Inhaled Tobramycin in BPD

Phase 1

Completed

• Conditions: Bronchopulmonary Dysplasia
• Interventions: Drug: Tobramycin solution for inhalation 78mg dose; Drug: Tobramycin solution for inhalation 150mg dose; Drug: Tobramycin solution for inhalation 300mg dose; Drug: Tobramycin solution for inhalation 216mg dose

• Registration Number: NCT04560179
• Lead Sponsor: Erik Allen Jensen

Brief Summary

This study is an open-label, phase 1, sequential dose escalation trial seeking to establish preliminary tolerability, efficacy, and pharmacokinetic data for up to 4 different doses of inhaled tobramycin administered to very preterm infants with BPD who are receiving invasive mechanical ventilation and have a pathogenic Gram-negative organism detected by tracheal aspirate culture.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-09-17
• Study First Submitted QC: 2020-09-17
• Study First Posted: 2020-09-23
• Study Start: 2022-03-22
• Primary Completion: 2023-12-31
• Study Completion: 2024-05-17
• Status Verified: 2024-12
• Results First Submitted: 2024-12-30
• Results First Submitted QC: 2024-12-30
• Last Update Submitted: 2024-12-30
• Results First Posted: 2025-01-31
• Last Update Posted: 2025-01-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

1. Male or female infants born <32 weeks' gestation
2. Diagnosed with BPD (use of supplemental oxygen or respiratory support at 36 weeks postmenstrual age )
3. Postmenstrual age ≥36 weeks at study enrollment
4. Treatment with invasive mechanical ventilation at enrollment without planned tracheal extubation within 7 days after enrollment
5. Tracheal aspirate culture positive for one of the following pathogenic GNR bacteria within 7 days prior to enrollment: Pseudomonas aeruginosa, Klebsiella species, Enterobacter species, Stenotrophomonas maltophilia, Escherichia coli, Acinetobacter baumannii, or Serratia marcescens
6. Parental/guardian permission (informed consent).

Exclusion Criteria

1. Serum creatinine >0.4mg/dL within 14 days prior to enrollment
2. Congenital or acquired disease of the kidney or renal collecting system that adversely affects renal function
3. Congenital or acquired hepatobiliary disease that adversely affects liver function
4. Treatment with a systemic antibiotic within 7 days prior to enrollment
5. Treatment with a nephrotoxic medication, excluding diuretics, within 48 hours prior to enrollment
6. Treatment with a neuromuscular blocker within 48 hours prior to enrollment
7. Known intolerance to aminoglycoside antibiotics
8. Current treatment with high frequency or other oscillating mechanical ventilation
9. Presence of a cancer diagnosis
10. Maternal family history of early onset hearing loss defined as the need for an assistive hearing device prescribed before 30 years of age
11. Endotracheal tube leak >20%.
12. Any prior use of an investigational drug [as part of an FDA approved Investigational New Drug (IND) protocol].
13. A subject who, in the judgement of the Investigator, is not an appropriate candidate for this research study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment Arm - 78mg	Tobramycin solution for inhalation 78mg dose	The phase 1 trial will begin with a dose of 78mg. All treatment arms will administer study drug every 12 hours for up to 14 days (28 doses). Up to 6 infants in this arm will receive the 78mg dose of tobramycin solution for inhalation administered via vibrating mesh nebulizer. During the trial, infants in each treatment arm will undergo blood and tracheal aspirate sampling and respiratory mechanics measurements at pre-specified time points to assess dose safety and potential efficacy. Continuous pulse oximetry monitoring for the duration of the trial will also occur. Clinical data will also be recorded daily throughout the trial in all participants.
Treatment Arm - 150mg	Tobramycin solution for inhalation 150mg dose	If tolerability is demonstrated in the 78mg treatment arm following the 3+3 trial design, up to 6 infants will then be enrolled and receive 150mg of tobramycin solution for inhalation every 12 hours. The same monitoring procedures will be performed in this treatment arm as in the prior.
Treatment Arm - 300mg	Tobramycin solution for inhalation 300mg dose	If tolerability is demonstrated in the 216mg treatment arm following the 3+3 trial design, up to 6 infants will then be enrolled and receive 150mg of tobramycin solution for inhalation every 12 hours. The same monitoring procedures will be performed in this treatment arm as in the prior.
Treatment Arm - 216mg	Tobramycin solution for inhalation 216mg dose	If tolerability is demonstrated in the 150mg treatment arm following the 3+3 trial design, up to 6 infants will then be enrolled and receive 150mg of tobramycin solution for inhalation every 12 hours. The same monitoring procedures will be performed in this treatment arm as in the prior.

Primary Outcome Measures

Name	Time	Method
Elevated Serum Tobramycin Trough or Creatinine or Severe Adverse Event	Any time during the 14-day trial	Trough serum tobramycin level (measured 11 hours after the administered dose) ≥1mcg/mL; increase in serum creatinine level by ≥0.3mg/dL above pre-trial baseline; increase in serum creatinine level \>1.5-fold above pre-trial baseline; urine output \<0.5mL/kg/hr for 12 consecutive hours; or any serious adverse event possibly attributable to the study drug

Secondary Outcome Measures

Name	Time	Method
New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%)	Any time during the 14-day trial
Obstruction of the Endotracheal Tube Requiring Tube Replacement	Any time during the 14-day trial
Unplanned Tracheal Extubation	Any time during the 14-day trial
Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin	Any time during the 14 day trial
Pre-discharge Failed Audiology Examination	up to 1 year of age
New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization	up to 1 year of age
Change in Tracheal Aspirate Pathogenic Bacterial Colony Forming Unit (CFU) Counts Measured by Quantitative Culture	During the 14-day trial
Change in the Fraction of Inspired Oxygen (FiO2), Ventilator Mean Airway Pressure (MAP), and Respiratory Severity Score (MAP x FiO2)	During the 14-day trial
Change in Intermittent Hypoxemia (SpO2<80% Lasting >/=10s), Prolonged Hypoxemia (SpO2<80% Lasting >1min), and Daily Proportion of Time in Hypoxemia	During the 14-day trial
Change in Tracheal Aspirate Cytokine Levels, Neutrophil to Total WBC Ratio, and Patterns in the Airway Microbiome	During the 14-day trial
Change in Dynamic Lung Compliance, Airway Resistance, Peak Expiratory Flow, and Carbon Dioxide (CO2) Elimination	During the 14-day trial

Trial Locations

Locations (1)

The Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States