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

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ClinicalTrials.gov Identifier: NCT01778634
Recruitment Status : Active, not recruiting
First Posted : January 29, 2013
Results First Posted : May 17, 2018
Last Update Posted : June 15, 2018
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Rose Viscardi, University of Maryland

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.

Condition or disease Intervention/treatment Phase
Ureaplasma Infections Drug: Azithromycin Drug: Placebo Phase 2

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  (Clinical Trial)
Actual Enrollment : 121 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase IIb Randomized, Placebo-controlled, Double-blind Trial of Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants
Study Start Date : July 2013
Actual Primary Completion Date : December 2016
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo (5% dextrose)
Placebo
Drug: Placebo
D5W
Other Name: 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 Name: Zithromax




Primary Outcome Measures :
  1. Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    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).


Secondary Outcome Measures :
  1. Number of Participants Who Survived Until 36 Wks Postmenstrual Age That Were Diagnosed With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age [ Time Frame: 36 weeks post menstrual age (one month prior to due date) ]
    Physiologic definition of BPD based on oxygen-saturation monitoring

  2. Number of Participants With Death or Neurodevelopmental Impairment [ Time Frame: 22-26 months ]
    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.

  3. Number of Participants With Pulmonary Impairment [ Time Frame: 6-26 months ]
    Parent report of recurrent wheezing and/or chronic cough

  4. Number of Participants Who Died [ Time Frame: 22-26 months ]
    Mortality from any cause

  5. Duration of Positive Pressure Support [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Combined number of days receiving mechanical ventilation plus non-invasive modes of positive pressure support.

  6. Duration of Oxygen Supplementation [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Receipt of supplemental oxygen

  7. Number of Participants Who Experienced Air Leaks [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray

  8. Number of Participants Who Received Postnatal Steroids [ Time Frame: 36 weeks ]
    Receipt of steroid medications (hydrocortisone, dexamethasone)

  9. Number of Participants Who Received Non-Study Antibiotics [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Received Non-study antibiotics following study drug intervention period.

  10. Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations [ Time Frame: Study day 1-day 7 ]
    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.


Other Outcome Measures:
  1. Number of Participants With Threshold Retinopathy of Prematurity (ROP) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination

  2. Number of Participants With Necrotizing Enterocolitis (NEC) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Necrotizing enterocolitis ≥ Bell Stage II by radiographic and clinical criteria.

  3. Number of Participants With Infections During the NICU Hospitalization [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Culture-confirmed bacterial or fungal infection based on culture from sterile site (blood, cerebral spinal fluid, or urine)

  4. Number of Participants With Severe Intraventicular Hemorrhage (IVH) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    Grade III or IV IVH confirmed by cranial ultrasound

  5. Number of Participants With Periventricular Leukomalacia (PVL) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ]
    The number of subjects with cranial ultrasound confirmed PVL

  6. Number of Participants With Patent Ductus Arteriosus (PDA) [ Time Frame: 14 days ]
    Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure.

  7. Number of Participants With Cardiac Arrhythmia [ Time Frame: 3 days ]
    EKG evidence of prolonged QT (QTc > 450 ms)



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Ages Eligible for Study:   up to 72 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01778634


Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35249-7335
United States, Delaware
Christiana Care Health Services
Newark, Delaware, United States, 19713
United States, Maryland
University of Maryland School of Medicine
Baltimore, Maryland, United States, 21201
Mercy Medical Center
Baltimore, Maryland, United States, 21202
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Tennessee
Monroe Carell Jr. Children's Hospital at Vanderbilt
Nashville, Tennessee, United States, 37232-9544
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908-0386
Sponsors and Collaborators
University of Maryland
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
Investigators
Study Chair: Rose M Viscardi, M.D. University of Maryland
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
Principal Investigator: Susan J Dulkerian, M.D. Mercy Medical Center
  Study Documents (Full-Text)

Documents provided by Rose Viscardi, University of Maryland:
Informed Consent Form  [PDF] January 30, 2017


Publications:
Responsible Party: Rose Viscardi, Professor of Pediatrics, University of Maryland
ClinicalTrials.gov Identifier: NCT01778634     History of Changes
Other Study ID Numbers: HP-00054998
R01HD067126 ( U.S. NIH Grant/Contract )
First Posted: January 29, 2013    Key Record Dates
Results First Posted: May 17, 2018
Last Update Posted: June 15, 2018
Last Verified: May 2018

Keywords provided by Rose Viscardi, University of Maryland:
Ureaplasma parvum
Ureaplasma urealyticum
prematurity
bronchopulmonary dysplasia
azithromycin

Additional relevant MeSH terms:
Infection
Communicable Diseases
Respiratory Tract Infections
Ureaplasma Infections
Respiratory Tract Diseases
Mycoplasmatales Infections
Gram-Negative Bacterial Infections
Bacterial Infections