<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/NCT03001479</url>
  </required_header>
  <id_info>
    <org_study_id>27563</org_study_id>
    <nct_id>NCT03001479</nct_id>
  </id_info>
  <brief_title>Noninferiority Trial of Liquid Human Milk Fortifier (HMF) Hydrolyzed Protein Versus Liquid HMF With Supplemental Liquid Protein</brief_title>
  <official_title>Extensively Hydrolyzed Liquid Human Milk Fortifier Versus Liquid Human Milk Fortifier With Supplemental Liquid Protein</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Louis University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St. Louis University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Breast milk is readily accepted as the ideal source of nutrition for almost all infants,&#xD;
      including premature or very low birth weight infants. However, these high-risk infants&#xD;
      require the addition of fortifiers to their milk in order to achieve sufficient levels of&#xD;
      calories, vitamins, and minerals for adequate growth. We are currently using a liquid human&#xD;
      milk fortifier which does not provide sufficient protein intake, requiring addition of a&#xD;
      liquid protein supplement. A new product has been released which provides sufficient protein&#xD;
      in the liquid HMF, without the acidification seen in previous products.&#xD;
&#xD;
      This is a prospective, randomized noninferiority study comparing the safety and efficacy of&#xD;
      the new HMF with additional protein to our current standard of adding additional protein&#xD;
      supplementation on top of the HMF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All infants admitted to the Neonatal Intensive Care Unit (NICU) at Cardinal Glennon at&#xD;
      gestational age &lt;32 weeks and birthweight &lt;1500g, and whose mothers intend to use breast milk&#xD;
      (maternal or donor) will be approached for study participation. Infants can be enrolled at&#xD;
      any point up until their feedings become fortified, typically around the 8th day of life.&#xD;
&#xD;
      Eligible infants whose parents consent for participation will be randomized to one of the two&#xD;
      study regimens. Sealed envelopes containing the subject treatment group will be prepared from&#xD;
      randomization schedules that are computer-generated using a pseudorandom permuted blocks&#xD;
      algorithm. Multiples will be randomized together to the same treatment group. The&#xD;
      randomization will be block stratified by birth weight (500-1000g and 1001-1500g). Infants&#xD;
      will have laboratory values to follow for signs of metabolic acidosis and nutritional status.&#xD;
      These labs (BMP, Magnesium, Phosphorous, Alkaline Phosphatase, and prealbumin) will be drawn&#xD;
      on study days 1, 15, and 30. Total blood volume for these labs is approximately 1.4 mL, and&#xD;
      may be obtained by venipuncture or heel stick. These labs are monitored for nutritional&#xD;
      sufficiency in very low birth weight infants already, the only change will be the timing that&#xD;
      the labs are obtained.&#xD;
&#xD;
      Infants will remain on their designated HMF until one of 3 different time points: 1) Infant&#xD;
      does not tolerate HMF and must be taken off, 2) Infant is no longer receiving breastmilk and&#xD;
      is transitioned to a premature formula, or 3) Infant is getting ready to go home and HMF is&#xD;
      removed from the feedings.&#xD;
&#xD;
      Hospitalization data will be collected on the infants until they are either discharged from&#xD;
      the NICU or until they reach 36 weeks corrected gestational age, whichever occurs first. Data&#xD;
      collected will include: birthweight, gestational age, gender, antenatal steroids, APGARs,&#xD;
      days of parenteral nutrition, day enteral feedings were initiated, daily enteral volume&#xD;
      intake, daily caloric and protein intake, day of HMF and/or liquid protein initiation. Lab&#xD;
      data will be recorded as noted above. Growth data will be recorded by daily weights and&#xD;
      weekly head circumferences and lengths. Intolerance will be assessed by incidence of feeding&#xD;
      intolerance, nil per os (NPO) time, change in diet due to intolerance, incidence of metabolic&#xD;
      acidosis, incidence of necrotizing enterocolitis, incidence of spontaneous intestinal&#xD;
      perforation, cause of death, and length of hospital stay. Data on NICU complications,&#xD;
      including late onset sepsis, retinopathy of prematurity, intraventricular hemorrhage,&#xD;
      bronchopulmonary dysplasia, and use of postnatal steroids (which can affect growth) will also&#xD;
      be recorded.&#xD;
&#xD;
      Neurodevelopmental data will be collected on the infants from their first Bayley evaluation&#xD;
      in the Nursery Follow-up clinic, usually performed at 15-18 months of age. We will record&#xD;
      cognitive, language, and motor scores. We will also collect information on therapy services&#xD;
      received, and incidence of blindness or deafness.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 13, 2017</start_date>
  <completion_date type="Actual">May 1, 2023</completion_date>
  <primary_completion_date type="Actual">May 1, 2020</primary_completion_date>
  <phase>N/A</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>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Weight gain, short term</measure>
    <time_frame>30 days</time_frame>
    <description>(grams) in first 30 days on HMF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Length, short term</measure>
    <time_frame>30 days</time_frame>
    <description>(cm) in first 30 days on HMF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Head circumference, short term</measure>
    <time_frame>30 days</time_frame>
    <description>(cm) in first 30 days on HMF</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Weight gain, long term</measure>
    <time_frame>36 weeks gestational age or time of hospital discharge</time_frame>
    <description>Weight (grams) at 36 weeks corrected gestational age or time of hospital discharge, whichever is first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length, long term</measure>
    <time_frame>36 weeks gestational age or time of hospital discharge</time_frame>
    <description>Length (cm) at 36 weeks corrected gestational age or time of hospital discharge, whichever is first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Head circumference, long term</measure>
    <time_frame>36 weeks gestational age or time of hospital discharge</time_frame>
    <description>Head circumference (cm) at 36 weeks corrected gestational age or time of hospital discharge, whichever is first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>feeding intolerance</measure>
    <time_frame>30 days</time_frame>
    <description>Signs of feeding intolerance, including loose stools, emesis, metabolic acidosis, necrotizing enterocolitis. Presence or absence of symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>neurodevelopmental outcomes</measure>
    <time_frame>18 months corrected gestational age</time_frame>
    <description>Bayley Scales of Infant Development III at 18 months of corrected gestational age</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">78</enrollment>
  <condition>Human Milk</condition>
  <condition>Premature Birth of Newborn</condition>
  <arm_group>
    <arm_group_label>Standard: Liquid HMF and liquid protein</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>This is our standard breast milk fortification in our NICU. One packet (5 mL) of Similac Human Milk Fortifier Concentrated Liquid is added to breast milk feedings when infants reach 100 ml/kg/day. A second packet is added the next day (10 mL total), to make 24 kcal/oz. After infants reach full feedings (160 ml/kg/d), 3 ml/kg of Similac Liquid Protein Fortifier is added (0.5 g/kg protein). This is increased to 6 ml/kg (1 g/kg protein) the next day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intervention: HMF Hydrolyzed Protein Concentrated Liquid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One packet (5 mL) of Similac Human Milk Fortifier Hydrolyzed Protein Concentrated Liquid is added to breast milk feedings when infants reach 100 ml/kg/day. A second packet is added the next day (10 mL total), to make 24 kcal/oz. Feedings then continue to be advanced to full volume (160 ml/kg/d).</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Similac Human Milk Fortifier Hydrolyzed Protein Concentrated Liquid</intervention_name>
    <description>HMF with additional hydrolyzed protein</description>
    <arm_group_label>Intervention: HMF Hydrolyzed Protein Concentrated Liquid</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Very low birth weight, premature infants admitted to the NICU at Cardinal Glennon&#xD;
&#xD;
          -  &lt;32 weeks gestational age and birthweight &lt;1500 grams&#xD;
&#xD;
          -  receiving maternal or donor breast milk&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Infants with an estimated gestational age &gt;32 weeks OR birthweight &gt;1500 grams&#xD;
&#xD;
          -  Infants who die before fortification of feedings&#xD;
&#xD;
          -  Infants receiving formula&#xD;
&#xD;
          -  Infants that did not receive feedings with HMF&#xD;
&#xD;
          -  Infants transferred to another hospital prior to discharge&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>2 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Catherine C Cibulskis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Louis University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cardinal Glennon Children's Medical Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 20, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>St. Louis University</investigator_affiliation>
    <investigator_full_name>Catherine Cibulskis, MD</investigator_full_name>
    <investigator_title>Assistant Professor of Pediatrics</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Premature Birth</mesh_term>
  </condition_browse>
  <!-- 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/NCT03001479
org study id: 27563
nct id: NCT03001479
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Breast milk is readily accepted as the ideal source of nutrition for almost all infants,
      including premature or very low birth weight infants. However, these high-risk infants
      require the addition of fortifiers to their milk in order to achieve sufficient levels of
      calories, vitamins, and minerals for adequate growth. We are currently using a liquid human
      milk fortifier which does not provide sufficient protein intake, requiring addition of a
      liquid protein supplement. A new product has been released which provides sufficient protein
      in the liquid HMF, without the acidification seen in previous products.

      This is a prospective, randomized noninferiority study comparing the safety and efficacy of
      the new HMF with additional protein to our current standard of adding additional protein
      supplementation on top of the HMF.
All infants admitted to the Neonatal Intensive Care Unit (NICU) at Cardinal Glennon at
      gestational age <32 weeks and birthweight <1500g, and whose mothers intend to use breast milk
      (maternal or donor) will be approached for study participation. Infants can be enrolled at
      any point up until their feedings become fortified, typically around the 8th day of life.

      Eligible infants whose parents consent for participation will be randomized to one of the two
      study regimens. Sealed envelopes containing the subject treatment group will be prepared from
      randomization schedules that are computer-generated using a pseudorandom permuted blocks
      algorithm. Multiples will be randomized together to the same treatment group. The
      randomization will be block stratified by birth weight (500-1000g and 1001-1500g). Infants
      will have laboratory values to follow for signs of metabolic acidosis and nutritional status.
      These labs (BMP, Magnesium, Phosphorous, Alkaline Phosphatase, and prealbumin) will be drawn
      on study days 1, 15, and 30. Total blood volume for these labs is approximately 1.4 mL, and
      may be obtained by venipuncture or heel stick. These labs are monitored for nutritional
      sufficiency in very low birth weight infants already, the only change will be the timing that
      the labs are obtained.

      Infants will remain on their designated HMF until one of 3 different time points: 1) Infant
      does not tolerate HMF and must be taken off, 2) Infant is no longer receiving breastmilk and
      is transitioned to a premature formula, or 3) Infant is getting ready to go home and HMF is
      removed from the feedings.

      Hospitalization data will be collected on the infants until they are either discharged from
      the NICU or until they reach 36 weeks corrected gestational age, whichever occurs first. Data
      collected will include: birthweight, gestational age, gender, antenatal steroids, APGARs,
      days of parenteral nutrition, day enteral feedings were initiated, daily enteral volume
      intake, daily caloric and protein intake, day of HMF and/or liquid protein initiation. Lab
      data will be recorded as noted above. Growth data will be recorded by daily weights and
      weekly head circumferences and lengths. Intolerance will be assessed by incidence of feeding
      intolerance, nil per os (NPO) time, change in diet due to intolerance, incidence of metabolic
      acidosis, incidence of necrotizing enterocolitis, incidence of spontaneous intestinal
      perforation, cause of death, and length of hospital stay. Data on NICU complications,
      including late onset sepsis, retinopathy of prematurity, intraventricular hemorrhage,
      bronchopulmonary dysplasia, and use of postnatal steroids (which can affect growth) will also
      be recorded.

      Neurodevelopmental data will be collected on the infants from their first Bayley evaluation
      in the Nursery Follow-up clinic, usually performed at 15-18 months of age. We will record
      cognitive, language, and motor scores. We will also collect information on therapy services
      received, and incidence of blindness or deafness.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: None (Open Label)
measure: Weight gain, short term
time frame: 30 days
description: (grams) in first 30 days on HMF
measure: Length, short term
time frame: 30 days
description: (cm) in first 30 days on HMF
measure: Head circumference, short term
time frame: 30 days
description: (cm) in first 30 days on HMF
measure: Weight gain, long term
time frame: 36 weeks gestational age or time of hospital discharge
description: Weight (grams) at 36 weeks corrected gestational age or time of hospital discharge, whichever is first
measure: Length, long term
time frame: 36 weeks gestational age or time of hospital discharge
description: Length (cm) at 36 weeks corrected gestational age or time of hospital discharge, whichever is first
measure: Head circumference, long term
time frame: 36 weeks gestational age or time of hospital discharge
description: Head circumference (cm) at 36 weeks corrected gestational age or time of hospital discharge, whichever is first
measure: feeding intolerance
time frame: 30 days
description: Signs of feeding intolerance, including loose stools, emesis, metabolic acidosis, necrotizing enterocolitis. Presence or absence of symptoms.
measure: neurodevelopmental outcomes
time frame: 18 months corrected gestational age
description: Bayley Scales of Infant Development III at 18 months of corrected gestational age
arm group label: Standard: Liquid HMF and liquid protein
arm group type: No Intervention
description: This is our standard breast milk fortification in our NICU. One packet (5 mL) of Similac Human Milk Fortifier Concentrated Liquid is added to breast milk feedings when infants reach 100 ml/kg/day. A second packet is added the next day (10 mL total), to make 24 kcal/oz. After infants reach full feedings (160 ml/kg/d), 3 ml/kg of Similac Liquid Protein Fortifier is added (0.5 g/kg protein). This is increased to 6 ml/kg (1 g/kg protein) the next day.
arm group label: Intervention: HMF Hydrolyzed Protein Concentrated Liquid
arm group type: Experimental
description: One packet (5 mL) of Similac Human Milk Fortifier Hydrolyzed Protein Concentrated Liquid is added to breast milk feedings when infants reach 100 ml/kg/day. A second packet is added the next day (10 mL total), to make 24 kcal/oz. Feedings then continue to be advanced to full volume (160 ml/kg/d).
intervention type: Dietary Supplement
intervention name: Similac Human Milk Fortifier Hydrolyzed Protein Concentrated Liquid
description: HMF with additional hydrolyzed protein
arm group label: Intervention: HMF Hydrolyzed Protein Concentrated Liquid
criteria: 
gender: All
minimum age: N/A
maximum age: 2 Weeks
healthy volunteers: No
last name: Catherine C Cibulskis, MD
role: Principal Investigator
affiliation: St. Louis University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: St. Louis University
investigator full name: Catherine Cibulskis, MD
investigator title: Assistant Professor of Pediatrics
mesh term: Premature Birth