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

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

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

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Mercy Medical Center, Johns Hopkins University, University of Virginia, University of Alabama at Birmingham, Christiana Care Health Services

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.

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).

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).

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

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.

Combined number of days receiving mechanical ventilation plus non-invasive modes of positive pressure support.

Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray

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.

Culture-confirmed bacterial or fungal infection based on culture from sterile site (blood, cerebral spinal fluid, or urine)

Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure.

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.

Hassan HE, Othman AA, Eddington ND, Duffy L, Xiao L, Waites KB, Kaufman DA, Fairchild KD, Terrin ML, Viscardi RM. Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia. J Clin Pharmacol. 2011 Sep;51(9):1264-75. doi: 10.1177/0091270010382021. Epub 2010 Nov 23.

Viscardi RM, Terrin ML, Magder LS, Davis NL, Dulkerian SJ, Waites KB, Ambalavanan N, Kaufman DA, Donohue P, Tuttle DJ, Weitkamp JH, Hassan HE, Eddington ND. Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2020 Nov;105(6):615-622. doi: 10.1136/archdischild-2019-318122. Epub 2020 Mar 13.