Enterocolitis, NecrotizingPhase 2NCT02784821
Antibiotic "Dysbiosis" in Preterm Infants
A Phase 2 study testing Antibiotic, Gastric fluid and Breast milk in people with Enterocolitis, Necrotizing and Bacteremia, run by University of Florida at 1 site in United States.
Trial summary
Prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities, including necrotizing enterocolitis (NEC), late-onset sepsis, bronchopulmonary dysplasia (BPD), and mortality. Read more about this study
- Who is it for?
- Ages 23 to 33 weeks
- Conditions the study is for
- Enterocolitis, Necrotizing, Bacteremia, Bronchopulmonary Dysplasia
- What is being tested?
- Antibiotic, Gastric fluid and Breast milk
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 98 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Jan 2017to 11 Sep 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 23 to 33 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- All infants less than 33 weeks gestation.
Who cannot join
- Infants who are non-viable at birth.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Antibiotic Effects on the Developing Microbiome, Metabolome and Morbidities in Preterm Neonates
Prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities, including necrotizing enterocolitis (NEC), late-onset sepsis, bronchopulmonary dysplasia (BPD), and mortality.
The hypothesis is that early and prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities. It is possible that the effect of this widespread antibiotic use outweighs the potential benefits. This study will randomize preterm infants born at less than 33 weeks gestation to either pre-emptive antibiotics or no-pre-emptive antibiotics.
The purpose of this research is to evaluate the risks and benefits of current practice to determine optimal levels of antibiotic use that protects the babies from infection with minimal effect on the microbiome and subsequent adverse outcomes related to overuse of antibiotics.
Read the detailed description
A majority of preterm very low birthweight (VLBW) infants are exposed to antibiotics. Surveys from large databases in the US show that the rate of culture proven bacteremia in these infants at birth is only between 1-2 percent.
Antibiotic use, especially when repeated, induces a perturbation ("dysbiosis") in gut microbiota that may not recover to the basal state. Antibiotic use increases the risk of subsequent disease and adverse outcomes. The dependence of the developing immune system on the intestinal microbiota is supported by emerging evidence from studies in animals demonstrating decreased resistance to subsequent disease with early exposure to antibiotics.
A retrospective review of 50,0261 neonates across 127 neonatal intensive care units (NICUs) from California showed a forty-fold variation in NICU antibiotic prescribing practice with similar burdens of proven infection and mortality. A large number of preterm infants are thus subjected to a potentially harmful course of antibiotics that provides no clear benefit. There remains a major gap in our understanding of antibiotic-related intestinal microbial dysbiosis and how this may result in disease.
There will be two aims. In the first aim, a prospective, randomized pilot study, will test the effects of pre-emptive postnatal antibiotics on the microbiome, metabolome and inflammatory responses in the neonate during the NICU course. The second aim will assess the effects of pre-emptive postnatal antibiotics on adverse outcomes in the neonate while in the NICU. The hypothesis is that higher antibiotic use will not be associated with decreased early onset sepsis and in fact, will be associated with increased adverse outcomes including retinopathy of prematurity, necrotizing enterocolitis, spontaneous ileal perforation, late onset sepsis, chronic lung disease, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, and mortality.
- Conditions
- Enterocolitis, Necrotizing, Bacteremia, Bronchopulmonary Dysplasia, Intraventricular Hemorrhage, Periventricular Leukomalacia, Chronic Lung Disease
- Being tested
- Antibiotic, Gastric fluid, Breast milk, Stool samples, Antibiotics
- Medical subject headings
- Enterocolitis, Necrotizing, Bacteremia, Bronchopulmonary Dysplasia, Leukomalacia, Periventricular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AntibioticDrug
Also called Ampicillin or Gentamicin or Cefotaxime
Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.
Gastric fluidOther
Also called Gastric aspirate
Microbiome evaluated using gastric aspirate.
Breast milkOther
Microbiome will be evaluated using mother's breast milk.
Stool samplesOther
Microbiome will be evaluated using infant's stool.
AntibioticsDrug
Also called Ampicillin or Gentamicin or Cefotaxime
Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.
| Study group | Role | What they receive |
|---|---|---|
| Group A - Antibiotics Indicated | Other | These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks.
The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime.
Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. Receives: Drug: Antibiotic; Other: Gastric fluid; Other: Breast milk; Other: Stool samples |
| Group B - antibiotics not indicated | Other | These neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors.
Antibiotics is not indicated for this group as standard of care.
Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. Receives: Other: Gastric fluid; Other: Breast milk; Other: Stool samples |
| Group CI/randomized to antibiotics | Other | This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime.
Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. Receives: Other: Gastric fluid; Other: Breast milk; Other: Stool samples; Drug: Antibiotics |
| Group CII/randomized to no antibiotics | Other | This group will be randomized not to receive standard of care antibiotics.
Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. Receives: Other: Gastric fluid; Other: Breast milk; Other: Stool samples |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death
Enrolled subjects' medical record will be reviewed to determine the number of patients with the composite outcome and the association between antibiotic administration and the components of the composite outcome
Measured: Until discharge from the NICU, up to 1 year
Secondary outcomes (5)
Number of Participants With Late Onset Sepsis
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed bacteremia after the first week of life (late onset sepsis) and the association between antibiotic administration and the development of late onset sepsis.
Measured: Until discharge from the NICU, up to 1 year
Number of Participants With Bronchopulmonary Dysplasia (BPD)
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed BPD and the association between antibiotic administration and diagnosis of BPD.
Measured: Until discharge from the NICU, up to 1 year
Number of Participants With Necrotizing Enterocolitis (NEC)
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed NEC and the association between antibiotic administration and necrotizing enterocolitis
Measured: Until discharge from the NICU, up to 1 year
Number of Deaths
Enrolled subjects' medical record will be reviewed to determine the number of death prior to discharge from neonatal intensive care unit
Measured: until discharge from the NICU, up to one year.
Length of Stay.
length of stay in NICU in days.
Measured: Average days +/- standard deviation of hospitalization, up to 15 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2016 (estimated)
- Study start16 Jan 2017
- Primary completion11 Sep 2019
- Study completion11 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Enterocolitis, NecrotizingStudies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 98 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Society for Pediatric Dermatology
- Responsible party
- Sponsor
- Investigators
- Josef Neu, MD, Principal investigator, University of Florida
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02784821
- Sponsor's protocol ID
- IRB201501045-N
- Other IDs
- R21HD088005
- Status last verified
- Jun 2024
- First submitted
- 3 May 2016
- Last updated
- 5 Jun 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ojeda A, Akinsuyi O, McKinley KL, Xhumari J, Triplett EW, Neu J, Roesch LFW. Increased antibiotic resistance in preterm neonates under early antibiotic use. mSphere. 2024 Oct 29;9(10):e0028624. doi: 10.1128/msphere.00286-24. Epub 2024 Oct 7.
PubMed 39373498Singh NK, Will L, Al-Mulaabed S, Ruoss L, Li N, de La Cruz D, Gurka M, Neu J. Antibiotics Use and Its Effects on the Establishment of Feeding Tolerance in Preterm Neonates. Am J Perinatol. 2024 May;41(S 01):e2248-e2253. doi: 10.1055/a-2108-1960. Epub 2023 Jun 12.
PubMed 37308133Russell JT, Lauren Ruoss J, de la Cruz D, Li N, Bazacliu C, Patton L, McKinley KL, Garrett TJ, Polin RA, Triplett EW, Neu J. Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants. Sci Rep. 2021 Jan 21;11(1):1943. doi: 10.1038/s41598-021-80982-6.
PubMed 33479274
Study at a glance
From the registry record, last updated by the sponsor on 5 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Antibiotic Effects on the Developing Microbiome, Metabolome and Morbidities in Preterm Neonates
- ClinicalTrials.gov ID
- NCT02784821
- Acronym / sponsor ID
- IRB201501045-N
- Conditions
- Enterocolitis, Necrotizing, Bacteremia, Bronchopulmonary Dysplasia, Intraventricular Hemorrhage, Periventricular Leukomalacia, Chronic Lung Disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 98 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Society for Pediatric Dermatology
- Study start
- 16 Jan 2017 (actual)
- Primary completion
- 11 Sep 2019 (actual)
- Study completion
- 11 Sep 2019 (actual)
- First posted
- 27 May 2016 (estimated)
- Results
- Posted 5 Jun 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities, including necrotizing enterocolitis (NEC), late-onset sepsis, bronchopulmonary dysplasia (BPD), and mortality.
The hypothesis is that early and prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities. It is possible that the effect of this widespread antibiotic use outweighs the potential benefits. This study will randomize preterm infants born at less than 33 weeks gestation to either pre-emptive antibiotics or no-pre-emptive antibiotics.
The purpose of this research is to evaluate the risks and benefits of current practice to determine optimal levels of antibiotic use that protects the babies from infection with minimal effect on the microbiome and subsequent adverse outcomes related to overuse of antibiotics.
Detailed description
A majority of preterm very low birthweight (VLBW) infants are exposed to antibiotics. Surveys from large databases in the US show that the rate of culture proven bacteremia in these infants at birth is only between 1-2 percent.
Antibiotic use, especially when repeated, induces a perturbation ("dysbiosis") in gut microbiota that may not recover to the basal state. Antibiotic use increases the risk of subsequent disease and adverse outcomes. The dependence of the developing immune system on the intestinal microbiota is supported by emerging evidence from studies in animals demonstrating decreased resistance to subsequent disease with early exposure to antibiotics.
A retrospective review of 50,0261 neonates across 127 neonatal intensive care units (NICUs) from California showed a forty-fold variation in NICU antibiotic prescribing practice with similar burdens of proven infection and mortality. A large number of preterm infants are thus subjected to a potentially harmful course of antibiotics that provides no clear benefit. There remains a major gap in our understanding of antibiotic-related intestinal microbial dysbiosis and how this may result in disease.
There will be two aims. In the first aim, a prospective, randomized pilot study, will test the effects of pre-emptive postnatal antibiotics on the microbiome, metabolome and inflammatory responses in the neonate during the NICU course. The second aim will assess the effects of pre-emptive postnatal antibiotics on adverse outcomes in the neonate while in the NICU. The hypothesis is that higher antibiotic use will not be associated with decreased early onset sepsis and in fact, will be associated with increased adverse outcomes including retinopathy of prematurity, necrotizing enterocolitis, spontaneous ileal perforation, late onset sepsis, chronic lung disease, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, and mortality.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group A - Antibiotics Indicated | Other | Drug: Antibiotic, Other: Gastric fluid, Other: Breast milk, Other: Stool samplesThese neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. |
| Group B - antibiotics not indicated | Other | Other: Gastric fluid, Other: Breast milk, Other: Stool samplesThese neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors. Antibiotics is not indicated for this group as standard of care. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. |
| Group CI/randomized to antibiotics | Other | Other: Gastric fluid, Other: Breast milk, Other: Stool samples, Drug: AntibioticsThis group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. |
| Group CII/randomized to no antibiotics | Other | Other: Gastric fluid, Other: Breast milk, Other: Stool samplesThis group will be randomized not to receive standard of care antibiotics. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome. |
Who may qualify
- Ages
- 23 to 33 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- All infants less than 33 weeks gestation.
Key exclusion criteria (1 listed)
- Infants who are non-viable at birth.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AntibioticAlso: Ampicillin or Gentamicin or CefotaximeBabies that are assigned to antibiotics receive therapy based on the clinical team's discretion. | Drug | Group A - Antibiotics Indicated |
| Gastric fluidAlso: Gastric aspirateMicrobiome evaluated using gastric aspirate. | Other | Group A - Antibiotics Indicated, Group B - antibiotics not indicated, Group CI/randomized to antibiotics, Group CII/randomized to no antibiotics |
| Breast milkMicrobiome will be evaluated using mother's breast milk. | Other | Group A - Antibiotics Indicated, Group B - antibiotics not indicated, Group CI/randomized to antibiotics, Group CII/randomized to no antibiotics |
| Stool samplesMicrobiome will be evaluated using infant's stool. | Other | Group A - Antibiotics Indicated, Group B - antibiotics not indicated, Group CI/randomized to antibiotics, Group CII/randomized to no antibiotics |
| AntibioticsAlso: Ampicillin or Gentamicin or CefotaximeBabies that are randomized to antibiotics receive therapy based on the clinical team's discretion. | Drug | Group CI/randomized to antibiotics |
Primary outcome
Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death
Time frame: Until discharge from the NICU, up to 1 year
Enrolled subjects' medical record will be reviewed to determine the number of patients with the composite outcome and the association between antibiotic administration and the components of the composite outcome
5 secondary outcomes
Number of Participants With Late Onset Sepsis
Time frame: Until discharge from the NICU, up to 1 year
Number of Participants With Bronchopulmonary Dysplasia (BPD)
Time frame: Until discharge from the NICU, up to 1 year
Number of Participants With Necrotizing Enterocolitis (NEC)
Time frame: Until discharge from the NICU, up to 1 year
Number of Deaths
Time frame: until discharge from the NICU, up to one year.
Length of Stay.
Time frame: Average days +/- standard deviation of hospitalization, up to 15 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jun 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39373498Ojeda A, Akinsuyi O, McKinley KL, Xhumari J, Triplett EW, Neu J, Roesch LFW. Increased antibiotic resistance in preterm neonates under early antibiotic use. mSphere. 2024 Oct 29;9(10):e0028624. doi: 10.1128/msphere.00286-24. Epub 2024 Oct 7.
- Derived from this study: PubMed 37308133Singh NK, Will L, Al-Mulaabed S, Ruoss L, Li N, de La Cruz D, Gurka M, Neu J. Antibiotics Use and Its Effects on the Establishment of Feeding Tolerance in Preterm Neonates. Am J Perinatol. 2024 May;41(S 01):e2248-e2253. doi: 10.1055/a-2108-1960. Epub 2023 Jun 12.
- Derived from this study: PubMed 33479274Russell JT, Lauren Ruoss J, de la Cruz D, Li N, Bazacliu C, Patton L, McKinley KL, Garrett TJ, Polin RA, Triplett EW, Neu J. Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants. Sci Rep. 2021 Jan 21;11(1):1943. doi: 10.1038/s41598-021-80982-6.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Josef Neu, MD principal investigator
University of Florida
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Antibiotic, Gastric fluid and Breast milk in people with Enterocolitis, Necrotizing and Bacteremia, run by University of Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Jun 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death (time frame: Until discharge from the NICU, up to 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02784821, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2024.