<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/NCT03838146</url>
  </required_header>
  <id_info>
    <org_study_id>12-002524b</org_study_id>
    <nct_id>NCT03838146</nct_id>
  </id_info>
  <brief_title>Influence of Maternal Exercise on Infant Skeletal Muscle and Metabolomics</brief_title>
  <official_title>Influence of Maternal Exercise on Infant Skeletal Muscle and Metabolomics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>East Carolina University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>American Heart Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>East Carolina University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The American Heart Association suggests that heart disease prevention should target pregnancy&#xD;
      and the first year of life; however, there is a fundamental gap in knowledge regarding the&#xD;
      effects of prenatal exercise on the prevention of heart disease.[1, 2] Insulin resistance in&#xD;
      skeletal muscle is believed to be a critical contributor to the metabolic syndrome which&#xD;
      increases the risk for cardiovascular disease (CVD). Conversely, exercise improves insulin&#xD;
      sensitivity and many other facets of skeletal muscle function and metabolism; however, it is&#xD;
      unclear if this positive effect can be &quot;imprinted&quot; in the skeletal muscle of the fetus with&#xD;
      maternal exercise and accordingly diminish CVD risk in offspring. Our previous studies found&#xD;
      that exercise during pregnancy leads to improved heart measures and reduced adiposity.[3-6]&#xD;
      These studies demonstrated the potential for maternal exercise to reduce risk for CVD, but&#xD;
      the cellular mechanisms involved, however, are not clearly evident. The proposed project will&#xD;
      fill this critical gap and assess the influence of maternal exercise intervention to&#xD;
      &quot;imprint&quot; progenitor stem cells in the fetus (umbilical cord tissue) to develop into insulin&#xD;
      sensitive skeletal muscle and also improve indices of infant morphometry and movement. Using&#xD;
      a randomized design, 160 women will perform either exercise intervention (aerobic training,&#xD;
      resistance training, or both) or usual care (controls). Infant cord tissue and blood will be&#xD;
      sampled at birth while blood will be sampled at 1 month of age. Similarly, infant neuromotor&#xD;
      and morphometric examinations will be performed at 1 month. and at 1-month of age via blood&#xD;
      sample, neuromotor, and morphometric examinations. The rationale for the project is to&#xD;
      elucidate the effects of maternal exercise on offspring health outcomes and determine&#xD;
      specific metabolic targets predictive of offspring long-term disease risk. The investigators&#xD;
      will test the central hypothesis that exercise during pregnancy alters skeletal muscle in a&#xD;
      manner which decreases the risk of heart disease in offspring. To test this central&#xD;
      hypothesis, the investigators will pursue two specific aims: Aim 1- Determine the ability of&#xD;
      regular maternal exercise to imprint key myocellular metabolic (insulin sensitivity)&#xD;
      properties of offspring mesenchymal stem cells (MSC), neuromotor function, and morphometry.&#xD;
      Aim 2- Determine the distinct abilities of regular maternal exercise to imprint the&#xD;
      metabolome of offspring MSC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Is offspring skeletal muscle function and metabolism imprinted by regular maternal exercise?&#xD;
      What offspring metabolome markers are altered with regular maternal exercise? The&#xD;
      investigators will use a randomized design of 160 women to either exercise intervention&#xD;
      (aerobic training, resistance training, or both) or usual care (controls). Infant cord tissue&#xD;
      and blood will be sampled at birth while blood will be sampled at 1 month of age. Similarly,&#xD;
      infant neuromotor and morphometric examinations will be performed at 1 month. and at 1-month&#xD;
      of age via blood sample, neuromotor, and morphometric examinations. The rationale for the&#xD;
      project is to elucidate the effects of maternal exercise on offspring health outcomes and&#xD;
      determine specific metabolic targets predictive of offspring long-term disease risk.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 1, 2018</start_date>
  <completion_date type="Actual">January 30, 2023</completion_date>
  <primary_completion_date type="Actual">January 30, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>comparing 3 exercise interventions to a control (non-exercise) group</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Care Provider, Investigator)</masking>
    <masking_description>the clinicians and investigators taking measures are blinded to group assignment</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Human Skeletal Muscles cells grown from MSCs will have insulin responsiveness measured</measure>
    <time_frame>At Birth</time_frame>
    <description>Western blot analysis of Akt phosphorylation will be conducted on cell lysates from myotubes under basal or following insulin-stimulation. Glycogen synthesis will be measured under basal and insulin-stimulated conditions. Data will be presented as % change in glycogen synthesis following insulin stimulation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Global and targeted metabolomics analysis will be conducted to map out pathways and mechanisms from regular maternal exercise. Docosahexaenoic acid (DHA), Eicosapentaenoic Acid (EPA), Docosapentaenoic Acid (DPA), and Arachidonic acid (ARA).</measure>
    <time_frame>At 16 weeks and 36 weeks gestation</time_frame>
    <description>Targeted quantitative LC/MS analysis of DHA and EPA from participants at 16 (pre-training intervention) and 36 weeks, DHA and EPA levels from umbilical cord tissue sample, and DHA and EPA levels from umbilical cord (infant) blood will be compared between groups.&#xD;
From our pathway analysis of identified metabolites of interest, we will be able to map the metabolites of interest within common pathways related to maternal exercise exposure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peabody Developmental Motor Scales, 2nd edition (PDMS-2) will be performed by a pediatric physical therapist (blinded to group classification) to measure gross motor skills of infants up to 12 months of age.</measure>
    <time_frame>at 1 month postnatal visit</time_frame>
    <description>3 of the 6 subtests can be used on 1 month olds. All items scored from 0-2, which include:&#xD;
Reflexes: 8-item subtest that measures child's ability to react to environmental events.&#xD;
Stationary: 30-item subtest that measures child's ability to control body within center of gravity and retain equilibrium&#xD;
Locomotion: 89-item subtest that measures child's ability to move from one place to another through crawling, walking, running, hopping, and jumping forward&#xD;
we only do the Reflexes Range (0-16), Stationary Range (0-60), and Locomotion Range (0-178) subtests. Each subtest score is also converted to percentile (comparing infant's behavior to the normative sample). All subtest score are summed to determine the Gross Motor Quotient (GMQ), and a GMQ percentile score will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>A trained (blinded) researcher will measure bicep, tricep, and subscapular skinfold measures, circumferences (abdominal, head, mid-upper arm), and lengths (body, femur, leg, humeral). All measures are recorded as mm.</measure>
    <time_frame>at 1 month postnatal visit</time_frame>
    <description>All measures will be taken in duplicate on the right side following published standards for skinfold and circumference location.&#xD;
Data will be used to compare individual skinfolds, sum of skinfolds and circumferences measures between groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>A trained (blinded) researcher will measure body weight on an infant scale</measure>
    <time_frame>at 1 month postnatal visit</time_frame>
    <description>Body weight will be done to the nearest tenth of a kilogram. Data will be used to compare body weight measures between groups</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">167</enrollment>
  <condition>Exercise</condition>
  <arm_group>
    <arm_group_label>Non-Exercise Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>This group will come in regularly for measurements, but will not have an exercise intervention. If necessary for retention of participants, then we will meet with controls 3 times a week to stress reduction techniques.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Resistance Type of Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group will participate in resistance exercise intervention 3 times per week from enrollment to delivery.The resistance training (RT) group will perform three sets of 12-15 repetitions of 10-12 resistance exercises in a circuit, with rest of 30-60 seconds between sets as needed. Participants will use a combination of Cybex machines (Cybex International, Medway, MA), resistance bands, and free weights. Routines will change every 3 weeks to add variety and improve compliance.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Combination Type of Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group will participate in combination (aerobic+resistance) exercise intervention 3 times per week from enrollment to delivery. The combination (CT) group will alternate between resistance and aerobic exercises. Participants will perform 4.5 minute bouts of aerobic exercise and perform four resistance exercises of 12-15 repetition that vary between aerobic bouts[17-19]. The aerobic exercise bouts will be performed on the aerobic machine of the participant's choosing as described above. The resistance routine will follow similar guidelines as the resistance group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aerobic Type of Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group will participate in aerobic exercise intervention 3 times per week from enrollment to delivery. The aerobic training (AT) group will perform a continuous aerobic exercise of their choosing (e.g., treadmill, ellipticals, stairs, Zumba, or outside walking/jogging). Participants' ability to choose an aerobic activity that they are comfortable with and enjoy is intended to improve compliance.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Types of Exercise</intervention_name>
    <description>moderate intensity exercise</description>
    <arm_group_label>Aerobic Type of Exercise</arm_group_label>
    <arm_group_label>Combination Type of Exercise</arm_group_label>
    <arm_group_label>Resistance Type of Exercise</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  &lt;16 weeks gestation&#xD;
&#xD;
          -  singleton pregnancy telephone/email contact&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  chronic conditions i.e. diabetes, hypertension, HIV, etc.&#xD;
&#xD;
          -  use of medications that affect fetal development;&#xD;
&#xD;
          -  use of alcohol, tobacco, or other drugs&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>our study focuses on exercise exposure during pregnancy, therefore, all participants are female.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>East Carolina University</name>
      <address>
        <city>Greenville</city>
        <state>North Carolina</state>
        <zip>27834</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>November 5, 2018</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>August 5, 2023</last_update_submitted>
  <last_update_submitted_qc>August 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>East Carolina University</investigator_affiliation>
    <investigator_full_name>Linda May</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>we will not be sharing individual data with other researchers</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/NCT03838146
org study id: 12-002524b
nct id: NCT03838146
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The American Heart Association suggests that heart disease prevention should target pregnancy
      and the first year of life; however, there is a fundamental gap in knowledge regarding the
      effects of prenatal exercise on the prevention of heart disease.[1, 2] Insulin resistance in
      skeletal muscle is believed to be a critical contributor to the metabolic syndrome which
      increases the risk for cardiovascular disease (CVD). Conversely, exercise improves insulin
      sensitivity and many other facets of skeletal muscle function and metabolism; however, it is
      unclear if this positive effect can be "imprinted" in the skeletal muscle of the fetus with
      maternal exercise and accordingly diminish CVD risk in offspring. Our previous studies found
      that exercise during pregnancy leads to improved heart measures and reduced adiposity.[3-6]
      These studies demonstrated the potential for maternal exercise to reduce risk for CVD, but
      the cellular mechanisms involved, however, are not clearly evident. The proposed project will
      fill this critical gap and assess the influence of maternal exercise intervention to
      "imprint" progenitor stem cells in the fetus (umbilical cord tissue) to develop into insulin
      sensitive skeletal muscle and also improve indices of infant morphometry and movement. Using
      a randomized design, 160 women will perform either exercise intervention (aerobic training,
      resistance training, or both) or usual care (controls). Infant cord tissue and blood will be
      sampled at birth while blood will be sampled at 1 month of age. Similarly, infant neuromotor
      and morphometric examinations will be performed at 1 month. and at 1-month of age via blood
      sample, neuromotor, and morphometric examinations. The rationale for the project is to
      elucidate the effects of maternal exercise on offspring health outcomes and determine
      specific metabolic targets predictive of offspring long-term disease risk. The investigators
      will test the central hypothesis that exercise during pregnancy alters skeletal muscle in a
      manner which decreases the risk of heart disease in offspring. To test this central
      hypothesis, the investigators will pursue two specific aims: Aim 1- Determine the ability of
      regular maternal exercise to imprint key myocellular metabolic (insulin sensitivity)
      properties of offspring mesenchymal stem cells (MSC), neuromotor function, and morphometry.
      Aim 2- Determine the distinct abilities of regular maternal exercise to imprint the
      metabolome of offspring MSC.
Is offspring skeletal muscle function and metabolism imprinted by regular maternal exercise?
      What offspring metabolome markers are altered with regular maternal exercise? The
      investigators will use a randomized design of 160 women to either exercise intervention
      (aerobic training, resistance training, or both) or usual care (controls). Infant cord tissue
      and blood will be sampled at birth while blood will be sampled at 1 month of age. Similarly,
      infant neuromotor and morphometric examinations will be performed at 1 month. and at 1-month
      of age via blood sample, neuromotor, and morphometric examinations. The rationale for the
      project is to elucidate the effects of maternal exercise on offspring health outcomes and
      determine specific metabolic targets predictive of offspring long-term disease risk.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: comparing 3 exercise interventions to a control (non-exercise) group
primary purpose: Prevention
masking: Double (Care Provider, Investigator)
masking description: the clinicians and investigators taking measures are blinded to group assignment
measure: Human Skeletal Muscles cells grown from MSCs will have insulin responsiveness measured
time frame: At Birth
description: Western blot analysis of Akt phosphorylation will be conducted on cell lysates from myotubes under basal or following insulin-stimulation. Glycogen synthesis will be measured under basal and insulin-stimulated conditions. Data will be presented as % change in glycogen synthesis following insulin stimulation.
measure: Global and targeted metabolomics analysis will be conducted to map out pathways and mechanisms from regular maternal exercise. Docosahexaenoic acid (DHA), Eicosapentaenoic Acid (EPA), Docosapentaenoic Acid (DPA), and Arachidonic acid (ARA).
time frame: At 16 weeks and 36 weeks gestation
description: Targeted quantitative LC/MS analysis of DHA and EPA from participants at 16 (pre-training intervention) and 36 weeks, DHA and EPA levels from umbilical cord tissue sample, and DHA and EPA levels from umbilical cord (infant) blood will be compared between groups.
From our pathway analysis of identified metabolites of interest, we will be able to map the metabolites of interest within common pathways related to maternal exercise exposure.
measure: Peabody Developmental Motor Scales, 2nd edition (PDMS-2) will be performed by a pediatric physical therapist (blinded to group classification) to measure gross motor skills of infants up to 12 months of age.
time frame: at 1 month postnatal visit
description: 3 of the 6 subtests can be used on 1 month olds. All items scored from 0-2, which include:
Reflexes: 8-item subtest that measures child's ability to react to environmental events.
Stationary: 30-item subtest that measures child's ability to control body within center of gravity and retain equilibrium
Locomotion: 89-item subtest that measures child's ability to move from one place to another through crawling, walking, running, hopping, and jumping forward
we only do the Reflexes Range (0-16), Stationary Range (0-60), and Locomotion Range (0-178) subtests. Each subtest score is also converted to percentile (comparing infant's behavior to the normative sample). All subtest score are summed to determine the Gross Motor Quotient (GMQ), and a GMQ percentile score will be determined.
measure: A trained (blinded) researcher will measure bicep, tricep, and subscapular skinfold measures, circumferences (abdominal, head, mid-upper arm), and lengths (body, femur, leg, humeral). All measures are recorded as mm.
time frame: at 1 month postnatal visit
description: All measures will be taken in duplicate on the right side following published standards for skinfold and circumference location.
Data will be used to compare individual skinfolds, sum of skinfolds and circumferences measures between groups
measure: A trained (blinded) researcher will measure body weight on an infant scale
time frame: at 1 month postnatal visit
description: Body weight will be done to the nearest tenth of a kilogram. Data will be used to compare body weight measures between groups
arm group label: Non-Exercise Control
arm group type: No Intervention
description: This group will come in regularly for measurements, but will not have an exercise intervention. If necessary for retention of participants, then we will meet with controls 3 times a week to stress reduction techniques.
arm group label: Resistance Type of Exercise
arm group type: Experimental
description: This group will participate in resistance exercise intervention 3 times per week from enrollment to delivery.The resistance training (RT) group will perform three sets of 12-15 repetitions of 10-12 resistance exercises in a circuit, with rest of 30-60 seconds between sets as needed. Participants will use a combination of Cybex machines (Cybex International, Medway, MA), resistance bands, and free weights. Routines will change every 3 weeks to add variety and improve compliance.
arm group label: Combination Type of Exercise
arm group type: Experimental
description: This group will participate in combination (aerobic+resistance) exercise intervention 3 times per week from enrollment to delivery. The combination (CT) group will alternate between resistance and aerobic exercises. Participants will perform 4.5 minute bouts of aerobic exercise and perform four resistance exercises of 12-15 repetition that vary between aerobic bouts[17-19]. The aerobic exercise bouts will be performed on the aerobic machine of the participant's choosing as described above. The resistance routine will follow similar guidelines as the resistance group.
arm group label: Aerobic Type of Exercise
arm group type: Experimental
description: This group will participate in aerobic exercise intervention 3 times per week from enrollment to delivery. The aerobic training (AT) group will perform a continuous aerobic exercise of their choosing (e.g., treadmill, ellipticals, stairs, Zumba, or outside walking/jogging). Participants' ability to choose an aerobic activity that they are comfortable with and enjoy is intended to improve compliance.
intervention type: Behavioral
intervention name: Types of Exercise
description: moderate intensity exercise
arm group label: Aerobic Type of Exercise
arm group label: Combination Type of Exercise
arm group label: Resistance Type of Exercise
criteria: 
gender: Female
gender based: Yes
gender description: our study focuses on exercise exposure during pregnancy, therefore, all participants are female.
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: East Carolina University
investigator full name: Linda May
investigator title: Associate Professor
sharing ipd: No
ipd description: we will not be sharing individual data with other researchers