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    Summary
    EudraCT Number:2020-005899-36
    Sponsor's Protocol Code Number:CLOU064C12301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-11-26
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-005899-36
    A.3Full title of the trial
    A randomized, double-blind, double-dummy, parallel-group study, comparing the efficacy and safety of remibrutinib versus teriflunomide in participants with relapsing multiple sclerosis, followed by extended treatment with open-label remibrutinib
    Studio randomizzato, in doppio cieco, con doppio placebo, a gruppi paralleli per confrontare l’efficacia e la sicurezza di remibrutinib verso teriflunomide in pazienti affetti da sclerosi multipla recidivante, seguito da un’estensione del trattamento con remibrutinib in aperto
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis, followed by long term treatment with remibrutinib
    Efficacia e sicurezza di remibrutinib rispetto a teriflunomide in pazienti affetti da sclerosi multipla recidivante, seguita da un trattamento a lungo termine con remibrutinib
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberCLOU064C12301
    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 SponsorNOVARTIS PHARMA AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA S.p.A.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Addressviale Luigi Sturzo 43
    B.5.3.2Town/ cityMilano (MI)
    B.5.3.3Post code20154
    B.5.3.4CountryItaly
    B.5.4Telephone number00390296541
    B.5.5Fax number0039029659066
    B.5.6E-mailinfo.studiclinici@novartis.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 nameremibrutinib
    D.3.2Product code [LOU064C1]
    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 INNRemibrutinib
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameLOU064C1
    D.3.9.4EV Substance CodeSUB204118
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 - EU/1/13/838/001-006
    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 [L04AA31]
    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 INNTeriflunomide
    D.3.9.1CAS number 108605-62-5
    D.3.9.2Current sponsor code-
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 3
    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.2.5The 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 namecolestiramina
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNCOLESTIRAMINA
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 4
    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.2.5The 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 nameCarbone vegetale polvere
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNCARBONE VEGETALE
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboCapsule, hard
    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
    Multiple Sclerosis
    Sclerosi Multipla
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    Sclerosi Multipla
    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
    Core part:
    Demonstrate that remibrutinib is superior to teriflunomide in reducing the frequency of confirmed relapses
    Extension part:
    To assess long-term safety, tolerability and efficacy parameters in participants treated with remibrutinib
    L’obiettivo primario di questo studio è di dimostrare che remibrutinib è superiore a teriflunomide nel ridurre la frequenza di recidive confermate. Il quesito clinico primario di interesse è: qual è l’effetto di remibrutinib rispetto a teriflunomide (Aubagio®) sulla frequenza di recidive confermate misurate tramite il tasso di recidiva annualizzato (Annual Relapse Rate – ARR) in p affetti da RMS, indipendentemente dall’interruzione del trattamento per qualsiasi motivo.
    E.2.2Secondary objectives of the trial
    Core
    Assess whether remibrutinib is superior to teriflunomide in
    ¿ Delaying disability progression based on the pooled data from both identical pivotal studies
    ¿ Reducing new inflammatory activity on MRI, based on MRI cohort data
    ¿ Reducing neuronal damage
    ¿ Disease-Activity-free status based on pooled data from both identical pivotal studies (MRI Cohort)
    Extension (exploratory)
    ¿Explore effect of remibrutinib versus terifunomide on brain MRI, relationship between remibrutinib exposure (PK) and efficacy and safety endpoints and relationship between potential biomarkers and their
    relationship with disease activity, disease course and treatment response
    ¿Perform exploratory pharmacogenetic analysis based on blood samples for DNA (optional)
    ¿ Explore the effect of remibrutinib versus teriflunomide on disease activity free status and effect of remibrutinib versus teriflunomide on disability progression independent of relapse activity
    See protocol for complete list of objectives
    Principali obiettivi secondari (Parte principale) Valutare se remibrutinib è superiore a teriflunomide nel ritardare la progressione della disabilità in base ai dati aggregati derivanti da entrambi gli identici studi pivotali. Il principale quesito clinico di interesse secondario è: valutare l’effetto di remibrutinib rispetto a teriflunomide sulla progressione della disabilità misurata tramite progressione della disabilità confermata a 3 mesi e a 6 mesi (3-month and 6-month Confirmed Disability Progression – 3mCDP, 6mCDP) in pazienti affetti da RMS, indipendentemente dall’interruzione del trattamento per qualsiasi motivo. . Per ulteriori dettagli, fare riferimento alla sinossi. Parte di estensione Valutare i parametri di sicurezza, tollerabilità ed efficacia a lungo termine in pazienti trattati con remibrutinib.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Pharmacogenetics
    Version: -
    Date: 20/10/2021
    Title: DNA sampling / Pharmacogenetics
    Objectives: The study includes an optional genetic research component. The purpose XML File Identifier: 5HuXcg6ZSiK3s7FJYadKJvBYnnI= Page 15/33 of genetic research may be to better understand the safety and efficacy of remibrutinib, or to learn more about human diseases, or to help develop ways to detect, monitor and treat diseases. As technology changes over time, the most appropriate technology will be used at the time the exploratory genetic research is performed. This may include the study of the entire genome. The use of DNA to search for biomarkers of disease and drug action is exploratory.

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: 2) MRI Cohort
    Only selected sites will participate in the MRI cohort; it is planned that approximately 400 participants will be included in this MRI cohort after signature of an additional (optional) consent. All eligible participants
    from these selected sites will undergo MRI scanning of the brain (see protocol for details).
    MRI scans will be transmitted by the sites to the central MRI reading center, designated by Novartis, for quality checks and central read.
    Further details on the image acquisition can be found in the MRI manual of the central MRI reading center. Details regarding the central read can be found in the central MRI reading center independent review charter.
    Each MRI scan performed for the study needs to be previewed by a local neuroradiologist/radiologist. The Investigator must be contacted in case of unexpected findings (e.g. not consistent with MS) detected on the MRI scan for safety actions and AE reporting.
    The MRIs required for the MRI cohort as part of this study are defined in the protocol. Routine MRIs that are mandated by the local treatment guidelines or local Health Authority will be conducted outside the trial (not sent to the central MRI reading center or included in the study database) for any participant.
    3) Additional Biomarker assessment
    Transcriptomic profiling may be assessed, using RNA from whole blood. mRNA expression patterns and patterns of other RNA species, will be derived from application of various technologies which may include
    sequencing of cDNA libraries related to the RNA extracted from blood.
    These analyses will be used to examine the effect of remibrutinib on transient RNA and may support the identification of pathways/markers that characterize the disease or response of treatment with remibrutinib.
    Due to exploratory nature, the data will not be recorded in the clinical database. For this Transcriptomics (RNA) assessment, PAXgene whole blood samples (one aliquot with 2.5 ml blood) will be collected at designated visits and stored for long-term storage. Transcriptomic assessment will be triggered based on results obtained in this study or other MS studies.
    4) PK sub-study
    There will be two pharmacokinetic assessments (PK) cohorts, for "rich"
    and "sparse" sampling. "Rich PK sampling" will be performed in a
    minimum of 160 randomized participants (to ensure these are available for 80 completers per treatment arm), and requires sampling at Day 28 (M1) at pre-dose (0 h) and post-dose at the following times after dosing: 0.5 hour (± 15 mins), 1.0 hour (±15 mins), 2.0 hours (±15 mins), 3.0
    hours (±30 mins) and 4.0 hours (±30 mins), and at M6 at pre-dose (0 h)
    and at 1.0 hour (±15 mins) post-dose. "Sparse PK sampling" will be performed in all other randomized participants and requires sampling at
    Day 28 (M1) and M6 at both pre-dose (0 h) and 1.0 hour (±15 mins) post-dose at both visits. PK assessments are only performed during the Core Part of the study.

    Farmacogenetica
    Versione: -
    Data: 20/10/2021
    Titolo: -
    Obiettivi: -

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Si prega di fare riferimento alla Lettera di accompagnamento.
    E.3Principal inclusion criteria
    1. Signed informed consent obtained prior to any assessment performed (confirm at screening visit)
    2. Male or female participants 18 to 55 years of age (inclusive) at screening
    3. Diagnosis of RMS according to the 2017 McDonald diagnostic criteria (this would include relapsing-remitting course (RRMS) or secondary progressive (SPMS) course with disease activity) as confirmed at screening visit.
    4. At least: 1 documented relapse within the previous year, OR 2 documented relapses within the previous 2 years, prior to screening, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12 months prior to screening
    5. EDSS score of 0 to 5.5 (inclusive) at screening and randomization
    6. Neurologically stable within 1 month prior to screening and randomization (including no MS relapse in this period)
    Please see protocol for complete detailed list of inclusion criteria
    • Consenso informato firmato ottenuto prima dell’effettuazione di qualsiasi valutazione (conferma alla visita di screening).
    • Partecipanti di sesso maschile o femminile di età compresa tra 18 e 55 anni (estremi inclusi) allo screening.
    • Diagnosi di RMS in base ai criteri diagnostici McDonald 2017 (questi comprendono RRMS o SPMS attiva) come confermato alla visita di screening.
    • Almeno: 1 recidiva documentata nell’anno precedente, OPPURE 2 recidive documentate nei 2 anni precedentilo screening, OPPURE 1 lesione attiva captante gadolinio nei 12 mesi precedenti lo screening.
    • Punteggio EDSS compreso tra 0 e 5.5 (estremi inclusi) allo screening e alla randomizzazione.
    • Pazienti neurologicamente stabili nel mese precedente lo screening e la randomizzazione (compresa l’assenza di recidive di sclerosi multipla in questo periodo). Inserire tutti i criteri di inclusione elencati nel protocollo
    E.4Principal exclusion criteria
    1. Diagnosis of primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria (Thompson et al 2018) at screening
    2. Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening
    3. History of clinically significant CNS disease (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy) or neurological disorders which may mimic MS at screening
    4. Ongoing substance abuse (drug or alcohol) or any other factor (e.g. serious psychiatric condition) that may interfere with the participant's ability to cooperate and comply with the study procedures prior to randomization
    5. History of malignancy of any organ system (other than complete resection of localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, at
    screening
    6. Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or Neurological symptoms consistent with PML prior to randomization
    7. Women of child bearing potential unless they are using highly effective methods of contraception while taking study treatment and for at least 4 weeks after stopping study medication
    8. Sexually active males, unless they agree to use a condom while taking study treatment and for at least 4 weeks after stopping double blind study medication
    Please see protocol for complete detailed list of exclusion criteria
    • Durata della malattia superiore a 10 anni in pazienti con punteggio EDSS uguale o inferiore a 2 allo screening.
    • Anamnesi di malattia clinicamente significativa del sistema nervoso centrale (Central Nervous System – CNS) (ad es. ictus, danno traumatico cerebrale o spinale, anamnesi o presenza di mielomiopatia) o disturbi neurologici che potrebbero mimare la MS allo screening.
    • Partecipanti con anamnesi confermata di leucoencefalopatia multifocale progressiva (Progressive Multifocal Leukoencephalopathy – PML) o sintomi neurologici coerenti con PML prima della randomizzazione.
    • Punteggio/risposta “Sì” all’item 4 o all’item 5 della sezione relativa all’ideazione suicidaria della scala C-SSRS (Columbia Suicide Severity Rating Scale), se tale ideazione si è manifestata nei 6 mesi precedenti, o “Sì” a qualsiasi item della sezione relativa al comportamento suicidario, ad eccezione della sezione relativa al comportamento autolesionista non suicidario (item incluso anch’esso nella sezione relativa al comportamento suicidario), se tale comportamento si è manifestato nei 2 anni precedenti, prima della randomizzazione.
    • Partecipanti che sono stati sottoposti a splenectomia.
    • Infezioni sistemiche batteriche, virali, parassitiche o micotiche attive clinicamente significative a giudizio dello sperimentatore prima della randomizzazione (ad es. infezioni che necessitano di ospedalizzazione o somministrazione di antibiotici per via endovenosa).
    • Malattia cronica attiva del sistema immunitario (compresa malattia stabile trattata con immunoterapia, ad es. leflunomide, metotrexato) diversa dalla MS (ad es. artrite reumatoide, lupus sistemico eritematoso, ecc.) ad eccezione di diabete e disturbi della tiroide ben controllati.
    • Pazienti con nota sindrome da immunodeficienza [sindrome da immunodeficienza acquisita (Acquired Immunodeficiency Syndrome - AIDS), carenza immunitaria ereditaria, carenza immunitaria farmaco-indotta], o che presentano un test positivo per anticorpi per virus dell’immunodeficienza umana (Human Immunodeficiency Virus – HIV), allo screening.
    • Intervallo QT a riposo corretto da formula di Fridericia (QTcF) = 450 msec (uomini) o = 460 msec (donne) pre-trattamento (prima della randomizzazione).
    • Utilizzo di farmaci non consentiti prima dello screening/della randomizzazione.
    • Necessità di trattamento anticoagulante [ad es. warfarin o nuovi anticoagulanti (Novel Anti-Coagulants – NOAC)] o utilizzo di duplice terapia anti-piastrinica (ad es. acido acetilsalicilico + clopidogrel). È consentito l’uso di acido acetilsalicilico fino a 100 mg/die o clopidogrel.
    • Rischio emorragico o disturbi della coagulazione significativi, allo screening.
    • Partecipanti che hanno ricevuto qualsiasi vaccino vivo o vivo-attenuato (compresi, a titolo esemplificativo ma non esaustivo, virus della varicella zoster o morbillo, polio orale, influenza nasale) nelle 6 settimane precedenti la randomizzazione o che necessitano di sottoporsi a tali vaccinazioni in qualsiasi momento durante il trattamento in studio.
    E.5 End points
    E.5.1Primary end point(s)
    Core part:
    Annualized relapse rate (ARR) of confirmed relapses
    Extension Part:
    ¿ Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
    ¿ ARR, number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate), time to 6mCDP (EDSS), change in SDMT, NfL, Patient Reported Outcomes scores
    Parte centrale:
    Tasso di recidiva annualizzato (ARR) di recidive confermate
    Parte di estensione:
    ¿ Eventi avversi, dati di laboratorio, segni vitali, elettrocardiogramma (ECG), Columbia Suicide Severity Rating
    ¿ ARR, numero di lesioni T2 nuove o ingrandite alla risonanza magnetica per anno (tasso di lesioni T2 annualizzato), tempo a 6mCDP (EDSS), variazione dei punteggi SDMT, NfL, esiti riportati dal paziente
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 30 months
    Fino a 30 mesi
    E.5.2Secondary end point(s)
    Core part:
    ¿ Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS)
    ¿ Time to 6-month confirmed disability progression (6mCDP) on EDSS
    ¿ Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate)
    ¿ Total number of Gd-enhancing T1 lesions per MRI scan
    ¿ Neurofilament light chain (NfL) concentration in serum
    ¿ Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), as assessed by absence of confirmed MS relapses, 6mCDP and new/enlarging T2 lesions on MRI
    Extension part (exploratory)
    ¿ Annualized rate of brain volume loss (BVL), based on percentage brain volume change from baseline
    ¿ Change from baseline in cortical grey matter volume, hemispheric white matter volume and thalamus volume
    ¿ Slowly Expanding Lesions (SEL) in MRI
    ¿ T2 lesions, ARR, 3mCDP, safety endpoints etc. (as applicable)
    ¿ NfL, GFAP, total IgG, total IgM, B-cells, T2 lesions, ARR, 3mCDP etc. (as applicable)
    ¿ Evaluate the relationship of genetic polymorphisms data with drug metabolism, the indication, the drug target pathway, and treatment response
    ¿ Percentage of participants with NEDA-4, as assessed by the absence of confirmed MS relapses, 6mCDP, new/enlarging T2 lesions on MRI and brain volume loss > -0.4%/year
    ¿ Time to 3mCDP, 6mCDP
    Parte centrale:
    ¿ Tempo alla progressione della disabilità confermata di 3 mesi (3mCDP) sulla scala estesa dello stato di disabilità (EDSS)
    ¿ Tempo alla progressione della disabilità confermata di 6 mesi (6mCDP) su EDSS
    ¿ Numero di lesioni T2 nuove o in espansione alla risonanza magnetica per anno (tasso di lesioni T2 annualizzato)
    ¿ Numero totale di lesioni T1 captanti Gd per risonanza magnetica
    ¿ Concentrazione della catena leggera del neurofilamento (NfL) nel siero
    ¿ Percentuale di partecipanti con No Evidence of Disease Activity-3 (NEDA-3), come valutato dall'assenza di recidive confermate della SM, 6mCDP e lesioni T2 nuove/ingrandite alla risonanza magnetica
    Parte di estensione (esplorativa)
    ¿ Tasso annualizzato di perdita di volume cerebrale (BVL), basato sulla variazione percentuale del volume cerebrale rispetto al basale
    ¿ Variazione rispetto al basale del volume della sostanza grigia corticale, del volume della sostanza bianca emisferica e del volume del talamo
    ¿ Lesioni a Lenta Espansione (SEL) in MRI
    ¿ Lesioni T2, ARR, 3mCDP, endpoint di sicurezza ecc. (se applicabile)
    ¿ NfL, GFAP, IgG totali, IgM totali, cellule B, lesioni T2, ARR, 3mCDP ecc. (se applicabile)
    ¿ Valutare la relazione dei dati sui polimorfismi genetici con il metabolismo del farmaco, l'indicazione, la via del target del farmaco e la risposta al trattamento
    ¿ Percentuale di partecipanti con NEDA-4, valutata in base all'assenza di recidive confermate della SM, 6mCDP, lesioni T2 nuove/ingrandite alla risonanza magnetica e perdita di volume cerebrale > -0,4%/anno
    ¿ Tempo a 3 mCDP, 6 mCDP
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 30 months
    Fino a 30 mesi
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tollerabilità
    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 Yes
    E.8.1.7.1Other trial design description
    Double-dummy
    Double-dummy
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    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 Information not present in EudraCT
    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
    Colombia
    Guatemala
    Malaysia
    Switzerland
    Hong Kong
    China
    India
    Russian Federation
    Serbia
    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
    LSLV
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days9
    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: 800
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 344
    F.4.2.2In the whole clinical trial 800
    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 who complete the core part of the study on study drug, can continue in the planned extension part. The investigator must provide follow-up medical care for all participants who do not enter the extension part or are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
    -
    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 Decision2022-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-09
    P. End of Trial
    P.End of Trial StatusOngoing
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