The Efficacy and Mechanisms of Oral Probiotics in Preventing Necrotizing Enterocolitis

Death Clinical Trial

Official title:

The Efficacy and Mechanisms of Oral Probiotics in Preventing Necrotizing Enterocolitis Among Very Low Birth Weight Infants With Formula-feeding

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02552706
• Other study ID #: LL2014006
• Status: Recruiting
• Phase: N/A
• First received: September 12, 2015
• Last updated: March 26, 2016
• Start date: September 2014
• Est. completion date: September 2017

Study information

• Verified date: September 2015
• Source: Shenzhen Bao'an Maternal and Child Health Hospital
• Contact: Yuefeng Li, M.D.
• Phone: 86+13751029103
• Email: liyuefeng111[@]sina.com
• Is FDA regulated: No
• Health authority: China: Shenzhen Science and Technology Innovation Committee
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate the efficacy and its mechanisms of oral mixture probiotics in preventing necrotizing enterocolitis among the preterm very low birth weight infants.

Description:

Necrotizing enterocolitis (NEC) remains the most catastrophic gastrointestinal emergencies in preterm very low birth weight (VLBW) infants.Although study showed it is a multifactorial disease, its pathogenesis is still not yet unclear currently. Prematurity and formula feeding is considered as the main risk factors.Gut microbiota disturbance and immature immune system is associated with NEC. A lot of studies had showed that oral probiotics can alter gut microbiota flora colonization and reduce the incidence of NEC,but the exact mechanism remains unclear.The aim of this study is to elucidate the clinical efficacy and possible molecular mechanism of oral mixture probiotics in preventing NEC among preterm VLBW infants.

Patient Registry procedures: First,randomized numbers was generated by the computer and sent to the principal investigator(PI) at each center when an infant was eligible for enrollment.Second, patient will be assigned randomly to experimental group or control group by PI.Finally,the PI at each center will be responsible for the accuracy,completeness or representativeness of medical records, registry forms,data collection.

Sample size determination: The incidence of death and NEC was around 20% recently.To reduce the incidence of NEC and death to 10% at discharge would require a 50% improvement.At 80% power at P = 0.05 (two-sided),the loss rate of 0.2, this would require 135 subjects per arm.

Statistical analysis:The two groups were compared by a Χ2-test for categorical variables,Mann-Whitney U Test were used when reporting medians.A P value of <0.05 was considered statistically significant.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 270
• Est. completion date: September 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 3 Days

Eligibility

Inclusion Criteria:

• Preterm infants ? 34 weeks gestational age and birth weight below 1500 gm and who survive to NICU are eligible for the trial.

Exclusion Criteria:

• severe asphyxia (stage III),

• fetal chromosomal anomalies,

• cyanotic congenital heart disease,

• congenital intestinal atresia, gastroschisis, omphalocele, active upper gastric intestinal bleeding,

• lacking/refused of parental consent,

• those who are fasted for >3 weeks during the study period.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Death
• Enterocolitis
• Enterocolitis, Necrotizing
• Necrotizing Enterocolitis

Intervention

Dietary Supplement:
• probiotics
Administration of mixture probiotics 500mg by mouth, one time or divided into 2-4 times depends on the feeding volume until to 36 weeks post menstrual age.
• glucose solution
Administration of 1 mL of a 5% glucose solution by mouth, one time or divided into 2-4 times depends on the feeding volume until to 36 weeks post menstrual age.

Locations

Country	Name	City	State
China	Longhua People's Hospital of Shenzhen	Shenzhen	Guangdong
China	Shenzhen Bao'an Maternal and Child Health Hospital	Shenzhen	Guangdong
China	Shenzhen People's Hospital	Shenzhen	Guangdong
China	Shenzhen Sixth People's Hospital	Shenzhen	Guangdong

Sponsors (5)

Lead Sponsor	Collaborator
Shenzhen Bao'an Maternal and Child Health Hospital	China Medical University Hospital, Longhua Hospital Of Baoan District, Shenzhen, Shenzhen People's Hospital, Shenzhen Sixth People's Hospital

Country where clinical trial is conducted

China, 

References & Publications (17)

Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a — View Citation

Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. 2010 May;125(5):921-30. doi: 10.1542/peds.2009-1301. Epub 2010 Apr 19. — View Citation

Di Gioia D, Aloisio I, Mazzola G, Biavati B. Bifidobacteria: their impact on gut microbiota composition and their applications as probiotics in infants. Appl Microbiol Biotechnol. 2014 Jan;98(2):563-77. doi: 10.1007/s00253-013-5405-9. Epub 2013 Nov 28. Re — View Citation

Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol. 2013 Jan 15;304(2):G132-4 — View Citation

Genzel-Boroviczény O, MacWilliams S, Von Poblotzki M, Zoppelli L. Mortality and major morbidity in premature infants less than 31 weeks gestational age in the decade after introduction of surfactant. Acta Obstet Gynecol Scand. 2006;85(1):68-73. — View Citation

Hackam DJ, Afrazi A, Good M, Sodhi CP. Innate immune signaling in the pathogenesis of necrotizing enterocolitis. Clin Dev Immunol. 2013;2013:475415. doi: 10.1155/2013/475415. Epub 2013 May 23. Review. — View Citation

Hall NJ, Eaton S, Pierro A. Royal Australasia of Surgeons Guest Lecture. Necrotizing enterocolitis: prevention, treatment, and outcome. J Pediatr Surg. 2013 Dec;48(12):2359-67. doi: 10.1016/j.jpedsurg.2013.08.006. Review. — View Citation

Huda S, Chaudhery S, Ibrahim H, Pramanik A. Neonatal necrotizing enterocolitis: Clinical challenges, pathophysiology and management. Pathophysiology. 2014 Feb;21(1):3-12. doi: 10.1016/j.pathophys.2013.11.009. Epub 2014 Feb 11. — View Citation

Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, Tsao LY, Chen CH, Su BH. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics. 2008 Oct;122(4):693-700. doi: 10.1542/peds.2007-3007. — View Citation

Liu Y, Fatheree NY, Mangalat N, Rhoads JM. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-?B signaling in the intestine. Am J Physiol Gastrointest Liver Physiol. 2012 Mar — View Citation

Lu P, Sodhi CP, Hackam DJ. Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis. Pathophysiology. 2014 Feb;21(1):81-93. doi: 10.1016/j.pathophys.2013.11.007. Epub 2013 Dec 22. — View Citation

Mshvildadze M, Neu J, Mai V. Intestinal microbiota development in the premature neonate: establishment of a lasting commensal relationship? Nutr Rev. 2008 Nov;66(11):658-63. doi: 10.1111/j.1753-4887.2008.00119.x. Review. — View Citation

Nair V, Soraisham AS. Probiotics and prebiotics: role in prevention of nosocomial sepsis in preterm infants. Int J Pediatr. 2013;2013:874726. doi: 10.1155/2013/874726. Epub 2013 Jan 14. — View Citation

Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD002971. Review. Update in: Cochrane Database Syst Rev. 2014;4:CD002971. — View Citation

Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007 May;92(3):F193-8. Epub 2006 Sep 19. Review. — View Citation

Sarowska J, Choroszy-Król I, Regulska-Ilow B, Frej-Madrzak M, Jama-Kmiecik A. The therapeutic effect of probiotic bacteria on gastrointestinal diseases. Adv Clin Exp Med. 2013 Sep-Oct;22(5):759-66. Review. — View Citation

Sharma R, Tepas JJ 3rd, Hudak ML, Mollitt DL, Wludyka PS, Teng RJ, Premachandra BR. Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis. J Pediatr Surg. 2007 Mar;42(3):45 — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	the influence of oral probiotics on gut microbiota and immunomodulatory	test fecal microbiota via high throughput sequencing and blood toll like receptor(TLR)2,TLR4,neclear factor kappa B(NF-KB)were detected using flow cytomtry.Inflammatory factors of blood were tested via Cytometric Bead Array(CBA).All above samples were obtained only from Shenzhen Bao'an Maternal and Child Health Hospital.The fecal DNA were first extracted at centre laboratory in aboved hospital and sent them to Beijing Genomics Institute(BGI) for further sequenceing ,if necessary, quantitative polymerase chain reaction(qPCR)of gut dominant bacterias related to late onset sepsis(LOS) will be tested for assessing the effect of oral probiotics on gut microbiota and underlying the mechanism. Flow cytometry analysis of TLR2,TLR4 and NF-KB were made by the senior laboratorian of our department and resposible for the accuracy of experimental result. CBA of inflammatory factors will be made by senting the blood samples to Beijing JIAMAY BIOLAB.	at birth, 2 and 4 weeks of life, 36 week correct gestational age.	No
Primary	the incidence of combined death and necrotizing enterocolitis		at 36 weeks correct gestational age	No
Secondary	the incidence of sepsis,intraventricular hemorrhage(IVH)(grade 3-4),feeding intolerance(FI),bronchopulmonary dysplasia(BPD),parenteral nutrition associated liver disease(PNALD)and retinopathyof prematurity(ROP).		participants will be followed for the duration of hospital stay, an expected average of 8 weeks	No