<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/NCT02983513</url>
  </required_header>
  <id_info>
    <org_study_id>MITP Preterm</org_study_id>
    <nct_id>NCT02983513</nct_id>
  </id_info>
  <brief_title>Early Intervention in Preterm Infants: Short and Long Term Developmental Outcome After a Parental Training Program</brief_title>
  <official_title>Early Intervention in Preterm Infants: Effects of a Parental Training Program on Neonatal Brain Development, Visual Functions and Neurobehavioral Outcome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Preterm infants, during their stay in the Neonatal Intensive Care Unit (NICU), face a period&#xD;
      of stressful environment, which may negatively impact early brain development and subsequent&#xD;
      neurobehavioral outcomes. This study aims to assess the effectiveness of training parents in&#xD;
      reducing stressful experiences early in life and in enhancing brain development and long term&#xD;
      developmental outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Very preterm birth is associated with motor, cognitive and behavioral problems.&#xD;
&#xD;
      Micro-structural brain abnormalities, even in the absence of focal lesions, have been&#xD;
      documented by neuroimaging studies in preterm infants at term corrected age and later in&#xD;
      childhood. These alterations in brain maturation occurring during the neonatal period may be&#xD;
      implicated in long-term neurobehavioral disorders later experienced by preterm babies.&#xD;
&#xD;
      However, there is increasing evidence that also negative environmental factors (intensive&#xD;
      care, excessive sensory stimulation, paucity of parental contact etc.) can affect later&#xD;
      outcomes.&#xD;
&#xD;
      Potential benefits of early dyadic interaction and preterm baby massage in reducing the&#xD;
      effects of the NICU stressor environment have been demonstrated. More recently, few studies&#xD;
      have investigated visual function in preterm infants focusing on the potential role of early&#xD;
      visual interaction to enhance attention and improve later neurodevelopment.&#xD;
&#xD;
      The role of early intervention strategies to improve neurodevelopment has been recently&#xD;
      emphasized.&#xD;
&#xD;
      Early intervention programs based on the concept of &quot;individualized care&quot; have proved to be&#xD;
      effective in promoting brain maturation and neurodevelopmental outcome. In this context,&#xD;
      early interventions as the Mother Infant Transaction Program (MITP) and the Premie Start,&#xD;
      both targeting parenting, have the greatest potential to have sustained effects on child&#xD;
      development.&#xD;
&#xD;
      In addition, recent studies have shown that exposure to stressful events in the neonatal&#xD;
      period can cause epigenetic modifications in children born preterm; in particular alteration&#xD;
      of serotonergic tone was observed, associated with methylation of the serotonin transporter&#xD;
      gene, which could be implicated in the etiology of behavioral disorders observed in these&#xD;
      children. In animal models these epigenetic effects appear to be influenced by maternal care&#xD;
      that can epigenetically modulate the offsprings' stress response.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2014</start_date>
  <completion_date type="Actual">January 2023</completion_date>
  <primary_completion_date type="Actual">April 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Neonatal Visual Assessment Battery to evaluate visual function</measure>
    <time_frame>40 weeks postmenstrual age</time_frame>
    <description>Neonatal Visual Function is assessed using the Visual Assessment Battery developed by Ricci et al. The assessment evaluates the following items: Ocular spontaneous motility, ability to fix and follow a target, reaction to colour, visual acuity and visual attention at distance. Each item is scored as normal (score 0) or abnormal (score 1). The global score is then calculated as the sum of all the individual items, as designed by the authors.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Neonatal Behavior</measure>
    <time_frame>2 months corrected age</time_frame>
    <description>Neonatal behavior is assessed using the Neonatal Behavior Assessment Scale that evaluates: habituation, social-interactive, motor system, state organization and regulation, autonomic system, reflexes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Brain development</measure>
    <time_frame>40 weeks postmenstrual age</time_frame>
    <description>Conventional and advanced MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Developmental outcome</measure>
    <time_frame>24 months corrected age</time_frame>
    <description>Children development is assessed using the Bayley Scales of Infant and Toddlers (Third edition) - including: cognitive, motor, language, social-emotional and adaptive behavior)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Epigenetic changes</measure>
    <time_frame>up to 48 weeks gestational age</time_frame>
    <description>epigenetic analysis is performed at birth on a cord blood sample (0.5 ml) and at hospital discharge on a peripheral blood sample (0.5 ml) collected according routine clinical procedures</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall duration of hospitalisation</measure>
    <time_frame>up to 48 weeks gestational age</time_frame>
    <description>number of days from admission to home discharge from NICU</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weight (in grams) at 40 weeks postmenstrual age</measure>
    <time_frame>40 week gestational age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length(in centimeters) at 40 weeks postmenstrual age</measure>
    <time_frame>40 week gestational age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Head circumference (in centimeters) at 40 weeks postmenstrual age</measure>
    <time_frame>40 week gestational age</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acquisition of full oral feeding</measure>
    <time_frame>up to 48 weeks gestational age</time_frame>
    <description>Postmenstrual age at the acquisition of full oral feeding</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feeding with Human milk</measure>
    <time_frame>up to 40 weeks gestational age</time_frame>
    <description>Feeding with human milk at 40 weeks postmenstrual age (yes or no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurodevelopmental outcome</measure>
    <time_frame>5-6 years of age</time_frame>
    <description>Children neurodevelopment is assessed using the Griffiths Development Scales (GMDS).&#xD;
Scores range from 50 to 150 General quotient mean 100 SD 12, sub scales mean 100 SD 16 Higher scores mean a better outcome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Behavioral outcome</measure>
    <time_frame>5-6 years of age</time_frame>
    <description>Children behavior is assessed using the Child Behavior Checklist. A T score above 70 is considered to be in the clinical range, a T score between 65 an 70 is considered borderline while a T score below 65 is considered normal</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuromotor outcome</measure>
    <time_frame>5-6 years of age</time_frame>
    <description>Children neuromotor is assessed using the Movement Assessment Battery for Children (Movement ABC).&#xD;
A score above 67 is considered to be in the normal range, a score between 57 an 67 is considered borderline while a score below 56 is considered pathological</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Attention outcome</measure>
    <time_frame>5-6 years of age</time_frame>
    <description>Child attention abilities is assessed using the Early Childhood Attention Battery (ECAB).&#xD;
Scaled scores range from 1 to 19. Lower scores indicate worst outcome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>L1 promoter methylation levels on buccal swab</measure>
    <time_frame>5-6 years of age</time_frame>
    <description>epigenetic analysis - L1 promoter methylation (Percent) assessment is performed on a buccal swab collected at follow-up assessment at 5-6 years.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">70</enrollment>
  <condition>Premature Birth</condition>
  <arm_group>
    <arm_group_label>Early Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The early intervention program is delivered during the NICU stay, according to the MITP and Premie Start Protocol, in order to train parents to: recognize signs of infant stress and alert-available behavior to promote mother-infant interaction; adopt principles of graded stimulation; optimize interactions and avoid overwhelming infants through facilitation strategies (for example, engage and support the visual attention of the newborn). The program is held in eight main sessions and one additional post-discharge session.&#xD;
In addition parents are trained and invited to daily promote preterm baby massage therapy and visual attention according to a detailed protocol.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard Care according to NICU protocols including Kangaroo Mother Care, nesting and minimal handling</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Early Intervention</intervention_name>
    <arm_group_label>Early Intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Gestational age between 25+0 and 29+6 weeks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  major brain lesions as documented by cranial ultrasound (intraventricular hemorrhage &gt;&#xD;
             2 grade, cystic periventricular leukomalacia)&#xD;
&#xD;
          -  neurosensorial deficits (retinopathy of prematurity &gt; stage 2)&#xD;
&#xD;
          -  genetic syndromes and/or major congenital malformations&#xD;
&#xD;
          -  major neonatal comorbidities&#xD;
&#xD;
        Mothers are selected according to the following inclusion criteria: age over 18 years, good&#xD;
        comprehension of Italian language, no obvious cognitive impairments or psychiatric&#xD;
        disorders, no drug addiction and no single-parent families.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>25 Weeks</minimum_age>
    <maximum_age>29 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Monica Fumagalli, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico</name>
      <address>
        <city>Milan</city>
        <zip>20122</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Newnham CA, Milgrom J, Skouteris H. Effectiveness of a modified Mother-Infant Transaction Program on outcomes for preterm infants from 3 to 24 months of age. Infant Behav Dev. 2009 Jan;32(1):17-26. doi: 10.1016/j.infbeh.2008.09.004. Epub 2008 Nov 20.</citation>
    <PMID>19026450</PMID>
  </reference>
  <reference>
    <citation>Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Morandi F, Beri S, Menozzi G, Mosca F, Borgatti R, Montirosso R. Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants. Front Behav Neurosci. 2015 Apr 21;9:99. doi: 10.3389/fnbeh.2015.00099. eCollection 2015.</citation>
    <PMID>25941480</PMID>
  </reference>
  <reference>
    <citation>Guzzetta A, D'Acunto MG, Carotenuto M, Berardi N, Bancale A, Biagioni E, Boldrini A, Ghirri P, Maffei L, Cioni G. The effects of preterm infant massage on brain electrical activity. Dev Med Child Neurol. 2011 Sep;53 Suppl 4:46-51. doi: 10.1111/j.1469-8749.2011.04065.x.</citation>
    <PMID>21950394</PMID>
  </reference>
  <reference>
    <citation>Ricci D, Cesarini L, Romeo DM, Gallini F, Serrao F, Groppo M, De Carli A, Cota F, Lepore D, Molle F, Ratiglia R, De Carolis MP, Mosca F, Romagnoli C, Guzzetta F, Cowan F, Ramenghi LA, Mercuri E. Visual function at 35 and 40 weeks' postmenstrual age in low-risk preterm infants. Pediatrics. 2008 Dec;122(6):e1193-8. doi: 10.1542/peds.2008-1888.</citation>
    <PMID>19047222</PMID>
  </reference>
  <reference>
    <citation>Ricci D, Romeo DM, Serrao F, Cesarini L, Gallini F, Cota F, Leone D, Zuppa AA, Romagnoli C, Cowan F, Mercuri E. Application of a neonatal assessment of visual function in a population of low risk full-term newborn. Early Hum Dev. 2008 Apr;84(4):277-80. doi: 10.1016/j.earlhumdev.2007.10.002. Epub 2007 Nov 8.</citation>
    <PMID>17996405</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>November 16, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 6, 2016</study_first_posted>
  <last_update_submitted>February 9, 2023</last_update_submitted>
  <last_update_submitted_qc>February 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Early intervention</keyword>
  <keyword>Brain Development</keyword>
  <keyword>Neurodevelopment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Premature Birth</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>individual patient consent would be required according to the EU GDPR and Italian regulations</ipd_description>
  </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/NCT02983513
org study id: MITP Preterm
nct id: NCT02983513
lead sponsor: 
has dmc: No
Preterm infants, during their stay in the Neonatal Intensive Care Unit (NICU), face a period
      of stressful environment, which may negatively impact early brain development and subsequent
      neurobehavioral outcomes. This study aims to assess the effectiveness of training parents in
      reducing stressful experiences early in life and in enhancing brain development and long term
      developmental outcomes.
Very preterm birth is associated with motor, cognitive and behavioral problems.

      Micro-structural brain abnormalities, even in the absence of focal lesions, have been
      documented by neuroimaging studies in preterm infants at term corrected age and later in
      childhood. These alterations in brain maturation occurring during the neonatal period may be
      implicated in long-term neurobehavioral disorders later experienced by preterm babies.

      However, there is increasing evidence that also negative environmental factors (intensive
      care, excessive sensory stimulation, paucity of parental contact etc.) can affect later
      outcomes.

      Potential benefits of early dyadic interaction and preterm baby massage in reducing the
      effects of the NICU stressor environment have been demonstrated. More recently, few studies
      have investigated visual function in preterm infants focusing on the potential role of early
      visual interaction to enhance attention and improve later neurodevelopment.

      The role of early intervention strategies to improve neurodevelopment has been recently
      emphasized.

      Early intervention programs based on the concept of "individualized care" have proved to be
      effective in promoting brain maturation and neurodevelopmental outcome. In this context,
      early interventions as the Mother Infant Transaction Program (MITP) and the Premie Start,
      both targeting parenting, have the greatest potential to have sustained effects on child
      development.

      In addition, recent studies have shown that exposure to stressful events in the neonatal
      period can cause epigenetic modifications in children born preterm; in particular alteration
      of serotonergic tone was observed, associated with methylation of the serotonin transporter
      gene, which could be implicated in the etiology of behavioral disorders observed in these
      children. In animal models these epigenetic effects appear to be influenced by maternal care
      that can epigenetically modulate the offsprings' stress response.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Double (Participant, Outcomes Assessor)
measure: Neonatal Visual Assessment Battery to evaluate visual function
time frame: 40 weeks postmenstrual age
description: Neonatal Visual Function is assessed using the Visual Assessment Battery developed by Ricci et al. The assessment evaluates the following items: Ocular spontaneous motility, ability to fix and follow a target, reaction to colour, visual acuity and visual attention at distance. Each item is scored as normal (score 0) or abnormal (score 1). The global score is then calculated as the sum of all the individual items, as designed by the authors.
measure: Neonatal Behavior
time frame: 2 months corrected age
description: Neonatal behavior is assessed using the Neonatal Behavior Assessment Scale that evaluates: habituation, social-interactive, motor system, state organization and regulation, autonomic system, reflexes.
measure: Brain development
time frame: 40 weeks postmenstrual age
description: Conventional and advanced MRI
measure: Developmental outcome
time frame: 24 months corrected age
description: Children development is assessed using the Bayley Scales of Infant and Toddlers (Third edition) - including: cognitive, motor, language, social-emotional and adaptive behavior)
measure: Epigenetic changes
time frame: up to 48 weeks gestational age
description: epigenetic analysis is performed at birth on a cord blood sample (0.5 ml) and at hospital discharge on a peripheral blood sample (0.5 ml) collected according routine clinical procedures
measure: overall duration of hospitalisation
time frame: up to 48 weeks gestational age
description: number of days from admission to home discharge from NICU
measure: Weight (in grams) at 40 weeks postmenstrual age
time frame: 40 week gestational age
measure: Length(in centimeters) at 40 weeks postmenstrual age
time frame: 40 week gestational age
measure: Head circumference (in centimeters) at 40 weeks postmenstrual age
time frame: 40 week gestational age
measure: Acquisition of full oral feeding
time frame: up to 48 weeks gestational age
description: Postmenstrual age at the acquisition of full oral feeding
measure: Feeding with Human milk
time frame: up to 40 weeks gestational age
description: Feeding with human milk at 40 weeks postmenstrual age (yes or no)
measure: Neurodevelopmental outcome
time frame: 5-6 years of age
description: Children neurodevelopment is assessed using the Griffiths Development Scales (GMDS).
Scores range from 50 to 150 General quotient mean 100 SD 12, sub scales mean 100 SD 16 Higher scores mean a better outcome
measure: Behavioral outcome
time frame: 5-6 years of age
description: Children behavior is assessed using the Child Behavior Checklist. A T score above 70 is considered to be in the clinical range, a T score between 65 an 70 is considered borderline while a T score below 65 is considered normal
measure: Neuromotor outcome
time frame: 5-6 years of age
description: Children neuromotor is assessed using the Movement Assessment Battery for Children (Movement ABC).
A score above 67 is considered to be in the normal range, a score between 57 an 67 is considered borderline while a score below 56 is considered pathological
measure: Attention outcome
time frame: 5-6 years of age
description: Child attention abilities is assessed using the Early Childhood Attention Battery (ECAB).
Scaled scores range from 1 to 19. Lower scores indicate worst outcome
measure: L1 promoter methylation levels on buccal swab
time frame: 5-6 years of age
description: epigenetic analysis - L1 promoter methylation (Percent) assessment is performed on a buccal swab collected at follow-up assessment at 5-6 years.
arm group label: Early Intervention
arm group type: Experimental
description: The early intervention program is delivered during the NICU stay, according to the MITP and Premie Start Protocol, in order to train parents to: recognize signs of infant stress and alert-available behavior to promote mother-infant interaction; adopt principles of graded stimulation; optimize interactions and avoid overwhelming infants through facilitation strategies (for example, engage and support the visual attention of the newborn). The program is held in eight main sessions and one additional post-discharge session.
In addition parents are trained and invited to daily promote preterm baby massage therapy and visual attention according to a detailed protocol.
arm group label: Standard Care
arm group type: No Intervention
description: Standard Care according to NICU protocols including Kangaroo Mother Care, nesting and minimal handling
intervention type: Behavioral
intervention name: Early Intervention
arm group label: Early Intervention
criteria: 
gender: All
minimum age: 25 Weeks
maximum age: 29 Weeks
healthy volunteers: No
last name: Monica Fumagalli, MD
role: Principal Investigator
affiliation: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
facility: 
country: Italy
citation: Newnham CA, Milgrom J, Skouteris H. Effectiveness of a modified Mother-Infant Transaction Program on outcomes for preterm infants from 3 to 24 months of age. Infant Behav Dev. 2009 Jan;32(1):17-26. doi: 10.1016/j.infbeh.2008.09.004. Epub 2008 Nov 20.
PMID: 19026450
citation: Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Morandi F, Beri S, Menozzi G, Mosca F, Borgatti R, Montirosso R. Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants. Front Behav Neurosci. 2015 Apr 21;9:99. doi: 10.3389/fnbeh.2015.00099. eCollection 2015.
PMID: 25941480
citation: Guzzetta A, D'Acunto MG, Carotenuto M, Berardi N, Bancale A, Biagioni E, Boldrini A, Ghirri P, Maffei L, Cioni G. The effects of preterm infant massage on brain electrical activity. Dev Med Child Neurol. 2011 Sep;53 Suppl 4:46-51. doi: 10.1111/j.1469-8749.2011.04065.x.
PMID: 21950394
citation: Ricci D, Cesarini L, Romeo DM, Gallini F, Serrao F, Groppo M, De Carli A, Cota F, Lepore D, Molle F, Ratiglia R, De Carolis MP, Mosca F, Romagnoli C, Guzzetta F, Cowan F, Ramenghi LA, Mercuri E. Visual function at 35 and 40 weeks' postmenstrual age in low-risk preterm infants. Pediatrics. 2008 Dec;122(6):e1193-8. doi: 10.1542/peds.2008-1888.
PMID: 19047222
citation: Ricci D, Romeo DM, Serrao F, Cesarini L, Gallini F, Cota F, Leone D, Zuppa AA, Romagnoli C, Cowan F, Mercuri E. Application of a neonatal assessment of visual function in a population of low risk full-term newborn. Early Hum Dev. 2008 Apr;84(4):277-80. doi: 10.1016/j.earlhumdev.2007.10.002. Epub 2007 Nov 8.
PMID: 17996405
responsible party type: Sponsor
mesh term: Premature Birth
sharing ipd: No
ipd description: individual patient consent would be required according to the EU GDPR and Italian regulations