Randomized, Placebo-Controlled, Double Blind, Multicenter Phase 2 Study to Explore Tolerability, Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Intravenous Multiple Infusions of NI-0101, an Anti-Toll Like Receptor 4 Monoclonal Antibody in Patients With Rheumatoid Arthritis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 90
- 试验地点
- 19
- 主要终点
- Proportion of patient achieving remission
研究概览
简要总结
This is a Phase 2, PoC, randomized, placebo-controlled, double blind, international multicentre study to explore the effect of a new antibody to treat patients with Rheumatoid Arthritis
详细描述
The study foresees the randomization of at least 81 moderate to severe, ACPA positive, RA patients who are inadequate responders to MTX, in two double blind arms (NI-0101:placebo, with a ratio of 2:1). Patients will receive NI-0101 or placebo infusions up to a maximum of 6 administrations (every two weeks for 12 weeks). All patients will continue receiving a stable dose of MTX. After 12 weeks, patients will enter the follow up period with monthly visits for a minimum of 12 weeks.
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
- Triple (Participant, Care Provider, 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
- •Male and female patients
- •Age >= 18 years old
- •BMI: < 30 and > 18
- •Diagnosis of RA according to 2010 ACR/EULAR criteria and with a disease duration of at least 6 months since diagnosis
- •Patient must present with active RA, characterized by at least 6 swollen joints out of 66 assessed and 6 tender joints out of 68 assessed and by the presence of synovitis (measured by ultrasound) in at least one of the 6 swollen joints
- •C-reactive protein (CRP) level > 0.7 mg/dL or if the CRP level is between 0.3 mg/dL and 0.7 mg/dL (included) then patient must also present an ESR > 30mm/hr
- •Patients must have received MTX treatment for at least 3 months and have been on a stable dose of MTX for at least 6 weeks prior to start of screening
- •ACPA-positive RA patients
- •Women must be postmenopausal (> 12 months without menses) or surgically sterile or using two effective contraception methods for at least 4 weeks prior to the randomization date and agree to continue contraception for the duration of their participation in the study (until the end of follow up period)
- •Sexually active male patients must use a barrier method of contraception during the course of the study (and until the end of the follow up period)
- •Patients must give written informed consent for study participation
排除标准
- •A documented history of an autoimmune disease other than RA by ACR classification, or Sjögren syndrome
- •Administration of cytotoxic drugs and immune suppressants (other than MTX) within 3 months prior to screening
- •Previous multiple administrations of any biological DMARD or targeted synthetic DMARD
- •Known primary immunodeficiency
- •Pregnant or breastfeeding women
- •Suspicion of active or latent tuberculosis
- •HIV, HCV, HBV infection
- •Infection reported during screening not recovered 72h prior to first dose
- •History of anaphylactic reactions to any protein therapeutics or excipients
- •Any history of malignancy, excluding cured basal or squamous cell carcinoma of the skin, or cervical in situ carcinoma
- •Clinically significant cardiac disease requiring medication, such as congestive heart failure, unstable angina, myocardial infarction within 6 months prior to randomization
- •Moderate to severe renal insufficiency, clinically relevant liver function test abnormalities or pancytopenia
- •Major psychiatric or neurological disorder
研究组 & 干预措施
NI-0101
A therapeutic humanized monoclonal antibody, administered by intravenous infusion every 2 weeks.
干预措施: NI-0101 (Drug)
Placebo
The placebo matches NI-0101 without active ingredient, administered by intravenous infusion every 2 weeks.
干预措施: Placebo (Other)
结局指标
主要结局
Proportion of patient achieving remission
时间窗: From randomization to 24 weeks after first treatment administration
Proportion of patient achieving remission (defined as DAS28 \< 2.6)
Incidence, severity, causality and outcomes of Adverse Events (AEs)
时间窗: From screening up to 24 weeks after first treatment administration
Incidence, severity, causality and outcomes of Adverse Events (AEs) (serious and non-serious), with particular attention being paid to infusion-related reactions and infections
Withdrawal for safety reasons
时间窗: From randomization up to 24 weeks after first treatment administration
Level of potential circulating antibodies against NI-0101
时间窗: From screening up to 24 weeks after first treatment administration
Level of potential circulating antibodies against NI-0101 to determine immunogenicity; i.e. the development of anti-drug antibodies (ADA).
Levels of CRP
时间窗: From screening up to 24 weeks after first treatment administration
Levels of C-Reactive protein (CRP)
EULAR response
时间窗: From randomization to 24 weeks after first treatment administration
Proportion of patients achieving European League Against Rheumatism (EULAR) response criteria - good, moderate and no response
Joint Count
时间窗: From screening to 24 weeks after first treatment administration
Mean number of Tender Joint Count/Swollen Joint Count.
SDAI score
时间窗: From randomization to 24 weeks after first treatment administration
Mean improvement from baseline in Simplified Disease Activity Index (SDAI) score
HAQ-DI score
时间窗: From randomization to 24 weeks after first treatment administration
Mean improvement from baseline in the Health Assessment Questionnaire without Disability Index (HAQ-DI) score
SF-36 score
时间窗: from randomization to 24 weeks after first treatment administration
Mean improvement from baseline in 36-Item Short-Form Health Survey (SF-36) score
DAS28-ESR
时间窗: From screening to 24 weeks after first treatment administration
Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and Erythrocyte Sedimentation Rate (ESR) levels - DAS28-ESR
CDAI score
时间窗: From randomization to 24 weeks after first treatment administration
Mean improvement from baseline in Clinical Disease Activity Index (CDAI) score scores
Evolution of laboratory parameters
时间窗: From screening up to 24 weeks after first treatment administration
ACR criteria
时间窗: From randomization to 24 weeks after first treatment administration
Proportion of patients achieving American College of Rheumatology Criteria (ACR20, ACR50 and ACR70)
Levels of inflammatory cytokines/chemokines
时间窗: From screening up to 24 weeks after first treatment administration
IL-6, TNFa, IP-10, MCP-1, sICAM, CXCL13
DAS28 CRP
时间窗: From screening to 24 weeks after first treatment administration
Measure of Disease Activity Scores (DAS) for Rheumatism in 28 tender or swollen joints and C-Reactive protein (CRP) - DAS28-CRP
Exploratory PK analysis - Cmax
时间窗: From randomization to 24 weeks after first treatment administration
Peak drug plasma concentration (Cmax)
Exploratory PK analysis - Tmax
时间窗: From screening up to 24 weeks after first treatment administration
Time when plasma concentration is at peak (Tmax)
Exploratory PK analysis - Ctrough
时间窗: From randomization to 24 weeks after first treatment administration
Plasma drug concentration immediately prior next dosing (Ctrough)
Exploratory PK analysis - AUC
时间窗: From randomization to 24 weeks after first treatment administration
Area under the plasma concentration versus time curve (AUC)
Exploratory PK analysis - CL
时间窗: From randomization to 24 weeks after first treatment administration
Systemic drug clearance (CL)
次要结局
未报告次要终点