E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active rheumatoid arthritis |
Artrite reumatóide activa moderada a grave |
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E.1.1.1 | Medical condition in easily understood language |
Rheumatoid arthritis |
Artrite reumatóide |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine whether baricitinib monotherapy is noninferior to MTX monotherapy in the treatment of patients with moderate to severe active RA who have had limited or no treatment with MTX and are naive to other conventional or biologic DMARDs, as assessed by the proportion of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24. |
determinar se a monoterapia com baricitinib não é inferior à monoterapia com MTX, no tratamento de doentes com AR ativa moderada a grave que receberam um tratamento limitado ou que não receberam tratamento com MTX e que não tomaram outros MARMD convencionais ou biológicos, como avaliado pela proporção de doentes que atingem uma melhoria de 20% de acordo com os critérios do American College of Rheumatology (ACR20) na Semana 24. |
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E.2.2 | Secondary objectives of the trial |
• proportion of patients achieving ACR20 at Week 24 for baricitinib plus MTX versus MTX monotherapy
• change from baseline to Week 24 in Health Assessment Questionnaire-Disability Index (HAQ-DI) score
• change from baseline to Week 24 in DAS28–high-sensitivity C reactive protein (hsCRP)
• change from baseline to Week 24 in structural joint damage as measured by modified Total Sharp Score (mTSS [van der Heijde method]) for baricitinib plus MTX versus MTX monotherapy
• area under the curve (AUC) up to Week 24 in HAQ-DI score for baricitinib monotherapy versus MTX monotherapy
• AUC up to Week 24 in DAS28-hsCRP score for baricitinib monotherapy versus MTX monotherapy
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•proporção doentes que atingem critérios ACR20 Sem 24 para baricitinib mais MTX versus mono MTX
•alteração desde o momento basal até à Sem 24 Índice de Incapacidade do Questionário de Avaliação da Saúde (HAQ-DI) •alteração desde o momento basal até à Sem 24 Índice de Atividade Doença 28 (DAS28) – proteína C reativa de alta sensibilidade (hsCRP), baricitinib mais MTX versus mono MTX
•alteração desde o momento basal até à Semana 24 nos danos estruturais articulações, na Pontuação Total Sharp modificada (mTSS [método van der Heijde) baricitinib mais MTX versus mono com MTX
•proporção doentes que atingem critérios ACR20 na Sem 24, mono baricitinib versus mono MTX
•(AUC) até à Semana 24 no resultado HAQ-DI, mono baricitinib versus mono MTX
•AUC até à Semana 24 na DAS28-hsCRP, mono baricitinib versus mon MTX
•alteração desde o momento basal até à Sem 24 nos danos estruturais nas articulações,avaliado mTSS (método van der Heijde) mono baricitinib versus monoterapia MTX |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Addendum - Approved 14-Aug-2012:
A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment with Disease Modifying Antirheumatic Drugs
The objectives of this addendum are:
• primarily, to evaluate the efficacy of baricitinib + methotrexate (MTX) compared to MTX monotherapy at Week 24 as assessed by changes from baseline in synovitis, osteitis, bone erosion, and joint space narrowing as measured by MRI of the dominant hand and wrist
• secondarily, to evaluate the efficacy of baricitinib + MTX compared to MTX monotherapy at Week 52 as assessed by changes from baseline in synovitis, osteitis, bone erosion, and joint space narrowing as measured by MRI of the dominant hand and wrist
• thirdly, to evaluate the efficacy of baricitinib monotherapy compared to MTX monotherapy at Weeks 24, and 52 as assessed by changes from baseline in synovitis, osteitis, bone erosion, and joint space narrowing as measured by MRI of the dominant hand and wrist
Austria Specific Addendum -Approved 6-Sep-2012:
A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment with Disease-Modifying Antirheumatic Drugs
According to the Austrian Act on Pharmaceutical Products (AMG, §30), female patients of childbearing potential are only allowed to participate in a clinical trial if non-pregnancy of these women is confirmed prior to and monthly during the clinical trial.
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Subestudo - aprovado 14 Agosto: Estudo aleatorizado, em dupla ocultação, controlado por substância activa, de Fase 3, para avaliação da eficácia e segurança de baricitinib (LY3009104) em doentes com artrite reumatóide activa, moderada a grave, que fizeram tratamento limitado ou não fizeram tratamento com fármacos anti-reumáticos modificadores da doença
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E.3 | Principal inclusion criteria |
• are at least 18 years of age
• have a diagnosis of adult-onset RA as defined by ACR/EULAR 2010 Criteria for the Classification of RA
• have documented history of positive rheumatoid factor and/or cyclic citrullinated peptide (CCP) antibody test
• have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints
• have a C-reactive protein (or hsCRP) measurement ≥1.2 times the upper limit of normal (ULN)
• have had limited or no treatment with MTX |
•Tiver pelo menos 18 anos de idade.
•Tiver artrite reumatóide com início na idade adulta.
•Tiver feito terapêutica com Metotrexato (MTX) durante um período igual ou inferior a 3 semanas.
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E.4 | Principal exclusion criteria |
• have received conventional DMARDs other than MTX (eg, gold salts, cyclosporine, leflunomide, azathioprine, hydroxychloroquine, sulfasalazine or any other immunosuppressives)
• are currently receiving corticosteroids at doses >10 mg per day of prednisone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids within 2 weeks of study entry or within 6 weeks of planned randomization
• have started treatment with NSAIDs or have been receiving an unstable dosing regimen of NSAIDs within 2 weeks of study entry or within 6 weeks of planned randomization
• have started a new physiotherapy treatment for RA in the 2 weeks prior to study entry
• have ever received any biologic DMARD
• have received interferon therapy within 4 weeks prior to study entry or are anticipated to require interferon therapy during the study
• have received any parenteral corticosteroid administered by intramuscular or intravenous (IV) injection within 2 weeks prior to study entry or within 6 weeks prior to planned randomization or are anticipated to require a parenteral injection of corticosteroids during the study
• have had 3 or more joints injected with intraarticular corticosteroids within 2 weeks prior to study entry or within 6 weeks prior to planned randomization
• have active fibromyalgia that, in the investigator’s opinion, would make it difficult to appropriately assess RA activity for the purposes of this study
• have a diagnosis of any systemic inflammatory condition other than RA, such as, but not limited to, juvenile chronic arthritis, spondyloarthropathy, Crohn’s disease, ulcerative colitis, psoriatic arthritis, or active vasculitis
o Patients with secondary Sjogren's syndrome are not excluded.
• have a diagnosis of Felty’s syndrome
• have had any major surgery within 8 weeks of study entry or will require major surgery during the study that, in the opinion of the investigator in consultation with Lilly or its designee, would pose an unacceptable risk to the patient
• have experienced any of the following within 12 weeks of study entry: myocardial infarction, unstable ischemic heart disease, stroke, or New York Heart Association Stage IV heart failure
• have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute a risk when taking investigational product or could interfere with the interpretation of data
• are largely or wholly incapacitated permitting little or no self care, such as, being bedridden or confined to a wheelchair
• have an eGFR based on the most recent available serum creatinine using the Modification of Diet in Renal Disease (MDRD) method of <40 mL/min/1.73 m2
• have a history of chronic liver disease with the most recent available aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the ULN or the most recent available total bilirubin ≥1.5 times the ULN
• have, or have a history of, lymphoproliferative disease; or signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or active primary or recurrent malignant disease; or have been in remission from clinically significant malignancy for <5 years
• have been exposed to a live vaccine within 12 weeks prior to planned randomization or are expected to need/receive a live vaccine during the course of the study (with the exception of herpes zoster vaccination)
• have a current or recent clinically serious viral, bacterial, fungal, or parasitic infection
• have had symptomatic herpes zoster infection within 12 weeks prior to study entry
• have a history of disseminated/complicated herpes zoster (eg, multidermatomal involvement, ophthalmic zoster, central nervous system involvement, postherpetic neuralgia)
• are immunocompromised and, in the opinion of the investigator, are at an unacceptable risk for participating in the study
• have a history of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
• have screening laboratory test values, including thyroid-stimulating hormone (TSH), outside the reference range for the population or investigative site that, in the opinion of the investigator, pose an unacceptable risk for the patient’s participation in the study
• have screening electrocardiogram (ECG) abnormalities that, in the opinion of the investigator or the sponsor, are clinically significant and indicate an unacceptable risk for the patient’s participation in the study
• have symptomatic herpes simplex at the time of study enrollment
• have evidence of active or latent TB as documented by a positive purified protein |
Administraçao medicamentos para a Artrite Reumatoide tais como, doses elevadas de esteróides, agentes anti-reumáticos modificadores da doença (MARMD) ou Interferão.Se tiver fibromialgia ativa ou uma condição inflamatória.Se tiver uma condição de saúde grave, antecedentes de abuso de drogas, cancro ou cirurgia recente que na opinião do médico do estudo possa implicar um aumento do risco . Se lhe tiver sido administrada uma vacina viva nas últimas 12 semanas com exceção para a vacina contra o vírus herpes zoster.
•Infeção recente grave nos últimos 30 dias.
Infeção sintomática de herpes zoster nas 12 semanas anteriores á entrada no estudo.
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E.5 End points |
E.5.1 | Primary end point(s) |
Endpoint 1: Proportion of patients achieving ACR20 (noninferiority of baricitinib monotherapy to MTX monotherapy)
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• proporção de doentes que atingem os critérios ACR20 na Semana 24, para a monoterapia com baricitinib versus monoterapia com MTX |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Enpoint 1: Week 24
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Enpoint 1: Semana 24
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E.5.2 | Secondary end point(s) |
Endpoint 2 - Proportion of patients achieving ACR20 (baricitinib plus MTX compared to MTX monotherapy)
Endpoint 3 - Change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)
Endpoint 4 - Change from baseline in DAS28-high-sensitivity C-reactive protein (hsCRP)
Endpoint 5 - Change from baseline in Modified Total Sharp Score (mTSS [van der Heijde method])
Endpoint 6 - AUC of HAQ-DI (baricitinib monotherapy compared to MTX monotherapy)
Endpoint 7 - AUC of DAS28-hsCRP (baricitinib monotherapy compared to MTX monotherapy)
Endpoint 8 -Proportion of patients achieving ACR20
Endpoint 9 - Proportion of patients achieving ACR50
Endpoint 10 - Proportion of patients achieving ACR70
Endpoint 11 - Proportion of patients achieving DAS28-hsCRP ≤3.2
Endpoint 12 - Proportion of patients achieving DAS28- hsCRP <2.6
Endpoint 13 - Proportion of patients achieving DAS28-ESR ≤3.2
Endpoint 14 - Proportion of patients achieving DAS28-ESR <2.6
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•proporção de doentes que atingem os critérios ACR20 na Semana 24, para baricitinib mais MTX versus monoterapia com MTX
•alteração desde o momento basal até à Semana 24 no resultado do Índice de Incapacidade do Questionário de Avaliação da Saúde (HAQ-DI), para baricitinib mais MTX versus monoterapia com MTX
•alteração desde o momento basal até à Semana 24 no Índice de Atividade da Doença 28 (DAS28) – proteína C reativa de alta sensibilidade (hsCRP), para baricitinib mais MTX versus monoterapia com MTX
•alteração desde o momento basal até à Semana 24 nos danos estruturais nas articulações, tal como avaliado pela Pontuação Total de Sharp modificada (mTSS [método van der Heijde]) para baricitinib mais MTX versus monoterapia com MTX
•proporção de doentes que atingem os critérios ACR20 na Semana 24, para a monoterapia com baricitinib versus monoterapia com MTX
•área sob a curva (AUC) até à Semana 24 no resultado HAQ-DI, para a monoterapia com baricitinib versus monoterapia com MTX
•AUC até à Semana 24 no resultado DAS28-hsCRP, para a monoterapia com baricitinib versus monoterapia com MTX
•alteração desde o momento basal até à Semana 24 nos danos estruturais nas articulações, tal como avaliado pela mTSS (método van der Heijde) para a monoterapia com baricitinib versus monoterapia com MTX
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Enpoints 2 to 7: Week 24
Enpoint 8: Weeks 12 and 52
Enpoints 9 to 14: Weeks 12, 24 and 52 |
Enpoints 2 to 7: Week 24
Enpoint 8: Semanas 12 e 52
Enpoints 9 a 14: Semanas 12, 24 e 52 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Austria |
Belgium |
Brazil |
Canada |
Germany |
Greece |
India |
Italy |
Japan |
Korea, Republic of |
Mexico |
Portugal |
Russian Federation |
South Africa |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial 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
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LVLS |
Ultimo doente ultima visita |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |