A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment With Disease-Modifying Antirheumatic Drugs
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 588
- 试验地点
- 1
- 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 therapy alone is noninferior to methotrexate (MTX) therapy alone in the treatment of moderate to severe active rheumatoid arthritis (RA) in those who have had limited or no treatment with MTX and are naive to other conventional or biologic disease-modifying antirheumatic drugs (DMARDs).
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 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) 2010 Criteria for the Classification of RA
- •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
- •Have a C-reactive protein (CRP) or high-sensitivity C-reactive protein (hsCRP) measurement ≥1.2 times the upper limit of normal (ULN)
- •Have had limited or no treatment with methotrexate (MTX)
排除标准
- •Have received conventional disease-modifying antirheumatic drugs (DMARDs) other than MTX (eg, gold salts, cyclosporine, leflunomide, azathioprine, hydroxychloroquine, sulfasalazine or any other immunosuppressives)
- •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 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
- •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 entry or are anticipated to require interferon therapy during the study
- •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 a 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 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 <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
- •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
Baricitinib
Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX placebo orally once weekly through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Baricitinib (Drug)
Baricitinib + MTX
Baricitinib 4 milligram (mg) administered orally once daily through Week 52. Participants received methotrexate (MTX) orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Baricitinib (Drug)
Baricitinib + MTX
Baricitinib 4 milligram (mg) administered orally once daily through Week 52. Participants received methotrexate (MTX) orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Methotrexate (Drug)
Baricitinib + MTX
Baricitinib 4 milligram (mg) administered orally once daily through Week 52. Participants received methotrexate (MTX) orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Folic Acid (Drug)
Baricitinib
Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX placebo orally once weekly through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: MTX Placebo (Drug)
Baricitinib
Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX placebo orally once weekly through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Folic Acid (Drug)
MTX
MTX administered orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Participants also received baricitinib placebo orally once daily. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Methotrexate (Drug)
MTX
MTX administered orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Participants also received baricitinib placebo orally once daily. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Baricitinib Placebo (Drug)
MTX
MTX administered orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Participants also received baricitinib placebo orally once daily. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly.
干预措施: Folic Acid (Drug)
结局指标
主要结局
Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)
时间窗: Week 24
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 time point were deemed non-responders.
次要结局
- Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)(Week 52)
- Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score(Baseline, Week 24)
- Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)(Baseline, Week 24)
- Change From Baseline in the Modified Total Sharp Score (mTSS)(Baseline, Week 24)
- Percentage of Participants Who Achieved a Simplified Disease Activity Index (SDAI) Score ≤3.3(Week 24)
- Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response(Week 12, Week 24, Week 52)
- Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response(Week 12, Week 24, Week 52)
- Change From Baseline in Clinical Disease Activity Index (CDAI) Score(Baseline, Week 24; Baseline, Week 52)
- Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)(Baseline, Week 24; Baseline, Week 52)
- Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission(Week 12, Week 24, Week 52)
- Change From Baseline in Joint Space Narrowing and Bone Erosion Scores(Baseline, Week 24; Baseline, Week 52)
- Change From Baseline in Duration of Morning Joint Stiffness(Baseline, Week 52)
- Change From Baseline in Worst Tiredness Numeric Rating Scale (NRS)(Baseline, Week 24; Baseline Week 52)
- Change From Baseline in Worst Joint Pain Numeric Rating Scale (NRS)(Baseline, Week 24; Baseline Week 52)
- Change From Baseline in Mental Component Score (MCS) and Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)(Baseline, Week 24; Baseline Week 52)
- Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores(Baseline, Week 24; Baseline Week 52)
- Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)(Baseline, Week 24; Baseline Week 52)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scores(Baseline, Week 24; Baseline Week 52)
- Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores(Baseline, Week 24; Baseline 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 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 24; Week 32; Pre-dose)