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

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

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.

Study Overview

• Status: Terminated
• Conditions: Ventilator-associated Pneumonia
• Intervention / Treatment: Drug: Intravenous placebo; Drug: Nebulized colimycin; Drug: Intravenous colimycin; Drug: Nebulized placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Patients receive simultaneously nebulized colimycin every 8 h and intravenous placebo administered once, twice or 3 times per day according to renal function	Drug: Intravenous placebo; administration once, twice or 3 times per day according to renal function; Drug: Nebulized colimycin; Nebulization is performed with a vibrating plate nebulizer (Aeroneb® Solo) every 8h
Active Comparator: Control group; Patients receive simultaneously intravenous colimycin administered once, twice or 3 times per day according to function renal and nebulized placebo every 8 h	Drug: Intravenous colimycin; administration once, twice or 3 times per day according to renal function; Drug: Nebulized placebo; Nebulization is performed with a vibrating plate nebulizer (Aeroneb® Solo) every 8h

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure of VAP caused by Gram-negative multidrug resistant bacteria	Clinical cure is defined as: resolution of clinical and biological signs of infection and improved radiological signs; and modified clinical pulmonary infection score (CPIS) less than 6; and negative culture of lower respiratory tract specimen or, successful weaning from invasive mechanical ventilation between day 5 and day 11; patient colonized with the same pathogen in the respiratory tract is considered as cured, if clinical and biological signs of infection resolved, radiological signs improved, CPIS < 6 and/or successful weaning from invasive mechanical ventilation has been obtained.	At end of therapy visit (day11) or before day11 if treatment is considered as failed.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiological cure rate		At end of therapy visit (day11) or before day11 if treatment is considered as failed.
VAP recurrence rate	VAP recurrence rate, defined as initial clinical cure of VAP with colimycin at day 11 followed by reappearance of clinical and biological signs of infection, CPIS greater than 6, and significant concentrations of Gram-negative MDR bacteria in lower respiratory tract specimen	day 28
Lung superinfection rate	Lung superinfection rate defined as reappearance of VAP caused by pathogens other than Gram-negative MDR bacteria isolated from lower respi¬ratory tract specimens from day 11 to day 28	day 11, day 28
Mortality		day 28 and day 90
Duration of mechanical ventilation		Participants will be followed for the duration of ICU stay, an expected average of 3 weeks
Length of ICU stay		Participants will be followed for the duration of ICU stay, an expected average of 2 months
Renal function during colimycin administration	Renal function is assessed by measuring daily serum creatinine during treatment period. Colimycin-induced renal function impairment is defined as an increase in serum creatinine level more than 1.5 times the pretreatment value	from Day 1 to Day 11
Side effects resulting from colimycin nebulization		from Day 1 to Day 11
Side effects resulting from colimycin intravenous administration		from Day 1 to day 28

Other Outcome Measures

Outcome Measure	Time Frame
Colistin plasma concentrations	from Day 3 and Day 10

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Qin LU, MD, PhD, Assistance Publique Hoptiaux de Paris

Publications and helpful links

General Publications

• Sole-Lleonart C, Rouby JJ, Chastre J, Poulakou G, Palmer LB, Blot S, Felton T, Bassetti M, Luyt CE, Pereira JM, Riera J, Welte T, Roberts JA, Rello J. Intratracheal Administration of Antimicrobial Agents in Mechanically Ventilated Adults: An International Survey on Delivery Practices and Safety. Respir Care. 2016 Aug;61(8):1008-14. doi: 10.4187/respcare.04519. Epub 2016 Mar 8.
• Sole-Lleonart C, Rouby JJ, Blot S, Poulakou G, Chastre J, Palmer LB, Bassetti M, Luyt CE, Pereira JM, Riera J, Felton T, Dhanani J, Welte T, Garcia-Alamino JM, Roberts JA, Rello J. Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis. Anesthesiology. 2017 May;126(5):890-908. doi: 10.1097/ALN.0000000000001570.
• Rello J, Rouby JJ, Sole-Lleonart C, Chastre J, Blot S, Luyt CE, Riera J, Vos MC, Monsel A, Dhanani J, Roberts JA. Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients. Clin Microbiol Infect. 2017 Sep;23(9):640-646. doi: 10.1016/j.cmi.2017.03.018. Epub 2017 Mar 25.
• Sole-Lleonart C, Roberts JA, Chastre J, Poulakou G, Palmer LB, Blot S, Felton T, Bassetti M, Luyt CE, Pereira JM, Riera J, Welte T, Qiu H, Rouby JJ, Rello J; ESGCIP Investigators. Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines. Clin Microbiol Infect. 2016 Apr;22(4):359-364. doi: 10.1016/j.cmi.2015.12.016. Epub 2015 Dec 23.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2017
• Primary Completion (Actual): March 27, 2018
• Study Completion (Actual): June 19, 2018

Study Registration Dates

• First Submitted: August 12, 2016
• First Submitted That Met QC Criteria: September 14, 2016
• First Posted (Estimate): September 20, 2016

Study Record Updates

• Last Update Posted (Actual): August 13, 2018
• Last Update Submitted That Met QC Criteria: August 10, 2018
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: ventilator-associated pneumonia; multidrug resistance; Gram-negative bacteria; Nebulized colistin; Intravenous colistin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Infective Agents; Anti-Bacterial Agents; Colistin
• Other Study ID Numbers: P130902; 2016-000389-41 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No