Efficacy and Safety of Colistimethate Sodium for Injection in The Treatment of Carbapenem-Resistant Enterobacteriaceae Infection

Study Overview
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Brief Summary
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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
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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.

Official Title
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Colistimethate Sodium for Injection in The Treatment of Carbapenem-Resistant Enterobacteriaceae Infection：a Prospective, Open-label, Randomized Controlled, Multicenter Clinical Trial

Conditions
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Carbapenem-Resistant Enterobacteriaceae Infection

Intervention / Treatment
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* Drug: treatment with or without colistin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who can provide written informed consent or their informed consent can be provided by legal guardian Patients who are hospitalized Adults ≥18 years and ≤90 years of age 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 72h before the randomization or rapid diagnostic detection. Rapid testing of respiratory or blood specimens utilizing Digital PCR(dPCR) technology 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. Respiratory or blood specimen obtained for culture within 72 hours prior to randomization, and after the onset of signs and symptoms of HAP or bloodstream infection (ideally before receipt of any systemic antibiotics). Patients whose APACHE II score is between 10 and 30. Exclusion Criteria: Patients who received polymyxin in the 72 hours prior to randomization. Patients who received antibiotics more than 24 hours in the 72 hours prior to randomization, and after treatment，conditions of patients improved. Patient with history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to Colistimethate Sodium for Injection or other ingredients of it. 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. 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. Patients with hematological malignancy such as leukemia, lymphoma and multiple myeloma. Patients with lung/heart transplantation or stem cell transplantation. 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. Patients with CKD receiving haemodialysis or peritoneal dialysis. Patients with an estimated creatinine clearance (CrCL) <16 mL/min when randomization is conducted. Patients expected to require haemodialysis or other renal support while on study therapy. Patients with chronic liver failure with portal hypertension, acute hepatic failure or acute decompensation of chronic hepatic failure. Patient had past or current history of epilepsy or seizure disorders, excluding febrile seizures of childhood. Patients who participated in other clinical trials within three months. Patient was pregnant or breastfeeding. If either urine or serum β-hCG test was positive, the patient was excluded. Patient who have been previously enrolled in this study. Other conditions exist researchers thought are not suitable.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: colistin group<br>For patients in this group, colistin based therapy is used. Colistin combined with metroperan or imipenem（MIC≤8mg/L），or colistin combined with tigecycline, or colistin combined with aminoglycosides (amikacin) are suggested to treat patients diagnosed with hospital-acquired pneumonia or bloodstream infection caused by carbapenem-resistant enterobacteriaceae. At the beginning of the intravenous use of Colistimethate Sodium for Injection，the load dose is 300mg CBA(about 9 million U)，and after 12-24 hours，the first maintenance dose should be given. The daily maintenance dose was 300-360mg CBA(9 million-10.9 million U), divided into two times (1/12h), for each time, 0.5-1 hour is needed to complete the infusion. Drug: colistin, other name: Colistimethate Sodium for Injection | Drug: treatment with or without colistin<br>* For patients in this treatment group, colistin based therapy is used. Colistin combined with metroperan or imipenem（MIC≤8mg/L），or colistin combined with tigecycline, or colistin combined with aminoglycosides (amikacin) are suggested to treat patients diagnosed with hospital-acquired pneumonia or bloodstream infection caused by carbapenem-resistant enterobacteriaceae. For patients in the control, best available treatment without colistin is uesed; Ceftazidime-avibactam, tigecycline combined with metroperan or imipenem（MIC≤8mg/L）, tigecycline combined with aminoglycosides (amikacin) are suggested to treat patients diagnosed with hospital-acquired pneumonia or bloodstream infection caused by carbapenem-resistant enterobacteriaceae.<br>|
| Active Comparator: control group<br>For patients in this group,best available treatment without colistin is used. Ceftazidime-avibactam, tigecycline combined with metroperan or imipenem（MIC≤8mg/L）, tigecycline combined with aminoglycosides (amikacin) are suggested to treat patients diagnosed with hospital-acquired pneumonia or bloodstream infection caused by carbapenem-resistant enterobacteriaceae.Dose of other drugs are listed below: 1-2g meropenem should be given every 8 hours，1g Imipenem every 8 hours or 6 hours，0.8g Amikacin everyday，2.5g ceftazidime-avibactam every 8 hours. A load dose of 200mg tigecycline is needed, followed by 100mg every 12 hours. | Drug: treatment with or without colistin<br>* For patients in this treatment group, colistin based therapy is used. Colistin combined with metroperan or imipenem（MIC≤8mg/L），or colistin combined with tigecycline, or colistin combined with aminoglycosides (amikacin) are suggested to treat patients diagnosed with hospital-acquired pneumonia or bloodstream infection caused by carbapenem-resistant enterobacteriaceae. For patients in the control, best available treatment without colistin is uesed; Ceftazidime-avibactam, tigecycline combined with metroperan or imipenem（MIC≤8mg/L）, tigecycline combined with aminoglycosides (amikacin) are suggested to treat patients diagnosed with hospital-acquired pneumonia or bloodstream infection caused by carbapenem-resistant enterobacteriaceae.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 14-day all cause mortality | the proportion of subjects who die within 14 days after randomization to the number of subjects in each group | from randomization to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 14-day clinical cure rate | the proportion of subjects who are thought as clinical effectiveness 14 days after randomization to the number of subjects in each group. | from randomization to day 14 | 
| 14-day efficacy rate | the proportion of subjects of who are thought as recovery 14 days after randomization to the number of subjects in each group. | from randomization to day 14 | 
| ICU free days within 28 days after randomization | days that patients are not treated in ICU within 28 days after randomization of each patient in each group. If the patient die within 28 days, it will be zero. | from randomization to day 28 | 
| 14-day microbiological cure rate | the proportion of subjects of microbiological cure to the number of subjects in each group 14 days after randomization. | from randomization to day 14 | 
| incidence of adverse events and severe adverse events in first 28 days | the proportion of patients who experience adverse events and severe adverse events within 14 days after randomization to the number of subjects in each group in first 14 days | from randomization to day 28 | 
| hospital mortality | the proportion of subjects who die when treated in hospital to the number of subjects in each group | to be evaluated up to 90 days post randomization | 
| 28-day all cause mortality | the proportion of subjects who die within 28 days after randomization to the number of subjects in each group | from randomization to day 28 | 
| ICU mortality | the proportion of subjects who die in ICU to the number of subjects in each group | to be evaluated up to 90 days post randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colistimethate Sodium for Injection, Hospital-acquired pneumonia, Bloodstream infection, Carbapenem-resistant Enterobacteriaceae