Randomized, Placebo Controlled Double Blind, Multi-center Phase II Proof-of-concept Study to Assess the Efficacy of AIN457 in Patients With Moderate to Severe Ankylosing Spondylitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Percentage of Participants Who Achieved ASAS20 Response
研究概览
简要总结
Evaluate the safety, tolerability and pharmacokinetics of AIN457 when administered as treatment of moderate to severe ankylosing spondylitis (AS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with moderate to severe AS fulfilling the modified New York criteria for a diagnosis of AS and whose disease was not controlled on NSAIDS (on at least one NSAID over a period of at least 3 months at maximum dose). Minimum disease activity for inclusion of patients was assessed based on the ASAS core set domains: back pain & nocturnal pain score ≥ 4 despite concurrent NSAID use, PLUS a BASDAI score ≥
- •Elevated CRP or ESR was not mandatory for study inclusion
- •No evidence of liver disease or liver injury as indicated by abnormal liver function tests such as serum glutamic oxaloacetic transaminase (SGOT/AST), serum glutamic pyruvic transaminase (SGPT/ALT), gamma glutamyl transpeptidase (GGT), alkaline phosphatase, or serum bilirubin. The investigator was guided by criteria as outlined under exclusion criteria
排除标准
- •For patients who were previously treated with TNF blockers, the following washout periods were required for these patients to be eligible to participate in the trial:
- •month washout period prior to baseline for alefacept
- •month washout period prior to baseline for adalimumab and certolizumab
- •month washout prior to baseline for etanercept or infliximab
- •For patients who were previously treated with immunosuppressive agents other than MTX, SSZ, and systemic corticosteroids, a 1-month washout period prior to baseline was required. Immunosuppressive agents included but were not limited to cyclosporine, mycophenolate, tacrolimus, and 5-aminosalicylic acid (5-ASA). Prednisone had to be kept at a stable dose 4 weeks before baseline and throughout the study and not to exceed 10 mg/day.
- •MTX had to be kept at a stable dose 4 weeks before baseline and throughout the study and not to exceed 25 mg/week.
- •SSZ had to be kept at a stable dose 4 weeks before baseline and throughout the study.
- •In case of previous leflunomide treatment, a wash-out with oral cholestyramine could be considered as an alternative wash-out procedure to increase the elimination of leflunomide. Based on the notion that cholestyramine reduces plasma levels of the active leflunomide metabolite by approximately 40% in 24 hours and by 49% in 48 hours, cholestyramine was to be given orally at a dose of 8 g t.i.d. daily for 10 days. The patient could then be dosed with study drug not earlier than 2 weeks after the start of the cholestyramine wash-out procedure.
- •Patients who were on NSAIDs had to be kept at a stable dose 4 weeks prior to baseline and throughout the study.
- •Positive human immunodeficient virus (HIV: ELISA and Western blot) test result, Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. Any active systemic infection within the past 2 weeks including a positive chest X-ray.
- •Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, psychiatric, chronic inflammatory diseases with the exception of psoriatic arthritis or other disease which in the clinical judgment of the investigator would make the patient unsuitable for the trial
研究组 & 干预措施
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 1 and 2 - 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)
Part 1 and 2 - AIN457 0.1 mg/kg
AIN457A 0.1 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)
Part 1 and 2 - AIN457 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)
结局指标
主要结局
Percentage of Participants Who Achieved ASAS20 Response
时间窗: 6 Weeks
Clinical response to treatment was assessed according to ASAS20 criteria. ASAS20 responder had improvement of 20% or more and absolute improvement of at least 1 units (on a scale of 0 \[least\] to 10 \[worst\]) from Baseline in at least 3 of the following 4 domains, with absence of deterioration (worsening of at least 20% an absolute Worsening of at least 1 unit) in the potential remaining domain: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (Bath Ankylosing Spondylitis Functional Index (BASFI)); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores
Change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score From Baseline to 6 Weeks After First Infusion in Part 2
时间窗: 6 Weeks
ASAS20 as described in Primary Outcome. ASAS40 responder had improvement of 40% or more and absolute improvement of at least 2 units (on a scale of 0 \[least\] to 10 \[worst\]) from Baseline in at least 3 of the following 4 domains, with no deterioration in the potential remaining domain: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (Bath Ankylosing Spondylitis Functional Index (BASFI)); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores). ASAS 5/6 responder had improvement of 20% or more) from Baseline in at least 5 of the following 6 domains: Patient's Global Assessment of Disease Activity; Total Back Pain visual analog scale (VAS); Function (BASFI); and Inflammation (mean of 2 morning stiffness-related Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] scores); Spinal Mobility (BASFI); Acute phase reactant (CRP)
次要结局
- Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 Over Time in Part 1(Day8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28)
- Number of Participants Who Achieved ASAS20, ASAS40, and ASAS 5/6 in Part 1 and 2 Combined(Day 8,15,29,week 6, 8, 10, 12, 16, 20, 24, 28)
- Magnetic Resonance Imaging (MRI) Inflammatory Scores at Baseline, Week 6 in Part 1(Baseline, week 6, week 28)
- Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1(Week 28)
- Pharmacokinetics (PK) of AIN457: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part 1 and 2(Week 28)
- PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1(Week 28)
- PK of AIN457: Observed Maximum Serum Concentration Following Drug Administration (Cmax) in Part 1 and 2(Week 28)
- 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(Week 28)
- 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 and 2(Week 28)
- PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1(Week 28)
- PK of AIN457: Systemic Clearance From Serum Following Intravenous Administration (CL) in Part 1 and 2(Week 28)
- PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1(Week 28)
- PK of AIN457: Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) in Part 1 and 2(Week 28)
- PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1(Week 28)
- PK of AIN457: Terminal Elimination Half-life (T1/2) in Part 1 and 2(Week 28)
- Mean Change Bath Ankylosing Spondylitis Metrology Index (BASMI) Score in Part 1 and 2(Baseline, day 8,15,29, week 6,8,10,12,16,20,24,28)
- Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1(Baseline, day 8,15,29,week, 6, 8,10,12,16,20,24,28)
- Mean Change in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in Part 1 and 2(Day 8,15,29,week, 6, 10,12,16,20,24,28)
- Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in Part 1 and 2(Baseline, day 8,15,29,week 6,8,10,12,16,20,24,28)
- Change From Baseline in the Health Related Quality of Life (HRQoL) by Using the SF-36 Physical Component, and the ASQoL (Ankylosing Spondylitis Quality of Life Instrument) in Part 1.(SF-36:Baseline, week 12, week 28; ASQoL: Baseline, Day 29, week 12, week 28)
- Change From Baseline in the Health Related Quality of Life (HRQoL) by Using the SF-36 Physical Component, and the ASQoL (Ankylosing Spondylitis Quality of Life Instrument) in Part 1 and 2.(SF-36: Baseline, week 12, week 28; ASQoL: Baseline, day 29, week 12, week 8)