- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01525316
Lactoferrin for Prevention of Sepsis in Infants (NEOLACTO)
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Lima, Peru, 0511
- Hospital Nacional Alberto Sabogal Sologuren
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Lima, Peru, 0511
- Hospital Nacional Cayetano Heredia
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Lima, Peru, 0511
- Hospital Nacional Guillermo Almenara Irigoyen
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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EXPERIMENTAL: Bovine Lactoferrin
Lactoferrin is a freeze-dried protein purified directly from fresh bovine milk.
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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.
Other Names:
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PLACEBO_COMPARATOR: Maltodextrin
Maltodextrin is an inert sugar.
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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First episode of late-onset sepsis or sepsis-associated death
Time Frame: 72hrs to 8 weeks of age
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The primary study outcome will be a composite outcome of the first episode of late-onset sepsis or sepsis-associated death.
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72hrs to 8 weeks of age
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Neurodevelopment
Time Frame: 12 to 24 months of corrected age
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Neurodevelopment at 24 months of corrected age, assessed by the Mullen Scale for Early Learning.
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12 to 24 months of corrected age
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Collaborators and Investigators
Publications and helpful links
General Publications
- 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.
- Ochoa TJ, Zegarra J, Cam L, Llanos R, Pezo A, Cruz K, Zea-Vera A, Carcamo 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.
- 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.
- Torres Roldan VD, Urtecho S M, Gupta J, Yonemitsu C, Carcamo CP, Bode L, Ochoa TJ. Human milk oligosaccharides and their association with late-onset neonatal sepsis in Peruvian very-low-birth-weight infants. Am J Clin Nutr. 2020 Jul 1;112(1):106-112. doi: 10.1093/ajcn/nqaa102.
- Ochoa TJ, Zegarra J, Bellomo S, Carcamo CP, Cam L, Castaneda A, Villavicencio A, Gonzales J, Rueda MS, Turin CG, Zea-Vera A, Guillen D, Campos M, Ewing-Cobbs L; NEOLACTO Research Group. Randomized Controlled Trial of Bovine Lactoferrin for Prevention of Sepsis and Neurodevelopment Impairment in Infants Weighing Less Than 2000 Grams. J Pediatr. 2020 Apr;219:118-125.e5. doi: 10.1016/j.jpeds.2019.12.038. Epub 2020 Feb 6.
- Medina-Alva P, Duque KR, Zea-Vera A, Bellomo S, Carcamo C, Guillen-Pinto D, Rivas M, Tori A, Zegarra J, Cam L, Castaneda A, Villavicencio A, Ochoa TJ. Combined predictors of neurodevelopment in very low birth weight preterm infants. Early Hum Dev. 2019 Mar;130:109-115. doi: 10.1016/j.earlhumdev.2019.01.019. Epub 2019 Feb 8.
- Rueda MS, Calderon-Anyosa R, Gonzales J, Turin CG, Zea-Vera A, Zegarra J, Bellomo S, Cam L, Castaneda A, Ochoa TJ; NEOLACTO Research Group. Antibiotic Overuse in Premature Low Birth Weight Infants in a Developing Country. Pediatr Infect Dis J. 2019 Mar;38(3):302-307. doi: 10.1097/INF.0000000000002055.
- Turin CG, Zea-Vera A, Rueda MS, Mercado E, Carcamo CP, Zegarra J, Bellomo S, Cam L, Castaneda A, Ochoa TJ; NEOLACTO Research Group. Lactoferrin concentration in breast milk of mothers of low-birth-weight newborns. J Perinatol. 2017 May;37(5):507-512. doi: 10.1038/jp.2016.265. Epub 2017 Jan 26.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- SIDISI 57710
- 1R01HD067694-01A1 (NIH)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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