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    Summary
    EudraCT Number:2014-005368-13
    Sponsor's Protocol Code Number:AGB001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-02-16
    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 number2014-005368-13
    A.3Full title of the trial
    A Randomized, Double-blind, Parallel Group, Multicenter Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of SAIT101 versus MabThera® versus Rituxan® in Patients with Rheumatoid Arthritis (RA).
    Studio multicentrico randomizzato, in doppio cieco, a gruppi paralleli per confrontare la farmacocinetica, la farmacodinamica, la sicurezza e l’efficacia di SAIT101 rispetto a MabThera® rispetto a Rituxan® in pazienti affetti da artrite reumatoide (AR).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Comparing SAIT101 to MabThera® or Rituxan® in Patients with Rheumatoid Arthritis (RA)
    Studio che compara SAIT101 rispetto a MabThera® rispetto a Rituxan® in pazienti affetti da artrite reumatoide (AR)
    A.3.2Name or abbreviated title of the trial where available
    A Study Comparing SAIT101 to MabThera® or Rituxan® in Patients with Rheumatoid Arthritis (RA)
    Studio che compara SAIT101 rispetto a MabThera® rispetto a Rituxan® in pazienti affetti da artrite r
    A.4.1Sponsor's protocol code numberAGB001
    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 SponsorARCHIGEN BIOTECH LIMITED
    B.1.3.4CountryUnited Kingdom
    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 supportArchigen Biotech Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQuintiles Ltd
    B.5.2Functional name of contact pointQuintiles Call Center
    B.5.3 Address:
    B.5.3.1Street AddressAlba Campus, Rosebank
    B.5.3.2Town/ cityLivingston, West Lothian
    B.5.3.3Post codeEH54 7EG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0000
    B.5.5Fax number0000
    B.5.6E-mailQEudraCThelpdesk@quintilescontact.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 nameSAIT101 (rituximab biosimilar)
    D.3.2Product code SAIT101
    D.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeSAIT101
    D.3.9.3Other descriptive nameRITUXIMAB
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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.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 MabThera®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    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.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRITUXIMAB
    D.3.9.3Other descriptive nameRITUXIMAB
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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.IMP: 3
    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 Rituxan®
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Inc. and Genentech USA, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRITUXIMAB
    D.3.9.3Other descriptive nameRITUXIMAB
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Rheumatoid Arthritis (RA)
    Artrite Reumatoide (AR) Grave
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis
    Artrite Reumatoide
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10039075
    E.1.2Term Rheumatoid arthritis and associated conditions
    E.1.2System Organ Class 100000004870
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to compare the pharmacokinetics (PK) of SAIT101 versus MabThera® versus Rituxan® in patients with RA.
    L’obiettivo primario dello studio è confrontare la farmacocinetica (pharmacokinetics, PK) di SAIT101
    rispetto a MabThera® rispetto a Rituxan® in pazienti affetti da artrite reumatoide (AR).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to compare the safety, additional PK , pharmacodynamics (PD), efficacy, tolerability and immunogenicity of SAIT101 versus MabThera® versus Rituxan® in in patients with rheumatoid arthritis (RA)
    Gli obiettivi secondari dello studio consistono nel confrontare sicurezza, dati aggiuntivi di PK,
    farmacodinamica (pharmacodynamics, PD), efficacia, tollerabilità e immunogenicità di SAIT101 rispetto a MabThera® rispetto a Rituxan® in pazienti affetti da artrite reumatoide (AR).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female outpatient, between 18 and 80 years of age at Screening
    2. Severe RA defined as:
    - Diagnosis of RA according to the revised (1987) ACR criteria for the classification of RA for at least 3 months prior to screening visit.
    - And ≥6 swollen joints and ≥6 tender/painful joints (from the 66/68 joint count system)
    - And C-reactive protein (CRP) ≥1.0 mg/dL or an ESR ≥28 mm/hour at Screening
    - And positive RF (≥20 units/mL) or anti-CCP antibodies (≥10 units/mL) at Screening
    3. Patients with severe RA who have had an inadequate response to at least 3 months’ treatment (according to the approved treatment and dosage) or intolerance (at Investigator's discretion and/or experience of intolerable AE or toxicity such as infusion related reaction, hypersensitivity, anaphylaxis or severe toxicity) to anti-TNF therapy (experience of severe AE or toxicity).
    4. Current treatment for RA on an outpatient basis:
    - Receiving MTX 7.5 - 25mg/week (oral or parenteral) for at least 12 weeks, including the last 4 weeks prior to Day 1 at a stable dose, via the same route of administration, dose, and formulation. Patients receiving a lower dose of MTX (<10 mg/week), stable for 4 weeks prior to Day 1, should be doing so as a result of a documented evidence of intolerance to higher doses of MTX.
    - Leflunomide must be withdrawn at least 12 weeks prior to Day 1 or a minimum of 4 weeks prior to Day 1 if after 11 days of standard cholestyramine washout.
    - All DMARDs different from MTX and leflunomide must be withdrawn at least 4 ~ 8 weeks prior to Day 1.
    - If receiving current treatment with oral corticosteroids, the dose must not exceed 10 mg/day prednisone or equivalent. During the 4 weeks prior to Day 1 the dose must be stable.
    - The most recent IM/intra-articular steroid injection should be 6 weeks prior to Day 1.
    - If receiving current treatment with NSAIDs at the time of Screening, the patient must remain on a stable dose for at least 3 weeks prior to Day 1.
    - Patients are willing to receive oral folic or folinic acid (at least 5 mg/week) or equivalent during the entire study (mandatory co-medication for MTX treatment), according to local standards and availability.
    5. Men and women of childbearing potential must use 2 forms of accepted and highly effective methods of contraception during the course of the treatment period and for at least 12 months after the last infusion of study drug. A man or women is of childbearing potential if, in the opinion of the investigator, he or she is biologically capable of having children and is sexually active. Examples of highly effective contraception include:
    - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 1:
    * oral
    * intravaginal
    * transdermal
    - progestogen-only hormonal contraception associated with inhibition of ovulation 1:
    * oral
    * injectable
    * implantable
    - intrauterine device (IUD)
    - intrauterine hormone-releasing system (IUS)
    - bilateral tubal occlusion
    - vasectomised partner
    - sexual abstinence
    The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
    6. Female patients of childbearing potential must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at each applicable visit thereafter. Females will be considered to be of non-childbearing potential if they fulfill one of the following criteria at Screening:
    - Postmenopausal defined as amenorrheic for at least 12 months following cessation of all exogenous treatments
    - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
    1. Uomini e donne di età compresa tra 18 e 80 anni allo Screening
    2. AR grave definita da
    - diagnosi di RA secondo i criteri ACR modificati (1987) per la classificazione delle RA da almeno 3 mesi prima della visita di screening.
    - E ≥ 6 delle articolazioni tumefatte e ≥ 6 articolazioni dolenti / dolorose (66/68 dal sistema di conta delle articolazioni)
    - E la proteina C-reattiva (CRP) ≥1.0 mg / dL o un ESR ≥28 mm / ora allo screening
    - E RF positivo (≥20 unità / mL) o anticorpi anti-CCP (≥10 unità / mL) allo screening
    3. Pazienti affetti da AR grave che hanno ottenuto una risposta inadeguata a un trattamento di durata pari almeno a 3 mesi (in base al trattamento e al dosaggio approvati) o abbiano manifestato intolleranza (definita a discrezione dello sperimentatore e/o come sviluppo di eventi avversi non tollerabili o di tossicità quali reazione correlata all’infusione, ipersensibilità, anafilassi o tossicità grave) alla terapia anti-TNF (sviluppo di evento avverso grave o tossicità).
    4. I pazienti devono essere in terapia con una dose settimanale stabile di
    MTX, 7,5-25 mg/settimana per almeno 12 settimane, comprese le
    ultime 4 settimane prima del Giorno 1 a una dose stabile (dosi inferiori
    di MTX, <10 mg/settimana, sono consentite solo se i soggetti hanno
    un’evidenza documentata di intolleranza a dosi più alte di MTX).
    - Leflunomide deve essere sospeso almeno 12 settimane prima del Giorno 1 o un minimo di 4 settimane prima del Giorno 1 se dopo 11 giorni dal wash-out di colestiramina standard.
    - Tutti i DMARDs diversi da MTX e leflunomide devono essere sospesi almeno 4 ~ 8 settimane prima della Giorno 1.
    - Se si ha un trattamento in corso con corticosteroidi per via orale, la dose non deve superare i 10 mg / die di prednisone o equivalente. Durante le 4 settimane precedenti il Giorno 1 la dose deve essere stabile.
    - L'iniezione di steroidi IM / intra-articolare più recente dovrebbe essere 6 settimane prima del giorno 1.
    - Se si ha un trattamento in corso con i FANS al momento dello screening, il paziente deve rimanere su una dose stabile per almeno 3 settimane prima del Giorno 1.
    - I pazienti sono disposti a ricevere acido folico o acido folinico per via orale (almeno 5 mg / settimana) o equivalente durante l'intero studio (obbligatorio co-farmaco per il trattamento MTX), secondo gli standard e le disponibilità locali.
    5. I pazienti di entrambi i sessi dovranno utilizzare due metodi contraccettivi accettati e altamente efficaci durante il periodo di trattamento e per almeno 12 mesi dopo l’ultima infusione di farmaco dello studio. Un uomo o una donna è in età fertile, se, a giudizio dello sperimentatore, e se uno di loro è biologicamente in grado di avere figli ed è sessualmente attivo/a. Esempi di contraccettivi altamente efficaci comprendono:
    • contraccezione ormonale combinata (contenente estrogeni e progesterone) associata a inibizione dell’ovulazione:
    - orale
    - intravaginale
    - transdermica
    • contraccezione ormonale contenente solo progesterone associata a inibizione dell’ovulazione:
    - orale
    - iniettabile
    - impiantabile
    • dispositivo intrauterino (intrauterine device, IUD)
    • sistema a rilascio intrauterino di ormoni (intrauterine hormone-releasing system, IUS)
    • chiusura tubarica bilaterale
    • compagno vasectomizzato
    • astinenza sessuale
    L'affidabilità dell'astinenza sessuale deve essere valutata in relazione alla durata della sperimentazione clinica e allo stile di vita del soggetto.
    6. I pazienti di sesso femminile in età fertile devono effettuare un test di gravidanza negativo su siero allo Screening (Visita 1) e un test di gravidanza negativo ad ogni visita seguente. Le donne saranno considerate potenzialmente non fertili se soddisfano uno dei seguenti criteri allo screening:
    - Post-menopausa definita come amenorrea per almeno 12 mesi dopo la cessazione di tutti i trattamenti esogeni
    - Documentazione di sterilizzazione chirurgica irreversibile isterectomia, ovariectomia bilaterale o salpingectomia bilaterale, ma non la chiusura delle tube.
    E.4Principal exclusion criteria
    1 Females who are pregnant, breastfeeding, or planning a pregnancy
    during the Treatment Period of and 12 months after the last infusion of
    study drug.
    2 Class IV as per the Classification of Global Functional Status in Rheumatoid Arthritis (as per ACR 1991 Revised Criteria) or wheelchair/bed-bound.
    3 History of or current inflammatory joint disease other than RA
    4 History of or current systemic autoimmune disorder with the exception of the secondary Sjögren's syndrome.
    5 Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection or positive test at screening.
    1 Donne in gravidanza, allattamento, o che stanno programmando una gravidanza durante il periodo di trattamento di e 12 mesi dopo l'ultima infusione del farmaco in studio.
    2 Classe IV secondo la classificazione dello stato globale funzionale nell'artrite reumatoide (come da ACR 1991 criteri modificati) o sedia a rotelle / allettato.
    3 Precedente o attuale malattia articolare infiammatoria diversa da AR
    4 Precedente o attuale malattia autoimmune sistemica ad eccezione della sindrome di Sjögren secondaria.
    5 Primaria o immunodeficienza secondaria (storia, o attualmente attiva), compresa precedente nota infezione da virus dell'immunodeficienza umana (HIV) o test positivo allo screening.
    E.5 End points
    E.5.1Primary end point(s)
    Pharmacokinetics 1. Area under the concentration-time curve from time 0 (immediately predose on Day 1) to last quantifiable concentration 2. AUC from time 0 to infinity 3. AUC from time 0 to Day 15 prior to infusion 4. Maximum concentration (Cmax) after Day 15 infusion 5. Trough concentration (Ctrough) before the second infusion on Day 15
    Farmacocinetica
    - Area sotto la curva (area under the curve, AUC) concentrazione-tempo dal tempo 0 (subito prima della
    somministrazione della dose al Giorno 1) fino all’ultima concentrazione quantificabile (AUC0-t)
    - AUC dal tempo 0 a infinito (AUC0-)
    - AUC dal tempo 0 al Giorno 15 prima dell’infusione (AUC0-g15)
    - Concentrazione massima (Cmax) dopo l’infusione del Giorno 15
    - Concentrazione minima (Cmin) prima della seconda infusione del Giorno 15
    E.5.1.1Timepoint(s) of evaluation of this end point
    Farmacocinetica: al basale Giorno 1 (tempo 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (parte A) e giorno 169 (parte B), a seconda dei casi
    Pharmacokinetics: Baseline Day 1 (time 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Part A) and Day 169 (Part B), as applicable
    E.5.2Secondary end point(s)
    Pharmacokinetics
    1.AUC from Week 2 to Week 24
    2. AUC from time 0 (immediately predose on Day 1) to Week 12
    3. Time of maximum concentration (Tmax) post infusion on Day 15
    4. Systemic clearance (CL)
    5. Volume of distribution (VD)
    6. Terminal half-life (t½)
    Pharmacodynamics
    1. Depletion of CD19+ B cell count at Week 24
    2. Time needed to B cell depletion
    3. Duration of CD19+ B cell depletion
    4. % CD19+ B-cell count vs. baseline at Week 24
    5. AUC of CD19+ B-cell count change at Week 24
    6. Change from Baseline in CD19+ B cell count during the study period
    7. Change from Baseline in IgG, IgM, and IgA levels at Weeks 24 and 52
    8. Change from Baseline in CRP levels at Weeks 8, 16, 24, 36, and 52
    Efficacy:
    1. Change in DAS28 score
    2. ACR20 response rates
    3. ACR50 response rates and ACR70 response rates
    4. Individual components of the ACR improvement criteria
    5. Change in DAS28-CRP
    6. Major clinical response (continuous ACR70 for at least 24 weeks)
    7. Clinical remission (defined by SDAI < 3.3)
    8. Proportion of patients with European League Against Rheumatism
    (EULAR) response
    Immunogenicity
    1. Incidence of HACA and neutralizing antibody
    Safety
    SAEs, AEs, ADRs, Vital signs, Clinical laboratory parameters including
    hematology, chemistry and urinalysis, Physical findings, Concomitant
    medication, incidence of rescue medication, where rescue medication is
    defined as the use of non-biologic DMARDs after Week 16 of the study, B cell recovery measured by a CD19+ B cell count after Week 24
    Farmacocinetica
    - AUC dalla Settimana 2 alla Settimana 24
    - AUC dal tempo 0 (subito prima della somministrazione della dose al Giorno 1) alla Settimana 12
    - Tempo di concentrazione massima (Tmax) dopo l’infusione al Giorno 15
    - Clearance (CL) sistemica
    - Volume di distribuzione (VD)
    - Emivita terminale (t½)
    Farmacodinamica
    - Deplezione della conta di cellule B CD19+ alla Settimana 24
    - Tempo necessario alla deplezione delle cellule B
    - Durata delle deplezione delle cellule B CD19+
    - % della conta di cellule B CD19+ rispetto al basale alla Settimana 24
    - AUC della variazione nella conta delle cellule B CD19+ alla Settimana 24
    - Variazione rispetto al basale nella conta delle cellule B CD19+ durante il periodo dello studio
    - Variazione rispetto al basale nei livelli di immunoglobuline (Ig) IgG, IgM e IgA alle Settimane 24 e 52
    - Variazione rispetto al basale nei livelli di CRP alle Settimane 8, 16, 24, 36 e 52
    Efficacia
    - Variazione rispetto al basale nel DAS28 alla Settimana 24
    - Variazioni rispetto al basale nel DAS28 alle Settimane 8, 16, 36 e 52
    - Tassi di risposta ACR20 alle Settimane 8, 16, 24, 36 e 52
    - Tasso di risposta ACR50 e tasso di risposta ACR70 alle Settimane 8, 16, 24, 36 e 52
    - Componenti individuali dei criteri di miglioramento ACR al Giorno 1 e alle Settimane 8, 16, 24, 36 e 52
    - Variazione rispetto al basale nella risposta DAS28-CRP (C-reactive protein [proteina C-reattiva]) alle
    Settimane 8, 16, 24, 36 e 52
    - Risposta clinica maggiore (ACR70 continuativa per almeno 24 settimane)
    - Remissione clinica (definita da un valore di SDAI [Indice semplificato di attività della malattia, Simplified Disease Activity Index] <3,3) alle Settimane 8, 16, 24, 36 e 52
    - Percentuale di pazienti con risposta secondo la Lega europea contro le malattie reumatiche (European League Against Rheumatism, EULAR) (risposta buona, risposta moderata o nessuna risposta) alle Settimane 8, 16, 24, 36 e 52
    Immunogenicità (HACA e anticorpo neutralizzante)
    - Incidenza degli anticorpi umani anti-chimerici (HACA) e dell’anticorpo neutralizzante al Giorno 1
    prima della somministrazione della dose e alle Settimane 1, 2, 4, 12, 16, 24, 36 e 52
    Sicurezza
    - Eventi avversi seri (serious adverse event, SAE), eventi avversi (EA), reazioni avverse al farmaco
    (adverse drug reaction, ADR)
    - Segni vitali
    - Parametri clinici di laboratorio, inclusi ematologia, chimica e analisi delle urine
    Reperti obiettivi
    - Farmaco concomitante, incidenza del farmaco di soccorso, ove per farmaco di soccorso si intende
    l’utilizzo di DMARD non biologici dopo la Settimana 16 dello studio
    - Recupero delle cellule B misurato da una conta delle cellule B CD19+ dopo la Settimana 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    Pharmacokinetics: Baseline Day 1 (time 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Part A) and Day 169 (Part B), as applicable Pharmacodynamics: Baseline Day 1 (time 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Part A) and Day 169, 253, 365 (Part B), as applicable Efficacy: Efficacy: Baseline, Week 24 // Baseline, Weeks 8, 16, 36, and 52 Immunogenicity: Day 1 predose and at Week 1, 2, 4, 12, 16, 24, 36, and 52 Safety: continuously
    Farmacocinetica: al basale Giorno 1 (tempo 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (parte A) e giorno 169 (parte B), a seconda dei casi
    Farmacodinamica: al basale Giorno 1 (tempo 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (parte A) e il giorno 169, 253, 365 (parte B), a seconda dei casi
    Efficacia: Efficacia: al basale, settimana 24 // al basale, settimane 8, 16, 36, e 52
    Immunogenicità: Giorno 1 pre-dose e alla Settimana 1, 2, 4, 12, 16, 24, 36, e 52
    Sicurezza: continuamente
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Immunogenicità
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study Yes
    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 Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 EEA39
    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
    Bosnia and Herzegovina
    Bulgaria
    Czech Republic
    Germany
    Hungary
    India
    Italy
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 254
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    the elderly
    Gli anziani
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 282
    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
    NA
    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 Decision2016-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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