Clinical trial NCT03866837: Prebiotic GOS and Lactoferrin With Iron Supplements
Official title: Prebiotic GOS and Lactoferrin for Beneficial Gut Microbiota With Iron Supplements
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Iron-deficiency
Keywords: Iron-deficiency
Iron supplementation
Galacto-oligosaccharides
Lactoferrin
Ferrous fumarate
Clinical trial
Microbiome
PolyFermS
Polyfermenter intestinal model
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Swiss Federal Institute of Technology
name: Jomo Kenyatta University of Agriculture and Technology
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2019-03-07
Enrollment: 288
Sex: ALL
Minimum age (years): 21
Maximum age (years): 27
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: The study is a single-center, double-blinded, randomized, 9-month clinical trial with a 2X2 factorial design to determine the efficacy of galacto-oligosaccharides and bovine lactoferrin in preserving a beneficial gut microbiota during iron supplementation in Kenyan infants.
Primary purpose: TREATMENT

Brief summary: The ultimate goal of this research is to develop a means to safely administer iron supplements to infants in settings with a high infection burden. The investigators will conduct a randomized clinical trial in 6 month-old Kenyan infants in conjunction with mechanistic microbiota studies using a novel long-term continuous polyfermenter platform inoculated with immobilized fecal microbiota from Kenyan infants. Oral iron supplements are associated with a significant 15% increase in the rate of diarrhea in children in malaria-endemic areas. The most recent studies have shown that prebiotic galacto-oligosaccharides (GOS) can provide partial amelioration of the adverse effects of iron supplementation by enhancing the growth of barrier populations of bifidobacteria and lactobacilli. The investigators hypothesize that the combination of GOS with bovine lactoferrin, adding iron sequestration as well as antimicrobial and immunomodulatory activities, will provide almost complete protection against the adverse effects of added iron on the intestinal microbiota.

Detailed description: Iron deficiency, the principal cause of anemia globally, affects more than two billion individuals, predominantly infants, children and women of childbearing age. Iron deficiency impairs cognitive and behavioral development in childhood, compromises immune responsiveness, decreases physical performance, and when severe, increases mortality among infants, children and pregnant women. Effective prevention and treatment of iron deficiency uses iron supplements or fortificants to increase oral iron intake. Generally, only a small fraction of the added iron is absorbed in the upper small intestine, with 80% or more passing into the colon. Because iron is an essential micronutrient for growth, proliferation, and persistence for most intestinal microbes, the increase in iron availability has profound effects on the composition and metabolism of intestinal microbiota. In particular, iron is a prime determinant of colonization and virulence for most enteric gram-negative bacteria, includingmSalmonella, Shigella and pathogenic Escherichia coli. Commensal intestinal microorganisms, principally of the genera Bifidobacterium and Lactobacillus, require little or no iron, provide a barrier effect and can inhibit pathogen growth by a variety of methods, including sequestration of iron, competition for nutrients and for intestinal epithelial sites stabilization of intestinal barrier function, and production of antibacterial peptides and organic acids that lower the pH. Increases in unabsorbed iron can promote the growth of virulent enteropathogens that overwhelm barrier strains and disrupt the gut microbiota.

We hypothesize that the combination of prebiotic GOS with bovine lactoferrin (bLF), adding iron sequestration, antimicrobial and immunomodulatory activities, will provide virtually complete protection against the adverse effects of added iron on the intestinal microbiota. Our research has two specific aims:

1. to conduct a randomized, controlled double-blind 9-month clinical trial in 6-month old Kenyan infants comparing the effects on gut microbiome composition among groups receiving in-home fortification for 6 months with micronutrient powders containing 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]) and (i) galacto-oligosaccharides (GOS; 7.5 g), (ii) bovine lactoferrin (bLF, 1.0 g), (iii) GOS (7.5 g) and bLF (1.0 g), and (iv) no GOS or bLF. Each infant will then be followed for an additional 3 months to determine the longer-term effects of the treatments.
2. to examine mechanisms of iron, prebiotic GOS and iron-sequestering bLF on microbiota composition, enteropathogen development, microbiota functions and metabolic activity, and inflammatory potential in vitro with treatments paralleling those in Specific Aim 1, using immobilized fecal microbiota from Kenyan infants to inoculate our established long-term continuous polyfermenter intestinal model (PolyFermS) to mimic Kenyan infant colon conditions, together with cellular studies.

Combining in vivo clinical and in vitro approaches will help guide formulation of safer iron supplements and fortificants and improve our understanding of the mechanisms whereby prebiotic GOS and iron-sequestering bLF support commensal microbiota to prevent iron-induced overgrowth by opportunistic enteropathogens.

Eligibility criteria: Inclusion Criteria:

* vaginal or cesarean delivery
* an infant age of 6 months (±3 weeks)
* mother ≥15 years of age
* infant still breastfeeding
* anticipated residence in the area for the study duration.

Exclusion Criteria:

* inability to provide informed consent
* hemoglobin \< 70 g/L
* Z scores for weight-for-age (WAZ) or weight-for-height (WHZ) \<3,
* any maternal or infant chronic illness
* administration of any infant vitamin or mineral supplements for the past 2 months
* history of infant antibiotic treatment within 7 days before study enrollment.

Primary outcomes:
measure: Ratio of Harmful to Beneficial Bacterial Genera in Fecal Microbiota as Determined by Quantitative Polymerase Chain Reaction (qPCR) at 1 Month
timeFrame: 1 month
Secondary outcomes:
measure: Ratio of Harmful to Beneficial Bacterial Genera in Fecal Microbiota as Determined by Quantitative Polymerase Chain Reaction (qPCR) at 6 Months
timeFrame: 6 months
measure: Ratio of Harmful to Beneficial Bacterial Genera in Fecal Microbiota as Determined by Quantitative Polymerase Chain Reaction (qPCR) at 9 Months
timeFrame: 9 months
measure: Microbiota Composition as Determined by Quantitative Polymerase Chain Reaction (qPCR).
timeFrame: 1, 6 and 9 months
measure: Number of Participants Who Experienced Diarrhea
timeFrame: Up to 9 months
measure: Number of Participants Who Experienced Malaria
timeFrame: Up to 9 months
measure: Proportion of Participants Who Experienced Anemia
timeFrame: Baseline, 1 month, 6 months, 9 months
measure: Proportion of Participants Who Experienced Iron Deficiency
timeFrame: Baseline, 1 month, 6 months, 9 months
measure: Proportion of Participants Who Experienced Iron Deficiency Anemia (IDA)
timeFrame: Baseline, 1 month, 6 months, 9 months
measure: Proportion of Participants Who Experienced Inflammation
timeFrame: Baseline, 1 month, 6 months, 9 months
measure: Number of Participants Who Experienced Respiratory Tract Infections
timeFrame: Up to 9 months
measure: Other Illnesses
timeFrame: Up to 9 months
Other outcomes:
Locations:
city: Nairobi
country: Kenya
facility: Jomo Kenyatta University of Agriculture and Technology
city: Zürich
country: Switzerland
facility: Swiss Federal Institute of Technology (ETH Zürich)
Study officials:
affiliation: Columbia University
name: Gary M Brittenham, MD
role: PRINCIPAL_INVESTIGATOR
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