Gainesville, Florida 32610


Purpose:

Mortality related to neonatal sepsis exceeds 1 million deaths worldwide; the highest risk of mortality is in preterm neonates, especially low birth weight (LBW), and very low birth weight (VLBW) neonates. The estimated cost of caring for these patients is approximately $700 million in the US alone. In an effort to help mature the neonatal immune system, several adjuvant therapies have been studied; however, none have been implemented in clinical practice. One of the most frequently considered targets for adjuvant therapy is toll-like receptors (TLRs). TLRs detect conserved molecular products of microorganisms (lipopolysaccharide (LPS), and initiate immunity and inflammation. Early adjuvant administration in VLBW infants may be a viable approach to reducing the incidence of early and late sepsis. This research study will characterize immune genomic expression and functional capacity at the time of birth in both term and preterm neonates and determine what effects, if any, that adjuvants have on this function. Additionally, this study will seek to determine if immune function correlates with certain microbiota.


Study summary:

Blood samples will be collected from three populations: preterm infants, term infants and healthy adult controls. In addition, a collection of meconium (<1mL) from the diaper of these term and preterm neonates; 1. Term neonates (gestational age 37-42 weeks) between birth and 72 hours of life who have blood collected for the following clinical indications: a. Blood will be collected at 0-72 hours of life from neonates that are undergoing state metabolic screens or for clinical evaluation jaundice. The sample will be obtained during the standard of care state metabolic screen or for clinical evaluation of jaundice. The neonate will only have an extra drop of blood placed (500-700 micro-liters) in a tube during the heel sticks. Neonates will only have 1 sample drawn throughout the duration of the study. 2. Preterm neonates (gestational age 24-37 weeks) consisting of two populations between birth and 72 hours of life who have blood collected for the following clinical indications: 1. Blood will be collected at 0-72 hours of life from neonates that are otherwise healthy and do not require additional laboratory testing who are undergoing state metabolic screens or for evaluation of jaundice. The neonate will only have an extra drop of blood placed (500-700 microliters) in a tube during the heel stick. Neonates will only have 1 sample drawn throughout the duration of the study. 2. A second group of premature neonates will have blood drawn for complications related to prematurity (sepsis work-up). The neonate will only have an extra drop of blood placed (500-700 micro-liters) in a tube during one of these clinical blood draws. 3. Healthy adult controls will have (4milleters) blood collected by way of vein puncture. For all infants, term and preterm, the following data will be collected at the time of blood collection: gender, gestational age, weight, mechanism of birth (vaginal vs cesarean section), evidence of infectious complication (chorioamnionitis, prolonged rupture of membranes, maternal group B strep colonization, hypoglycemia), use of perinatal antibiotics or steroids, laboratory values available in the electronic medial record (CBC, CMP, Lactic acid, CRP) and Apgar scores will be collected from each patient. Additionally the clinical outcomes of these patients, term and preterm,will be collected until time of discharge but not to exceed 90 days.


Criteria:

Preterm and Term neonates 0-72 hours old Inclusion Criteria: - Consent to participate in the study Exclusion Criteria: - non- survivable condition Healthy Adult Controls Inclusion Criteria: - Consent to participate in the study - Age >18 years old, <55 years old Exclusion Criteria: - Age <18 years old, >55 years old - Severe pre-existing organ dysfunction - Oncolytic therapy within 14 days - HIV positive status - Current use of chronic steroids


Study is Available At:


Original ID:

IRB201500447 -N


NCT ID:

NCT02554630


Secondary ID:

R01GM097531


Study Acronym:


Brief Title:

Novel Mechanisms and Approaches to Treat Neonatal Sepsis


Official Title:

Novel Mechanisms and Approaches to Treat Neonatal Sepsis: Adjuvant Therapies, Host Microbiome, and Genomic Expression and Functional Capacity of Innate Immune Cells


Overall Status:

Recruiting


Study Phase:

N/A


Genders:

N/A


Minimum Age:

N/A


Maximum Age:

55 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

University of Florida


Oversight Authority:

United States: Federal Government


Reasons Why Stopped:


Study Type:

Observational


Study Design:


Number of Arms:

0


Number of Groups:

3


Total Enrollment:

200


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Shawn Larson, MD
Principal Investigator
University of Florida
Primary Contact:Joy Perkins, RN
352-294-5687
joy.perkins@surgery.ufl.edu

Study Dates

Start Date:February 2016
Completion Date:January 2021
Completion Type:Anticipated
Primary Completion Date:October 2020
Primary Completion Type:Anticipated
Verification Date:October 2019
Last Changed Date:October 16, 2019
First Received Date:September 17, 2015

Study Outcomes

Outcome Type:Secondary Outcome
Measure:Microbiome Influences Immune Cell Function
Time Frame:Day 1
Safety Issues:False
Description:Correlated immune deficiencies with differences in the microbiome at the time of birth will be documented by using microbiomic differences present at the time of birth in term vs preterm neonates using Illumina 16s rRNA technology. This system uses highly
Outcome Type:Secondary Outcome
Measure:Ex-vivo Adjuvant Therapies Effect On Immune Cell Genomic Expression
Time Frame:Day 1
Safety Issues:False
Description:The implementation of adjuvants in both murine and human models has shown improved function of immune effector cells as well as in clinical outcomes. Adjuvant treatment of mice with TLR agonists stimulates polymorphonuclear leukocytes (PMN) recruitment an
Outcome Type:Secondary Outcome
Measure:Ex-vivo Adjuvant Therapies On Immune Function
Time Frame:Day 1
Safety Issues:False
Description:The implementation of adjuvants in both murine and human models has shown improved function of immune effector cells as well as in clinical outcomes. Adjuvant treatment of mice with TLR agonists stimulates polymorphonuclear leukocytes (PMN) recruitment an
Outcome Type:Secondary Outcome
Measure:Immune Function Correlation with Clinical Outcomes
Time Frame:90 days
Safety Issues:False
Description:The clinical course of these neonates will be followed for incidence of infectious complications including sepsis as evident by culture results. Therefore, allowing the investigators to determine if immunologic deficits present at birth correlate with cli
Outcome Type:Primary Outcome
Measure:Functional immunologic analysis
Time Frame:Day 1
Safety Issues:False
Description:Functional capacity will be confirmed directly by observing chemotaxis and quantifying generation of reactive oxygen species (ROS), rate of phagocytosis, and bacterial killing ability. Additionally, a cytokine analysis, and an evaluation for the prevalenc
Outcome Type:Primary Outcome
Measure:Genomic analysis
Time Frame:Day 1
Safety Issues:False
Description:The genomic profile will be interpreted using Ingenuity Pathway Analysis (IPA) software to make functional predictions. Additionally, a cytokine analysis, and an evaluation for the prevalence of myeloid derived suppressor cells (MDSCs) that have been show

Study Interventions

Intervention Type:Other
Name:Adjuvant
Description:Blood will be incubated, ex-vivo, with one of the adjuvant therapies or no adjuvant and then, using microfluidic techniques the immune genomic profile and the functional capacity of immune cells will be assessed.
Arm Name:Preterm Neonate
Other Name:Lippopolysaccaride
Intervention Type:Other
Name:Blood Collection
Description:Blood collection will be performed on all groups.
Arm Name:Preterm Neonate

Study Arms

Study Arm Type:Other
Arm Name:Healthy Adult Control
Description:Healthy Adult aged 18-55 years will undergo a single blood collection by the way of vein puncture. Microfluidic techniques, utilizing whole blood, will be employed to evaluate the genomic profile and functional capacity of immune cells. Adjuvant drugs will be employed ex-vivo to determine if adjuvant therapies change genomic expression and bolster immune function.
Study Arm Type:Other
Arm Name:Term Neonates
Description:Neonates of gestational age 37-42 weeks. Blood collection will be performed at the time of a clinically required heelstick or blood draw. Microfluidic techniques, utilizing whole blood, will be employed to characterize the baseline genomic profile and functional capacity of immune cells. Adjuvant drugs will be employed ex-vivo to determine if adjuvant therapies change genomic expression and bolster immune function. Meconium will be collected for microbiome analysis. Clinical outcomes will be rec
Study Arm Type:Other
Arm Name:Preterm Neonate
Description:Neonates of gestational age 24-37 weeks. Blood collection will be performed at the time of a clinically required heelstick or blood draw. Microfluidic techniques, utilizing whole blood, will be employed to characterize the baseline genomic profile and functional capacity of immune cells. Adjuvant drugs will be employed ex-vivo to determine if adjuvant therapies change genomic expression and bolster immune function. Meconium will be collected for microbiome analysis. Clinical outcomes will be rec

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:University of Florida
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Institute of General Medical Sciences (NIGMS)

Samples and Retentions

Sample Retention:Samples With DNA
Description: Blood Sample Meconium Sample
Study Population: Preterm neonates 0-72 hours old Term Neonates 0-72 hours old Healthy Adult Controls 18-55 years old
Sample Method:Non-Probability Sample

Study References

Reference Type:Reference
Citation:Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, Lavoie PM, Furlong J, Fortuno ES 3rd, Hajjar AM, Hawkins NR, Self SG, Wilson CB. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol. 2009 Dec 1;183(11):7150-60. doi: 10.4049/jimmunol.0901481. Epub 2009 Nov 16.
PMID:19917677
Reference Type:Reference
Citation:Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease--a clinician's guide. Nat Clin Pract Rheumatol. 2007 Nov;3(11):651-60. Review.
PMID:17968336
Reference Type:Reference
Citation:Cuenca AG, Cuenca AL, Gentile LF, Efron PA, Islam S, Moldawer LL, Kays DW, Larson SD. Delayed emergency myelopoiesis following polymicrobial sepsis in neonates. Innate Immun. 2015 May;21(4):386-91. doi: 10.1177/1753425914542445. Epub 2014 Aug 7.
PMID:25106654
Reference Type:Reference
Citation:Gentile LF, Nacionales DC, Lopez MC, Vanzant E, Cuenca A, Cuenca AG, Ungaro R, Szpila BE, Larson S, Joseph A, Moore FA, Leeuwenburgh C, Baker HV, Moldawer LL, Efron PA. Protective immunity and defects in the neonatal and elderly immune response to sepsis. J Immunol. 2014 Apr 1;192(7):3156-65. doi: 10.4049/jimmunol.1301726. Epub 2014 Mar 3.
PMID:24591376
Reference Type:Reference
Citation:Gessler P, Nebe T, Birle A, Haas N, Kachel W. Neutrophil respiratory burst in term and preterm neonates without signs of infection and in those with increased levels of C-reactive protein. Pediatr Res. 1996 May;39(5):843-8.
PMID:8726239
Reference Type:Reference
Citation:Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, Rodesch CK, Albertine KH, Petti CA, Weyrich AS, Zimmerman GA. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009 Jun 18;113(25):6419-27. doi: 10.1182/blood-2008-07-171629. Epub 2009 Feb 12.
PMID:19221037
Reference Type:Reference
Citation:Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol. 2010 Jun;37(2):307-37. doi: 10.1016/j.clp.2010.04.001. Review.
PMID:20569810
Reference Type:Reference
Citation:Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, Ungaro R, Levy O, Moldawer LL. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood. 2008 Sep 1;112(5):1750-8. doi: 10.1182/blood-2008-01-130500. Epub 2008 Jun 30.
PMID:18591384
Reference Type:Reference
Citation:PrabhuDas M, Adkins B, Gans H, King C, Levy O, Ramilo O, Siegrist CA. Challenges in infant immunity: implications for responses to infection and vaccines. Nat Immunol. 2011 Mar;12(3):189-94. doi: 10.1038/ni0311-189.
PMID:21321588
Reference Type:Reference
Citation:Cuenca AG, Wynn JL, Moldawer LL, Levy O. Role of innate immunity in neonatal infection. Am J Perinatol. 2013 Feb;30(2):105-12. doi: 10.1055/s-0032-1333412. Epub 2013 Jan 7. Review.
PMID:23297181
Reference Type:Reference
Citation:Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S. 3.6 million neonatal deaths--what is progressing and what is not? Semin Perinatol. 2010 Dec;34(6):371-86. doi: 10.1053/j.semperi.2010.09.011. Review.
PMID:21094412
Reference Type:Reference
Citation:Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003 Mar 1;167(5):695-701. Epub 2002 Nov 14.
PMID:12433670

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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