NICU Antibiotics and Outcomes Trial (NANO)

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.

Study Overview

• Status: Completed
• Conditions: Microbial Colonization; Late-Onset Neonatal Sepsis; Necrotizing Enterocolitis of Newborn; Extreme Prematurity; Death; Neonatal; Early-Onset Neonatal Sepsis
• Intervention / Treatment: Drug: Ampicillin; Drug: Gentamycin; Drug: Normal saline

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.

• Study Type: Interventional
• Enrollment (Actual): 359
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36688
      • USA Children's and Women's Hospital
  • California
    • San Diego, California, United States, 92123
      • Sharp Mary Birch Hospital for Women & Newborns
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8064
      • Yale University School of Medicine
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Flordia Health
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Research Foundation Inc./Kosair Charities Pediatric Clinical Research Unit
  • New York
    • New York, New York, United States, 10032-3702
      • The Trustees of Columbia University in the City of New York
    • Rochester, New York, United States, 14642
      • Golisano Children's Hospital at University of Rochester
    • Valhalla, New York, United States, 10595
      • Maria Fareri Children's Hospital at Westchester Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Atrium Health Wake Forest Baptist
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Medical College
    • Philadelphia, Pennsylvania, United States, 19104
      • Pennsylvania Hospital/The Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19107
      • Alfred I. duPont for Children of the Nemours Foundation
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Womens Hospital
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 4 hours (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Ampicillin; Intravenous ampicillin; Drug: Gentamycin; Intravenous gentamycin
Placebo Comparator: Placebo; Infants will receive a volume matched placebo of normal saline while completing an evaluation for early-onset neonatal sepsis.	Drug: Normal saline; Intravenous normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.

Collaborators and Investigators

• Sponsor: Michael Morowitz
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2020
• Primary Completion (Actual): January 15, 2026
• Study Completion (Actual): January 15, 2026

Study Registration Dates

• First Submitted: June 2, 2019
• First Submitted That Met QC Criteria: June 21, 2019
• First Posted (Actual): June 25, 2019

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: antibiotics; premature birth; human microbiome
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Death; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Neonatal Sepsis; Premature Birth; Communicable Diseases; Perinatal Death; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Carbohydrates; Glycosides; Amides; Crystalloid Solutions; Isotonic Solutions; Solutions; Aminoglycosides; Penicillin G; beta-Lactams; Lactams; Penicillins; Ampicillin; Gentamicins; Saline Solution
• Other Study ID Numbers: STUDY20110298; R01HD097578 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No