<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/NCT03775785</url>
  </required_header>
  <id_info>
    <org_study_id>1/2018</org_study_id>
    <nct_id>NCT03775785</nct_id>
  </id_info>
  <brief_title>Targeted vs Standard Fortification of Breast Milk</brief_title>
  <official_title>Effect of Targeted vs Standard Fortification of Breast Milk on Growth and Development of Preterm Infants (≤ 32 Weeks): a Randomised Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Princess Anna Mazowiecka Hospital, Warsaw, Poland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medical University of Warsaw</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute of Mother and Child</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Princess Anna Mazowiecka Hospital, Warsaw, Poland</source>
  <oversight_info>
    <has_dmc>No</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>
      BACKGROUND:&#xD;
&#xD;
      Human milk (HM) is recommended for all very low birth infants (VLBW)). Breast-milk is highly&#xD;
      variable in nutrient content, failing to meet the nutritional demands of VLBW. Fortification&#xD;
      of HM is recommended to prevent extra-uterine growth retardation and associated poor&#xD;
      neurodevelopmental outcome. However, standard fortification with fixed dose multicomponent&#xD;
      fortifier does not account for the variability in milk composition. Targeted fortification is&#xD;
      a promising alternative and needs further investigation.&#xD;
&#xD;
      The aim of the study is to evaluate if targeted fortification of human milk may optimize&#xD;
      growth and development in preterm infants.&#xD;
&#xD;
      STUDY DESIGN:&#xD;
&#xD;
      Randomized single blind controlled trial.&#xD;
&#xD;
      METHODS &amp; ANALYSIS:&#xD;
&#xD;
      We will recruit preterm infants (≤ 32 weeks of gestation) within the first 7 days of life.&#xD;
      After reaching 80 ml/kg/day of enteral feeding, patients will be randomised to receive&#xD;
      standard fortification (HMF, Nutricia) or targeted fortification (modular components: Bebilon&#xD;
      Bialko, Nutricia - protein, Fantomalt, Nutricia - carbohydrates, Calogen, Nutricia - lipids).&#xD;
      The intervention will continue until 37 weeks of post-conception age, or hospital discharge.&#xD;
      Parents and outcome assessors will be blinded to the intervention.&#xD;
&#xD;
      The primary outcome - weight gain velocity will be measured starting from the day infants&#xD;
      regain their birth weight up to 4 weeks, then weekly until discharge.&#xD;
&#xD;
      Secondary outcomes such as neurodevelopment at 12 months of corrected age (CA) will be&#xD;
      assessed with Bayley Scale of Development III, repeated at 36 months of CA. Additionally a&#xD;
      Wescheler Preschool and Primary Scale of Intelligence IV test will be applied at 3,5 years of&#xD;
      CA. Secondary outcomes such as length and head growth, body composition will be assesed at&#xD;
      discharge and at 4 months. Incidence of necrotizing enterocolitis (NEC), sepsis, retinopathy&#xD;
      of prematurity (ROP) and bronchopulmonary dysplasia (BPD) will also be followed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design and setting This is a multi-centre superiority randomised parallel group, 1:1&#xD;
      allocation study. Patients will be recruited at three departments of neonatology and&#xD;
      intensive care units: Department of Neonatology and Neonatal Intensive Care, Division of&#xD;
      Neonatal Intensive Care (Medical University of Warsaw), and the Institute of Mother and&#xD;
      Child. Follow up will be carried out at the Department of Paediatrics.&#xD;
&#xD;
      The study is lead by the Department of Neonatology and Neonatal Intensive Care (KAROWA) with&#xD;
      approximately 3000 (100 ≤ 32 weeks of gestation) deliveries per year and 12 intensive care&#xD;
      and 40 high dependency neonatal beds.&#xD;
&#xD;
      Recruitment Recruitment will take place between June 2019 and December 2020. Parents of&#xD;
      infants born at less than 32 weeks of gestation will be approached within the first week of&#xD;
      life.&#xD;
&#xD;
      Randomisation After reaching 80 ml/kg/day of enteral feeding, patients will be randomised to&#xD;
      receive standard fortification (SF) or targeted fortification (TF) (proteins, lipids,&#xD;
      carbohydrates). Allocation will be performed electronically.&#xD;
&#xD;
      Interventions Human milk fortification procedure Milk fortification will be done twice a day&#xD;
      (8 am and 8 pm) for each following 12 hour nursing shift (Appendix 1).&#xD;
&#xD;
      A 10 mL aliquot from each batch of native breast milk will be used for macronutrient analysis&#xD;
      using a human milk analyser Miris® as per protocol. The remaining batch will first be&#xD;
      fortified with the standard fortifier. Macronutrient analysis will determine how much extra&#xD;
      fat, protein, and/or carbohydrate is needed to obtain target fortified breast milk.&#xD;
&#xD;
      An experienced laboratory technician will perform milk analysis in the neonatal intensive&#xD;
      care unit (NICU) research laboratory at KAROWA twice per week at 10:00 am (Monday/Friday)&#xD;
      from batches collected from the two previous days. Milk samples from other sites will be&#xD;
      delivered by medical transport in secure freezing containers at 8:00 am.&#xD;
&#xD;
      The mean of three measurements per batch (3 x 2-3ml) will be used to calculate the required&#xD;
      amount of extra fat, protein, and carbohydrate for the following 3 days of fortification&#xD;
      using a predefined Excel spread sheet (Microsoft Inc, Redmond, Washington). Milk analysis&#xD;
      will be performed in both treatment arms; however only the intervention group will receive&#xD;
      TF. Results, together with required amounts of macronutrients, will be emailed to the&#xD;
      participating centres before noon the same day.&#xD;
&#xD;
      The defined macronutrient concentration in breast milk is 4.4 g/100 mL of fat, 3 g/100 mL of&#xD;
      protein, and 8.8 g/ 100 mL of carbohydrate to meet the European Society for Paediatric&#xD;
      Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines (6.6 g/kg/d of fat, 4.5&#xD;
      g/kg/d of protein, and 13.2 g/kg/d of carbohydrate) assuming an intake of 150 mL/kg/d.&#xD;
&#xD;
      Target fortification will be done in 3 steps:&#xD;
&#xD;
        1. Determination of macronutrients concentration in own mothers´s milk (OMM)/human donor&#xD;
           milk (HDM).&#xD;
&#xD;
        2. Standard fortification (SF) (human milk fortifier - HMF).&#xD;
&#xD;
        3. Targeted fortification (TF): adding fat, protein, and/or carbohydrate to achieve target&#xD;
           levels of macronutrients.&#xD;
&#xD;
      In cases where a macronutrient component after SF will exceed the target value, only the&#xD;
      other deficient macronutrient components will be adjusted.&#xD;
&#xD;
      Safety Prescription of TF will be completed before noon. Bedside nurses will prepare batches&#xD;
      of fortified breast milk including the additives for TF.&#xD;
&#xD;
      Data from breast milk analyses, fortification, and enteral intake will be documented daily.&#xD;
      Acid base status, blood urea nitrogen (BUN), and glucose will be determined as per NICU&#xD;
      routine.&#xD;
&#xD;
      The intervention will continue until 37 weeks of post-conception age, or hospital discharge.&#xD;
      Parents and outcome assessors will be blinded to the intervention.&#xD;
&#xD;
      Randomization A study number together with the allocated treatment will be assigned by the&#xD;
      platform. Patient's data along with the result of the allocation will be sent to statistical&#xD;
      team. The randomisation list will remain with the statistical team for the whole duration of&#xD;
      the study. Randomisation will be conducted without any influence of the principal&#xD;
      investigators, clinicians, recruitment or follow up staff.&#xD;
&#xD;
      Blinding The decision to start fortification will be made by the attending physician blinded&#xD;
      to the intervention allocated. An employee outside the research team will feed data into the&#xD;
      computer in separate datasets so that the researchers can analyse data without having access&#xD;
      to information about the allocation.&#xD;
&#xD;
      Sample size The sample size required to compare two means in two-sided equality test was&#xD;
      estimated based on results from a prior double blind, randomised clinical trial,&#xD;
      investigating the effect of target fortification vs standard fortification of breast milk on&#xD;
      the changes of anthropometric parameters and body composition in preterm children. It was&#xD;
      determined, that a mean difference of weight gain 1.9 g/kg/day between groups would be&#xD;
      clinically important and feasible during intervention. between the study groups with a power&#xD;
      of 80% and α=0.05, a sample of 91 infants is needed in each study group. Allowing for 10% of&#xD;
      loss to follow-up, the target number of 200 premature infants will be recruited.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</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>
    <intervention_model_description>This is a multi-centre superiority randomised parallel group, 1:1 allocation study.&#xD;
After reaching 80 ml/kg/day of enteral feeding, patients will be randomised to receive standard fortification-SF (Bebilon HMF, Nutricia) or targeted fortification -TF (proteins, lipids,carbohydrates). Allocation will be performed electronically.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The decision to start fortification will be made by the attending physician blinded to the intervention allocated. An employee outside the research team will feed data into the computer in separate datasheets so that the researchers can analyse data without having access to information about the allocation.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Growth</measure>
    <time_frame>from birth at postmentrual age &lt;32 to up to 37 weeks of post-conceptional age</time_frame>
    <description>weight will be assessed every day.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Velocity of weight gain in grams</measure>
    <time_frame>from birth at postmentrual age &lt;32 to up to 37 weeks of post-conceptional age</time_frame>
    <description>weight will be assessed every day.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Neurodevelopmental outcome</measure>
    <time_frame>at 12 and 36 weeks of corrected age.</time_frame>
    <description>the number of infants with mental development index (MDI) Bayley Scale of Development III</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Necrotizing enterocolitis (NEC)</measure>
    <time_frame>from birth at postmentrual age &lt;32 to up to 37 weeks of post-gestational age</time_frame>
    <description>The number of patients NEC &gt;1 stage as defined by Bell's criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bronchopulmonary dysplasia (BPD)</measure>
    <time_frame>from 28 days at postmentrual age &lt;32 to up to 37 weeks of post gestational age</time_frame>
    <description>The number of patients with (BPD) defined as oxygen requirement of &gt; 21% at 28 days of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Late onset sepsis (LOS)</measure>
    <time_frame>from 72 hours of life at postmentrual age &lt;32 up to 37 weeks of post gestational age</time_frame>
    <description>The number of patients with LOS defined as a positive blood culture or a positive cerebral spinal fluid culture</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retinopathy of prematurity (ROP)</measure>
    <time_frame>from 3 weeks of life at postmentrual age &lt;32 to 37 weeks of post gestational age</time_frame>
    <description>The number of patients with ROP &gt; grade I as defined as the World Health Organisation criteria</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>BPD - Bronchopulmonary Dysplasia</condition>
  <condition>NEC - Necrotizing Enterocolitis</condition>
  <condition>Weight Gain</condition>
  <condition>VLBW - Very Low Birth Weight Infant</condition>
  <condition>ROP - Retinopathy of Prematurity</condition>
  <arm_group>
    <arm_group_label>tailored enteral nutrition</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tailored Human milk fortification procedure Tailored milk fortification will be done twice a day (8 am and 8 pm) for each following 12 hour nursing shift. Standard fortification will be added first. The remainder amount of protein, lipids and carbohydrates required to meet the recommended by ESPGHAN doses will be acheived by adding single ingrediant nutrients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>standard enteral nutrition</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard fortification will be added according to the unit protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Tailored enteral nutrition</intervention_name>
    <description>The mean of three measurements per batch (3 x 2-3ml) will be used to calculate the required amount of extra fat, protein, and carbohydrate for the following 3 days of fortification using a predefined Excel spread sheet (Microsoft Inc, Redmond, Washington).&#xD;
The intervention will consist of adding fat, protein, and/or carbohydrate to achieve target levels of macronutrients.&#xD;
The defined macronutrient concentration in breast milk is 4.4 g/100 mL of fat, 3 g/100 mL of protein, and 8.8 g/ 100 mL of carbohydrate to meet the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines (6.6 g/kg/d of fat, 4.5 g/kg/d of protein, and 13.2 g/kg/d of carbohydrate) assuming an intake of 150 mL/kg/d.</description>
    <arm_group_label>tailored enteral nutrition</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients eligible for the trial must comply with all of the following at randomization:&#xD;
&#xD;
          1. Gestational age at birth ≤ 32 weeks&#xD;
&#xD;
          2. Enteral feeding of at least 80ml/kg/day&#xD;
&#xD;
          3. Donor or maternal milk based enteral feeding (at least 50%)&#xD;
&#xD;
          4. Parenteral/legal guardian consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. &gt;50% formula based enteral feeding&#xD;
&#xD;
          2. Small for gestational age (birth weight &lt; 3rd percentile)&#xD;
&#xD;
          3. Congenital abnormalities which increase the risk of NEC&#xD;
&#xD;
          4. NEC&#xD;
&#xD;
          5. Withdrawal of feeding &gt; 7 days&#xD;
&#xD;
          6. Sepsis&#xD;
&#xD;
          7. Death&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>32 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Neonatology and Neonatal Intensive Care Warsaw Medical University</name>
      <address>
        <city>Warsaw</city>
        <zip>00-315</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joanna Seliga-Siwecka, MD PhD</last_name>
      <phone>+48225966155</phone>
      <email>seliga.joanna@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Joanna Seliga-Siwecka</last_name>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Division of Neonatology and Neonatal Intensive Care, 1st Department of Obstetrics and Gynaecology, The Medical University of Warsaw</name>
      <address>
        <city>Warszawa</city>
        <zip>02-015</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Justyna Romańska, MD</last_name>
      <phone>+48225830340</phone>
      <email>justyna_romanska@gazeta.pl</email>
    </contact>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>December 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>December 30, 2021</last_update_submitted>
  <last_update_submitted_qc>December 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Princess Anna Mazowiecka Hospital, Warsaw, Poland</investigator_affiliation>
    <investigator_full_name>Joanna Seliga-Siwecka</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>enteral nutrition</keyword>
  <keyword>fortification</keyword>
  <keyword>tailored enteral nutrition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enterocolitis</mesh_term>
    <mesh_term>Enterocolitis, Necrotizing</mesh_term>
    <mesh_term>Bronchopulmonary Dysplasia</mesh_term>
    <mesh_term>Retinopathy of Prematurity</mesh_term>
    <mesh_term>Body Weight</mesh_term>
    <mesh_term>Birth Weight</mesh_term>
    <mesh_term>Weight Gain</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Deidentified participation data will be available on request from the corresponding author. Data reuse will be permitted for meta-analysis.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Data will be available for 24 months after data analysis completion.</ipd_time_frame>
    <ipd_access_criteria>researchers</ipd_access_criteria>
  </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/NCT03775785
org study id: 1/2018
nct id: NCT03775785
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
BACKGROUND:

      Human milk (HM) is recommended for all very low birth infants (VLBW)). Breast-milk is highly
      variable in nutrient content, failing to meet the nutritional demands of VLBW. Fortification
      of HM is recommended to prevent extra-uterine growth retardation and associated poor
      neurodevelopmental outcome. However, standard fortification with fixed dose multicomponent
      fortifier does not account for the variability in milk composition. Targeted fortification is
      a promising alternative and needs further investigation.

      The aim of the study is to evaluate if targeted fortification of human milk may optimize
      growth and development in preterm infants.

      STUDY DESIGN:

      Randomized single blind controlled trial.

      METHODS & ANALYSIS:

      We will recruit preterm infants (≤ 32 weeks of gestation) within the first 7 days of life.
      After reaching 80 ml/kg/day of enteral feeding, patients will be randomised to receive
      standard fortification (HMF, Nutricia) or targeted fortification (modular components: Bebilon
      Bialko, Nutricia - protein, Fantomalt, Nutricia - carbohydrates, Calogen, Nutricia - lipids).
      The intervention will continue until 37 weeks of post-conception age, or hospital discharge.
      Parents and outcome assessors will be blinded to the intervention.

      The primary outcome - weight gain velocity will be measured starting from the day infants
      regain their birth weight up to 4 weeks, then weekly until discharge.

      Secondary outcomes such as neurodevelopment at 12 months of corrected age (CA) will be
      assessed with Bayley Scale of Development III, repeated at 36 months of CA. Additionally a
      Wescheler Preschool and Primary Scale of Intelligence IV test will be applied at 3,5 years of
      CA. Secondary outcomes such as length and head growth, body composition will be assesed at
      discharge and at 4 months. Incidence of necrotizing enterocolitis (NEC), sepsis, retinopathy
      of prematurity (ROP) and bronchopulmonary dysplasia (BPD) will also be followed.
Study design and setting This is a multi-centre superiority randomised parallel group, 1:1
      allocation study. Patients will be recruited at three departments of neonatology and
      intensive care units: Department of Neonatology and Neonatal Intensive Care, Division of
      Neonatal Intensive Care (Medical University of Warsaw), and the Institute of Mother and
      Child. Follow up will be carried out at the Department of Paediatrics.

      The study is lead by the Department of Neonatology and Neonatal Intensive Care (KAROWA) with
      approximately 3000 (100 ≤ 32 weeks of gestation) deliveries per year and 12 intensive care
      and 40 high dependency neonatal beds.

      Recruitment Recruitment will take place between June 2019 and December 2020. Parents of
      infants born at less than 32 weeks of gestation will be approached within the first week of
      life.

      Randomisation After reaching 80 ml/kg/day of enteral feeding, patients will be randomised to
      receive standard fortification (SF) or targeted fortification (TF) (proteins, lipids,
      carbohydrates). Allocation will be performed electronically.

      Interventions Human milk fortification procedure Milk fortification will be done twice a day
      (8 am and 8 pm) for each following 12 hour nursing shift (Appendix 1).

      A 10 mL aliquot from each batch of native breast milk will be used for macronutrient analysis
      using a human milk analyser Miris® as per protocol. The remaining batch will first be
      fortified with the standard fortifier. Macronutrient analysis will determine how much extra
      fat, protein, and/or carbohydrate is needed to obtain target fortified breast milk.

      An experienced laboratory technician will perform milk analysis in the neonatal intensive
      care unit (NICU) research laboratory at KAROWA twice per week at 10:00 am (Monday/Friday)
      from batches collected from the two previous days. Milk samples from other sites will be
      delivered by medical transport in secure freezing containers at 8:00 am.

      The mean of three measurements per batch (3 x 2-3ml) will be used to calculate the required
      amount of extra fat, protein, and carbohydrate for the following 3 days of fortification
      using a predefined Excel spread sheet (Microsoft Inc, Redmond, Washington). Milk analysis
      will be performed in both treatment arms; however only the intervention group will receive
      TF. Results, together with required amounts of macronutrients, will be emailed to the
      participating centres before noon the same day.

      The defined macronutrient concentration in breast milk is 4.4 g/100 mL of fat, 3 g/100 mL of
      protein, and 8.8 g/ 100 mL of carbohydrate to meet the European Society for Paediatric
      Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines (6.6 g/kg/d of fat, 4.5
      g/kg/d of protein, and 13.2 g/kg/d of carbohydrate) assuming an intake of 150 mL/kg/d.

      Target fortification will be done in 3 steps:

        1. Determination of macronutrients concentration in own mothers´s milk (OMM)/human donor
           milk (HDM).

        2. Standard fortification (SF) (human milk fortifier - HMF).

        3. Targeted fortification (TF): adding fat, protein, and/or carbohydrate to achieve target
           levels of macronutrients.

      In cases where a macronutrient component after SF will exceed the target value, only the
      other deficient macronutrient components will be adjusted.

      Safety Prescription of TF will be completed before noon. Bedside nurses will prepare batches
      of fortified breast milk including the additives for TF.

      Data from breast milk analyses, fortification, and enteral intake will be documented daily.
      Acid base status, blood urea nitrogen (BUN), and glucose will be determined as per NICU
      routine.

      The intervention will continue until 37 weeks of post-conception age, or hospital discharge.
      Parents and outcome assessors will be blinded to the intervention.

      Randomization A study number together with the allocated treatment will be assigned by the
      platform. Patient's data along with the result of the allocation will be sent to statistical
      team. The randomisation list will remain with the statistical team for the whole duration of
      the study. Randomisation will be conducted without any influence of the principal
      investigators, clinicians, recruitment or follow up staff.

      Blinding The decision to start fortification will be made by the attending physician blinded
      to the intervention allocated. An employee outside the research team will feed data into the
      computer in separate datasets so that the researchers can analyse data without having access
      to information about the allocation.

      Sample size The sample size required to compare two means in two-sided equality test was
      estimated based on results from a prior double blind, randomised clinical trial,
      investigating the effect of target fortification vs standard fortification of breast milk on
      the changes of anthropometric parameters and body composition in preterm children. It was
      determined, that a mean difference of weight gain 1.9 g/kg/day between groups would be
      clinically important and feasible during intervention. between the study groups with a power
      of 80% and α=0.05, a sample of 91 infants is needed in each study group. Allowing for 10% of
      loss to follow-up, the target number of 200 premature infants will be recruited.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a multi-centre superiority randomised parallel group, 1:1 allocation study.
After reaching 80 ml/kg/day of enteral feeding, patients will be randomised to receive standard fortification-SF (Bebilon HMF, Nutricia) or targeted fortification -TF (proteins, lipids,carbohydrates). Allocation will be performed electronically.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The decision to start fortification will be made by the attending physician blinded to the intervention allocated. An employee outside the research team will feed data into the computer in separate datasheets so that the researchers can analyse data without having access to information about the allocation.
measure: Growth
time frame: from birth at postmentrual age <32 to up to 37 weeks of post-conceptional age
description: weight will be assessed every day.
measure: Velocity of weight gain in grams
time frame: from birth at postmentrual age <32 to up to 37 weeks of post-conceptional age
description: weight will be assessed every day.
measure: Neurodevelopmental outcome
time frame: at 12 and 36 weeks of corrected age.
description: the number of infants with mental development index (MDI) Bayley Scale of Development III
measure: Necrotizing enterocolitis (NEC)
time frame: from birth at postmentrual age <32 to up to 37 weeks of post-gestational age
description: The number of patients NEC >1 stage as defined by Bell's criteria
measure: Bronchopulmonary dysplasia (BPD)
time frame: from 28 days at postmentrual age <32 to up to 37 weeks of post gestational age
description: The number of patients with (BPD) defined as oxygen requirement of > 21% at 28 days of life
measure: Late onset sepsis (LOS)
time frame: from 72 hours of life at postmentrual age <32 up to 37 weeks of post gestational age
description: The number of patients with LOS defined as a positive blood culture or a positive cerebral spinal fluid culture
measure: Retinopathy of prematurity (ROP)
time frame: from 3 weeks of life at postmentrual age <32 to 37 weeks of post gestational age
description: The number of patients with ROP > grade I as defined as the World Health Organisation criteria
arm group label: tailored enteral nutrition
arm group type: Experimental
description: Tailored Human milk fortification procedure Tailored milk fortification will be done twice a day (8 am and 8 pm) for each following 12 hour nursing shift. Standard fortification will be added first. The remainder amount of protein, lipids and carbohydrates required to meet the recommended by ESPGHAN doses will be acheived by adding single ingrediant nutrients.
arm group label: standard enteral nutrition
arm group type: No Intervention
description: Standard fortification will be added according to the unit protocol.
intervention type: Dietary Supplement
intervention name: Tailored enteral nutrition
description: The mean of three measurements per batch (3 x 2-3ml) will be used to calculate the required amount of extra fat, protein, and carbohydrate for the following 3 days of fortification using a predefined Excel spread sheet (Microsoft Inc, Redmond, Washington).
The intervention will consist of adding fat, protein, and/or carbohydrate to achieve target levels of macronutrients.
The defined macronutrient concentration in breast milk is 4.4 g/100 mL of fat, 3 g/100 mL of protein, and 8.8 g/ 100 mL of carbohydrate to meet the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines (6.6 g/kg/d of fat, 4.5 g/kg/d of protein, and 13.2 g/kg/d of carbohydrate) assuming an intake of 150 mL/kg/d.
arm group label: tailored enteral nutrition
criteria: 
gender: All
minimum age: N/A
maximum age: 32 Weeks
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
country: Poland
responsible party type: Principal Investigator
investigator affiliation: Princess Anna Mazowiecka Hospital, Warsaw, Poland
investigator full name: Joanna Seliga-Siwecka
investigator title: Principal Investigator
mesh term: Enterocolitis
mesh term: Enterocolitis, Necrotizing
mesh term: Bronchopulmonary Dysplasia
mesh term: Retinopathy of Prematurity
mesh term: Body Weight
mesh term: Birth Weight
mesh term: Weight Gain
sharing ipd: Yes
ipd description: Deidentified participation data will be available on request from the corresponding author. Data reuse will be permitted for meta-analysis.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Data will be available for 24 months after data analysis completion.
ipd access criteria: researchers