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Iron Supplementation and Intestinal Health

Primary Purpose

Anemia of Prematurity, Very Low Birth Weight Infant

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
2mg/kg/day Iron Sulfate
6 mg/kg/day Iron Sulfate
Sponsored by
University of South Florida
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Anemia of Prematurity focused on measuring intestinal dysbiosis

Eligibility Criteria

1 Day - 6 Months (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • <1500 g at birth, expected to live beyond 2 weeks, not yet started on oral iron supplementation (OIS), with mother at least 18 years of age, and parental consent.

Exclusion Criteria:

  • congenital intestinal defects, history of intestinal infection or perforation before OIS. Infants who require epogen for religious reason to prevent them from getting blood transfusions will be excluded from the study.

Sites / Locations

  • Tampa General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Low Iron Sulfate Supplementation

High Iron Sulfate Supplementation

Arm Description

Participants will be given 2 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study iron dose until 36 week corrected gestational age or discharge, whichever comes first.

Participants will be given 6 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study iron dose until 36 week corrected gestational age or discharge, whichever comes first.

Outcomes

Primary Outcome Measures

Change in stool bacterial percentages from before to after iron supplementation
Comparing the changes in the median percentages of stool bacteria between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron
Change in fecal calprotectin from before to after iron supplementation
Comparing the mean fecal calprotectin levels, an inflammatory stool biomarker, between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron.
Change in urine Claudin-3 and I-FABP from before to after iron supplementation
Comparing the mean urine claudin-3 and I-FABP levels, biomarkers for intestinal barrier function, between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron

Secondary Outcome Measures

Rate of auditory myelination
Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge.
Level of Iron storage
Comparing the mean Ferritin levels between the two groups at 4 weeks after birth

Full Information

First Posted
July 20, 2020
Last Updated
June 6, 2023
Sponsor
University of South Florida
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT04497012
Brief Title
Iron Supplementation and Intestinal Health
Official Title
Enteral Iron Supplementation and Intestinal Health in Preterm Infants
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 17, 2020 (Actual)
Primary Completion Date
November 30, 2024 (Anticipated)
Study Completion Date
July 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of South Florida
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a randomized double-blinded study of enteral iron supplementation in Very Low Birth Weight infants. The subjects will be randomized into low dose (2 mg/kg/day) and high dose (6 mg/kg/day) of daily iron supplementation. The primary outcomes are intestinal health including microbiome, inflammation, and barrier function.
Detailed Description
Infants and mothers will be recruited at a single academic level III NICU at Tampa General Hospital, Tampa, FL. Inclusion criteria infants: <1500 g at birth, expected to live beyond 2 weeks, not yet started on oral iron supplementation (OIS), and parental consent. Exclusion criteria infants: congenital intestinal defects, history of intestinal infection or perforation before OIS. Infants who require epogen for religious reason to prevent them from getting blood transfusions will be excluded from the study. Intervention: Participants will be randomized to either 6 mg/kg/day or 2 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study OIS doses until 36 week corrected gestational age or discharge, whichever comes first. Sample collection and testing: Stool and urine collection: We will collect weekly stool and urine samples non-invasively starting at enrollment until study completion. Samples will be collected from soiled diapers. Blood tests: We will collect C-reactive protein (CRP) and ferritin level at 4 weeks after birth at the same time as other routine labs (complete blood count, reticulocyte count, and liver function test). Monaural auditory brainstem response (ABR): for each ear will be performed at 36 weeks corrected gestational age or at discharge under the supervision of an audiologist who is blinded to the infants assigned iron doses and test results (stool microbiome, blood and urine tests). Monitoring: iron supplementation dose will be increased by 2 mg/kg/day if ferritin level <100 mg/dL and the dose will be held if ferritin level >400 mg/dL. Ferritin level will be rechecked every 2 weeks until normalized. Hematocrit and reticulocyte count will be monitored by the medical team.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anemia of Prematurity, Very Low Birth Weight Infant
Keywords
intestinal dysbiosis

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Randomize subjects to low and high dose iron supplementations
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The participants, care givers, medical teams, investigator, and outcome assessors are blinded from the iron treatment dose for the duration of the study. Only research pharmacists and members of the Data and Safety Monitor Board are unblinded during the study period. In an event when the medical team urgently needs to know the iron dose the participant is receiving for proper clinical management of the subject, the principal investigator or a designee will be notified by cell phone. Their contact information are located in the medical workrooms and the unit pharmacy. The principal investigator or the designee will immediately call the research pharmacy phone to request an emergency unblinding of that particular participant. The principal investigator will inform IRB and the sponsor of the unblinding event within 24 hours.
Allocation
Randomized
Enrollment
183 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Low Iron Sulfate Supplementation
Arm Type
Active Comparator
Arm Description
Participants will be given 2 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study iron dose until 36 week corrected gestational age or discharge, whichever comes first.
Arm Title
High Iron Sulfate Supplementation
Arm Type
Active Comparator
Arm Description
Participants will be given 6 mg/kg/day total of elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are at least 14 days old. The total iron doses will be provided by fortification of feeds and liquid iron sulfate and will be weight adjusted once a week. The participants will receive the study iron dose until 36 week corrected gestational age or discharge, whichever comes first.
Intervention Type
Drug
Intervention Name(s)
2mg/kg/day Iron Sulfate
Other Intervention Name(s)
Low dose iron supplementation
Intervention Description
Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.
Intervention Type
Drug
Intervention Name(s)
6 mg/kg/day Iron Sulfate
Other Intervention Name(s)
High dose iron supplementation
Intervention Description
Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.
Primary Outcome Measure Information:
Title
Change in stool bacterial percentages from before to after iron supplementation
Description
Comparing the changes in the median percentages of stool bacteria between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron
Time Frame
from baseline to 1 week and 2 weeks after iron supplementation started
Title
Change in fecal calprotectin from before to after iron supplementation
Description
Comparing the mean fecal calprotectin levels, an inflammatory stool biomarker, between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron.
Time Frame
from baseline to 1 week and 2 weeks after iron supplementation started
Title
Change in urine Claudin-3 and I-FABP from before to after iron supplementation
Description
Comparing the mean urine claudin-3 and I-FABP levels, biomarkers for intestinal barrier function, between the two groups. Change = post-iron (1 week, 2 weeks after iron and at discharge) - pre-iron
Time Frame
from baseline to 1 week and 2 weeks after iron supplementation started
Secondary Outcome Measure Information:
Title
Rate of auditory myelination
Description
Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge.
Time Frame
up to 36 weeks corrected gestational age
Title
Level of Iron storage
Description
Comparing the mean Ferritin levels between the two groups at 4 weeks after birth
Time Frame
at 4 weeks after birth

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: <1500 g at birth, expected to live beyond 2 weeks, not yet started on oral iron supplementation (OIS), with mother at least 18 years of age, and parental consent. Exclusion Criteria: congenital intestinal defects, history of intestinal infection or perforation before OIS. Infants who require epogen for religious reason to prevent them from getting blood transfusions will be excluded from the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marcia Kneusel
Phone
813-844-3395
Email
mkneusel@usf.edu
Facility Information:
Facility Name
Tampa General Hospital
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marcia Kneusel
Phone
813-844-3395

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
20817366
Citation
Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010 Nov;24(6):221-5. doi: 10.1016/j.blre.2010.08.001.
Results Reference
result
PubMed Identifier
22419305
Citation
Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database Syst Rev. 2012 Mar 14;(3):CD005095. doi: 10.1002/14651858.CD005095.pub2.
Results Reference
result
PubMed Identifier
20962160
Citation
Zimmermann MB, Chassard C, Rohner F, N'goran EK, Nindjin C, Dostal A, Utzinger J, Ghattas H, Lacroix C, Hurrell RF. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am J Clin Nutr. 2010 Dec;92(6):1406-15. doi: 10.3945/ajcn.110.004564. Epub 2010 Oct 20.
Results Reference
result
PubMed Identifier
25143342
Citation
Jaeggi T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, Boekhorst J, Timmerman HM, Swinkels DW, Tjalsma H, Njenga J, Mwangi A, Kvalsvig J, Lacroix C, Zimmermann MB. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015 May;64(5):731-42. doi: 10.1136/gutjnl-2014-307720. Epub 2014 Aug 20.
Results Reference
result
PubMed Identifier
28753958
Citation
Tang M, Frank DN, Hendricks AE, Ir D, Esamai F, Liechty E, Hambidge KM, Krebs NF. Iron in Micronutrient Powder Promotes an Unfavorable Gut Microbiota in Kenyan Infants. Nutrients. 2017 Jul 19;9(7):776. doi: 10.3390/nu9070776.
Results Reference
result
PubMed Identifier
23452586
Citation
Krebs NF, Sherlock LG, Westcott J, Culbertson D, Hambidge KM, Feazel LM, Robertson CE, Frank DN. Effects of different complementary feeding regimens on iron status and enteric microbiota in breastfed infants. J Pediatr. 2013 Aug;163(2):416-23. doi: 10.1016/j.jpeds.2013.01.024. Epub 2013 Feb 26.
Results Reference
result

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Iron Supplementation and Intestinal Health

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