Addition of Tobramycin Inhalation in the Treatment of Ventilator Associated Pneumonia (VAPORISE)

Ventilator Associated Pneumonia: Addition of Tobramycin Inhalation Antibiotic Treatment to Standard IV Antibiotic Treatment

This study evaluates the addition of tobramycin inhalation treatment to standard intravenous therapy in the treatment of ventilator associated pneumonia.

Study Overview

• Status: Completed
• Conditions: Ventilator Associated Pneumonia (VAP)
• Intervention / Treatment: Drug: tobramycin inhalation; Drug: placebo

Detailed Description

Rationale: Approximately 9-27% of mechanically ventilated patients in the intensive care unit (ICU) develop ventilator-associated pneumonia (VAP). Patients in whom VAP develops have a higher mortality rate up to 50%, stay longer in the intensive care unit (ICU), and require more resources than those without the disease. Despite the availability of modern ICU care and modern antibiotics, the overall clinical cure rate after 72 hours of antibiotic treatment for VAP is only 40%. The cure rate for Pseudomonas aeruginosa is even lower. It is unclear why VAP cure rates are so low. The ATS guidelines recommend IV antibiotic treatment (IV AB), especially directed against gram-negative microorganisms. However, the relatively poor response rates seen with intravenous therapy of VAP and the emergence of MDR organisms makes new treatment options desirable. The ATS/IDSA VAP guidelines recommend that "adjunctive therapy with an inhaled aminoglycoside or polymyxin (colistin) for MDR Gram-negative pneumonia should be considered, especially in patients who are not improving". It is therefore necessary to investigate whether adjunctive therapy with inhalation Tobramycin could ameliorate prognosis. The recommendations by the Society of Infectious Diseases Pharmacists are similar.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3000CA
    • Erasmus MC
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic

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:

• Mechanical ventilation 48 hours or more
• New or progressive radiologic pulmonary infiltrate

Together with at least two of the following three criteria (< 24 h):

• temperature >38°C
• leukocytosis >12,000/mm3 or leucopenia <4,000/mm3
• purulent respiratory secretions

Exclusion Criteria:

• patients with allergy to tobramycin
• pregnancy
• expected to die within 72 hours after enrollment

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: tobramycin inhalation; twice daily tobramycin inhalation (Bramitob) 300 mg and standard intravenous antibiotics treatment	Drug: tobramycin inhalation; tobramycin inhalation 300 mg twice daily; Other Names: Bramitob
Placebo Comparator: Placebo; twice daily placebo inhalation and standard intravenous antibiotics treatment	Drug: placebo; NaCl 0.9% inhalation 4 ml twice daily; Other Names: NaCl 0.9% inhalation 4 ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
response after 72 h of treatment	non response is considered when at least one of the following is present; No improvement of the arterial O2 tension to inspired O2 fraction ratio; Persistence of fever (≥38°C) or hypothermia (<35.5°C) together with purulent respiratory secretions; increase in the pulmonary infiltrates on chest radiograph of greater than or equal to 50%; occurrence of septic shock or multiple organ dysfunction syndrome, defined as three or more organ system failures not present on Day 1	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate	30-day and 90- day mortality rate	day 30
Mortality rate	30-day and 90- day mortality rate	day 90
ICU survival		day 90
Absence of hospital admittance at day 60		day 60
Discharge from the ICU	Patients will be followed during ICU stay and evaluated at discharge from ICU, expected average time of discharge is 10 days	up to 60 days
Ventilator free days at day 28		up to 28 days
Adverse events		day 1
Adverse events		day 4
Adverse events		day 8
Adverse events		day 14
Adverse events		day 30
Adverse events		day 90
Day of normalisation of CRP		day 1
Day of normalisation of CRP		day 4
Day of normalisation of CRP		day 8
Day of normalisation of CRP		day 14
Day of normalisation of CRP		day 30
Day of normalisation of CRP		day 90
Eradication of pathogens		day 4
Eradication of pathogens		day 8
Eradication of pathogens		day 14
Eradication of pathogens		day 30
Eradication of pathogens		day 90
Clinical Pulmonary Infectious Score (CPIS)		Day 1
Clinical Pulmonary Infectious Score (CPIS)		Day 4
Clinical Pulmonary Infectious Score (CPIS)		Day 8
Clinical Pulmonary Infectious Score (CPIS)		Day 14
Clinical Pulmonary Infectious Score (CPIS)		discharge ICU, expected average time of discharge is 10 days
APACHE II score		Day 1
APACHE II score		Day 4
APACHE II score		Day 8
APACHE II score		Day 14
APACHE II score		discharge ICU, expected average time of discharge is 10 days
Multiple Organ Dysfunction score (MODS)		Day 1
Multiple Organ Dysfunction score (MODS)		Day 4
Multiple Organ Dysfunction score (MODS)		Day 8
Multiple Organ Dysfunction score (MODS)		Day 14
Multiple Organ Dysfunction score (MODS)		discharge ICU, expected average time of discharge is 10 days
Sequential Organ Failure Assessment score (SOFA)		Day 1
Sequential Organ Failure Assessment score (SOFA)		Day 4
Sequential Organ Failure Assessment score (SOFA)		Day 8
Sequential Organ Failure Assessment score (SOFA)		Day 14
Sequential Organ Failure Assessment score (SOFA)		discharge ICU, expected average time of discharge is 10 days
Lung Injury Score (LIS)		Day 1
Lung Injury Score (LIS)		Day 4
Lung Injury Score (LIS)		Day 8
Lung Injury Score (LIS)		Day 14
Lung Injury Score (LIS)		discharge ICU, expected average time of discharge is 10 days
Day of normalisation of procalcitonin (PCT)		day 1
Day of normalisation of procalcitonin (PCT)		day 4
Day of normalisation of procalcitonin (PCT)		day 8
Day of normalisation of procalcitonin (PCT)		day 14
Day of normalisation of procalcitonin (PCT)		day 30
Day of normalisation of procalcitonin (PCT)		day 90
Day of normalisation of chest X-ray		day 1
Day of normalisation of chest X-ray		day 4
Day of normalisation of chest X-ray		day 8
Day of normalisation of chest X-ray		day 14
Day of normalisation of chest X-ray		day 30
Day of normalisation of chest X-ray		day 90

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Menno Van der Eerden, MD, PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): March 1, 2020
• Study Completion (Actual): July 1, 2020

Study Registration Dates

• First Submitted: March 13, 2015
• First Submitted That Met QC Criteria: May 11, 2015
• First Posted (Estimate): May 12, 2015

Study Record Updates

• Last Update Posted (Actual): August 18, 2021
• Last Update Submitted That Met QC Criteria: August 17, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• 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; Tobramycin
• Other Study ID Numbers: VAP-2014; 2014-001406-17 (EudraCT Number)