Inhaled Tobramycin in BPD

Phase 1 Feasibility Trial of Inhaled Tobramycin in Preterm Infants With Bronchopulmonary Dysplasia

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Drug: Tobramycin solution for inhalation 78mg dose; Drug: Tobramycin solution for inhalation 150mg dose; Drug: Tobramycin solution for inhalation 216mg dose; Drug: Tobramycin solution for inhalation 300mg dose

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Erik A Jensen, MD MSCE; Phone Number: 2676482720; Email: jensene@chop.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm - 78mg; 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.	Drug: Tobramycin solution for inhalation 78mg dose; Inhaled tobramycin - 78mg administered every 12 hours for 14 days.
Experimental: Treatment Arm - 150mg; 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.	Drug: Tobramycin solution for inhalation 150mg dose; Inhaled tobramycin - 150mg administered every 12 hours for 14 days.
Experimental: Treatment Arm - 216mg; 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.	Drug: Tobramycin solution for inhalation 216mg dose; Inhaled tobramycin - 216mg administered every 12 hours for 14 days.
Experimental: Treatment Arm - 300mg; 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.	Drug: Tobramycin solution for inhalation 300mg dose; Inhaled tobramycin - 300mg administered every 12 hours for 14 days.
No Intervention: Observational Arm; Enrolled infants who are eligible to participate in the phase-1 trial may be enrolled in an untreated observational cohort at parental discretion. This cohort will undergo collection of clinical and respiratory mechanics data for 14 days after enrollment but will not receive the study drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Elevated serum tobramycin trough or creatinine or severe adverse event	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	Any time during the 14-day trial

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Erik Allen Jensen
• Collaborators: University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: September 17, 2020
• First Submitted That Met QC Criteria: September 17, 2020
• First Posted (Actual): September 23, 2020

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia; Anti-Infective Agents; Anti-Bacterial Agents; Pharmaceutical Solutions; Tobramycin
• Other Study ID Numbers: 19-016800

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No