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Prebiotic GOS and Lactoferrin With Iron Supplements

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ClinicalTrials.gov Identifier: NCT03866837
Recruitment Status : Not yet recruiting
First Posted : March 7, 2019
Last Update Posted : March 12, 2019
Sponsor:
Collaborators:
Swiss Federal Institute of Technology (ETH Zürich)
Jomo Kenyatta University of Agriculture and Technology
Information provided by (Responsible Party):
Gary M Brittenham, MD, Columbia University

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 hypothesis underlying this project is that co-administration of prebiotic galacto-oligosaccharides (GOS) and bovine lactoferrin (bLF) during iron supplementation will promote development of a beneficial, protective gut microbiota that will prevent iron-induced increases of opportunistic enteropathogens. 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. The period from 6 months to 1 year of age is vital both for iron nutrition and for the establishment of a healthy gut microbiome that promotes immune system development, local immune homeostasis and limits pathogen colonization. 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. This 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 with 5 mg iron (as sodium iron EDTA [2.5 mg] and ferrous fumarate [2.5 mg]) and (i) galacto-oligosaccharides (GOS; 7.5 mg), (ii) bovine lactoferrin (bLF, 1.0 g), (iii) GOS (7.5 mg) 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 microbiota composition, metabolic activity, and inflammatory potential in vitro with treatments paralleling those in Specific Aim 1, using immobilized fecal microbiota from Kenyan infants to inoculate a long-term continuous polyfermenter intestinal model, and cellular studies.

Condition or disease Intervention/treatment Phase
Iron-deficiency Dietary Supplement: Galacto-oligosaccharides Dietary Supplement: Bovine lactoferrin Dietary Supplement: Multiple micronutrient powders with 5 mg iron Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 288 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Stratified randomization will be carried out by the Trial Statistician using computer-generated randomly permuted blocks of size 2, 4 or 6 with stratification by gender and assignment of eligible infants to one of the 4 intervention groups using 4 color codes. Allocation will be known solely by the Trial Statistician and the Clinical Trial Safety Officer and concealed from all other study personnel.
Primary Purpose: Treatment
Official Title: Prebiotic GOS and Lactoferrin for Beneficial Gut Microbiota With Iron Supplements
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Study group A: GOS
This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA [2.5 mg] and ferrous fumarate [2.5 mg]) and galacto-oligosaccharides (GOS), 7.5 mg.
Dietary Supplement: Galacto-oligosaccharides
Galacto-oligosaccharides are classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration, are components of cow's milk and have been used repeatedly in clinical trials without adverse effects.

Dietary Supplement: Multiple micronutrient powders with 5 mg iron
The multiple micronutrient powders are composed of Vitamin A, 400 μg; Vitamin D, 5 μg; Tocopherol Equivalents, 5 mg; Thiamine, 0.5 mg; Riboflavin, 0.5 mg; Vitamin B6, 0.5 mg; Folic Acid, 90 μg; Niacin, 6 mg; Vitamin B12, 0.9 μg; Vitamin C, 30 mg; Copper, 0.56 mg; Iodine, 90 μg; Selenium, 17 μg; Zinc, 4.1 mg; Phytase, 190 FTU; Iron, 5 mg [(as Ferrous fumarate, 2.5 mg and sodium iron ethylenediaminetetraacetate (NaFeEDTA), 2.5 mg].

Active Comparator: Study group B: bLF
This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA [2.5 mg] and ferrous fumarate [2.5 mg]), bovine lactoferrin (bLF), 1.0 g.
Dietary Supplement: Bovine lactoferrin
Bovine lactoferrin is classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration, is a component of cow's milk and has been used repeatedly in clinical trials without adverse effects.

Dietary Supplement: Multiple micronutrient powders with 5 mg iron
The multiple micronutrient powders are composed of Vitamin A, 400 μg; Vitamin D, 5 μg; Tocopherol Equivalents, 5 mg; Thiamine, 0.5 mg; Riboflavin, 0.5 mg; Vitamin B6, 0.5 mg; Folic Acid, 90 μg; Niacin, 6 mg; Vitamin B12, 0.9 μg; Vitamin C, 30 mg; Copper, 0.56 mg; Iodine, 90 μg; Selenium, 17 μg; Zinc, 4.1 mg; Phytase, 190 FTU; Iron, 5 mg [(as Ferrous fumarate, 2.5 mg and sodium iron ethylenediaminetetraacetate (NaFeEDTA), 2.5 mg].

Active Comparator: Study group C: GOS + bLF
This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA [2.5 mg] and ferrous fumarate [2.5 mg]), galacto-oligosaccharides (GOS), 7.5 mg, and bovine lactoferrin (bLF), 1.0 g.
Dietary Supplement: Galacto-oligosaccharides
Galacto-oligosaccharides are classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration, are components of cow's milk and have been used repeatedly in clinical trials without adverse effects.

Dietary Supplement: Bovine lactoferrin
Bovine lactoferrin is classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration, is a component of cow's milk and has been used repeatedly in clinical trials without adverse effects.

Dietary Supplement: Multiple micronutrient powders with 5 mg iron
The multiple micronutrient powders are composed of Vitamin A, 400 μg; Vitamin D, 5 μg; Tocopherol Equivalents, 5 mg; Thiamine, 0.5 mg; Riboflavin, 0.5 mg; Vitamin B6, 0.5 mg; Folic Acid, 90 μg; Niacin, 6 mg; Vitamin B12, 0.9 μg; Vitamin C, 30 mg; Copper, 0.56 mg; Iodine, 90 μg; Selenium, 17 μg; Zinc, 4.1 mg; Phytase, 190 FTU; Iron, 5 mg [(as Ferrous fumarate, 2.5 mg and sodium iron ethylenediaminetetraacetate (NaFeEDTA), 2.5 mg].

Placebo Comparator: Study group D
This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA [2.5 mg] and ferrous fumarate [2.5 mg]) alone, with no galacto-oligosaccharides (GOS), and no bovine lactoferrin (bLF).
Dietary Supplement: Multiple micronutrient powders with 5 mg iron
The multiple micronutrient powders are composed of Vitamin A, 400 μg; Vitamin D, 5 μg; Tocopherol Equivalents, 5 mg; Thiamine, 0.5 mg; Riboflavin, 0.5 mg; Vitamin B6, 0.5 mg; Folic Acid, 90 μg; Niacin, 6 mg; Vitamin B12, 0.9 μg; Vitamin C, 30 mg; Copper, 0.56 mg; Iodine, 90 μg; Selenium, 17 μg; Zinc, 4.1 mg; Phytase, 190 FTU; Iron, 5 mg [(as Ferrous fumarate, 2.5 mg and sodium iron ethylenediaminetetraacetate (NaFeEDTA), 2.5 mg].




Primary Outcome Measures :
  1. Ratio of harmful to beneficial bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 1 month [ Time Frame: 1 month ]
    The primary outcome measure will be the ratio of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) to beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 1 month.


Secondary Outcome Measures :
  1. Ratio of harmful to beneficial bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 6 months [ Time Frame: 6 months ]
    A key secondary outcome measure will be the ratio of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) to beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 6 months.

  2. Ratio of harmful to beneficial bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 9 months [ Time Frame: 9 months ]
    A key secondary outcome measure will be the ratio of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) to beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 9 months.

  3. Microbiota composition as determined by quantitative polymerase chain reaction (qPCR). [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the microbiota composition among study groups as determined by quantitative polymerase chain reaction (qPCR)

  4. Diarrhea [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of diarrhea among study groups

  5. Malaria [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of malaria among study groups

  6. Anemia [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of anemia among study groups

  7. Iron deficiency [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of iron deficiency among study groups

  8. Iron deficiency anemia [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of iron deficiency anemia among study groups

  9. Inflammation [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of inflammation among study groups

  10. Respiratory tract infections [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of inflammation among study groups

  11. Other illnesses [ Time Frame: 1, 6 and 9 months ]
    A secondary outcome measure will be the prevalence of other illnesses among study groups



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Weeks to 27 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • vaginal 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
  • any history of infant antibiotic treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03866837


Contacts
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Contact: Gary M Brittenham, MD 212 305 7005 gmb31@columbia.edu
Contact: Zhezhen Jin 212 305 9404 zj7@cumc.columbia.edu

Locations
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Kenya
Jomo Kenyatta University of Agriculture and Technology Not yet recruiting
Nairobi, Kenya, 00200
Contact: Simon M Karanja, PhD    0675870001    Simon Karanja <skaranja@jkuat.ac.ke>   
Switzerland
Swiss Federal Institute of Technology (ETH Zürich) Not yet recruiting
Zürich, Switzerland, 8092
Contact: Michael B Zimmermann, MD    +41 44 632 86 57    michael.zimmermann@hest.ethz.ch   
Contact: Verena Jäger    +41 44 632 84 21    verena.jaeger@hest.ethz.ch   
Sponsors and Collaborators
Columbia University
Swiss Federal Institute of Technology (ETH Zürich)
Jomo Kenyatta University of Agriculture and Technology
Investigators
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Principal Investigator: Gary M Brittenham, MD Columbia University

Publications:

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Responsible Party: Gary M Brittenham, MD, Professor of Pediatrics and Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT03866837     History of Changes
Other Study ID Numbers: R01DK115449 ( U.S. NIH Grant/Contract )
First Posted: March 7, 2019    Key Record Dates
Last Update Posted: March 12, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gary M Brittenham, MD, Columbia University:
Iron-deficiency
Iron supplementation
Galacto-oligosaccharides
Lactoferrin
Ferrous fumarate
Clinical trial
Microbiome
PolyFermS
Polyfermenter intestinal model

Additional relevant MeSH terms:
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Anemia, Iron-Deficiency
Anemia, Hypochromic
Anemia
Hematologic Diseases
Iron Metabolism Disorders
Metabolic Diseases
Iron
Trace Elements
Ferrous fumarate
Micronutrients
Lactoferrin
Nutrients
Growth Substances
Physiological Effects of Drugs
Anti-Infective Agents