Intestinal Permeability in Preterm Infants

Prematurity Clinical Trial

— IPPI  

Official title:

Gut Permeability in Very Low Birth Weight Infants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01756040
• Other study ID #: HP-00049647
• Status: Completed
• Phase: Phase 1
• Start date: February 1, 2013
• Est. completion date: August 31, 2021

Study information

• Verified date: November 2023
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 211
• Est. completion date: August 31, 2021
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 4 Days

Eligibility

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

Related Conditions & MeSH terms

• Intestinal Permeability
• Premature Birth
• Prematurity

Intervention

Drug:
• 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

Locations

Country	Name	City	State
United States	University of Maryland Medical Center	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

References & Publications (13)

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Occurrence of Necrotizing Enterocolitis	Frequency of = Stage 2 Necrotizing enterocolitis	0-28 days postnatal
Other	Percent Participants Exposed to Antibiotics Prior to La/Rh Measurement	Percent of participants with antibiotic exposure prior to La/Rh measurement	7-10 days postnatal
Other	Postnatal Age Full Feeds Reached	Postnatal age when all nutrition is provided by enteral feeds	0-100 days postnatal
Primary	Intestinal Permeability	Intestinal Permeability measured by urinary excretion of orally administered lactulose/rhamnose (La/Rh ratio)	7-10 days postnatal
Secondary	Stool Alpha-1 Antitrypsin	Stool alpha-1 antitrypsin concentrations	7-10 days postnatal
Secondary	Stool Microbiota Relative Abundance	Relative abundance (%) Clostridiales species	7-10 days postnatal
Secondary	Breastmilk Feeding Duration Prior to La/Rh Measurement	Number of days breast milk feeding prior to La/Rh measurement between d7-10 days of age.	7-10 days postnatal