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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 48
- 试验地点
- 54
- 主要终点
- The proportion of subjects who achieved clinical cure
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
High-dose TQD3524 + Meropenem for injection
TQD3524: 3.75mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days TQD3524 : 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: Meropenem for injection (Drug)
Colistimethate Sodium for Injection + Meropenem for injection (High-dose control)
Colistimethate Sodium for Injection: 2.5mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days Colistimethate Sodium for Injection: 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: Colistimethate Sodium for Injection (Drug)
Colistimethate Sodium for Injection + Meropenem for injection (Low-dose control)
Colistimethate Sodium for Injection: 2.5mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days Colistimethate Sodium for Injection: 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: Colistimethate Sodium for Injection (Drug)
Low-dose TQD3524 + Meropenem for injection
TQD3524: 2.5mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days TQD3524 : 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: TQD3524 (Drug)
Low-dose TQD3524 + Meropenem for injection
TQD3524: 2.5mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days TQD3524 : 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: Meropenem for injection (Drug)
High-dose TQD3524 + Meropenem for injection
TQD3524: 3.75mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days TQD3524 : 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: TQD3524 (Drug)
Colistimethate Sodium for Injection + Meropenem for injection (High-dose control)
Colistimethate Sodium for Injection: 2.5mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days Colistimethate Sodium for Injection: 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: Meropenem for injection (Drug)
Colistimethate Sodium for Injection + Meropenem for injection (Low-dose control)
Colistimethate Sodium for Injection: 2.5mg/kg, q12h, intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days Colistimethate Sodium for Injection: 70mg, q12h, nebulized inhalation, for a duration of 7 to 14 days, with a maximum of 21 days Meropenem for injection: 2g, q8h,intravenous drip, for a duration of 7 to 14 days, with a maximum of 21 days
干预措施: Meropenem for injection (Drug)
结局指标
主要结局
The proportion of subjects who achieved clinical cure
时间窗: Up to 28 days
The proportion of subjects who achieved clinical cure in the modified intention-to-treat (mITT) population at the treatment-end visit (TOC) based on clinical efficacy evaluation.
The percentage difference in subjects achieving clinical cure between the experimental group and the control group
时间窗: Up to 28 days
During the TOC visit, the percentage difference in subjects achieving clinical cure between the modified intention-to-treat (mITT) populations of the test group and the control group.
次要结局
- The bacterial clearance rate(Up to 28 days)
- The proportion of subjects who achieved clinical cure(Up to 21 days)
- The proportion of subjects who achieved clinical cure(Up to 28 days)
- All-cause mortality(Up to 28 days)
- Average duration of mechanical ventilation(Up to 28 days)
- Average length of hospital stay(Up to 28 days)
- Change in APACHE II score(Up to 28 days)
- Change value of procalcitonin(Up to 28 days)
- The proportion of patients experiencing adverse reactions(Up to 28 days)