Prosthetic Joint Infection
Conditions
Keywords
biofilm, antibiotic-resistant infections
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.
Interventions
A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody
Sponsors
University of California, Los Angeles
Biomedical Advanced Research and Development Authority
Wellcome Trust
Sinai Hospital of Baltimore
Gulfcoast Research Institute
Phoenix Clinical Research
University of Florida
University of Alabama at Birmingham
The Methodist Hospital Research Institute
University of Virginia
University of Southern California
Trellis Bioscience LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study is double-blind and placebo-controlled.
Intervention model description
Phase 1, Double-Blinded, Single Ascending Dose Study
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Abnormal Serum Chemistries and Hematology | 16 weeks | clinically significant abnormal laboratory results 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 Vital Signs (Heart Rate) | 16 weeks | clinically significant abnormal heart rates 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 (Temperature) | 16 weeks | clinically significant abnormal temperatures will be reviewed |
| Incidence of Abnormal Physical Examination Findings | 16 weeks | clinically significant abnormal physical exam findings will be reviewed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess the pharmacodynamics (PD) of TRL1068 (CRP) | 16 weeks | Inflammatory biomarker CRP |
| 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 (Colony Forming Units (CFUs) prosthesis) | 1 week | Number of CFUs from sonicated prosthetic device |
| Assess the pharmacodynamics (PD) of TRL1068 (CFUs spacer) | 12 weeks | Number of CFUs from sonicated orthopedic spacer |
| 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 |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory outcome measure to assess quality of life | 24 weeks | Patient-Reported Outcomes Measurement Information System - Physical Function (PROMIS-PF) Short Form 6b from placebo and TRL1068 treated groups will be compared. This questionnaire has a score range from 6-30, with higher scores indicating higher functioning than lower scores. |
| Exploratory outcome measure to determine inflammation (IL-6) | 16 weeks | The mean levels of Interleukin-6 (IL-6) from placebo and TRL1068 treated groups will be compared. |
| Exploratory outcome measure to determine inflammation (ESR) | 16 weeks | The mean levels of erythrocyte sedimentation rate (ESR) from placebo and TRL1068 treated groups will be compared. |
| Exploratory outcome measure to determine inflammation (CRP) | 16 weeks | The mean levels of C reactive protein (CRP) from placebo and TRL1068 treated groups will be compared. |
| Exploratory outcome measure inflammation in the synovial fluid | 1 week | The mean synovial fluid total leukocyte cell counts of the consolidated placebo and TRL1068 treated groups will be compared. |
| Exploratory outcome measure to determine CFUs | 12 weeks | The number of subjects with Colony Forming Units (CFUs) per mL ≥ 1 from sonicated prosthetic devices from placebo and TRL1068 treated groups will be compared. |
| Exploratory outcome measure to determine infection in synovial fluid | 1 week | The number of subjects with CFUs/mL ≥ 1 from the synovial fluid from placebo and TRL1068 treated groups will be compared. |
| Exploratory outcome measure to determine inflammation (IL-10) | 16 weeks | The mean levels of Interleukin-10 (IL-10) from placebo and TRL1068 treated groups will be compared. |
Countries
United States
Outcome results
None listed