Study to Evaluate Safety and Activity of TRL1068 in Prosthetic Joint Infections
- Conditions
- Prosthetic Joint Infection
- Interventions
- Drug: TRL1068, a human monoclonal antibody
- Registration Number
- NCT04763759
- Lead Sponsor
- Trellis Bioscience LLC
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose Level 3- 30 mg/kg TRL1068, a human monoclonal antibody Randomized 5:2 (TRL1068:placebo) via IV infusion Dose Level 1- 6mg/kg TRL1068, a human monoclonal antibody Randomized 3:1 (TRL1068:placebo) via IV infusion Dose Level 2- 15mg/kg TRL1068, a human monoclonal antibody Randomized 5:2 (TRL1068:placebo) via IV infusion
- Primary Outcome Measures
Name Time Method Incidence of Abnormal Physical Examination Findings 16 weeks clinically significant abnormal physical exam findings will be reviewed
Incidence of Abnormal Vital Signs (Blood Pressure) 16 weeks clinically significant abnormal blood pressures will be reviewed
Incidence of Abnormal Vital Signs (Heart Rate) 16 weeks clinically significant abnormal heart rates will be reviewed
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) 24 weeks mortality and any other reported AEs and SAEs will be reviewed
Incidence of Abnormal Serum Chemistries and Hematology 16 weeks clinically significant abnormal laboratory results will be reviewed
Incidence of Abnormal Vital Signs (Temperature) 16 weeks clinically significant abnormal temperatures will be reviewed
- Secondary Outcome Measures
Name Time Method Measure TRL1068 levels in synovial fluid on Day 8 and compare with plasma PK 1 week Serum and synovial concentrations of TRL1068 will be determined by ELISA
Assess the pharmacodynamics (PD) of TRL1068 (CFUs spacer) 12 weeks Number of CFUs from sonicated orthopedic spacer
Assess the pharmacodynamics (PD) of TRL1068 (CRP) 16 weeks Inflammatory biomarker CRP
Assess the pharmacodynamics (PD) of TRL1068 (IL-10) 16 weeks Inflammatory biomarker IL-10
Assess the pharmacodynamics (PD) of TRL1068 (reinfection) 24 weeks Assessment for reinfection including need for further surgical interventions and overall outcome
Assess the immunogenicity of TRL1068 as measured by anti-drug antibodies (ADAs) 16 weeks Anti-drug antibodies (ADA), i.e. anti-TRL1068 antibodies in serum will determined by electrochemiluminescence assay.
Characterize the pharmacokinetics (PK) of a single IV infusion of TRL1068 16 weeks Serum and synovial concentrations of TRL1068 will be determined by ELISA
Assess the pharmacodynamics (PD) of TRL1068 (Colony Forming Units (CFUs) prosthesis) 1 week Number of CFUs from sonicated prosthetic device
Assess the pharmacodynamics (PD) of TRL1068 (ESR) 16 weeks Inflammatory biomarker ESR
Assess the pharmacodynamics (PD) of TRL1068 (IL-6) 16 weeks Inflammatory biomarker IL-6
Trial Locations
- Locations (9)
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Phoenix Clinical Research
🇺🇸Tamarac, Florida, United States
UCLA
🇺🇸Santa Monica, California, United States
Gulfcoast Research Institute
🇺🇸Sarasota, Florida, United States
USC
🇺🇸Los Angeles, California, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
University of Alabama
🇺🇸Birmingham, Alabama, United States
Houston Methodist Research Institute
🇺🇸Houston, Texas, United States
University of Florida
🇺🇸Gainesville, Florida, United States