A Randomized Controlled Trial Investigating if Antibiotic Use in the First 48 Hours of Life Adversely Impacts the Preterm Infant Microbiome

• Sponsor: University of Chicago (Other)
• Overall Status: Completed
• CT.gov ID: NCT02477423
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arms: 2
• Duration (Months): 47
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether antibiotics given immediately after birth alter the development of the developing preterm infant's microbiome, which may further alter overall clinical outcomes.

Condition or Disease	Intervention/Treatment	Phase
Premature Birth of Newborn; Enterocolitis, Necrotizing	Drug: Ampicillin; Drug: Gentamicins; Drug: Placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized Controlled Trial Investigating if Antibiotic Use in the First 48 Hours of Life Adversely Impacts the Preterm Infant Microbiome
• Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Jun 1, 2019
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Randomized & Blinded - Receiving Antibiotics The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life.	Drug: Ampicillin; Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.; Drug: Gentamicins; Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.
Placebo Comparator: Randomized & Blinded - Receiving Placebo The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life.	Drug: Placebo; Normal saline will be given as placebo for those in the placebo comparator group.

Outcome Measures

Primary Outcome Measures

1. Richness of the Preterm Infant Microbiome [2 weeks]

   Number of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) detected in each sample. A higher richness means that a higher number of species of archaea and bacteria was detected in a sample.

2. Shannon Diversity of the Preterm Infant Microbiome [2 weeks]

   Function of richness and evenness of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) within each sample. A higher Shannon diversity means that a sample had a combination of a higher number of species of archaea and bacteria, and/or a more even relative abundance of those species within a sample.

Secondary Outcome Measures

1. Chronic Lung Disease of Infancy (CLD) [4-12 weeks]

   Premature infants who require > 21% FiO2 for at least 28 days and/or at 36 weeks corrected gestation

2. Necrotizing Enterocolitis (NEC) [4-12 weeks]

   Any patient showing signs/symptoms of this acute neonatal gastrointestinal disease, including abdominal distension, bloody stools, systemic illness, and radiographic changes (pneumatosis intestinalis, portal venous gas, free intraperitoneal gas).

3. Retinopathy of Prematurity (ROP) [4-12 weeks]

   Cases of ROP as diagnosed by the pediatric ophthalmologist

4. Intraventricular Hemorrhage (IVH) [4-12 weeks]

   Cases of IVH present on any head ultrasound obtained during patient's hospitalization

5. Death [18 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 6 Hours
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria for antibiotic randomization:

1. Infant must be born between the gestational ages of 28 0/7 weeks and 34 6/7 weeks

-AND-

1. Infant must be born at investigator's home institution.

-AND-

1. Infant must be considered to have a low risk of infection by one of the following criteria:

2. Delivered for maternal indications (Cesarean section or induction of labor for maternal health, including pre-eclampsia, placental abruption, history of intrauterine fetal demise (IUFD)/abruption, multiple gestation requiring preterm delivery, etc) -OR-

3. Delivered due to preterm labor to a mother without the diagnosis of chorioamnionitis/maternal fever or prolonged rupture of membranes >18 hours

Exclusion Criteria for antibiotic randomization:

1. Signs of clinical illness within the first 3 hours of life:

2. 5-minute Apgar <5

3. Requiring vasoactive drugs

4. Seizures

5. Significant respiratory distress requiring supplemental oxygen >40%

6. Immature:Total (I:T) Ratio of >0.2 on initial complete blood count (CBC)

7. Congenital anomalies, including renal anomalies requiring serum antibiotic level monitoring

ANY infant born between the gestational ages of 28 0/7 weeks and 34 6/7 weeks who do not meet inclusion criteria, with parental consent, can participate in the stool analysis only arm of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Medical Center - Comer Children's Hospital	Chicago	Illinois	United States	60637

Sponsors and Collaborators

• University of Chicago

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 30, 2018

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT02477423
• Other Study ID Numbers: IRB15-0053
• First Posted: Jun 22, 2015
• Last Update Posted: Oct 8, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Chicago: Microbiome; Antibiotics
• Additional relevant MeSH terms: Enterocolitis; Enterocolitis, Necrotizing; Premature Birth; Gentamicins; Ampicillin

Study Results

Participant Flow

Recruitment Details	Patients in the study were enrolled from The University of Chicago Comer Children's Hospital, a level IV NICU in Chicago, Illinois, as well as Northshore University HealthSystem Evanston Hospital, a level III NICU in Evanston, Illinois from 2015-2018.

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Period Title: Overall Study
STARTED	12	15
COMPLETED	11	11
NOT COMPLETED	1	4

Baseline Characteristics

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo	Total
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicin: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.	Total of all reporting groups
Overall Participants	12	15	27
Age, Customized (weeks) [Mean (Full Range) ]
Gestational Age	32.6	31.9	32.3
Sex: Female, Male (Count of Participants)
Female	5 41.7%	7 46.7%	12 44.4%
Male	7 58.3%	8 53.3%	15 55.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 91.7%	14 93.3%	25 92.6%
White	1 8.3%	1 6.7%	2 7.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Richness of the Preterm Infant Microbiome
Description	Number of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) detected in each sample. A higher richness means that a higher number of species of archaea and bacteria was detected in a sample.
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	11	11
Mean (Standard Deviation) [16S rRNA gene amplicon sequence variants]	12.8 (5.3)	11 (6.9)

2. Primary Outcome

Title	Shannon Diversity of the Preterm Infant Microbiome
Description	Function of richness and evenness of 16S rRNA gene amplicon sequence variants (i.e., proxy for prokaryote species-like groupings) within each sample. A higher Shannon diversity means that a sample had a combination of a higher number of species of archaea and bacteria, and/or a more even relative abundance of those species within a sample.
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	11	11
Mean (Standard Deviation) [Shannon diversity]	5 (3.6)	3.8 (3.3)

3. Secondary Outcome

Title	Chronic Lung Disease of Infancy (CLD)
Description	Premature infants who require > 21% FiO2 for at least 28 days and/or at 36 weeks corrected gestation
Time Frame	4-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	12	15
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Necrotizing Enterocolitis (NEC)
Description	Any patient showing signs/symptoms of this acute neonatal gastrointestinal disease, including abdominal distension, bloody stools, systemic illness, and radiographic changes (pneumatosis intestinalis, portal venous gas, free intraperitoneal gas).
Time Frame	4-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	12	15
Count of Participants [Participants]	0 0%	0 0%

5. Secondary Outcome

Title	Retinopathy of Prematurity (ROP)
Description	Cases of ROP as diagnosed by the pediatric ophthalmologist
Time Frame	4-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	12	15
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Intraventricular Hemorrhage (IVH)
Description	Cases of IVH present on any head ultrasound obtained during patient's hospitalization
Time Frame	4-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	12	15
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

Title	Death
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized & Blinded - Receiving Antibiotics	Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicins: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
Measure Participants	12	15
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	3 years
Arm/Group Title	Randomized & Blinded - Receiving Antibiotics		Randomized & Blinded - Receiving Placebo
Arm/Group Description	The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive routine ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Ampicillin: Ampicillin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization. Gentamicin: Gentamicin will be given as routine antibiotic coverage for those in the active arm, as the standard initial antibiotic used within the neonatal unit. It may also be used for patients who are not eligible for randomization.		The infants within this arm of the study meet the inclusion criteria as being low risk. They will be randomized to receive placebo (saline) in place of ampicillin and gentamicin for the initial 48 hours of their life as a routine rule-out sepsis. Stool samples will be collected throughout hospitalization and at 18 months of life. Placebo: Normal saline will be given as placebo for those in the placebo comparator group.
All Cause Mortality
	Randomized & Blinded - Receiving Antibiotics		Randomized & Blinded - Receiving Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/15 (0%)
Serious Adverse Events
	Randomized & Blinded - Receiving Antibiotics		Randomized & Blinded - Receiving Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Randomized & Blinded - Receiving Antibiotics		Randomized & Blinded - Receiving Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.