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
Overview
- Phase
- Phase 3
- Intervention
- Methotrexate
- Conditions
- Rheumatoid Arthritis
- Sponsor
- Eli Lilly and Company
- Enrollment
- 1307
- Locations
- 48
- Primary Endpoint
- Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
The purpose of this study is to determine whether baricitinib is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to methotrexate (MTX) treatment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have a diagnosis of adult-onset Rheumatoid Arthritis (RA) as defined by the American College of Rheumatology/ European League Against Rheumatism (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 (CRP) or high-sensitivity C-reactive protein (hsCRP) measurement ≥6 milligram per Liter (mg/L)
- •Have had regular use of methotrexate (MTX) for at least the 12 weeks prior to study entry at a dose that is considered acceptable to adequately assess clinical response.
- •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
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 non-steroidal anti-inflammatory drugs (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 or combination of any 3 conventional disease-modifying antirheumatic drugs (cDMARDs)
- •Are currently receiving or have received cDMARDs (eg, 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 4 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 biologic disease-modifying antirheumatic drugs (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 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
Arms & Interventions
Placebo
Placebo administered orally once daily through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Methotrexate
Placebo
Placebo administered orally once daily through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Adalimumab Placebo
Placebo
Placebo administered orally once daily through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Baricitinib Placebo
Baricitinib
Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Baricitinib
Baricitinib
Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Methotrexate
Baricitinib
Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Adalimumab Placebo
Adalimumab
Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Adalimumab
Adalimumab
Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Methotrexate
Adalimumab
Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Intervention: Baricitinib Placebo
Outcomes
Primary Outcomes
Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)
Time Frame: Week 12
ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). "ACR20 Responder" is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain due to arthritis, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinued study or drug or were rescued before analysis timepoint were deemed non-responders.
Secondary Outcomes
- Change From Baseline in the Modified Total Sharp Score (mTSS)(Baseline, Week 24)
- Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score(Baseline, Week 12)
- Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)(Baseline, Week 12)
- Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) and 70% (ACR70) Response(Week 12, Week 24, Week 52)
- Change From Baseline in Clinical Disease Activity Index (CDAI) Score(Baseline, Week 12, Week 24, Week 52)
- Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) Score ≤3.3(Week 12, Week 24, Week 52)
- Percentage of Participants Achieving American College of Rheumatology European League Against Rheumatism (ACR/EULAR) Remission - Boolean Remission(Week 12, Week 24, Week 52)
- Median of Individual Participant Mean Duration of Morning Joint Stiffness in the Prior 7 Days as Collected in Electronic Diaries(Week 12)
- Mean Severity of Morning Joint Stiffness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries(Week 12)
- Mean Worst Tiredness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries(Week 12)
- Mean Worst Joint Pain NRS in the Prior 7 Days as Collected in Electronic Diaries(Week 12)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Scores(Baseline, Week 12, Week 24, Week 52)
- Change From Baseline in Mental Component Score (MCS), Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)(Baseline, Week 12, Week 24, Week 52)
- Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores(Baseline, Week 12, Week 24, Week 52)
- Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)(Baseline, Week 12, Week 24, Week 52)
- Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores(Baseline, Week 12, Week 24, Week 52)
- Change From Baseline in Joint Space Narrowing (JSN) and Bone Erosion Scores(Baseline, Week 24, Week 52)
- Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib(Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 12; Week 24; Week 32: Pre-dose)
- Population PK: Area Under the Concentration Versus Time Curve at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib(Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 12; Week 24; Week 32: Pre-dose)