Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia (COLIVAP)
Primary Purpose
Ventilator-associated Pneumonia
Status
Terminated
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Intravenous colimycin
Intravenous placebo
Nebulized colimycin
Nebulized placebo
Sponsored by
About this trial
This is an interventional treatment trial for Ventilator-associated Pneumonia focused on measuring Nebulized colistin, Intravenous colistin, ventilator-associated pneumonia, multidrug resistance, Gram-negative bacteria
Eligibility 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
Sites / Locations
- Hôpital Pitié-Salpêtriere
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Experimental group
Control group
Arm Description
Patients receive simultaneously nebulized colimycin every 8 h and intravenous placebo administered once, twice or 3 times per day according to renal function
Patients receive simultaneously intravenous colimycin administered once, twice or 3 times per day according to function renal and nebulized placebo every 8 h
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Microbiological cure rate
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
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
Mortality
Duration of mechanical ventilation
Length of ICU stay
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
Side effects resulting from colimycin nebulization
Side effects resulting from colimycin intravenous administration
Full Information
NCT ID
NCT02906722
First Posted
August 12, 2016
Last Updated
August 10, 2018
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT02906722
Brief Title
Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia
Acronym
COLIVAP
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
Study Type
Interventional
2. Study Status
Record Verification Date
November 2017
Overall Recruitment Status
Terminated
Why Stopped
Lack of inclusion
Study Start Date
July 31, 2017 (Actual)
Primary Completion Date
March 27, 2018 (Actual)
Study Completion Date
June 19, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief 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.
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:
To compare the microbiological cure rate at end of treatment
To compare the VAP recurrence rate after end of treatment
To compare the lung superinfection rate after end of treatment
To compare 28 day- and 90 day-mortality
To compare duration of mechanical ventilation
To compare length of ICU stay
To compare renal function during colimycin administration
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
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.
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.
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
Combined intravenous administration of other antimicrobials are authorized
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ventilator-associated Pneumonia
Keywords
Nebulized colistin, Intravenous colistin, ventilator-associated pneumonia, multidrug resistance, Gram-negative bacteria
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Experimental group
Arm Type
Experimental
Arm Description
Patients receive simultaneously nebulized colimycin every 8 h and intravenous placebo administered once, twice or 3 times per day according to renal function
Arm Title
Control group
Arm Type
Active Comparator
Arm Description
Patients receive simultaneously intravenous colimycin administered once, twice or 3 times per day according to function renal and nebulized placebo every 8 h
Intervention Type
Drug
Intervention Name(s)
Intravenous colimycin
Intervention Description
administration once, twice or 3 times per day according to renal function
Intervention Type
Drug
Intervention Name(s)
Intravenous placebo
Intervention Description
administration once, twice or 3 times per day according to renal function
Intervention Type
Drug
Intervention Name(s)
Nebulized colimycin
Intervention Description
Nebulization is performed with a vibrating plate nebulizer (Aeroneb® Solo) every 8h
Intervention Type
Drug
Intervention Name(s)
Nebulized placebo
Intervention Description
Nebulization is performed with a vibrating plate nebulizer (Aeroneb® Solo) every 8h
Primary Outcome Measure Information:
Title
Clinical cure of VAP caused by Gram-negative multidrug resistant bacteria
Description
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.
Time Frame
At end of therapy visit (day11) or before day11 if treatment is considered as failed.
Secondary Outcome Measure Information:
Title
Microbiological cure rate
Time Frame
At end of therapy visit (day11) or before day11 if treatment is considered as failed.
Title
VAP recurrence rate
Description
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
Time Frame
day 28
Title
Lung superinfection rate
Description
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
Time Frame
day 11, day 28
Title
Mortality
Time Frame
day 28 and day 90
Title
Duration of mechanical ventilation
Time Frame
Participants will be followed for the duration of ICU stay, an expected average of 3 weeks
Title
Length of ICU stay
Time Frame
Participants will be followed for the duration of ICU stay, an expected average of 2 months
Title
Renal function during colimycin administration
Description
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
Time Frame
from Day 1 to Day 11
Title
Side effects resulting from colimycin nebulization
Time Frame
from Day 1 to Day 11
Title
Side effects resulting from colimycin intravenous administration
Time Frame
from Day 1 to day 28
Other Pre-specified Outcome Measures:
Title
Colistin plasma concentrations
Time Frame
from Day 3 and Day 10
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qin LU, MD, PhD
Organizational Affiliation
Assistance Publique Hoptiaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Pitié-Salpêtriere
City
Paris
ZIP/Postal Code
75013
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
26957647
Citation
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.
Results Reference
background
PubMed Identifier
28248714
Citation
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.
Results Reference
background
PubMed Identifier
28347790
Citation
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.
Results Reference
background
PubMed Identifier
26723563
Citation
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.
Results Reference
background
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Nebulized and Intravenous Colistin in Ventilator Associated-pneumonia
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