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NICU Antibiotics and Outcomes Trial (NANO)

Primary Purpose

Microbial Colonization, Extreme Prematurity, Early-Onset Neonatal Sepsis

Status
Recruiting
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Ampicillin
Gentamycin
Normal saline
Sponsored by
Michael Morowitz
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Microbial Colonization focused on measuring premature birth, human microbiome, antibiotics

Eligibility Criteria

undefined - 4 Hours (Child)All SexesDoes not accept healthy volunteers

I. Inclusion criteria: We will enroll newborn infants with gestational age of 23-28 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 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 proven GBS colonization or indication for intrapartum antibiotic prophylaxis that did not receive adequate antibiotic treatment according to specialty specific guidelines (i.e. penicillin, ampicillin, and cefazolin)
    • 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

Sites / Locations

  • Sharp Mary Birch Hospital for Women & NewbornsRecruiting
  • Yale University School of MedicineRecruiting
  • University of South Flordia HealthRecruiting
  • University of Kansas Medical Center
  • University of Louisville Research Foundation Inc./Kosair Charities Pediatric Clinical Research UnitRecruiting
  • Children's Mercy
  • SUNY Downstate Medical CenterRecruiting
  • The Trustees of Columbia University in the City of New YorkRecruiting
  • Golisano Children's Hospital at University of Rochester
  • Maria Fareri Children's Hospital at Westchester Medical CenterRecruiting
  • Penn State Medical CollegeRecruiting
  • Pennsylvania Hospital/The Children's Hospital of PhiladelphiaRecruiting
  • Alfred I. duPont for Children of the Nemours FoundationRecruiting
  • Magee Womens HospitalRecruiting
  • University of Texas Health Science Center at San AntonioRecruiting
  • Mount Sinai HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Empiric antibiotics

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
Death
Death is defined as death during the index hospitalization.

Full Information

First Posted
June 2, 2019
Last Updated
July 10, 2023
Sponsor
Michael Morowitz
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT03997266
Brief Title
NICU Antibiotics and Outcomes Trial
Acronym
NANO
Official Title
NICU Antibiotics and Outcomes Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 5, 2020 (Actual)
Primary Completion Date
September 1, 2025 (Anticipated)
Study Completion Date
June 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Michael Morowitz
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Microbial Colonization, Extreme Prematurity, Early-Onset Neonatal Sepsis, Late-Onset Neonatal Sepsis, Necrotizing Enterocolitis of Newborn, Death; Neonatal
Keywords
premature birth, human microbiome, antibiotics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
802 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Empiric antibiotics
Arm Type
Active Comparator
Arm Description
Infants will receive standard antibiotic coverage of ampicillin and gentamycin at site approved dosing guidelines while completing an evaluation for early-onset neonatal sepsis.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Infants will receive a volume matched placebo of normal saline while completing an evaluation for early-onset neonatal sepsis.
Intervention Type
Drug
Intervention Name(s)
Ampicillin
Intervention Description
Intravenous ampicillin
Intervention Type
Drug
Intervention Name(s)
Gentamycin
Intervention Description
Intravenous gentamycin
Intervention Type
Drug
Intervention Name(s)
Normal saline
Intervention Description
Intravenous normal saline
Primary Outcome Measure Information:
Title
Composite incidence of NEC, LOS, or death
Description
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.
Time Frame
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 Measure Information:
Title
NEC
Description
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.
Time Frame
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.
Title
LOS
Description
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.
Time Frame
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.
Title
Death
Description
Death is defined as death during the index hospitalization.
Time Frame
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 Pre-specified Outcome Measures:
Title
Microbial diversity within infant fecal samples
Description
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.
Time Frame
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.

10. Eligibility

Sex
All
Maximum Age & Unit of Time
4 Hours
Accepts Healthy Volunteers
No
Eligibility Criteria
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: 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 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 Infants with respiratory insufficiency requiring invasive mechanical ventilation and FiO2 > 0.40 or non-invasive ventilation and FiO2 > 0.60 at time of randomization Infants with ongoing hemodynamic instability requiring vasopressors or fluid boluses at time of randomization Clinician concern infant is at high risk for sepsis due to infant physical exam findings or clinical history of mother or infant Major congenital anomalies Infants not anticipated to survive beyond 72 hours Infants who have received antibiotics prior to randomization Mothers that are <18 years old at time of enrollment
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael J Morowitz, MD
Phone
412-692-5976
Email
michael.morowitz@chp.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kathryn C Little, RN
Phone
412-841-2745
Email
littlekc@upmc.edu
Facility Information:
Facility Name
Sharp Mary Birch Hospital for Women & Newborns
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anup C Katheria, MD
Email
anup.katheria@sharp.com
First Name & Middle Initial & Last Name & Degree
Catherine Salcido, RN
Email
catherine.salcido@sharp.com
First Name & Middle Initial & Last Name & Degree
Anup C Katheria, MD
Facility Name
Yale University School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520-8064
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Bizzarro, MD
Email
matthew.bizzarro@yale.edu
First Name & Middle Initial & Last Name & Degree
Christine Henry
Email
christine.henry@yale.edu
First Name & Middle Initial & Last Name & Degree
Matthew Bizzarro, MD
Facility Name
University of South Flordia Health
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tara Randis
Email
trandis@usf.edu
First Name & Middle Initial & Last Name & Degree
Marcia Kneusel, RNC
Phone
813-844-3395
Email
mkneusel@usf.edu
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Individual Site Status
Withdrawn
Facility Name
University of Louisville Research Foundation Inc./Kosair Charities Pediatric Clinical Research Unit
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Taminaruth Singh, MD
Email
tamina.singh@louisville.edu
First Name & Middle Initial & Last Name & Degree
Jennifer Hay
Email
jenn.hay@louisville.edu
First Name & Middle Initial & Last Name & Degree
Taminaruth Singh, MD
Facility Name
Children's Mercy
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Individual Site Status
Withdrawn
Facility Name
SUNY Downstate Medical Center
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11203
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacob Aranda, MD
Email
jacob.aranda@downstate.edu
First Name & Middle Initial & Last Name & Degree
Khadija Sikriti, MD
Email
khadija.sikriti@downstate.edu
First Name & Middle Initial & Last Name & Degree
Jacob Aranda, MD
Facility Name
The Trustees of Columbia University in the City of New York
City
New York
State/Province
New York
ZIP/Postal Code
10032-3702
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Richard A Polin, MD
Email
rap32@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Caitlin Ehret
Email
ce2310@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Richard A Polin, MD
Facility Name
Golisano Children's Hospital at University of Rochester
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ronnie Guillet, MD
Email
ronnie_guillet@urmc.rochester.edu
First Name & Middle Initial & Last Name & Degree
Rachel Jones
Email
rachel_jones3@urmc.rochester.edu
First Name & Middle Initial & Last Name & Degree
Carl D'Angio, MD
Facility Name
Maria Fareri Children's Hospital at Westchester Medical Center
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
LaGamma Edmund, MD
Email
edmund_lagamma@nymc.edu
First Name & Middle Initial & Last Name & Degree
Clare Giblin, RN
Phone
914-493-1442
Email
clare.giblin@wmchealth.org
Facility Name
Penn State Medical College
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chintan Gandhi, MD
Phone
717-531-5656
Email
cgandhi@pennstatehealth.psu.edu
First Name & Middle Initial & Last Name & Degree
Chelsea Winters
Phone
717-531-5656
Email
cwinters2@pennstatehealth.psu.edu
Facility Name
Pennsylvania Hospital/The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karen M Puopolo, MD,PhD
Email
karen.puopolo@pennmedicine.upenn.edu
First Name & Middle Initial & Last Name & Degree
Toni Mancini
Email
toni.mancini@pennmedicine.upenn.edu
First Name & Middle Initial & Last Name & Degree
Karen M Puopolo, MD,PhD
Facility Name
Alfred I. duPont for Children of the Nemours Foundation
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zubair Aghai, MD
Email
zubair.aghai@nemours.org
First Name & Middle Initial & Last Name & Degree
Margaret Lafferty
Email
margaret.lafferty@nemours.org
First Name & Middle Initial & Last Name & Degree
Zubair Aghai, MD
Facility Name
Magee Womens Hospital
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael J Morowitz, MD
Phone
412-692-5986
Email
michael.morowitz@chp.edu
First Name & Middle Initial & Last Name & Degree
Kathryn C Little, RN
Phone
412-841-2745
Email
littlekc@upmc.edu
First Name & Middle Initial & Last Name & Degree
Michael J Morowitz, MD
First Name & Middle Initial & Last Name & Degree
Toby Yanowitz, MD
Facility Name
University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joseph R Cantey, MD
Email
cantey@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Dianna Anzueto
Email
anzuetod@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Joseph R Cantey, MD
Facility Name
Mount Sinai Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G1X5
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ashraf Kharrat
Email
ashraf.kharrat@sinaihealth.ca
First Name & Middle Initial & Last Name & Degree
Ayah Al Bizri
Email
ayah.albizri@sinaihealth.ca
First Name & Middle Initial & Last Name & Degree
Ashraf Kharrat, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35606829
Citation
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.
Results Reference
derived

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NICU Antibiotics and Outcomes Trial

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