A Randomized, Double-Blind, Multicenter, 3 Stage, Efficacy and Safety Study of NI-071 and US-Licensed Remicade® (Infliximab) for the Treatment of Patients With Rheumatoid Arthritis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 683
- 试验地点
- 1
- 主要终点
- Stage 1: Percentage of Participants Who Achieved 20 Percent (%) American College of Rheumatology C-reactive Protein (ACR20-CRP) Response Rate at Week 22
研究概览
简要总结
The purpose of this study was to demonstrate similarity of NI-071 (proposed biosimilar to infliximab) to US REMICADE® (reference product) in terms of safety and efficacy in participants with rheumatoid arthritis (RA) not adequately responding to methotrexate (MTX).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
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
- •Patients with a diagnosis of rheumatoid arthritis (RA) as defined by the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria.
- •Patients have active RA, as confirmed by the following criteria:
- •≥6 swollen joints and ≥6 tender joints at screening and baseline (28-joint count).
- •Either C-reactive protein (CRP) ≥0.7 mg/dL (≥7.0 mg/L) or erythrocyte sedimentation rate (ESR) ≥28 mm/h at screening.
- •Patients taking methotrexate (MTX) (oral or parenteral) for at least 3 months prior to screening and at a stable dose of between 10 and 25 mg/week for at least 8 weeks. Concomitant folic/folinic acid at a dose of at least 5 mg/week is to be taken during the study; patients can start treatment with folic/folinic acid at screening if not already receiving it.
- •If the patient is currently taking non-steroidal anti-inflammatory drugs (NSAIDs), the patient must be on a stable dose for at least 4 weeks prior to screening and during the study.
- •Patients who are ≥18 and ≤75 years of age at screening.
排除标准
- •Patients who are rated as Class IV according to the 1991 ACR revised criteria for classification of global functional status for RA.
- •Patients who have received disease-modifying anti rheumatic drugs (DMARDs), other than MTX, within a period prior to screening shorter than the washout period appropriate to the pharmacodynamic profile of the specific drug.
- •Patients who have received immunosuppressive drugs within 4 weeks prior to screening. Patients on a stable dose of oral corticosteroids (≤10 mg/day prednisone or equivalent) for ≥4 weeks prior to screening are permitted.
- •Patients who have received intra-articular, intramuscular, intravenous, or epidural injection of corticosteroids within 4 weeks prior to screening.
- •Patients who have received intra-articular sodium hyaluronate injections within 4 weeks prior to screening.
- •Patients who have received surgical therapy for RA such as synovectomy or arthroplasty within 6 months prior to screening.
- •Patients who have received arthrocentesis within 4 weeks prior to screening.
- •Patients who have had prior treatment with infliximab.
- •Patients who have had prior treatment with >1 biological drug or >1 protein kinase inhibitor for RA either as part of clinical management or during a clinical study.
- •Patients who have had prior treatment with tumor necrosis factor alpha (TNF-α) inhibitors for RA who had lack of efficacy as per clinical judgment (primary failure). Patients who have discontinued TNF-α inhibitors for RA (other than infliximab) for any reason other than lack of efficacy are allowed.
- •Presence of chronic or acute infection at screening, including positive result for active tuberculosis (TB).
- •Patients with an acute infection requiring parenteral antibiotics within 4 weeks of study dosing or requiring oral/topical antibiotics within 2 weeks of study dosing.
研究组 & 干预措施
Stages 1, 2 and 3: NI-071 Group
Participants received intravenous (IV) infusion of NI-071 at a dose of 3 milligrams/kilograms (mg/kg) at Weeks 0, 2, 6, 14 during stage 1 and at Weeks 22, 30, 38, 46, and 54 during stage 2. Participants were followed up to Week 62 (Stage 3).
干预措施: NI-071 (Drug)
Stage 1: Remicade-US Group
Participants received IV infusion of Remicade-US (infliximab) at a dose of 3 mg/kg at Weeks 0, 2, 6, 14 during stage 1.
干预措施: Remicade (Drug)
Stage 2 and Stage 3: Remicade US to Remicade-US Group
Participants who received Remicade US during stage 1; were re-randomized during stage 2 to continue Remicade-US dose 3 mg/kg from Week 22 through Week 54 with every 8 weeks dosing intervals. Participants were followed up to Week 62 (Stage 3).
干预措施: Remicade (Drug)
Stage 2 and Stage 3: Remicade US to Switch Group
Participants who received Remicade US during stage 1; were re-randomized during stage 2 and received IV infusion of NI-071 at Week 22 followed by Remicade-US at Week 30, followed by NI-071 at Weeks 38, 46, and 54. Participants were followed up to week 62 (Stage 3).
干预措施: NI-071 (Drug)
Stage 2 and Stage 3: Remicade US to Switch Group
Participants who received Remicade US during stage 1; were re-randomized during stage 2 and received IV infusion of NI-071 at Week 22 followed by Remicade-US at Week 30, followed by NI-071 at Weeks 38, 46, and 54. Participants were followed up to week 62 (Stage 3).
干预措施: Remicade (Drug)
结局指标
主要结局
Stage 1: Percentage of Participants Who Achieved 20 Percent (%) American College of Rheumatology C-reactive Protein (ACR20-CRP) Response Rate at Week 22
时间窗: At Week 22
ACR20 was defined as a dichotomous variable, for which a participant was defined as either a responder or a non-responder. Participant was defined as a responder if all of the following criteria are met: i) A 20% improvement from baseline in the tender/painful joint count. ii) A 20% improvement from baseline in the swollen joint count. iii) A 20% improvement from baseline in at least 3 of the following 5 variables: a) Participant global assessment of disease activity visual analog scale (VAS) (0=very good, no symptoms;100=very poor, severe symptoms), b) Physician global assessment of disease activity (VAS) (0= no symptoms;100=severe symptoms), c) Participant pain assessment (VAS) (0=very good, no symptoms;100=very poor, severe symptoms), d) Health Assessment Questionnaire-Disability Index (HAQ-DI), total score ranging from 0-3 with lower scores meaning less disability, e) CRP.
Stage 2 and 3: Area Under the Serum Concentration-time Curve Interval (AUCtau) of NI-071 and Remicade US
时间窗: Week 46: Pre-dose, 1 hour after infusion, at end of infusion, at 4 hours and 24 hours after infusion and at Week 47, Week 48, Week 50, Week 52, and Week 54 post-dose
AUCtau of NI-071 and Remicade US in stage 2 and 3 was reported. As this was an interchangeability study, the NI-071 and Remicade only were the comparators and then switch study showed same measurement in relationship to the non-switched participants. Hence, combined data was assessed and collected in participants from Remicade US to Switch Group.
Stage 2 and 3: Maximum Observed Serum Concentration (Cmax) of NI-071 and Remicade US
时间窗: Week 46: Pre-dose, 1 hour after infusion, at end of infusion, at 4 hours and 24 hours after infusion and at Week 47, Week 48, Week 50, Week 52, and Week 54 post-dose
Cmax of NI-071 and Remicade US was reported. As this was an interchangeability study, the NI-071 and Remicade only were the comparators and then switch study showed same measurement in relationship to the non-switched participants. Hence, combined data was assessed and collected in participants from Remicade US to Switch Group.
次要结局
- Stage 1: Change From Baseline in the Disease Activity Score Based on 28 Joints (DAS28) C-reactive Protein (CRP) at Weeks 2, 6, 14, 18, and 22(Baseline, Weeks 2, 6, 14, 18, and 22)
- Stage 2 and 3: Change From Baseline in the Disease Activity Score Based on 28 Joints (DAS28) C-reactive Protein (CRP) at Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62(Baseline, Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 2 and 3: Percentage of Participants Who Achieved 20 Percent (%) American College of Rheumatology C-reactive Protein (ACR-CRP) Response Rate(At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 1: Percentage of Participants Who Achieved >=50% American College of Rheumatology C-reactive Protein (ACR50-CRP) Response Rate(At Weeks 2, 6, 14, 18, and 22)
- Stage 2 and 3: Percentage of Participants Who Achieved >=50% American College of Rheumatology C-reactive Protein (ACR50-CRP) Response Rate(At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 2 and Stage 3: Percentage of Participants Who Achieved >=50% American College of Rheumatology (ACR50) Response Using ESR(At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 1: Change From Baseline in the Disease Activity Score Based on 28 Joints (DAS28)-Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 6, 14, 18, and 22(Baseline, Weeks 2, 6, 14, 18, and 22)
- Stage 2 and 3: Change From Baseline in the Disease Activity Score Based on 28 Joints (DAS28)-Erythrocyte Sedimentation Rate (ESR) at Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62(Baseline, Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 2 and 3: Percentage of Participants Who Achieved Greater Than or Equal to (>=) 20% American College of Rheumatology (ACR20) Response Using Erythrocyte Sedimentation Rate (ESR)(At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 1: Percentage of Participants Who Achieved 20 Percent (%) American College of Rheumatology C-reactive Protein (ACR-CRP) Response Rate(At Weeks 2, 6, 14, 18, and 22)
- Stage 1: Percentage of Participants Who Achieved Greater Than or Equal to (>=) 20% American College of Rheumatology (ACR20) Response Using Erythrocyte Sedimentation Rate (ESR)(At Weeks 2, 6, 14, 18, and 22)
- Stage 2 and 3: Percentage of Participants Who Achieved >=70% American College of Rheumatology C-reactive Protein (ACR70-CRP) Response Rate(At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 1: Percentage of Participants Who Achieved >=50% American College of Rheumatology (ACR50) Response Using ESR(At Weeks 2, 6, 14, 18, and 22)
- Stage 2 and 3: Percentage of Participants Who Achieved >=70% American College of Rheumatology (ACR70) Response Using ESR(At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 1: Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 6, 14, 18, and 22(Baseline, Weeks 2, 6, 14, 18, and 22)
- Stage 2 and 3: Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62(Baseline, Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Stage 1: Change From Baseline in Routine Assessment of Patient Index Data 3 (RAPID3) Scores at Weeks 2, 6, 14, 18, and 22(Baseline, Weeks 2, 6, 14, 18, and 22)
- Stage 1: Percentage of Participants Who Achieved >=70% American College of Rheumatology C-reactive Protein (ACR70-CRP) Response Rate(At Weeks 2, 6, 14, 18, and 22)
- Stage 1: Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Total Score at Weeks 14 and 22(Baseline, Weeks 14 and 22)
- Stage 1: Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Score for Physical and Mental Components at Weeks 14 and 22(Baseline, Weeks 14 and 22)
- Stage 2 and 3: Minimum Observed Serum Concentration (Cmin) of NI-071 and Remicade US(Week 46: Pre-dose, 1 hour after infusion, at end of infusion, at 4 hours and 24 hours after infusion and at Week 47, Week 48, Week 50, Week 52, and Week 54 post-dose)
- Stage 1: Number of Participants With Positive Serum Anti-drug Antibodies (ADA)(Baseline, Weeks 2, 6, 14, and 22)
- Stage 1: Percentage of Participants Who Achieved >=70% American College of Rheumatology (ACR70) Response Using ESR(At Weeks 2, 6, 14, 18, 22)
- Stage 2 and 3: Time to Reach the Maximum Serum Concentration (Tmax) of NI-071 and Remicade US(Week 46: Pre-dose, 1 hour after infusion, at end of infusion, at 4 hours and 24 hours after infusion and at Week 47, Week 48, Week 50, Week 52, and Week 54 post-dose)
- Stage 2 and 3: Number of Participants With Positive Serum Anti-drug Antibodies (ADA)(At Weeks 30, 38, 46, 54, and 62)
- Stage 2 and 3: Number of Participants With Positive Serum Neutralizing Antibodies(At Weeks 30, 38, 46, 54, and 62)
- Stage 2 and 3: Change From Baseline in Routine Assessment of Patient Index Data 3 (RAPID3) Scores At Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62(Baseline, Weeks 26, 30, 34, 38, 42, 46, 50, 54, 58, and 62)
- Number of Participants With TEAEs of Special Interest(Baseline up to Week 62)
- Stage 1: Number of Participants With Positive Serum Neutralizing Antibodies(Baseline, Weeks 2, 6, 14, and 22)
- Stage 2 and 3: Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Total Score at Weeks 38 and 62(Baseline, Weeks 38 and 62)
- Stage 2 and 3: Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Score for Physical and Mental Components at Weeks 38 and 62(Baseline, Weeks 38 and 62)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs(Baseline up to Week 62)