NICU Antibiotics and Outcomes Trial

Microbial Colonization Clinical Trial

— NANO  

Official title:

NICU Antibiotics and Outcomes Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03997266
• Other study ID #: PRO18010284
• Secondary ID: 1R01HD097578-01
• Status: Recruiting
• Phase: Phase 4
• Start date: August 5, 2020
• Est. completion date: June 1, 2026

Study information

• Verified date: January 2024
• Source: University of Pittsburgh
• Contact: Michael J Morowitz, MD
• Phone: 412-692-5976
• Email: michael.morowitz[@]chp.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of the NANO trial is to study the longstanding clinical practice of empirically administering intravenous antibiotics to extremely low birthweight (ELBW) infants in the first days of life. In this 802-subject multicenter placebo-controlled randomized clinical trial, the hypothesis to be tested is that the incidence of adverse outcomes is higher in babies receiving empiric antibiotics (EA) in the first week of life compared to babies receiving placebo. The study targets a population of ELBW infants in whom the clinical decision to use or not use EA is currently most challenging -- infants that are clinically stable that did not have a known exposure to intraamniotic infection and were not born preterm for maternal indications. The primary outcome is the composite outcome of late-onset sepsis (LOS), necrotizing enterocolitis (NEC), or death during the index hospitalization. Secondary safety outcomes will include total antibiotic days, days to full enteral feedings, and common morbidities in preterm infants that have previously been linked to EA, e.g. retinopathy of prematurity and bronchopulmonary dysplasia. Weight and length z-score, and head circumference, are standard measures to be collected weekly by clinical team per a standardized protocol.

Description:

Randomization and blinding. Physicians will screen infants based on inclusion/exclusion criteria. The site coordinator will confirm eligibility with the treating physician and input patient data into the web based system. Once data is inputted, the coordinator will randomize eligible families 1:1 using web-based block randomization stratified by study site to receive EA or placebo. Multiples (i.e. siblings) will be randomized to the same treatment arm. Randomization will be sent to the investigational pharmacy via email, where study drug will be drawn. Participants, treating clinicians, and study staff will all be blinded to allocation. Outcome assessors and statistical summaries for trial monitoring will be unaware of group allocation. Unblinded data evaluation during the trial will be restricted to a designated study statistician and the Data and Safety Monitoring Board (DSMB). Investigators will be unblinded and analyses initiated only after all data collection forms are completed, data queries resolved, and data are locked for analysis.

Intervention. Following randomization, the coordinator will contact the attending physician, nurse practitioner and/or other providers as appropriate, and nurse to inform them that randomization has been completed. The intervention consists of administering either conventional EA or placebo while completing an evaluation for early onset sepsis. Timing of drug administration will be closely monitored. Enrolled subjects will receive EITHER ampicillin and gentamicin at site approved dosing guidelines OR volume matched equivalent of normal saline. These dosing regimens are derived from updated published guidelines for neonates. No masking is required as each of these solutions is clear.

The study drug will be ordered and in many cases discontinued just as EA would normally be ordered and discontinued; specifically, this means that the drugs will be ordered and administered within 4 hours of life and then discontinued at the discretion of the attending neonatologist. Typically this occurs when blood culture results are deemed negative (expected in > 95% of study subjects). The study protocol will allow the first dose of study drug to be administered as late as 4 hours after delivery. Research coordinators will follow daily orders on all study subjects.

Fecal sample collection. Samples will be obtained exclusively for research purposes, and there will be no testing of patients beyond obtaining microbiome samples, and recording demographic data and clinical history. Spontaneously expelled fecal samples for microbiome analyses will be obtained weekly from study subjects through the first 8 weeks of life, and monthly thereafter until death or discharge.

Infant blood draw. An additional research blood sample for genetic analysis will be drawn one time and should be done at the time of clinical blood draws. However, if this blood draw is missed, it can be done in the neonate's first week of life. A volume of 0.3 to 0.4mL will be drawn in EDTA tubes and shaken well. After the sample is collected, it will be frozen for shipment. The blood draw will be performed by NICU personnel who routinely draw blood on preterm babies. It will be either the bedside nurse or the respiratory therapist depending on whether the blood is drawn from an umbilical catheter or by heelstick.

Maternal vaginal swab and rectal swabs at delivery will be collected. If a rectal swab was not collected at the time of delivery, a maternal fecal sample during the first week postpartum will be collected in its place. Samples will be cryopreserved at -80C.

An electronic database will be used to track sample collection and storage history.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 802
• Est. completion date: June 1, 2026
• Est. primary completion date: September 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 4 Hours

Eligibility

I. Inclusion criteria: We will enroll newborn infants with gestational age of 23-30 weeks 6 days infants at participating study sites will be eligible.

II. Exclusion criteria:

1. Infants born for maternal indications via caesarean section with rupture of membranes at delivery, without attempts to induce labor, and without concern for maternal infection

2. Infants at high risk of EOS

• Infants born to mothers with intrapartum fever (> 38C) or clinical diagnosis of chorioamnionitis

• Infants born to mothers with previous infant with GBS disease/infection

3. Infants with respiratory insufficiency requiring invasive mechanical ventilation and FiO2 > 0.40 or non-invasive ventilation and FiO2 > 0.60 at time of randomization

4. Infants with ongoing hemodynamic instability requiring vasopressors or fluid boluses at time of randomization

5. Clinician concern infant is at high risk for sepsis due to infant physical exam findings or clinical history of mother or infant

6. Major congenital anomalies

7. Infants not anticipated to survive beyond 72 hours

8. Infants who have received antibiotics prior to randomization

9. Mothers that are <18 years old at time of enrollment

Related Conditions & MeSH terms

• Communicable Diseases
• Death; Neonatal
• Early-Onset Neonatal Sepsis
• Enterocolitis
• Enterocolitis, Necrotizing
• Extreme Prematurity
• Infections
• Late-Onset Neonatal Sepsis
• Microbial Colonization
• Necrotizing Enterocolitis of Newborn
• Neonatal Sepsis
• Sepsis
• Toxemia

Intervention

Drug:
• Ampicillin
Intravenous ampicillin
• Gentamycin
Intravenous gentamycin
• Normal saline
Intravenous normal saline

Locations

Country	Name	City	State
Canada	Mount Sinai Hospital	Toronto	Ontario
United States	SUNY Downstate Medical Center	Brooklyn	New York
United States	Penn State Medical College	Hershey	Pennsylvania
United States	Children's Mercy	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Louisville Research Foundation Inc./Kosair Charities Pediatric Clinical Research Unit	Louisville	Kentucky
United States	USA Children's and Women's Hospital	Mobile	Alabama
United States	Yale University School of Medicine	New Haven	Connecticut
United States	The Trustees of Columbia University in the City of New York	New York	New York
United States	Alfred I. duPont for Children of the Nemours Foundation	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital/The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	Golisano Children's Hospital at University of Rochester	Rochester	New York
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Sharp Mary Birch Hospital for Women & Newborns	San Diego	California
United States	University of South Flordia Health	Tampa	Florida
United States	Maria Fareri Children's Hospital at Westchester Medical Center	Valhalla	New York
United States	Atrium Health Wake Forest Baptist	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Michael Morowitz	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Microbial diversity within infant fecal samples	Bacterial DNA will be sequenced according to established protocols. In analyses of these samples, we shall investigate three important parameters, namely, alpha diversity (Richness and Shannon Index), beta diversity, and the differential abundance of individual bacterial taxa.	Weekly stool samples will be collected for the first 8 weeks of life and then monthly through death or discharge from the subject's birth hospital , assessed up to 50 weeks.
Primary	Composite incidence of NEC, LOS, or death	NEC will be assessed by clinical presentation and an abdominal x-ray obtained and read by a certified radiologist. NEC will be defined strictly by Bell's stage II or III criteria for moderate or advanced NEC. To reduce overlap between NEC and diagnosis of spontaneous intestinal perforation, the diagnosis of NEC will only be considered in infants > 7 days of age. LOS is defined as defined as a positive blood culture obtained after 72 hours of life and intent to treat with antibiotics for 5 days or more. Death is defined as death during the index hospitalization.	From the time and day of randomization through the subject's date of death from any cause or discharge from the birth hospital, whichever comes first, assessed up until 50 weeks.
Secondary	NEC	NEC will be assessed by clinical presentation and an abdominal x-ray obtained and read by a certified radiologist. NEC will be defined strictly by Bell's stage II or III criteria for moderate or advanced NEC. To reduce overlap between NEC and diagnosis of spontaneous intestinal perforation, the diagnosis of NEC will only be considered in infants > 7 days of age.	From the time and day of randomization through the subject's date of death from any cause or discharge from the birth hospital, whichever comes first, assessed up until 50 weeks.
Secondary	LOS	LOS is defined as defined as a positive blood culture obtained after 72 hours of life and intent to treat with antibiotics for 5 days or more.	From the time and day of randomization through the subject's date of death from any cause or discharge from the birth hospital, whichever comes first, assessed up until 50 weeks.
Secondary	Death	Death is defined as death during the index hospitalization.	From the time and day of randomization through the subject's date of death from any cause or discharge from the birth hospital, whichever comes first, assessed up until 50 weeks.