E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active rheumatoid arthritis |
Artrite reumatoide attiva da moderata 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 | 14.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10028395 |
E.1.2 | Term | Musculoskeletal and connective tissue disorders |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
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 4 mg QD is superior to placebo in the treatment of patients with moderately to severely active RA who have had an inadequate response to a TNF inhibitor, despite ongoing treatment with cDMARDs, as assessed by the proportion of patients achieving ACR20 at Week 12. |
L’obiettivo primario dello studio è determinare se baricitinib 4 mg QD sia superiore a placebo nel trattamento dei pazienti affetti da AR attiva da moderata a grave che hanno presentato una risposta inadeguata a un inibitore del TNF, nonostante il trattamento in corso con cDMARD, determinato in base alla percentuale di pazienti che hanno raggiunto un miglioramento del 20% nei criteri dell’American College of Rheumatology (ACR20) dopo 12 settimane. |
|
E.2.2 | Secondary objectives of the trial |
- change from baseline to Week 12 in Health Assessment Questionnaire- Disability Index (HAQ-DI) score (baricitinib 4mg compared to placebo) - change from baseline to Week 12 in DAS28-high-sensitivity C-reactive protein (hsCRP) (baricitinib 4mg compared to placebo) - proportion of patients achieving ACR20 at Week 12 (baricitinib 2mg compared to placebo) - change from baseline to Week 12 in HAQ-DI score (baricitinib 2mg compared to placebo) - change from baseline to Week 12 in DAS28-hsCRP (baricitinib 2mg compared to placebo) |
Gli obiettivi secondari principali dello studio sono: • valutare l’efficacia di baricitinib 4 mg QD rispetto a placebo, determinata come: o variazione dal basale alla settimana 12 del punteggio HAQ-DI (Health Assessment Questionnaire-Disability Index) o variazione dal basale alla settimana 12 del punteggio DAS28 (Disease Activity Score 28) – proteina C reattiva ad alta sensibilità (hsCRP) • valutare l’efficacia di baricitinib 2 mg QD rispetto a placebo, determinata come: o percentuale di pazienti che raggiungono la risposta ACR20 alla settimana 12 o variazione dal basale alla settimana 12 del punteggio HAG-DI o variazione dal basale alla settimana 12 di DAS28-hsCRP. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 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 (or hsCRP) measurement ≥1 times the upper limit of normal (ULN) • have been treated at approved doses with at least 1 biologic TNF- α inhibitor and either:- experienced insufficient efficacy or loss of efficacy - experienced intolerance of such treatment • have had regular use of at least 1 cDMARD for at least the 12 weeks prior to study entry with a continuous, nonchanging dose for at least 8 weeks prior to study entry |
-almeno 18 anni di età - diagnosi di Artrite reumatoide adult-onset definita dai criteri ACR/EULAR 2010 -AR da moderata a severa definita dalla presenza di 6/68 articolazioni molli e almeno 6/66 articolazioni tumefatte-livelli di proteina c reattiva > o uguali ad 1 ULN - precedente trattamento con almeno 1 biologico inibitore dell'Alfa TNF:efficacia insufficiente o mancante - precedente terapia con almeno 1 cDMARD per almeno 12 settimane prima dell'entrata in studio con una dose continua, stabile per almeno 8 settimane prima dell'entrata in studio. |
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E.4 | Principal exclusion criteria |
• have received a biologic treatment for RA within 28 days of planned randomization• 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• are currently receiving concomitant treatment with MTX,hydroxychloroquine, and sulfasalazine• 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 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 - 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 have 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 have signs or symptoms suggestive of possible phoproliferative disease,including lymphadenopathy or splenomegaly; or have 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 |
-trattamento con un biologico entro i 28 giorni dalla randomizzazione - in trattamento con corticosteroidi > 10 mg al giorno, prednisone o equivalente, o ne abbiano ricevuto una dose non stabile nelle 2 settimane dall'ingfresso in studio e nelle 6 precedenti la randomizzazione - inizio di una terapia con NSAIDs entro le 2 settimane dall'ingresso in studio o nelle 6 settimane precedenti la randomizzazione - in trattamento con MTX, idrossiclorochina e sulfasazine - somministrazione parenterale di corticosteroidi intramuscolo o endovena entro le 2 settimane dall'ingresso in studio o entro le 6 settimane prima della randomizzazione - iniezione di corticosteroidi a 3 o più articolazioni entro le 2 settimane dall'ingresso in studio o nelle 6 precedenti la randomizzazione - fibromialgia attiva - disagnosi di qualsiasi condizione sistemica infiammatoria oltre all'AR - diagnosi di sindrome di Felty- Intervento chirurginìco nelle 8 settimane precedenti l'ingresso in studio- infarto del miocardio, patologie cardiache ischemiche instabili, stroke, etc nelle 12 settimane precedenti l'ingresso in studio - patologie cardiovascolari, respiratorie, epatiche, gastrointestinali, endocrine, ematologiche, neurologiche o neuropsichiatriche o qualsiasi altra patologia che possa costituire un rischio per l'assunzione del farmaco o con l'interpretazione dei dati -eGFR basato sul più recente valore di creatinina sierica valutato usando il metodo MDRD < 40 mL/min/1.73 m2 - anamnesi di patologie epatiche croniche AST o ALT > 1.5 ULN o Bilirubina > 1.5 ULN - anamnesi di patologie linfoproliferative - vaccinazione live nelle 12 settimane prima della randomizzazione - attuale o recente infezione virale seria, batterica, fungina o parassitaria - infezione da Herpes Zooster nelle 12 settimane precedenti l'ingresso in studio - complicazioni da Herpes Zooster - soggetti immunocompromessi - anamnesi di HBV, HCV o HIV attive - TSH fuori dai ranges - ECG non nei limiti della norma - Herpes Simplex sintomatico - attiv a latente TB |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients achieving ACR20 response (baricitinib 4mg compared to placebo) |
Percentuele dei pazienti che raggiungono la risposta ACR20 (Baricitinib 4mg vs placebo) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Health Assessment Questionnaire-Disability Index (HAQ-DI) score - DAS28-high-sensitivity C-reactive protein (hsCRP) - Proportion of patients achieving ACR20 response (baricitinib 2mg compared to placebo) - Proportion of patients achieving ACR20 response - 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 DAS28-ESR ≤3.2; proportion of patients achieving DAS28- ESR <2.6 |
-Questionario di valutazione per lindice di disabilità (HAQ-DI) -DAS28-High-Sensitivity proteina C reattiva (hsCRP) - Porzione di pazienti che raggiungona la ACR20 (bvaricitinib 2 mg vs placebo) - porzione di pazienti che raggiungono la ACR20 -Porzione di pazienti che raggiungono la ACR 50 e ACR 70 - porzione di pazienti che raggiungono la DAS28-hsCRP> o uguale 3.2; porzione di pazienti che raggiungono una DAS28 - ESR < 2.6 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Health Assessment Questionnaire-Disability Index (HAQ-DI) score: Change from baseline to Weeks 12 and 24 - DAS28-high-sensitivity C-reactive protein (hsCRP): Change from baseline to Weeks 12 and 24 - Proportion of patients achieving ACR20 response (baricitinib 2mg compared to placebo): Week 12 XML File Identifier: VJPsbbVN4tTxude5VbJxE+29JUk= Page 16/29 - Proportion of patients achieving ACR20 response: Week 24 - Proportion of patients achieving ACR50 and ACR70 response: Weeks 12 and 24 - proportion of patients achieving DAS28-hsCRP ≤3.2; proportion of patients achieving DAS28- hsCRP <2.6: Weeks 12 and 24 - proportion of patients achieving DAS28-ESR ≤3.2; proportion of patients achieving DAS28- ESR <2.6: Weeks 12 and 24 |
- Questionario di valutazione per l'indice di disabilità: variazioni dal baseline alle settimane 12 e 24 -DAS28 high sensitivity della proteina C reattina (hsCRP): variazioni dal basale alle settimane 12 e 24 - porzione di pazienti che raggiungono la ACR20(baricitinib vs placebo: settimana 12 -porzione di pazienti che raggiungono la ACR20: settimana 24 -porzione di pazienti che raggiungono la ACR50 e ACR70: settimane 12 e 24 -porzione di pazienti che raggiungono il valore DAS28-hsCRP> o uguale 3.2;porzione di pazienti che raggiungono il valore DAS28-hsCRP>2.6: settimana 12 e 24 -porzione di pazienti che raggiungona la DAS28-ESR<2.6: settimane 12 e 24 |
|
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) | No |
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 | 50 |
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 |
Canada |
Croatia |
India |
Israel |
Japan |
Korea, Republic of |
Mexico |
Turkey |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 23 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 26 |
E.8.9.2 | In all countries concerned by the trial days | 0 |