Clinical trial NCT04763759: Study to Evaluate Safety and Activity of TRL1068 in Prosthetic Joint Infections
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Prosthetic Joint Infection
Keywords: biofilm
antibiotic-resistant infections
Lead sponsor: Trellis Bioscience LLC
Sponsor class: INDUSTRY
Collaborators: name: University of California, Los Angeles
name: Biomedical Advanced Research and Development Authority
name: Wellcome Trust
name: Sinai Hospital of Baltimore
name: Gulfcoast Research Institute
name: Phoenix Clinical Research
name: University of Florida
name: University of Alabama at Birmingham
name: The Methodist Hospital Research Institute
name: University of Virginia
name: University of Southern California
First posted: 2021-02-21
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 1, Double-Blinded, Single Ascending Dose Study
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Abnormal Physical Examination Findings
timeFrame: 16 weeks
measure: Incidence of Abnormal Serum Chemistries and Hematology
timeFrame: 16 weeks
measure: Incidence of Abnormal Vital Signs (Temperature)
timeFrame: 16 weeks
measure: Incidence of Abnormal Vital Signs (Blood Pressure)
timeFrame: 16 weeks
measure: Incidence of Abnormal Vital Signs (Heart Rate)
timeFrame: 16 weeks
measure: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 24 weeks
Secondary outcomes:
measure: Characterize the pharmacokinetics (PK) of a single IV infusion of TRL1068
timeFrame: 16 weeks
measure: Measure TRL1068 levels in synovial fluid on Day 8 and compare with plasma PK
timeFrame: 1 week
measure: Assess the pharmacodynamics (PD) of TRL1068 (Colony Forming Units (CFUs) prosthesis)
timeFrame: 1 week
measure: Assess the pharmacodynamics (PD) of TRL1068 (CFUs spacer)
timeFrame: 12 weeks
measure: Assess the pharmacodynamics (PD) of TRL1068 (CRP)
timeFrame: 16 weeks
measure: Assess the pharmacodynamics (PD) of TRL1068 (ESR)
timeFrame: 16 weeks
measure: Assess the pharmacodynamics (PD) of TRL1068 (IL-6)
timeFrame: 16 weeks
measure: Assess the pharmacodynamics (PD) of TRL1068 (IL-10)
timeFrame: 16 weeks
measure: Assess the pharmacodynamics (PD) of TRL1068 (reinfection)
timeFrame: 24 weeks
measure: Assess the immunogenicity of TRL1068 as measured by anti-drug antibodies (ADAs)
timeFrame: 16 weeks
Other outcomes:
measure: Exploratory outcome measure to determine CFUs
timeFrame: 12 weeks
measure: Exploratory outcome measure to determine inflammation (CRP)
timeFrame: 16 weeks
measure: Exploratory outcome measure to determine inflammation (ESR)
timeFrame: 16 weeks
measure: Exploratory outcome measure to determine inflammation (IL-6)
timeFrame: 16 weeks
measure: Exploratory outcome measure to determine inflammation (IL-10)
timeFrame: 16 weeks
measure: Exploratory outcome measure to determine infection in synovial fluid
timeFrame: 1 week
measure: Exploratory outcome measure inflammation in the synovial fluid
timeFrame: 1 week
measure: Exploratory outcome measure to assess quality of life
timeFrame: 24 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Los Angeles
country: United States
facility: USC
state: California
city: Santa Monica
country: United States
facility: UCLA
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Sarasota
country: United States
facility: Gulfcoast Research Institute
state: Florida
city: Tamarac
country: United States
facility: Phoenix Clinical Research
state: Florida
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Houston
country: United States
facility: Houston Methodist Research Institute
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of California, Los Angeles
name: Nicholas Bernthal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sinai Hospital of Baltimore
name: Janet Conway, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gulfcoast Research Institute
name: Edward Stolarski, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Phoenix Clinical Research
name: Richard Berkowitz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Luis Pulido, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Sameer Naranje, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Methodist Hospital Research Institute
name: Stephen Incavo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UVA
name: Ian Duensing, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Daniel Oakes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Conway J, Delanois RE, Mont MA, Stavrakis A, McPherson E, Stolarski E, Incavo S, Oakes D, Salvagno R, Adams JS, Kisch-Hancock A, Tenorio E, Leighton A, Ryser S, Kauvar LM, Bernthal NM. Phase 1 study of the pharmacokinetics and clinical proof-of-concept activity of a biofilm-disrupting human monoclonal antibody in patients with chronic prosthetic joint infection of the knee or hip. Antimicrob Agents Chemother. 2024 Aug 7;68(8):e0065524. doi: 10.1128/aac.00655-24. Epub 2024 Jul 16.
citation: Estelles A, Woischnig AK, Liu K, Stephenson R, Lomongsod E, Nguyen D, Zhang J, Heidecker M, Yang Y, Simon RJ, Tenorio E, Ellsworth S, Leighton A, Ryser S, Gremmelmaier NK, Kauvar LM. A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2292-301. doi: 10.1128/AAC.02588-15. Print 2016 Apr.
citation: Xiong YQ, Estelles A, Li L, Abdelhady W, Gonzales R, Bayer AS, Tenorio E, Leighton A, Ryser S, Kauvar LM. A Human Biofilm-Disrupting Monoclonal Antibody Potentiates Antibiotic Efficacy in Rodent Models of both Staphylococcus aureus and Acinetobacter baumannii Infections. Antimicrob Agents Chemother. 2017 Sep 22;61(10):e00904-17. doi: 10.1128/AAC.00904-17. Print 2017 Oct.