A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Tumor Necrosis Factor Inhibitors
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 527
- 试验地点
- 1
- 主要终点
- Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response - Placebo Versus Baricitinib 4 mg
研究概览
简要总结
The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to a tumor necrosis factor (TNF) inhibitor, despite ongoing treatment with conventional disease-modifying antirheumatic drugs (cDMARDs).
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 ≥ (greater than or equal to) 1 times the upper limit of normal (ULN)
- •Have been treated at approved doses with at least 1 biologic tumor necrosis factor (TNF)- alpha inhibitor for at least 3 months and either:
- •experienced insufficient efficacy or loss of efficacy
- •experienced intolerance of such treatment
- •Have had regular use of at least 1 conventional disease-modifying antirheumatic drugs (cDMARD) for at least the 12 weeks prior to study entry with a continuous, nonchanging dose for at least 8 weeks prior to study entry
排除标准
- •Have received a biologic treatment for RA within 28 days of planned randomization; have received rituximab within 6 months of planned randomization
- •Are currently receiving corticosteroids at doses > (greater than) 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 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 methotrexate (MTX), hydroxychloroquine, and sulfasalazine or combination of any 3 cDMARDs
- •Have received any parenteral corticosteroid administered by intramuscular or intravenous (IV) 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 active fibromyalgia that, in the investigator's opinion, 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 Sjogren's syndrome are not excluded.)
- •Have a diagnosis of Felty's syndrome
- •Have had any major surgery within 8 weeks of 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 have 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 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 < (less than) 40 milliliter per minute per 1.73 m^2 (mL/min/1.73 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 ULN or the most recent available total bilirubin ≥1.5 times the ULN
- •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, 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 (e.g. Fridericia's corrected QT interval >500 millisecond [msec])
- •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. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 milligram (mg) orally once daily through Week 24.
Participants will continue to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study.
干预措施: Placebo (Drug)
Placebo
Placebo administered orally once daily through Week 24. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 milligram (mg) orally once daily through Week 24.
Participants will continue to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study.
干预措施: cDMARD (Drug)
Baricitinib 2 mg
Baricitinib 2 mg administered orally once daily through Week 24. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 24.
Participants will continue to take background cDMARD therapy throughout study.
干预措施: Baricitinib (Drug)
Baricitinib 2 mg
Baricitinib 2 mg administered orally once daily through Week 24. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 24.
Participants will continue to take background cDMARD therapy throughout study.
干预措施: cDMARD (Drug)
Baricitinib 4 mg
Baricitinib 4 mg administered orally once daily through Week 24. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 24.
Participants will continue to take background cDMARD therapy throughout study.
干预措施: Baricitinib (Drug)
Baricitinib 4 mg
Baricitinib 4 mg administered orally once daily through Week 24. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 24.
Participants will continue to take background cDMARD therapy throughout study.
干预措施: cDMARD (Drug)
结局指标
主要结局
Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response - Placebo Versus Baricitinib 4 mg
时间窗: Week 12
ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. 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 discontinue study or drug or are rescued before analysis timepoint are deemed non-responders.
次要结局
- Change From Baseline in the Disease Activity Score Based on a 28-Joint Count (DAS-28) High Sensitivity C-Reactive Protein (hsCRP) - Placebo Versus Baricitinib 4 mg(Baseline, Week 12)
- Change From Baseline in HAQ-DI Score - Placebo Versus Baricitinib 4 mg(Baseline, Week 12)
- Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission - Simplified Disease Activity Index (SDAI) ≤3.3 - Placebo Versus Baricitinib 4 mg(Week 12)
- Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response(Week 12 and Week 24)
- Change From Baseline in DAS28 - Erythrocyte Sedimentation Rate (ESR)(Baseline, Week 12)
- Percentage of Participants Achieving ACR20 Response - Placebo Versus Baricitinib 2 mg(Week 12)
- Change From Baseline in HAQ-DI Score - Placebo Versus Baricitinib 2 mg(Baseline, Week 12)
- Change From Baseline in the DAS28 - hsCRP - Placebo Versus Baricitinib 2 mg(Baseline, Week 12)
- Percentage of Participants Achieving ACR/EULAR Remission - SDAI ≤3.3 - Placebo Versus Baricitinib 2 mg(Week 12)
- Percentage of Participants Achieving ACR20 Response(Week 24)
- Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response(Week 12 and Week 24)
- Change From Baseline in Clinical Disease Activity Index Score(Baseline, Week 24)
- Change From Baseline in Measures of SDAI Score(Baseline, Week 24)
- Percentage of Participants Achieving ACR/EULAR Remission - Boolean Remission(Week 24)
- Change From Baseline in Duration of Participant Reported Outcome - Morning Joint Stiffness(Baseline, Week 24)
- Change From Baseline in Worst Tiredness Numeric Rating Scale (NRS)(Baseline, Week 24)
- Change From Baseline in Worst Joint Pain NRS(Baseline, Week 24)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale Scores(Baseline, Week 12, Week 24)
- 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)
- Change From Baseline in European Quality of Life-5 Dimensions-5 Level Scores(Baseline, Week 12, Week 24)
- Percentage Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores(Baseline, Week 12, Week 24)
- Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of Baricitinib(Week 0 (Baseline): 15 min. post-dose, 1 hour post-dose. Week 4 (Day 28 ±2 days): 2 to 4 hours post-dose. Week 8 (Day 56 ±3 days): 4 to 6 hours post-dose. Week 12 (Day 84 ±3 days): Pre-dose. Week 24 (Day 168 ±5 days): Pre-dose.)
- Population PK: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib(Week 0 (Baseline): 15 min. post-dose, 1 hour post-dose. Week 4 (Day 28 ±2 days): 2 to 4 hours post-dose. Week 8 (Day 56 ±3 days): 4 to 6 hours post-dose. Week 12 (Day 84 ±3 days): Pre-dose. Week 24 (Day 168 ±5 days): Pre-dose.)