A Phase II Multicenter, Randomized, Double-blind, Placebo Controlled, Dose-range Finding Study to Evaluate the Safety and Efficacy of ALX-0061 Administered Subcutaneously in Subjects With Moderate to Severe Active Systemic Lupus Erythematosus
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 312
- 试验地点
- 118
- 主要终点
- Number and Percentage of Subjects Who Achieved a Response at Week 24 According to the Modified British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (mBICLA) Score
研究概览
简要总结
Primary objective:
To assess the efficacy and safety of different dose regimens of ALX-0061 administered subcutaneously (s.c.) to subjects with moderate to severe active, seropositive systemic lupus erythematosus (SLE) compared to placebo.
Secondary objectives:
To assess the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, flare rate, steroid reduction and health-related quality of life, with different dose regimens of ALX-0061.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 64 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Man or woman ≥ 18 years and < 65 years of age
- •Have a diagnosis of SLE for at least 6 months prior to screening and fulfill the 1997 American College of Rheumatology (ACR) or 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria
- •Have moderate to severe active SLE
- •Have seropositive disease at screening
- •Subject must be at least on one or more of the treatments for SLE as listed in the protocol
- •Others as defined in the protocol
排除标准
- •Have an A score on the revised BILAG-2004 other than in the mucocutaneous and/or musculoskeletal system at screening and at baseline for the organ systems that can be clinically assessed
- •Have a systemic inflammatory disease other than SLE
- •Clinically significant infection treated or needing treatment
- •Any active or recurrent viral infection that based on the Investigator´s clinical assessment makes the subject unsuitable for the study
- •Have received prior therapy blocking the interleukin-6 (IL-6) pathway
- •Others as defined in the protocol
研究组 & 干预措施
ALX-0061 225 mg q2w
ALX-0061 225 mg every 2 weeks (q2w).
***
Vobarilizumab (ALX-0061) was supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 225 mg q2w received 2 s.c. injections q2w:
Syringe A with ALX-0061 (1 mL) q2w starting at Day 1, up to and including Week 46.
Syringe B with ALX-0061 (0.5 mL) q2w starting at Day 1, up to and including Week 46.
干预措施: ALX-0061 (Biological)
ALX-0061 75 mg q4w
ALX-0061 75 mg every 4 weeks (q4w).
***
Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 75 mg q4w received 2 s.c. injections q2w:
Syringe A with placebo (1 mL) q2w starting at Day 1, up to and including Week 46.
Syringe B with ALX-0061 (0.5 mL) q4w at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44, and syringe B with placebo (0.5 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46.
干预措施: ALX-0061 (Biological)
Placebo
Two s.c. injections with placebo every 2 weeks (q2w).
***
Placebo was supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to the placebo group received 2 s.c. injections q2w:
Syringe A with placebo (1 mL) q2w starting at Day 1, up to and including Week 46.
Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46.
干预措施: Placebo (Biological)
ALX-0061 75 mg q4w
ALX-0061 75 mg every 4 weeks (q4w).
***
Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 75 mg q4w received 2 s.c. injections q2w:
Syringe A with placebo (1 mL) q2w starting at Day 1, up to and including Week 46.
Syringe B with ALX-0061 (0.5 mL) q4w at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44, and syringe B with placebo (0.5 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46.
干预措施: Placebo (Biological)
ALX-0061 150 mg q4w
ALX-0061 150 mg every 4 weeks (q4w).
***
Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 150 mg q4w received 2 s.c. injections q2w:
Syringe A with ALX-0061 (1 mL) q4w at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44, and syringe A with placebo (1 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46.
Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46.
干预措施: Placebo (Biological)
ALX-0061 150 mg q2w
ALX-0061 150 mg every 2 weeks (q2w).
***
Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 150 mg q2w received 2 s.c. injections q2w:
Syringe A with ALX-0061 (1 mL) q2w starting at Day 1, up to and including Week 46.
Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46.
干预措施: Placebo (Biological)
ALX-0061 150 mg q2w
ALX-0061 150 mg every 2 weeks (q2w).
***
Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 150 mg q2w received 2 s.c. injections q2w:
Syringe A with ALX-0061 (1 mL) q2w starting at Day 1, up to and including Week 46.
Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46.
干预措施: ALX-0061 (Biological)
ALX-0061 150 mg q4w
ALX-0061 150 mg every 4 weeks (q4w).
***
Vobarilizumab (ALX-0061) and placebo were supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL and 1.0 mL in pre-filled single-use syringes. To maintain the blind, subjects randomly assigned to ALX-0061 150 mg q4w received 2 s.c. injections q2w:
Syringe A with ALX-0061 (1 mL) q4w at Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44, and syringe A with placebo (1 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46.
Syringe B with placebo (0.5 mL) q2w starting at Day 1, up to and including Week 46.
干预措施: ALX-0061 (Biological)
结局指标
主要结局
Number and Percentage of Subjects Who Achieved a Response at Week 24 According to the Modified British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (mBICLA) Score
时间窗: At Week 24 visit
The primary endpoint was evaluated by determining if there was a dose-response relationship between the mBICLA response rate at Week 24 and the dose administered, using the Multiple Comparison Procedure - Modelling (MCP-Mod) methodology. The existence of several candidate parametric models was assumed and multiple comparison techniques were used to choose the model(s) most likely to represent the true underlying dose-response curve. The selected model could further be used to guide the choice of adequate doses. mBICLA responders were defined as subjects who met all of the following criteria: 1. BILAG-2004 normal improvement: all A scores at Baseline improved to B, C or D, and all B scores improved to C or D. 2. No worsening in disease activity: no new BILAG-2004 A scores and ≤ 1 new increase to B. 3. No worsening of total mSLEDAI-2K score from Baseline. 4. No significant deterioration (\< 10% worsening from Baseline) in PGA. 5. No treatment failure (including the premature
次要结局
- Number and Percentage of Subjects With Modified Systemic Lupus Erythematosus Responder Index (mSRI-4) Response at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With BILAG-2004 Normal Improvement in Musculoskeletal System at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With BILAG-2004 Normal Improvement in Mucocutaneous System at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With mSRI-8 Response at Week 24 and Week 48.(At Week 24 and Week 48)
- Number and Percentage of Subjects With BILAG-2004 Normal Improvement at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Patient's Global Assessment at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects Whose Daily Dose of Steroids Was Reduced Without Severe Flares During Weeks 40-48(Between Week 40 and Week 48)
- Number and Percentage of Subjects Who Discontinued Prednisone (or Equivalent) by Week 48 Without Experiencing a Severe Flare(Up to and including Week 48)
- Number and Percentage of Subjects Who Were Treatment-emergent (TE) Anti-drug Antibody (ADA) Positive(From first administration of ALX-0061 up to and including follow-up)
- Number and Percentage of Subjects With mSRI-7 Response at Week 24 and Week 48(At Week 24 and Week 48)
- BILAG-2004 Total Score at Baseline, Week 24 and Week 48(At Baseline, Week 24 and Week 48)
- Change From Baseline in Physician's Global Assessment (PGA) at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Proteinuria at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects Experiencing Severe Flares According to mSLEDAI-2K Flare Index (mSFI) From Baseline to Week 24 and Week 48(From Baseline to Week 24 and Week 48)
- Change From Baseline in 28 Joint Count Tenderness (TJC28) Score at Week 24 and Week 48(At Week 24 and Week 48)
- Actual Values of Fibrinogen Concentrations at Baseline, Week 24, and Week 48(At Baseline, Week 24, and Week 48)
- Number and Percentage of Subjects With mBICLA Response at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With mSRI-5 Response at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With mSRI-6 Response at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With BILAG-2004 Enhanced Improvement at Week 24 and Week 48(At Week 24 and Week 48)
- Number and Percentage of Subjects With Persistent Minimal or no Activity in 9 Organ Systems According to BILAG-2004 Systems Tally at Week 24 and Week 48(At Week 24 and Week 48)
- Number of Subjects Who Were Treatment-emergent Urine Sediment Positive at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Creatinine Clearance Estimation (eGFR) at Week 24 and Week 48(At Week 24 and Week 48)
- Percent Change From Baseline in Daily Dose of Steroids at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Physical Component Scores of Short Form (36) Health Survey (SF-36) at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Mental Component Scores of SF-36 at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Modified Systemic Lupus Erythematosus Disease Activity Index 2000 (mSLEDAI-2K) Score at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Serum Creatinine at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in 28 Joint Count Swollenness (SJC28) Score at Week 24 and Week 48(At Week 24 and Week 48)
- Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score at Week 12, Week 24 and Week 48(At Week 12, Week 24 and Week 48)
- Change From Baseline in CLASI Damage Score at Week 12, Week 24 and Week 48(At Week 12, Week 24 and Week 48)
- Actual Values of Anti-double-stranded (ds) DNA Concentrations at Baseline, Week 24, and Week 48(at Baseline, Week 24, and Week 48)
- Actual Values of Complement C4 Concentrations at Baseline, Week 24, and Week 48(At Baseline, Week 24, and Week 48)
- Number of and Percentage Treatment Failures From Baseline to Week 24 and Week 48(From Baseline to Week 24 and Week 48)
- Number and Percentage of Subjects Experiencing Severe Flares According to BILAG-2004 Flare Index From Baseline to Week 24 and Week 48(From Baseline to Week 24 and Week 48)
- ALX-0061 Serum Concentrations at Week 24 and Week 48(At Week 24 and Week 48)
- Actual Values of Soluble Interleukin 6 Receptor (sIL-6R) Concentrations at Baseline, Week 24, and Week 48(At Baseline, Week 24, and Week 48)
- Actual Values of C-reactive Protein (CRP) Concentrations at Baseline, Week 24, and Week 48(At Baseline, Week 24, and Week 48)
- Actual Values of Complement C3 Concentrations at Baseline, Week 24, and Week 48(At Baseline, Week 24, and Week 48)
- Actual Values for Hemolytic Complement Component 50 (CH50) at Baseline, Week 24, and Week 48(At Baseline, Week 24, and Week 48)