| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active rheumatoid arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 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 rheumatoid arthritis (RA) despite methotrexate treatment MTX-IR, as assessed by the proportion of patients achieving ACR20 at Week 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
•change from baseline to Week 12 in duration of morning joint stiffness compared to placebo as collected in electronic diaries
•change from baseline to Week 12 in severity of morning joint stiffness compared to placebo as collected in electronic diaries
•change from baseline to Week 12 in “worst tiredness” compared to placebo as collected in electronic diaries
•change from baseline to Week 12 in “worst pain” compared to placebo as collected in electronic diaries |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Entry 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 (Aletaha et al. 2010)
• 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 ≥6 mg/L
• have had regular use of MTX for at least the 12 weeks prior to study entry at a dose that, in accordance with local clinical practice, is considered acceptable to adequately assess clinical response. The dose of MTX must have been a stable, unchanging oral dose of 7.5 to 25 mg/week (or the equivalent injectable dose) for at least the 8 weeks prior to study entry.
• are able to read, understand, and give written informed consent
Enrollment Criteria:
• have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints assessed at Visit 1 and Visit 2 at the time of randomization
• have an hsCRP measurement ≥6 mg/L based on Visit 1 laboratory results by central laboratory testing
• 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 (radiographic images acquired within 4 weeks of study entry may be submitted to the central reader to confirm eligibility) |
|
| E.4 | Principal exclusion criteria |
Entry Criteria:
•are currently receiving corticosteroids at doses >10 mg of prednisone per day 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 randomization
•are currently receiving concomitant treatment with MTX, hydroxychloroquine,sulfasalazine
•are currently receiving or have received cDMARDs other than MTX, hydroxychloroquine,sulfasalazine 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 bDMARD
•have received interferon therapy within 4 weeks prior to study entry or anticipated to require interferon therapy during the study
•have received any parenteral corticosteroid administered by IM or IV inj. within 2 weeks prior entry or within 6 weeks prior to randomization or are anticipated to require parenteral inj. of corticosteroids during the study
•had 3 or more joints injected with intraarticular corticosteroids within 2 weeks prior to study entry or within 6 weeks prior to randomization
•have any condition or contraindication for adalimumab
•have active fibromyalgia that would make it difficult to appropriately assess RA activity for the study
•have a diagnosis of any systemic inflammatory condition other than RA
•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
•have experienced within 12 weeks of study entry:myocardial infarction,unstable ischemic heart disease,stroke,NYHAS4 heart failure
•have a history or presence of cardiovascular,respiratory, hepatic,gastrointestinal,endocrine,hematological,neurological, neuropsychiatric disorders or any other serious and/or unstable illness
•are largely/wholly incapacitated permitting little/no self-care
•have an eGFR<40 mL/min/1.73m2
•have a history of chronic liver disease
•have a history of, lymphoproliferative disease or signs or symptoms suggestive of possible lymphoproliferative disease 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 randomization or are expected to receive a live vaccine during the study
•have a current/recent clinically serious viral,bacterial,fungal, parasitic infection
•have had symptomatic herpes zoster infection within 12 weeks prior to study entry
•have a history of disseminated/complicated herpes zoster
•are immunocompromised
•have a history of active HBV,HCV,HIV
•have had contact with a person with active TB and did not receive prophylaxis
•have evidence of active TB and did not receive TRT
•are pregnant,nursing
•are females of childbearing potential who do not agree to use 2 forms of highly effective birth control
•are males who do not agree to use 2 forms of highly effective birth control
•have donated >500 mL of blood within 30 days prior to study entry
•have history of chronic alcohol abuse,intravenous drug abuse,other illicit drug abuse within the 2 years prior to study entry
•have previously been randomized in this study or any other study
investigating baricitinib
•are unable or unwilling to make themselves available for the duration of the study
•have received prior treatment with an oral JAK inhibitor
•are investigator site personnel affiliated with the study and/or their families
•are Lilly,Incyte employees, either’s designee
•are currently enrolled in or have discontinued within 30 days of study entry from a clinical trial with an IP or nonapproved use of a drug or device
Enrollment Criteria:
•have screening laboratory test values, including TSH,outside the reference range
•have any of the following specific abnormalities on screening laboratory tests:AST or ALT >1.5 times the ULN,total bilirubin ≥1.5 times the ULN,hemoglobin <10.0 g/dL,total white blood cell count <2500 cells/L, neutropenia,lymphopenia,thrombocytopenia,eGFR<40mL/min/1.73m2
•have screening ECG abnormalities which are clinically significant and indicate risk for patients
•have symptomatic herpes simplex during the enrollment
•have evidence of active or latent TB
•have a positive test for HBV
•have HCV
•have evidence of HIV infection and/or positive HIV antibodies
•Are women ≥40 and <60 years with a cessation of menses for at least 12 months, have FSH value<40mIU/mL, and do not agree to use 2 forms of methods of birth control,unless they are congenitally or surgically sterile.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients achieving ACR20 response compared to placebo . |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Change from baseline to Week 12. |
|
| E.5.2 | Secondary end point(s) |
1.Modified Total Sharp Score (mTSS [van der Heijde method])
2.Health Assessment Questionnaire-Disability Index (HAQ-DI)
3.DAS28-high-sensitivity C-reactive protein (hsCRP)
4.Proportion of patients achieving ACR20 compared to adalimumab
5.Duration of morning joint stiffness compared to
placebo as collected in electronic diaries
6.Severity of morning joint stiffness compared to
placebo as collected in electronic diaries
7.“Worst tiredness” compared to placebo as collected
in electronic diaries
8.“Worst pain” compared to placebo as collected in
electronic diaries |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Modified Total Sharp Score (mTSS): change from baseline to Week 24
2.Health Assessment Questionnaire-Disability Index (HAQ-DI):change from baseline to Week 12
3.DAS28-high-sensitivity C-reactive protein (hsCRP):change from baseline to Week 12
4.Proportion of patients achieving ACR20:at Week 12
5.Duration of morning joint stiffness compared to
placebo as collected in electronic diaries:change from baseline to Week 12
6.Severity of morning joint stiffness compared to
placebo as collected in electronic diaries:change from baseline to Week 12
7.“Worst tiredness” compared to placebo as collected
in electronic diaries:change from baseline to Week 12
8.“Worst pain” compared to placebo as collected in
electronic diaries:change from baseline to Week 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 | 3 |
| 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 |
| Belgium |
| Canada |
| China |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 28 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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