A Phase 1/2 Study to Evaluate the Safety, PK and Efficacy of TNP-2092 Administered Via IA Injection in PJI Participants

Официальное название

A Phase 1/2 Study to Evaluate the Safety, PK and Efficacy of TNP-2092 Administered Via IA Injection in Participants With Early or Acute Hematogenous PJI Requiring or Not Requiring DAIR After TKA, or Requiring Long-term Antibiotic Therapy

Обзор

This is a Phase 1/2, randomized, controlled, open-label, proof-of-concept study to evaluate the safety and tolerability, local and systemic PK profiles of TNP-2092 administered via IA injection on the basis of vancomycin IV and oral antibiotics therapy in participants with early (within 1 month of TKA) or acute hematogenous (within 3 weeks of infectious symptoms) PJI requiring or not requiring DAIR therapy after TKA, or requiring long-term antibiotic suppression therapy for PJI (including PJI occurring after various joint replacements and revision surgeries).

Подробное описание

The study population is participants with confirmed or suspected Gram-positive bacteria causing early (ie, within 1 month of TKA) or acute hematogenous (within 3 weeks of infection symptoms) PJI requiring or not requiring DAIR therapy following TKA, or requiring long-term antibiotic suppression therapy for PJI (including PJI occurring after various joint replacement and revision surgeries). Participants will undergo screening assessments within 7 days prior to study start.

Вмешательства

• Препарат TNP-2092 for injection
  TNP-2092 for injection, 100 mg/vial, Intra-articular administration (IA), 10ml (50 mg) once daily for 14 days. TNP-2092 dose volume, dose, frequency, and duration can be adjusted according to the sentinel group synovial fluid TNP-2092 concentration, PK characteristics, and safety results at the EA visit.
• Препарат Vancomycin Hydrochloride for Injection (IA)
  Vancomycin Hydrochloride for Injection, 0.5 g/vial, Intra-articular administration, 10 mL (0.5 g) once daily for 14 days.
• Препарат Vancomycin Hydrochloride for Injection (IV)
  Vancomycin Hydrochloride for Injection, 0.5 g/vial, Intravenous infusion, 250 mL (1 g) q12h ± 1h per day, for 14 days.
• Препарат Oral antibiotics
  Rifampicin capsules: 0.15 g/capsule. 0.45 g (3 capsules) orally once daily within 1 h before breakfast for 8 weeks (56 days). Levofloxacin Tablets: 0.5 g/tablet. 0.5 g (1 tablet) orally once daily within 1 hour before breakfast for 8 weeks (56 days). If susceptibility testing results show resistance to rifampicin and/or levofloxacin, or intolerance by the patient 's participant, treatment with oral minocycline hydrochloride capsules will be substituted as follows:Minocycline hydrochloride caps
• Препарат Background Treatment
  Background treatment will be determined by the investigator.

Первичные конечные точки

• Safety and Tolerability of TNP-2092 by Assessment of the Number of Adverse Events (AEs) [Срок оценки: Day 1 to Day 187]

Вторичные конечные точки (12)

• TNP-2092 concentrations in synovial fluid [Срок оценки: At 12, 24 hours after the first dose of TNP-2092, before dosing on Day 7, before the last dose, and at 12, 24, 48 hours after the last dose.]
• Maximum Observed Plasma Concentration (Cmax) of TNP-2092 after the first dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24 hours after the first dose]
• Time to Reach the Maximum Observed Plasma Concentration (Tmax) after the first dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24 hours after the first dose]
• Area under the curve from the time of dosing to the last measurable concentration (AUC 0-t) after the first dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24 hours after the first dose]
• Area under the curve from the time of dosing to infinity (AUC 0-∞) after the first dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24 hours after the first dose]
• Elimination half-life (t 1/2) after the first dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24 hours after the first dose]
• Maximum observed concentration at steady state (Cmax, ss) after the last dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24, 48 hours after the last dose]
• Time to maximum concentration at steady state (Tmax, ss) after the last dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24, 48 hours after the last dose]
• Area under the curve from the time of dosing to the last measurable concentration at steady state (AUC 0-t, ss) after the last dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24, 48 hours after the last dose]
• Area under the curve from the time of dosing to infinity at steady state (AUC 0-∞, ss) after the last dose [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24, 48 hours after the last dose]
• Area under the curve over the dosing interval at steady state (AUC 0-tau, ss) [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24 hours after the last dose]
• Elimination half-life at steady state (t 1/2, ss) [Срок оценки: Before administration (within 1 hour), 1, 4, 12, 24, 48 hours after the last dose]

Критерии участия

Критерии включения

• Early (within 1 month of TKA) or acute hematogenous (within 3 weeks of infectious symptoms) PJI requires or does not require DAIR therapy after TKA, or results of treatment for PJI (including PJI occurring after various joint replacements and revision surgeries) did not meet the clinical cure criteria and requiring long-term antibiotic suppression therapy as judged by investigators before enrollment.
• Suspected or confirmed PJI was caused by a Gram-positive bacterial infection, including methicillin-resistant and ciprofloxacin-resistant Staphylococcus aureus and Staphylococcus epidermidis, as judged by the investigator.
• Agree to be hospitalized for 2 weeks with local intra-articular injection.
• 18 years of age or older (of either sex) at the time of signing the informed consent form (ICF).
• The implanted prosthetic joint was well fixed.
• No sinus tract that communicates with the prosthesis.
• Body mass index (BMI) ≥ 18 kg/m\^2 and ≤ 34 kg/m\^2.
• Agree to voluntarily use effective contraception from signing the ICF through 8 weeks after the last dose of investigational product (in case of premature withdrawal from the study) or through completion of the end-of-study visit. Male participants must refrain from donating sperm during this period.

Критерии исключения

• History of hypersensitivity or intolerance to any of the following agents: vancomycin or TNP-2092.
• Definite PJI of Gram-negative infection, fungal infection, or Enterococcus infection, or Mycobacterium infection, or Gram-positive mixed Gram-negative and/or fungal infection.
• Definite systemic infection (sepsis).
• Expected survival less than 1 years.
• Female participant is pregnant, lactating, or has a positive screening/baseline pregnancy test.
• Surgical or medical conditions that, in the opinion of the investigator, could affect the participant's ability to participate in the study, or affect the administration of investigational product, or affect the interpretation of study results, including but not limited to active malignancy, metabolic disease, alcohol or drug abuse, or clinically significant laboratory abnormalities.
• Presence of serious liver, blood, or immune system disorders as evidenced by the following:

• Acute hepatitis of any cause within the past year.
• Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels > 2 times the upper limit of normal (ULN).
• Presence of end-stage liver disease-related manifestations such as ascites or hepatic encephalopathy.
• Current or anticipated neutropenia (ie, neutrophil count < 0.5 x 10\^9/L).
• Chemotherapy for cancer, radiation therapy, or potent noncorticosteroid immunosuppressants (eg, cyclosporine, azathioprine, tacrolimus, immunomodulatory monoclonal antibody therapy, etc) within the past 3 months or corticosteroids (≥ 40 mg prednisone/day) for more than 14 days within 30 days prior to randomization.
• Positive AIDS antibody screening.
• History or evidence of severe renal disease or creatinine clearance < 30 mL/min based on the Cockcroft-Gault formula.
• Treatment with an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention.
• Participants who, in the opinion of the investigator, were unable to comply with the protocol and study drug administration procedures or complete the clinical study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• The First Affiliated Hospital of Xinjiang Medical University — Ürümqi

Идентификаторы

NCT: NCT06889701 · TNP-2092-IA-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗