<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04497012</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00041470</org_study_id>
    <nct_id>NCT04497012</nct_id>
  </id_info>
  <brief_title>Iron Supplementation and Intestinal Health</brief_title>
  <official_title>Enteral Iron Supplementation and Intestinal Health in Preterm Infants</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of South Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of South Florida</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized double-blinded study of enteral iron supplementation in Very Low Birth&#xD;
      Weight infants. The subjects will be randomized into low dose (2 mg/kg/day) and high dose (6&#xD;
      mg/kg/day) of daily iron supplementation. The primary outcomes are intestinal health&#xD;
      including microbiome, inflammation, and barrier function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Infants and mothers will be recruited at a single academic level III NICU at Tampa General&#xD;
      Hospital, Tampa, FL. Inclusion criteria infants: &lt;1500 g at birth, expected to live beyond 2&#xD;
      weeks, not yet started on oral iron supplementation (OIS), and parental consent. Exclusion&#xD;
      criteria infants: congenital intestinal defects, history of intestinal infection or&#xD;
      perforation before OIS. Infants who require epogen for religious reason to prevent them from&#xD;
      getting blood transfusions will be excluded from the study.&#xD;
&#xD;
      Intervention: Participants will be randomized to either 6 mg/kg/day or 2 mg/kg/day total of&#xD;
      elemental iron once a day when they are consuming 150-160 ml/kg/day of enteral feeds and are&#xD;
      at least 14 days old. The total iron doses will be provided by fortification of feeds and&#xD;
      liquid iron sulfate and will be weight adjusted once a week. The participants will receive&#xD;
      the study OIS doses until 36 week corrected gestational age or discharge, whichever comes&#xD;
      first.&#xD;
&#xD;
      Sample collection and testing:&#xD;
&#xD;
        1. Stool and urine collection: We will collect weekly stool and urine samples&#xD;
           non-invasively starting at enrollment until study completion. Samples will be collected&#xD;
           from soiled diapers.&#xD;
&#xD;
        2. Blood tests: We will collect C-reactive protein (CRP) and ferritin level at 4 weeks&#xD;
           after birth at the same time as other routine labs (complete blood count, reticulocyte&#xD;
           count, and liver function test).&#xD;
&#xD;
        3. Monaural auditory brainstem response (ABR): for each ear will be performed at 36 weeks&#xD;
           corrected gestational age or at discharge under the supervision of an audiologist who is&#xD;
           blinded to the infants assigned iron doses and test results (stool microbiome, blood and&#xD;
           urine tests).&#xD;
&#xD;
      Monitoring: iron supplementation dose will be increased by 2 mg/kg/day if ferritin level &lt;100&#xD;
      mg/dL and the dose will be held if ferritin level &gt;400 mg/dL. Ferritin level will be&#xD;
      rechecked every 2 weeks until normalized. Hematocrit and reticulocyte count will be monitored&#xD;
      by the medical team.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 17, 2020</start_date>
  <completion_date type="Anticipated">July 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">November 30, 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomize subjects to low and high dose iron supplementations</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <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.&#xD;
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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in stool bacterial percentages from before to after iron supplementation</measure>
    <time_frame>from baseline to 1 week and 2 weeks after iron supplementation started</time_frame>
    <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</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in fecal calprotectin from before to after iron supplementation</measure>
    <time_frame>from baseline to 1 week and 2 weeks after iron supplementation started</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in urine Claudin-3 and I-FABP from before to after iron supplementation</measure>
    <time_frame>from baseline to 1 week and 2 weeks after iron supplementation started</time_frame>
    <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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of auditory myelination</measure>
    <time_frame>up to 36 weeks corrected gestational age</time_frame>
    <description>Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Level of Iron storage</measure>
    <time_frame>at 4 weeks after birth</time_frame>
    <description>Comparing the mean Ferritin levels between the two groups at 4 weeks after birth</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">183</enrollment>
  <condition>Anemia of Prematurity</condition>
  <condition>Very Low Birth Weight Infant</condition>
  <arm_group>
    <arm_group_label>Low Iron Sulfate Supplementation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Iron Sulfate Supplementation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>2mg/kg/day Iron Sulfate</intervention_name>
    <description>Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.</description>
    <arm_group_label>Low Iron Sulfate Supplementation</arm_group_label>
    <other_name>Low dose iron supplementation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6 mg/kg/day Iron Sulfate</intervention_name>
    <description>Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.</description>
    <arm_group_label>High Iron Sulfate Supplementation</arm_group_label>
    <other_name>High dose iron supplementation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  &lt;1500 g at birth, expected to live beyond 2 weeks, not yet started on oral iron&#xD;
             supplementation (OIS), with mother at least 18 years of age, and parental consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  congenital intestinal defects, history of intestinal infection or perforation before&#xD;
             OIS. Infants who require epogen for religious reason to prevent them from getting&#xD;
             blood transfusions will be excluded from the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Day</minimum_age>
    <maximum_age>6 Months</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Marcia Kneusel</last_name>
    <phone>813-844-3395</phone>
    <email>mkneusel@usf.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Tampa General Hospital</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33606</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marcia Kneusel</last_name>
      <phone>813-844-3395</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <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.</citation>
    <PMID>20817366</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>22419305</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>20962160</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>25143342</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>28753958</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>23452586</PMID>
  </results_reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 31, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2020</study_first_posted>
  <last_update_submitted>June 6, 2023</last_update_submitted>
  <last_update_submitted_qc>June 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of South Florida</investigator_affiliation>
    <investigator_full_name>Thao (Tina) Ho</investigator_full_name>
    <investigator_title>Neonatologist</investigator_title>
  </responsible_party>
  <keyword>intestinal dysbiosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Birth Weight</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Iron</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04497012
org study id: Pro00041470
nct id: NCT04497012
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
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:

        1. 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.

        2. 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).

        3. 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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomize subjects to low and high dose iron supplementations
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.
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
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
measure: Change in fecal calprotectin from before to after iron supplementation
time frame: from baseline to 1 week and 2 weeks after iron supplementation started
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.
measure: 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
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
measure: Rate of auditory myelination
time frame: up to 36 weeks corrected gestational age
description: Comparing the mean auditory latency levels between the two groups at 36 weeks corrected gestational age or at discharge.
measure: Level of Iron storage
time frame: at 4 weeks after birth
description: Comparing the mean Ferritin levels between the two groups at 4 weeks after birth
arm group label: Low Iron Sulfate Supplementation
arm group type: Active Comparator
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 group label: High Iron Sulfate Supplementation
arm group type: Active Comparator
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: 2mg/kg/day Iron Sulfate
description: Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.
arm group label: Low Iron Sulfate Supplementation
other name: Low dose iron supplementation
intervention type: Drug
intervention name: 6 mg/kg/day Iron Sulfate
description: Iron Sulfate will be given in liquid form via nasal or oral gastric tube with feeds.
arm group label: High Iron Sulfate Supplementation
other name: High dose iron supplementation
criteria: 
gender: All
minimum age: 1 Day
maximum age: 6 Months
healthy volunteers: Accepts Healthy Volunteers
last name: Marcia Kneusel
phone: 813-844-3395
email: mkneusel@usf.edu
facility: 
status: Recruiting
contact: 
country: United States
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.
PMID: 20817366
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.
PMID: 22419305
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.
PMID: 20962160
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.
PMID: 25143342
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.
PMID: 28753958
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.
PMID: 23452586
responsible party type: Principal Investigator
investigator affiliation: University of South Florida
investigator full name: Thao (Tina) Ho
investigator title: Neonatologist
mesh term: Birth Weight
mesh term: Iron
sharing ipd: No