Tobramycin Nebulization to Prevent Multidrug-Resistant Ventilator-Associated Pneumonia (TOP-MDRVAP)
Tobramycin Nebulization to Prevent Multidrug-Resistant Ventilator-Associated Pneumonia: A Prospective, Multicenter, Double-Blind, Randomized Controlled Trial
The TOP-MDRVAP trial will test whether inhaled tobramycin can safely prevent pneumonia caused by multidrug-resistant bacteria in adults who need a breathing machine. Tobramycin is an antibiotic. Multidrug-resistant bacteria are bacteria that resist treatment with several types of antibiotics. Pneumonia that develops in patients receiving breathing support through a breathing tube is called ventilator-associated pneumonia (VAP). This study will evaluate tobramycin as a preventive treatment, rather than as treatment for existing VAP.
The study plans to enroll 574 adults aged 18 years or older in intensive care units (ICUs) at several hospitals. Participants must have received breathing support through a tube for 72 to 96 hours and be expected to need this support for at least another 72 hours. They must have at least one risk factor for infection with multidrug-resistant bacteria and must not have suspected or confirmed VAP when entering the study.
Participants will be assigned by chance to one of two groups, with an equal chance of entering either group. One group will receive tobramycin inhalation solution, 300 mg in 5 mL, twice daily for 3 consecutive days. The other group will receive 5 mL of 0.9% saline, a saltwater solution containing no antibiotic, on the same schedule. A nebulizer will turn the solution into a fine mist delivered through the breathing tube.
Both groups will receive standard measures to prevent VAP. Participants, their representatives, the healthcare professionals providing their direct care, and the researchers assessing outcomes will not know which study treatment each participant receives.
The main question is whether fewer participants develop VAP caused by multidrug-resistant bacteria within 28 days after assignment to a study group. Researchers will also compare the occurrence of VAP from any cause, antibiotic use, time receiving breathing support, time spent in the ICU and hospital, and deaths within 28 and 90 days.
Participants will be monitored for possible side effects, including kidney problems, narrowing of the airways, and complications involving the breathing tube or equipment. Samples will be tested for bacteria and antibiotic resistance. Follow-up will continue for up to 90 days after assignment, using hospital records or telephone contact to assess survival and recovery milestones, including discharge and the end of breathing support.
Studie Overzicht
Toestand
Interventie / Behandeling
Studietype
Inschrijving (Geschat)
Fase
- Fase 4
Contacten en locaties
Studiecontact
- Naam: Gensheng Zhang
- Telefoonnummer: +86 18806812331
- E-mail: genshengzhang@zju.edu.cn
Studie Contact Back-up
- Naam: Kai Zhang
- Telefoonnummer: +86 15150686177
- E-mail: zhangkai1993@zju.edu.cn
Studie Locaties
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Zhejiang
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Hangzhou, Zhejiang, China, 310000
- Second Affiliated Hospital of Zhejiang University School of Medicine
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Contact:
- Gensheng Zhang
- Telefoonnummer: +86 18806812331
- E-mail: genshengzhang@zju.edu.cn
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Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
Accepteert gezonde vrijwilligers
Geslachten die in aanmerking komen voor studie
Beschrijving
Inclusion Criteria:
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Age ≥18 years at enrollment.
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Invasive mechanical ventilation through an endotracheal tube for ≥72 hours and ≤96 hours, measured from the time of intubation, with an anticipated requirement for at least another 72 hours of invasive mechanical ventilation, as assessed by the attending physician.
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At least one of the following risk factors for multidrug-resistant (MDR) bacterial infection:
3.1 Exposure to systemic antibiotics for ≥24 hours within the 30 days before enrollment.
3.2 Current hospitalization for at least 120 hours before randomization. 3.3 Septic shock requiring vasoactive medication to maintain a mean arterial pressure ≥65 mmHg, with a blood lactate level >2 mmol/L.
3.4 Moderate-to-severe acute respiratory distress syndrome (ARDS), according to the Berlin definition, with a PaO2/FiO2 ratio ≤200 mmHg and positive end-expiratory pressure (PEEP) ≥5 cm H2O.
3.5 Current renal replacement therapy, including continuous renal replacement therapy or intermittent hemodialysis.
3.6 A history of MDR bacterial colonization or infection within the previous 12 months, documented by clinical culture.
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Written informed consent obtained from the patient or the patient's legally authorized representative.
Exclusion Criteria:
- Suspected or confirmed ventilator-associated pneumonia (VAP) on the day of enrollment, based on the attending physician's clinical judgment.
- Continuous invasive mechanical ventilation for more than 96 hours before enrollment.
- Planned extubation within the next 24 hours.
- Previous tracheostomy.
- A history of allergy to tobramycin or any other aminoglycoside antibiotic.
- Use of tobramycin within the 7 days before enrollment; ongoing treatment with any aminoglycoside antibiotic at enrollment; or a clinical indication for intravenous treatment with any aminoglycoside antibiotic at enrollment.
- Chronic kidney disease (stages 4-5) with a baseline estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m², or acute kidney injury meeting the protocol-specified Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 criteria: serum creatinine increased to three times baseline, serum creatinine >353.6 μmol/L, urine output <0.3 mL/kg/hour for more than 24 hours, or anuria for more than 12 hours. Patients currently receiving renal replacement therapy are exempt from this renal exclusion criterion.
- Expected survival of no more than 48 hours, as assessed by the attending physician.
- Pregnancy, indicated by a positive serum or urine human chorionic gonadotropin (hCG) test, or breastfeeding.
- Concurrent participation in another interventional clinical study involving nebulized antibiotics or other ventilator-associated pneumonia prevention interventions.
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Preventie
- Toewijzing: Gerandomiseerd
- Interventioneel model: Parallelle opdracht
- Masker: Verviervoudigen
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
|---|---|
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Experimenteel: Nebulized Tobramycin
Participants receive tobramycin inhalation solution, 300 mg in 5 mL per dose, administered through the endotracheal tube using a vibrating mesh nebulizer twice daily for 3 consecutive days (6 planned doses). The intervention is administered to prevent multidrug-resistant ventilator-associated pneumonia (MDR-VAP). Participants also receive standard ventilator-associated pneumonia (VAP) prevention measures. |
Tobramycin inhalation solution (300 mg/5 mL) is administered at a dose of 300 mg (5 mL) twice daily for 3 consecutive days, for a total of 6 planned doses. The ready-to-use solution is administered without additional dilution through the endotracheal tube using a vibrating mesh nebulizer connected to the ventilator circuit. Each nebulization continues until the nebulizer reservoir is empty. The intervention is administered to prevent multidrug-resistant ventilator-associated pneumonia (MDR-VAP), in addition to standard VAP prevention measures. |
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Placebo-vergelijker: Nebulized 0.9% Sodium Chloride Placebo
Participants receive 5 mL of 0.9% sodium chloride solution (normal saline) as a placebo, administered through the endotracheal tube using a vibrating mesh nebulizer twice daily for 3 consecutive days (6 planned doses). Participants also receive standard ventilator-associated pneumonia (VAP) prevention measures. |
A 5 mL dose of 0.9% sodium chloride solution (normal saline) is administered as a placebo twice daily for 3 consecutive days, for a total of 6 planned doses. The solution is delivered through the endotracheal tube using the same type of vibrating mesh nebulizer, administration schedule, and nebulization procedure as the tobramycin intervention. Each nebulization continues until the nebulizer reservoir is empty. Participants also receive standard VAP prevention measures. |
Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
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28-Day Cumulative Incidence of Multidrug-Resistant Ventilator-Associated Pneumonia
Tijdsspanne: From randomization through Day 28.
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Percentage of randomized participants with a first episode of multidrug-resistant ventilator-associated pneumonia (MDR-VAP), adjudicated by an independent blinded endpoint adjudication committee. VAP develops after 48 hours of mechanical ventilation, including within 48 hours after weaning or extubation. Diagnosis requires new or progressive infiltrates, consolidation, or ground-glass opacities on chest X-ray or CT plus at least two of: temperature >38°C, purulent airway secretions, and white blood cell count >10 x 10^9/L or <4 x 10^9/L. MDR-VAP additionally requires a positive quantitative lower respiratory tract culture (tracheal aspirate ≥10^5 CFU/mL; bronchoalveolar lavage ≥10^4 CFU/mL; protected specimen brush ≥10^3 CFU/mL) with a causative bacterium resistant to at least three antimicrobial classes. |
From randomization through Day 28.
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Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
|
Incidence Density of Multidrug-Resistant Ventilator-Associated Pneumonia
Tijdsspanne: From randomization through Day 28.
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Number of first episodes of multidrug-resistant ventilator-associated pneumonia per 1,000 invasive mechanical ventilation days accumulated during the assessment period. |
From randomization through Day 28.
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28-Day Incidence of Ventilator-Associated Pneumonia From Any Cause
Tijdsspanne: From randomization through Day 28.
|
28-Day Incidence of Ventilator-Associated Pneumonia From Any Cause |
From randomization through Day 28.
|
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Systemic Antibiotic Use Expressed as Antibiotic-Days
Tijdsspanne: From randomization through Day 28.
|
Cumulative systemic antibiotic use during the assessment period, expressed as antibiotic-days. |
From randomization through Day 28.
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Days of Exposure to Systemic Antibiotics
Tijdsspanne: From randomization through Day 28.
|
Number of days on which a participant receives at least one systemic antibiotic during the assessment period. Each day with systemic antibiotic exposure is counted once, regardless of the number of antibiotics administered. |
From randomization through Day 28.
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Duration of Mechanical Ventilation
Tijdsspanne: From randomization through Day 28.
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Total duration of invasive and noninvasive mechanical ventilation, measured in days, during the assessment period. |
From randomization through Day 28.
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Intensive Care Unit Length of Stay
Tijdsspanne: From randomization to ICU discharge, assessed up to Day 90.
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Duration of intensive care unit stay, measured in days from randomization to ICU discharge, with follow-up through Day 90. |
From randomization to ICU discharge, assessed up to Day 90.
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Hospital Length of Stay
Tijdsspanne: From randomization to hospital discharge, assessed up to Day 90.
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Duration of hospital stay, measured in days from randomization to hospital discharge, with follow-up through Day 90. |
From randomization to hospital discharge, assessed up to Day 90.
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28-Day All-Cause Mortality
Tijdsspanne: From randomization through Day 28.
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Percentage of participants who die from any cause within 28 days after randomization. |
From randomization through Day 28.
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90-Day All-Cause Mortality
Tijdsspanne: From randomization through Day 90.
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Percentage of participants who die from any cause within 90 days after randomization. Survival status is obtained from hospital records or telephone follow-up. |
From randomization through Day 90.
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Incidence of Ventilator-Associated Pneumonia Caused by Tobramycin-Susceptible Gram-Negative Bacteria
Tijdsspanne: From randomization through Day 28.
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Percentage of participants who develop ventilator-associated pneumonia caused by gram-negative bacteria that are susceptible to tobramycin on in vitro antimicrobial susceptibility testing. |
From randomization through Day 28.
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Incidence of Ventilator-Associated Events
Tijdsspanne: From randomization through Day 28.
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Percentage of participants who develop a ventilator-associated event, assessed using the protocol-specified 2023 Centers for Disease Control and Prevention/National Healthcare Safety Network definitions. Assessments include ventilator-associated conditions, infection-related ventilator-associated complications, and possible ventilator-associated pneumonia. |
From randomization through Day 28.
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Incidence of New-Onset Acute Kidney Injury
Tijdsspanne: From randomization through Day 28.
|
Percentage of participants without acute kidney injury at baseline who develop Kidney Disease: Improving Global Outcomes (KDIGO) stage 1 or higher acute kidney injury during the assessment period. |
From randomization through Day 28.
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Daily Trajectory of the Clinical Pulmonary Infection Score
Tijdsspanne: Assessed daily from randomization until extubation or Day 28, whichever occurs first.
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Daily Clinical Pulmonary Infection Score (CPIS) values and their longitudinal changes during the assessment period, calculated using available clinical data. |
Assessed daily from randomization until extubation or Day 28, whichever occurs first.
|
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Time to First Successful Spontaneous Breathing Trial
Tijdsspanne: From randomization through Day 28.
|
Time, measured in days, from randomization to the first successful spontaneous breathing trial (SBT) during the assessment period. |
From randomization through Day 28.
|
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Detection Rate of Tobramycin-Resistant Bacteria
Tijdsspanne: From randomization through Day 28.
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Rate of isolation of tobramycin-resistant bacteria from respiratory specimens or blood cultures during the assessment period. |
From randomization through Day 28.
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Composite Incidence of Serious Nebulization-Related Adverse Effects
Tijdsspanne: From randomization through Day 28.
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Percentage of participants experiencing at least one serious adverse effect related to nebulization, including increased expiratory filter resistance, bronchospasm, or endotracheal tube obstruction. |
From randomization through Day 28.
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Andere uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
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Longitudinal Changes in Respiratory Microbiome Alpha Diversity
Tijdsspanne: Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
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Longitudinal changes in respiratory microbiome alpha diversity, assessed by 16S ribosomal RNA amplicon sequencing in participants enrolled in the microbiome substudy. |
Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
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Longitudinal Changes in Respiratory Microbiome Beta Diversity
Tijdsspanne: Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
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Longitudinal changes in respiratory microbiome beta diversity, assessed by 16S ribosomal RNA amplicon sequencing in participants enrolled in the microbiome substudy. |
Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
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Longitudinal Changes in Antibiotic Resistance Gene Abundance
Tijdsspanne: Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
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Longitudinal changes in antibiotic resistance gene abundance in respiratory samples, assessed by metagenomic next-generation sequencing. |
Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
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Longitudinal Changes in Antibiotic Resistance Gene Diversity
Tijdsspanne: Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
|
Longitudinal changes in antibiotic resistance gene diversity in respiratory samples, assessed by metagenomic next-generation sequencing. |
Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.
|
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Tobramycin Concentration-Time Profile in Epithelial Lining Fluid
Tijdsspanne: During the 3-day study treatment period.
|
Tobramycin concentrations in epithelial lining fluid over time in participants enrolled in the pharmacokinetic substudy. |
During the 3-day study treatment period.
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Plasma Tobramycin Concentration-Time Profile
Tijdsspanne: During the 3-day study treatment period.
|
Plasma tobramycin concentrations over time in participants enrolled in the pharmacokinetic substudy. |
During the 3-day study treatment period.
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Medewerkers en onderzoekers
Medewerkers
Studie record data
Bestudeer belangrijke data
Studie start (Geschat)
Primaire voltooiing (Geschat)
Studie voltooiing (Geschat)
Studieregistratiedata
Eerst ingediend
Eerst ingediend dat voldeed aan de QC-criteria
Eerst geplaatst (Werkelijk)
Updates van studierecords
Laatste update geplaatst (Werkelijk)
Laatste update ingediend die voldeed aan QC-criteria
Laatst geverifieerd
Meer informatie
Termen gerelateerd aan deze studie
Trefwoorden
Aanvullende relevante MeSH-voorwaarden
Andere studie-ID-nummers
- 2026-0634
Plan Individuele Deelnemersgegevens (IPD)
Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?
Beschrijving IPD-plan
De-identified individual participant data underlying the results reported in the primary publication of the TOP-MDRVAP trial will be shared, together with a data dictionary. The dataset will include baseline characteristics, treatment allocation, and data supporting the reported efficacy and safety outcomes. Direct identifiers and the participant identification linkage file will not be shared. Data will be made available through controlled access for approved research proposals, subject to participant consent, institutional and ethics requirements, and applicable data-protection regulations.
IPD-tijdsbestek voor delen
Data and supporting documents will be available beginning 6 months after publication of the primary trial results and ending 5 years after that publication.
IPD-toegangscriteria voor delen
Access will be available to qualified researchers who submit a methodologically sound proposal for secondary analyses or individual participant data meta-analyses. Requests should be submitted to the principal investigator through the study contact listed in the trial registry. The principal investigator and the study Executive Committee will review the scientific merit, feasibility, and data-protection safeguards of each request. Approved applicants must sign a data use agreement limiting use to the approved research, prohibiting participant re-identification and unauthorized onward sharing, and requiring secure data storage. Data will be provided by secure electronic transfer after any required institutional, ethics, or regulatory approvals have been obtained.
IPD delen Ondersteunend informatietype
- LEERPROTOCOOL
- SAP
Informatie over medicijnen en apparaten, studiedocumenten
Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel
Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct
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