Anemia of PrematurityPhase 4NCT04497012
Iron Supplementation and Intestinal Health
A Phase 4 study testing 2mg/kg/day Iron Sulfate and 6 mg/kg/day Iron Sulfate in people with Anemia of Prematurity and Very Low Birth Weight Infant, run by University of South Florida at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 day to 6 monthsHealthy volunteers can take part
- Conditions the study is for
- Anemia of Prematurity, Very Low Birth Weight Infant
- What is being tested?
- 2mg/kg/day Iron Sulfate and 6 mg/kg/day Iron Sulfate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 183 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Nov 2020to 31 Jul 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 6 months
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- <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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
Tampa General Hospital
Tampa, Florida, 33606
Marcia Kneusel, 813-844-3395
About this study
Official title: Enteral Iron Supplementation and Intestinal Health in Preterm Infants
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.
Read the 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.
- Being tested
- 2mg/kg/day Iron Sulfate, 6 mg/kg/day Iron Sulfate
- Keywords
- intestinal dysbiosis
- Medical subject headings
- Anemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
2mg/kg/day Iron SulfateDrug
Also called Low dose iron supplementation
Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.
6 mg/kg/day Iron SulfateDrug
Also called High dose iron supplementation
Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.
| Study group | Role | What they receive |
|---|---|---|
| Low Iron Sulfate Supplementation | Active comparator | 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. Receives: Drug: 2mg/kg/day Iron Sulfate |
| High Iron Sulfate Supplementation | Active comparator | 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. Receives: Drug: 6 mg/kg/day Iron Sulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: from baseline to 1 week and 2 weeks after iron supplementation started
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.
Measured: from baseline to 1 week and 2 weeks after iron supplementation started
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
Measured: from baseline to 1 week and 2 weeks after iron supplementation started
Secondary outcomes (2)
Rate of auditory myelination
Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge.
Measured: up to 36 weeks corrected gestational age
Level of Iron storage
Comparing the mean Ferritin levels between the two groups at 4 weeks after birth
Measured: at 4 weeks after birth
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Aug 2020
- Study start17 Nov 2020
- Primary completion30 Mar 2025 (estimated)
- Study completion31 Jul 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Anemia of PrematurityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomize subjects to low and high dose iron supplementations
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 183 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of South Florida
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Thao (Tina) Ho, University of South Florida
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04497012
- Sponsor's protocol ID
- Pro00041470
- Status last verified
- Jan 2024
- First submitted
- 20 Jul 2020
- Last updated
- 22 Jan 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010 Nov;24(6):221-5. doi: 10.1016/j.blre.2010.08.001.
PubMed 20817366Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD005095. doi: 10.1002/14651858.CD005095.pub2.
PubMed 22419305Zimmermann 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.
PubMed 20962160Jaeggi 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.
PubMed 25143342Tang 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.
PubMed 28753958Krebs 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.
PubMed 23452586Gibbons JA, Nelson RM, Dabrowski CN, Narkhede A, Szalacha LA, Kneusel ML, Maru JS, Huszar MR, Hoang LK, Schiavo V, Eddins AC, Georgieff MK, Neu J, Donovan SM, Groer MW, Ho TT. Enteral iron dose effect on iron storage, intestinal barrier, and gut microbiome in preterm infants: a randomized clinical trial. Am J Clin Nutr. 2026 Aug;124(2):101389. doi: 10.1016/j.ajcnut.2026.101389. Epub 2026 Jun 9.
PubMed 42264152
Study at a glance
From the registry record, last updated by the sponsor on 22 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Enteral Iron Supplementation and Intestinal Health in Preterm Infants
- ClinicalTrials.gov ID
- NCT04497012
- Acronym / sponsor ID
- Pro00041470
- Keywords
- intestinal dysbiosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 183 participants (estimated)
- Lead sponsor
- University of South FloridaUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 17 Nov 2020 (actual)
- Primary completion
- 30 Mar 2025 (estimated)
- Study completion
- 31 Jul 2025 (estimated)
- First posted
- 4 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomize subjects to low and high dose iron supplementations
| Arm | Type | Receives |
|---|---|---|
| Low Iron Sulfate Supplementation | Active comparator | Drug: 2mg/kg/day Iron SulfateParticipants 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. |
| High Iron Sulfate Supplementation | Active comparator | Drug: 6 mg/kg/day Iron SulfateParticipants 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. |
Who may qualify
- Ages
- 1 day to 6 months
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- <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.
Key exclusion criteria (1 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 2mg/kg/day Iron SulfateAlso: Low dose iron supplementationIron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds. | Drug | Low Iron Sulfate Supplementation |
| 6 mg/kg/day Iron SulfateAlso: High dose iron supplementationIron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds. | Drug | High Iron Sulfate Supplementation |
Primary outcome
Change in stool bacterial percentages from before to after iron supplementation
Time frame: from baseline to 1 week and 2 weeks after iron supplementation started
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
Time frame: from baseline to 1 week and 2 weeks after iron supplementation started
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
Time frame: from baseline to 1 week and 2 weeks after iron supplementation started
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
2 secondary outcomes
Rate of auditory myelination
Time frame: up to 36 weeks corrected gestational age
Level of Iron storage
Time frame: at 4 weeks after birth
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2025.
- Results publication: PubMed 20817366Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010 Nov;24(6):221-5. doi: 10.1016/j.blre.2010.08.001.
- Results publication: PubMed 22419305Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD005095. doi: 10.1002/14651858.CD005095.pub2.
- Results publication: PubMed 20962160Zimmermann 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 publication: PubMed 25143342Jaeggi 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 publication: PubMed 28753958Tang 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 publication: PubMed 23452586Krebs 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.
- Derived from this study: PubMed 42264152Gibbons JA, Nelson RM, Dabrowski CN, Narkhede A, Szalacha LA, Kneusel ML, Maru JS, Huszar MR, Hoang LK, Schiavo V, Eddins AC, Georgieff MK, Neu J, Donovan SM, Groer MW, Ho TT. Enteral iron dose effect on iron storage, intestinal barrier, and gut microbiome in preterm infants: a randomized clinical trial. Am J Clin Nutr. 2026 Aug;124(2):101389. doi: 10.1016/j.ajcnut.2026.101389. Epub 2026 Jun 9.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing 2mg/kg/day Iron Sulfate and 6 mg/kg/day Iron Sulfate in people with Anemia of Prematurity and Very Low Birth Weight Infant, run by University of South Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 22 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Marcia Kneusel (813-844-3395, mkneusel@usf.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in stool bacterial percentages from before to after iron supplementation (time frame: from baseline to 1 week and 2 weeks after iron supplementation started). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04497012, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2025.