A Randomized, Double Blind, Placebo-controlled, Dose Escalation Study of the Safety, Tolerability and Pharmacokinetics of AIN457 in Rheumatoid Arthritis Patients With Pharmacodynamics Assessed in an Expanded Cohort at the Maximum Tolerated Dose
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 104
- 试验地点
- 1
- 主要终点
- PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants
研究概览
简要总结
Evaluate the safety, tolerability and pharmacokinetics of AIN457 when administered as a single dose (intravenous infusion) in patients with active rheumatoid arthritis in combination with a stable dose of methotrexate. And to compare efficacy on the dose groups.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Care Provider)
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
- •Male and female patients with active rheumatoid arthritis in combination with a stable dose of methotrexate aged 18-75 years may participate in this trial.
- •Post menopausal or surgically sterile female patients are allowed. Women of child-bearing potential may participate if they are on a stable dose of methotrexate and if they are practicing effective contraception for at least 6 months prior to screening, willing to use 2 forms of contraception, including at least 1 barrier method during the study and for at least 2 months following the completion/discontinuation of the study.
- •Patients must have a diagnosis of active rheumatoid arthritis of stages I, II or III (ACR 1987 revised classification for criteria for RA). Disease duration of at least 6 months prior to randomization is essential;
排除标准
- •Current treatment with anti-TNF-α or anti IL-1 therapy (or other biological therapy).
- •Patients with congestive heart failure or poorly controlled diabetes mellitus (HbA1c value ≥10%).
- •Presence of any major chronic inflammatory autoimmune diseases like psoriasis, psoriatic arthritis, spondyloarthropathy, inflammatory bowel disease or SLE that can mimic rheumatoid arthritis diagnosis or that can interfere with efficacy evaluation in the study.
- •History of renal trauma, glomerulonephritis or patient with one kidney.
- •Pregnant or breastfeeding women will be excluded.
- •A positive tuberculin skin test.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Part 1 - AIN457A 0.3 mg/kg
AIN457A 0.3 mg/kg was administered intravenously as a single dose.
干预措施: AIN457 (Biological)
Part 1 - AIN457A 1.0 mg/kg
AIN457A 1.0 mg/kg was administered intravenously as a single dose.
干预措施: AIN457 (Biological)
Part 1 - AIN457A 3.0 mg/kg
AIN457A 3.0 mg/kg was administered intravenously as a single dose.
干预措施: AIN457 (Biological)
Part 1 - AIN457A 10 mg/kg
AIN457A 10.0 mg/kg was administered intravenously as a single dose.
干预措施: AIN457 (Biological)
Part 1 - Placebo
Placebo to AIN457A was administered intravenously as a single dose.
干预措施: Placebo (Drug)
Parts 2 and 3 - AIN457A 1.0 mg/kg
AIN457A 1.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.
干预措施: AIN457 (Biological)
Parts 2 and 3 - AIN457A 3.0 mg/kg
AIN457A 3.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.
干预措施: AIN457 (Biological)
Parts 2 and 3 - AIN457A 10 mg/kg
AIN457A 10.0 mg/kg was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.
干预措施: AIN457 (Biological)
Parts 2 and 3 - Placebo
Placebo to AIN457A was administered intravenously as 2 doses 21 days apart, i.e. the first dose on day 1 and the second dose on day 22.
干预措施: Placebo (Drug)
Part 1 - Healthy Volunteers - AIN457A 3 mg/kg
AIN457A 3.0 mg/kg was administered intravenously as a single dose.
干预措施: AIN457 (Biological)
Part 1 - Healthy Volunteers - AIN457A 10 mg/kg
AIN457A 10 mg/kg was administered intravenously as a single dose.
干预措施: AIN457 (Biological)
Part 1 - Healthy Volunteers - Placebo
Placebo to AIN457A was administered intravenously as a single dose.
干预措施: Placebo (Drug)
结局指标
主要结局
PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Pharmacokinetics PK of AIN457: Cmax in Parts 2 and 3 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Pharmacokinetics PK of AIN457: Vz in Parts 2 and 3 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
PK of AIN457: Area Under the Serum Concentration-time Cure From Time Zero to the Time of Last Quantifiable Concentration (AUClast), Area Under the Serum Concentration-time Curve From Time Zero to (AUCinf) in Part 1 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Pharmacokinetics PK of AIN457: Tmax in Parts 2 and 3 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Percentage of Parts 2 and 3 Participants Who Achieved American College of Rheumatology Response of 20 (ACR20)
时间窗: Day 43
Clinical response to treatment was assessed according to ACR20 criteria. A participant was defined as an ACR20 responder if the following 3 conditions were met: 1) ≥20% improvement in the number of tender joints, 2) ≥20% improvement in the number of swollen joint and 3) ≥20% improvement in three of the following five domains: patient global assessment, physician global assessment, patient pain assessment, health assessment questionnaire (HAQ) and acute phase reactant.
Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 29, 36, 43, 57, 71, 85, 99 and 113.
Pharmacokinetics PK of AIN457: AUClast and AUCinf in Parts 2 and 3 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Pharmacokinetics PK of AIN457: CL in Parts 2 and 3 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
Pharmacokinetics PK of AIN457: T1/2 in Parts 2 and 3 Participants
时间窗: Day 113
Serum samples were collected pre-dose and 0.5, 2, 4, 7, 12 and 24 hours post infusion on day 1, and on days 2, 5, 8, 15, 22, 23, 26, 29, 36, 43, 57, 71, 85, 99 and 113. On day 22, samples were collected pre-dose and 0.5, 1, 2, 4, 7 and 24 hours post infusion.
次要结局
- Disease Activity Score (DAS28) of Parts 2 and 3 Participants(Day 43)
- Percentage of Parts 2 and 3 Participants Who Achieved ACR50 and ACR70(Day 43)