<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/NCT03797157</url>
  </required_header>
  <id_info>
    <org_study_id>RegionOstergotland</org_study_id>
    <nct_id>NCT03797157</nct_id>
  </id_info>
  <brief_title>Human Milk Fortification in Extremely Preterm Infants</brief_title>
  <acronym>N-forte</acronym>
  <official_title>Nordic Study on Human Milk Fortification in Extremely Preterm Infants: a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thomas Abrahamsson, MD, PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sahlgrenska University Hospital, Sweden</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Region Uppsala</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Vasterbottens lans landsting</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Prolacta Bioscience</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Region Stockholm</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ostergotland County Council, Sweden</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>
      This is a randomised controlled multi-centre trial comparing the effect of diet&#xD;
      supplementation of a human breast milk-based nutrient fortifier (H2MF®) with standard bovine&#xD;
      protein-based nutrient fortifier in 222 extremely preterm infants (born before gestational&#xD;
      week 28+0) exclusively fed with human breast milk (own mother´s milk and/or donor milk). The&#xD;
      infants will be randomised to receive either the human breast-milk based H2MF® or the&#xD;
      standard bovine protein-based nutrient fortifier when oral feeds have reached &lt;100 ml/kg/day.&#xD;
&#xD;
      The randomised intervention, stratified by centre, will continue until the target gestational&#xD;
      week 34+0. The infant must not be fed with formula during the intervention period. The&#xD;
      allocation will be concealed before inclusion, but after randomisation the study is not&#xD;
      blinded.&#xD;
&#xD;
      Primary endpoint of the intervention is the composite variable necrotizing enterocolitis&#xD;
      (NEC), sepsis and mortality.&#xD;
&#xD;
      The enrolled infants are characterised with clinical data including growth, feeding&#xD;
      intolerance, use of enteral and parenteral nutrition, treatment, antibiotics and&#xD;
      complications collected daily in a study specific case report form from birth until discharge&#xD;
      from the hospital (not longer than gestational week 44+0). A follow up focusing on&#xD;
      neurological development, growth and feeding problems will be performed at 2 years of age&#xD;
      (corrected) and 5.5 years of age.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomised controlled multi-centre trial comparing the effect of diet&#xD;
      supplementation of a human breast milk-based nutrient fortifier (H2MF®) with standard bovine&#xD;
      protein-based nutrient fortifier in 222 extremely preterm infants (born before gestational&#xD;
      week 28+0) exclusively fed with human breast milk (own mother´s milk and/or donor milk). The&#xD;
      infants will be randomised to receive either the human breast-milk based H2MF® or the&#xD;
      standard bovine protein-based nutrient fortifier when oral feeds have reached &lt;100 ml/kg/day.&#xD;
      If fortification with extra enteral lipids is needed during the intervention period, the&#xD;
      infants receiving H2MF® will be supplemented with the human milk-based Prolact CR®, while the&#xD;
      infants receiving standard bovine protein-based fortification will be supplemented with the&#xD;
      standard lipid products used at the unit. The study subject will be enrolled at level III&#xD;
      neonatal intensive care unit (NICU)s. Only infants with a home clinic with the logistics to&#xD;
      maintain the intervention until gestational week 34+0 will be included.&#xD;
&#xD;
      The randomised intervention, stratified by centre, will continue until the target gestational&#xD;
      week 34+0. The infant must not be fed with formula during the intervention period. The&#xD;
      allocation will be concealed before inclusion, but after randomisation the study is not&#xD;
      blinded. It would not be possible to prescribe the fortifier and prepare of the breast milk&#xD;
      in a blinded fashion, since the fortifiers are not exactly equal in nutrient content and also&#xD;
      look different. Instead the assessment of several of the outcomes will be made blinded, such&#xD;
      as the assessment of X-ray images in NEC cases.&#xD;
&#xD;
      The enrolled infants are characterised with clinical data including growth, feeding&#xD;
      intolerance, use of enteral and parenteral nutrition, treatment, antibiotics and&#xD;
      complications collected daily in a study specific case report form from birth until discharge&#xD;
      from the hospital (not longer than gestational week 44+0). A follow up focusing on&#xD;
      neurological development, growth and feeding problems will be performed at 2 years of age&#xD;
      (corrected).&#xD;
&#xD;
      Since it is often difficult to distinguish between the diagnoses of NEC and sepsis, and their&#xD;
      clinical consequences, the investigator's primary endpoint of the intervention is the&#xD;
      composite variable NEC, sepsis and mortality. Secondary endpoints are feeding intolerance and&#xD;
      other severe complication such as Bronchopulmonary dysplasia (BPD), Retinopathy of&#xD;
      prematurity (ROP) and neurological impairment. Stool, urine and blood samples are also&#xD;
      collected for microbiology, metabolomic and immunology analysis in order to study underlying&#xD;
      mechanisms. Health economic analyses will be made to evaluate the costs and benefits of an&#xD;
      introduction of human milk-based fortifier in NICUs in the Nordic countries.&#xD;
&#xD;
      Analyses will be conducted using an intention to treat approach. An evaluation will be&#xD;
      performed when 20 infants have been included to evaluate feasibility and make it possible to&#xD;
      adjust the protocol for the remaining part of the study. Safety analyses will be performed by&#xD;
      an independent data and safety monitoring board (DSMB) when 50, 100 and 150 infants have been&#xD;
      included. A sample size re-estimation will be made by an independent statistician when 150&#xD;
      infants have been included. Thus, the definitive sample size might be increased (never&#xD;
      decreased) based on this interim analysis. The study can be terminated before 322 infants&#xD;
      have been enrolled based on a decision of the sponsor and the DSMB, if the primary outcome is&#xD;
      significantly lower (with a significance level &lt;0.001) in the H2MF® than in the standard&#xD;
      fortification group in the interim analysis made after 150 infants have completed the&#xD;
      neonatal period. The study subject will be enrolled at level III NICUs in the Nordic&#xD;
      Countries. All study subjects will be followed during the neonatal period until discharge&#xD;
      (not longer than gestational week 44+0) and also be included in a follow up at 2 and 5.5&#xD;
      years of age based on the national follow up program for extremely preterm infants.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2027</completion_date>
  <primary_completion_date type="Actual">September 1, 2022</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The incidence of the composite of necrotizing enterocolitis, culture-proven sepsis and mortality</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>An infant should have had any of these diagnoses to fulfil the criterion</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The incidence of the composite of necrotizing enterocolitis and culture-proven sepsis</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>An infant should have had any of these diagnoses to fulfil the criterion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of the composite of necrotizing enterocolitis culture-proven sepsis, bronchopulmonary dysplasia, retinopathy of prematurity and mortality (Mortality and morbidity index)</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>An infant should have had any of these diagnoses to fulfil the criterion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach full enteral feeds</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>The day of life the infant has received at least 150 mL/kg enteral feeds</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of feeding interruptions</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>Number of days feedings held for ≥12 hours or feeds reduced by &gt;50% (ml/kg/d) not due to a clinical procedure or transitioning to the breast</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Numbers of days with parenteral nutrition</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>Number of days of parental amino acid and/or lipid infusion. Only days when the enteral feed &lt;150mL/kg/day should be included</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of large gastric aspirates per day</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
    <description>≥100% pre-feed volume (2 hours feeding volume if continuous feeding). Lower limit=2 ml/kg.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stool frequency</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to regain birth weight</measure>
    <time_frame>From birth until discharge from hospital (but not longer than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in head circumference in centimeters</measure>
    <time_frame>At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in weight in gram</measure>
    <time_frame>At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in length in centimeters</measure>
    <time_frame>At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The mortality incidence</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of necrotising enterocolitis: Bell´s stage II-III</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence spontaneous intestinal perforation</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of abdominal surgery</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence culture-proven sepsis</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of suspected sepsis, not culture-proven</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of pneumonia</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>Pathological X-ray confirmed by an independent radiologist, need of increased respiratory support/oxygen and laboratory inflammatory response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of bronchopulmonary dysplasia</measure>
    <time_frame>At gestational week 36+0</time_frame>
    <description>Need of extra oxygen, continuous positive air pressure (CPAP) or ventilator at gestational week 36+0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of retinopathy of the prematurity</measure>
    <time_frame>From birth until gestational week 42+0</time_frame>
    <description>Classified into stage I-V. The diagnosis is set after gestational week 42+0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of intraventricular haemorrhage</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>Classified into grade I-IV according to Papile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of periventricular leukomalacia</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>Criteria according to de Vries</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days with intensive care</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>Need of respirator or CPAP until discharge (not later than gestational week 44+0).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay at the hospital</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>Gestational week and day at discharge (not later than gestational week 44+0).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of need of feeding tube</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>Gestational week and day when the infant does not need it anymore (not later than gestational week 44+0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive development at 2 years</measure>
    <time_frame>At 2 years of age</time_frame>
    <description>Bayleys III, PARCA-R (Parental Report of Children´s Abilities-Revised) and ASQ-3 (Ages and stages questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of cerebral palsy at 2 years</measure>
    <time_frame>At 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of epilepsy at 2 years</measure>
    <time_frame>At 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of squint and/or impaired vision at 2 years</measure>
    <time_frame>At 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of impaired hearing at 2 years</measure>
    <time_frame>At 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of infants needing extra oxygen and/or ventilatory support after discharge from the hospital at the neonatal period</measure>
    <time_frame>From gestational week 44 until 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of wheeze and/or asthma</measure>
    <time_frame>From birth until 2 years of life</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of severe infections after discharge from the neonatal unit</measure>
    <time_frame>From gestational week 44 until 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of infants needing feeding tube after discharge from the hospital at the neonatal period</measure>
    <time_frame>From gestational week 44 until 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of infants needing extra nutritional support after discharge from the hospital at the neonatal period</measure>
    <time_frame>From gestational week 44 until 2 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of neurocognitive development at 5.5 years</measure>
    <time_frame>At 5.5 years of age</time_frame>
    <description>Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI-IV TM) and Movement ABC-2: the total scale points as well as the points of sub scales (motor, cognitive, language) will be presented. The prevalence of infants with a realist below 2 standard deviations will be defined to have mental retardation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of cerebral palsy at 5.5 years</measure>
    <time_frame>At 5.5 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of epilepsy at 5.5 years of age</measure>
    <time_frame>At 5.5 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of squint and/or impaired vision at 5.5 years of age</measure>
    <time_frame>At 5.5 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of children with impaired hearing at 5.5 years of age</measure>
    <time_frame>At 5.5 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The prevalence of wheeze and/or asthma at 5.5 years of age</measure>
    <time_frame>At 5.5 years of age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microbiome composition in stool samples</measure>
    <time_frame>At 1, 2, 3 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>The relative abundance and diversity of microbial taxa will be analyses with next generation sequencing and be related till the study intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of subclasses of T and B cells and granulocytes in blood samples</measure>
    <time_frame>At 1, 2 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>T helper subsets (TH1, Th2, TH17, Treg), T cells subsets associated with the intestinal mucosa (gamma/delta-T cells, MAIT cells) and neutrophils will be assessed using masscytometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of immune markers in plasma</measure>
    <time_frame>At 1, 2 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>Pre planned analyses are anti-inflammatory (e.g. IL-10) and proinflammatory (e.g. TNF) cytokines and chemokines (e.g. CXCL11, CCL18).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of growth factors in plasma samples</measure>
    <time_frame>At 1, 2 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>The levels of growth factors such as IGF-1 and the associated IGFBP-3 will be analysed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of lipids in plasma samples</measure>
    <time_frame>At 1, 2 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>Fatty acids in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of neurotransmitters in plasma samples</measure>
    <time_frame>At 1, 2 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>Neurotransmitters such as GABA and serotonin in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of metabolic peptides in urine samples</measure>
    <time_frame>At 1, 2, 3 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>Metabolic peptide will be measured with proton nuclear magnetic resonance spectroscopy (NMR), liquid chromatography (LC) and mass spectroscopy couple to gas chromatography (GC-MC).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of markers of central nervous system (CNS) damage in plasma samples</measure>
    <time_frame>At 1, 2 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>Markers of CNS damage such as neurofilament light protein will be measured in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of proteins in breast milk samples</measure>
    <time_frame>At 1, 2, 3 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>Protein composition will be measured with multiplex methods</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of human milk oligosaccharides in breast milk samples</measure>
    <time_frame>At 1, 2, 3 and 4 weeks of age and gestational week 36+0</time_frame>
    <description>The levels of human milk oligosaccharides will be measured with high-performance anion-exchange chromatography with pulsed amperometric detection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health care costs</measure>
    <time_frame>From birth until discharge from hospital (but not loner than gestational week 44+0)</time_frame>
    <description>The number of days at each level of care will be recorded until discharge from the hospital (not longer than gestational week 44+0). The cost will be calculated by multiplying the number of days at each level of care by the average cost</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">229</enrollment>
  <condition>Necrotizing Enterocolitis</condition>
  <condition>Sepsis</condition>
  <condition>Mortality</condition>
  <arm_group>
    <arm_group_label>H2MF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Human milk-based breast milk fortifier</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard fortifier</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard care: bovine milk-based breast milk fortifier</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>H2MF</intervention_name>
    <description>H2MF is a human milk-based breastmilk fortifier for preterm infants</description>
    <arm_group_label>H2MF</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Bovine milk-based fortifier</intervention_name>
    <description>Bovine milk-based fortifier is the standard breast milk fortifier in Sweden</description>
    <arm_group_label>Standard fortifier</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Gestational age at birth 22+0-27+6: based on prenatal ultrasonography.&#xD;
&#xD;
          -  Enteral feeds &lt; 100 mL/kg/day at the day of randomisation.&#xD;
&#xD;
          -  Written informed consent from the legal guardians of the infant.&#xD;
&#xD;
          -  The home clinic of the infant has the logistics of maintaining the intervention until&#xD;
             gestational week 34+0&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lethal or complicated malformation known at the time of inclusion&#xD;
&#xD;
          -  Chromosomal anomalies known at the time of inclusion&#xD;
&#xD;
          -  No realistic hope for survival at the time of inclusion&#xD;
&#xD;
          -  Gastrointestinal malformation known at the time of inclusion&#xD;
&#xD;
          -  Abdominal surgery before the time of inclusion&#xD;
&#xD;
          -  Participation in another intervention trial aiming at having an effect on growth,&#xD;
             nutrition, feeding intolerance or severe complications such as NEC and sepsis&#xD;
&#xD;
          -  Infants having nutrient fortifier or formula prior to randomisation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas R Abrahamsson, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Region Östergötland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Queen Silvia Children´s Hospital</name>
      <address>
        <city>Göteborg</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Crown Princess Victoria Children´s Hospital</name>
      <address>
        <city>Linköping</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norrlands Universitetssjukhus</name>
      <address>
        <city>Umeå</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Akademiska Barnsjukhuset</name>
      <address>
        <city>Uppsala</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>January 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>December 12, 2022</last_update_submitted>
  <last_update_submitted_qc>December 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Ostergotland County Council, Sweden</investigator_affiliation>
    <investigator_full_name>Thomas Abrahamsson, MD, PhD</investigator_full_name>
    <investigator_title>Principal Investigator, MD PhD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enterocolitis</mesh_term>
    <mesh_term>Enterocolitis, Necrotizing</mesh_term>
  </condition_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/NCT03797157
org study id: RegionOstergotland
nct id: NCT03797157
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a randomised controlled multi-centre trial comparing the effect of diet
      supplementation of a human breast milk-based nutrient fortifier (H2MF®) with standard bovine
      protein-based nutrient fortifier in 222 extremely preterm infants (born before gestational
      week 28+0) exclusively fed with human breast milk (own mother´s milk and/or donor milk). The
      infants will be randomised to receive either the human breast-milk based H2MF® or the
      standard bovine protein-based nutrient fortifier when oral feeds have reached <100 ml/kg/day.

      The randomised intervention, stratified by centre, will continue until the target gestational
      week 34+0. The infant must not be fed with formula during the intervention period. The
      allocation will be concealed before inclusion, but after randomisation the study is not
      blinded.

      Primary endpoint of the intervention is the composite variable necrotizing enterocolitis
      (NEC), sepsis and mortality.

      The enrolled infants are characterised with clinical data including growth, feeding
      intolerance, use of enteral and parenteral nutrition, treatment, antibiotics and
      complications collected daily in a study specific case report form from birth until discharge
      from the hospital (not longer than gestational week 44+0). A follow up focusing on
      neurological development, growth and feeding problems will be performed at 2 years of age
      (corrected) and 5.5 years of age.
This is a randomised controlled multi-centre trial comparing the effect of diet
      supplementation of a human breast milk-based nutrient fortifier (H2MF®) with standard bovine
      protein-based nutrient fortifier in 222 extremely preterm infants (born before gestational
      week 28+0) exclusively fed with human breast milk (own mother´s milk and/or donor milk). The
      infants will be randomised to receive either the human breast-milk based H2MF® or the
      standard bovine protein-based nutrient fortifier when oral feeds have reached <100 ml/kg/day.
      If fortification with extra enteral lipids is needed during the intervention period, the
      infants receiving H2MF® will be supplemented with the human milk-based Prolact CR®, while the
      infants receiving standard bovine protein-based fortification will be supplemented with the
      standard lipid products used at the unit. The study subject will be enrolled at level III
      neonatal intensive care unit (NICU)s. Only infants with a home clinic with the logistics to
      maintain the intervention until gestational week 34+0 will be included.

      The randomised intervention, stratified by centre, will continue until the target gestational
      week 34+0. The infant must not be fed with formula during the intervention period. The
      allocation will be concealed before inclusion, but after randomisation the study is not
      blinded. It would not be possible to prescribe the fortifier and prepare of the breast milk
      in a blinded fashion, since the fortifiers are not exactly equal in nutrient content and also
      look different. Instead the assessment of several of the outcomes will be made blinded, such
      as the assessment of X-ray images in NEC cases.

      The enrolled infants are characterised with clinical data including growth, feeding
      intolerance, use of enteral and parenteral nutrition, treatment, antibiotics and
      complications collected daily in a study specific case report form from birth until discharge
      from the hospital (not longer than gestational week 44+0). A follow up focusing on
      neurological development, growth and feeding problems will be performed at 2 years of age
      (corrected).

      Since it is often difficult to distinguish between the diagnoses of NEC and sepsis, and their
      clinical consequences, the investigator's primary endpoint of the intervention is the
      composite variable NEC, sepsis and mortality. Secondary endpoints are feeding intolerance and
      other severe complication such as Bronchopulmonary dysplasia (BPD), Retinopathy of
      prematurity (ROP) and neurological impairment. Stool, urine and blood samples are also
      collected for microbiology, metabolomic and immunology analysis in order to study underlying
      mechanisms. Health economic analyses will be made to evaluate the costs and benefits of an
      introduction of human milk-based fortifier in NICUs in the Nordic countries.

      Analyses will be conducted using an intention to treat approach. An evaluation will be
      performed when 20 infants have been included to evaluate feasibility and make it possible to
      adjust the protocol for the remaining part of the study. Safety analyses will be performed by
      an independent data and safety monitoring board (DSMB) when 50, 100 and 150 infants have been
      included. A sample size re-estimation will be made by an independent statistician when 150
      infants have been included. Thus, the definitive sample size might be increased (never
      decreased) based on this interim analysis. The study can be terminated before 322 infants
      have been enrolled based on a decision of the sponsor and the DSMB, if the primary outcome is
      significantly lower (with a significance level <0.001) in the H2MF® than in the standard
      fortification group in the interim analysis made after 150 infants have completed the
      neonatal period. The study subject will be enrolled at level III NICUs in the Nordic
      Countries. All study subjects will be followed during the neonatal period until discharge
      (not longer than gestational week 44+0) and also be included in a follow up at 2 and 5.5
      years of age based on the national follow up program for extremely preterm infants.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: The incidence of the composite of necrotizing enterocolitis, culture-proven sepsis and mortality
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: An infant should have had any of these diagnoses to fulfil the criterion
measure: The incidence of the composite of necrotizing enterocolitis and culture-proven sepsis
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: An infant should have had any of these diagnoses to fulfil the criterion
measure: The incidence of the composite of necrotizing enterocolitis culture-proven sepsis, bronchopulmonary dysplasia, retinopathy of prematurity and mortality (Mortality and morbidity index)
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: An infant should have had any of these diagnoses to fulfil the criterion
measure: Time to reach full enteral feeds
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: The day of life the infant has received at least 150 mL/kg enteral feeds
measure: Number of feeding interruptions
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: Number of days feedings held for ≥12 hours or feeds reduced by >50% (ml/kg/d) not due to a clinical procedure or transitioning to the breast
measure: Numbers of days with parenteral nutrition
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: Number of days of parental amino acid and/or lipid infusion. Only days when the enteral feed <150mL/kg/day should be included
measure: Number of large gastric aspirates per day
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
description: ≥100% pre-feed volume (2 hours feeding volume if continuous feeding). Lower limit=2 ml/kg.
measure: Stool frequency
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Time to regain birth weight
time frame: From birth until discharge from hospital (but not longer than gestational week 44+0)
measure: Change in head circumference in centimeters
time frame: At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).
measure: Change in weight in gram
time frame: At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).
measure: Change in length in centimeters
time frame: At 7, 14, 21 and 28 days, the end of intervention (gestational week 34+0), gestational week 36+0, at discharge from neonatal ward (or at gestational week 44+0, whatever comes first) and at 2 years of age (corrected) and 5.5 years of age (uncorrected).
measure: The mortality incidence
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of necrotising enterocolitis: Bell´s stage II-III
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence spontaneous intestinal perforation
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of abdominal surgery
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence culture-proven sepsis
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of suspected sepsis, not culture-proven
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
measure: The incidence of pneumonia
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: Pathological X-ray confirmed by an independent radiologist, need of increased respiratory support/oxygen and laboratory inflammatory response
measure: The incidence of bronchopulmonary dysplasia
time frame: At gestational week 36+0
description: Need of extra oxygen, continuous positive air pressure (CPAP) or ventilator at gestational week 36+0
measure: The incidence of retinopathy of the prematurity
time frame: From birth until gestational week 42+0
description: Classified into stage I-V. The diagnosis is set after gestational week 42+0
measure: The incidence of intraventricular haemorrhage
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: Classified into grade I-IV according to Papile
measure: The incidence of periventricular leukomalacia
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: Criteria according to de Vries
measure: Number of days with intensive care
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: Need of respirator or CPAP until discharge (not later than gestational week 44+0).
measure: Length of stay at the hospital
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: Gestational week and day at discharge (not later than gestational week 44+0).
measure: Length of need of feeding tube
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: Gestational week and day when the infant does not need it anymore (not later than gestational week 44+0)
measure: Neurocognitive development at 2 years
time frame: At 2 years of age
description: Bayleys III, PARCA-R (Parental Report of Children´s Abilities-Revised) and ASQ-3 (Ages and stages questionnaire)
measure: Prevalence of cerebral palsy at 2 years
time frame: At 2 years of age
measure: Prevalence of epilepsy at 2 years
time frame: At 2 years of age
measure: Prevalence of squint and/or impaired vision at 2 years
time frame: At 2 years of age
measure: Prevalence of impaired hearing at 2 years
time frame: At 2 years of age
measure: The number of infants needing extra oxygen and/or ventilatory support after discharge from the hospital at the neonatal period
time frame: From gestational week 44 until 2 years of age
measure: The incidence of wheeze and/or asthma
time frame: From birth until 2 years of life
measure: The incidence of severe infections after discharge from the neonatal unit
time frame: From gestational week 44 until 2 years of age
measure: The number of infants needing feeding tube after discharge from the hospital at the neonatal period
time frame: From gestational week 44 until 2 years of age
measure: The number of infants needing extra nutritional support after discharge from the hospital at the neonatal period
time frame: From gestational week 44 until 2 years of age
measure: The prevalence of neurocognitive development at 5.5 years
time frame: At 5.5 years of age
description: Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI-IV TM) and Movement ABC-2: the total scale points as well as the points of sub scales (motor, cognitive, language) will be presented. The prevalence of infants with a realist below 2 standard deviations will be defined to have mental retardation.
measure: The prevalence of cerebral palsy at 5.5 years
time frame: At 5.5 years of age
measure: The prevalence of epilepsy at 5.5 years of age
time frame: At 5.5 years of age
measure: The prevalence of squint and/or impaired vision at 5.5 years of age
time frame: At 5.5 years of age
measure: The prevalence of children with impaired hearing at 5.5 years of age
time frame: At 5.5 years of age
measure: The prevalence of wheeze and/or asthma at 5.5 years of age
time frame: At 5.5 years of age
measure: Microbiome composition in stool samples
time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
description: The relative abundance and diversity of microbial taxa will be analyses with next generation sequencing and be related till the study intervention
measure: Levels of subclasses of T and B cells and granulocytes in blood samples
time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
description: T helper subsets (TH1, Th2, TH17, Treg), T cells subsets associated with the intestinal mucosa (gamma/delta-T cells, MAIT cells) and neutrophils will be assessed using masscytometry
measure: Levels of immune markers in plasma
time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
description: Pre planned analyses are anti-inflammatory (e.g. IL-10) and proinflammatory (e.g. TNF) cytokines and chemokines (e.g. CXCL11, CCL18).
measure: Levels of growth factors in plasma samples
time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
description: The levels of growth factors such as IGF-1 and the associated IGFBP-3 will be analysed.
measure: Levels of lipids in plasma samples
time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
description: Fatty acids in plasma
measure: Levels of neurotransmitters in plasma samples
time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
description: Neurotransmitters such as GABA and serotonin in plasma
measure: Levels of metabolic peptides in urine samples
time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
description: Metabolic peptide will be measured with proton nuclear magnetic resonance spectroscopy (NMR), liquid chromatography (LC) and mass spectroscopy couple to gas chromatography (GC-MC).
measure: Levels of markers of central nervous system (CNS) damage in plasma samples
time frame: At 1, 2 and 4 weeks of age and gestational week 36+0
description: Markers of CNS damage such as neurofilament light protein will be measured in plasma
measure: Levels of proteins in breast milk samples
time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
description: Protein composition will be measured with multiplex methods
measure: Levels of human milk oligosaccharides in breast milk samples
time frame: At 1, 2, 3 and 4 weeks of age and gestational week 36+0
description: The levels of human milk oligosaccharides will be measured with high-performance anion-exchange chromatography with pulsed amperometric detection.
measure: Health care costs
time frame: From birth until discharge from hospital (but not loner than gestational week 44+0)
description: The number of days at each level of care will be recorded until discharge from the hospital (not longer than gestational week 44+0). The cost will be calculated by multiplying the number of days at each level of care by the average cost
arm group label: H2MF
arm group type: Experimental
description: Human milk-based breast milk fortifier
arm group label: Standard fortifier
arm group type: Active Comparator
description: Standard care: bovine milk-based breast milk fortifier
intervention type: Dietary Supplement
intervention name: H2MF
description: H2MF is a human milk-based breastmilk fortifier for preterm infants
arm group label: H2MF
intervention type: Dietary Supplement
intervention name: Bovine milk-based fortifier
description: Bovine milk-based fortifier is the standard breast milk fortifier in Sweden
arm group label: Standard fortifier
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Thomas R Abrahamsson, MD, PhD
role: Principal Investigator
affiliation: Region Östergötland
facility: 
facility: 
facility: 
facility: 
facility: 
country: Sweden
responsible party type: Sponsor-Investigator
investigator affiliation: Ostergotland County Council, Sweden
investigator full name: Thomas Abrahamsson, MD, PhD
investigator title: Principal Investigator, MD PhD
mesh term: Enterocolitis
mesh term: Enterocolitis, Necrotizing
sharing ipd: No