Study on the Safety and Efficacy of Polymyxin E2 Methanesulfonate for Injection in the Treatment of Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia Caused by Carbapenem-Resistant Gram-Negative Bacteria

Official title

Randomized, Double-blind, Parallel-controlled, Multicenter Phase II Clinical Study to Evaluate the Efficacy and Safety of Polymyxin E2 Mesylate Intravenous Infusion Combined With Nebulized Inhalation in the Treatment of Hospital-acquired Bacterial Pneumonia/Ventilator-associated Bacterial Pneumonia Caused by Carbapenem-resistant Gram-negative Bacteria

Overview

Study on the Safety and Efficacy of Polymyxin E2 Methanesulfonate for Injection in the Treatment of Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia Caused by Carbapenem-Resistant Gram-Negative Bacteria.

Interventions

• Drug TQD3524
  After entering the body, TQD3524 can be hydrolyzed into polymyxin E2 and its derivatives, exerting bactericidal effects .
• Drug Meropenem for injection
  Meropenem for injection is a β-lactam.
• Drug Colistimethate Sodium for Injection
  Colistimethate Sodium for Injection is a prodrug of polymyxin E. After entering the body, polymyxin E mesylate is hydrolyzed to polymyxin E (colistin), which exerts bactericidal activity.

Primary outcome measures

• The proportion of subjects who achieved clinical cure [Time frame: Up to 28 days]
• The percentage difference in subjects achieving clinical cure between the experimental group and the control group [Time frame: Up to 28 days]

Secondary outcome measures (10)

• The bacterial clearance rate [Time frame: Up to 28 days]
• The proportion of subjects who achieved clinical cure [Time frame: Up to 21 days]
• The proportion of subjects who achieved clinical cure [Time frame: Up to 21 days]
• The proportion of subjects who achieved clinical cure [Time frame: Up to 28 days]
• All-cause mortality [Time frame: Up to 28 days]
• Average duration of mechanical ventilation [Time frame: Up to 28 days]
• Average length of hospital stay [Time frame: Up to 28 days]
• Change in APACHE II score [Time frame: Up to 28 days]
• Change value of procalcitonin [Time frame: Up to 28 days]
• The proportion of patients experiencing adverse reactions [Time frame: Up to 28 days]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years old (based on the date of signing the informed consent form);
• The subject (or their guardian) voluntarily signed the informed consent form；
• Acute pulmonary infection with hospitalization duration exceeding 48 hours or within 7 days after discharge; or acute pulmonary infection patients who have undergone mechanical ventilation via oral or nasal tracheal intubation for at least 48 hours;
• Chest imaging examination (X-ray or CT) within 72 hours prior to randomization reveals characteristics of new or worsening pulmonary infiltration;
• At least one of the following physical signs or laboratory abnormalities: ① fever (temperature ≥38℃); ② hypothermia (temperature ≤35℃); ③ elevated peripheral white blood cell count (WBC ≥10×10\^9/L); ④ decreased white blood cell count (WBC ≤4.5×10\^9/L); ⑤ more than 15% of immature neutrophils such as band forms in peripheral blood;
• At least one of the following clinical symptoms is present: ① new or acute worsening of pulmonary symptoms or signs, such as cough, dyspnea, increased respiratory rate (respiratory rate > 25 breaths per minute), expectoration, or the need for mechanical ventilation; ② hypoxemia (arterial blood gas oxygen partial pressure below 60 mmHg at standard atmospheric pressure, or a progressive decrease in the ratio of oxygen partial pressure to inspired oxygen concentration (PaO2/FiO2)); ③ deteriorating oxygenation requiring replacement of ventilation support system to improve oxygenation, or a change in the level of positive end-expiratory pressure support; ④ new respiratory secretions requiring suction;
• A specific carbapenem-resistant Gram-negative bacterium was cultured from qualified lower respiratory tract specimens within the first five days/screening period, with in vitro susceptibility testing confirming resistance to carbapenems；
• Female subjects without reproductive potential must meet at least one of the following criteria: a) cessation of regular menstruation for at least 12 consecutive months; b) having undergone hysterectomy and/or bilateral oophorectomy. Female subjects with reproductive potential must have a negative serum pregnancy test result at the screening visit and agree to use reliable contraception throughout the study period;
• Male subjects must agree to adopt reliable contraceptive measures throughout the entire study period.

Exclusion criteria

• Those who currently suffer from epilepsy/myasthenia gravis or have a history of seizures (excluding febrile seizures in childhood)/myasthenia gravis;
• Those who are undergoing hemodialysis or peritoneal dialysis;
• Combined infections with other lung microbiota: viral pneumonia, fungal pneumonia, pulmonary tuberculosis, atypical pathogen infections, etc；
• Current concurrent infection of other parts/organs;
• Patients with concurrent refractory septic shock, who still exhibit persistent hypotension despite adequate fluid resuscitation or vasopressor therapy prior to randomization;
• Individuals with immune deficiency or compromised immune function, including but not limited to: human immunodeficiency virus infection, hematological malignancies, bone marrow transplantation, immunosuppressive therapy, and systemic corticosteroid treatment (defined as a daily dose equivalent to prednisone ≥20mg and a treatment duration >14 days);
• During the screening period, any of the following laboratory abnormalities is present: aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels are more than 5 times the upper limit of normal, or AST and/or ALT levels are more than 3 times the upper limit of normal and total bilirubin levels are more than 1.5 times the upper limit of normal, or neutrophil count < 1.0×10\^9/L, or platelet count < 60×10\^9/L; creatinine clearance rate (cLcr) ≤ 50 mL/min;
• Suffering from lung diseases that can interfere with treatment response assessment;
• Patients with lung abscess, empyema, and mechanical obstructive pneumonia;
• New York Heart Association (NYHA) class III-IV heart failure;
• Transplant patients；
• Patients with an estimated survival time of less than 1 month according to the clinical judgment of the researchers;
• Individuals with allergic reactions to polymyxins or carbapenems;
• Sbjects requiring >2 systemic antimicrobial drugs for the treatment of Gram-negative bacterial infections;
• Patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than 30;
• Women who are pregnant or breastfeeding;
• Use potentially effective antibiotics to treat carbapenem resistant gram-negative bacterial infections within 72 hours prior to randomization, and the treatment duration exceeds 24 hours；
• When the culture results of samples from the first 5 days/screening period are available, it is found that the subject has Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia (HAP/VAP) caused by gram-negative bacteria that are expected to have no response to polymyxin drugs;
• Subjects who have participated in other clinical trials within 30 days prior to the first dose of medication;
• Other factors determined by the researcher that make the subject unsuitable for participating in this study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 27 centers

• The First Affiliated Hospital of Bengbu Medical College — Bengbu
• Beijing Tsinghua Changgung Hospital — Beijing
• The First Affiliated Hospital of Chongqing Medical University — Chongqing
• Foshan Nanhai District People's Hospital — Foshan
• The First Clinical College of Guangzhou Medical University — Guangzhou
• Peking University Shenzhen Hospital — Shenzhen
• The Fifth Affiliated Hospital, Sun Yat-sen University — Zhuhai
• The Second Hospital Of Hebei Medical University — Shijiazhuang
• … and 19 more centers

Identifiers

NCT: NCT07512596 · TQD3524-II-02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗