A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects With Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti-TNF-α Therapy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 56
- 主要终点
- Change From Baseline in Disease Activity Score (DAS28) as Measured by C-Reactive Protein (CRP) at Week 12
研究概览
简要总结
The purpose of this study is to assess the safety and efficacy of MK-8457 + Methotrexate (MTX) in participants with active rheumatoid arthritis (RA) and an inadequate response or intolerance to anti-tumor necrosis factor α (anti-TNF-α) therapy. The primary hypothesis of this study is that among participants with active RA, MK-8457 100 mg twice daily (BID) + MTX will be superior to placebo + MTX as measured by the change in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) after 12 weeks of treatment.
详细描述
In the Base Study, participants were to receive blinded MK-8457 100 mg + MTX or matched placebo + MTX for up to 24 weeks. At Week 12 and 18, efficacy evaluation was conducted to assess eligibility for early escape, defined as <20% improvement in tender and swollen joint counts. Participants who completed the Base Study and those eligible for early escape could enroll in the 76-week Safety Extension in which participants were to receive open-label MK-8457 100 mg BID + MTX.
All participants must have been treated with MTX for at least 3 months prior to Screening and have been receiving a stable dose of MTX for at least 4 weeks prior to Screening. In addition, each participant must have either failed treatment with 1 or 2 anti-TNF-α therapies or was intolerant to anti-TNF-α therapy prior to Screening. For participants who failed therapy, the treatment with anti-TNF-α therapies must have been for at least 3 months.
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
- Double (Participant, Investigator)
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
- •Diagnosis of rheumatoid arthritis for at least 6 months prior to screening
- •Active rheumatoid arthritis as defined by the presence of >= 6 swollen joints (of 66 count) and >= 6 tender joints (of 68 joint count)
- •C-reactive protein blood level >0.9 mg/dL or an elevated erythrocyte sedimentation rate (ESR) >28 mm/hr and evidence of synovitis on imaging
- •American College of Rheumatology Functional Class I, II, or III
- •Received methotrexate for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening. The dose of methotrexate must remain stable through Week 24 of the study.
- •Failed treatment with 1 or 2 anti-tumor necrosis factor alpha (anti-TNF-α) therapies or was intolerant to anti-TNF-α therapy prior to screening
- •If using non-steroidal anti-inflammatory drugs or other analgesics, participant must be on a stable dose
- •No history of either untreated latent or active tuberculosis (TB) prior to baseline
- •Participants of reproductive potential must agree to remain abstinent or use 2 acceptable methods of birth control
排除标准
- •Presence of inflammatory disease other than rheumatoid arthritis, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease
- •Hospitalization due to an acute cardiovascular event, cardiovascular illness, or cardiovascular surgery within 6 months of screening
- •Participant has a transplanted organ, excluding corneal transplant, performed > 3 months prior to the first dose of trial medication
- •History of, or current ongoing ,chronic or recurrent infectious disease
- •Positive hepatitis B surface antigen or hepatitis C test result
- •Human immunodeficiency virus (HIV) positive
- •User of recreational or illicit drugs or has had a history (within the previous 2 years) of drug or alcohol abuse or dependence
- •Prior exposure to fostamatinib or other spleen tyrosine kinase inhibitors
- •Prior exposure to 3 or more anti-TNF therapeutic agents
- •Has been treated for RA with a marketed biologic agent (other than anti-TNF therapeutic agents) and failed the agent due to lack of efficacy
- •Currently participating in another interventional clinical trial or has participated in an interventional clinical trial within 4 weeks prior to screening
- •Severe opportunistic infection within the 6 months prior to screening
研究组 & 干预措施
Base Study: MK-8457
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
干预措施: MK-8457 100 mg (Drug)
Base Study: MK-8457
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
干预措施: Methotrexate (Drug)
Base Study: Placebo
Participants received placebo BID orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
干预措施: Methotrexate (Drug)
Base Study: Placebo
Participants received placebo BID orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
干预措施: Dose-match placebo (Drug)
Safety Extension: MK-8457
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Safety Extension was to last up to 76 weeks.
干预措施: MK-8457 100 mg (Drug)
Safety Extension: MK-8457
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Safety Extension was to last up to 76 weeks.
干预措施: Methotrexate (Drug)
结局指标
主要结局
Change From Baseline in Disease Activity Score (DAS28) as Measured by C-Reactive Protein (CRP) at Week 12
时间窗: Baseline and Week 12
The DAS28-CRP is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints; 0=absent, 1=present; TEN28), swollen joints (28 joints; 0=absent, 1=present; SW28), CRP (an inflammatory marker, decrease indicates improvement), and Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) (0=doing very well to 100=doing very poor; GH). It is defined as follows: DAS28-CRP = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH + 0.96. The DAS28-CRP is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. This outcome measure applied to Base Study participants only.
次要结局
- Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12(Week 12)
- Percentage of Participants Achieving an ACR20 Response at Week 24(Week 24)
- Change From Baseline in the Health Assessment Questionnaire Disability (HAQ Disability Index) at Week 12(Baseline and Week 12)
- Change From Baseline in DAS28-CRP at Week 24(Baseline and Week 24)
- Percentage of Participants Achieving an ACR50 Response at Week 24(Week 24)
- Change From Baseline in the HAQ Disability Index at Week 24(Baseline and Week 24)
- Percentage of Participants Achieving an ACR50 Response at Week 12(Week 12)