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

Prosthetic Joint Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04763759
• Other study ID #: TRL1068-101
• Status: Completed
• Phase: Phase 1
• Start date: February 8, 2021
• Est. completion date: March 13, 2024

Study information

• Verified date: April 2024
• Source: Trellis Bioscience LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: March 13, 2024
• Est. primary completion date: March 13, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis, Infectious
• Communicable Diseases
• Infections
• Prosthetic Joint Infection

Intervention

Drug:
• TRL1068, a human monoclonal antibody
A human IgG1? (G1m1,17 (z,a); Km3 allotype) monoclonal antibody

Locations

Country	Name	City	State
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	University of Virginia	Charlottesville	Virginia
United States	University of Florida	Gainesville	Florida
United States	Houston Methodist Research Institute	Houston	Texas
United States	USC	Los Angeles	California
United States	UCLA	Santa Monica	California
United States	Gulfcoast Research Institute	Sarasota	Florida
United States	Phoenix Clinical Research	Tamarac	Florida

Sponsors (12)

Lead Sponsor	Collaborator
Trellis Bioscience LLC	Biomedical Advanced Research and Development Authority, Gulfcoast Research Institute, Phoenix Clinical Research, Sinai Hospital of Baltimore, The Methodist Hospital Research Institute, University of Alabama at Birmingham, University of California, Los Angeles, University of Florida, University of Southern California, University of Virginia, Wellcome Trust

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory outcome measure to determine CFUs	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.	12 weeks
Other	Exploratory outcome measure to determine inflammation (CRP)	The mean levels of C reactive protein (CRP) from placebo and TRL1068 treated groups will be compared.	16 weeks
Other	Exploratory outcome measure to determine inflammation (ESR)	The mean levels of erythrocyte sedimentation rate (ESR) from placebo and TRL1068 treated groups will be compared.	16 weeks
Other	Exploratory outcome measure to determine inflammation (IL-6)	The mean levels of Interleukin-6 (IL-6) from placebo and TRL1068 treated groups will be compared.	16 weeks
Other	Exploratory outcome measure to determine inflammation (IL-10)	The mean levels of Interleukin-10 (IL-10) from placebo and TRL1068 treated groups will be compared.	16 weeks
Other	Exploratory outcome measure to determine infection in synovial fluid	The number of subjects with CFUs/mL = 1 from the synovial fluid from placebo and TRL1068 treated groups will be compared.	1 week
Other	Exploratory outcome measure inflammation in the synovial fluid	The mean synovial fluid total leukocyte cell counts of the consolidated placebo and TRL1068 treated groups will be compared.	1 week
Other	Exploratory outcome measure to assess quality of life	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.	24 weeks
Primary	Incidence of Abnormal Physical Examination Findings	clinically significant abnormal physical exam findings will be reviewed	16 weeks
Primary	Incidence of Abnormal Serum Chemistries and Hematology	clinically significant abnormal laboratory results will be reviewed	16 weeks
Primary	Incidence of Abnormal Vital Signs (Temperature)	clinically significant abnormal temperatures will be reviewed	16 weeks
Primary	Incidence of Abnormal Vital Signs (Blood Pressure)	clinically significant abnormal blood pressures will be reviewed	16 weeks
Primary	Incidence of Abnormal Vital Signs (Heart Rate)	clinically significant abnormal heart rates will be reviewed	16 weeks
Primary	Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	mortality and any other reported AEs and SAEs will be reviewed	24 weeks
Secondary	Characterize the pharmacokinetics (PK) of a single IV infusion of TRL1068	Serum and synovial concentrations of TRL1068 will be determined by ELISA	16 weeks
Secondary	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
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (Colony Forming Units (CFUs) prosthesis)	Number of CFUs from sonicated prosthetic device	1 week
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (CFUs spacer)	Number of CFUs from sonicated orthopedic spacer	12 weeks
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (CRP)	Inflammatory biomarker CRP	16 weeks
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (ESR)	Inflammatory biomarker ESR	16 weeks
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (IL-6)	Inflammatory biomarker IL-6	16 weeks
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (IL-10)	Inflammatory biomarker IL-10	16 weeks
Secondary	Assess the pharmacodynamics (PD) of TRL1068 (reinfection)	Assessment for reinfection including need for further surgical interventions and overall outcome	24 weeks
Secondary	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