Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia — COLIVAP  

Ventilator-associated Pneumonia Clinical Trial

Official title: Efficacy of Nebulized Versus Intravenous Colimycin for Treating Ventilator-associated Pneumonia Caused by Gram-negative Multidrug-resistant Bacteria: a Prospective, Multicenter, Randomized and Double-blind Study

Status Terminated

Clinical Trial Summary

Few antimicrobials are available to treat ventilated associated pneumonia (VAP) caused by Gram negative multi-resistant (MDR) bacteria. Colimycin often remains the only active antibiotic. The aim of the study is to demonstrate the superiority of nebulized colimycin over intravenous colimycin to treat VAP caused by Gramnegative MDR bacteria.

Clinical Trial Description

VAP is the most frequent nosocomial infection in critically ill patients and affects length of stay and cost in Intensive Care Unit. The increased incidence of nosocomial infections caused by MDR bacteria becomes a major health problem worldwide.

Nowadays, few antimicrobials are available to treat Gram negative MDR VAP. Colimycin often remains the only active antibiotic. Treating VAP by intravenous (IV) colimycin has two main limitations: risk of renal toxicity and low tissue penetration. Nebulization of colimycin offers the possibility of generating high lung tissue concentrations, rapid bactericidal effects and low systemic accumulation in experimental models. To date however, there is no study comparing clinical effectiveness of nebulized and intravenous colimycin.

We make the hypothesis that nebulized colimycin increases the clinical cure rate of VAP caused by Gram negative MDR bacteria compared to IV colimycin.

Primary Objective: To demonstrate the superiority of nebulized colimycin over intravenous colimycin for treating VAP caused by Gram-negative MDR bacteria.

Secondary Objectives:

1. To compare the microbiological cure rate at end of treatment

2. To compare the VAP recurrence rate after end of treatment

3. To compare the lung superinfection rate after end of treatment

4. To compare 28 day- and 90 day-mortality

5. To compare duration of mechanical ventilation

6. To compare length of ICU stay

7. To compare renal function during colimycin administration

8. To compare side effects resulting from colimycin nebulization and intravenous administration

Ancillary study:

In some centers, blood samples will be performed to measure colistin peak and trough plasma concentrations

Study design:

This is a randomized, multicenter, double-blind and phase III study

1. Randomization:

Patients are randomly assigned to experimental group or control group:

Control group: patients receive simultaneously intravenous colimycin and nebulized placebo.

Experimental group: patients receive simultaneously nebulized colimycin and intravenous infusion of placebo.

Dosing adjustment is according to renal function for intravenous infusion of colimycin or placebo.

2. Aerosol generation: Nebulization is performed with a vibrating plate nebulizer (Aeroneb® Solo) with following ventilator settings:

• Constant flow and volume-controlled mode

• Inspiratory/expiratory ratio of 1

• Tidal volume of 6-8 ml/kg

• Respiratory frequency of 12-18/min

• End-inspiratory pause of 20% To standardize nebulization procedure, a checklist form is completed by the nurse in charge of the patient.

3. Duration of treatment:

• 10 days in each group

• In intubated patients, weaning test is authorized after 4 days of treatment. If patient is extubated, aerosols are discontinued whereas intravenous infusions are continued (placebo or antibiotic) until day 10

• In tracheostomized patients: 10-day treatment for nebulized and intravenous therapy

4. Combined intravenous administration of other antimicrobials are authorized

5. Serum and microbiological samples

• Serum creatinine measured daily from baseline to day 11

• Lower respiratory tract specimens at day 5 and day 11 in intubated patients

6. Survival follow-up at day 28 and 90 days

Study population: Adult mechanical ventilated patients with VAP caused by Gram-negative MDR bacteria.

Sample size and Power consideration: Data will be analyzed with triangular test. Assuming a clinical cure rate at day 11 of 65% in the group treated with nebulized colimycin and of 45% in the group treated with intravenous colimycin, a mean sample size of 134 patients is required to provide 80% power, with a two-sided type I error rate of 5%. The 90th percentile of the number of patients to include is 196. ;

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Ventilator-Associated
• Ventilator-associated Pneumonia

• NCT number: NCT02906722
• Study type: Interventional
• Source: Assistance Publique - Hôpitaux de Paris
• Status: Terminated
• Phase: Phase 3
• Start date: July 31, 2017
• Completion date: June 19, 2018