A Clinical Study of YK-1169 Versus Ceftazidime-Avibactam in Adults With Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

This is a Phase III, randomized, double-blind, parallel-group, active-controlled, multicenter study in China enrolling approximately 590 adult participants diagnosed with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. The study aims to evaluate the efficacy and safety of YK-1169 compared with ceftazidime-avibatan sodium for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Each study site enrolled participants using a 1:1 competitive randomization scheme via the International Web-based Randomization System (IWRS).

Inclusion criteria

• Obtain a signed, ethics committee-approved informed consent form prior to the start of the trial
• Age 18 to 75 years (inclusive)
• Study participants with HABP/VABP requiring antibiotic treatment
• Study participants who meet the following clinical, imaging, and microbiological criteria
• Patients meeting the following clinical, imaging, and microbiological criteria: (1) Clinical criteria: Presence of at least one of the following clinical manifestations: ① New-onset or acutely worsening pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (respiratory rate greater than 25 breaths per minute), sputum production, or the need for mechanical ventilation; ② Hypoxemia (arterial blood oxygen partial pressure <60 mmHg at sea level, or a progressive decline in the oxygen partial pressure to inspired oxygen ratio (PaO₂/FiO₂)); ③ Deteriorating oxygenation requiring a change in ventilatory support to improve oxygenation, or a change in the level of positive end-expiratory pressure (PEEP); ④ Newly developed respiratory secretions requiring suctioning. In addition, the patient must exhibit at least one of the following clinical signs or laboratory abnormalities: ① Documented fever (body temperature ≥38°C); ② Hypothermia (body temperature ≤35°C); ③ Total peripheral blood white blood cell count ≥10,000/mm³; ④ Total peripheral blood white blood cell count ≤ 4,500/mm³; ⑤ Peripheral blood smear showing more than 15% immature neutrophils (e.g., band cells). (2) Imaging Criteria A chest imaging study performed within 48 hours prior to randomization showing new or progressive infiltrates suggestive of bacterial pneumonia. (3) Microbiological Criteria: Sufficient, qualified sputum (defined as <10 squamous epithelial cells and >25 white blood cells per low-power field in the microscopic specimen) or respiratory secretion specimens (e.g., bronchoalveolar lavage fluid) should be collected from all study participants and sent to the laboratory for Gram-stained smear microscopy, bacterial culture, and in vitro antimicrobial susceptibility testing. Pathogens isolated from bacterial cultures should be sent to a central microbiology laboratory for species identification and susceptibility testing, specifically determination of the minimum inhibitory concentration (MIC). In addition to bacterial culture, non-culture-based methods such as PCR may be used to detect bacterial and other pathogens. This will aid in the screening of HABP/VABP study participants for those who are positive for bacterial and other pathogens
• Study participants (including their partners) must have no plans to conceive between the time they sign the informed consent form and 3 months after the final administration of the study drug, must voluntarily use effective contraception, and must have no plans to donate sperm or eggs

Exclusion criteria

• Study participants who received effective antibiotic therapy for more than 24 hours within 72 hours prior to randomization. (Study participants who received antibiotic therapy for more than 24 hours within 72 hours prior to randomization but for whom the treatment failed may still be eligible for enrollment); (The investigator shall confirm treatment failure based on clinically available information, such as vital signs, physical examination, laboratory tests, and/or imaging studies)
• Individuals with known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia, or chemical pneumonia (including aspiration of gastric contents or inhalation injury)
• Individuals with known concomitant invasive aspergillosis, mucormycosis, or other highly lethal fungal infections
• Individuals with acute central nervous system infections
• Individuals with cystic fibrosis
• Patients with lung abscess
• Patients with advanced primary or metastatic lung malignancies
• Study participants with refractory septic shock, defined as persistent hypotension at the time of randomization despite adequate fluid resuscitation or vasopressor therapy
• Study participants currently undergoing hemodialysis or peritoneal dialysis
• Study participants with a history of epilepsy, or those requiring continued treatment with probenecid, valproic acid, or sodium valproate
• Evidence of any of the following serious immune system disorders:

• Current or anticipated neutropenia, defined as <500 neutrophils/mm³;
• Known human immunodeficiency virus (HIV) infection;
• Receipt of cancer chemotherapy, radiation therapy, or potent non-hormonal immunosuppressive agents (e.g., cyclosporine, azathioprine, tacrolimus, immunomodulatory monoclonal antibody therapies, etc.) within the past 3 months, or use of glucocorticoids equivalent to or exceeding 40 mg of prednisone daily for more than 14 days within the past 30 days
• Study participants with one or more of the following laboratory abnormalities in baseline specimens: estimated creatinine clearance ≤60 mL/min calculated using the Cockcroft-Gault formula (see Appendix 3); Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin levels > 3 times the upper limit of normal (ULN); neutrophil count < 0.5 × 10⁹/L, platelet count < 50 × 10⁹/L
• Acute Physiology and Chronic Health Evaluation (APACHE) II score > 35
• Female study participants with a positive pregnancy test at screening or who are currently breastfeeding
• Participants who have participated in any other clinical trial within 30 days prior to the start of this study
• Participants who have received YK-1169 treatment prior to screening
• Study participants with a history of allergy to cephalosporins, or a history of severe allergy to any other type of β-lactam antibiotic (e.g., penicillins, monobactams) other than cephalosporins (Note: For β-lactam antibiotics, a history of mild rash followed by uneventful re-exposure is not a contraindication for inclusion)
• Any situation or condition deemed by the investigator to potentially jeopardize the safety of the study participant or the quality of the study data