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NICU Antibiotics and Outcomes Trial (NANO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03997266
Recruitment Status : Not yet recruiting
First Posted : June 25, 2019
Last Update Posted : April 17, 2020
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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 4

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.

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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 : June 2020
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : June 2024


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




Primary Outcome Measures :
  1. Composite incidence of NEC, LOS, or death [ 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. ]
    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. NEC [ 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. ]
    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.

  2. LOS [ 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. ]
    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.

  3. Death [ 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. ]
    Death is defined as death during the index hospitalization.


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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 within 6 hours of 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 more than one fluid bolus 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: Alyssa M Harris, MS 412-692-8003 harrisam4@upmc.edu

Locations
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United States, California
Sharp Mary Birch Hospital for Women & Newborns
San Diego, California, United States, 92123
Contact: Anup C Katheria, MD       anup.katheria@sharp.com   
Contact: Katherine Baker       Katherine.baker@sharp.com   
Principal Investigator: Anup C Katheria, MD         
United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06520-8064
Contact: Sarah N Taylor, MD       sarah.n.taylor@yale.edu   
Contact: Christine Henry       christine.henry@yale.edu   
Principal Investigator: Sarah N Taylor, MD         
United States, Kentucky
University of Louisville Research Foundation Inc./Kosair Charities Pediatric Clinical Research Unit
Louisville, Kentucky, United States, 40202
Contact: Taminaruth Singh, MD       tamina.singh@louisville.edu   
Contact: Kristen Gossett       kristen.lee@louisville.edu   
Principal Investigator: Taminaruth Singh, MD         
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Contact: Katherine Gregory, MD       kgregory1@bwh.harvard.edu   
Contact: Jennifer Filatava       EFILATAVA@BWH.HARVARD.EDU   
Principal Investigator: Katherine Gregory, MD         
United States, Missouri
Children's Mercy
Kansas City, Missouri, United States, 64108
Contact: Vankatesh Sampath, MBBS       vsampath@cmh.edu   
Contact: Cheri Gauldin       cagauldin@cmh.edu   
Principal Investigator: Vankatesh Sampath, MBBS         
United States, New York
The Trustees of Columbia University in the City of New York
New York, New York, United States, 10032-3702
Contact: Richard A Polin, MD       rap32@cumc.columbia.edu   
Contact: Caitlin Ehret       ce2310@cumc.columbia.edu   
Principal Investigator: Richard A Polin, MD         
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Contact: Karen M Puopolo, MD,PhD       karen.puopolo@pennmedicine.upenn.edu   
Contact: Joan Giannetta       giannetta@email.chop.edu   
Principal Investigator: Karen M Puopolo, MD,PhD         
Alfred I. duPont for Children of the Nemours Foundation
Philadelphia, Pennsylvania, United States, 19107
Contact: Zubair Aghai, MD       zubair.aghai@nemours.org   
Contact: Margaret Lafferty       margaret.lafferty@nemours.org   
Principal Investigator: Zubair Aghai, MD         
United States, Texas
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
Contact: Joseph R Cantey, MD       cantey@uthscsa.edu   
Contact: Robin Tragus       tragus@uthscsa.edu   
Principal Investigator: Joseph R Cantey, MD         
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22903
Contact: David Kaufman, MD       dak4r@hscmail.mcc.virginia.edu   
Contact: Eileen Sembrowich       ecs3b@virginia.edu   
Principal Investigator: David Kaufman, MD         
Sponsors and Collaborators
Michael Morowitz
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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Responsible Party: Michael Morowitz, Associate Professor, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03997266    
Other Study ID Numbers: PRO18010284
1R01HD097578-01 ( U.S. NIH Grant/Contract )
First Posted: June 25, 2019    Key Record Dates
Last Update Posted: April 17, 2020
Last Verified: April 2020
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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Sepsis
Toxemia
Neonatal Sepsis
Communicable Diseases
Infection
Enterocolitis
Enterocolitis, Necrotizing
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Infant, Newborn, Diseases
Gentamicins
Ampicillin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action