Clinical trial NCT05355207: Study to Evaluate Safety and Activity of TRL1068 in Chronic Rhinosinusitis
Official title: Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of TRL1068 in Subjects With Acute Exacerbation of Chronic Rhinosinusitis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Chronic Rhinosinusitis With Nasal Polyps
Keywords: biofilm
antibiotic-resistant infections
Lead sponsor: Trellis Bioscience LLC
Sponsor class: INDUSTRY
First posted: 2022-05-02
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single group, all subjects will receive 15 mg/kg of TRL1068 on Day 1
Primary purpose: TREATMENT

Brief summary: TRL1068 is expected to eliminate the pathogen-protecting biofilm in Chronic Rhinosinusitis, thus making these bacteria substantially more susceptible to established antibiotic treatment regimens. This initial study is to assess overall safety and pharmacokinetics (PK) of TRL1068. The goal of the development program is to demonstrate effectiveness of TRL1068 in difficult to treat bacterial infections such as in CRS.

Detailed description: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with significant morbidity and decreased quality of life. Defects in the epithelial cell barrier, increased exposure to pathogenic and colonized bacteria, and dysregulation of the host immune system are all thought to play prominent roles in disease pathogenesis. Colonization with S. aureus or P. aureus are associated with recalcitrant disease and biofilm formation, making eradication difficult.

Distribution of topical solutions in the unoperated sinuses has been observed to be less than 2% of the total irrigation volume, with almost no penetration in the frontal and sphenoid sinuses. For those patients with mucosal edema from infection and chronic inflammation, distribution is probably significantly less when applied topically. Intravenously administered TRL1068 is expected to achieve effective anti-biofilm levels throughout the sinonasal space for several weeks. TRL1068 is a monoclonal human antibody that rapidly eliminates biofilm at very low concentrations, thus making the targeted bacterial pathogens substantially more sensitive to standard of care antibiotic treatment regimen and greatly accelerating clinical improvement and potential for bacterial eradication.

Eligibility criteria: Inclusion Criteria:

1. Age 18 to 85 years, inclusive
2. Diagnosis of chronic rhinosinusitis with:

   1. Acute exacerbation of CRSwNP with increased sinonasal discharge OR
   2. Acute exacerbation post-functional endoscopic sinus surgery (FESS) with increased sinonasal discharge AND
   3. Sinonasal culture positive for SA or PA without concomitant fungal infection in culture or PCR
3. Symptoms and culture results justify initiation of topical and/or systemic antibiotic treatment
4. Willing and able to provide written informed consent
5. Willing to perform and comply with all study procedures including attending clinic visits as scheduled
6. Men and women of child bearing 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) for 28 days before receiving the investigational product (IP) and through Day 50.

Exclusion Criteria:

1. Active malignancy, or history of malignancy or chemotherapy within the past 2 years other than history of localized or surgical removal of focal skin cancer, or cervical cancer in situ treated successfully in the past by local treatment (including but not limited to cryotherapy or laser therapy) or by hysterectomy
2. Any chronic or acute bacterial infection other than acute exacerbation of CRS
3. Concomitant intrasinal culture or 16S PCR indicative of concomitant fungal infection
4. Allergic fungal rhinosinusitis, characterized by elevated antifungal IgE and eosinophilic mucus
5. Receiving or recently received another investigational drug (within 30 days of Day 1, or 5 half-lives of the investigational drug, whichever is longer)
6. Received a COVID-19 vaccine or booster within 14 days of planned Day 1 or planned COVID-19 vaccination within 14 days after Day 1
7. Positive serum test for pregnancy, pregnant, or nursing women
8. 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
9. 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 exam findings
timeFrame: 6 weeks
measure: Incidence of abnormal serum chemistries and hematology
timeFrame: 6 weeks
measure: Incidence of abnormal vital signs (temperature)
timeFrame: 6 weeks
measure: Incidence of abnormal vital signs (blood pressure)
timeFrame: 6 weeks
measure: Incidence of abnormal vital signs (heart rate)
timeFrame: 6 weeks
measure: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 7 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in serum (Cmax)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in serum (Cmin)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in serum (Tmax)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in serum (AUCLAST)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in serum (AUCINF)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in intrasinal concentrations (Cmax)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in intrasinal concentrations (Cmin)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in intrasinal concentrations (Tmax)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in intrasinal concentrations (AUCLAST)
timeFrame: 6 weeks
measure: Characterize the pharmacokinetics (PK) of TRL1068 in intrasinal concentrations (AUCINF)
timeFrame: 6 weeks
measure: Characterize the pharmacodynamics (PD) of TRL1068 (time to resolution of bacterial pathogen infection)
timeFrame: 6 weeks
measure: Characterize the pharmacodynamics (PD) of TRL1068 (time to resolution of signs and symptoms of acute exacerbation)
timeFrame: 6 weeks
measure: Assess the immunogenicity of TRL1068 as measured by anti-drug antibodies (ADAs)
timeFrame: 6 weeks
Secondary outcomes:
measure: Assess the incidence of improvement of baseline symptoms of chronic rhinosinusitis (CRS) after intravenous TRL1068
timeFrame: 7 weeks
measure: Assess time to improvement of baseline symptoms of CRS as compared with previous duration of acute exacerbations
timeFrame: 7 weeks
Other outcomes:
measure: Assess the effects of treatment on the intrasinal microbiome
timeFrame: 6 weeks
Locations:
Study officials:
References:
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.