Inhaled Tobramycin in BPD

Study Overview
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Brief Summary
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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.

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

Conditions
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Bronchopulmonary Dysplasia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female infants born <32 weeks' gestation Diagnosed with BPD (use of supplemental oxygen or respiratory support at 36 weeks postmenstrual age ) Postmenstrual age ≥36 weeks at study enrollment Treatment with invasive mechanical ventilation at enrollment without planned tracheal extubation within 7 days after enrollment 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 Parental/guardian permission (informed consent). Exclusion Criteria: Serum creatinine >0.4mg/dL within 14 days prior to enrollment Congenital or acquired disease of the kidney or renal collecting system that adversely affects renal function Congenital or acquired hepatobiliary disease that adversely affects liver function Treatment with a systemic antibiotic within 7 days prior to enrollment Treatment with a nephrotoxic medication, excluding diuretics, within 48 hours prior to enrollment Treatment with a neuromuscular blocker within 48 hours prior to enrollment Known intolerance to aminoglycoside antibiotics Current treatment with high frequency or other oscillating mechanical ventilation Presence of a cancer diagnosis Maternal family history of early onset hearing loss defined as the need for an assistive hearing device prescribed before 30 years of age Endotracheal tube leak >20%. Any prior use of an investigational drug [as part of an FDA approved Investigational New Drug (IND) protocol]. A subject who, in the judgement of the Investigator, is not an appropriate candidate for this research study.

Ages Eligible for Study
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Minimum Age: 4 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 dose escalation trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm - 78mg<br>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<br>* Inhaled tobramycin - 78mg administered every 12 hours for 14 days.<br>|
| Experimental: Treatment Arm - 150mg<br>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<br>* Inhaled tobramycin - 150mg administered every 12 hours for 14 days.<br>|
| Experimental: Treatment Arm - 216mg<br>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<br>* Inhaled tobramycin - 216mg administered every 12 hours for 14 days.<br>|
| Experimental: Treatment Arm - 300mg<br>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<br>* Inhaled tobramycin - 300mg administered every 12 hours for 14 days.<br>|
| No Intervention: Observational Arm<br>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?
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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 | Measure Description | 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 |