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

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

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.

Study Overview

• Status: Completed
• Conditions: Ureaplasma Infections
• Intervention / Treatment: Drug: Placebo; Drug: Azithromycin

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).

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249-7335
      • University of Alabama at Birmingham
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Care Health Services
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9544
      • Monroe Carell Jr. Children's Hospital at Vanderbilt
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0386
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 hours to 3 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Threshold Retinopathy of Prematurity (ROP)	Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Number of Participants With Necrotizing Enterocolitis (NEC)	Necrotizing enterocolitis ≥ Bell Stage II by radiographic and clinical criteria.	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Number of Participants With Infections During the NICU Hospitalization	Culture-confirmed bacterial or fungal infection based on culture from sterile site (blood, cerebral spinal fluid, or urine)	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Number of Participants With Severe Intraventicular Hemorrhage (IVH)	Number of Participants with Grade III or IV IVH confirmed by cranial ultrasound	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Number of Participants With Periventricular Leukomalacia (PVL)	The number of Participants with cranial ultrasound confirmed PVL	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Number of Participants With Patent Ductus Arteriosus (PDA)	Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure.	14 days
Number of Participants With Cardiac Arrhythmia	Number of Participants with EKG evidence of prolonged QT (QTc > 450 ms)	3 days

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: Johns Hopkins University; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Alabama at Birmingham; Christiana Care Health Services; University of Virginia; Mercy Medical Center
• Investigators: Study Chair: Rose M Viscardi, M.D., University of Maryland, College Park; Principal Investigator: Pamela Donohue, ScD, Johns Hopkins University; Principal Investigator: Namasivayam Ambalavanan, M.D., University of Alabama at Birmingham; Principal Investigator: David A Kaufman, M.D., University of Virginia; Principal Investigator: Michael L Terrin, M.D., University of Maryland, College Park; Principal Investigator: Susan J Dulkerian, M.D., Mercy Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): November 3, 2020

Study Registration Dates

• First Submitted: January 22, 2013
• First Submitted That Met QC Criteria: January 24, 2013
• First Posted (Estimate): January 29, 2013

Study Record Updates

• Last Update Posted (Actual): November 30, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: prematurity; bronchopulmonary dysplasia; azithromycin; Ureaplasma urealyticum; Ureaplasma parvum
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Mycoplasmatales Infections; Infections; Communicable Diseases; Respiratory Tract Infections; Ureaplasma Infections; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: HP-00054998; R01HD067126 (U.S. NIH Grant/Contract)