NICU Antibiotics and Outcomes Trial

NCT ID: NCT03997266

Last Updated: 2025-09-23

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 802 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-05
• Study Completion Date: 2027-06-01

Brief 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.

Detailed 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.

Conditions

Microbial Colonization; Extreme Prematurity; Early-Onset Neonatal Sepsis; Late-Onset Neonatal Sepsis; Necrotizing Enterocolitis of Newborn; Death; Neonatal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Empiric antibiotics

Infants will receive standard antibiotic coverage of ampicillin and gentamycin at site approved dosing guidelines while completing an evaluation for early-onset neonatal sepsis.

Group Type: ACTIVE_COMPARATOR

Ampicillin

Intervention Type: DRUG

Intravenous ampicillin

Gentamycin

Intervention Type: DRUG

Intravenous gentamycin

Placebo

Infants will receive a volume matched placebo of normal saline while completing an evaluation for early-onset neonatal sepsis.

Group Type: PLACEBO_COMPARATOR

Normal saline

Intervention Type: DRUG

Intravenous normal saline

Interventions

Ampicillin

Intravenous ampicillin

Intervention Type: DRUG

Gentamycin

Intravenous gentamycin

Intervention Type: DRUG

Normal saline

Intravenous normal saline

Intervention Type: DRUG

Eligibility Criteria

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

• Maximum Eligible Age: 4 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Michael Morowitz

OTHER

Sponsor Role: lead

Responsible Party

Michael Morowitz

Associate Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

USA Children's and Women's Hospital

Mobile, Alabama, United States

Sharp Mary Birch Hospital for Women & Newborns

San Diego, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

University of South Flordia Health

Tampa, Florida, United States

University of Louisville Research Foundation Inc./Kosair Charities Pediatric Clinical Research Unit

Louisville, Kentucky, United States

The Trustees of Columbia University in the City of New York

New York, New York, United States

Golisano Children's Hospital at University of Rochester

Rochester, New York, 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, United States

Penn State Medical College

Hershey, Pennsylvania, United States

Pennsylvania Hospital/The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Alfred I. duPont for Children of the Nemours Foundation

Philadelphia, Pennsylvania, United States

Magee Womens Hospital

Pittsburgh, Pennsylvania, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Countries

United States

References

Morowitz MJ, Katheria AC, Polin RA, Pace E, Huang DT, Chang CH, Yabes JG. The NICU Antibiotics and Outcomes (NANO) trial: a randomized multicenter clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants. Trials. 2022 May 23;23(1):428. doi: 10.1186/s13063-022-06352-3.

Reference Type: DERIVED

PMID: 35606829 (View on PubMed)

Other Identifiers

R01HD097578

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY20110298

Identifier Type: -

Identifier Source: org_study_id