Prosthetic Joint Infection (PJI)
Conditions
Brief summary
This is a Phase 2b, randomized, controlled, open-label clinical study evaluating the efficacy, safety, and local PK profiles of TNP-2092 administered via IA injection on a background of antibiotic treatment in participants with early postoperative (within 3 months after index arthroplasty) or acute hematogenous (within 4 weeks of infection) PJI after knee arthroplasty, without debridement, and in participants with chronic PJI (including PJI occurring after various joint arthroplasties and revision arthroplasties) requiring long-term antibiotic suppressive treatment.
Detailed description
The study population comprises participants with early postoperative (within 3 months of index arthroplasty) or acute hematogenous (within 4 weeks of infection symptoms) PJI after knee arthroplasty, or participants with chronic PJI requiring long-term antibiotic suppressive treatment (including PJI occurring after various joint arthroplasties and revision arthroplasties).
Interventions
Starting on D1, administer by intra-articular injection either once daily or once weekly. Participants in Arm A will receive once-daily dosing for 14 days, and participants in Arm B and Arm C will receive once-weekly dosing for 4 weeks. Doses should be administered at approximately the same time whenever possible (no more than 1 hour earlier or later than the time of the first dose).
DRUGVancomycin Hydrochloride for Injection
Participants receive empiric treatment with vancomycin 1 g administered via IV infusion every 12 hours (q12h). For participants aged 65 years or older, the vancomycin dose may be adjusted to 0.5 g q12h; during the study, it may also be adjusted according to renal function.
DRUGOral antibiotics
After 14 days of IV infusion, participants who meet the criteria for IV to oral switch may switch to oral antibiotic treatment (minocycline or levofloxacin, as determined by the investigator). After 7 days of IV infusion, if IV administration cannot be continued due to tolerability or other reasons, participants may also switch to oral antibiotic treatment if they meet the criteria for IV to oral switch. Oral treatment lasts 56-63 days and combined IV plus oral treatment lasts a total of 10 weeks (70 days). * Levofloxacin tablets: 0.5 g (1 tablet) orally once daily, taken within 1 hour before breakfast, for 56-63 days. * Minocycline hydrochloride capsules: administered orally twice daily; the first dose is 200 mg (2 capsules), and all subsequent doses are 100 mg (1 capsule), for 56-63 days.
DRUGAppropriate intravenous and/or oral antibiotics
The investigator will select appropriate intravenous and/or oral antibiotics based on the participant's condition and with reference to domestic and international guidelines, to be continued for 10 weeks (70 days).
Sponsors
TenNor Therapeutics (Zhongshan) Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Eligible participants diagnosed with early postoperative or acute hematogenous PJI after knee arthroplasty will be randomized 1:1 to Arm A (TNP-2092 IA once daily for 14 days) and Arm B (TNP-2092 IA once weekly for 4 weeks), with 10 participants per arm; participants with chronic PJI requiring long-term antibiotic suppressive therapy (including PJI occurring after various joint arthroplasties and revision arthroplasties) will be assigned to Arm C (TNP-2092 IA once weekly for 4 weeks), with a maximum of 20 participants.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Participants with PJI that is early postoperatively (within 3 months of index arthroplasty) or acute hematogenous (within 4 weeks of infectious symptoms) after knee arthroplasty; or participants with chronic PJI requiring long-term antibiotic suppressive therapy (including PJI occurring after any type of joint arthroplasty or revision arthroplasty). 2. PJI that, in the investigator's judgment, is suspected or confirmed to be caused by Gram-positive bacteria. 3. Agrees to receive local IA injection of TNP-2092. 4. Age ≥18 years and ≤80 years at the time of signing the informed consent form (ICF), regardless of sex. 5. The implanted joint prosthesis is well fixed. 6. No sinus tract in the affected joint. 7. Body mass index (BMI) ≥18 kg/m² and ≤40 kg/m². 8. Female participants who are of childbearing potential and those who are \<2 years postmenopausal and have not been permanently sterilized must have a negative pregnancy test at baseline and agree to voluntarily use effective contraception from the time of signing the ICF until 8 weeks after the last study treatment. Female participants who are not of childbearing potential (i.e., have undergone tubal ligation, hysterectomy, or bilateral oophorectomy, or are ≥2 years postmenopausal) or whose partner has undergone a vasectomy do not need to use contraception. If a male participant's female partner is of childbearing potential, the male participant must agree to voluntarily use effective contraception and must avoid donating sperm from the time of signing the ICF until 8 weeks after the last study treatment.
Exclusion criteria
1. Known history of hypersensitivity or intolerance to any of the following medications: vancomycin or TNP-2092. 2. Confirmed PJI caused by Gram-positive bacteria mixed with other pathogens, or PJI caused solely by fungi, mycobacteria, or Gram-negative bacteria infection. 3. Documented sepsis or septicemia. 4. Life expectancy of less than 1 year. 5. Female participants who are pregnant or breastfeeding. 6. Any surgical or medical condition that, in the investigator's opinion, may affect the participant's ability to participate in the study, affect administration of the investigational product, or affect interpretation of the study results, including but not limited to active malignancy, metabolic disease, alcohol or drug abuse, or clinically significant laboratory abnormalities. 7. Presence of severe hepatic, hematologic, or immune system disease, as evidenced by any of the following: a Acute hepatitis of any cause within the past year. b Serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 2 × upper limit of normal (ULN), or total bilirubin \> 1.5 × ULN. c Manifestations associated with end-stage liver disease, such as ascites or hepatic encephalopathy. d Current or anticipated neutropenia (i.e., neutrophil count \< 0.5 × 10⁹/L). e Receipt of cancer chemotherapy, radiotherapy, or potent non-corticosteroid immunosuppressants (e.g., cyclosporine, azathioprine, tacrolimus, immunomodulatory monoclonal antibody therapy, etc.) within the past 3 months, or receipt of corticosteroid therapy for more than 14 days (≥40 mg prednisone/day) within 30 days before enrollment; or participants expected to require immunosuppressive therapy during the study. 8. Positive HIV antibody results during screening. 9. History of severe renal disease or evidence of such disease, or creatinine clearance \< 30 mL/min calculated using the Cockcroft-Gault formula. 10. Receipt of another investigational drug within 30 days or 5 half-lives (whichever is longer) before the first dose of the investigational product in this study, or participation in a medical device clinical study. 11. In the investigator's opinion, the participant is unable to comply with the protocol and investigational product administration procedures or to complete the clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment failure rate | Within 6 months after the initiation of study treatment | Participants will be considered as treatment failures if any of the following criteria are met: * Failure to meet the intravenous (IV) to oral switch criteria at the end of background intravenous treatment (only for early postoperative or acute hematogenous PJI participants) * The end of IA treatment (EOIA) assessment is non-response. * The end of treatment(EOT) assessment is non- response. * Requiring surgical treatment or systemic antibiotic treatment beyond the study regimen for the primary infected joint during the study. * Death due to the primary joint infection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment failure rate | Within 12 months after the initiation of study treatment | — |
| End of IA treatment (EOIA) response rate | On day 15 (D15) for participants receiving daily TNP-2092 dosing, on D29 for participants receiving weekly TNP-2092 dosing | Participants will be considered as responders if the following criterion is met: a Evaluation of the primary infection site shows improvement compared to baseline, defined as improvement in pain, erythema, edema, or wound drainage in the infected joint. Specifically, improvement in pain is defined as a pain score lower than baseline or ≤3 points. |
| End of treatment (EOT) response rate | On Day71 | Participants will be considered as responders if all of the following criteria are met: a Serum C-reactive protein (CRP) ≤ 10 mg/L, or lower than baseline level and ≤ 20 mg/L. b Joint pain resolved (numeric rating scale score lower than baseline) or tolerable (numeric rating scale score 0-3 points). c The score of injected joint function scale is higher than baseline. |
| Adverse Events (AEs) | Day 1 to Day 361 | An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug. |
| Concentrations of TNP-2092 in synovial fluid | Arm A: collected within 1 hour before administration on Day 2, Day 7, and Day 14; Arm B and Arm C: collected within 1 hour before administration on Day 8, Day 15, and Day 22. | Synovial fluid concentrations of TNP-2092 were measured by a specific and validated assay. |
Countries
China
Contacts
CONTACTCao Li
CONTACTJing Chen
Outcome results
None listed