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

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT01778634
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), Mercy Medical Center (Other), Johns Hopkins University (Other), University of Virginia (Other), University of Alabama at Birmingham (Other), Christiana Care Health Services (Other)
• Enrollment: 121
• Locations: 7
• Arms: 2
• Duration (Months): 88.1
• Patients Per Site: 17.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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 Design

• Study Type: Interventional
• 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: Jul 1, 2013
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Nov 3, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma [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 With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age [36 weeks post menstrual age (one month prior to due date)]

   Number of Participants who survived until 36 wks postmenstrual age with Physiologic defined bronchopulmonary dysplasia (BPD) based on oxygen-saturation monitoring

2. Number of Participants With Death or Neurodevelopmental Impairment [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 [6-26 months]

   Parent report of recurrent wheezing and/or chronic cough

4. Number of Participants Who Died [22-26 months]

   Number of Participants who died from any cause

5. Duration of Positive Pressure Support [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 [Participants will be followed for the duration of hospital stay, an expected average of 10 weeks]

   Cumulative number of days of receipt of supplemental oxygen

7. Number of Participants Who Experienced Air Leaks [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 [36 weeks]

   Receipt of steroid medications (hydrocortisone, dexamethasone)

9. Number of Participants Who Received Non-Study Antibiotics [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 [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) [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) [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 [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) [Participants will be followed for the duration of hospital stay, an expected average of 10 weeks]

   Number of Participants with Grade III or IV IVH confirmed by cranial ultrasound

5. Number of Participants With Periventricular Leukomalacia (PVL) [Participants will be followed for the duration of hospital stay, an expected average of 10 weeks]

   The number of Participants with cranial ultrasound confirmed PVL

6. Number of Participants With Patent Ductus Arteriosus (PDA) [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 [3 days]

   Number of Participants with EKG evidence of prolonged QT (QTc > 450 ms)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Hours to 72 Hours
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249-7335
2	Christiana Care Health Services	Newark	Delaware	United States	19713
3	University of Maryland School of Medicine	Baltimore	Maryland	United States	21201
4	Mercy Medical Center	Baltimore	Maryland	United States	21202
5	Johns Hopkins University	Baltimore	Maryland	United States	21287
6	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232-9544
7	University of Virginia	Charlottesville	Virginia	United States	22908-0386

Sponsors and Collaborators

• University of Maryland, Baltimore
• 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, 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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 30, 2017
• Informed Consent Form - Jan 30, 2017

More Information

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.

• Responsible Party: Rose Viscardi, Professor of Pediatrics, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT01778634
• Other Study ID Numbers: HP-00054998; R01HD067126
• First Posted: Jan 29, 2013
• Last Update Posted: Nov 30, 2020
• Last Verified: Nov 1, 2020

• Keywords provided by Rose Viscardi, Professor of Pediatrics, University of Maryland, Baltimore: Ureaplasma parvum; Ureaplasma urealyticum; prematurity; bronchopulmonary dysplasia; azithromycin
• Additional relevant MeSH terms: Infections; Communicable Diseases; Respiratory Tract Infections; Ureaplasma Infections; Azithromycin

Study Results

Participant Flow

Recruitment Details	Recruitment period July 1, 2013- August 31, 2016 at 7 U.S. hospital Neonatal Intensive Care Units (NICUs).

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Period Title: Overall Study
STARTED	61	60
COMPLETED	61	60
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin	Total
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days	Total of all reporting groups
Overall Participants	61	60	121
Age (weeks gestation) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks gestation]	26.2 (1.4)	26.2 (1.4)	26.2 (1.4)
Sex: Female, Male (Count of Participants)
Female	29 47.5%	34 56.7%	63 52.1%
Male	32 52.5%	26 43.3%	58 47.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 3.3%	2 1.7%
Not Hispanic or Latino	61 100%	58 96.7%	119 98.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.6%	0 0%	1 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	43 70.5%	21 35%	64 52.9%
White	15 24.6%	36 60%	51 42.1%
More than one race	2 3.3%	3 5%	5 4.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	61 100%	60 100%	121 100%
Ureaplasma-positive (Count of Participants)
Count of Participants [Participants]	25 41%	19 31.7%	44 36.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma
Description	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).
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	37 60.7%	55 91.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.51
	Confidence Interval	(2-Sided) 95%; 2.53 to 22.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age
Description	Number of Participants who survived until 36 wks postmenstrual age with Physiologic defined bronchopulmonary dysplasia (BPD) based on oxygen-saturation monitoring
Time Frame	36 weeks post menstrual age (one month prior to due date)

Outcome Measure Data

Analysis Population Description

Participants who survived until assessment timepoint 36 weeks post menstrual age (1 month before due date)

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	54	56
Count of Participants [Participants]	18 29.5%	25 41.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Generalized Estimating Equations
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	.11
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized Estimating Equations with an identity link

3. Secondary Outcome

Title	Number of Participants With Death or Neurodevelopmental Impairment
Description	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.
Time Frame	22-26 months

Outcome Measure Data

Analysis Population Description

Participants who died prior to the 22-26 months assessment timepoint and participants who were assessed for neurodevelopmental impairments

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	52	53
Count of Participants [Participants]	17 27.9%	25 41.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments	P values are based on GEE to account for twins
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	GEE
	Comments

4. Secondary Outcome

Title	Number of Participants With Pulmonary Impairment
Description	Parent report of recurrent wheezing and/or chronic cough
Time Frame	6-26 months

Outcome Measure Data

Analysis Population Description

All participants enrolled and randomized in the trial

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	12 19.7%	15 25%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments	P values are based on GEE to account for twins. The counts provided refer to to the numbers actually observed. The analysis to determine the p value accounted for the missing 11 patients using multiple imputation.
Statistical Test of Hypothesis	p-Value	0.62
	Comments
	Method	GEE with multiple imputation
	Comments

5. Secondary Outcome

Title	Number of Participants Who Died
Description	Number of Participants who died from any cause
Time Frame	22-26 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	6 9.8%	5 8.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Median (Inter-Quartile Range) [days]	36	39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	To include non-survivors as bad values of this outcome we imputed a high value for the participants who died. Note, because we analyzed the data using a nonparametric test, the actual value doesn't affect the analysis, only the rank of the value.
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Duration of Oxygen Supplementation
Description	Cumulative number of days of receipt of supplemental oxygen
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Median (Inter-Quartile Range) [days]	68	73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments	To include non-survivors as bad values of this outcome we imputed a high value for the participants who died. Note, because we analyzed the data using a nonparametric test, the actual value doesn't affect the analysis, only the rank of the value.
	Method	Wilcoxon test after multiple outputation
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	5
	Confidence Interval	(2-Sided) 95%; -15 to 26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bootstrap

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The participants who had air leak at baseline (prior to randomization) were excluded from analysis (3 placebo and 5 azithromycin).

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	57	55
Count of Participants [Participants]	4 6.6%	7 11.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Number of Participants Who Received Postnatal Steroids
Description	Receipt of steroid medications (hydrocortisone, dexamethasone)
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	14 23%	15 25%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.44 to 2.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	14 23%	8 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Generalized Estimating Equations
	Comments

11. Secondary Outcome

Title	Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations
Description	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.
Time Frame	Study day 1-day 7

Outcome Measure Data

Analysis Population Description

No plasma samples from placebo group were analyzed for azithromycin concentrations

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	0	15
Measure number of serum samples concentrations	0	27
Number [serum conc outside predicted interval]	4

12. Other Pre-specified Outcome

Title	Number of Participants With Threshold Retinopathy of Prematurity (ROP)
Description	Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks

Outcome Measure Data

Analysis Population Description

The number of participants who survived to receive at least 1 eye exam for retinopathy of prematurity

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	56	56
Count of Participants [Participants]	4 6.6%	11 18.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Generalized Estimating Equation
	Comments

13. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	5 8.2%	4 6.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

14. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	14 23%	8 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Generalized Estimating Equations
	Comments

15. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

The participants who had a Grade III or IV IVH at baseline (prior to randomization) were excluded (2 placebo and 4 Azithromycin).

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	59	56
Count of Participants [Participants]	2 3.3%	7 11.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.091
	Comments
	Method	Fisher Exact
	Comments

16. Other Pre-specified Outcome

Title	Number of Participants With Periventricular Leukomalacia (PVL)
Description	The number of Participants with cranial ultrasound confirmed PVL
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	5 8.2%	4 6.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

17. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants who did not have PDA at baseline (prior to randomization). Participants with PDA at baseline were excluded from analysis (5 placebo and 5 azithromycin.

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	56	55
Count of Participants [Participants]	21 34.4%	25 41.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Generalized Estimating Equations
	Comments

18. Other Pre-specified Outcome

Title	Number of Participants With Cardiac Arrhythmia
Description	Number of Participants with EKG evidence of prolonged QT (QTc > 450 ms)
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (5% Dextrose)	Azithromycin
Arm/Group Description	Placebo Placebo: D5W	Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
Measure Participants	61	60
Count of Participants [Participants]	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (5% Dextrose), Azithromycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	3 years 6 months
Arm/Group Title	Placebo (5% Dextrose)		Azithromycin
Arm/Group Description	Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days		Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days
All Cause Mortality
	Placebo (5% Dextrose)		Azithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/61 (9.8%)		5/60 (8.3%)
Serious Adverse Events
	Placebo (5% Dextrose)		Azithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/61 (63.9%)		44/60 (73.3%)
Blood and lymphatic system disorders
Anemia	6/61 (9.8%)		5/60 (8.3%)
White blood cell count >40,000 cells/mm3	4/61 (6.6%)		3/60 (5%)
Thrombocytopenia	2/61 (3.3%)		2/60 (3.3%)
Cardiac disorders
Patent Ductus Arteriosus	12/61 (19.7%)		17/60 (28.3%)
Eye disorders
Retinopathy of prematurity	3/60 (5%)		11/58 (19%)
Gastrointestinal disorders
Necrotizing enterocolitis	3/61 (4.9%)		3/60 (5%)
Intestinal Perforation	4/61 (6.6%)		3/60 (5%)
Ileal stricture	0/61 (0%)		1/60 (1.7%)
Hepatobiliary disorders
Cholestasis	5/61 (8.2%)		5/60 (8.3%)
Infections and infestations
Sepsis	9/61 (14.8%)		6/60 (10%)
Urinary tract infection	4/61 (6.6%)		0/60 (0%)
Metabolism and nutrition disorders
Blood Urea Nitrogen > 60 mg/dL	4/61 (6.6%)		0/60 (0%)
Hypercalcemia	2/61 (3.3%)		0/60 (0%)
Hypochloremia	0/61 (0%)		1/60 (1.7%)
Hypernatremia	2/61 (3.3%)		1/60 (1.7%)
Hypokalemia	0/61 (0%)		2/60 (3.3%)
Hyponatremia	1/61 (1.6%)		1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	6/61 (9.8%)		5/60 (8.3%)
Respiratory Failure	3/61 (4.9%)		1/60 (1.7%)
Apnea	4/61 (6.6%)		3/60 (5%)
Other (Not Including Serious) Adverse Events
	Placebo (5% Dextrose)		Azithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/61 (83.6%)		51/60 (85%)
Blood and lymphatic system disorders
Leukocytosis	12/61 (19.7%)		11/60 (18.3%)
Thrombocytopenia	12/61 (19.7%)		4/60 (6.7%)
Anemia	16/61 (26.2%)		12/60 (20%)
Gastrointestinal disorders
Vomiting	1/61 (1.6%)		1/60 (1.7%)
Gastric residual >50% volume of feed	1/61 (1.6%)		3/60 (5%)
Abdominal Distension	2/61 (3.3%)		3/60 (5%)
Loose stools	1/61 (1.6%)		0/60 (0%)
Hepatobiliary disorders
Abnormal liver function test	0/61 (0%)		1/60 (1.7%)
conjugated hyperbilirubinemia	14/61 (23%)		8/60 (13.3%)
Hyperbilirubinemia	7/61 (11.5%)		9/60 (15%)
Infections and infestations
Oral thrush	1/61 (1.6%)		0/60 (0%)
Metabolism and nutrition disorders
metabolic acidosis	18/61 (29.5%)		19/60 (31.7%)
Metabolic alkalosis	6/61 (9.8%)		8/60 (13.3%)
Elevated Blood Urea Nitrogen	28/61 (45.9%)		26/60 (43.3%)
Hyperkalemia	21/61 (34.4%)		20/60 (33.3%)
Hypernatremia	8/61 (13.1%)		13/60 (21.7%)
Renal and urinary disorders
Elevated serum creatinine	1/61 (1.6%)		2/60 (3.3%)
Skin and subcutaneous tissue disorders
IV site reaction	1/61 (1.6%)		0/60 (0%)
Rash	0/61 (0%)		1/60 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.