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    Summary
    EudraCT Number:2011-004171-36
    Sponsor's Protocol Code Number:S101-RGL-003
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-01-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-004171-36
    A.3Full title of the trial
    A Randomized, Double-blind, Parallel Group, Multicenter Trial to Compare the Efficacy, Safety, Pharmacodynamics and Pharmacokinetics of SAIT101 to MabThera® in Subjects with Severe Rheumatoid Arthritis (RA)
    Estudio multicéntrico aleatorizado, doble ciego y de grupos paralelos para comparar la eficacia, la seguridad, la farmacodinámica y la farmacocinética del SAIT101 con respecto a MabThera® en pacientes con artritis reumatoide (AR) grave.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing SAIT101 to MabThera® in Subjects with Severe Rheumatoid Arthritis (RA)
    Estudio que compara SAIT101 con respecto a MabThera® en pacientes con artritis reumatoide (AR) grave.
    A.4.1Sponsor's protocol code numberS101-RGL-003
    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 SponsorSamsung Electronics Co. Ltd.
    B.1.3.4CountryKorea, Republic of
    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 supportSamsung Electronics Co. Ltd.
    B.4.2CountryKorea, Republic of
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQuintiles Limited
    B.5.2Functional name of contact pointQuintiles Contact Centre
    B.5.3 Address:
    B.5.3.1Street AddressThe Alba Campus, Rosebank
    B.5.3.2Town/ cityLivingston
    B.5.3.3Post codeEH54 7EG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+1862261 3634
    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
    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.3.9.3Other descriptive nameChimeric human/mouse anti-CD-20 monoclonal antibody
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 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.3.1Product nameMabThera®
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    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 (AR) Grave.
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis (RA)
    Artritis Reumatoide (AR).
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    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 Part A of the study is to compare the PK of SAIT101 to MabThera® in subjects with severe RA.
    The primary objective of the whole study is to compare the efficacy of SAIT101 to MabThera® in subjects with severe RA.
    El objetivo principal de la parte A del estudio es comparar la FC de SAIT101 con respecto a MabThera® en pacientes con AR grave.
    El objetivo principal del estudio en su totalidad es comparar la eficacia de SAIT101 con respecto a MabThera ® en pacientes con AR grave.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the whole study are to compare the PD, safety, tolerability and immunogenicity of SAIT101 to MabThera® in subjects with severe RA.
    Los objetivos secundarios del estudio son comparar la FD, la seguridad, la tolerabilidad y la inmunogenicidad de SAIT101 con respecto a MabThera® en pacientes con AR grave.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Ability and willingness to provide written informed consent, prior to any study specific procedures, and to comply with the requirements of the protocol.
    2. Male or female outpatient, at least 18 years of age at Screening.
    3. Severe active RA defined as:
    (a) Diagnosis of RA according to the revised (1987) ACR criteria for the classification of RA for at least 3 months prior to study entry (see Appendix 3).
    (b) Radiological confirmation of bone erosion (X-ray. Existing evidence [X-ray not more than 1 year old] is also accepted).
    (c) ? 6 swollen joints and ? 6 tender/painful joints (from the 66/68 joint count system).
    (d) hsCRP ? 1.0 mg/dL and/or an ESR ? 28 mm/hour at Screening.
    (e) Positive RF (? 20 units/mL) and/or anti CCP antibodies (? 10 units/mL) at Screening.
    4. Currently receiving, or have previously received, DMARDs, including one or more TNF inhibitor therapies, for the treatment of RA at a label approved dose for at least 3 months, and have had an inadequate or intolerable response to at least one of those administrations. Documented evidence of the inadequate or intolerable response should be available. NB: All biologic DMARDs, including TNF inhibitor therapies, and IL-1 and IL-6 inhibitors are subject to a washout period prior to randomization.
    5. Current treatment for RA on an outpatient basis:
    (a) Receiving MTX 10-25 mg/week (oral or parenteral) for at least 3 months, including the last 1 month prior to randomization at a stable dose, via the same route of administration and formulation. Subjects receiving a lower dose of MTX (< 10 mg/week), stable for 1 month prior to randomization, should be doing so as a result of a documented evidence of intolerance to higher doses of MTX.
    (b) Subjects may be taking oral hydroxychloroquine provided that the dose is not greater than 400 mg/day and has been stable for a minimum of 3 months prior to Day 1. The hydroxychloroquine treatment will need to be continued at a stable dose with the same formulation until the end of the study.
    (c) Leflunomide must be withdrawn at least 3 months prior to the beginning of the treatment period or a minimum of 1 month prior to the beginning of the treatment period if after 11 days of standard cholestyramine washout.
    (d) All DMARDs different from MTX, hydroxycholoquine and leflunomide must be withdrawn at least 1 month prior to the beginning of the treatment period.
    (e) If receiving current treatment with oral corticosteroids, the dose must not exceed 10 mg/day prednisolone or equivalent. During the 1 month prior to Day 1 the dose must be stable (see Section 5.1.3).
    (f) The most recent steroid injection should be ?6 weeks prior to Day 1.
    (g) If receiving current treatment with NSAIDs at the time of Screening, the subject must remain on a stable dose for at least 3 weeks prior to Day 1.
    (h) Subjects are willing to receive oral folic acid (at least 5 mg/week) or equivalent during the entire study (mandatory co-medication for MTX treatment).
    6. For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, intrauterine device, physical barrier) during the course of the treatment period and for at least 12 months after the last dose of investigational product.
    7. Female subjects 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.
    8. Female subjects must not be actively breast-feeding throughout the entire study period and until 12 months after their final dose with investigational product.
    1. Capacidad y voluntad de otorgar el consentimiento informado por escrito, antes de cualquier procedimiento específico del estudio, y de cumplir los requisitos del protocolo.
    2. Pacientes ambulatorios de ambos sexos, con una edad mínima de 18 años en el momento de la selección.
    3. AR activa grave, definida por lo siguiente:
    (a) Diagnóstico de AR, según los criterios revisados del ACR (1987) para la clasificación de la AR, durante al menos tres meses antes de la inclusión en el estudio (véase el apéndice 3).
    (b) Confirmación radiológica de la presencia de erosiones óseas (radiografías; también se aceptan los datos existentes [radiografías de menos de un año de antigüedad]).
    (c) Seis o más articulaciones inflamadas y seis o más articulaciones dolorosas (según el sistema de valoración de 66/68 articulaciones).
    (d) PCRas ? 1,0 mg/dl o VSG ? 28 mm/h en el período de selección.
    (e) Positividad para el FR (? 20 unidades/ml) o para anticuerpos anti-CCP (? 10 unidades/ml) en el período de selección.
    4. Haber recibido o estar recibiendo FARME, incluidos uno o más inhibidores del TNF, para el tratamiento de la AR y con una dosis aprobada en la ficha técnica durante al menos tres meses, así como haber presentado una respuesta insuficiente o intolerancia a al menos uno de los tratamientos administrados. Debe haber datos documentados de respuesta insuficiente o intolerancia. Nota: todos los FARME biológicos, incluidos los inhibidores del TNF y los inhibidores de la IL-1 e IL-6, están sujetos a un período de lavado antes de la aleatorización (véase la tabla 7).
    5. Tratamiento presente para la AR en régimen ambulatorio:
    (a) MTX 10-25 mg/semana (oral o parenteral) durante al menos tres meses, incluido el mes previo a la aleatorización, en una dosis estable, por la misma vía de administración y con la misma formulación. Los sujetos que estén recibiendo una dosis de MTX más baja (menos de 10 mg/semana), estable durante un mes antes de la aleatorización, deberán tener datos documentados de intolerancia a dosis superiores de MTX.
    (b) Los sujetos podrán tomar hidroxicloroquina oral siempre que la dosis no sea superior a 400 mg/día y se haya mantenido estable durante al menos tres meses antes del día 1. El tratamiento con hidroxicloroquina deberá mantenerse en una dosis estable con la misma formulación hasta el final del estudio.
    (c) Leflunomida deberá suspenderse al menos tres meses antes del inicio del período de tratamiento, o al menos un mes antes del inicio del período de tratamiento si se realiza un lavado de 11 días con colestiramina.
    (d) Todos los FARME distintos de MTX, hidroxicloroquina y leflunomida deberán suspenderse al menos un mes antes del inicio del período de tratamiento.
    (e) En caso de tratamiento presente con corticoides orales, la dosis no podrá superar los 10 mg/día de prednisolona o equivalente. La dosis deberá mantenerse estable durante el mes previo al día 1 (véase el apartado 5.1.3).
    (f) La última inyección de corticoides deberá haberse administrado como mínimo seis semanas antes del día 1.
    (g) En caso de estar en tratamiento con AINE en el momento de la selección, la dosis deberá mantenerse estable durante al menos tres semanas antes del día 1.
    (h) Los sujetos están dispuestos a recibir ácido fólico por vía oral (al menos 5 mg/semana) o equivalente durante todo el estudio (medicamento concomitante obligatorio para el tratamiento con MTX).
    6. En los sujetos en edad fértil (varones y mujeres), uso de un método anticonceptivo fiable (como anticonceptivo hormonal, parche, dispositivo intrauterino o barrera física) durante el período de tratamiento y hasta al menos 12 meses después de la última dosis del producto en investigación.
    7. Las mujeres en edad fértil deberán tener un resultado negativo en la prueba de embarazo en suero realizada en la selección (visita 1) y, posteriormente, un resultado negativo en las pruebas de embarazo en orina realizadas en las visitas pertinentes.
    8. Las mujeres no podrán estar en período de lactancia activa durante todo el estudio y hasta 12 meses después de la última dosis del producto en investigación.
    E.4Principal exclusion criteria
    1. Females who are pregnant, nursing, or planning a pregnancy during the period of the study.
    2. American College of Rheumatology functional Class IV or wheelchair/bed bound.
    3. Have any significant systemic involvement with RA such as vasculitis, pulmonary fibrosis or Felty?s syndrome.
    4. History of or current inflammatory joint disease other than RA (including but not limited to gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy or Lyme disease) or other systemic autoimmune disorder, with the exception of the secondary Sjögren's syndrome, (including but not limited to systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome).
    5. History of infected prosthetic joint.
    6. Positive serological test for HBsAg and HBcAb or for hepatitis C serology.
    7. History of HIV infection.
    8. History of active/latent tuberculosis (TB), as determined by TB test.
    9. Subjects with acute clinical manifestations of herpes zoster virus.
    10. Subjects with history of severe herpes zoster defined by involvement of more than one dermatome, ophthalmic involvement and/or requiring hospital admission within 5 years prior to Baseline.
    11. Active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization within 3 months prior to Baseline or requiring treatment with i.v. anti infective agents within 6 weeks prior to Baseline or oral anti-infective agents within 2 weeks prior to Baseline.
    12. Any significant cardiac disease (e.g. coronary artery disease with unstable angina, coronary heart failure NYHA Class III and IV, familial long QT syndrome, uncontrolled cardiac disease).
    13. History of moderate to severe COPD and/or history of severe COPD exacerbation(s) within the last 12 months.
    14. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids.
    15. Administration of a live/attenuated vaccine in the 1 month prior to randomization.
    16. History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the investigational product.
    17. Hypogammaglobulinemia (IgG < 5.0 g/L and/or IgM < 0.20 g/L).
    18. Subjects having undergone a splenectomy.
    19. Subjects with hemoglobin < 8.5 g/dL, WBC count < 3000 cells/µL, absolute neutrophil count (ANC) < 2000 cells/µL, lymphocyte count < 800 cells/µL or platelet count < 100,000 cells/µL at Screening. If a subject has findings marginally below this limit, re testing is allowed, at the investigator?s discretion, within the 30 day period between Visit 1 and 2.
    20. AST, ALT, GGT or alkaline phosphatase levels > 1.5 times (for Part A) or > 3 times (for Part B) the ULN at Screening or serum creatinine > 2 times ULN. The AST and ALT may be repeated once within the Screening period if the initial result exceeds this limit, and the lesser value accepted if it meets this criterion.
    21. Subjects with a history of solid-organ transplantation.
    22. History of cancer within the last 5 years treated with anti-cancer chemotherapy, including solid tumors and hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinomas of the skin or carcinoma in situ of the cervix uteri that have been excised and cured).
    23. Subjects with a current or past history of alcohol or drug abuse.
    24. Any surgical procedure within 3 months prior to Baseline, with the exception of surgical procedures for dental prosthesis.
    25. Previous treatment with a B cell modulating or B cell depletion therapy, such as, but not limited to: rituximab, belimumab, ocrelizumab and other experimental treatments.
    26. Injectable corticosteroids within 6 weeks prior to Baseline.
    27. Participation in a previous clinical study within 3 months of Screening. Subjects who have received treatment with a drug that has not received regulatory approval for any indication within 3 months or a minimum of 5 half-lives, whichever is longer, of the initial dose of investigational product.
    28. Subjects who, based on the investigator?s judgment, have a clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation, such as diabetes mellitus type 1 or unstable type 2. Conditions may also include cardiovascular, vascular disease, pulmonary, hepatic, renal, or neurological as determined by medical history, physical examination, laboratory tests or ECG.
    29. Subjects who, in the judgment of the investigator, are likely to be non-compliant or uncooperative during the study.
    30. Subjects who have participated in any clinical study involving SAIT101.
    1. Mujeres embarazadas, en lactancia o con intención de quedarse embarazadas durante el estudio.
    2. Clase funcional IV del American College of Rheumatology o paciente en silla de ruedas o postrado en cama.
    3. Afectación sistémica importante asociada a la AR, como vasculitis, fibrosis pulmonar o síndrome de Felty.
    4. Presencia/antecedentes de artropatía inflamatoria distinta de la AR u otros trastornos autoinmunitarios sistémicos con la excepción del síndrome de Sjögren secundario.
    5. Antecedentes de infección de una prótesis articular.
    6. Resultado serológico positivo para el antígeno de superficie del virus de la hepatitis B y los anticuerpos contra el antígeno central del virus de la hepatitis B o para el virus de la hepatitis C.
    7. Antecedentes de infección por el virus de la inmunodeficiencia humana.
    8. Antecedentes de tuberculosis activa o latente, determinada mediante una prueba de tuberculosis.
    9. Manifestaciones clínicas agudas de infección por el virus del herpes zóster.
    10. Antecedentes de herpes zóster grave, definido como la afectación de más de un dermatoma, afectación oftálmica o necesidad de ingreso hospitalario, en los 5 años anteriores al momento basal.
    11. Infección activa de cualquier tipo (excepto micosis de lechos ungueales) o cualquier episodio importante de infección que requiera hospitalización en los 3 meses previos a la visita basal, tratamiento con antibióticos intravenosos en las 6 semanas previas a la visita basal o tratamiento con antibióticos orales en las 2 semanas previas a la visita basal.
    12. Cardiopatía importante.
    13. Antecedentes de enfermedad pulmonar obstructiva crónica (EPOC) moderada o grave o de exacerbaciones graves de la EPOC en los 12 meses precedentes.
    14. Trastornos no controlados, como asma, psoriasis o enfermedad inflamatoria intestinal, en los que las exacerbaciones suelan tratarse con corticoides orales o parenterales.
    15. Vacunación con vacunas de microorganismos vivos/atenuados en el mes previo a la aleatorización.
    16. Antecedentes de reacción alérgica grave o reacción anafiláctica a un fármaco biológico o de hipersensibilidad a alguno de los componentes del producto en investigación.
    17. Hipogammaglobulinemia (IgG < 5,0 g/l o IgM < 0,20 g/l).
    18. Antecedentes de esplenectomía.
    19. Hemoglobina < 8,5 g/dl, recuento de leucocitos < 3.000 células/µl, recuento absoluto de neutrófilos (RAN) < 2.000 células/µl, recuento de linfocitos < 800 células/µl o recuento de plaquetas < 100.000 células/µl en la selección. Si un sujeto presenta resultados ligeramente por debajo de estos límites, se podrá repetir la determinación, a criterio del investigador, durante el período de 30 días entre las visitas 1 y 2.
    20. Valores de aspartato aminotransferasa, alanina aminotransferasa, gammaglutamil transpeptidasa o fosfatasa alcalina más de 1,5 veces el límite superior de la normalidad (LSN, en la parte A) o más de tres veces el LSN (en la parte B) en la selección o de creatinina sérica más de dos veces el LSN. El análisis de AST y ALT podrá repetirse una vez dentro del período de selección si el resultado inicial supera este límite y se aceptará el valor más bajo si cumple este criterio.
    21. Antecedentes de trasplante de órgano sólido.
    22. Antecedentes de cáncer en los 5 años precedentes tratado con quimioterapia, incluidos tumores sólidos, neoplasias malignas hematológicas y carcinoma in situ (excepto los carcinomas basocelular y espinocelular de piel y el carcinoma cervicouterino in situ que hayan sido extirpados y curados).
    23. Antecedentes/presencia de alcoholismo o drogadicción.
    24. Intervención quirúrgica de cualquier tipo en los 3 meses previos al momento basal, salvo las intervenciones para colocar prótesis dentales.
    25. Tto. previo con un fármaco regulador de los linfocitos B o que causa depleción de linfocitos B, como rituximab, belimumab, ocrelizumab y otros fármacos experimentales.
    26. Corticoides por vía parenteral en las seis semanas previas a la visita basal.
    27. Participación en un ensayo clínico en los 3 meses previos a la selección. Sujetos que hayan recibido tratamiento con un fármaco que no haya recibido la aprobación de las autoridades sanitarias en ninguna indicación en los 3 meses previos o el período equivalente, como mínimo, a 5 semividas, lo que suponga más tiempo, de la administración de la primera dosis del producto en investigación.
    28. Sujetos que, presentan un trastorno médico o quirúrgico de importancia clínica o inestable que impide participar de forma segura y completa en el estudio, como diabetes mellitus de tipo 1 o de tipo 2 inestable. También pueden ser enfermedades cardiovasculares, vasculares, pulmonares, hepáticas, renales o neurológicas determinadas mediante la anamnesis, la exploración física, las pruebas analíticas o el electrocardiograma.
    29. Sujetos que, probablemente no cumplan o sean poco colaboradores durante el estudio.
    30. Participación previa en un estudio clínico con SAIT101.
    E.5 End points
    E.5.1Primary end point(s)
    ? The primary PK endpoints for Part A are the area under the concentration-time curve from time 0 (immediately pre-dose at Day 1) to the time of the last quantifiable concentration (AUC0-t) at Week 24 and the maximum concentration (Cmax) post infusion on Day 15.
    ? The primary efficacy variable for the whole study is the ACR20 response rate.
    - Los criterios de valoración principales de la FC en la parte A son el área bajo la curva de concentración-tiempo desde el momento 0 (inmediatamente antes de la administración el día 1) hasta el momento de la última concentración cuantificable (AUC0-t) en la semana 24 y la concentración máxima (Cmáx) después de la infusión el día 15.
    - La variable principal de la eficacia del estudio en su totalidad es la tasa de respuestas ACR20.
    E.5.1.1Timepoint(s) of evaluation of this end point
    ? AUC time curve from time 0 (immediately pre-dose at Day 1) to the time of the last quantifiable concentration (AUC0-t) at Week 24 and Cmax post infusion on Day 15.
    ? ACR20 response rate at Week 24.
    - Área bajo la curva desde el momento 0 (inmediatamente antes de la administración el día 1) hasta el momento de la última concentración cuantificable (AUC0-t) en la semana 24 y la concentración máxima (Cmáx) después de la infusión el día 15.
    - Tasa de respuestas ACR20 en la semana 24.
    E.5.2Secondary end point(s)
    ? ACR20 response rates.
    ? ACR50 response rate and ACR70 response rate.
    ? Individual components of the ACR improvement criteria:
    o Swollen and tender joint count (the 66/68 joint count system)
    o Subject?s assessment of pain (assessed on 1-100 mm Visual Analogue Scale [VAS])
    o Physician?s global assessment of disease activity (assessed on 1-100 mm VAS)
    o Subject?s assessment of disease activity (assessed on 1-100 mm VAS)
    o Subject?s assessment of disability (Health Assessment Questionnaire Disability Index)
    o C-reactive protein level
    ? Change in the disease activity score based on a 28 joint count.
    ? Major clinical response (continuous ACR70).
    ? Proportion of subjects with European League Against Rheumatism response (good response, moderate response or no structural joint damage).
    ? Assessment of structural joint damage.
    - Tasa de respuestas ACR20.
    - Tasa de respuestas ACR50 y tasa de respuestas ACR70.
    - Componentes individuales de los criterios de mejoría ACR:
    oNúmero de articulaciones inflamadas y dolorosas (sistema de valoración de 66/68 articulaciones).
    oEvaluación del dolor por el paciente (mediante una escala analógica visual [EAV] de 1 a 100 mm).
    oEvaluación general de la actividad de la enfermedad por el médico (mediante una EAV de 1 a 100 mm).
    oEvaluación de la actividad de la enfermedad por el sujeto (mediante una EAV de 1 a 100 mm).
    oEvaluación de la discapacidad por el sujeto (índice de discapacidad del cuestionario de evaluación de la salud, HAQ-DI).
    oConcentración de proteína C reactiva.
    - Variación de la puntuación de actividad de la enfermedad basada en la valoración de 28 articulaciones.
    - Respuesta clínica principal (ACR70 continua).
    - Proporción de sujetos con respuesta de la Liga Europea contra el Reumatismo (respuesta buena, respuesta moderada o ausencia de daño articular estructural).
    - Evaluación del daño articular estructural.
    E.5.2.1Timepoint(s) of evaluation of this end point
    ? ACR20 response rates at Weeks 4, 8, 12, 16 and 52.
    ? ACR50 response rate and ACR70 response rate at Weeks 4, 8, 12, 16, 24 and 52.
    ? Individual components of the ACR improvement criteria at Day 1 and at Weeks 4, 8, 12, 16, 24 and 52:
    ? Change in the disease activity score based on a 28 joint count from Baseline to Weeks 4, 8, 12, 16, 24 and 52.
    ? Major clinical response (continuous ACR70 for at least 24 weeks).
    ? Proportion of subjects with European League Against Rheumatism response at Weeks 4, 8, 12, 16, 24 and 52.
    ? Assessment of structural joint damage at Screening and Week 52.
    - Tasa de respuestas ACR20 en las semanas 4, 8, 12, 16 y 52.
    - Tasa de respuestas ACR50 y tasa de respuestas ACR70 en las semanas 4, 8, 12, 16, 24 y 52.
    - Componentes individuales de los criterios de mejoría ACR el día 1 y en las semanas 4, 8, 12, 16, 24 y 52:
    - Variación de la puntuación de actividad de la enfermedad basada en la valoración de 28 articulaciones entre el momento basal y las semanas 4, 8, 12, 16, 24 y 52.
    - Respuesta clínica principal (ACR70 continua durante 24 semanas como mínimo).
    - Proporción de sujetos con respuesta de la Liga Europea contra el Reumatismo en las semanas 4, 8, 12, 16, 24 y 52.
    - Evaluación del daño articular estructural en el período de selección y en la semana 52.
    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 No
    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
    Part A is Phase I to collect PK data for IMP PR1
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Adaptive design Phase I/III
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA64
    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
    Argentina
    Brazil
    Canada
    Korea, Republic of
    Mexico
    Romania
    Russian Federation
    South Africa
    Switzerland
    Taiwan
    Turkey
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months11
    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 months3
    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: 496
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 245
    F.4.2.2In the whole clinical trial 616
    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)
    After the end of the study, the study drug will no longer be available to the patients. Patients continued care may involve a different drug or treatment, which the hospital, together with the Study Doctor, consider the most suitable alternative
    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 Decision2012-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2013-06-30
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