NICU Antibiotics and Outcomes (NANO) Follow-up Study (NANO-FU)

NICU Antibiotics and Outcomes Follow-Up Study

The NANO follow-up study is designed to determine whether a simple, cost-effective intervention- withholding antibiotics at birth- reduces clinically relevant outcomes such as behavioral and neurological impairment at 2 years of age. This study will be the largest study evaluating the effects of early antibiotics in children with comprehensive measures of neurodevelopment linked to genomic variants and microbiota interactions.

Study Overview

• Status: Not yet recruiting
• Conditions: Premature Birth; Antibiotics; Neurodevelopment
• Intervention / Treatment: Drug: Ampicillin; Drug: Gentamicin; Drug: Placebo

Detailed Description

The multidisciplinary team launched the NANO (NICU Antibiotics and Outcomes) Trial to study the longstanding clinical practice of empirically administering intravenous antibiotics to very preterm infants. The NANO trial is an 802-patient,13-site randomized blinded controlled trial (R01HD09757801) discerning whether administration of antibiotics within the first three days of life increases the incidence of short-term, life-threatening complications among very preterm infants.

The proposed NANO follow-up study will build upon the parent NANO trial to determine whether avoiding antibiotics in very preterm infants - a simple, cost-effective intervention - improves neurodevelopmental and behavioral outcomes during the toddler years. Evaluation of children enrolled in the proposed NANO follow-up study will include serial comprehensive, standardized assessments of motor, cognitive, behavioral and adaptive outcomes. To support retention and provide an important early assessment, a first virtual visit at 1 year of age will include the Hammersmith Infant Neurologic Exam (HINE) and the Developmental Assessment of Young Children, Second Edition (DAYC-2). A second comprehensive follow-up visit in person at 2 years will include the Bayley Scales of Infant Development 4th ed., Gross Motor Function Classification System, Child Behavior Checklist for ages 1.5-5, and the Modified Checklist for Autism in Toddlers, Revised, with Follow-up.

In the NANO follow-up trial, outcomes will be assessed using the Desirability of outcome ranking (DOOR), an innovative, patient-centered statistical approach used in clinical trials to evaluate the global benefits and risks of an intervention. The ordinal neonatal follow-up endpoint composite scale, to be named neoDOOR, will be developed by both clinicians and families. Stakeholder meetings will develop consensus rankings of individual and composite outcomes of different severities reported by the above developmental assessments. Neonatal biospecimens collected during the parent NANO trial will allow for additional exploratory analyses evaluating interactions among genetics, environment, and microbiota with antibiotic exposure and long-term outcomes. Through these assessments and evaluation, the investigators will provide substantial evidence for the use (or non-use) of early antibiotics for very preterm infants at birth.

• Study Type: Interventional
• Enrollment (Estimated): 802
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anup Katheria, MD; Phone Number: 8589394170; Email: anup.katheria@sharp.com
• Study Contact Backup: Name: Rebecca Dorner, MD; Email: rebecca.dorner@sharp.com

Study Locations

• Canada
  • Toronto, Canada
    • Sinai Health System
    • Contact: Ashraf Kharrat, MD; Email: Ashraf.Kharrat@sinaihealth.ca
• United States
  • California
    • San Diego, California, United States, 92123
      • Sharp Mary Birch Hospital for Women & Newborns
      • Principal Investigator: Anup C Katheria, MD
      • Contact: Anup C Katheria, MD; Phone Number: 858-939-4170; Email: anup.katheria@sharp.com
      • Contact: Felix T Ines, RCP-RRT; Phone Number: 858-939-4136; Email: felix.ines@sharp.com
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University
      • Contact: Angela Montgomery, MD; Email: angela.montgomery@yale.edu
  • Florida
    • Tampa, Florida, United States, 33620
      • University of South Florida
      • Contact: Tara Randis, MD; Email: trandis@usf.edu
  • Kentucky
    • Louisville, Kentucky, United States, 40292
      • University of Louisville
      • Contact: Elizabeth Schumacher; Email: eschumacher@louisville.edu
      • Contact: Tamina Singh, MD; Email: tamina.singh@louisville.edu
  • New York
    • Brooklyn, New York, United States, 11203
      • State University of New York Downstate
      • Contact: Jacob Aranda, MD; Email: jacob.aranda@downstate.edu
    • New York, New York, United States, 10027
      • Columbia University
      • Contact: Rich Polin; Email: rap32@cumc.columbia.edu
    • Rochester, New York, United States, 14611
      • University of Rochester
      • Contact: Carl D'Angio, MD; Email: Carl_Dangio@URMC.Rochester.edu
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • The Pennsylvania State University
      • Contact: Chintan Gandhi, MD; Email: cgandhi@pennstatehealth.psu.edu
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
      • Contact: Karen Puopolo, MD; Email: Karen.Puopolo@pennmedicine.upenn.edu
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson Medical College of Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • The University of Pittsburgh Medical Center
      • Contact: Michael Morowitz, MD; Email: michael.morowitz@chp.edu
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
      • Contact: Leslie-Anne Dietrich; Email: dietrichL3@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Families that have agreed to participate and are enrolled in the parent NANO trial will be eligible for the NANO follow-up study. There will be no exclusions for eligible children entering the follow-up study.

Parent NANO trial Criteria:

I. Inclusion criteria: We will enroll newborn infants with gestational age of 23.0-30.6 weeks born to mothers 18 years or older at participating study sites. Only inborn infants at participating study sites will be eligible.

II. Exclusion criteria:

1. Infants at low risk for early onset sepsis-Infants born for maternal indications via caesarean section with rupture of membranes within 6 hours, without attempts to induce labor, and without concern for maternal infection
2. Infants at high risk for early onset sepsis- Infants born to mothers with intrapartum fever (> 38ºC) or clinical diagnosis of chorioamnionitis (suspected or definite), infants born to mothers with proven Group B Streptococcus colonization or indication for intrapartum antibiotic prophylaxis that did not receive adequate antibiotic treatment according to specialty specific guidelines, (i.e., penicillin, ampicillin, cefazolin), infant born to mother with previous infant with GBS disease/infection
3. Infants with respiratory insufficiency requiring invasive mechanical ventilation and fraction of inspired oxygen> 0.40 or non-invasive ventilation and fraction of inspired oxygen > 0.60 at time of randomization
4. Infants with ongoing hemodynamic instability requiring vasopressors or more than one fluid bolus at time of randomization
5. Clinician concern for sepsis due to 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.

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: Very preterm infants that receive empiric antibiotic treatment in the first 48 hours of life; Neonates in this group will have been enrolled and randomized into the NANO trial and received a blinded 48 hour course of empiric antibiotic treatment.	Drug: Ampicillin; Intravenous Ampicillin; Drug: Gentamicin; Intravenous Gentamicin
Placebo Comparator: Very preterm infants that do not receive empiric antibiotic treatment in the first 48 hours of life; Neonates in this group will have been enrolled and randomized into the NANO trial and received a blinded 48 hour course of placebo.	Drug: Placebo; Intravenous Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of neurodevelopmental impairment or Death	The first primary outcome will be a composite of newborn or childhood death OR one of following: cognitive or motor composite scores <80 on the Bayley-4, Gross Motor Function Classification Score score ≥2, bilateral blindness, severe functional hearing impairment. The incidence of the composite outcome will be compared between the placebo and early antibiotic groups.	24 months corrected gestational age
DOOR probability Distribution	The second primary outcome will be a comparison of the DOOR probability of more desirable outcomes at 2 years using a novel ordinal endpoint scale developed during the trial. Outcomes to be included in the rank are as follows: death, cognitive/language/motor composite scores<80 on the Bayley-4, Gross Motor Function Classification Score ≥2, bilateral blindness, severe functional hearing impairment, Child Behavior Checklist (CBCL) scores >70, autism risk scores (MCHAT R/F) of ≥2, and medical measures, such as need for oxygen support. The distribution of the finalized neoDOOR will be compared between the placebo and empiric antibiotic groups.	24 months corrected gestational age

Collaborators and Investigators

• Sponsor: Sharp HealthCare
• Collaborators: Children's Hospital of Philadelphia; University of South Florida; Yale University; University of Pittsburgh; Penn State University; The University of Texas Health Science Center at San Antonio; Mount Sinai Hospital, Canada; Morgan Stanley Children's Hospital; University of Louisville; State University of New York - Downstate Medical Center; Jefferson Medical College of Thomas Jefferson University; Sharp Mary Birch Hospital for Women & Newborns; Westchester Medical Center
• Investigators: Principal Investigator: Anup Katheria, MD, Sharp HealthCare

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: May 24, 2021
• First Submitted That Met QC Criteria: July 28, 2023
• First Posted (Actual): August 4, 2023

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: July 28, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Ampicillin; Gentamicins
• Other Study ID Numbers: NANO Follow-Up

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available per NICHD requirements (National Institute of Child Health and Human Development).
• IPD Sharing Time Frame: 2 years after primary publication
• IPD Sharing Access Criteria: An archived dataset with documentation will be made available for additional uses by outside investigators, in collaboration with the study investigators. We will work with NICHD program staff to develop a broad data sharing plan over time.
• IPD Sharing Supporting Information Type: SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No