E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active rheumatoid arthritis |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 15.1 |
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 |
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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 4 mg QD is superior to placebo in the treatment of patients with moderately to severely active RA who have had inadequate response to or are intolerant to at least 1 cDMARD (cDMARD-IR [inadequate response] patients) and who have not received a biologic DMARD, as assessed by the proportion of patients achieving ACR20 at Week 12. |
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E.2.2 | Secondary objectives of the trial |
- change from baseline to Week 12 in Health Assessment Questionnaire-Disability Index (HAQ-DI) score
- change from baseline to Week 12 in DAS28-high-sensitivity C-reactive protein (hsCRP)
- proportion of patients achieving ACR20 at Week 12 (baricitinib 2mg compared to placebo) |
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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 |
Protocol Addendum I4V-MC-JADX(1) Approved: 22-Aug-2012:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs with Moderately to Severely Active Rheumatoid Arthritis.
ECG Addendum - Approved: 22-Aug-2012
Primary objective is to compare the change from baseline in QTcF interval at approximately 90 minutes following first dose of investigational product (Week 0) and at Week 1, Week 4, and Week 12 between baricitinib 4 mg QD and placebo.
Country-specific protocol addendum for Czech Republic - I4V-MC-JADX(3) - Approved: 06-Sep-2012:
A Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Therapy
As per local Regulation, this addendum specifies that in Czech Republic the PPD skin testing and chest x-rays conducted when screening subjects for tuberculosis will be required to be assessed by a pneumologist.
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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 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 ≥1.2 times the upper limit of normal (ULN)
• have had an insufficient response or are intolerant to cDMARDs and either:
- have had regular use of a 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
- For patients not receiving a cDMARD at the time of entry, the investigator will document in the patient’s history that the patient had failed, was unable to tolerate, or had a contraindication to treatment with a cDMARD.
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E.4 | Principal exclusion criteria |
• 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 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 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 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 lymphoproliferative 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 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 (eg, Fridericia’s corrected QT interval >500 msec)
• have symptomatic herpes simplex at the time of study enrollment
• have evidence of active or latent TB |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients achieving ACR20 response (baricitinib 4mg compared to placebo): |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- DAS28-high-sensitivity C-reactive protein (hsCRP):
- Proportion of patients achieving ACR20 response (baricitinib 2mg compared to placebo) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 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 |
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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) | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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 |
Belgium |
Canada |
Croatia |
Czech Republic |
Germany |
Hungary |
India |
Italy |
Japan |
Korea, Republic of |
Mexico |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
Spain |
Taiwan |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |