Lactoferrin for Prevention of Sepsis in Infants
Condition: Late Onset Neonatal Sepsis
MeSH terms: Sepsis; Toxemia; Neonatal Sepsis
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Bovine Lactoferrin; Maltodextrin
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 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.; 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.
Other intervention name(s): Lactoferrin
Intervention MeSH terms: Lactoferrin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Late Onset Neonatal Sepsis; Neonates; Lactoferrin; Infections; Prevention; Neurodevelopment