nyilatkozat aláírásának időpontjában.
    - A szűréskor gMG diagnózissal rendelkező résztvevők, akiknél a generalizált izomgyengeség megfelel az MG diagnózis klinikai kritériumainak, az MGFA klinikai osztályozás II., III. vagy IV. osztály meghatározása szerint, és valószínűleg nem igényel légzőkészüléket a vizsgálat időtartama alatt a vizsgálatvezető megítélése szerint.
    - Pozitív anti-AChR vagy anti-MuSK autoantitest szerológiai vizsgálat a szűréskor VAGY
    - Szeronegatív mind anti-AChR, mind anti-MuSK autoantitestekre, és a következő 3 teszt közül ≥1 korábban már alátámasztotta a diagnózist:
    a.) Rendellenes neuromuszkuláris transzmisszió az anamnézisben, egyrostos elektromiográfiával vagy ismétlődő idegstimulációval igazolva
    b.) Pozitív edrophonium-klorid teszt az anamnézisben
    c.) A résztvevő gMG tünetei javulást mutattak orális acetilkolinészteráz-gátló kezeléssel az orvos értékelése szerint
    - A résztvevőnek a szűréskor és az 1. napi viziten az MG-ADL skálán ≥6-os pontszámmal kell rendelkeznie, ahol a pontszámnak több mint a fele a nem szemre vonatkozó részekből adódik össze.
    E.4Principal exclusion criteria
    Participants are excluded from the study if any of the following criteria apply:
    - MGFA Class I (ocular MG) or Class V
    - Participants having undergone thymectomy within 6 months of screening or having a planned thymectomy during the trial period.
    - The participant has a history of infection or may be at risk for infection: A history of active or latent tuberculosis (TB); Participants at risk of developing or having reactivation of hepatitis; Persistent chronic or active recurring infection requiring treatment with antibiotics, antivirals, or antifungals; Fever within 4 weeks of the Screening Visit (≥38°C; however, if due to brief and mild ear, nose, throat viral infection participant may be included based on the Investigator’s judgment); A history of infection with human immunodeficiency virus (HIV); A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid organ, stem cell, and bone marrow transplantation) and/or antirejection therapy
    - Any malignancy within the past 5 years prior Screening Visit (except for effectively treated carcinoma in situ of the cervix, adequately treated non-metastatic squamous or basal cell carcinoma of the skin and malignant thymoma that have been resected or are considered as cured by any treatment with no evidence of metastatic disease for ≥3 years) will be exclusionary
    - Conditions that may predispose the participant to excessive bleeding
    - Confirmed screening ALT >3 × ULN
    - The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
    A résztvevők nem választhatók be a vizsgálatba, ha az alábbi kritériumok bármelyike teljesül:

    - MGFA szerinti I. osztály (okuláris MG) vagy V. osztály
    - Thymectomia (a csecsemőmirigy műtéti eltávolítása) a szűrést megelőző 6 hónapon belül, vagy tervezett thymectomia a vizsgálati időszak alatt.
    - A résztvevő kórtörténetében fertőzés szerepel, vagy a fertőzés fokozott kockázatának van kitéve: Aktív vagy látens tuberkulózis (TBC) a kórelőzményben; A résztvevőnél hepatitisz kialakulásának vagy reaktiválódásának kockázata áll fent; Perzisztens krónikus vagy aktív visszatérő fertőzés, amely antibiotikumokkal, vírusellenes vagy gombaellenes szerekkel történő kezelést igényel; Láz a szűrési vizittől számított 4 héten belül (≥ 38°C; azonban rövid és enyhe fül-, orr-, torok vírusfertőzés miatt lázas résztvevőt be lehet választani a vizsgáló megítélése alapján); Humán immundeficiencia vírus (HIV) -fertőzés a kórtörténetben; A kórtörténetben T-limfocita vagy T-limfocita-receptor oltás, transzplantáció (beleértve a szerv, az őssejt és a csontvelő transzplantációt) és/vagy a kilökődésgátló kezelés szerepel,
    - A szűrési vizit előtti 5 éven belül bármilyen rosszindulatú betegség (kivéve a méhnyak sikerrel kezelt in situ karcinómáját, a megfelelően kezelt, nem áttétes laphámsejtes vagy bazálsejtes bőrkarcinómát és a malignus timómát, amely rezekálva lett, vagy bármilyen kezelés után gyógyultnak lehet tekinteni a ≥3 éve nem igazolt metasztatikus betegség alapján).
    - Olyan betegségek, amelyek a beteget fokozott vérzékenységre hajlamosítják.
    - Megerősített szűrési ALT >3 × normál felső határérték.
    - A fent felsoroltak nem tartalmaznak minden olyan szempontot, amely alapján a beteg klinikai vizsgálatban való részvétele eldönthető lenne.
    E.5 End points
    E.5.1Primary end point(s)
    1 - DB period: Change from baseline in MG-ADL total score ; The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs symptoms that are typically affected in MG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0 to 24).
    2 - OLE: Number of participants with adverse events (AEs) /SAEs ; Incidence of adverse events (AEs) and serious adverse events (SAEs)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 : Baseline, Week 26
    2 : From Week 26 until Week 130
    E.5.2Secondary end point(s)
    1 - Change from baseline in QMG total score ; Quantitative Myasthenia Gravis is clinician-reported outcome/assessment to assess muscle weakness in people with MG. The QMG consists of 13 items ranging from 0 to 3 with 3 being the most severe.
    2 - Change from baseline in MGII total score ; The Myasthenia Gravis Impairment Index (MGII) is a measure of MG impairment focused on the severity of MG impairment and the concept of fatigability. Consists of a 22-item patient-reported questionnaire with 6 clinician assessment items. Higher scores indicate greater disease severity.
    3 - Change from baseline in MG-QOL15 survey score ; The MG-QoL15 is a 15-item measure of people with MG QoL instrument that will be self-reported by the participant. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items).
    4 - Proportion of participants with ≥ 2-point reduction from baseline in MG-ADL total score
    5 - Proportion of participants with ≥ 3-point reduction from baseline in QMG total score
    6 - DB: Number of participants with AEs /SAEs
    7 - OLE: Change from baseline in MG-ADL total score
    8 - OLE: Proportion of participants achieving a reduction from baseline in daily dose of oral corticosteroids (OCS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2, 3 : DB period: Baseline, Week 26
    OLE: Baseline, Week 130

    4, 5 : DB period: From Baseline until Week 26
    OLE: From Baseline until Week 130

    6 : From Baseline until Week 26
    7 : Baseline, Week 130
    8 : From Baseline until Week 130
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Canada
    China
    Germany
    Hungary
    Italy
    Japan
    Poland
    Russian Federation
    Spain
    United Kingdom
    United States
    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 years
    E.8.9.1In the Member State concerned months60
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months60
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 192
    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)
    None
    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 Decision2021-11-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-02-21
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