A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel-Group, Phase 2b Study of LY3009104 in Patients With Active Rheumatoid Arthritis on Background Methotrexate Therapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 301
- 试验地点
- 1
- 主要终点
- Percentage of Participants in the 4 mg and 8 mg Dose Groups Who Achieved an American College of Rheumatology 20 (ACR20) Responder Index Response Baseline Through Week 12
研究概览
简要总结
The purpose of this trial is to evaluate the safety and efficacy of LY3009104 in participants with Rheumatoid Arthritis (RA).
详细描述
This study consists of the following:
- Screening period: 4 to 28-days
- Part A: a 12-week blinded, placebo controlled treatment period
- Part B: a 12-week blinded extension period
- Part C: an optional 52-week open-label extension period
- Part D: an additional optional 52-week open-label extension period
- Follow up period: 28 days
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must have active RA
- •Must regularly use methotrexate (MTX) for at least 12 weeks before your participation in this study
- •Must have American College of Rheumatology (ACR) functional class I, II, or III
- •Must have C-reactive protein (CRP) measurement > 1.2 times upper limit of normal (ULN) or Erythrocyte Sedimentation Rate (ESR) > ULN [28 millimeters/hour (mm/hr)]
- •Have laboratory values that in the opinion of the investigator do not pose an unacceptable risk to the participants if study drug would be administered
- •Must have venous access sufficient to allow blood sampling as per the protocol
- •Must be reliable and willing to be available for the duration of the study and are willing to follow study procedures
- •Must be able to read, understand, and give written informed consent approved by Lilly or its designee and the ethical review board (ERB) governing the site
- •Male participants: agree to use 2 forms of highly effective methods of birth control with female partners of childbearing potential during the study
- •If you are a woman and you could become pregnant during this study, you must talk to the study doctor about birth control. You are required to use 2 forms of highly effective methods of birth control to avoid getting pregnant during the study
- •If you are a post-menopausal woman, you must be at least 45 years of age and have not menstruated for the last 12 months
- •If you are a woman between 40 and 45 years of age, test negative for pregnancy, and have not menstruated during the last 12 months only, you must have an additional blood test
- •For participants receiving corticosteroids, you must be on a dose not to exceed 10 mg of prednisone daily (or equivalent) and have been on the same dosing regimen for at least 6 weeks prior to randomization
- •Continue to meet inclusion criteria for Parts A and B as applicable
- •Part D only: have completed the 52 weeks (Week 24 to Week 76) of participation in Part C of the study without permanent study drug discontinuation and have not completed the Follow-Up Visit (approximately 28 days after the last dose of study drug)
排除标准
- •Must not have received any parenteral corticosteroid administered by intra-articular, intramuscular (IM), or intravenous (IV) injection within 6 weeks prior to baseline
- •Must not be concomitantly using non-steroidal anti-inflammatory drugs (NSAIDS), unless you are on a stable dose within the last 4 weeks
- •Must not have received any prior biologic disease modifying anti-rheumatic drug (DMARD) therapy [such as Tumor necrosis factor-alpha (TNFα), interleukin (IL)-1, IL-6, T-cell or B-cell target therapies)
- •Must not have used DMARDs other than methotrexate (MTX), hydroxychloroquine, or sulfasalazine within the last 8 weeks
- •Must not have used leflunomide within the last 12 weeks and have not received cholestyramine to speed up the elimination of leflunomide from your body
- •Must not have previously been randomized, completed or withdrawn from this study or any other study investigating LY3009104
- •Must not have received prior treatment with an oral JAK inhibitor
- •Must not have a current or recent (within the last 30 days) viral, bacterial, fungal, or parasitic infection
- •Must not have had a serious infection (for example, pneumonia, cellulitis, or bone or joint infections) or atypical mycobacterial infection within the last 6 months
- •Must not have had symptomatic herpes zoster or herpes simplex infection within the last 90 days or have a history of disseminated/complicated herpes zoster
- •Must not have evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies
- •Must not have evidence of hepatitis C virus (HCV) or active hepatitis B
- •Must not have evidence or suspicion of active or latent tuberculosis (TB)
- •Must not have another serious disorder or illness
- •Must not be exposed to a live vaccine within the last 12 weeks
- •Must not have donated more than 500 milliliters (mL) of blood within the last month
- •Must not have had surgery on a joint that is to be assessed in the study within the last 2 months, or will require such during the study
- •Must not be currently enrolled in, or discontinued within the last 30 days from a clinical trial involving an investigational drug or device or off-label use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
- •Presence of significant uncontrolled cerebro-cardiovascular [for example (eg), myocardial infarction (MI), unstable angina (UA), unstable arterial hypertension, severe heart failure or cerebrovascular accident], respiratory, hepatic, renal, gastrointestinal (GI), endocrine, hematologic or neuropsychiatric disorders, or abnormal laboratory values that in the opinion of the investigator pose an unacceptable risk to the participant if study drug would be administered
研究组 & 干预措施
1 mg LY3009104 once daily
Administered orally once daily for initial 12 weeks followed by randomization to either 4 mg LY3009104 once daily or 2 mg LY3009104 twice daily for an additional 12 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: LY3009104 (Drug)
1 mg LY3009104 once daily
Administered orally once daily for initial 12 weeks followed by randomization to either 4 mg LY3009104 once daily or 2 mg LY3009104 twice daily for an additional 12 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Methotrexate (Drug)
2 mg LY3009104 once daily
Administered orally once daily for 24 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: LY3009104 (Drug)
2 mg LY3009104 once daily
Administered orally once daily for 24 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Methotrexate (Drug)
4 mg LY3009104 once daily
Administered orally once daily for 24 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: LY3009104 (Drug)
4 mg LY3009104 once daily
Administered orally once daily for 24 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Methotrexate (Drug)
8 mg LY3009104 once daily
Administered orally once daily for 24 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: LY3009104 (Drug)
8 mg LY3009104 once daily
Administered orally once daily for 24 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Methotrexate (Drug)
Placebo once daily
Placebo administered orally once daily for initial 12 weeks followed by randomization to either 4 mg LY3009104 once daily or 2 mg LY3009104 twice daily for an additional 12 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Placebo (Drug)
Placebo once daily
Placebo administered orally once daily for initial 12 weeks followed by randomization to either 4 mg LY3009104 once daily or 2 mg LY3009104 twice daily for an additional 12 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Methotrexate (Drug)
2 mg LY3009104 twice daily
(Not utilized in Part A) After 12 weeks treatment with 1 mg LY3009104 once daily or Placebo once daily in Part A, administered orally twice daily for 12 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: LY3009104 (Drug)
2 mg LY3009104 twice daily
(Not utilized in Part A) After 12 weeks treatment with 1 mg LY3009104 once daily or Placebo once daily in Part A, administered orally twice daily for 12 weeks. After 24 weeks of treatment participants will be eligible to participate in an open-label extension period (Part C). Part C: 4 mg or 8 mg administered orally once daily for 52 additional weeks. After 76 weeks of treatment participants will be eligible to participate in an additional open-label extension period (Part D). Part D: 4 mg administered orally once daily for 52 additional weeks.
干预措施: Methotrexate (Drug)
结局指标
主要结局
Percentage of Participants in the 4 mg and 8 mg Dose Groups Who Achieved an American College of Rheumatology 20 (ACR20) Responder Index Response Baseline Through Week 12
时间窗: Baseline through Week 12
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.
次要结局
- Percentage of Participants Who Achieved an ACR70 Response Baseline Through Weeks 76 and 128(Baseline through Weeks 76 and 128)
- Mean Change From Baseline to Weeks 76 and 128 in DAS28-CRP(Baseline, Weeks 76 and 128)
- Percentage of Responders According to European League Against Rheumatism Responder Index Based on 28-joint Count (EULAR28) Baseline Through Weeks 12 and 24(Baseline through Weeks 12 and 24)
- Percentage of Participants Meeting Low Disease Activity and Remission Based on the 28 Diarthrodial Joint Count (DAS28) Baseline Through Weeks 12 and 24(Baseline through Weeks 12 and 24)
- Percentage of Participants Who Achieved an ACR20 Responder Index Response Baseline Through Week 12 - Model Based Dose Response(Baseline through Week 12)
- Percentage of Participants Who Achieved an ACR20 Responder Index Response Baseline Through Week 24(Baseline through Weeks 2, 4, 8, 12, 16, 20, 24)
- Percentage of Participants Who Achieved an ACR20 Response Baseline Through Weeks 76 and 128(Baseline through Weeks 76 and 128)
- Percentage of Participants Who Achieved an ACR 50 Responder Index Response Baseline Through Week 24(Baseline through Weeks 2, 4, 8, 12, 16, 20, 24)
- Percentage of Participants Who Achieved an ACR50 Response Baseline Through Weeks 76 and 128(Baseline through Weeks 76 and 128)
- Mean Change From Baseline to Weeks 12 and 24 in Disease Activity Score (DAS) Based on the 28 Diarthrodial Joint Count and CRP Level (DAS28-CRP)(Baseline, Weeks 12 and 24)
- Percentage of Responders According to EULAR28 Baseline Through Weeks 76 and 128(Baseline, Weeks 76 and 128)
- Percentage of Participants Meeting Low Disease Activity and Remission Based on the 28 Diarthrodial Joint Count (DAS28) Baseline Through Weeks 76 and 128(Baseline through Weeks 76 and 128)
- Mean Change From Baseline Through Week 12 in Duration (Minutes) of Morning Stiffness(Baseline, Weeks 4, 8, 12)
- Percentage of Participants Who Achieved an ACR70 Responder Index Response Baseline Through Week 24(Baseline through Weeks 2, 4, 8, 12, 16, 20, 24)
- Mean Change From Baseline to Weeks 12 and 24 in Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity and Patient's Assessment of Pain(Baseline, Weeks 12 and 24)
- Mean Change From Baseline to Weeks 76 and 128 in Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity and Patient's Assessment of Pain(Baseline, Weeks 76 and 128)
- Percentage of Participants Who Achieved an ACR50 Response Baseline Through Week 12 - Model Based Dose Response(Baseline through Week 12)
- ACR Percent Improvement (ACR-N)(Baseline through Week 12)
- Mean Change From Baseline to Weeks 12 and 24 in Tender and Swollen Joint Counts (TJC and SJC)(Baseline, Weeks 12 and 24)
- Mean Change From Baseline to Weeks 76 and 128 in TJC and SJC(Baseline, Weeks 76 and 128)
- Mean Change From Baseline to Weeks 12 and 24 in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score(Baseline, Weeks 12 and 24)
- Mean Change From Baseline to Weeks 76 and 128 in HAQ-DI Score(Baseline, Weeks 76 and 128)
- Mean Change From Baseline to Weeks 12 and 24 in High-Sensitivity C-Reactive Protein (hsCRP)(Baseline, Weeks 12 and 24)
- Mean Change From Baseline to Weeks 76 and 128 in hsCRP(Baseline, Weeks 76 and 128)
- Mean Change From Baseline to Weeks 12 and 24 in Erythrocyte Sedimentation Rate (ESR)(Baseline, Weeks 12 and 24)
- Mean Change From Baseline to Weeks 76 and 128 in ESR(Baseline, Weeks 76 and 128)
- Mean Change From Baseline to Week 12 in Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores(Baseline, Week 12)
- Mean Change From Baseline to Week 12 in Brief Pain Inventory Modified Short Form (BPI-sf Modified) Worst-Pain-in-the Past-24-hours Item Score(Baseline, Week 12)
- Mean Change From Baseline to Week 12 in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Score(Baseline, Week 12)
- Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of LY3009104(Baseline through 24 weeks)
- Population PK: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau,ss) of LY3009104(Baseline through 24 weeks)
- Mean Change From Baseline Through Week 12 in the ENSEMBLE Minimum Data Set 1.0(Baseline, 12 weeks)