Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia (COLIVAP)

Assistance Publique - Hôpitaux de Paris

Status and phase: Terminated; Phase 3

Conditions: Ventilator-associated Pneumonia

Treatments: Drug: Intravenous placebo; Drug: Intravenous colimycin; Drug: Nebulized placebo; Drug: Nebulized colimycin

Study type: Interventional

Funder types: Other

Identifiers

NCT02906722

2016-000389-41 (EudraCT Number)

P130902

Details and patient eligibility

About

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.

Full 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.

Enrollment: 7 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion criteria

• Age older than 18 yr
• Invasive mechanical ventilation for more than 48 h Tracheostomized patients receiving intermittent mechanical ventilation can be included
• VAP caused by Gram-negative MDR bacteria resistant to all β-lactams and fluoroquinolones

Exclusion criteria

• Extrapulmonary Gram-negative MDR infection requiring intravenous colimycin
• VAP associated with bacteremia requiring combined treatment by nebulized and intravenous colimycin
• Hypersensitivity to colistimethate, colistin base, polymyxins and/or their excipients
• Porphyria
• Severe hypoxemia defined as PaO2 / FiO2< 100; if veno-venous ECMO is initiated, the patient can be included
• Severe brain injury (initial Glasgow coma score < 8) during the first 7 days before randomization
• Myasthenia
• cystic fibrosis
• Refusal to participate in the study
• Participation in any clinical study of a therapeutic investigational product within 30 days prior to the first day of inclusion
• No affiliation to social health insurance
• Patient under guardianship
• Pregnancy

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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7 participants in 2 patient groups

Experimental group

Experimental group

Description:

Patients receive simultaneously nebulized colimycin every 8 h and intravenous placebo administered once, twice or 3 times per day according to renal function

Treatment:

Drug: Nebulized colimycin

Drug: Intravenous placebo

Control group

Active Comparator group

Description:

Patients receive simultaneously intravenous colimycin administered once, twice or 3 times per day according to function renal and nebulized placebo every 8 h

Treatment:

Drug: Intravenous colimycin

Drug: Nebulized placebo