Prospective Pilot Clinical Trial of Azithromycin Treatment In Respiratory Syncytial Virus (RSV)- Induced Respiratory Failure In Children

Prospective Pilot Clinical Trial of Azithromycin Treatment In RSV-induced Respiratory Failure In Children

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02707523

Enrollment

Registered

2016-03-14

Start date

2016-01-01

Completion date

2020-06-20

Last updated

2020-07-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Respiratory Syncytial Virus

Keywords

RSV, respiratory support, ICU, Azithromycin

Brief summary

This randomized, double-blind, placebo-controlled phase 2 trial will be conducted at a single tertiary pediatric intensive care unit (PICU). The study will include children with RSV infection who were admitted to the pediatric intensive care unit and require respiratory support via positive pressure ventilation (invasive and noninvasive).

Detailed description

Eligible participants include all children admitted to the PICU at Children's of Alabama with a diagnosis of RSV infection and requiring positive pressure ventilation, invasive or noninvasive, including bilevel positive airway pressure (BiPAP) or high flow nasal cannula (HFNC) oxygen (ie, \>1 L/kg/min of flow, with 5 L/min flow for children weighing \<5 kg). During hospitalization, all patients will be treated according to the American Academy of Pediatrics guidelines for the management of bronchiolitis, primarily supportive care. Participants will then be randomized according to a permuted-block design to receive either placebo (saline) or AZM (Fresenius Kabi) at 10mg/kg/d (ie, standard dose) or 20mg/kg/d (ie, high dose) intravenously every 24 hours for 3 days. All biologic samples collected will be analyzed in the PI's lab at the University of Alabama at Birmingham. Drug pharmacokinetics will be performed at the Pharmaceutical Sciences Research Institute of Samford University, Birmingham, AL.

Interventions

DRUGAzithromycin 10 mg

DRUGAzithromycin 20mg

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Participant, clinical providers and study staff are masked to the intervention. The random assignment of treatment was determined by random permutation. A statistician generated the randomization schedule and provided the randomization schedule (with randomization IDs) in an excel file to the study pharmacist in charge of dispensing the appropriate treatment.

Eligibility

Sex/Gender

ALL

Age

No minimum to 16 Years

Healthy volunteers

Inclusion criteria

* Admission to the PICU with RSV infection * Need for positive pressure ventilation (invasive and non-invasive) * Randomization and drug/placebo initiation within 48 hours of admission to Pediatric Intensive Care Unit

Exclusion criteria

* Azithromycin use within 7 days of PICU admission * Contraindication to azithromycin use including: * Patients with electrocardiogram QT interval corrected for heart rate (Qtc) ≥ 450 ms * Patients with significant hepatic impairment (direct bilirubin \>1.5 mg/dL) * Known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug * Cardiac arrhythmia * History of pyloric stenosis * Immunocompromised children (any cause) * Current use of any medication known to cause QT prolongation

Design outcomes

Primary

Measure	Time frame	Description
Pharmacokinetic-Lung Half Life of AZM	From baseline to 72 hours post treatment	Measurement of AZM half life in the lung
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	Baseline through Day 3	To determine the safety profile of AZM at 10 mg/kg and 20 mg/kg IV X 3 days in children with RSV-induced respiratory failure
Nasal Total Matrix Metalloproteinase (MMP)-9 Level	Day 3	To determine the concentration of total MMP-9 levels in the nasal compartment
Pharmacokinetic-Plasma Half Life of AZM	From baseline to 72 hours post treatment	Measurement of AZM half life in the plasma

Secondary

Measure	Time frame	Description
Duration of Oxygenation in Days	Pre-treatment through 2 weeks	Duration of oxygenation in days for enrolled subjects
Duration of PICU Stay in Days	Pre-treatment through 2 weeks	Duration of PICU stay in days for enrolled subjects
Duration of Hospitalization in Days	Pre-treatment through 2 weeks	Duration of hospitalization in days for enrolled subjects
Duration of Mechanical Ventilation in Days	Pre-treatment through 2 weeks	Duration of mechanical ventilation in days for enrolled subjects
Duration of BiPAP in Days	Pre-treatment through 2 weeks	Duration of BiPAP in days for enrolled subjects
Duration of High Flow Nasal Cannula in Days	Pre-treatment through 2 weeks	Duration of High Flow Nasal Cannula in days for enrolled subjects

Other

Measure	Time frame	Description
Lung Matrix Metalloproteinase (MMP) Level	Day 3	To determine the concentration of MMP-9 levels in the lung compartment

Countries

United States

Participant flow

Participants by arm

Arm	Count
Control Placebo controlled (normal saline) daily for 3 days	16
Azithromycin (10 mg/kg) 10 mg/kg IV Azithromycin daily for 3 days	16
Azithromycin (20 mg/kg) 20 mg/kg IV Azithromycin daily for 3 days	16
Total	48

Baseline characteristics

Characteristic	Control	Total	Azithromycin (20 mg/kg)	Azithromycin (10 mg/kg)
Age, Continuous	10.8 months STANDARD_DEVIATION 11	17.5 months STANDARD_DEVIATION 23	20.2 months STANDARD_DEVIATION 23	21.6 months STANDARD_DEVIATION 29
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants	46 Participants	15 Participants	15 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	5 Participants	12 Participants	2 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	10 Participants	34 Participants	14 Participants	10 Participants
Region of Enrollment United States	16 Participants	48 Participants	16 Participants	16 Participants
Sex: Female, Male Female	7 Participants	22 Participants	7 Participants	8 Participants
Sex: Female, Male Male	9 Participants	26 Participants	9 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 16	0 / 16	0 / 16
other Total, other adverse events	0 / 16	0 / 16	0 / 16
serious Total, serious adverse events	0 / 16	0 / 16	0 / 16

Outcome results

Primary

Nasal Total Matrix Metalloproteinase (MMP)-9 Level

To determine the concentration of total MMP-9 levels in the nasal compartment

Time frame: Day 3

Arm	Measure	Value (MEAN)	Dispersion
Control	Nasal Total Matrix Metalloproteinase (MMP)-9 Level	545 ng/ml	Standard Deviation 708
Azithromycin (10 mg/kg)	Nasal Total Matrix Metalloproteinase (MMP)-9 Level	267 ng/ml	Standard Deviation 301
Azithromycin (20 mg/kg)	Nasal Total Matrix Metalloproteinase (MMP)-9 Level	413 ng/ml	Standard Deviation 814

Primary

Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0

To determine the safety profile of AZM at 10 mg/kg and 20 mg/kg IV X 3 days in children with RSV-induced respiratory failure

Time frame: Baseline through Day 3

Arm	Measure	Value (NUMBER)
Control	Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	0 participants
Azithromycin (10 mg/kg)	Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	0 participants
Azithromycin (20 mg/kg)	Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	0 participants

Primary

Pharmacokinetic-Lung Half Life of AZM

Measurement of AZM half life in the lung

Time frame: From baseline to 72 hours post treatment

Arm	Measure	Value (MEAN)	Dispersion
Control	Pharmacokinetic-Lung Half Life of AZM	0 hours	Standard Deviation 0
Azithromycin (10 mg/kg)	Pharmacokinetic-Lung Half Life of AZM	78 hours	Standard Deviation 31
Azithromycin (20 mg/kg)	Pharmacokinetic-Lung Half Life of AZM	385 hours	Standard Deviation 63

Primary

Pharmacokinetic-Plasma Half Life of AZM

Measurement of AZM half life in the plasma

Time frame: From baseline to 72 hours post treatment

Arm	Measure	Value (MEAN)	Dispersion
Control	Pharmacokinetic-Plasma Half Life of AZM	0 hours	Standard Deviation 0
Azithromycin (10 mg/kg)	Pharmacokinetic-Plasma Half Life of AZM	76 hours	Standard Deviation 17
Azithromycin (20 mg/kg)	Pharmacokinetic-Plasma Half Life of AZM	102 hours	Standard Deviation 33

Secondary