A Ph II/III Seamless, Multi-center, Randomized, Double-blind, Placebo-controlled Study of the Reduction in Signs and Symptoms and Inhibition of Structural Damage During Treatment With Tocilizumab Versus Placebo in Patients With Ankylosing Spondylitis Who Have Failed Non-steroidal Anti-inflammatory Drugs and Are naïve to TNF Antagonist Therapy NSAIDs
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 306
- 主要终点
- Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
研究概览
简要总结
This randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of RoActemra/Actemra (tocilizumab) in patients with ankylosing spondylitis (AS) who have failed treatment with non-steroidal anti-inflammatory drugs and are naïve to tumor necrsos factor (TNF) antagonist therapy. In Part 1 of the study, patients will be randomized to receive either RoActemra/Actemra 8 mg/kg intravenously (IV) or placebo every 4 weeks for 12 weeks. In Part 2, patients will be randomized to receive RoActemra at either 8 mg/kg or 4 mg/kg IV or placebo every 4 weeks for 24 weeks. The double-blind treatment period will be followed by open-label treatment with RoActemra/Actemra 8 mg/kg iv every 4 weeks until Week 208 for all patients. Anticipated time on study treatment is 208 weeks.
详细描述
This study was planned as a Phase II/III seamless, multicenter, randomized, double-blind, placebo-controlled study in patients with AS who were naïve to TNF antagonist therapy. The study consisted of 2 parts, each preceded by a screening visit and followed by a common open-label extension phase. Recruitment into Part 2 commenced after completion of enrollment for Part 1.
Part 1 was designed as a Phase II study exploring the efficacy and safety of tocilizumab therapy versus placebo. Part 1 was intended to determine whether Part 2 of the study would continue, based on a Week 12 analysis.
Part 2 was designed to provide pivotal Phase III efficacy and safety data for tocilizumab in patients with AS. Approximately 400 patients were to be enrolled. Once randomization into Part 1 was complete, randomization into Part 2 of the study was to be initiated.
Based on the results of the Week 12 Part 1 analyses of the primary endpoint (ASAS20) and secondary endpoints, and in consideration of all available safety data, a benefit/risk assessment was made and it was decided to halt the study because of lack of overall efficacy. Most patients did not complete the 24-week double-blind treatment period in Part 2.
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
- 未提供
排除标准
- •Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months after randomization
- •Total ankylosis of spine (as determined by investigator)
- •Inflammatory rheumatic disease other than ankylosing spondylitis
- •Active, acute uveitis at baseline
- •Treatment with tumor necrosis factor (TNF) antagonist therapy at any time prior to baseline
- •Intra-articular or tendon injections or parenteral corticosteroids within 4 weeks prior to screening
- •History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- •Active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infection
- •History of or currently active primary or secondary immunodeficiency
- •Body weight > 150 kg
研究组 & 干预措施
Part 1: Placebo
Participants received intravenous infusions of placebo once every 4 weeks until Week 12. Following the Week 12 visit, participants who completed Part 1 of the study received open-label 8 mg/kg tocilizumab through Week 208.
干预措施: Placebo (Drug)
Part 1: Tocilizumab
Participants received intravenous infusions of 8 mg/kg tocilizumab once every 4 weeks until Week 12. Following the Week 12 visit, participants who completed Part 1 of the study received open-label 8 mg/kg tocilizumab through Week 208.
干预措施: tocilizumab (Biological)
Part 2: Placebo
Participants received intravenous infusions of placebo once every 4 weeks until Week 24. Participants who did not attain an ASsessment in Ankylosing Spondylitis-20 (ASAS20) response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.
干预措施: Placebo (Drug)
Part 2: Tocilizumab 4 mg/kg
Participants received intravenous infusions of 4 mg/kg tocilizumab once every 4 weeks until Week 24. Participants who did not attain an ASAS20 response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.
干预措施: tocilizumab (Biological)
Part 2: Tocilizumab 8 mg/kg
Participants received intravenous infusions of 8 mg/kg tocilizumab once every 4 weeks until Week 24. Participants who did not attain an ASAS20 response at Week 16 were, at the investigator's discretion, eligible to receive open-label escape therapy consisting of 8 mg/kg tocilizumab. After Week 24, participants were to receive open-label treatment with 8 mg/kg tocilizumab every 4 weeks until Week 104. At the completion of Week 104, all Part 2 participants were to receive tocilizumab 8 mg/kg in the common open-label extension phase, however the study was terminated prior to any participants reaching this stage.
干预措施: tocilizumab (Biological)
结局指标
主要结局
Part 1: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
时间窗: Baseline and Week 12
ASAS is composed of four domains. To achieve an ASAS20 response required improvement of ≥20% and ≥ 1 unit (10 mm) in at least 3 domains and no worsening of ≥ 20 % and ≥ 1 unit (10 mm) in the remaining domain. * The patient's global assessment of current disease status, measured on a 100 mm visual analog scale (VAS), from symptom-free / no AS symptoms (0) to maximum AS disease severity (100). * The patient's overall assessment of the severity of spinal pain based on responses to 2 questions assessed on a 100 mm VAS, from no pain (0) to most severe pain (100). The spinal pain score is the mean of these 2 questions. * The function component was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI). The patient provides self-assessment of 10 questions on a 100 mm VAS. The BASFI score is the mean of these values. * The inflammation component of the ASAS was determined by the mean of questions 5 and 6 of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).
Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 12
时间窗: Baseline and Week 12
ASAS is composed of four domains. To achieve an ASAS20 response required improvement of ≥20% and ≥ 1 unit (10 mm) in at least 3 domains and no worsening of ≥ 20 % and ≥ 1 unit (10 mm) in the remaining domain. * The patient's global assessment of current disease status, measured on a 100 mm visual analog scale (VAS), from symptom-free / no AS symptoms (0) to maximum AS disease severity (100). * The patient's overall assessment of the severity of spinal pain based on responses to 2 questions assessed on a 100 mm VAS, from no pain (0) to most severe pain (100). The spinal pain score is the mean of these 2 questions. * The function component was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI). The patient provides self-assessment of 10 questions on a 100 mm VAS. The BASFI score is the mean of these values. * The inflammation component of the ASAS was determined by the mean of questions 5 and 6 of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).
次要结局
- Part 2: Percentage of Participants Achieving a 20% Improvement in Assessment in Ankylosing Spondylitis (ASAS20) at Week 24(Baseline and Week 24)
- Percentage of Participants Who Achieved a Value <2 in Each of the 4 ASAS Parameters at Week 12(Week 12)
- Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 12(Baseline and Week 12)
- Part 2: Percentage of Participants Achieving a 40% Improvement in Assessment in Ankylosing Spondylitis (ASAS40) at Week 24(Baseline and Week 24)
- Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)(Baseline and Week 12)
- Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI)(Baseline and Week 12)
- Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI)(Baseline and Week 12)
- Change From Baseline in C-Reactive Protein(Baseline and Week 12)
- Part 2: Area Under the Plasma Concentration Versus Time Curve of Tocilizumab(Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).)
- Part 2: Peak Plasma Concentration of Tocilizumab(Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).)
- Part 2: Elimination Half-life of Tocilizumab(Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).)
- Part 2: Clearance of Tocilizumab(Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).)
- Part 2: Volume of Distribution of Tocilizumab(Week 12, pre-dose and at the end of infusion, on the 2nd and 7th day of Week 12, 14 days post-dose (Week 14) and 28 days post-dose (pre-dose of Week 16 infusion).)
- Change From Baseline in the Level of Interleukin-6(Baseline and Week 12)
- Change From Baseline in Level of Soluble Interleukin-6 Receptor(Baseline and Week 12)
- Number of Participants With Anti-tocilizumab Antibodies(From Baseline until end of study (a maximum treatment duration of 40 weeks).)
- Part 2: Radiographic Change According to the Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)(Baseline and Week 104)
- Part 2: Percentage of Participants With a Reduction of Magnetic Resonance Imaging (MRI) Proven Spinal Inflammation(Baseline and Week 24)
- Part 1: The Number of Participants With Adverse Events(Up to 40 weeks)