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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,307
- 试验地点
- 48
- 主要终点
- Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
- •Have any condition or contraindication for adalimumab that would preclude the participant from participating in this protocol
- •Have active fibromyalgia that 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, active vasculitis or gout(participants with secondary Sjögren's syndrome are not excluded)
- •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 that, in the opinion of the investigator in consultation with Lilly or its designee, would pose an unacceptable risk to the participant
- •Have experienced any of the following within 12 weeks of study entry: myocardial infarction, unstable ischemic heart disease, stroke, or 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 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, or 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 participant'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 participant's participation in the study
- •Have symptomatic herpes simplex at the time of study enrollment
- •Have evidence of active or latent tuberculosis (TB)
研究组 & 干预措施
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.
干预措施: Methotrexate (Drug)
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.
干预措施: Adalimumab Placebo (Drug)
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.
干预措施: Baricitinib Placebo (Drug)
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.
干预措施: Baricitinib (Drug)
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.
干预措施: Methotrexate (Drug)
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.
干预措施: Adalimumab Placebo (Drug)
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.
干预措施: Adalimumab (Drug)
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.
干预措施: Methotrexate (Drug)
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.
干预措施: Baricitinib Placebo (Drug)
结局指标
主要结局
Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)
时间窗: 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.
次要结局
- 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)