Clinical trial NCT06051513: Efficacy and Safety of Colistimethate Sodium for Injection in The Treatment of Carbapenem-Resistant Enterobacteriaceae Infection
Official title: Colistimethate Sodium for Injection in The Treatment of Carbapenem-Resistant Enterobacteriaceae Infection：a Prospective, Open-label, Randomized Controlled, Multicenter Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Carbapenem-Resistant Enterobacteriaceae Infection
Keywords: Colistimethate Sodium for Injection
Hospital-acquired pneumonia
Bloodstream infection
Carbapenem-resistant Enterobacteriaceae
Lead sponsor: Southeast University, China
Sponsor class: OTHER
First posted: 2023-09-25
Enrollment: 404
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Colistin can be used to treat the infection caused by carbapenem-resistant enterobacteriaceae(CRE). In China, patients diagnosed with Hospital-acquired-pneumonia (HAP)or bloodstream infection caused by CRE are recruited, and randomly assigned to two groups, and in one group the patients accept treatment with colistin, however in another group, the patients accept treatment without colistin. The efficacy and safety of the treatment between the two groups are compared.

Detailed description: The study will be conducted in accordance with good clinical practice and with the guidelines set out in the Declaration of Helsinki. After approval from local and national ethics committees, patients diagnosed with Hospital-acquired-pneumonia (HAP)or bloodstream infection caused by CRE from 14 centres in China will be recruited. All patients will be randomized to receive treatment with or without colistin in the ICU. The purpose of this study is to investigate the efficacy and safety of colistin when used to treat patients with CRE infection. The primary outcome is 14-day all cause mortality and the second outcomes include 14-day clinical cure rate, 14-day efficacy rate, ICU free days within 28 days after randomization，14-day microbiological cure rate，incidence of adverse events and severe adverse events in first 14 days, hospital mortality, 28-day all cause mortality, ICU mortality. Clopper-Pearson method is used to calculate the 95% confidence interval of mortality, Miettinen and Nurminen method is used to detect the difference between the two groups.

Eligibility criteria: Inclusion Criteria:

1. Patients who can provide written informed consent or their informed consent can be provided by legal guardian
2. Patients who are hospitalized
3. Adults ≥18 years and ≤85 years of age
4. Patients suspected of or diagnosed with hospital-acquired pneumonia (HAP, in a patient hospitalised for more than 48 hours or developing within 7 days after discharge from a hospital) or bloodstream infection caused carbapenem-resistant enterobacteriaceae (CRE) based on the culture results of the sample collected 5 days before the randomization or rapid diagnostic detection.

   Rapid testing of respiratory or blood specimens should be used to enable early identification of CRE infection pneumonia. Patients can be randomized based on the results of the rapid test while awaiting results of cultures from the local laboratory. However, if the sample does not grow CRE in the local microbiology laboratory culture, these patients will be withdrawn from the study drug treatment.

   Patients with HAP should fulfil one of the following systemic signs: 1)Fever (temperature \>38°C) or hypothermia (rectal/core temperature \<35°C);2)White blood cell (WBC) count \>10,000 cells/mm3, or WBC count \<4500 cells/mm3, or \>15% band forms and fulfil at least two of the following respiratory signs or symptoms:1)a new onset of cough (or worsening of cough);2)production of purulent sputum or endotracheal secretions;3)auscultatory findings consistent with pneumonia/pulmonary consolidation (e.g., rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony);4)dyspnoea, tachypnoea or hypoxaemia (O2 saturation \<90% or pO2 \<60 mmHg while breathing room air).

   Patients with bloodstream infection should fulfil one of the following criterion:1)fever(≥38 ℃);2)chills;3)hypotension(systolic \<90 mmHg, requiring vasopressors to maintain mean arterial pressure ≥60 mmHg,decreased by 30mmHg from baseline) ,and isolation of CRE from at least two blood culture collected from two different sites.
5. Respiratory or blood specimen obtained for culture within 5 days prior to randomization, and after the onset of signs and symptoms of HAP or bloodstream infection (ideally before receipt of any systemic antibiotics).
6. Patients whose APACHE II score is between 10 and 30.

Exclusion Criteria:

1. Patients who received polymyxin for more than 48 hours in the 72 hours prior to randomization.
2. Patients who received antibiotics more than 24 hours in the 72 hours prior to randomization, and after treatment，conditions of patients improved.
3. Patient with history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to Colistimethate Sodium for Injection or other ingredients of it.
4. Evidence of active concurrent pneumonia requiring additional antimicrobials treatment caused by Streptococcus pneumoniae，Haemophilus influenzae，Methicillin-resistant staphylococcus aureus，Vancomycin-resistant enterococcus，Mycoplasma pneumonia，Legionella pneumophila, respiratory syncytial virus, influenza virus, parainfluenza virus, Middle East Respiratory Virus, Mycobacteria, Aspergillus, Mucormycosis, Candida,etc. If these organisms are identified but it is deemed by the Investigator that no treatment is warranted and their presence does not significantly change the prognosis of the patient, then the patient may be considered for this study.
5. Patients who are diagnosed with primary lung cancer (including small cell lung cancer/non-small cell lung cancer patients) or other malignancy transferred to the lungs or other known post obstructive pneumonia. Patients who is known or suspected of active tuberculosis, cystic fibrosis, lung abscess, pyothorax or obstructive pneumonia.
6. Patients with hematological malignancy such as leukemia, lymphoma and multiple myeloma.
7. Patients with lung/heart transplantation or stem cell transplantation.
8. Patient was immunocompromised and at risk of infection by opportunistic pathogens including, but not limited to the following:1) HIV (AIDS or CD4 \<200). 2) chemoradiotherapy within 3 months prior to randomisation. 3) Immunosuppressive therapy including maintenance corticosteroids (0.5 mg/kg prednisone per day or other equivalent glucocorticoid). 4) Absolute neutrophil count \<500/mm3.
9. Patients with chronic liver failure with portal hypertension, acute hepatic failure or acute decompensation of chronic hepatic failure.
10. Patients who participated in other clinical trials within three months.
11. Patient was pregnant or breastfeeding. If either urine or serum β-hCG test was positive, the patient was excluded.
12. Patient who have been previously enrolled in this study.
13. Patients who have condionts that may affect the trial.
14. Other conditions exist researchers thought are not suitable.

Primary outcomes:
measure: 14-day all cause mortality
timeFrame: from randomization to day 14
Secondary outcomes:
measure: 14-day clinical cure rate
timeFrame: from randomization to day 14
measure: 14-day efficacy rate
timeFrame: from randomization to day 14
measure: ICU free days within 28 days after randomization
timeFrame: from randomization to day 28
measure: 14-day microbiological cure rate
timeFrame: from randomization to day 14
measure: incidence of adverse events and severe adverse events within first 28 days
timeFrame: from randomization to day 28
measure: hospital mortality
timeFrame: to be evaluated up to 90 days post randomization
measure: 28-day all cause mortality
timeFrame: from randomization to day 28
measure: ICU mortality
timeFrame: to be evaluated up to 90 days post randomization
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial People's Hospital
state: Anhui
city: Hefei
country: China
facility: The First Hospital of Anhui Medical University
state: Anhui
city: Jinjiang
country: China
facility: Jinjiang Municipal Hospitall
state: Fujian
city: Huai'an
country: China
facility: Huai'an First People's Hospital
state: Jiangsu
city: Lianyungang
country: China
facility: The First Hospital of Lianyungang
state: Jiangsu
city: Nanjing
country: China
facility: Zhongda Hospital Affiliated to Southeast University
state: Jiangsu
city: Nantong
country: China
facility: Affiliated Hospital of Nantong University
state: Jiangsu
city: Suzhou
country: China
facility: Suzhou Municipal Hospitial
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Taizhou
country: China
facility: JiangsuTaizhou People's Hospital
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi No.2 People's Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Central Hospital
state: Jiangsu
city: Yancheng
country: China
facility: Yancheng No.1 People's Hospital
state: Jiangsu
city: Yangzhou
country: China
facility: Northern Jiangsu People's Hospital
state: Jiangsu
city: Yixing
country: China
facility: Yixing People's Hospital
state: Jiangsu
Study officials:
affiliation: Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University
name: Yingzi Huang, MD
role: STUDY_CHAIR
References: