A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to at Least One Biologic Disease-modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 145
- 试验地点
- 41
- 主要终点
- Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis.
详细描述
This is a 28-week (up to 4-week screening period, 12-week treatment period, and 12-week safety follow-up period), multicenter, randomized, double-blind, placebo-controlled, multiple dose, proof-of-concept study with PK lead-in designed to assess the safety, PK, efficacy and PD of KPL-404 in subjects with moderate to severe, active Rheumatoid Arthritis (RA) who have an inadequate response to or are intolerant to a Janus kinase inhibitor (JAKi) AND/OR at least one biologic disease-modifying anti-rheumatic drug (bDMARD). The objectives of the study are to evaluate safety, efficacy, and PD of KPL-404 compared with placebo across the estimated therapeutic range and to characterize PK across varying dose levels of KPL-404.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Body weight ≥ 40 to ≤ 140 kg for all cohorts.
- •Diagnosis of RA for ≥ 3 months fulfilling the 2010 American College of Rheumatology (ACR)/European Union League Against Rheumatism (EULAR) classification criteria for RA and that is categorized as ACR RA functional Class 1-
- •Treated with a biological disease-modifying anti-rheumatic drug (bDMARDs) AND/OR Janus kinase inhibitor (JAKi) therapy for RA for ≥ 3 months and had inadequate response or had to discontinue bDMARD AND/OR JAKi therapy due to intolerance or toxicity, regardless of treatment duration.
- •Currently receiving conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) therapy ≥ 3 months and on a stable dose for ≥ 4 weeks before the first dose of investigational product.
- •The following csDMARDs are allowed: oral or parenteral methotrexate ([MTX]; 7.5 to 25 mg/week), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day).
- •A combination of up to 2 background csDMARDs is allowed, except the combination of MTX and leflunomide.
- •Meets all of the following disease activity criteria:
- •Six or more swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at screening and baseline visits;
- •Level of high-sensitivity C-reactive protein ≥ 3 mg/L (by central laboratory);
- •Documented seropositivity for serum Rheumatoid Factor (RF) and/or Anti-citrullinated protein antibody (ACPA) (>ULN) at screening or by prior laboratory evaluation.
- •Has completed a locally approved authorized COVID-19 vaccine regimen according to local guidance at least 3 weeks before the first dose of the Investigational Product.
- •Must have discontinued all bDMARDs or JAKi prior to the first dose of investigational product. The washout period for bDMARDs or JAKi prior to the first dose of investigational product is specified below. For bDMARDs or JAKi not listed below washout should be at least 5 times the mean elimination half-life of a drug:
- •≥ 4 weeks for etanercept;
- •≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, and sarilumab;
- •≥ 1 year for rituximab;
- •≥ 2 weeks for JAKi (either investigational or commercially available treatment).
- •Voluntarily sign and date an informed consent form approved by independent ethics committee/Institutional Review Board (IRB)
排除标准
- •Prior exposure to any other anti-CD40/CD40L agent.
- •Inadequate response to 5 or more classes of advanced targeted therapies (bDMARD or tsDMARD; e.g., TNF inhibitors, IL-6 receptor inhibitors, T-cell costimulatory inhibitors, anti-CD-20 antibodies, JAK inhibitors). This does not include prior discontinuation due to drug intolerance.
- •Injectable corticosteroids (including intra-articular) or treatment with > 10 mg/day dose oral prednisone or equivalent within 8 weeks prior to randomization.
- •History of any arthritis with onset prior to age 16 years or current diagnosis of inflammatory joint disease other than RA (Current diagnosis of secondary Sjogren's syndrome is permitted).
- •History of thromboembolic event or a significant risk of future thromboembolic events
- •Clinically significant active infection including signs/symptoms suggestive of infection, any significant recurrent or chronic infection, or subjects at a high risk of infection
- •History of cancer within the last 5 years from screening, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured.
- •History of any of the following cardiovascular conditions:
- •Moderate to severe congestive heart failure (New York Heart Association class III or IV);
- •Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
- •Uncontrolled hypertension as defined by a confirmed systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
- •Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) > 500 msec.
研究组 & 干预措施
Cohort 1 KPL-404 2 mg/kg Every 2 Weeks (q2wk)
KPL-404 2 mg/kg subcutaneous (SC) q2wk for 12 weeks
干预措施: KPL-404 (Drug)
Cohort 1 Placebo
Placebo SC q2wk for 12 weeks
干预措施: Placebo (Drug)
Cohort 2 KPL-404 5 mg/kg q2wk
KPL-404 5 mg/kg SC q2wk for 12 weeks
干预措施: KPL-404 (Drug)
Cohort 2 Placebo
Placebo SC q2wk for 12 weeks
干预措施: Placebo (Drug)
Cohort 3 KPL-404 5 mg/kg qwk
KPL-404 5mg/kg SC once weekly (qwk) for 12 weeks
干预措施: KPL-404 (Drug)
Cohort 3 KPL-404 5 mg/kg q2wk
KPL-404 5mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks
干预措施: KPL-404 (Drug)
Cohort 3 KPL-404 5 mg/kg q2wk
KPL-404 5mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks
干预措施: Placebo (Drug)
Cohort 3 Placebo
Placebo SC qwk for 12 weeks
干预措施: Placebo (Drug)
Cohort 4 KPL-404 400 mg q4wk
KPL-404 SC every 4 weeks (q4wk) for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8.
干预措施: KPL-404 (Drug)
Cohort 4 Placebo
Placebo SC q4wk for 12 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: From first dose of study drug to 24 weeks
Adverse event (AE): any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. Serious AE (SAE): AE that: results in death; is immediately life-threatening; requires in-patient hospitalization/prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital abnormality/birth defect; is an important medical event. TEAEs: AEs not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug during treatment period. AE severity: mild (Grade \[Gr\] 1); moderate (Gr 2); severe (Gr 3); potentially life threatening (Gr 4); death (Gr 5). AEs of special interest: thrombosis, serious infection, serious and non-serious bacterial infections, eye disorders, and anaphylaxis/hypersensitivity reactions.
Cohorts 1 and 2: Maximum Serum Concentration (Cmax)
时间窗: Days 1 (Dose 1) and 57 (Dose 4)
Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau)
时间窗: Days 1 (Dose 1) and 57 (Dose 4)
Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12
时间窗: Baseline, Week 12
DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale \[VAS\] scale of 0-100 mm), and CRP (milligram per liter). DAS28-CRP score ranges from 0 to 9.4. The lower the DAS28-CRP score is, the better the participant has response (remission = score \< 2.6, low disease activity = score \< 3.2). A negative value in change from BL indicates an improvement.
次要结局
- Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12(Baseline, Week 12)
- Cohorts 3 and 4: Number of Participants With TEAEs(From first dose of study drug to 24 weeks)
- Cohort 3 and 4: Cmax(Days 1 (Dose 1) and 57 (Dose 4 or 8))
- Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12(Baseline, Week 12)
- Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12(Baseline, Week 12)
- Cohort 3 and 4: AUCtau(Days 1 (Dose 1) and 57 (Dose 4 or 8))
- Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12(Baseline, Week 12)