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    Summary
    EudraCT Number:2014-005368-13
    Sponsor's Protocol Code Number:AGB001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-07-15
    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 ConcernedSpain - AEMPS
    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).
    Estudio aleatorizado, doble ciego, de grupos paralelos, multicéntrico para comparar la farmacocinética, farmacodinámica, seguridad y eficacia de SAIT101 frente a MabThera® frente a Rituxan® en pacientes con artritis 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)
    Estudio comparador de SAIT101 frente a MabThera® o Rituxan® en pacientes con artritis reumatoide (AR).
    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 number+34954001876
    B.5.5Fax number+34954001876
    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 infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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.3.9.4EV 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 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.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 infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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.3.9.4EV 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 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.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 and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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.3.9.4EV 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 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
    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)
    Artritis Reumatoide Grave (AR)
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis
    Artritis 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 19.0
    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.
    El objetivo principal del estudio es comparar la farmacocinética (FC) de SAIT101 frente a MabThera® frente a Rituxan® en pacientes con artritis 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)
    Los objetivos secundarios del estudio son comparar la seguridad, la FC adicional, la farmacodinámica (FD), la eficacia, la tolerabilidad y la inmunogenicidad de SAIT101 frente a MabThera® frente a Rituxan® en pacientes con artritis 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. Paciente ambulatorio, hombre o mujer, de entre 18 y 80 años de edad en la selección.
    2. AR grave definida como:
    - Diagnóstico de AR de acuerdo con los criterios revisados (1987) del ACR para la clasificación de la AR durante al menos 3 meses antes de la visita de selección.
    - Y ≥6 articulaciones inflamadas y ≥6 articulaciones dolorosas/doloridas (del sistema de recuento de 66/68 articulaciones).
    - Y proteína C reactiva (PCR) ≥1,0 mg/dl o una VES ≥28 mm/hora en la selección.
    - Y FR positivo (≥20 unidades/ml) o anticuerpos anti-PCC (≥10 unidades/ml) en la selección.
    3. Pacientes con AR grave que han tenido una respuesta inadecuada a al menos 3 meses de tratamiento (de acuerdo con el tratamiento y la posología aprobados) o intolerancia (a discreción del investigador y/o haber sufrido un AA o toxicidad intolerable, como por ejemplo una reacción relacionada con la infusión, hipersensibilidad, anafilaxia o toxicidad grave) a un tratamiento anti-TNF (haber sufrido toxicidad o AA severo).
    4. Tratamiento ambulatorio actual para la AR:
    - Tratamiento con MTX a 7,5-25 mg/semana (por vía oral o parenteral) durante un mínimo de 12 semanas, incluidas las 4 últimas semanas antes del día 1 a una dosis estable, por la misma vía de administración, a la misma dosis y con la misma formulación. Los pacientes que estén tomando una dosis inferior de MTX (<10 mg/semana), estable durante 4 semanas antes del día 1, deben documentar que lo hacen como consecuencia de una intolerancia a dosis más elevadas de MTX.
    - Se deberá retirar el tratamiento con leflunomida como mínimo 12 semanas antes del día 1 o como mínimo 4 semanas antes del día 1 si es después de 11 días de reposo farmacológico estándar de colestiramina.
    - Todos los FARME distintos de MTX y leflunomida deben retirarse al menos 4 a 8 semanas antes del día 1.
    - En el caso de recibir un tratamiento actual con corticosteroides orales, la dosis no debe superar los 10 mg/día de prednisona o equivalente. Durante las 4 semanas previas al día 1, la dosis debe ser estable.
    - La inyección IM/intrarticular de esteroides más reciente debe haberse administrado ≥6 semanas antes del día 1.
    - Si está recibiendo tratamiento actual con AINE en el momento de la selección, el paciente debe permanecer con una dosis estable durante un mínimo de 3 semanas antes del día 1.
    - Pacientes dispuestos a recibir ácido fólico o folínico oral (un mínimo de 5 mg/semana) o equivalente durante todo el estudio (comedicación obligatoria para el tratamiento con MTX), de acuerdo con las normas locales y la disponibilidad.
    5. Los hombres y mujeres en edad fértil deben utilizar dos métodos anticonceptivos altamente eficaces y aceptados durante el transcurso del periodo de tratamiento y durante un mínimo de 12 meses después de la última infusión del fármaco del estudio. Un hombre o una mujer están en edad fértil si, en opinión del investigador, es biológicamente capaz de tener hijos y es sexualmente activo/a. Entre los ejemplos de métodos anticonceptivos altamente eficaces se incluyen:
    - anticonceptivos hormonales combinados (que contengan estrógeno y progestágeno) asociados con la inhibición de la ovulación 1:
    * oral
    * intravaginal
    * transdérmico
    - anticonceptivos hormonales de progestágeno solamente asociados a la inhibición de la ovulación 1:
    * oral
    * inyectable
    * implantable
    - dispositivo intrauterino (DIU)
    - sistema intrauterino liberador de hormonas (SIU)
    - ligadura de trompas bilateral
    - pareja con vasectomía
    - abstinencia sexual
    La fiabilidad de la abstinencia debe evaluarse en relación con la duración del ensayo clínico y el estilo de vida preferido y habitual del paciente.
    6. Las pacientes de sexo femenino en edad fértil deben presentar una prueba de embarazo en suero negativa en la selección (visita 1) y una prueba de embarazo en orina negativa en cada visita posterior que corresponda. Se considerará que las mujeres no están en edad fértil si cumplen uno de los siguientes criterios en la selección:
    - Posmenopáusica se define como que ha tenido amenorrea durante un mínimo de 12 meses después de interrumpir todos los tratamientos exógenos.
    - Documentación de una esterilización quirúrgica irreversible por histerectomía, ovariectomía bilateral o salpingectomía bilateral, pero no ligadura de trompas.
    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 Mujeres que estén embarazadas, en periodo de lactancia o que planeen quedarse embarazadas durante el periodo de tratamiento y 12 meses después de la última infusión del fármaco del estudio.
    2 Clase IV según la Clasificación del estado funcional global en la artritis reumatoide (de acuerdo con los criterios revisados de 1991 del ACR) o en silla de ruedas/postrado en la cama.
    3 Antecedentes de o enfermedad inflamatoria articular actual distinta a la AR.
    4 Antecedentes de o trastorno autoinmunitario sistémico actual con excepción del síndrome de Sjögren secundario.
    5 Inmunodeficiencia primaria o secundaria (antecedentes de esta o actualmente activa), incluidos los antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH) o una prueba con resultado positivo en la selección
    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
    Farmacocinética:

    1. Área bajo la curva de concentración-tiempo desde el momento 0 (inmediatamente antes de la dosis del día 1) hasta la última concentración cuantificable (ABC0-t)
    2. ABC desde el momento 0 hasta el infinito (ABC0-)
    3. ABC desde el momento 0 hasta el día 15 antes de la infusión (ABC0-d15)
    4. Concentración máxima (Cmáx.) después de la infusión del día 15
    5. Concentración mínima (Cmín.) antes de la segunda infusión del día 15
    E.5.1.1Timepoint(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
    Farmacocinética: Día base 1 (momento 0), 3, 8, 17, 29, 57, 85, 113, 141 (Parte A) y día 169 (Parte B), según proceda.
    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
    Farmacocinética

    1. ABC desde la semana 2 a la semana 24 (ABCs2-s24)
    2. ABC desde el momento 0 (inmediatamente antes de la dosis del día 1) hasta la semana 12
    (ABC0-s12)
    3. Momento de la concentración máxima (Tmáx.) después de la infusión del día 15
    4. Aclaramiento (clearance, CL) sistémico
    5. Volumen de distribución (VD)
    6. Semivida terminal (t½)

    Farmacodinámica
    1. Disminución del recuento de linfocitos B CD19+ en la semana 24
    2. Tiempo necesario para la disminución de linfocitos B
    3. Duración de la disminución de linfocitos B CD19+
    4. Porcentaje del recuento de linfocitos B CD19+ en comparación con el inicio en la semana 24
    5. ABC del cambio en el recuento de linfocitos B CD19+ en la semana 24
    6. Cambio con respecto al inicio en el recuento de linfocitos B CD19+ durante el periodo del estudio
    7. Cambio con respecto al inicio en los niveles de inmunoglobulina (Ig) IgG, IgM e IgA en las semanas 24 y 52
    8. Cambio con respecto al inicio en los niveles de PCR en las semanas 8, 16, 24, 36 y 52

    Eficacia
    1. Cambio en la puntuación DAS28
    2. Tasas de respuesta de ACR20
    3. Tasa de respuesta de ACR50 y tasa de respuesta de ACR70
    4. Componentes individuales de los criterios de mejora de ACR
    5. Cambio en DAS28-PCR
    6. Respuesta clínica importante (ACR70 continuo durante al menos 24 semanas)
    7. Remisión clínica (definida por SDAI <3,3)
    8. Proporción de pacientes con respuesta (buena respuesta, respuesta moderada o ausencia de respuesta) de la Liga Europea contra el Reumatismo (European League Against Rheumatism, EULAR)

    Inmunogenicidad
    1. Incidencia de anticuerpos antiquiméricos humanos (HACA) y anticuerpos neutralizante

    Seguridad
    AAGs, AAs, Contantes vistales, parámetros analíticos clínicos, incluidos hematología, bioquímica y análisis de orina, hallazgos físicos, Medicación concomitante, incidencia de medicación de rescate, donde la medicación de rescate se define como el uso de FARME no biológicos después de la semana 16 del estudio, Recuperación de linfocitos B medida por un recuento de linfocitos B CD19+ después de la semana 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
    Farmacocinética: Día base 1 (momento 0), 3, 8, 17, 29, 57, 85, 113, 141 (Parte A) y día 169 (Parte B), según proceda.

    Farmacodinámica: Día base 1 (momento 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Parte A) y día 169, 253, 365 (Parte B), según proceda.

    Eficacia: Día base, Semana 24 // Día Base, Semanas 8, 16, 36 y 52

    Inmunogenicidad: Día 1 antes de la dosis y en semana 1, 2, 4 ,12, 16, 24, 36, y 52

    Seguridad: 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 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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Inmunogenicidad
    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 No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Biosimilar
    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 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
    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
    LVLP
    Ultimo paciente / última visita
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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: 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 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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    the elderly
    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
    Ninguno
    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 Decision2016-09-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-11-07
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