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    Summary
    EudraCT Number:2018-004558-30
    Sponsor's Protocol Code Number:BIOP-US
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-05-21
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2018-004558-30
    A.3Full title of the trial
    A 3-arm, randomized, open-label, parallel active controlled, multicenter international study to compare the response of ultrasound-assessed synovitis to baricitinib, alone and combined with methotrexate versus etanercept in rheumatoid arthritis patients with inadequate response to methotrexate. Searching for synovium predictors of response.
    Estudo internacional, multicêntrico, ativo, paralelo, controlado, aberto, randomizado, com 3 ramos de tratamento para comparar a resposta da inflamação sinovial avaliada por ecografia ao baricitinib administrado isoladamente e em combinação com metotrexato versus etanercepte em doentes com artrite reumatoide e resposta insuficiente para o metotrexato. Busca por preditores sinoviais de resposta terapêutica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 3-arm, randomized, open-label, parallel active controlled, multicenter international study to compare the response of ultrasound-assessed synovitis to baricitinib, alone and combined with methotrexate versus etanercept in rheumatoid arthritis patients with inadequate response to methotrexate. Searching for synovium predictors of response.
    Estudo internacional, multicêntrico, ativo, paralelo, controlado, aberto, randomizado, com 3 ramos de tratamento para comparar a resposta da inflamação sinovial avaliada por ecografia ao baricitinib administrado isoladamente e em combinação com metotrexato versus etanercepte em doentes com artrite reumatoide e resposta insuficiente para o metotrexato. Busca por preditores sinoviais de resposta terapêutica
    A.4.1Sponsor's protocol code numberBIOP-US
    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 SponsorFundación Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLilly S.A., Spain
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlpha Bioresearch S.L.
    B.5.2Functional name of contact pointTeresa Bricio
    B.5.3 Address:
    B.5.3.1Street AddressC/ López de Hoyos 155, 3rd Floor. Offices 6-7
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28002
    B.5.3.4CountrySpain
    B.5.4Telephone number0034917452520
    B.5.5Fax number0034917450653
    B.5.6E-mailregulatory@alphabioresearch.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 Yes
    D.2.1.1.1Trade name Olumiant
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    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 nameOlumiant
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBARICITINIB
    D.3.9.1CAS number 1187594-09-7
    D.3.9.4EV Substance CodeSUB180983
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 Enbrel
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    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 nameEnbrel
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNETANERCEPT
    D.3.9.1CAS number 185243-69-0
    D.3.9.4EV Substance CodeSUB01984MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP 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 Ledertrexato
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Lda.
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    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 nameMetotrexato
    D.3.2Product code Metotrexato
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmetotrexato
    D.3.9.1CAS number 59-05-2
    D.3.9.2Current sponsor codeMethotrexate
    D.3.9.3Other descriptive nameMETHOTREXATE SODIUM
    D.3.9.4EV Substance CodeSUB03225MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2,5 to 2,5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Metex Pen
    D.2.1.1.2Name of the Marketing Authorisation holderMedac Gesellschaft für klinische Spezialpräparate mbH
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    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 nameMethotrexate
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMethotrexate
    D.3.9.1CAS number 59-05-02
    D.3.9.2Current sponsor codeMethotrexate
    D.3.9.3Other descriptive nameMETHOTREXATE
    D.3.9.4EV Substance CodeSUB08856MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number7,5 to 25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    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
    rheumatoid arthritis
    artrite reumatoide
    E.1.1.1Medical condition in easily understood language
    rheumatoid arthritis
    artrite reumatoide
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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 main objective of the study is to demonstrate non-inferiority of the response of MSKUS-assessed synovitis (i.e. B-mode and Doppler mode synovitis) to baricitinib treatment, alone plus combined with MTX (arm1 + arm2) vs. etanercept plus MTX (arm 3) in IR-MTX patients. Non-inferiority will be claimed if changes in MSKUS-assessed synovitis with baricitinib (alone and combined with MTX) after 12 weeks of treatment is at least 80% of changes in the etanercept + MTX group in the same period using a non-inferiority test for two means.
    O objetivo principal do estudo é demonstrar, através da avaliação por MSKUS da inflamação sinovial (ou seja, sinovite em modo B e modo Doppler) a não inferioridade da resposta, ao tratamento com Baricitinib, isoladamente e combinado com MTX (braço1 + braço2) versus Etanercept com MTX (braço 3) em pacientes IR-MTX. Será considerada, através de avaliação por MSKUS de inflamação sinovial, como não inferioridade se as alterações, com Baricitinib (isoladamente e combinado com MTX) depois de 12 semanas de tratamento são pelo menos 80 % das alterações no grupo de Etanercept com MTX, no mesmo período utilizando um teste de não inferioridade para comparar as duas médias.
    E.2.2Secondary objectives of the trial
    • To compare the grade of B-mode- and Doppler-detected residual synovitis in IR-MTX RA patients who achieve clinical remission or low disease activity (i.e. DAS28 <3.2) at 4 weeks, 12 weeks and 24 weeks on baricitinib + MTX vs baricitinib monotherapy vs + etanercept + MTX.
    • To evaluate the predictive value of MSKUS-assessed response to baricitinib (monotherapy and combined with MTX) at week 4 in relation to clinical and MSKUS response at week 12 and 24.
    • To histologically evaluate synovial biopsies, obtained at baseline (26, 27) in baricitinib + MTX treated patients in comparison to that observed in etanercept + MTX therapy, in correlation with the results obtained by MSKUS studies. The gene expression and synthesis of proinflammatory mediators (TNF, IL6, IL1, COX2, MCP1, pSTAT1, pSTAT2, pSTAT3, SOCS1, SOCS2, SOCS3, pERK, pAKT…) by real-time PCR and Western-Blot techniques will be assessed.
    ...
    • Comparar o grau de sinovite residual detectada no modo B e Doppler em pacientes com AR com IR-MTX que alcançam remissão clínica ou baixa atividade da doença (ou seja, DAS28 <3,2) com 4 semanas, 12 semanas e 24 semanas com baricitinibe + MTX versus baricitinibe monoterapia vs + etanercept + MTX.
    • Avaliar o valor preditivo da resposta avaliada por MSKUS ao baricitinib (monoterapia e combinado com MTX) na semana 4 em relação à resposta clínica e MSKUS na semana 12 e 24.
    • Avaliar histologicamente as biópsias sinoviais, obtidas no início do estudo (26, 27), em pacientes tratados com baricitinibe + MTX em comparação ao observado na terapia com etanercepte + MTX, em correlação com os resultados obtidos pelos estudos com MSKUS. A expressão gênica e a síntese de mediadores pró-inflamatórios (TNF, IL6, IL1, COX2, MCP1, pSTAT1, pSTAT2, pSTAT3, SOCS1, SOCS2, SOCS3, pERK, pAKT ...) por técnicas de PCR em tempo real e Western-Blot serão avaliadas.
    ...
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient able to provide written informed consent
    2. Mentally competent to understand and willing to undergo the scheduled study procedures, including study questionnaires as established in the protocol.
    3. Female or male, from 18 to 75 years of age at the moment of informed consent signature.
    4. Patient with RA diagnosed according to 2010 ACR/EULAR Classification Criteria for RA.
    5. Moderate to severe disease activity (according to Disease Activity Score for 28 joints (DAS28) ≥ 3.2).
    6. Inadequate response to MTX, which must have been received during, at least, 3 months prior to baseline visit and be on a stable dose of ≤ 25 mg/week.
    7. Patients who fulfils the pre-requisites for biologic and targeted synthetic disease modifying antirheumatic drugs (DMARD) therapy according to National recommendations/regulations (eg, absence of active infections, absence of latent tuberculosis, recommendations regarding previous cancer, vaccination recommendations,…).
    8. Written acceptance to use highly effective contraception i.e. intrauterine device (IUD); hormonal therapy (progestin alone or combined with estrogen) associated with inhibition of ovulation such as oral pill, injection, implant, transdermal patch or vaginal ring; tubal ligation, partner’s vasectomy; or sexual abstinence for the entire duration of study participation including six months after stop of study treatment.
    1. Paciente capaz de dar o seu consentimento informado por escrito.
    2. Mentalmente competente para entender e disposto a submeter-se aos procedimentos de estudos programados, incluídos os questionários de estudo estabelecidos no protocolo.
    3. Mulher ou homem, de 18 a 75 anos de idade no momento da assinatura do consentimento informado.
    4. Paciente com AR diagnosticada de acordo com os critérios de classificação ACR/EULAR de 2010 para AR.
    5. Atividade da doença de moderada a grave (de acordo com a pontuação de atividade da doença para 28 articulações (DAS28) ≥ 3,2).
    6. Resposta inadequada ao MTX, que deve ter sido recebido durante pelo menos 3 meses antes da visita de referência e estar numa dose estável de ≤ 25mg/semana.
    7. Pacientes que satisfazem os pré-requisitos para a terapêutica com medicamentos antirreumáticos sintéticos ou biológicos modificadores da doença (DMARD), de acordo com as recomendações/regulamentos nacionais (por exemplo, ausência de infeções ativas, ausência de tuberculose latente, recomendações em relação a cancro anterior, recomendações de vacinação,...).
    8. Aceitação por escrito do uso de contracepção altamente eficaz, ou seja, dispositivo intrauterino (DIU); terapia hormonal (progesterona isolada ou combinada con estrogênio), associada à inibição da ovulação, como pílula oral, injeção, implante, adesivo transdérmico ou anel vaginal; ligadura tubária, vasectomia do parceiro; ou abstinência sexual ao longo de sua participação no estudo incluindo seis meses após a interrupção do tratamento em estudo.
    E.4Principal exclusion criteria
    1. Patient considered by the investigator to be unsuitable for the study treatment and/or rescue medication (RM) based on the prescription drug labeling, their medical history, physical examination, concomitant medication (CM) and concomitant systemic diseases.
    2. Complications during the period prior to randomisation, in the investigator's opinion.
    3. Hypersensitivity or allergy to the study medication.
    4. Patients taking any concomitant medication, which could be susceptible to interact with the study drugs.
    5. Patients in treatment with any medication that could affect the evaluation of the study treatment’s efficacy. DMARDs other than methotrexate are not allowed at study inclusion. If the patient has received other DMARD, eg hidroxicloroquine, leflunomide, sulphasalazine,....These drugs must have been stopped at least 3 months before inclusion. Regarding NSAID or corticosteroids, concomitant stable doses of nonsteroidal anti-inflammatory drugs, analgesics for pain relief if necessary. or corticosteroids (≤ 7.5mg of prednisone or the equivalent daily) will be allowed during the trial period.
    6. Patients on anticoagulant treatment
    7. Pregnant or lactating women.
    8. Patients and/or female partners of male patients not using highly effective method of birth control i.e. intrauterine device (IUD); hormonal therapy (progestin alone or combined with estrogen) associated with inhibition of ovulation such as oral pill, injection, implants, transdermal patch or vaginal ring; tubal ligation, partner’s vasectomy; or sexual abstinence.
    1. Paciente considerado pelo investigador como inadequado para o tratamento do estudo e/ou para a medicação de resgate (RM) em função da rotulagem dos medicamentos receitados, do seu historial médico , exame físico, medicação concomitante (CM) e doenças sistémicas concomitantes.
    2. Complicações durante o período anterior à randomização, de acordo com o critério do investigador.
    3. Hipersensibilidade ou alergia à medicação do estudo.
    4. Pacientes que tomam qualquer medicamento concomitante, que possa ser suscetível de interagir com o medicamento do estudo.
    5. Pacientes em tratamento com qualquer medicamento que possa afetar a avaliação da eficácia do tratamento do estudo. Não são permitidos DMARDs diferentes do metotrexato na inclusão do estudo. Se o paciente recebeu outro DMARD, por exemplo, hidroxicloroquina, leflunomida, sulfassalazina, ..Estes medicamentos devem ter sido interrompidos pelo menos 3 meses antes da inclusão. Em relação aos AINEs ou corticosteróides, doses estáveis concomitantes de anti-inflamatórios não esteróides, analgésicos para alívio da dor, se necessário, ou corticosteróides (≤ 7,5 mg de prednisona ou o equivalente diário) serão permitidos durante o período experimental.
    6. Pacientes em tratamento anticoagulante.
    7. Mulheres grávidas ou lactantes.
    8. Pacientes e/ou parceiros do sexo feminino de pacientes masculinos participantes, que não usam um método anticoncepcional altamente eficaz de controle da gravidez, por exemplo, dispositivo intra-uterino (DIU), terapia hormonal (progesterona isolada ou combinada com estrogênio) associada à inibição da ovulação, como pílula oral, injeção, implantes, adesivo transdérmico ou anel vaginal; ligadura tubária, vasectomia do parceiro; ou abstinência sexual.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy: The primary outcome considered in this trial is the decrease in join inflammation detected by MSKUS (B-mode and Doppler mode synovitis).
    Safety: Safety evaluation will be assessed through physical examination, possible adverse events (related or not to the treatment under study) and analytical parameters. During each study visit all the safety variables must be recorded in medical records and e-CRF.
    Eficácia: A principal variável considerado neste ensaio é a diminuição da inflamação na articulação detetada por MSKUS (sinovite em modo B e em modo Doppler).
    Segurança: A avaliação da segurança será realizada através de um exame físico, possíveis eventos adversos (relacionados ou não com o tratamento no estudo) e os parâmetros analíticos. Durante cada visita do estudo, todas as variáveis de segurança devem ser registadas nos registos médicos e no e-CRF.


    E.5.1.1Timepoint(s) of evaluation of this end point
    4, 12, 24 weeks
    Semanas 4, 12, 24
    E.5.2Secondary end point(s)
    Secondary: The secondary endpoints will be:
    • Time-point of significant change in B-mode and Doppler synovitis according to treatment group (4 weeks, 12 weeks, 24 weeks).
    • Presence and amount of subclinical B-mode and Doppler synovitis in patients reaching DAS28-defined clinical remission and low disease activity at 4 weeks, 12 weeks and 24 weeks, according to treatment group.
    • Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) at 4 weeks, 12 weeks and 24 weeks, according to treatment group.
    • Correlation between presence of MSKUS-assessed synovitis, synovial histological alterations and the presence of proinflammatory citokines (TNF, IL6, IL1, COX2, MCP1, RANKL, OPG…) in serum and synovial tissue, at baseline in all patients and after 12 weeks in patients classified as non-responders, according to treatment group.
    • Changes in PROM as assessed by the Health Assessment Questionnaire–Disability Index (HAQ-DI), from baseline to 24 weeks.
    As variáveis secundárias serão:
    • Momento determinado da alteração significativa de sinovite no modo B e Doppler consoante o grupo de tratamento (4 semanas, 12 semanas, 24 semanas).
    • Presença e quantidade de sinovite subclínica em modo B e modo Doppler, em pacientes que alcançaram a remissão clínica definida por DAS28 e uma baixa atividade da doença às 4 semanas, 12 semanas e 24 semanas, consoante o grupo de tratamento.
    • Índice de atividade da doença simplificado (SDAI) e índice de atividade clínica da doença (CDAI) às 4 semanas, 12 semanas e 24 semanas, dependendo do grupo de tratamento.
    • Correlação entre a presença de sinovite avaliada por MSKUS, as alterações histológicas sinoviais e a presença de citocinas pró-inflamatórias (TNF, IL6, IL1, COX2, MCP1, RANKL, OPG) em soro e tecido sinovial, na visita basal em todos os pacientes e depois de 12 semanas em pacientes classificados como não responsivos, consoante o grupo de tratamento.
    • Alterações nas PROMs de acordo com o avaliado pelo Questionário de Avaliação da Saúde - Índice de Incapacidade (HAQ-ID), desde o início até às 24 semanas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    4, 12, 24 weeks
    Semanas 4, 12, 24
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    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 Yes
    E.8.2.3.1Comparator description
    Etanercept
    Etanercept
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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: Last Patient Last Visit
    Última Visita do Último Paciente
    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 years2
    E.8.9.2In all countries concerned by the trial months0
    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: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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 Yes
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 186
    F.4.2.2In the whole clinical trial 186
    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)
    Usual Clinical Practice
    Prática Clínica Usual
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-09-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-03
    P. End of Trial
    P.End of Trial StatusOngoing
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