Intestinal Permeability in Preterm Infants

NCT01756040 | Completed Phase 1 Results DMC

• 1 other identifier: HP-00049647
• Study Type: interventional
• Target: 211
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Prematurity; Intestinal Permeability

Keywords

intestinal permeability; preterm infants; dual sugar test; intestinal microbiota

Outcome Measures

Primary Outcomes (1)

• Intestinal Permeability

  Intestinal Permeability measured by urinary excretion of orally administered lactulose/rhamnose (La/Rh ratio)

  7-10 days postnatal

Secondary Outcomes (3)

• Stool Alpha-1 Antitrypsin

  7-10 days postnatal

• Stool Microbiota Relative Abundance

  7-10 days postnatal

• Breastmilk Feeding Duration Prior to La/Rh Measurement

  7-10 days postnatal

Other Outcomes (3)

• Occurrence of Necrotizing Enterocolitis

  0-28 days postnatal

• Percent Participants Exposed to Antibiotics Prior to La/Rh Measurement

  7-10 days postnatal

• Postnatal Age Full Feeds Reached

  0-100 days postnatal

Study Arms (1)

Lactulose - rhamnose solution

OTHER

Preterm Infants age 24-32 weeks gestation

Drug: Lactulose -rhamnose solution

Interventions

Lactulose -rhamnose solution DRUG

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

Also known as: dual sugar solution

Lactulose - rhamnose solution

Eligibility Criteria

• Age: Up to 4 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Related Publications (16)

• 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.

  PMID: 18832585 BACKGROUND

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

  PMID: 8125384 BACKGROUND

• 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.

  PMID: 22888267 BACKGROUND

• 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.

  PMID: 22892368 BACKGROUND

• 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.

  PMID: 7065710 BACKGROUND

• 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.

  PMID: 11283883 BACKGROUND

• 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.

  PMID: 11756641 BACKGROUND

• 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.

  PMID: 15798461 BACKGROUND

• 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.

  PMID: 9473094 BACKGROUND

• 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.

  PMID: 16148815 BACKGROUND

• 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.

  PMID: 3089818 BACKGROUND

• 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.

  PMID: 12496227 BACKGROUND

• 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.

  PMID: 8583288 BACKGROUND

• 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.

  PMID: 39397156 DERIVED

• 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.

  PMID: 37070830 DERIVED

• 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.

  PMID: 28159311 DERIVED

MeSH Terms

Conditions

Premature Birth

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Results Point of Contact

• Title: Rose Marie Viscardi, M.D.
• Organization: University of Maryland Baltimore

rviscard@som.umaryland.edu

410-328-6003

Study Officials

• Alessio Fasano, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Rose M Viscardi, MD

  University of Maryland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: University of Maryland

Study Record Dates

• First Submitted: December 19, 2012
• First Posted: December 24, 2012
• Study Start: February 1, 2013
• Primary Completion: August 31, 2021
• Study Completion: August 31, 2021
• Last Updated: November 18, 2023
• Results First Posted: November 18, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)