Intestinal Permeability in Preterm Infants

NCT ID: NCT01756040

Last Updated: 2023-11-18

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

211 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-02-01

Study Completion Date

2021-08-31

Brief Summary

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Necrotizing enterocolitis (NEC) is a life-threatening, gastrointestinal emergency characterized by increased intestinal permeability, affects approximately 7 to 10% of infants \<1500 g birthweight, and typically occurs within 7 to 14 days of birth. Mortality is as high as 30-50%. Prematurity is the greatest risk factor for the development of NEC due to the physiological immaturity of the gastrointestinal tract and altered or abnormal gut microbiota. Several studies have demonstrated that the initiation of an intense systemic and local inflammatory cascade leads to intestinal necrosis. The human intestine is lined by a single layer of cells exquisitely responsive to multiple stimuli and is populated by a complex climax community of microbial partners. Under normal circumstances, these intestinal cells form a tight but selective barrier to "friends and foes": microbes and most environmental substances are held at bay, but nutrients are absorbed efficiently. Epithelial barrier integrity is itself dynamic and matures over time starting soon after birth, though the mechanisms regulating dynamic permeability are poorly understood. Low birth weight, prematurity, and early postnatal age are associated with a leaky gut. Although intestinal permeability is higher at birth in preterm than term infants, there is usually rapid maturation of the intestinal barrier over the first few days of life in both populations. The investigators hypothesize that increased levels of measures of intestinal permeability (urine lactulose/rhamnose (LA/Rh), and fecal alpha1- antitrypsin will identify infants at high risk for NEC and that intestinal probiotic strains will be associated with intestinal barrier maturation. The purpose of the study is to determine whether clinical factors in combination with non-invasive stool test such as antitrypsin (A1AT) and microbiota composition profile are associated with intestinal permeability determined by excretion of non-metabolized sugar probes in urine (LA/Rh ratio). These studies may lead to a non-invasive screening test to identify preterm infants at risk for NEC.

Detailed Description

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The proposed study will evaluate the intestinal permeability measured by the urinary La/Rh ratio at one timepoint between d7-10 of life in 200 preterm infants 24-32 weeks gestation in preparation for a future study of probiotics to improve intestinal permeability in this population.

Primary Objective: To estimate mean and variance in IP measured by urinary Lactulose/Rhamnose ratio at 7-10d of life in neonates born between 24 and 32 weeks of gestational age.

Secondary Objectives

1\) To assess stool microbiome characteristics in association with intestinal permeability in preterm infants measured by the urinary lactulose/rhamnose ratio.

Conditions

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Prematurity Intestinal Permeability

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

SCREENING

Blinding Strategy

NONE

Study Groups

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Lactulose - rhamnose solution

Preterm Infants age 24-32 weeks gestation

Group Type OTHER

Lactulose -rhamnose solution

Intervention Type DRUG

Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue

Interventions

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Lactulose -rhamnose solution

Measurement of intestinal permeability by use of mon- digestible sugars known not to cross the intestinal barrier in normal healthy intestinal tissue

Intervention Type DRUG

Other Intervention Names

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dual sugar solution

Eligibility Criteria

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Inclusion Criteria

* \<5 days
* Gestational age 24-32 weeks

Exclusion Criteria

* Nonviable or planned withdrawal of care
* Significant GI dysfunction (e.g. heme-positive stools, abdominal distension (girth \>2 cm baseline), or bilious emesis/aspirates.
* Triplet or higher order multiple
* Severe asphyxia
* Lethal chromosome abnormalities
* Cyanotic congenital heart disease
* Intestinal atresia or perforation
* Abdominal wall defects
* Known galactosemia or other galactose intolerance
Maximum Eligible Age

4 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Maryland, Baltimore

OTHER

Sponsor Role lead

Responsible Party

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Rose Viscardi

University of Maryland

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Alessio Fasano, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Rose M Viscardi, MD

Role: PRINCIPAL_INVESTIGATOR

University of Maryland

Locations

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University of Maryland Medical Center

Baltimore, Maryland, United States

Site Status

Countries

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United States

References

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Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol. 2008 Nov;173(5):1243-52. doi: 10.2353/ajpath.2008.080192. Epub 2008 Oct 2.

Reference Type BACKGROUND
PMID: 18832585 (View on PubMed)

Bjarnason I. Intestinal permeability. Gut. 1994 Jan;35(1 Suppl):S18-22. doi: 10.1136/gut.35.1_suppl.s18.

Reference Type BACKGROUND
PMID: 8125384 (View on PubMed)

van Wijck K, Bessems BA, van Eijk HM, Buurman WA, Dejong CH, Lenaerts K. Polyethylene glycol versus dual sugar assay for gastrointestinal permeability analysis: is it time to choose? Clin Exp Gastroenterol. 2012;5:139-50. doi: 10.2147/CEG.S31799. Epub 2012 Jul 19.

Reference Type BACKGROUND
PMID: 22888267 (View on PubMed)

van Wijck K, Verlinden TJ, van Eijk HM, Dekker J, Buurman WA, Dejong CH, Lenaerts K. Novel multi-sugar assay for site-specific gastrointestinal permeability analysis: a randomized controlled crossover trial. Clin Nutr. 2013 Apr;32(2):245-51. doi: 10.1016/j.clnu.2012.06.014. Epub 2012 Aug 11.

Reference Type BACKGROUND
PMID: 22892368 (View on PubMed)

Beach RC, Menzies IS, Clayden GS, Scopes JW. Gastrointestinal permeability changes in the preterm neonate. Arch Dis Child. 1982 Feb;57(2):141-5. doi: 10.1136/adc.57.2.141.

Reference Type BACKGROUND
PMID: 7065710 (View on PubMed)

Piena-Spoel M, Albers MJ, ten Kate J, Tibboel D. Intestinal permeability in newborns with necrotizing enterocolitis and controls: Does the sugar absorption test provide guidelines for the time to (re-)introduce enteral nutrition? J Pediatr Surg. 2001 Apr;36(4):587-92. doi: 10.1053/jpsu.2001.22288.

Reference Type BACKGROUND
PMID: 11283883 (View on PubMed)

Rouwet EV, Heineman E, Buurman WA, ter Riet G, Ramsay G, Blanco CE. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res. 2002 Jan;51(1):64-70. doi: 10.1203/00006450-200201000-00012.

Reference Type BACKGROUND
PMID: 11756641 (View on PubMed)

Albers MJ, Steyerberg EW, Hazebroek FW, Mourik M, Borsboom GJ, Rietveld T, Huijmans JG, Tibboel D. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Ann Surg. 2005 Apr;241(4):599-606. doi: 10.1097/01.sla.0000157270.24991.71.

Reference Type BACKGROUND
PMID: 15798461 (View on PubMed)

Piena M, Albers MJ, Van Haard PM, Gischler S, Tibboel D. Introduction of enteral feeding in neonates on extracorporeal membrane oxygenation after evaluation of intestinal permeability changes. J Pediatr Surg. 1998 Jan;33(1):30-4. doi: 10.1016/s0022-3468(98)90355-4.

Reference Type BACKGROUND
PMID: 9473094 (View on PubMed)

Malagon I, Onkenhout W, Klok M, van der Poel PF, Bovill JG, Hazekamp MG. Gut permeability in neonates after a stage 1 Norwood procedure. Pediatr Crit Care Med. 2005 Sep;6(5):547-9. doi: 10.1097/01.pcc.0000175990.72753.97.

Reference Type BACKGROUND
PMID: 16148815 (View on PubMed)

Noone C, Menzies IS, Banatvala JE, Scopes JW. Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Eur J Clin Invest. 1986 Jun;16(3):217-25. doi: 10.1111/j.1365-2362.1986.tb01332.x.

Reference Type BACKGROUND
PMID: 3089818 (View on PubMed)

van Elburg RM, Fetter WP, Bunkers CM, Heymans HS. Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch Dis Child Fetal Neonatal Ed. 2003 Jan;88(1):F52-5. doi: 10.1136/fn.88.1.f52.

Reference Type BACKGROUND
PMID: 12496227 (View on PubMed)

Catassi C, Bonucci A, Coppa GV, Carlucci A, Giorgi PL. Intestinal permeability changes during the first month: effect of natural versus artificial feeding. J Pediatr Gastroenterol Nutr. 1995 Nov;21(4):383-6. doi: 10.1097/00005176-199511000-00003.

Reference Type BACKGROUND
PMID: 8583288 (View on PubMed)

Roskes L, Chamzas A, Ma B, Medina AE, Gopalakrishnan M, Viscardi RM, Sundararajan S. Early human milk feeding: Relationship to intestinal barrier maturation and postnatal growth. Pediatr Res. 2025 May;97(6):2065-2073. doi: 10.1038/s41390-024-03622-5. Epub 2024 Oct 14.

Reference Type DERIVED
PMID: 39397156 (View on PubMed)

Mahdally SM, Izquierdo M, Viscardi RM, Magder LS, Crowley HM, Bafford AC, Drachenberg CB, Farfan MJ, Fasano A, Sztein MB, Salerno-Goncalves R. Secretory-IgA binding to intestinal microbiota attenuates inflammatory reactions as the intestinal barrier of preterm infants matures. Clin Exp Immunol. 2023 Oct 13;213(3):339-356. doi: 10.1093/cei/uxad042.

Reference Type DERIVED
PMID: 37070830 (View on PubMed)

Saleem B, Okogbule-Wonodi AC, Fasano A, Magder LS, Ravel J, Kapoor S, Viscardi RM. Intestinal Barrier Maturation in Very Low Birthweight Infants: Relationship to Feeding and Antibiotic Exposure. J Pediatr. 2017 Apr;183:31-36.e1. doi: 10.1016/j.jpeds.2017.01.013. Epub 2017 Jan 31.

Reference Type DERIVED
PMID: 28159311 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

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HP-00049647

Identifier Type: -

Identifier Source: org_study_id

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