Clinical trial NCT06621251: Study to Evaluate the Efficacy and Safety of TRL1068 for the Treatment of Prosthetic Joint Infection
Official title: Phase 2 Study to Evaluate the Efficacy and Safety of TRL1068 for the Treatment of Chronic Prosthetic Joint Infection of the Knee or Hip Without Exchange Arthroplasty
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Prosthetic Joint Infections of Hip
Prosthetic Joint Infections of Knee
Keywords: biofilm
antibiotic-resistant infections
Lead sponsor: Trellis Bioscience LLC
Sponsor class: INDUSTRY
First posted: 2024-10-01
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: TRL1068 is expected to eliminate the pathogen-protecting biofilm in the prosthetic joint and surrounding tissue, thus making pathogens substantially more susceptible to established antibiotic treatment regimens. This Phase 2 study is designed to assess efficacy and safety of TRL1068 in combination with a DAIR (debridement, antibiotics, and implant retention) procedure for chronic prosthetic joint infections of the knee and hip, specifically, eliminating the need for the standard of care 2-stage exchange surgery, so that the original prosthesis can be retained.

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 and in the first-in-human Phase 1 study TRL1068-101 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:

1. Age 18 to 85 years, inclusive
2. Chronic PJI:

   1. Systemic Host Grade of A or B \[McPherson 2011\] (Appendix 3) and either
   2. First chronic PJI of the hip or knee, confirmed by synovial fluid aspirate culture or
   3. Recurrent chronic PJI of the hip or knee confirmed by synovial fluid aspirate culture
3. Willing to be randomized to either:

   1. Receive TRL1068 and to be scheduled for DAIR between Day 15 + 7 days (i.e., between days 15-22) and 10 weeks of targeted antibiotic treatment or
   2. Participate in an observational study arm that receives SoC (i.e., two-stage prosthetic joint replacement) and

   i. Sonication of the explanted prosthesis and performance of synovial fluid aspirates ii. Consents to conduct of stage 2 (implantation of new prosthesis)
4. At least 1 positive bacterial culture without concomitant fungal infection from the infected joint (a joint aspirate within 28 days prior to Screening is acceptable)
5. All identified pathogen(s) are susceptible to the planned antibiotic regimen
6. Availability of radiology assessments of the affected joint without signs of loosening of the prosthesis or presence of osteomyelitis
7. Willing and able to provide written informed consent
8. Willing to perform and comply with all study procedures, including attending clinic visits as scheduled
9. Men and women of childbearing potential (WOCBP) must be willing to practice a highly effective method of contraception that may include, but is not limited to, abstinence, sex only with persons of the same sex, monogamous relationship with vasectomized partner, vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal methods, intrauterine device (IUD), or use of spermicide combined with a barrier method (e.g., condom, diaphragm) through Day 365.

Exclusion Criteria:

1. PJI associated with presence of concomitant fungal infection or bacterial pathogens that, even when in planktonic form (i.e., when released from biofilm), cannot be adequately treated with available antibiotics.
2. More than one draining sinus and single draining sinus of \> 1 cm
3. Less than 3 years life expectancy based on underlying morbidities
4. Expected to receive chronic suppressive antibiotic therapy
5. Congestive heart failure; New York Heart Association (NYHA) Functional Classification of Heart Failure Grade \> 3B
6. Uncontrolled diabetes, defined as hemoglobin A1c \> 7.4%.
7. BMI \> 45
8. Any acute illness within 14 days of Day 1 that could confound the evaluation of safety evaluation of TRL1068, especially local or systemic fungal and other known or suspected bacterial infections
9. Receiving or recently received another investigational drug (within 30 days of Day 1, or 5 half-lives of the investigational drug, whichever is longer)
10. Received any vaccine within 14 days prior to Day 1
11. Positive serum pregnancy test for WOCBP, or nursing women
12. History of drug or alcohol abuse that, in the opinion of the Investigator, would interfere with the patient's ability to comply with all study requirements
13. Any other comorbidity or condition that, in the opinion of the Investigator would make the patient unsuitable for the study or unable to comply with the study requirements.

Primary outcomes:
measure: Efficacy of TRL1068 in eliminating the need for an SoC 2-stage exchange arthroplasty
timeFrame: Day 365
Secondary outcomes:
measure: Duration (days) with resolved PJI
timeFrame: Day 365
measure: Incidence of recurrent PJI across treatment groups
timeFrame: Day 365
measure: Incidence of PJI reinfection across treatment groups
timeFrame: Day 365
measure: Incidence, duration and severity of AEs or SAEs of secondary infections
timeFrame: Day 365
measure: Musculoskeletal Infection Society (MSIS) Scores
timeFrame: Day 365
measure: Quality of life PROMIS-PF Short Form 6b
timeFrame: Day 365
measure: Resource utilization: duration of hospitalization as a result of PJI, SoC or surgical wound infection
timeFrame: Day 365
measure: Resource utilization: need to stay in a rehabilitation center or other institution, e.g., nursing home as a result of PJI, SoC or surgical wound infection
timeFrame: Day 365
measure: Incidence, duration and severity of AEs and SAEs across treatment groups
timeFrame: Day 365
Other outcomes:
measure: Immunogenicity of TRL1068 as measured by anti-drug antibodies (ADAs)
timeFrame: Day 365
measure: Pharmacokinetics - serum and synovial concentrations of TRL1068
timeFrame: Day 365
measure: Pharmacodynamics - inflammatory biomarkers - CRP
timeFrame: Day 365
measure: Pharmacodynamics - inflammatory biomarkers - ESR
timeFrame: Day 365
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
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 Baltimore
state: Maryland
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Wilmington
country: United States
facility: M3 Wake Research Associates
state: North Carolina
city: Galveston
country: United States
facility: University of Texas Medical Branch at Galveston
state: Texas
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
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.