| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active rheumatoid arthritis |
| Artrite reumatoide ativa moderada a grave |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis |
| Artrite reumatoide |
|
| 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 |
|
| 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 is superior to placebo in the treatment of patients with moderately to severely active RA despite MTX treatment (i.e., MTX IR), as assessed by the proportion of patients achieving ACR20 at Week 12. |
| determinar se o baricitinib é superior ao placebo, no tratamento de doentes com artrite reumatoide (AR) moderada a gravemente ativa, apesar do tratamento com metotrexato (ou seja, resposta inadequada ao metotrexato [MTX-IR]), conforme avaliado pela proporção de doentes que atingem uma melhoria de 20% nos critérios do American College of Rheumatology (ACR20) na Semana 12. |
|
| E.2.2 | Secondary objectives of the trial |
? change from baseline to Week 24 in structural joint damage as measured by modified Total Sharp Score (mTSS [van der Heijde method]) compared to placebo
? change from baseline to Week 12 in Health Assessment Questionnaire-Disability Index (HAQ-DI) score compared to placebo
? change from baseline to Week 12 in DAS28-high-sensitivity C-reactive protein (hsCRP) compared to placebo
? proportion of patients achieving ACR20 response at Week 12 compared to adalimumab
? proportion of patients achieving DAS28-hsCRP ?3.2 and DAS28-hsCRP <2.6 at Week 12, Week 24, and Week 52
? change from baseline to Week 16 and Week 52 in structural joint damage as measured by mTSS
? proportion of patients achieving DAS28-ESR ?3.2 and DAS28-ESR <2.6 at Week 12, Week 24, and Week 52 |
•alteração momento basal á Sem24 danos estruturais nas articulações, pela Pontuação Total Sharp modificada (mTSS [método van der Heijde] comparação c/ placebo
•alteração momento basal à Sem12 Índice deIncapacidade Quest Avaliação Saúde HAQ-DI comparação c/ placebo
•alteração momento basal à Sem12 Índice de Atividade Doença modificado inclui contagem 28 articulações diartroidais DAS28 proteína C reativa alta sensibilidade (hsCRP) comparação c/ placebo •proporção de doentes atingem resposta ACR20 Sem 12, comparação adalimumab •alteração momento basal Sem12 duração rigidez matinal articulações comparação c/placebo, informações diarios eletr
•alteração momento basal Sem12 gravidade rigidez matinal articulações comparação c/ placebo, informações dos diarios eletrónicos
•alteração momento basal Sem12"pior fadiga" comparação c/ placebo, informações diarios eletrónicos
•alteração desde momento basalSem12 "pior dor”
comparação c/placebo, informações dosdiarios eletrónicos
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
?are at least 18 years of age
?have a diagnosis of adult-onset RA as defined by the ACR/EULAR 2010 Criteria for the Classification of RA
?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 (CRP) (or hsCRP) measurement >= 6mg/L times the upper limit of normal (ULN)
?have had regular use of MTX for at least the 12 weeks prior to study entry at a dose that is considered acceptable to adequately assess clinical response.
?have at least 1 joint erosion in hand, wrist, or foot joints based on radiographic interpretation by the central reader and be rheumatoid factor or anticyclic citrullinated peptide (anti-CCP) antibody positive; or have at least 3 joint erosions in hand, wrist, or foot joints based on radiographic interpretation by the central reader regardless of rheumatoid factor or anti-CCP antibody status |
• 18 anos de idade ou mais.
•Diagostico de artrite reumatóide (AR) com início na idade adulta.
•As radiografias às mãos e aos pés tem que mostrar que as articulações foram danificadas pela AR e o resultado da análise laboratorial tem que ser positivo para AR.
•Estar actualmente a receber tratamento concomitante com metotrexato (MTX).
|
|
| E.4 | Principal exclusion criteria |
? are currently receiving corticosteroids at doses >10 mg of prednisone per day (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
? are currently receiving concomitant treatment with MTX, hydroxychloroquine, and sulfasalazine
? are currently receiving or have received cDMARDs (eg, gold salts, cyclosporine, azathioprine, or any other immunosuppressives) other than MTX, hydroxychloroquine (up to 400 mg/day), or sulfasalazine (up to 3000 mg/day) within 8 weeks prior to study entry
? have received leflunomide in the 12 weeks prior to study entry 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 injection within 2 weeks prior to study entry or within 6 weeks prior to planned randomization or are anticipated to require 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 any condition or contraindication for adalimumab that would preclude the patient from participating in this protocol
? have active fibromyalgia that 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 Sjögren?s syndrome are not excluded.
? have a diagnosis of Felty?s syndrome
? have had any major surgery within 8 weeks prior to 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, 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 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, or 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 |
• Administraçao de outros medicamentos para a AR, como por exemplo doses elevadas de esteróides, medicamentos anti-reumáticos modificadores da doença (MARMD) ou Interferão. •Alguma vez ter recebido qualquer MARMD biológico (como por exemplo o factor de necrose tumoral (TNF), interleucina-1, interleucina-6 (IL-6), ou terapêutica dirigidas aos linfócitos T ou aos
linfócitos B).
• Ter levado injecções de corticosteróides intra-articulares em três ou mais articulações.
• Ter fibromialgia activa ou uma doença inflamatória.
• Ter um problema de saúde grave, história de abuso de substâncias, cancro ou cirurgia recente que, na opinião do médico do estudo, constituam um risco aumentado .
•Exposiçao a uma vacina viva nas últimas 12 semanas, à excepção da vacina do herpes zoster.
•Infecção grave recente, nos últimos 30 dias.
•Infecção sintomática por herpes zoster (“zona”) nas 12 semanas anteriores à entrada no estudo.
•História de herpes zoster disseminado/complicado.
•História de hepatite B activa, vírus da hepatite C, tuberculose (TB) ou VIH
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients achieving ACR20 response compared to placebo . |
| determinar se o baricitinib é superior ao placebo, no tratamento de doentes com artrite reumatóide (AR) ativa moderada a grave, apesar do tratamento com metotrexato (ou seja, resposta inadequada ao metotrexato [MTX-IR]), conforme avaliado pela proporção de doentes que atingem uma melhoria de 20% nos critérios do American College of Rheumatology (ACR20) na Semana 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Change from baseline to Week 12. |
| Alteraçoes desde o momento basal até ás 12 semanas |
|
| E.5.2 | Secondary end point(s) |
- Modified Total Sharp Score (mTSS [van der Heijde method])
- Health Assessment Questionnaire Disability Index (HAQ-DI)
- DAS28-high-sensitivity C-reactive protein (hsCRP)
- Proportion of patients achieving ACR50 and ACR70 response
- proportion of patients achieving DAS28-hsCRP ?3.2; proportion of patients achieving DAS28- hsCRP <2.6
- proportion of patients achieving ACR20 response compared to adalimumab
- proportion of patients achieving DAS28-ESR ?3.2; proportion of patients achieving DAS28-ESR <2.6 |
• 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]) em comparação com o placebo
• alteração desde o momento basal até à Semana 12 no resultado do Índice de Incapacidade do Questionário de Avaliação da Saúde (HAQ-DI), em comparação com o placebo
• alteração desde o momento basal até à Semana 12 no Índice de Atividade da Doença modificado para incluir a contagem de 28 articulações diartroidais (DAS28) – proteína C reativa de alta sensibilidade (hsCRP), em comparação com o placebo
• proporção de doentes que atingem a resposta de ACR20 na Semana 12, em comparação com o adalimumab
• alteração desde o momento basal até à Semana 12 na duração da rigidez matinal das articulações em comparação com o placebo, conforme informações recolhidas nos diários eletrónicos
• alteração desde o momento basal até à Semana 12 na gravidade da rigidez matinal das articulações em comparação com o placebo, conforme informações recolhidas nos diários eletrónicos
• alteração desde o momento basal até à Semana 12 na "pior fadiga" em comparação com o placebo, conforme informações recolhidas nos diários eletrónicos
• alteração desde o momento basal até à Semana 12 na "pior dor” em comparação com o placebo, conforme informações recolhidas nos diários eletrónicos
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Modified Total Sharp Score (mTSS [van der Heijde method]): Change from baseline to Week 24 and 52
- Health Assessment Questionnaire Disability Index (HAQ-DI): Change from baseline to Week 12
- DAS28-high-sensitivity C-reactive protein (hsCRP): Change from baseline to Week 12
- Proportion of patients achieving ACR50 and ACR70 response: Change from baseline to Week 12, 24 and 52
- proportion of patients achieving DAS28-hsCRP ?3.2; proportion of patients achieving DAS28- hsCRP <2.6: Weeks 12, 24 and 52
- proportion of patients achieving ACR20 response compared to adalimumab: Weeks 12
- proportion of patients achieving DAS28-ESR ?3.2; proportion of patients achieving DAS28-ESR <2.6: Weeks 12, 24 and 52 |
Pontuaçao Total de Sharp modificada: Alteraçao observada entre o momento basal e a semana 24
-pontuaçao do Índice de Discapacidade questionario de avaliaçao da
Saude (HAD-DI): alteraçao observada entre o momento basal e a semana 12
- Pontuaçao DAS28- proteína C reactiva de alta sensibilidade: alteraçao observada entre o momento basal e a semana 12
- A Proporçao de doentes que alcancem uma resposta ACR20 na semana 12.
- Duraçao da rigidez articular matutina:alteraçao entre a o momento basal e a semana 12-
- Em relaçao á intensidad e e rigidez articular matutina: alteraçao entre a visita basal e a semana 12
- em relaçao com o cansaço mais intenso": alteraçao entre o momento basal e a semana 12 |
|
| 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 | Yes |
| 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 | 67 |
| 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 |
| Australia |
| Belgium |
| Canada |
| China |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Japan |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| LVLS |
| Ultima visita ultimo doente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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