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

NCT ID: NCT04763759

Last Updated: 2024-11-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-08
• Study Completion Date: 2024-03-13

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.

Conditions

Prosthetic Joint Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Dose Level 1- 6mg/kg

Randomized 3:1 (TRL1068:placebo) via IV infusion

Group Type: EXPERIMENTAL

TRL1068, a human monoclonal antibody

Intervention Type: DRUG

A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody

Dose Level 2- 15mg/kg

Randomized 5:2 (TRL1068:placebo) via IV infusion

Group Type: EXPERIMENTAL

TRL1068, a human monoclonal antibody

Intervention Type: DRUG

A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody

Dose Level 3- 30 mg/kg

Randomized 5:2 (TRL1068:placebo) via IV infusion

Group Type: EXPERIMENTAL

TRL1068, a human monoclonal antibody

Intervention Type: DRUG

A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody

Interventions

TRL1068, a human monoclonal antibody

A human IgG1κ (G1m1,17 (z,a); Km3 allotype) monoclonal antibody

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, Los Angeles

OTHER

Sponsor Role: collaborator

Biomedical Advanced Research and Development Authority

FED

Sponsor Role: collaborator

Wellcome Trust

OTHER

Sponsor Role: collaborator

Sinai Hospital of Baltimore

OTHER

Sponsor Role: collaborator

Gulfcoast Research Institute

UNKNOWN

Sponsor Role: collaborator

Phoenix Clinical Research

OTHER

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: collaborator

The Methodist Hospital Research Institute

OTHER

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: collaborator

University of Southern California

OTHER

Sponsor Role: collaborator

Trellis Bioscience LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicholas Bernthal, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Janet Conway, MD

Role: PRINCIPAL_INVESTIGATOR

Sinai Hospital of Baltimore

Edward Stolarski, MD

Role: PRINCIPAL_INVESTIGATOR

Gulfcoast Research Institute

Richard Berkowitz, MD

Role: PRINCIPAL_INVESTIGATOR

Phoenix Clinical Research

Luis Pulido, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Sameer Naranje, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Stephen Incavo, MD

Role: PRINCIPAL_INVESTIGATOR

The Methodist Hospital Research Institute

Ian Duensing, MD

Role: PRINCIPAL_INVESTIGATOR

UVA

Daniel Oakes, MD

Role: PRINCIPAL_INVESTIGATOR

University of Southern California

Locations

University of Alabama

Birmingham, Alabama, United States

USC

Los Angeles, California, United States

UCLA

Santa Monica, California, United States

University of Florida

Gainesville, Florida, United States

Gulfcoast Research Institute

Sarasota, Florida, United States

Phoenix Clinical Research

Tamarac, Florida, United States

Sinai Hospital of Baltimore

Baltimore, Maryland, United States

Houston Methodist Research Institute

Houston, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 39012102 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26833157 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28717038 (View on PubMed)

Other Identifiers

TRL1068-101

Identifier Type: -

Identifier Source: org_study_id