Clinical trial NCT01525316: Lactoferrin for Prevention of Sepsis in Infants
Official title: Lactoferrin for Prevention of Sepsis in Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Late Onset Neonatal Sepsis
Keywords: Late Onset Neonatal Sepsis
Neonates
Lactoferrin
Infections
Prevention
Neurodevelopment
Lead sponsor: Universidad Peruana Cayetano Heredia
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2012-02-02
Enrollment: 414
Sex: ALL
Minimum age (years): 1
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: First episode of late-onset sepsis or sepsis-associated death
timeFrame: 72hrs to 8 weeks of age
Secondary outcomes:
measure: Neurodevelopment
timeFrame: 12 to 24 months of corrected age
Other outcomes:
Locations:
city: Lima
country: Peru
facility: Hospital Nacional Alberto Sabogal Sologuren
city: Lima
country: Peru
facility: Hospital Nacional Cayetano Heredia
city: Lima
country: Peru
facility: Hospital Nacional Guillermo Almenara Irigoyen
Study officials:
affiliation: Universidad Peruana Cayetano Heredia
name: Theresa J Ochoa, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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