A Phase 1, Blinded, Single Ascending Dose Study to Evaluate Safety, Pharmacokinetics, and Activity of TRL1068 in Subjects with Prosthetic Joint Infection of the Knee or Hip, Undergoing Primary Two Stage Exchange Arthroplasty
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 15
- 试验地点
- 9
- 主要终点
- Incidence of Abnormal Physical Examination Findings
研究概览
简要总结
TRL1068 is expected to eliminate the pathogen-protecting biofilm in the prosthetic joint and surrounding tissue, thus making these pathogens substantially more susceptible to established antibiotic treatment regimens. This initial study is designed to assess overall safety and pharmacokinetics (PK) of TRL1068. The overall goal of the development program is to demonstrate that TRL1068 can facilitate effectiveness of a single stage joint replacement or preservation of the original infected prosthetic joint in a substantial proportion of patients with PJI.
详细描述
Approximately 75% of all clinically significant human infections are estimated to be biofilm-related. Prosthetic joint infections are a classical example of difficult to eradicate infections associated with biofilm. Most Prosthetic Joint Infection (PJI) cases are caused by staphylococcal species (~70%) with an increasing number being antibiotic-resistant (MRSA). In the US, two-stage revision is the standard of care for replacement of an infected prosthetic joint, and is associated with substantial costs and prolonged immobility. TRL1068 is a fully human antibody that has been shown in pre-clinical studies to disrupt biofilm. TRL1068 targets a highly conserved epitope on the DNABII family of bacterial DNA binding proteins that includes histone-like (HU) and integration host factor (IHF) proteins of clinically relevant Gram-positive and Gram-negative bacteria. The DNABII epitope bound by TRL1068 has no homologs in the human proteome.
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)
盲法说明
The study is double-blind and placebo-controlled.
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of PJI of the knee or hip
- •Identified pathogen(s) must be susceptible to antibiotic regimen
- •Planned/scheduled for primary two-stage exchange arthroplasty
- •BMI < 40 kg/m²
- •Willing and able to provide written informed consent
- •Willing to perform and comply with all study procedures including attending clinic visits as scheduled.
- •Men and women of child bearing potential (WOCBP) must be willing to practice a highly effective method of contraception
排除标准
- •Evidence of active infection other than bacterial PJI of the knee or hip
- •Inability to receive or intolerant to pathogen-appropriate systemic or oral antibiotic therapy
- •Chronic obstructive pulmonary disease (COPD)
- •Child-Pugh score > 6
- •Congestive heart failure
- •Immunocompromised individuals, including those receiving immunosuppressive doses of corticosteroids
- •Active malignancy, or history of malignancy or chemotherapy within the past 2 years
- •Active or history of autoimmune disease
- •Uncontrolled diabetes, defined as hemoglobin A1c > 7.4%
- •Clinically significant abnormality on electrocardiogram (ECG) that would preclude subject from undergoing two-stage exchange arthroplasty
- •Clinically significant serum chemistry or hematology abnormalities
- •Any acute illness within 14 days of Day 1 that could confound the evaluation of safety evaluation
- •Known or suspected intolerance or hypersensitivity to any biologic medication
- •Received a therapeutic antibody or biologic within the 6 months prior to Screening
- •Positive serum test for pregnancy, pregnant, or nursing women
- •Positive reverse transcription polymerase chain reaction (RT -PCR) or alternative (antigen) test for acute respiratory syndrome coronavirus 2
- •History of drug or alcohol abuse that, in the opinion of the Investigator, would interfere with the subject's ability to comply with the study requirements
- •Any other comorbidity or condition that, in the opinion of the Investigator would make the subject unsuitable for the study or unable to comply with the study requirements
研究组 & 干预措施
Dose Level 1- 6mg/kg
Randomized 3:1 (TRL1068:placebo) via IV infusion
干预措施: TRL1068, a human monoclonal antibody (Drug)
Dose Level 2- 15mg/kg
Randomized 5:2 (TRL1068:placebo) via IV infusion
干预措施: TRL1068, a human monoclonal antibody (Drug)
Dose Level 3- 30 mg/kg
Randomized 5:2 (TRL1068:placebo) via IV infusion
干预措施: TRL1068, a human monoclonal antibody (Drug)
结局指标
主要结局
Incidence of Abnormal Physical Examination Findings
时间窗: 16 weeks
clinically significant abnormal physical exam findings will be reviewed
Incidence of Abnormal Vital Signs (Blood Pressure)
时间窗: 16 weeks
clinically significant abnormal blood pressures will be reviewed
Incidence of Abnormal Vital Signs (Heart Rate)
时间窗: 16 weeks
clinically significant abnormal heart rates will be reviewed
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: 24 weeks
mortality and any other reported AEs and SAEs will be reviewed
Incidence of Abnormal Serum Chemistries and Hematology
时间窗: 16 weeks
clinically significant abnormal laboratory results will be reviewed
Incidence of Abnormal Vital Signs (Temperature)
时间窗: 16 weeks
clinically significant abnormal temperatures will be reviewed
次要结局
- Assess the pharmacodynamics (PD) of TRL1068 (Colony Forming Units (CFUs) prosthesis)(1 week)
- Measure TRL1068 levels in synovial fluid on Day 8 and compare with plasma PK(1 week)
- Assess the pharmacodynamics (PD) of TRL1068 (CFUs spacer)(12 weeks)
- Assess the pharmacodynamics (PD) of TRL1068 (CRP)(16 weeks)
- Assess the pharmacodynamics (PD) of TRL1068 (IL-10)(16 weeks)
- Assess the pharmacodynamics (PD) of TRL1068 (reinfection)(24 weeks)
- Assess the immunogenicity of TRL1068 as measured by anti-drug antibodies (ADAs)(16 weeks)
- Characterize the pharmacokinetics (PK) of a single IV infusion of TRL1068(16 weeks)
- Assess the pharmacodynamics (PD) of TRL1068 (ESR)(16 weeks)
- Assess the pharmacodynamics (PD) of TRL1068 (IL-6)(16 weeks)