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    Summary
    EudraCT Number:2012-002714-40
    Sponsor's Protocol Code Number:RPC01-201
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-03-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-002714-40
    A.3Full title of the trial
    A PHASE 2/3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED (PART A) AND DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE CONTROLLED (PART B), PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RPC1063 ADMINISTERED ORALLY TO RELAPSING MULTIPLE SCLEROSIS PATIENTS
    STUDIO DI FASE II/III, MULTICENTRICO, RANDOMIZZATO, IN DOPPIO CIECO, CONTROLLATO VERSO PLACEBO (PARTE A) E IN DOPPIO CIECO, A DOPPIO MASCHERAMENTO (DOUBLE-DUMMY), CON CONTROLLO ATTIVO (PARTE B), A GRUPPI PARALLELI PER VALUTARE L'EFFICACIA E LA SICUREZZA DI RPC1063 SOMMINISTRATO PER VIA ORALE A PAZIENTI CON SCLEROSI MULTIPLA RECIDIVANTE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A CLINICAL STUDY TO EVALUATE IN A BLINDED AND SCIENTIFIC WAY THE EFFICACY AND SAFETY OF THE NEW MEDICINAL PRODUCT RPC1063 IN PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS
    Studio clinico per valutare in cieco ed in modo scientifico l’efficacia e la sicurezza di un nuovo medicinale RPC1063 in pazienti con sclerosi multipla recidivante.
    A.4.1Sponsor's protocol code numberRPC01-201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01628393
    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 SponsorReceptos, Inc.
    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 supportReceptos, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointSabine Krofczik
    B.5.3 Address:
    B.5.3.1Street AddressHansastrasse 32
    B.5.3.2Town/ cityMunchen
    B.5.3.3Post code80686
    B.5.3.4CountryGermany
    B.5.4Telephone number4989380 38 298
    B.5.5Fax number4989578 77 400
    B.5.6E-mailsabine.krofczik@ppdi.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 name0.25 mg RPC1063
    D.3.4Pharmaceutical form Capsule
    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 INNRPC1063
    D.3.9.2Current sponsor codeRPC1063
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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 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 name0.5 mg RPC1063
    D.3.4Pharmaceutical form Capsule
    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 INNRPC1063
    D.3.9.2Current sponsor codeRPC1063
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.50
    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: 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 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 name1 mg RPC1063
    D.3.4Pharmaceutical form Capsule
    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 INNRPC1063
    D.3.9.2Current sponsor codeRPC1063
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 4
    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 Avonex
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Limited
    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 nameAvonex
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAvonex
    D.3.9.1CAS number 220581-49-7
    D.3.9.3Other descriptive nameINTERFERON BETA-1A
    D.3.9.4EV Substance CodeSUB12440MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboCapsule
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular 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
    Sclerosi Multipla recidivante
    E.1.1.1Medical condition in easily understood language
    RELAPSING MULTIPLE SCLEROSIS
    Sclerosi Multipla recidivante
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10048393
    E.1.2Term Multiple sclerosis relapse
    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
    Part A
    To demonstrate the superior clinical efficacy of RPC1063 compared to placebo by showing a reduction in the cumulative number of total gadolinium enhancing (GdE) lesions from Week 12 to Week 24 in patients with relapsing multiple sclerosis (RMS).
    Part B
    To assess whether the clinical efficacy of RPC1063 is superior to interferon (IFN) β-1a (Avonex®) in reducing the rate of clinical relapses at the end of Month 24 in patients with RMS.
    Parte A
    Dimostrare la superiorità di RPC1063 in termini di efficaci clinica rispetto al placebo mediante una riduzione del numero cumulativo di lesioni captanti il gadolinio (GdE) totali dalla Settimana 8 alla Settimana 24 in pazienti affetti da sclerosi multipla recidivante (RMS).
    Parte B
    Valutare se l'efficacia clinica di RPC1063 è superiore all'interferone (IFN) β-1a (Avonex®) nel ridurre il del tasso di ricadute alla fine del Mese 24 nei pazienti affetti da RMS.
    E.2.2Secondary objectives of the trial
    Part A
    - assess the proportion of patients who are free of GdE lesions at Week 24
    -assess the effect of RPC1063 on the cumulative number of new/enlarging T2 lesions from W12 to W24
    -compare the clinical efficacy of RPC1063 to placebo in pts with RMS by reduction in ARR & proportion of relapse free pts at W24
    -assess the safety, tolerability, PK and PD of RPC1063 in pts with RMS
    Part B
    -assess the effect of RPC1063 on the proportion of patients with new/enlarging T2 lesions at M24
    -evaluate whether the efficacy of RPC1063 is superior to IFN β-1a in delaying the accumulation of disability, measured by MSFC and by the SLCLA.
    -evaluate whether the efficacy of RPC1063 is superior to IFN β-1a in delaying the accumulation of disability, as assessed by the EDSS
    -assess the effect of RPC1063 on brain atrophy over 24m
    -evaluate the effect of RPC1063 on patient-reported quality of life as assessed by the MSQOL-54
    -assess the safety & tolerability of RPC1063 in pts with RMS
    Parte A
    •Valutare la proporzione di pazienti liberi da lesioni GdE alla Settimana 24
    •Valutare l'effetto di RPC1063 sul numero cumulativo delle lesioni in T2 nuove/in espansione dalla Settimana 12 alla Settimana 24
    •Confrontare l'efficacia clinica di RPC1063 verso il placebo in pazienti affetti da RMS valutata da una riduzione del tasso annuale di recidiva (ARR) e dalla proporzione di pazienti liberi da ricaduta alla Settimana 24
    •Valutare la sicurezza e la tollerabilità di RPC1063 in pazienti affetti da RMS
    •Valutare la farmacocinetica (PK) e la farmacodinamica (PD) di RPC1063 in pazienti affetti da RMS
    Parte B
    •Valutare l'effetto di RPC1063 sulla proporzione di pazienti con lesioni in T2 nuove/in espansione al Mese 24
    •Valutare se l'efficacia di RPC1063 è superiore a quella dell'IFN beta 1a nel ritardare l'accumulo di disabilità in base alla scala MSFC e alla funzione visiva misurata con il test SLCLA
    Vedere il protocollo per gli altri obiettivi secondari.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Per Protocol dated 14 September 2012.

    1.MS, as diagnosed by the revised 2010 McDonald criteria
    2.Exhibiting a relapsing clinical course consistent with RMS and history of brain MRI lesions consistent with MS
    3.Ages 18-55 years, inclusive
    4.EDSS score between 0 and 5.0 at baseline
    5.Meet one of the following disease activity criteria:
    a.At least 1 documented relapse within the last 12 months prior to screening
    OR
    b.At least 1 documented relapse occurred within the last 24 months prior to screening and documented evidence of at least 1 GdE lesion on brain MRI within the last 12 months prior to randomization
    6.No history of relapse with onset from 30 days prior to screening until randomization; during this period, patients must have been clinically stable, without systemic corticosteroid treatment or adrenocorticotrophic hormone (ACTH)
    7.Ability to provide written informed consent and to be compliant with the schedule of protocol assessments
    8.Patients of reproduction potential (males and females) must practice an acceptable method of birth control (acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long acting injectable contraceptive, vasectomy or double-barrier method [condom or diaphragm with spermicide]) during study participation and for 30 days after their last dose of treatment of study medication or abstinence
    9.Documentation of positive Varicella Zoster virus (VZV) IgG antibody status
    1. SM, diagnosticata in base ai criteri di McDonald del 2010
    2. Decorso clinico con ricadute coerente con la RMS e anamnesi di lesioni cerebrali alla RM coerenti con la SM
    3. Età compresa fra 18 e 55 anni, inclusi
    4. Punteggio EDSS tra 0 e 5,0 al basale
    5. Presenza di uno dei seguenti criteri di attività della malattia:
    a. Almeno 1 ricaduta documentata negli ultimi 12 mesi precedenti lo screening
    OPPURE
    b. Almeno 1 ricaduta documentata negli ultimi 24 mesi precedenti lo screening ed evidenza documentata di almeno 1 lesione GdE sulla RM cerebrale negli ultimi 12 mesi precedenti la randomizzazione
    6. Nessuna anamnesi di ricaduta con insorgenza da 30 giorni prima dello screening alla randomizzazione; durante questo periodo, i pazienti devono essere stati clinicamente stabili, senza trattamento con corticosteroidi o ormone adrenocorticotropo (ACTH)
    7. Capacità di fornire un consenso informato scritto e di attenersi al programma di valutazioni del protocollo
    8. I pazienti potenzialmente fertili (maschi e femmine) devono utilizzare un metodo contraccettivo accettabile (per questo studio i metodi contraccettivi accettabili comprendono: sterilizzazione chirurgica, dispositivi intrauterini, contraccettivo orale, cerotto contraccettivo, contraccettivo iniettabile a lunga durata d'azione, vasectomia oppure metodo a doppia barriera [preservativo o diaframma con spermicida]) durante la partecipazione allo studio e per i 30 giorni successivi all'ultima dose di trattamento sperimentale, oppure devono praticare l'astinenza
    9. Documentata positività agli anticorpi IgG del virus varicella zoster (VZV)
    E.4Principal exclusion criteria
    Per Protocol dated 14 September 2012.

    1.Primary progressive MS at screening
    2.Disease duration of more than 15 years in patients with an EDSS ≤ 2.0
    3.Contraindications to MRI or Gadolinium contrast, including known allergy to Gadolinium contrast dyes, renal insufficiency, claustrophobia, weight ≥ 300 lb (≥ 136 kg), pacemaker, cochlear implants, intracranial vascular clips
    4.Incompatibility with beta IFN use (e.g. intolerable side effects) (Part B only)
    Exclusions Related to General Health:
    5.Pregnancy, lactation, or a positive serum beta human chorionic gonadotrophin (hCG) measured during screening
    6.Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the patient at risk by participating in the study in the opinion of treating investigator
    7.Clinically relevant cardiovascular conditions, including history or presence of ischemic heart disease, myocardial infarction, congestive heart failure, stroke, transient ischemic attack, sick sinus syndrome, recurrent syncope, second degree or higher AV block, prolonged QTcF interval (QTcF > 450 msec males, > 470 msec females), other clinically significant conduction abnormalities or any other significant cardiac condition that could jeopardize a patient’s health during the course of the study in the opinion of treating investigator
    8.Resting heart rate less than 55 bpm
    9.History of diabetes mellitus
    10.History of uveitis
    11.Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal infection of nail beds]) or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or oral antibiotics within 14 days prior to screening
    12.History or known presence of recurrent or chronic infection (e.g., hepatitis A, B, C, or E, human immunodeficiency virus (HIV), syphilis, TB); recurring urinary tract infections could be allowed
    13.History of cancer, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved)
    14.Suicide attempts in the past or current signs of major depression
    15.History of alcohol or drug abuse within 1 year prior to randomization
    16.History of or currently active primary or secondary immunodeficiency
    Exclusions Related to Medications:
    17.Prior use of any investigational agent within 6 months prior to enrollment
    18.Receipt of a live vaccine within 4 weeks prior to screening
    19.Non-lymphocyte-depleting disease-modifying MS agents (e.g., glatiramer acetate, interferons) must be discontinued from signing of informed consent until randomization
    20.Previous treatment with lymphocyte-depleting therapies (e.g., alemtuzumab, anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation)
    21.Treatment with other immunosuppressant agents such as azathioprine, cyclosporine, methotrexate, or mycophenolate within 6 months prior to randomization
    22.Systemic corticosteroid therapy or ACTH use within 30 days prior to screening.
    23.Prior treatment with lymphocyte trafficking blockers (e.g., natalizumab, fingolimod, other S1PR agonists).
    24.Treatment with intravenous immune globulin (IVIg), plasmapheresis, within 3 months prior to randomization
    25.Previous treatment with any monoclonal antibody
    26.Intolerance of or contraindication to oral or IV corticosteroids
    27.Use of therapies that are not allowed based on CYP3A4 metabolism within 4 weeks prior to randomization
    28.Treatment with medications with a known impact on the cardiac conduction system (e.g., beta blockers, calcium channel blockers, Class Ia or Class III anti-arrhythmic drugs)
    Exclusions Related to Laboratory Results:
    29.Vitamin B12 below the lower limit of normal
    30.Positive rapid plasma reagin
    31.Serum creatinine > 1.4 mg/dL for women or > 1.6 mg/dL for men
    32.Liver function impairment or persisting elevations of aspartate aminotransferase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) > 1.5 times the upper limit of normal (ULN), or direct bilirubin > 1.5 times the ULN
    33.Platelet count < 100,000/mcL
    34.Hemoglobin < 8.5 g/dL
    35.Neutrophils < 1.5/mcL
    36.Absolute white blood cell (WBC) count < 3500/mcL; absolute lymphocyte count < 800/mcL
    37.Clinically significant findings on brain MRI scan consistent with conditions other than MS
    38.ECG showing any clinically significant abnormality (e.g., acute ischemia, significant heart conduction abnormality (e.g. left bundle branch block))
    39.FEV1 and FVC < 70% of predicted values at screening
    40.Presence of > 20 gadolinium-enhancing lesions on baseline brain MRI scan
    1. SM progressiva primaria allo screening
    2. Durata della malattia superiore a 15 anni in pazienti con EDSS ≤ 2,0
    3. Controindicazioni alla RM o al mezzo di contrasto gadolinio, compresi allergia nota ai coloranti di contrasto a base di gadolinio, insufficienza renale, claustrofobia, peso ≥ 300 lb (≥ 136 kg), pacemaker, impianti cocleari, clip vascolari intracraniche
    4. Incompatibilità con l'uso di IFN beta (ad es. effetti collaterali intollerabili) (solo Parte B)
    Esclusioni legate allo stato di salute generale:
    5. Gravidanza, allattamento o positività delle beta-hCG (gonadotropina corionica umana) nel siero misurata durante lo screening
    6. Malattia epatica, neurologica, polmonare, oftalmologica, endocrina, renale o altra importante malattia sistemica clinicamente rilevante che rende difficile l'attuazione del protocollo o l'interpretazione dei risultati dello studio o che metterebbe a rischio il paziente come conseguenza della partecipazione allo studio secondo il giudizio del Treating Investigator.
    7. Disturbi cardiovascolari clinicamente rilevanti, comprese anamnesi o presenza di malattia cardiaca ischemica, infarto del miocardio, insufficienza cardiaca congestizia, ictus, attacco ischemico transitorio, sindrome del nodo del seno, sincope ricorrente, blocco atrioventricolare di secondo grado o superiore, intervallo QTcF prolungato (QTcF > 450 msec maschi, > 470 msec femmine), altre anomalie della conduzione cardiaca clinicamente significative o qualsiasi altro disturbo cardiaco significativo che potrebbe mettere a rischio la salute del paziente durante lo studio secondo il giudizio dello sperimentatore responsabile del trattamento
    8. Frequenza cardiaca a riposo inferiore a 55 bpm
    9. Anamnesi di diabete mellito
    10. Anamnesi di uveite
    11. Infezione batterica, virale, fungina, micobatterica attiva nota o altra infezione (comprese tubercolosi [TB] o malattia micobatterica atipica [ma esclusa l’infezione fungina dei letti ungueali]) o qualsiasi episodio importante di infezione che richieda ospedalizzazione o trattamento con antibiotici IV entro 30 giorni dallo screening o antibiotici per via orale nei 14 giorni precedenti lo screening
    12. Anamnesi o presenza nota di infezione cronica ricorrente (ad es., epatite A, B, C o E, virus dell’immunodeficienza umana (HIV), sifilide, TB); possono essere ammesse le infezioni ricorrenti delle vie urinarie
    13. Anamnesi di cancro, compresi tumori solidi e neoplasie ematologiche (con l’eccezione di carcinoma della pelle a cellule basali e a cellule squamose in situ escissi e risolti)
    14. Tentativi di suicidio in passato o segni attuali di depressione grave
    15. Anamnesi di abuso di alcol o droghe nell'anno precedente la randomizzazione
    16. Immunodeficienza primaria o secondaria in anamnesi o in atto
    Esclusioni legate a farmaci:
    17. Uso di qualsiasi agente sperimentale nei 6 mesi precedenti l'arruolamento
    18. Assunzione di un vaccino vivo nelle 4 settimane precedenti lo screening
    19. È necessario sospendere l'assunzione di agenti modificanti la malattia per la SM che non causano deplezione linfocitaria (ad es., glatiramer acetato, interferoni) dal momento della firma del consenso informato fino alla randomizzazione
    20. Precedente trattamento con terapie che causano deplezione linfocitaria (ad es., alemtuzumab, anti-CD4, cladribina, rituximab, ocrelizumab, ciclofosfamide, mitoxantrone, irradiazione corporea totale, trapianto di midollo osseo)
    21. Trattamento con altri agenti immunosoppressivi ad esempio azatioprina, ciclosporina, metotrexato o micofenolato nei 6 mesi precedenti la randomizzazione
    22. Terapia con corticosteroidi sistemici o uso di ACTH nei 30 giorni precedenti lo screening
    23. Precedente trattamento con inibitori del ricircolo linfocitario (e.g., natalizumab, fingolimod, altri agonisti del recettore S1P)
    24. Trattamento con immunoglubuline per uso endovenoso (IVIg), plasmaferesi, nei 3 mesi precedenti la randomizzazione
    25. Precedente trattamento con qualsiasi anticorpo monoclonale
    26. Intolleranza o controindicazioni alla terapia con corticosteroidi per via orale o IV
    27. Uso di terapie non consentite basate sul metabolismo del CYP3A4 nelle 4 settimane precedenti la randomizzazione
    28. Trattamento con farmaci con un noto impatto sul sistema di conduzione cardiaca (ad es., beta-bloccanti, calcio-antagonisti, farmaci antiaritmici di classe Ia o classe III)
    Esclusioni legate ai risultati di laboratorio:
    29. Vitamina B12 al di sotto del limite inferiore della norma
    30. Positività al test della reagina plasmatica rapida
    31. Creatinina sierica maggiore di 1,4 mg/dL per le donne o maggiore di 1,6 mg/dL per gli uomini
    Per gli altri criteri di eclusioni vedasi il protocollo
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    Part A: Total number of GdE lesions, assessed on brain MRIs from Week 12 to Week 24
    Part B: ARR at the end of Month 24
    Parte A: Numero totale delle lesioni GdE, valutate sulle RM cerebrali dalla Settimana 8 alla Settimana 24
    Parte B: ARR alla fine del Mese 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please see section E.5.1 above
    Vedere la sezione sopra E.5.1
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    Part A:
    Key Secondary Endpoints (rank ordered):
    • The number of GdE lesions at Week 24
    • Total number of new or enlarging hyperintense T2-weighted brain MRI lesions from Week 12 to Week 24
    •ARR at the end of Week 24
    Part B:
    Key Secondary Endpoints (rank ordered):
    •The number of new or enlarging hyperintense T2-weighted brain MRI lesions at Month 24
    •Change in MSFC score and visual function as measured by the SLCLA
    •Time to onset of sustained disability progression as defined by a sustained worsening in EDSS of 1.0 points or more, confirmed after 12 weeks
    •Time to onset of sustained disability progression as defined by a sustained worsening in EDSS of 1.0 points or more, confirmed after 24 weeks
    •The change in brain atrophy on brain MRI scans from baseline to 24 months
    •Change in MSQOL-54 score at 24 months
    Parte A:
    Principali endpoint secondari (classificati in ordine):
    • Numero di lesioni GdE alla Settimana 24
    • Numero totale di lesioni iperintense nuove o in espansione nelle immagini di RM cerebrale T2-pesate dalla Settimana 12 alla Settimana 24
    • ARR alla fine della Settimana 24
    Parte B:
    Principali endpoint secondari (classificati in ordine):
    • Numero di lesioni iperintense nuove o in espansione nelle immagini di RM cerebrale T2-pesate al Mese 24
    • Variazione del punteggio MSFC e della funzione visiva misurata secondo SLCLA
    • Tempo all'insorgenza della progressione prolungata della disabilità definita da un peggioramento prolungato dell'EDSS di 1,0 o più punti, confermato dopo 12 settimane
    • Tempo all'insorgenza della progressione prolungata della disabilità definita da un peggioramento prolungato dell'EDSS di 1,0 o più punti, confermato dopo 24 settimane
    • Variazione dell'atrofia cerebrale sulle RM del cervello dal basale fino ai 24 mesi
    • Variazione del punteggio MSQOL-54 dopo 24 mesi
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see section E.5.2 above
    Vedere la sezione sopra E.5.2
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) 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
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA78
    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
    Georgia
    Israel
    Russian Federation
    Serbia
    Ukraine
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1280
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 596
    F.4.2.2In the whole clinical trial 1280
    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)
    Standard of care
    Terapia siandard
    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 Decision2013-05-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-09
    P. End of Trial
    P.End of Trial StatusCompleted
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