Study to Evaluate Safety and Activity of TRL1068 in Prosthetic Joint Infections

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Prosthetic Joint Infection

Intervention / Treatment
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* Drug: TRL1068, a human monoclonal antibody


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1, Double-Blinded, Single Ascending Dose Study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1- 6mg/kg<br>Randomized 3:1 (TRL1068:placebo) via IV infusion | Drug: TRL1068, a human monoclonal antibody<br>* A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody<br>|
| Experimental: Dose Level 2- 15mg/kg<br>Randomized 5:2 (TRL1068:placebo) via IV infusion | Drug: TRL1068, a human monoclonal antibody<br>* A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody<br>|
| Experimental: Dose Level 3- 30 mg/kg<br>Randomized 5:2 (TRL1068:placebo) via IV infusion | Drug: TRL1068, a human monoclonal antibody<br>* A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Abnormal Physical Examination Findings | clinically significant abnormal physical exam findings will be reviewed | 16 weeks | 
| Incidence of Abnormal Serum Chemistries and Hematology | clinically significant abnormal laboratory results will be reviewed | 16 weeks | 
| Incidence of Abnormal Vital Signs (Temperature) | clinically significant abnormal temperatures will be reviewed | 16 weeks | 
| Incidence of Abnormal Vital Signs (Blood Pressure) | clinically significant abnormal blood pressures will be reviewed | 16 weeks | 
| Incidence of Abnormal Vital Signs (Heart Rate) | clinically significant abnormal heart rates will be reviewed | 16 weeks | 
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | mortality and any other reported AEs and SAEs will be reviewed | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the pharmacokinetics (PK) of a single IV infusion of TRL1068 | Serum and synovial concentrations of TRL1068 will be determined by ELISA | 16 weeks | 
| Measure TRL1068 levels in synovial fluid on Day 8 and compare with plasma PK | Serum and synovial concentrations of TRL1068 will be determined by ELISA | 1 week | 
| Assess the pharmacodynamics (PD) of TRL1068 (Colony Forming Units (CFUs) prosthesis) | Number of CFUs from sonicated prosthetic device | 1 week | 
| Assess the pharmacodynamics (PD) of TRL1068 (CFUs spacer) | Number of CFUs from sonicated orthopedic spacer | 12 weeks | 
| Assess the pharmacodynamics (PD) of TRL1068 (CRP) | Inflammatory biomarker CRP | 16 weeks | 
| Assess the pharmacodynamics (PD) of TRL1068 (ESR) | Inflammatory biomarker ESR | 16 weeks | 
| Assess the pharmacodynamics (PD) of TRL1068 (IL-6) | Inflammatory biomarker IL-6 | 16 weeks | 
| Assess the pharmacodynamics (PD) of TRL1068 (IL-10) | Inflammatory biomarker IL-10 | 16 weeks | 
| Assess the pharmacodynamics (PD) of TRL1068 (reinfection) | Assessment for reinfection including need for further surgical interventions and overall outcome | 24 weeks | 
| Assess the immunogenicity of TRL1068 as measured by anti-drug antibodies (ADAs) | Anti-drug antibodies (ADA), i.e. anti-TRL1068 antibodies in serum will determined by electrochemiluminescence assay. | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biofilm, antibiotic-resistant infections