<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/NCT03258957</url>
  </required_header>
  <id_info>
    <org_study_id>CZZ-MILK</org_study_id>
    <nct_id>NCT03258957</nct_id>
  </id_info>
  <brief_title>Pilot Study of the Feasibility of Feeding Preterm Infants With Fresh Versus Frozen Mother's Own Breast Milk in the NICU</brief_title>
  <official_title>Pilot Study of the Feasibility of Feeding Preterm Infants With Fresh Versus Frozen Mother's Own Breast Milk in the NICU</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Huiqing Sun</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Nanjing Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nanjing Maternity and Child Health Care Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shanghai First Maternity and Infant Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Third Xiangya Hospital of Central South University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Children's Hospital of Fudan University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mount Sinai Hospital, Canada</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Zhengzhou Children's Hospital, China</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Necrotizing enterocolitis (NEC) is a severe inflammatory disorder of the intestine that&#xD;
      primarily affects very low birth weight (&lt;1,500 g)/very preterm infants (≤32 weeks'&#xD;
      gestation); it is also the leading cause of death in the neonatal intensive care unit&#xD;
      (NICU).Perhaps the best form of treatment for NEC is prevention. Mother's breast milk is best&#xD;
      for preventing NEC. Breast milk contains both nutritional components (proteins, amino acids,&#xD;
      fats, carbohydrates, vitamins, and minerals) and bioactive components (macrophages, T cells,&#xD;
      cytokines, hormones, and growth factors) that have antimicrobial and anti-inflammatory&#xD;
      properties.The current NICU breast milk feeding procedure exists as a means of ensuring that&#xD;
      infants have consistent access to their mother's breast milk even if the mother is not able&#xD;
      to spend time in the NICU. The process also allows for stricter quality and infection&#xD;
      control, as well as computerised inventory and monitoring via electronic health&#xD;
      records.However, the process deprives infants of the benefits of the cellular content of&#xD;
      breast milk, including the stem cells.The primary objective of this study isto evaluate the&#xD;
      feasibility and safety ofproviding very preterm infants (born at &lt;30 weeks' gestation) with&#xD;
      fresh milk (within 4 hours of expression).While we acknowledge that as a pilot the study will&#xD;
      not be powered to detect a statistically significant difference, our secondary objective is&#xD;
      to identify if this approach has the potential to improve infant outcomes, particularly with&#xD;
      regards to the occurrence of NEC.&#xD;
&#xD;
      Our hypothesis is that it is feasible for many mothers to provide at least 1 feed of fresh&#xD;
      breast milk (&lt;4 hours post expression per day, and is not frozen, chilled or pasteurized) and&#xD;
      that this may decrease the prevalence of NEC&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background Necrotizing enterocolitis (NEC) is a severe inflammatory disorder of the intestine&#xD;
      that primarily affects very low birth weight (&lt;1,500 g)/very preterm infants (≤32 weeks'&#xD;
      gestation); it is also the leading cause of death in the neonatal intensive care unit (NICU).&#xD;
      The incidence of NEC (≥stage 2) in very preterm infants across Canada is 5% and increases as&#xD;
      gestational age at birth decreases, with an incidence of 13% in infants born at &lt;25 weeks'&#xD;
      gestation and 10% in infants born at &lt;29 weeks' gestation. Overall mortality from the disease&#xD;
      has been reported to range from 15 to 30%, with more severe cases of NEC having a higher&#xD;
      mortality rate.For infants who survive there is a significant risk of long-term complications&#xD;
      and morbidity including neurodevelopmental issues.&#xD;
&#xD;
      Currently there is no known effective treatment for NEC. Infants are initially managed&#xD;
      medically through bowel rest (cessation of oral feeds), abdominal decompression,&#xD;
      administration of broad spectrum antibiotics, and provision of supportive care including&#xD;
      parental nutrition, ventilator support, and blood transfusions as necessary. Should bowel&#xD;
      perforation occur then surgery is required to remove damaged tissue and gas build up through&#xD;
      laparotomy and/or primary peritoneal drainage.&#xD;
&#xD;
      Perhaps the best form of treatment for NEC is prevention. Mother's breast milk is best for&#xD;
      preventing NEC. Breast milk contains both nutritional components (proteins, amino acids,&#xD;
      fats, carbohydrates, vitamins, and minerals) and bioactive components (macrophages, T cells,&#xD;
      cytokines, hormones, and growth factors) that have antimicrobial and anti-inflammatory&#xD;
      properties. More recently, Hassiotou4 showed that breast milk is also a rich source of&#xD;
      pleuripotent stem cells that when ingested by the infant, enter the blood stream and are&#xD;
      incorporated into major organ systems in the infant. Although their function is unknown, it&#xD;
      is possible that they benefit the infant through growth or regeneration. The evidence&#xD;
      strongly suggests that fresh breast milk may have a protective effect against both infection&#xD;
      and NEC. When mother's own breast milk is not available the options are donor breast milk or&#xD;
      formula. The use of formula in low birth weight/preterm infants has been reported to increase&#xD;
      the risk of developing NEC when compared with donor breast milk.&#xD;
&#xD;
      However, current practices related to handling and use of human milk raise questions about&#xD;
      whether we are deriving maximum benefit from their use. Currently, in the standard neonatal&#xD;
      intensive care unit (NICU) breast milk expressed by mothers of preterm infants is frozen and&#xD;
      stored in the milk bank. When the infant requires oral feeds an order is placed with the milk&#xD;
      bank, the oldest batch of milk defrosted, fortifier added as needed, and the milk then sent&#xD;
      to the NICU for use. The act of freezing breast milk,either at -20°C or -80°C, along with the&#xD;
      passage of time decreases the energy content and reduces the levels of several of the most&#xD;
      useful components in the milk, including fat, carbohydrate,secretory immunoglobulin&#xD;
      A,lactoperoxidase,lysozyme, antibacterial factors,and antioxidants. In addition to the&#xD;
      decrease in these components, any stem cells in the milk have a half-life of 4 hours, so the&#xD;
      defrosted milk does not contain any stem cells.&#xD;
&#xD;
      The current NICU breast milk feeding procedure exists as a means of ensuring that infants&#xD;
      have consistent access to their mother's breast milk even if the mother is not able to spend&#xD;
      time in the NICU. The process also allows for stricter quality and infection control, as well&#xD;
      as computerised inventory and monitoring via electronic health records.However, the process&#xD;
      deprives infants of the benefits of the cellular content of breast milk, including the stem&#xD;
      cells.&#xD;
&#xD;
      Objective The primary objective of this study isto evaluate the feasibility and safety&#xD;
      ofproviding very preterm infants (born at &lt;30 weeks' gestation) with fresh milk (within 4&#xD;
      hours of expression).While we acknowledge that as a pilot the study will not be powered to&#xD;
      detect a statistically significant difference, our secondary objective is to identify if this&#xD;
      approach has the potential to improve infant outcomes, particularly with regards to the&#xD;
      occurrence of NEC.&#xD;
&#xD;
      Our hypothesis is that it is feasible for many mothers to provide at least 1 feed of fresh&#xD;
      breast milk (&lt;4 hours post expression per day, and is not frozen, chilled or pasteurized) and&#xD;
      that this may decrease the prevalence of NEC.&#xD;
&#xD;
      Design Study design The study will be a prospective cohort analytic design. Mothers who agree&#xD;
      to be enrolled in the study will be assigned to the intervention group. In the intervention&#xD;
      group, mothers will be asked to provide at least 1 feed of fresh milk (i.e. within 4 hours of&#xD;
      milk expression) per day. Mothers who do not agree to provide fresh milk but are willing to&#xD;
      allow their information to be collected and analyzed will be assigned to the control group.&#xD;
      In the control group, the current standards of breast milk handling and feeding apply.&#xD;
&#xD;
      Study population The study population will include infants and their mothers admitted to&#xD;
      participating NICUs (Zhengzhou Hospital, Nanjing Maternity and Child Health Hospital, Nanjing&#xD;
      Children's Hospital, Zhejiang Maternity Hospital, Xiangya Second Hospital, Shanghai First&#xD;
      Maternity Hospital, Nanjing Maternal and Child Health Hospital, Children's Hospital of Fudan&#xD;
      University) which admits, on average, 500 infants per year who would be eligible for&#xD;
      inclusion in the study. The goal is to enroll 100 infants in each of the intervention and&#xD;
      control groups in the study. Eligible infants will include those born at &lt;30 weeks&#xD;
      gestation,and who have never received infant formula. For inclusion in the intervention&#xD;
      group, the mother must bewilling to commit to providingat least 1 feed of fresh breast milk a&#xD;
      day, 7 days a week. Infants with major congenital anomalies, receiving palliative care, or&#xD;
      where illness of the mother or infant prevents the administration of breast milk feeds in the&#xD;
      first week of the infant's life will be excluded from the trial.Infants whose mothers are&#xD;
      unable to commit to providing at least 1 feed of fresh breast milk a day but who are willing&#xD;
      to have their data collected may be included in the control group.&#xD;
&#xD;
      Enrollment Eligible mothers will be approached at their first visit to the NICU following&#xD;
      their infant's admission. Ideally enrollment should occur before the infant's first oral&#xD;
      feed. All mothers enrolled in the study will follow the standard protocol in their NICU for&#xD;
      feeding their infant breast milk.&#xD;
&#xD;
      Outcomes Outcomes will be measured from birth until discharge or transfer to another neonatal&#xD;
      unit.&#xD;
&#xD;
      The primary outcomeof the study will be:&#xD;
&#xD;
      1. Feasibility as defined by the percentage of mothers who can provide at least 1 feed of&#xD;
      fresh milk a day from study enrollment until the infants are 32 weeks CGA, including:&#xD;
&#xD;
        1. Rates of enrollment in the intervention and control groups&#xD;
&#xD;
        2. Rate of retention in the study&#xD;
&#xD;
        3. Compliance with the study protocol&#xD;
&#xD;
             1. Number of days with at least 1 feeds of fresh milk (within 4 hours of expression)&#xD;
&#xD;
             2. Number of feeds per day with fresh milk&#xD;
&#xD;
             3. Number of feeds using frozen mother's own milk or donor milk&#xD;
&#xD;
             4. Number and type of critical incident reports including feeding errors 2. The&#xD;
                secondary outcomes of the study will be (definitions as per Canadian Neonatal&#xD;
                Network):&#xD;
&#xD;
      (1)NEC stage 2 or above (2)NEC stage 1 (3)Mortality (4)Need for surgery for NEC (5)Late-onset&#xD;
      sepsis (6)Growth as measured by weight, length, head circumference (7)Retinopathy of&#xD;
      prematurity (8)Bronchopulmonary dysplasia Study Procedures Feeding protocol Standard&#xD;
      procedures - feeding and milk fortification: Infants born at &lt;30 weeks' gestation are&#xD;
      initially provided with nutrition intravenously (total parenteral nutrition, TPN). If the&#xD;
      infant is not suffering from any condition that affects gastrointestinal system functioning,&#xD;
      oral feeds are introduced as early as possible. Milk is introduced into the stomach through a&#xD;
      nasogastric (NG) tube according to a schedule that is dependent on the infant's weight at&#xD;
      birth. The amount of milk is very small at first and then gradually increased if the infant&#xD;
      tolerates the milk. The frequency of feeding varies but is most often every 2 hours or every&#xD;
      3 hours depending on the weight of the infant. As the amount of milk being fed to the infant&#xD;
      increases, the amount of TPN provided is decreased until the infant is receiving all its&#xD;
      nutrition from milk (see typical Feeding Guidelines appended to this protocol).&#xD;
&#xD;
      Once the infant is receiving all its nutrition from milk ('full enteral feeds'), fortifiers&#xD;
      and other nutritional supplements are added to each feed. The first supplement added is human&#xD;
      milk fortifier, four days later extra protein is also added , and then a further 3 days later&#xD;
      vitamins and iron are added to each feed (see Feeding Guideline).&#xD;
&#xD;
      Mother's own expressed breast milk is the food of choice, following by donor breast milk, and&#xD;
      then formula. The supplementation or replacement of mother's own milk by donor milk or&#xD;
      formula is dependent on the mother's ability to produce milk in sufficient quantity for all&#xD;
      feeds. Often in the first few days of life very preterm infants are fed donor milk as the&#xD;
      mother may not have started producing breast milk at that point or may still be recovering&#xD;
      from the birth. Mothers may also produce less milk than is needed, either initially or&#xD;
      throughout the breast feeding period, so some feeds may be supplemented with donor milk or&#xD;
      formula.&#xD;
&#xD;
      In every case where expressed breast milk is used currently, the milk is collected from the&#xD;
      mother and frozen in the milk bank. Each evening the feeds for the following day are ordered&#xD;
      and the oldest batch of breast milk defrosted and prepared. Infants move from enteral feeds&#xD;
      to breast feeding when they are clinically judged to be able to do so.&#xD;
&#xD;
      Intervention protocol - overview:The exact same standard procedures for feeding (timing of&#xD;
      initiation, amount, frequency, and supplementation with donor milk as needed) and&#xD;
      fortification will be followed for study participants. Only infants who have not previously&#xD;
      received infant formula are eligible. The only difference in feeding will be that for at&#xD;
      least 1 feed per day the breast milk fed to the infant will be fresh, not previously frozen.&#xD;
      'Fresh' breast milk is defined as milk that was expressed less than 4 hours prior to the time&#xD;
      it is fed to the infant, and is not frozen, chilled or pasteurized. The reason for this time&#xD;
      window is that the half-life of stem cellsbreast milk is only about 4 hours.&#xD;
&#xD;
      Intervention protocol - details: Mothers will be asked to be present in the NICU and pump&#xD;
      breast milk for a 'fresh' feedat least 1 time per day, 7 days a week using the Medela&#xD;
      Symphony pump applied to both breasts.As this is a &quot;real world&quot; study, the actual volume of&#xD;
      fresh milk feeds is not as important as the number of feeds because feed volumes are&#xD;
      determined by a standard protocol in the NICU, and volumes of feeds administered must conform&#xD;
      to the ability of the infant to tolerate the feeds, and cannot be dosed according to a&#xD;
      pre-set amount. Breast milk will be expressed into a sterile plastic container as per&#xD;
      standard NICU protocol. The container will be labelled with the mother's bar code and&#xD;
      immediately given to a nurse dedicated to the implementation of this study (1.0FTE, see study&#xD;
      budget). The nurse will take the milk to the milk preparation area where the details of the&#xD;
      milk and feeds will be entered into a database and then she will prepare and bring the milk&#xD;
      back to the NICU to be fed to the infant. The milk will not be heated.&#xD;
&#xD;
      Any additional milk expressed by the mother in the NICU or at homethat exceeds the 4 hour&#xD;
      window will be transferred to a sterile container, frozen, and stored in the milk bank for&#xD;
      use when the mother is not available to provide fresh milk. Milk collection and handling for&#xD;
      feeds of previously frozen milk will be as per standard NICU protocol.&#xD;
&#xD;
      Provision of breast milk in this manner will commence when the infant is able to tolerate&#xD;
      enteral feeds and continue until the infant is discharged from hospital.Mothers will also be&#xD;
      encouraged to express breast milk when they are away from the unit and bring it into the unit&#xD;
      as per standard NICU protocols. In cases where a mother is not able to produce enough breast&#xD;
      milk for all her infant's feeds, the remaining feeds that are not being provided as fresh or&#xD;
      frozen mother's own breast milk may be supplemented using donor milk.Infants enrolled in the&#xD;
      study who develop NEC will cease the study protocol and receive treatment as per the NICU&#xD;
      standard protocol.&#xD;
&#xD;
      Mothers who provide less than 1 feed of fresh milk every day will remain in the study. This&#xD;
      will enable us to determine the feasibility of expecting mothers to provide at least 1 feed&#xD;
      of fresh milk a day, and the percentage of mothers who can actually do so.&#xD;
&#xD;
      Safety For an individual patient, the feeding protocol will be stopped if there is an&#xD;
      occurrence of NEC or any other medical condition that necessitates that feeds be stopped as&#xD;
      per standard practice.&#xD;
&#xD;
      All cases of mortality, NEC, sepsis, and critical incidence reports (including mix-up of milk&#xD;
      destined for individual infants, infection that is related to feeds, missed feeds arising&#xD;
      from delays in milk preparation, and any other incident that raises concerns of the&#xD;
      clinicians) that occur in infants enrolled in the study will be critically reviewed by a Data&#xD;
      Safety and Monitoring Committee and the study stopped if concerns regarding the safety of the&#xD;
      study are raised.Stopping criteria and decisions will be decided by the Data Safety and&#xD;
      Monitoring Committee.&#xD;
&#xD;
      Preparation (2 months): REB approval will be obtained. Education for staff regarding the&#xD;
      study protocol will be developed and rolled out. Education for staff will include in-service&#xD;
      sessions that will be held before the study period begins. The necessary unit policies will&#xD;
      be developed and implemented.&#xD;
&#xD;
      Enrollment period (9 months): Enrollment into the study will continue until 100 infants and&#xD;
      their mothers have completed the intervention protocoland 100 infants and their mothers have&#xD;
      completed the control protocol.&#xD;
&#xD;
      Analysis (1 month): Data collection will be analysed and results reported.&#xD;
&#xD;
      Data collection Infant outcomes: Outcomes data will be collected on paper and entered into a&#xD;
      database for subsequent analysis. Study-specific variables will include compliance with&#xD;
      intervention protocol, the number and volume of stem cell rich fresh milk feeds provided to&#xD;
      study infants on each day, and the response of the infant following the feed (see attached&#xD;
      data forms).&#xD;
&#xD;
      Infant and maternal characteristics: In addition to infant outcomes, data on maternal and&#xD;
      infant characteristics, as well as predisposing factors will be collected.&#xD;
&#xD;
      Statistical analysis Justification for sample size:The mean number of infants born at &lt;30&#xD;
      weeks' gestation and admitted to participating NICUs in 2014 was over 500 per year. We expect&#xD;
      that 25% of mothers will consent to be in the intervention group. If the admission&#xD;
      rateremains similar during the study period, there should be ample feasibility to complete&#xD;
      the study.&#xD;
&#xD;
      In 2013 the mean annual rate of NEC was 9.3% in infants born at &lt;29 weeks' gestation, so we&#xD;
      would expect to see 9 cases of NEC in the control group. Although the study will not be&#xD;
      powered to detect a statistically significant difference, the occurrence of 5 or less cases&#xD;
      of NEC in the intervention group may be an indication that further study is warranted.&#xD;
&#xD;
      Analyses: The primary outcomes of feasibility (rate of consent, rate of enrolment, rate of&#xD;
      retention, and compliance with the intervention protocol) and safety (number of critical&#xD;
      incidence reports) will be reported.The incidence of NEC and other secondary outcomes will be&#xD;
      compared between the two groups using descriptive methods.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2016</start_date>
  <completion_date type="Actual">December 31, 2017</completion_date>
  <primary_completion_date type="Actual">December 31, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility of fresh breast milk</measure>
    <time_frame>3 year</time_frame>
    <description>Feasibility as defined by the percentage of mothers who can provide at least 1 feed of fresh milk a day from study enrollment until the infants are 32 weeks CGA</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>NEC</measure>
    <time_frame>3 year</time_frame>
    <description>NEC more than stage 2 NEC stage 1 Need for surgery for NEC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>3 year</time_frame>
    <description>Compare the mortality between two groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>sepsis</measure>
    <time_frame>3 year</time_frame>
    <description>Late-onset sepsis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Growth</measure>
    <time_frame>3 year</time_frame>
    <description>Growth as measured by weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retinopathy of prematurity</measure>
    <time_frame>3 year</time_frame>
    <description>Retinopathy of prematurity was screened and analysed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bronchopulmonary dysplasia</measure>
    <time_frame>3 year</time_frame>
    <description>Retinopathy of prematurity was defined and compared between two groups</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Necrotizing Enterocolitis</condition>
  <arm_group>
    <arm_group_label>Fresh milk group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In the intervention group, mothers will be asked to provide at least 1 feed of fresh milk (i.e. within 4 hours of milk expression) per day.Other time, feed frozen milk.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Fresh Milk</intervention_name>
    <description>Mothers will be asked to provide at least 1 feed of fresh milk (i.e. within 4 hours of milk expression) per day, other time, feed frozen milk</description>
    <arm_group_label>Fresh milk group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Eligible infants will include those born at &lt;30 weeks gestation,and who have never&#xD;
             received infant formula. For inclusion in the intervention group, the mother must&#xD;
             bewilling to commit to providingat least 1 feed of fresh breast milk a day, 7 days a&#xD;
             week&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Infants with major congenital anomalies, receiving palliative care, or where illness&#xD;
             of the mother or infant prevents the administration of breast milk feeds in the first&#xD;
             week of the infant's life will be excluded from the trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Hour</minimum_age>
    <maximum_age>3 Days</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shuying Luo, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Zhengzhou Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Zhengzhou Children's Hospital</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>450018</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>May 12, 2017</study_first_submitted>
  <study_first_submitted_qc>August 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 23, 2017</study_first_posted>
  <last_update_submitted>September 3, 2018</last_update_submitted>
  <last_update_submitted_qc>September 3, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Zhengzhou Children's Hospital, China</investigator_affiliation>
    <investigator_full_name>Huiqing Sun</investigator_full_name>
    <investigator_title>The director of neonatal intensive care unit</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>
  <!-- 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/NCT03258957
org study id: CZZ-MILK
nct id: NCT03258957
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Necrotizing enterocolitis (NEC) is a severe inflammatory disorder of the intestine that
      primarily affects very low birth weight (<1,500 g)/very preterm infants (≤32 weeks'
      gestation); it is also the leading cause of death in the neonatal intensive care unit
      (NICU).Perhaps the best form of treatment for NEC is prevention. Mother's breast milk is best
      for preventing NEC. Breast milk contains both nutritional components (proteins, amino acids,
      fats, carbohydrates, vitamins, and minerals) and bioactive components (macrophages, T cells,
      cytokines, hormones, and growth factors) that have antimicrobial and anti-inflammatory
      properties.The current NICU breast milk feeding procedure exists as a means of ensuring that
      infants have consistent access to their mother's breast milk even if the mother is not able
      to spend time in the NICU. The process also allows for stricter quality and infection
      control, as well as computerised inventory and monitoring via electronic health
      records.However, the process deprives infants of the benefits of the cellular content of
      breast milk, including the stem cells.The primary objective of this study isto evaluate the
      feasibility and safety ofproviding very preterm infants (born at <30 weeks' gestation) with
      fresh milk (within 4 hours of expression).While we acknowledge that as a pilot the study will
      not be powered to detect a statistically significant difference, our secondary objective is
      to identify if this approach has the potential to improve infant outcomes, particularly with
      regards to the occurrence of NEC.

      Our hypothesis is that it is feasible for many mothers to provide at least 1 feed of fresh
      breast milk (<4 hours post expression per day, and is not frozen, chilled or pasteurized) and
      that this may decrease the prevalence of NEC
Background Necrotizing enterocolitis (NEC) is a severe inflammatory disorder of the intestine
      that primarily affects very low birth weight (<1,500 g)/very preterm infants (≤32 weeks'
      gestation); it is also the leading cause of death in the neonatal intensive care unit (NICU).
      The incidence of NEC (≥stage 2) in very preterm infants across Canada is 5% and increases as
      gestational age at birth decreases, with an incidence of 13% in infants born at <25 weeks'
      gestation and 10% in infants born at <29 weeks' gestation. Overall mortality from the disease
      has been reported to range from 15 to 30%, with more severe cases of NEC having a higher
      mortality rate.For infants who survive there is a significant risk of long-term complications
      and morbidity including neurodevelopmental issues.

      Currently there is no known effective treatment for NEC. Infants are initially managed
      medically through bowel rest (cessation of oral feeds), abdominal decompression,
      administration of broad spectrum antibiotics, and provision of supportive care including
      parental nutrition, ventilator support, and blood transfusions as necessary. Should bowel
      perforation occur then surgery is required to remove damaged tissue and gas build up through
      laparotomy and/or primary peritoneal drainage.

      Perhaps the best form of treatment for NEC is prevention. Mother's breast milk is best for
      preventing NEC. Breast milk contains both nutritional components (proteins, amino acids,
      fats, carbohydrates, vitamins, and minerals) and bioactive components (macrophages, T cells,
      cytokines, hormones, and growth factors) that have antimicrobial and anti-inflammatory
      properties. More recently, Hassiotou4 showed that breast milk is also a rich source of
      pleuripotent stem cells that when ingested by the infant, enter the blood stream and are
      incorporated into major organ systems in the infant. Although their function is unknown, it
      is possible that they benefit the infant through growth or regeneration. The evidence
      strongly suggests that fresh breast milk may have a protective effect against both infection
      and NEC. When mother's own breast milk is not available the options are donor breast milk or
      formula. The use of formula in low birth weight/preterm infants has been reported to increase
      the risk of developing NEC when compared with donor breast milk.

      However, current practices related to handling and use of human milk raise questions about
      whether we are deriving maximum benefit from their use. Currently, in the standard neonatal
      intensive care unit (NICU) breast milk expressed by mothers of preterm infants is frozen and
      stored in the milk bank. When the infant requires oral feeds an order is placed with the milk
      bank, the oldest batch of milk defrosted, fortifier added as needed, and the milk then sent
      to the NICU for use. The act of freezing breast milk,either at -20°C or -80°C, along with the
      passage of time decreases the energy content and reduces the levels of several of the most
      useful components in the milk, including fat, carbohydrate,secretory immunoglobulin
      A,lactoperoxidase,lysozyme, antibacterial factors,and antioxidants. In addition to the
      decrease in these components, any stem cells in the milk have a half-life of 4 hours, so the
      defrosted milk does not contain any stem cells.

      The current NICU breast milk feeding procedure exists as a means of ensuring that infants
      have consistent access to their mother's breast milk even if the mother is not able to spend
      time in the NICU. The process also allows for stricter quality and infection control, as well
      as computerised inventory and monitoring via electronic health records.However, the process
      deprives infants of the benefits of the cellular content of breast milk, including the stem
      cells.

      Objective The primary objective of this study isto evaluate the feasibility and safety
      ofproviding very preterm infants (born at <30 weeks' gestation) with fresh milk (within 4
      hours of expression).While we acknowledge that as a pilot the study will not be powered to
      detect a statistically significant difference, our secondary objective is to identify if this
      approach has the potential to improve infant outcomes, particularly with regards to the
      occurrence of NEC.

      Our hypothesis is that it is feasible for many mothers to provide at least 1 feed of fresh
      breast milk (<4 hours post expression per day, and is not frozen, chilled or pasteurized) and
      that this may decrease the prevalence of NEC.

      Design Study design The study will be a prospective cohort analytic design. Mothers who agree
      to be enrolled in the study will be assigned to the intervention group. In the intervention
      group, mothers will be asked to provide at least 1 feed of fresh milk (i.e. within 4 hours of
      milk expression) per day. Mothers who do not agree to provide fresh milk but are willing to
      allow their information to be collected and analyzed will be assigned to the control group.
      In the control group, the current standards of breast milk handling and feeding apply.

      Study population The study population will include infants and their mothers admitted to
      participating NICUs (Zhengzhou Hospital, Nanjing Maternity and Child Health Hospital, Nanjing
      Children's Hospital, Zhejiang Maternity Hospital, Xiangya Second Hospital, Shanghai First
      Maternity Hospital, Nanjing Maternal and Child Health Hospital, Children's Hospital of Fudan
      University) which admits, on average, 500 infants per year who would be eligible for
      inclusion in the study. The goal is to enroll 100 infants in each of the intervention and
      control groups in the study. Eligible infants will include those born at <30 weeks
      gestation,and who have never received infant formula. For inclusion in the intervention
      group, the mother must bewilling to commit to providingat least 1 feed of fresh breast milk a
      day, 7 days a week. Infants with major congenital anomalies, receiving palliative care, or
      where illness of the mother or infant prevents the administration of breast milk feeds in the
      first week of the infant's life will be excluded from the trial.Infants whose mothers are
      unable to commit to providing at least 1 feed of fresh breast milk a day but who are willing
      to have their data collected may be included in the control group.

      Enrollment Eligible mothers will be approached at their first visit to the NICU following
      their infant's admission. Ideally enrollment should occur before the infant's first oral
      feed. All mothers enrolled in the study will follow the standard protocol in their NICU for
      feeding their infant breast milk.

      Outcomes Outcomes will be measured from birth until discharge or transfer to another neonatal
      unit.

      The primary outcomeof the study will be:

      1. Feasibility as defined by the percentage of mothers who can provide at least 1 feed of
      fresh milk a day from study enrollment until the infants are 32 weeks CGA, including:

        1. Rates of enrollment in the intervention and control groups

        2. Rate of retention in the study

        3. Compliance with the study protocol

             1. Number of days with at least 1 feeds of fresh milk (within 4 hours of expression)

             2. Number of feeds per day with fresh milk

             3. Number of feeds using frozen mother's own milk or donor milk

             4. Number and type of critical incident reports including feeding errors 2. The
                secondary outcomes of the study will be (definitions as per Canadian Neonatal
                Network):

      (1)NEC stage 2 or above (2)NEC stage 1 (3)Mortality (4)Need for surgery for NEC (5)Late-onset
      sepsis (6)Growth as measured by weight, length, head circumference (7)Retinopathy of
      prematurity (8)Bronchopulmonary dysplasia Study Procedures Feeding protocol Standard
      procedures - feeding and milk fortification: Infants born at <30 weeks' gestation are
      initially provided with nutrition intravenously (total parenteral nutrition, TPN). If the
      infant is not suffering from any condition that affects gastrointestinal system functioning,
      oral feeds are introduced as early as possible. Milk is introduced into the stomach through a
      nasogastric (NG) tube according to a schedule that is dependent on the infant's weight at
      birth. The amount of milk is very small at first and then gradually increased if the infant
      tolerates the milk. The frequency of feeding varies but is most often every 2 hours or every
      3 hours depending on the weight of the infant. As the amount of milk being fed to the infant
      increases, the amount of TPN provided is decreased until the infant is receiving all its
      nutrition from milk (see typical Feeding Guidelines appended to this protocol).

      Once the infant is receiving all its nutrition from milk ('full enteral feeds'), fortifiers
      and other nutritional supplements are added to each feed. The first supplement added is human
      milk fortifier, four days later extra protein is also added , and then a further 3 days later
      vitamins and iron are added to each feed (see Feeding Guideline).

      Mother's own expressed breast milk is the food of choice, following by donor breast milk, and
      then formula. The supplementation or replacement of mother's own milk by donor milk or
      formula is dependent on the mother's ability to produce milk in sufficient quantity for all
      feeds. Often in the first few days of life very preterm infants are fed donor milk as the
      mother may not have started producing breast milk at that point or may still be recovering
      from the birth. Mothers may also produce less milk than is needed, either initially or
      throughout the breast feeding period, so some feeds may be supplemented with donor milk or
      formula.

      In every case where expressed breast milk is used currently, the milk is collected from the
      mother and frozen in the milk bank. Each evening the feeds for the following day are ordered
      and the oldest batch of breast milk defrosted and prepared. Infants move from enteral feeds
      to breast feeding when they are clinically judged to be able to do so.

      Intervention protocol - overview:The exact same standard procedures for feeding (timing of
      initiation, amount, frequency, and supplementation with donor milk as needed) and
      fortification will be followed for study participants. Only infants who have not previously
      received infant formula are eligible. The only difference in feeding will be that for at
      least 1 feed per day the breast milk fed to the infant will be fresh, not previously frozen.
      'Fresh' breast milk is defined as milk that was expressed less than 4 hours prior to the time
      it is fed to the infant, and is not frozen, chilled or pasteurized. The reason for this time
      window is that the half-life of stem cellsbreast milk is only about 4 hours.

      Intervention protocol - details: Mothers will be asked to be present in the NICU and pump
      breast milk for a 'fresh' feedat least 1 time per day, 7 days a week using the Medela
      Symphony pump applied to both breasts.As this is a "real world" study, the actual volume of
      fresh milk feeds is not as important as the number of feeds because feed volumes are
      determined by a standard protocol in the NICU, and volumes of feeds administered must conform
      to the ability of the infant to tolerate the feeds, and cannot be dosed according to a
      pre-set amount. Breast milk will be expressed into a sterile plastic container as per
      standard NICU protocol. The container will be labelled with the mother's bar code and
      immediately given to a nurse dedicated to the implementation of this study (1.0FTE, see study
      budget). The nurse will take the milk to the milk preparation area where the details of the
      milk and feeds will be entered into a database and then she will prepare and bring the milk
      back to the NICU to be fed to the infant. The milk will not be heated.

      Any additional milk expressed by the mother in the NICU or at homethat exceeds the 4 hour
      window will be transferred to a sterile container, frozen, and stored in the milk bank for
      use when the mother is not available to provide fresh milk. Milk collection and handling for
      feeds of previously frozen milk will be as per standard NICU protocol.

      Provision of breast milk in this manner will commence when the infant is able to tolerate
      enteral feeds and continue until the infant is discharged from hospital.Mothers will also be
      encouraged to express breast milk when they are away from the unit and bring it into the unit
      as per standard NICU protocols. In cases where a mother is not able to produce enough breast
      milk for all her infant's feeds, the remaining feeds that are not being provided as fresh or
      frozen mother's own breast milk may be supplemented using donor milk.Infants enrolled in the
      study who develop NEC will cease the study protocol and receive treatment as per the NICU
      standard protocol.

      Mothers who provide less than 1 feed of fresh milk every day will remain in the study. This
      will enable us to determine the feasibility of expecting mothers to provide at least 1 feed
      of fresh milk a day, and the percentage of mothers who can actually do so.

      Safety For an individual patient, the feeding protocol will be stopped if there is an
      occurrence of NEC or any other medical condition that necessitates that feeds be stopped as
      per standard practice.

      All cases of mortality, NEC, sepsis, and critical incidence reports (including mix-up of milk
      destined for individual infants, infection that is related to feeds, missed feeds arising
      from delays in milk preparation, and any other incident that raises concerns of the
      clinicians) that occur in infants enrolled in the study will be critically reviewed by a Data
      Safety and Monitoring Committee and the study stopped if concerns regarding the safety of the
      study are raised.Stopping criteria and decisions will be decided by the Data Safety and
      Monitoring Committee.

      Preparation (2 months): REB approval will be obtained. Education for staff regarding the
      study protocol will be developed and rolled out. Education for staff will include in-service
      sessions that will be held before the study period begins. The necessary unit policies will
      be developed and implemented.

      Enrollment period (9 months): Enrollment into the study will continue until 100 infants and
      their mothers have completed the intervention protocoland 100 infants and their mothers have
      completed the control protocol.

      Analysis (1 month): Data collection will be analysed and results reported.

      Data collection Infant outcomes: Outcomes data will be collected on paper and entered into a
      database for subsequent analysis. Study-specific variables will include compliance with
      intervention protocol, the number and volume of stem cell rich fresh milk feeds provided to
      study infants on each day, and the response of the infant following the feed (see attached
      data forms).

      Infant and maternal characteristics: In addition to infant outcomes, data on maternal and
      infant characteristics, as well as predisposing factors will be collected.

      Statistical analysis Justification for sample size:The mean number of infants born at <30
      weeks' gestation and admitted to participating NICUs in 2014 was over 500 per year. We expect
      that 25% of mothers will consent to be in the intervention group. If the admission
      rateremains similar during the study period, there should be ample feasibility to complete
      the study.

      In 2013 the mean annual rate of NEC was 9.3% in infants born at <29 weeks' gestation, so we
      would expect to see 9 cases of NEC in the control group. Although the study will not be
      powered to detect a statistically significant difference, the occurrence of 5 or less cases
      of NEC in the intervention group may be an indication that further study is warranted.

      Analyses: The primary outcomes of feasibility (rate of consent, rate of enrolment, rate of
      retention, and compliance with the intervention protocol) and safety (number of critical
      incidence reports) will be reported.The incidence of NEC and other secondary outcomes will be
      compared between the two groups using descriptive methods.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Feasibility of fresh breast milk
time frame: 3 year
description: Feasibility as defined by the percentage of mothers who can provide at least 1 feed of fresh milk a day from study enrollment until the infants are 32 weeks CGA
measure: NEC
time frame: 3 year
description: NEC more than stage 2 NEC stage 1 Need for surgery for NEC
measure: Mortality
time frame: 3 year
description: Compare the mortality between two groups
measure: sepsis
time frame: 3 year
description: Late-onset sepsis
measure: Growth
time frame: 3 year
description: Growth as measured by weight
measure: Retinopathy of prematurity
time frame: 3 year
description: Retinopathy of prematurity was screened and analysed
measure: Bronchopulmonary dysplasia
time frame: 3 year
description: Retinopathy of prematurity was defined and compared between two groups
arm group label: Fresh milk group
arm group type: Experimental
description: In the intervention group, mothers will be asked to provide at least 1 feed of fresh milk (i.e. within 4 hours of milk expression) per day.Other time, feed frozen milk.
intervention type: Other
intervention name: Fresh Milk
description: Mothers will be asked to provide at least 1 feed of fresh milk (i.e. within 4 hours of milk expression) per day, other time, feed frozen milk
arm group label: Fresh milk group
criteria: 
gender: All
minimum age: 1 Hour
maximum age: 3 Days
healthy volunteers: Accepts Healthy Volunteers
last name: Shuying Luo, MD
role: Study Chair
affiliation: Zhengzhou Children's Hospital
facility: 
country: China
responsible party type: Sponsor-Investigator
investigator affiliation: Zhengzhou Children's Hospital, China
investigator full name: Huiqing Sun
investigator title: The director of neonatal intensive care unit
mesh term: Enterocolitis
mesh term: Enterocolitis, Necrotizing