Lactoferrin for Prevention of Sepsis in Infants

Late Onset Neonatal Sepsis Clinical Trial

— NEOLACTO  

Official title:

Lactoferrin for Prevention of Sepsis in Infants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01525316
• Other study ID #: SIDISI 57710
• Secondary ID: 1R01HD067694-01A
• Status: Completed
• Phase: Phase 3
• Start date: May 2012
• Est. completion date: October 2016

Study information

• Verified date: December 2021
• Source: Universidad Peruana Cayetano Heredia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators propose a clinical trial in premature infants to determine the effect of orally-administered bovine lactoferrin on occurrence of severe infections and to determine whether as a result of decreased infections, infants' growth and development improve after daily lactoferrin supplementation, due to its antimicrobial and anti-inflammatory properties. If successful, the use of lactoferrin as a protective protein could profoundly affect clinical care of neonates both in the developed and developing world.

Description:

Neonatal mortality is an important global public health challenge. Approximately 4 million neonatal deaths per year occur in developing countries, accounting for 40% all of deaths in children under 5. Infection, birth asphyxia and consequences of premature birth/low birth weight are responsible for the majority of these deaths. Although advances in neonatal intensive care led to improved survival of premature infants, sepsis continues to be an important cause of morbidity and mortality worldwide.

Lactoferrin, an iron-binding protein with multiple physiological functions (anti-microbial, anti-inflammatory, and immunomodulatory), is one of the most important proteins present in mammalian milk. Our hypothesis is that lactoferrin given as a daily oral food supplement to preterm infants will improve their health by mimicking its protective role in milk. There is a vast literature showing in vitro and animal model benefits of lactoferrin. However, there are few clinical studies designed to translate this knowledge into patient care. A recent Italian study showed that lactoferrin given to low-birth weight infants reduces incidence of sepsis (17% vs. 6%) and death. Whether lactoferrin has an effect in higher risk populations and an impact on subsequent neurodevelopment and growth remains to be determined.

Specific aim 1: The investigators will test the hypothesis that bovine lactoferrin supplementation prevents serious infections in preterm infants. The investigators will conduct a randomized placebo-controlled double blind study in 414 premature infants < 2000 g in Neonatal Units in Lima, Peru to determine whether bovine lactoferrin prevents late-onset sepsis or sepsis-associated death.

This hypothesis is based on lactoferrin´s antimicrobial and immunomodulating activities. Lactoferrin protects against pathogens in multiple ways: it sequesters iron essential for bacterial growth; binds to lipopolysaccharide (LPS) on the cell surface of Gram negative bacteria, disrupting the bacterial cell membrane; it has anti-lipoteichoic acid (against Gram positive organisms) and anti-Candida cell wall activities. The investigators have found that lactoferrin not only inhibits growth; it impairs virulence of some of the major pathogens by decreasing their ability to adhere or to invade mammalian cells, and by binding to, or degrading, specific virulence proteins. Lactoferrin may protect infants from sepsis by blocking attachment and invasion of organisms in the gut.

Specific aim 2: The investigators will test the hypothesis that bovine lactoferrin supplementation promotes better neurodevelopment and growth outcomes in preterm infants assessed by the Mullen Scales of Early Learning, a standardized neurologic exam and growth measurements at 12, 18 and 24 months corrected age.

It is postulated that exposure of the preterm brain to inflammatory mediators during infectious episodes contribute to brain (white matter) injury and poor developmental outcome. It has been demonstrated that breast milk has a beneficial effect on neurodevelopment outcomes in preterm infants. The investigators hypothesize that lactoferrin is the major factor in milk responsible for this effect due to its antimicrobial and immunomodulatory properties: it reduces inflammation by decreasing production of tumor necrosis factor α and other pro-inflammatory molecules, and by regulating the immune response, protecting against severe inflammation related to infection and septic shock. In addition, the investigators hypothesize that lactoferrin will improve growth by decreasing the frequency of growth-impairing infections and by lactoferrin effect on intestinal cell proliferation, differentiation and maturation.

The use of lactoferrin as a broad-spectrum non-pathogen specific antimicrobial protective protein is an innovative approach. If successful this study will profoundly affect clinical care of neonates both in the developed and developing world.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 414
• Est. completion date: October 2016
• Est. primary completion date: October 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 72 Hours

Eligibility

Inclusion Criteria:

• Neonates with a birth weight between 500g and 2000g

• Neonates born in, or referred to the Neonatal Intermediate and Intensive Care Units of one of the participating hospitals in the first 72 hours of life.

Exclusion Criteria:

• Neonates with underlying gastrointestinal problems that prevent oral intake.

• Neonates with predisposing conditions that profoundly affect growth and development (chromosomal abnormalities, structural brain anomalies, severe congenital abnormalities).

• Neonates who have a family history of cow milk allergy.

• Neonates that, according to the investigator criteria, will not have the chance to complete the subsequent study visits (patients that before one month old would not be living in Lima).

• Neonates whose parents decline to participate.

Related Conditions & MeSH terms

• Late Onset Neonatal Sepsis
• Neonatal Sepsis
• Sepsis
• Toxemia

Intervention

Dietary Supplement:
• Bovine Lactoferrin
Infants will receive oral bovine lactoferrin (200 mg/Kg/day divided in three dosis) for 8 weeks. Lactoferrin will be dissolved in human milk or infant formula or in a 5% glucose solution. Each dose will be dissolved in a small volume so the maximum lactoferrin concentration will be 25mg/mL.
• Maltodextrin
Infants will receive oral maltodextrin (200mg/Kg/day in three divided dosis) for 8 weeks. Maltodextrin will be dissolved in human milk or infant formula or in a 5% glucose solution. Each dose will be dissolved in a small volume so the maximum maltodextrin concentration will be 25mg/mL.

Locations

Country	Name	City	State
Peru	Hospital Nacional Alberto Sabogal Sologuren	Lima
Peru	Hospital Nacional Cayetano Heredia	Lima
Peru	Hospital Nacional Guillermo Almenara Irigoyen	Lima

Sponsors (2)

Lead Sponsor	Collaborator
Universidad Peruana Cayetano Heredia	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

Peru, 

References & Publications (3)

Akin IM, Atasay B, Dogu F, Okulu E, Arsan S, Karatas HD, Ikinciogullari A, Turmen T. Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Am J Perinatol. 2014 Dec;31(12):1111-20. doi: 10.1055/s-0034-1371704. Epub 2014 May 16. — View Citation

Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, Stolfi I, Decembrino L, Laforgia N, Vagnarelli F, Memo L, Bordignon L, Saia OS, Maule M, Gallo E, Mostert M, Magnani C, Quercia M, Bollani L, Pedicino R, Renzullo L, Betta P, Mosca F, Ferrari F, Magaldi R, Stronati M, Farina D; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA. 2009 Oct 7;302(13):1421-8. doi: 10.1001/jama.2009.1403. — View Citation

Ochoa TJ, Zegarra J, Cam L, Llanos R, Pezo A, Cruz K, Zea-Vera A, Cárcamo C, Campos M, Bellomo S; NEOLACTO Research Group. Randomized controlled trial of lactoferrin for prevention of sepsis in peruvian neonates less than 2500 g. Pediatr Infect Dis J. 2015 Jun;34(6):571-6. doi: 10.1097/INF.0000000000000593. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	First episode of late-onset sepsis or sepsis-associated death	The primary study outcome will be a composite outcome of the first episode of late-onset sepsis or sepsis-associated death.	72hrs to 8 weeks of age
Secondary	Neurodevelopment	Neurodevelopment at 24 months of corrected age, assessed by the Mullen Scale for Early Learning.	12 to 24 months of corrected age