Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether intravenous azithromycin is effective in eradicating Ureaplasma respiratory tract infection in preterm infants born at 24 to 28 weeks gestation.

Detailed Description
-----------------
The study design will be a double-blind, placebo-controlled clinical trial to test the efficacy and safety of azithromycin 20 mg/kg x 3 days to eradicate Ureaplasma spp from the respiratory tract of preterm infants 24 weeks 0 days to 28 weeks 6 days gestation exposed to positive pressure ventilation. The primary outcome will be survival with microbiological eradication of Ureaplasma defined as survival to discharge or transfer with 3 negative cultures obtained post-therapy. Secondary outcomes will include physiologic BPD at 36 weeks post-menstrual age (PMA), overall mortality, incidence of co-morbidities of prematurity such as intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bacterial and fungal nosocomial infection, pulmonary air leak, patent ductus arteriosus, retinopathy of prematurity, number of days of positive pressure ventilation, number of days of oxygen supplementation, use of postnatal steroids, and use of non-study antibiotics. At 6 and 18 months adjusted age, a pulmonary outcome questionnaire will be administered by phone or in person interview. At 18-22 months adjusted age, neurodevelopmental outcomes will be assessed by 1) Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III); 2) Amiel-Tison neurologic examination; 3) Gross Motor Function Classification System; and 4) medical record review for hearing impairment with or without amplification and vision impairment (vision <20/200).

Official Title
-----------------
A Phase IIb Randomized, Placebo-controlled, Double-blind Trial of Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants

Conditions
-----------------
Ureaplasma Infections

Intervention / Treatment
-----------------
* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Gestational age 24 weeks 0 days-28weeks 6 days by best obstetrical estimate <72 h age Positive pressure ventilation for at least 1 hour duration during the first 72 hours of life Presence of indwelling intravenous line for drug administration Exclusion Criteria: Any patient judged to be non-viable or for whom withdrawal of life support is planned Patients with major lethal congenital anomalies Triplets or higher order multiples Patients delivered for maternal indications (low risk of Ureaplasma colonization) Patients with EKG QT interval corrected for heart rate (Qtc) ≥ 450 ms Patients with significant hepatic impairment (direct bilirubin >1.5 mg/dL) Patients exposed to other systemic macrolide Patients with clinically suspected Ureaplasma central nervous system (CNS) infection or other confirmed bacterial/viral infection Patients participating in other clinical trials involving investigational products.

Ages Eligible for Study
-----------------
Minimum Age: 2 Hours
Maximum Age: 72 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (5% dextrose)<br>Placebo | Drug: Placebo<br>* D5W<br>* Other names: equal volume of 5% dextrose water;|
| Experimental: Azithromycin<br>Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days | Drug: Azithromycin<br>* Azithromycin intravenous 20 mg/kg every 24 h x 3 days<br>* Other names: Zithromax;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma | Bacterial clearance (eradication) will be defined as 3 negative cultures obtained 2 and 5 days post-third dose and 21 d of age. Survival is defined as survival at time of discharge or transfer from the neonatal intensive care unit (NICU). | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age | Number of Participants who survived until 36 wks postmenstrual age with Physiologic defined bronchopulmonary dysplasia (BPD) based on oxygen-saturation monitoring | 36 weeks post menstrual age (one month prior to due date) | 
| Number of Participants With Death or Neurodevelopmental Impairment | Neurodevelopmental impairment will be assigned if any of the following are present at 22-26 months adjusted age: moderate to severe cerebral palsy, bilateral blindness, bilateral hearing impairment requiring amplification, Gross Motor Function Classification System score ≥ 2, or Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III) cognitive or motor score <70. | 22-26 months | 
| Number of Participants With Pulmonary Impairment | Parent report of recurrent wheezing and/or chronic cough | 6-26 months | 
| Number of Participants Who Died | Number of Participants who died from any cause | 22-26 months | 
| Duration of Positive Pressure Support | Combined number of days receiving mechanical ventilation plus non-invasive modes of positive pressure support. | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | 
| Duration of Oxygen Supplementation | Cumulative number of days of receipt of supplemental oxygen | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | 
| Number of Participants Who Experienced Air Leaks | Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | 
| Number of Participants Who Received Postnatal Steroids | Receipt of steroid medications (hydrocortisone, dexamethasone) | 36 weeks | 
| Number of Participants Who Received Non-Study Antibiotics | Received Non-study antibiotics following study drug intervention period. | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | 
| Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations | Number of serum azithromycin concentrations that fell outside the 90% prediction interval determined by 200 simulated replicates based on the population PK of azithromycin in preterm infants. | Study day 1-day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ureaplasma parvum, Ureaplasma urealyticum, prematurity, bronchopulmonary dysplasia, azithromycin