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NICU Antibiotics and Outcomes Trial (NANO)

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ClinicalTrials.gov Identifier: NCT03997266
Recruitment Status : Not yet recruiting
First Posted : June 25, 2019
Last Update Posted : June 25, 2019
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Michael Morowitz, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Microbial Colonization Extreme Prematurity Early-Onset Neonatal Sepsis Late-Onset Neonatal Sepsis Necrotizing Enterocolitis of Newborn Death; Neonatal Drug: Ampicillin Drug: Gentamycin Drug: Normal saline Phase 3

Detailed Description:

Randomization and blinding. For each infant born to a mother that has provided consent, a coordinator will assess eligibility. Thus, there will be a two-part screening to first determine maternal eligibility, and then to determine infant eligibility. Investigative pharmacists 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. 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 (75 mg/kg/dose every 8 hours) and gentamicin (5 mg/kg/dose every 48 hours) 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. A maternal vaginal swab at delivery and a maternal fecal sample during the first week postpartum will also be collected. Samples will be cryopreserved at -80C. An electronic database will be used to track sample collection and storage history.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 802 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: NICU Antibiotics and Outcomes Trial
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Active Comparator: Empiric antibiotics
Infants will receive standard antibiotic coverage of ampicillin (75 mg/kg/dose every 8 hours) and gentamycin (5 mg/kg/dose given every 48 hours) 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




Primary Outcome Measures :
  1. Composite incidence of NEC, LOS, or death [ Time Frame: From the time and day or 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. ]
    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 :
  1. Total antibiotic days [ Time Frame: From the time and day or 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. ]
    total number of calendar days that the subject received any intravenous or oral antibiotics

  2. Days to full enteral feedings [ Time Frame: From the time and day or 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. ]
    receiving a total volume of enteral nutrition that will support the infant's metabolism and growth without supplemental parental nutrition.

  3. Weight z-scores [ Time Frame: Weight z-scores will be calculated weekly after randomization through discharge from the subjetcs birth hospital up until 50 weeks. ]
    A z-score is a standard score that can placed on a normal distribution curve. The z-score is obtained using the baby's weight and gestational age

  4. Length z-scores [ Time Frame: Length z-scores will be calculted weekly from randomization through discharge from the subject's birth hospital up until 50 weeks ]
    An Infant length z-score is based on a measurement with the infant in the in the recumbent position using a calibrated length board. Length will be recorded in centimeters.

  5. Head circumference [ Time Frame: Head circumference will be assessed and recorded weekly from randomization through discharge from the subject's birth hospital up until 50 weeks ]
    Head circumference or OFC is measured over the most prominent part on the back of the infants' head (occiput) and just above the eyebrows (supraorbital ridges). This will be done using a flexible, non-stretchable tape measure and will be recorded in centimeters.

  6. Retinopathy of prematurity (ROP) [ Time Frame: ROP will be assessed from randomization throught the subject's death or discharge from the birth hospital through 50 weeks. ]
    ROP is the interruption of the normal progression of retinal vascularization or retinal detachment in premature infants. ROP is diagnosed by direct examination performed by a neonatal ophthalmologist as clinically indicated.

  7. Bronchopulmonary dysplasia [ Time Frame: From 36 weeks post menstrual age until death or discharge from the birth hospital up until 50 weeks. ]
    Bronchopulmonary dysplasia (BPD) is a chronic lung disease defined by the Vermont Oxford Network (VON) definition as an FiO2 requirement at 36 weeks post menstrual age.

  8. Intraventricular hemorrhage (IVH) [ Time Frame: From randomization until day of life 28 up until 5 weeks. ]
    Subependymal, intraventricular, or intraparenchymal hemorrhage on cranial US, MRI, or CT.

  9. Periventricular leukomalacia [ Time Frame: From randomization throught the subject's death or discharge from the birth hospital up until 50 weeks. ]
    Cystic periventricular leukomalacia on cranial US, MRI, or CT.


Other Outcome Measures:
  1. Microbial diversity within infant fecal samples [ 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. ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   23 Weeks to 28 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria: We will enroll newborn infants born at participating study sites with gestational age of 23-28 weeks.

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 born to mothers with intrapartum fever (> 38ºC) or clinical diagnosis of chorioamnionitis
  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 for sepsis due to physical exam findings, e.g. lethargy
  6. Major congenital anomalies
  7. Infants not anticipated to survive beyond 72 hours
  8. Infants who have received antibiotics prior to randomization. Note: Lab values will not be used as exclusion criteria.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03997266


Contacts
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Contact: Michael J Morowitz, MD 412-692-5976 michael.morowitz@chp.edu
Contact: Robyn W Baker, BSN 412-641-3145 rbaker@magee.edu

Sponsors and Collaborators
Michael Morowitz
National Institutes of Health (NIH)

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Responsible Party: Michael Morowitz, Associate Professor, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03997266     History of Changes
Other Study ID Numbers: PRO18010284
1R01HD097578-01 ( U.S. NIH Grant/Contract )
First Posted: June 25, 2019    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Michael Morowitz, University of Pittsburgh:
premature birth
human microbiome
antibiotics
Additional relevant MeSH terms:
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Enterocolitis
Enterocolitis, Necrotizing
Anti-Infective Agents
Sepsis
Toxemia
Neonatal Sepsis
Communicable Diseases
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Infant, Newborn, Diseases
Anti-Bacterial Agents
Gentamicins
Ampicillin
Antibiotics, Antitubercular
Antitubercular Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action