Bronchopulmonary Dysplasia
Conditions
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.
Interventions
DRUGTobramycin solution for inhalation 216mg dose
Inhaled tobramycin - 216mg administered every 12 hours for 14 days.
DRUGTobramycin solution for inhalation 300mg dose
Inhaled tobramycin - 300mg administered every 12 hours for 14 days.
DRUGTobramycin solution for inhalation 78mg dose
Inhaled tobramycin - 78mg administered every 12 hours for 14 days.
DRUGTobramycin solution for inhalation 150mg dose
Inhaled tobramycin - 150mg administered every 12 hours for 14 days.
Sponsors
University of Florida
Erik Allen Jensen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 dose escalation trial.
Eligibility
Sex/Gender
ALL
Age
4 Weeks to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| 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 |
| Change in Tracheal Aspirate Pathogenic Bacterial Colony Forming Unit (CFU) Counts Measured by Quantitative Culture | During the 14-day trial |
Countries
United States
Participant flow
Pre-assignment details
A total of 27 infants were enrolled into the study protocol and underwent collection of a screening tracheal aspirate culture to determine eligibility for the entry into the phase 1 drug trial. Of these 27, 16 (59%) infants had a tracheal aspirate culture positive for an eligible Gram-negative pathogen. OF these 16, all were enrolled into the phase 1 drug trial. No parents/guardians elected to enroll their child in the untreated observational arm prior to completion of all dose levels.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Tobramycin solution for inhalation 78mg dose: Inhaled tobramycin - 78mg administered every 12 hours for 14 days. | 4 |
| 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.
Tobramycin solution for inhalation 150mg dose: Inhaled tobramycin - 150mg administered every 12 hours for 14 days. | 3 |
| 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.
Tobramycin solution for inhalation 216mg dose: Inhaled tobramycin - 216mg administered every 12 hours for 14 days. | 3 |
| 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.
Tobramycin solution for inhalation 300mg dose: Inhaled tobramycin - 300mg administered every 12 hours for 14 days. | 6 |
| 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. | 0 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Arm - 78mg | Treatment Arm - 150mg | Treatment Arm - 216mg | Treatment Arm - 300mg | Observational Arm | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 3 Participants | 3 Participants | 6 Participants | 0 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 3 Participants | 5 Participants | 0 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 4 participants | 3 participants | 3 participants | 6 participants | — | 16 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 0 / 3 | 1 / 3 | 1 / 6 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 4 | 1 / 3 | 1 / 3 | 1 / 6 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 0 | 0 / 0 |
Outcome results
Primary
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
Time frame: Any time during the 14-day trial
Population: No infants were enrolled into the observational arm. 1 of the 16 enrolled infants (treatment arm - 78mg) was withdrawn early from the trial by the medical team and was not assessed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | Elevated Serum Tobramycin Trough or Creatinine or Severe Adverse Event | 0 Participants |
| Treatment Arm - 150mg | Elevated Serum Tobramycin Trough or Creatinine or Severe Adverse Event | 0 Participants |
| Treatment Arm - 216mg | Elevated Serum Tobramycin Trough or Creatinine or Severe Adverse Event | 0 Participants |
| Treatment Arm - 300mg | Elevated Serum Tobramycin Trough or Creatinine or Severe Adverse Event | 1 Participants |
| Observational Arm | Elevated Serum Tobramycin Trough or Creatinine or Severe Adverse Event | 0 Participants |
Secondary
Change in Dynamic Lung Compliance, Airway Resistance, Peak Expiratory Flow, and Carbon Dioxide (CO2) Elimination
Time frame: During the 14-day trial
Secondary
Change in Intermittent Hypoxemia (SpO2<80% Lasting >/=10s), Prolonged Hypoxemia (SpO2<80% Lasting >1min), and Daily Proportion of Time in Hypoxemia
Time frame: During the 14-day trial
Secondary
Change in the Fraction of Inspired Oxygen (FiO2), Ventilator Mean Airway Pressure (MAP), and Respiratory Severity Score (MAP x FiO2)
Time frame: During the 14-day trial
Secondary
Change in Tracheal Aspirate Cytokine Levels, Neutrophil to Total WBC Ratio, and Patterns in the Airway Microbiome
Time frame: During the 14-day trial
Secondary
Change in Tracheal Aspirate Pathogenic Bacterial Colony Forming Unit (CFU) Counts Measured by Quantitative Culture
Time frame: During the 14-day trial
Population: CFU counts were not measured by the microbiology lab on tracheal aspirate samples; only presence/absence of pathogens was recorded owing to variable consistency of sputum samples. No infants were enrolled into the observational arm.
Secondary
Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin
Time frame: Any time during the 14 day trial
Population: No infants were enrolled into the observational arm. Infants who were screened but not eligible did not receive study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin | 3 Participants |
| Treatment Arm - 150mg | Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin | 0 Participants |
| Treatment Arm - 216mg | Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin | 1 Participants |
| Treatment Arm - 300mg | Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin | 0 Participants |
| Observational Arm | Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin | 0 Participants |
| Screened But Not Eligible | Desaturation (SpO2 <80% for >10 Seconds) During Administration of Inhaled Tobramycin | 0 Participants |
Secondary
New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization
Time frame: up to 1 year of age
Population: No infants were enrolled into the observational arm. 1 of the 16 enrolled infants (treatment arm - 78mg) was withdrawn early from the trial by the medical team and was not assessed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization | 0 Participants |
| Treatment Arm - 150mg | New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization | 0 Participants |
| Treatment Arm - 216mg | New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization | 0 Participants |
| Treatment Arm - 300mg | New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization | 0 Participants |
| Observational Arm | New Intra-patient Microbial Resistance to Tobramycin During the Primary Hospitalization | 0 Participants |
Secondary
New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%)
Time frame: Any time during the 14-day trial
Population: No infants were enrolled into the observational arm. 1 of the 16 enrolled infants (treatment arm - 78mg) was withdrawn early from the trial by the medical team and was not assessed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%) | 0 Participants |
| Treatment Arm - 150mg | New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%) | 0 Participants |
| Treatment Arm - 216mg | New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%) | 0 Participants |
| Treatment Arm - 300mg | New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%) | 0 Participants |
| Observational Arm | New Onset or Worsened Coughing Associated With a Change in Respiratory Status (SpO2 <80% for >10 Seconds; Need for Increase in FiO2 by >20%) | 0 Participants |
Secondary
Obstruction of the Endotracheal Tube Requiring Tube Replacement
Time frame: Any time during the 14-day trial
Population: No infants were enrolled into the observational arm. 1 of the 16 enrolled infants (treatment arm - 78mg) was withdrawn early from the trial by the medical team and was not assessed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | Obstruction of the Endotracheal Tube Requiring Tube Replacement | 0 Participants |
| Treatment Arm - 150mg | Obstruction of the Endotracheal Tube Requiring Tube Replacement | 0 Participants |
| Treatment Arm - 216mg | Obstruction of the Endotracheal Tube Requiring Tube Replacement | 0 Participants |
| Treatment Arm - 300mg | Obstruction of the Endotracheal Tube Requiring Tube Replacement | 0 Participants |
| Observational Arm | Obstruction of the Endotracheal Tube Requiring Tube Replacement | 0 Participants |
Secondary
Pre-discharge Failed Audiology Examination
Time frame: up to 1 year of age
Population: 14 of the 16 phase 1 trial participants were assessed for failed audiology examination. The remaining two died prior to testing.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | Pre-discharge Failed Audiology Examination | 1 Participants |
| Treatment Arm - 150mg | Pre-discharge Failed Audiology Examination | 1 Participants |
| Treatment Arm - 216mg | Pre-discharge Failed Audiology Examination | 0 Participants |
| Treatment Arm - 300mg | Pre-discharge Failed Audiology Examination | 1 Participants |
| Observational Arm | Pre-discharge Failed Audiology Examination | 0 Participants |
Secondary
Unplanned Tracheal Extubation
Time frame: Any time during the 14-day trial
Population: No infants were enrolled into the observational arm. 1 of the 16 enrolled infants (treatment arm - 78mg) was withdrawn early from the trial by the medical team and was not assessed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm - 78mg | Unplanned Tracheal Extubation | 0 Participants |
| Treatment Arm - 150mg | Unplanned Tracheal Extubation | 0 Participants |
| Treatment Arm - 216mg | Unplanned Tracheal Extubation | 0 Participants |
| Treatment Arm - 300mg | Unplanned Tracheal Extubation | 0 Participants |
| Observational Arm | Unplanned Tracheal Extubation | 0 Participants |