| 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 | 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 |
|
| 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. |
|
| 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 for baricitinib plus MTX versus MTX monotherapy
•change from baseline to Week 24 in DAS28–high-sensitivity C reactive protein (hsCRP) for baricitinib plus MTX versus MTX monotherapy
•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
•proportion of patients achieving ACR20 at Week 24 for baricitinib monotherapy 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
•change from baseline to Week 24 in structural joint damage as measured by mTSS for baricitinib monotherapy versus MTX monotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Entry Criteria- 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 (Aletaha et al. 2010)
•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
a.If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC for entry or enrollment purposes.
•have a C-reactive protein (or hsCRP) measurement ≥1.2 times the upper limit of normal (ULN) based on the most recent data (if available)
•have had limited or no treatment with MTX
a.Patients may have received up to 3 weeks of MTX therapy (administered as a single dose each week) and still be eligible for inclusion in this study.
•are able to read, understand, and give written informed consent
Enrollment Criteria-Inclusion 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 ≥1.2 times the ULN based on Visit 1 laboratory results by central laboratory testing
•are rheumatoid factor or anti-CCP antibody positive on screening laboratory test
|
|
| E.4 | Principal exclusion criteria |
Entry Criteria-Exclusion Criteria:
•have received conventional DMARDs other than MTX
•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 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
•have received any parenteral corticosteroid administered by IM or IV injection within 2 weeks prior to study entry or within 6 weeks prior to planned randomization
•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 would make it difficult to appropriately assess RA activity
•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 of study entry
•have experienced within 12 weeks of study entry: myocardial infarction,unstable ischemic heart disease,stroke,NYHA SIV 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
•are largely/wholly incapacitated permitting little or no self care
•have an eGFR<40 mL/min/1.73 m2
•have a history of chronic liver disease
•have lymphoproliferative disease; or signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy,splenomegaly,active primary,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 randomization or expected to need/receive a live vaccine during the study
•have a current or recent 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 household contact with a person with active TB and did not receive prophylaxis
•have evidence of active TB and did not receive treatment
•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 a history of chronic alcohol abuse,IV 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 this study and/or their families
•are Lilly or Incyte employees or either’s designee
•are currently enrolled in or have discontinued within 30 days of study entry from a clinical trial involving an IP or nonapproved use of a drug or device
Enrollment Criteria-Exclusion 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/ ,neutropenia,lymphopenia,thrombocytopenia,eGFR <40 mL/min/1.73 m2
•have screening ECG abnormalities that are clinically significant and indicate an unacceptable risk for the patient
•have symptomatic herpes simplex at the time of enrollment
•have evidence of active or latent TB
•have a positive HBV
•have HCV
•have evidence of HIV infection and/or positive HIV antibodies
•are women ≥40 and <60 years of age who have had a cessation of menses for at least 12 months, have a FSH value <40 mIU/mL, and do not agree to use 2 forms of highly effective methods of birth control
•have a known hypersensitivity to baricitinib, MTX, or any component of these products |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Proportion of patients achieving ACR20 (noninferiority of baricitinib monotherapy to MTX monotherapy)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
2.Proportion of patients achieving ACR20 (baricitinib plus MTX versus MTX monotherapy)
3.Change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)(baricitinib plus MTX versus MTX monotherapy)
4.Change from baseline in DAS28-high-sensitivity C-reactive protein (hsCRP)(baricitinib plus MTX vesrsus MTX monotherapy)
5.Change from baseline in Modified Total Sharp Score (mTSS [van der Heijde method])(baricitinib plus MTX versus MTX monotherapy)
6.Proportion of patients achieving ACR20(baricitinib monotherapy versus MTX monotherapy)
7.AUC of HAQ-DI (baricitinib monotherapy versus MTX monotherapy)
8.AUC of DAS28-hsCRP (baricitinib monotherapy versus MTX monotherapy)
9.Change from baseline in mTSS (baricitinib monotherapy versus MTX monotherapy)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
2.Week 24
3.Week 24
4.Week 24
5.Week 24
6.Week 24
7.Week 24
8.:Week 24
9.Week 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) | 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 | 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 |
|
| 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 | 5 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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