A Study of Baricitinib (LY3009104) in Participants With Rheumatoid Arthritis (RA)

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as baricitinib in participants with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate therapy.

Official Title
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A Randomized, Double-Blind, Placebo-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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Baricitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of adult-onset RA as defined by the ACR/European League Against Rheumatism (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 CRP (or hsCRP) measurement ≥ 6 mg/liter (L) based on the most recent data (if available). 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. The dose of MTX is expected to remain stable throughout the study and may be adjusted only for safety reasons. 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 within 2 weeks of study entry or within 6 weeks of planned randomization 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 or combination of any 3 conventional disease modifying anti-rheumatic drugs (cDMARDs). Are currently receiving or have received cDMARDs (for example, 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 (or within 4 weeks prior to study entry if the standard 11 days of cholestyramine is used to washout leflunomide). Have started a new physiotherapy treatment for RA in the 2 weeks prior to study entry. Have ever received any biologic DMARD (such as tumor necrosis factor (TNF), interleukin-1, interleukin-6 (IL-6), or T-cell- or B-cell-targeted therapies). 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 or hyaluronic acid within 2 weeks prior to study entry or within 6 weeks prior to planned randomization. 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, active vasculitis or gout. Have an estimated glomerular filtration rate (eGFR) based on the most recent available serum creatinine using the Modification of Diet in Renal Disease (MDRD) method of <40 milliliters/minute/1.73 meters squared (m^2). Have a history of chronic liver disease with the most recent available aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN) or the most recent available total bilirubin 1.5 times the ULN. Have a current or recent (<30 days prior to study entry) clinically serious viral, bacterial, fungal, or parasitic infection. Have a history of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Have had household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB. Have evidence of active TB or have previously had evidence of active TB and did not receive appropriate and documented treatment. Are pregnant or nursing at the time of study entry. Are females of childbearing potential who do not agree to use 2 forms of highly effective birth control when engaging in intercourse while enrolled in the study and for at least 28 days following the last dose of orally administered investigational product. Are males who do not agree to use 2 forms of highly effective birth control while engaging in sexual intercourse with female partners of childbearing potential while enrolled in the study and for at least 28 days following the last dose of orally administered investigational product. Have previously been randomized in this study or any other study investigating baricitinib. Have received prior treatment with an oral janus kinase inhibitor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baricitinib<br>4 milligrams (mg) baricitinib administered orally once a day for 52 weeks. Participants with renal impairment will receive 2 mg baricitinib orally once a day for 52 weeks. Participants will continue to take background methotrexate (MTX) therapy throughout study. Other background therapies, including non-steroidal anti-inflammatory drugs (NSAIDs) and low dose oral corticosteroids, are permitted during the study for participants who are on stable doses of these treatments at baseline. | Drug: Baricitinib<br>* Administered orally<br>* Other names: INCB 028050;|
| Placebo Comparator: Placebo<br>Placebo administered orally once a day through week 24. At week 24, participants will be given 4 mg or 2 mg (participants with renal impairment) baricitinib orally once a day through Week 52. Participants will continue to take background MTX therapy throughout study. Other background therapies, including NSAIDs and low dose oral corticosteroids, are permitted during the study for participants who are on stable doses of these treatments at baseline. | Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 20% Improvement in American College of Rheumatology Criteria (ACR20) | ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). An ACR20 Responder is a participant who had ≥20% improvement from baseline in both 68 tender and 66 swollen joint counts and ≥20% improvement in at least 3 of 5 criteria: Patient's and Physician's Global Assessment of Disease Activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) (assessment of participant's physical function), pain due to RA, and hsCRP. Participants who discontinue before analysis time point are treated as non-responders. Percentage of participants achieving ACR20 response = (number of ACR20 responders) / (number of participants analyzed) * 100. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in the Health Assessment Questionnaire Disability Index (HAQ-DI) Score | The HAQ-DI questionnaire assesses the participant's self-perception on the degree of difficulty [0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area were averaged to calculate HAQ-DI scores, which ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition. | Baseline, Week 12 | 
| Change From Baseline to Week 12 in Disease Activity Score Modified to Include the 28 Diarthroidal Joint Count (DAS28)-High Sensitivity C-Reactive Protein (hsCRP) | Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count-28 (TJC28), swollen joint count-28 (SJC28), CRP (mg/L), and Patient's Global Assessment of Disease Activity using VAS (patient's global VAS). DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*patient's global VAS+0.96. Scores ranged from 1.0-9.4, where lower scores indicated less disease activity, and remission was DAS28-CRP <2.6. A decrease in DAS28-CRP indicated an improvement in participant's condition. | Baseline, Week 12 | 
| Proportion of Participants Achieving a Simplified Disease Activity Index (SDAI) Score < or Equal to 3.3 | SDAI is a tool for measurement of disease activity in RA that integrates TJC28, SJC28, acute phase response using C-reactive protein (milligrams per liter), Participant's Global Assessment of Disease Activity using VAS centimeters (cm), and Physician's Global Assessment of Disease Activity using VAS (cm). The SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. An index-based definition of remission occurs with an SDAI score ≤3.3. | Week 12 | 
| Median Duration of Morning Joint Stiffness in the 7 Days Prior to Week 12 | Participants recorded the duration of their morning joint stiffness (MJS) in hours and minutes into paper diaries daily. If morning joint stiffness duration was longer than 12 hours (720 minutes), it was truncated to 720 minutes for statistical presentations and analyses. The average value across the 7 days preceding each visit was calculated. A decrease in duration of morning joint stiffness indicated an improvement in the participant's condition. | Week 12 | 
| Mean Severity of Morning Joint Stiffness in the 7 Days Prior to Week 12 | Participants rated the severity of their morning joint stiffness by selecting a number from 0 to 10 that best described their overall level of morning joint stiffness from the time they woke up, where 0 represents no joint stiffness and 10 represents joint stiffness as bad as you can imagine. Participants reported their severity daily in paper diaries. The average value across the 7 days preceding each visit was calculated. | Week 12 | 
| Mean Worst Tiredness Numeric Rating Scale (NRS) in the 7 Days Prior to Week 12 | Participants rated their tiredness by selecting a number from 0 to 10 that best described their worst tiredness during the last 24 hours, where 0 represents no tiredness and 10 represents as bad as you can imagine. Participants reported their worst tiredness in paper diaries. The average value across the 7 days preceding each visit is calculated. | Week 12 | 
| Mean Worst Pain NRS in the 7 Days Prior to Week 12 | Participants rated their joint pain by selecting a number from 0 to 10 that best described their worst joint pain during the last 24 hours, where 0 represents no pain and 10 represents pain as bad as you can imagine. Participants reported their worst joint pain in daily paper diaries. The average value across the 7 days preceding each visit was calculated. | Week 12 |