<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/NCT01687127</url>
  </required_header>
  <id_info>
    <org_study_id>H11-03009</org_study_id>
    <secondary_id>CIHR Application Nr. 247226</secondary_id>
    <nct_id>NCT01687127</nct_id>
  </id_info>
  <brief_title>Impact of High-dose Folic Acid Supplementation on Pathways Linked to DNA Formation</brief_title>
  <official_title>Metabolic Consequences of High-Dose Folic Acid Supplementation on Kinetics of 1-Carbon Metabolism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of British Columbia</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>
      Periconceptional supplementation with folic acid - the synthetic form of the B-vitamin folate&#xD;
      - reduces the occurrence of adverse pregnancy outcomes such as spina bifida. The underlying&#xD;
      biochemical mechanisms for how folic acid affects health outcomes however are unknown. The&#xD;
      naturally occurring form 5-methyltetrahydrofolate (5-MTHF) is now available and discussed as&#xD;
      an adequate substitute to folic acid. This study aims to determine the effect of folic acid&#xD;
      compared to 5-MTHF on cellular mechanisms. Stable isotope tracer protocols will be used that&#xD;
      allow determining the effect of folic acid on the dynamics of metabolic pathways in the human&#xD;
      body.&#xD;
&#xD;
      Hypothesis: Supplementation with high-dose folic acid alters the turnover rate of folate&#xD;
      dependent pathways in healthy humans; but 5-MTHF does not. Genetic variations in a key enzyme&#xD;
      of the folate metabolism will aggravate the effect of folic acid on the metabolic pathways.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">January 1, 2024</start_date>
  <completion_date type="Anticipated">December 31, 2026</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2026</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>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Plateau enrichment of infused amino acid tracers and related metabolites to quantify turnover rates of folate dependent pathways</measure>
    <time_frame>24 weeks</time_frame>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>One-carbon Metabolism in Healthy Individuals</condition>
  <arm_group>
    <arm_group_label>Folic acid supplementation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Folic acid will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>5-MTHF supplementation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The calcium salt of 5-methyltetrahydrofolate (5-MTHF; Brand name &quot;Metafolin&quot;) will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Folic acid</intervention_name>
    <description>Supplement</description>
    <arm_group_label>Folic acid supplementation</arm_group_label>
    <other_name>Pteroylmonoglutamic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>5-methyltetrahydrofolate, calcium salt</intervention_name>
    <description>Supplement</description>
    <arm_group_label>5-MTHF supplementation</arm_group_label>
    <other_name>5-MTHF</other_name>
    <other_name>Metafolin (brand name)</other_name>
    <other_name>Levomefolic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Generally healthy&#xD;
&#xD;
          -  Body mass index of between 19-24 kg/m2&#xD;
&#xD;
          -  Normal folate, vitamin B12, and B6 status&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to swallow tablets&#xD;
&#xD;
          -  Unable to receive intravenous catheters&#xD;
&#xD;
          -  Use of vitamin supplements, amino acid or protein supplements for more than six months&#xD;
             before study participation&#xD;
&#xD;
          -  Chronic consumption of a high-protein diet (e.g. Atkins Diet)&#xD;
&#xD;
          -  Medical conditions such as diabetes, asthma, cancer, cardiovascular disease, a history&#xD;
             of neural tube defect (such as spina bifida) affected pregnancy, have had&#xD;
             gastrointestinal surgery, abnormal kidney, thyroid function, or psychiatric illness,&#xD;
             or any other chronic disease&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Smoking, use of recreational drugs, and/or consumption of more than one alcohol drink&#xD;
             per day or more than seven per week.&#xD;
&#xD;
          -  Use of long-term prescription medication such as hormonal contraceptives,&#xD;
             antidepressants, anticonvulsants, anticoagulants, or other chronic medication&#xD;
&#xD;
          -  Blood donation in the last three months prior to study start&#xD;
&#xD;
          -  Unable to provide informed consent, or unable to read and write English&#xD;
&#xD;
          -  Low compliance to intervention as determined by early steady-state or reduction in&#xD;
             blood folate concentrations&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yvonne Lamers, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of British Columbia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yvonne Lamers, PhD</last_name>
    <phone>604-827-1776</phone>
    <email>yvonne.lamers@ubc.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Amy McMahon, PhD</last_name>
    <phone>604-822-1250</phone>
    <email>amy.mcmahon@ubc.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Children's and Women's Health Centre of BC (incl. Sunny Hill), Child and Family Research Institute</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 4H4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <contact>
      <last_name>Yvonne Lamers, PhD</last_name>
      <phone>604-827-1776</phone>
      <email>yvonne.lamers@ubc.ca</email>
    </contact>
    <contact_backup>
      <last_name>Amy McMahon, PhD</last_name>
      <phone>604-822-1250</phone>
      <email>amy.mcmahon@ubc.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Jehannine C Austin, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Amanda Skoll, MD, FRCSC</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>September 13, 2012</study_first_submitted>
  <study_first_submitted_qc>September 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2012</study_first_posted>
  <last_update_submitted>August 14, 2023</last_update_submitted>
  <last_update_submitted_qc>August 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Yvonne Lamers</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>folic acid</keyword>
  <keyword>folate</keyword>
  <keyword>5-methyltetrahydrofolate</keyword>
  <keyword>supplements</keyword>
  <keyword>women</keyword>
  <keyword>one-carbon metabolism</keyword>
  <keyword>methionine</keyword>
  <keyword>DNA methylation</keyword>
  <keyword>in vivo kinetics</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Vitamin B Complex</mesh_term>
    <mesh_term>Calcium</mesh_term>
  </intervention_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/NCT01687127
org study id: H11-03009
secondary id: CIHR Application Nr. 247226
nct id: NCT01687127
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Periconceptional supplementation with folic acid - the synthetic form of the B-vitamin folate
      - reduces the occurrence of adverse pregnancy outcomes such as spina bifida. The underlying
      biochemical mechanisms for how folic acid affects health outcomes however are unknown. The
      naturally occurring form 5-methyltetrahydrofolate (5-MTHF) is now available and discussed as
      an adequate substitute to folic acid. This study aims to determine the effect of folic acid
      compared to 5-MTHF on cellular mechanisms. Stable isotope tracer protocols will be used that
      allow determining the effect of folic acid on the dynamics of metabolic pathways in the human
      body.

      Hypothesis: Supplementation with high-dose folic acid alters the turnover rate of folate
      dependent pathways in healthy humans; but 5-MTHF does not. Genetic variations in a key enzyme
      of the folate metabolism will aggravate the effect of folic acid on the metabolic pathways.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Plateau enrichment of infused amino acid tracers and related metabolites to quantify turnover rates of folate dependent pathways
time frame: 24 weeks
arm group label: Folic acid supplementation
arm group type: Experimental
description: Folic acid will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism.
arm group label: 5-MTHF supplementation
arm group type: Experimental
description: The calcium salt of 5-methyltetrahydrofolate (5-MTHF; Brand name "Metafolin") will be given orally in form of tablets. A supplement of 1 mg will be taken daily for 12 weeks. Thereafter, a supplement of 5 mg will be taken daily for 12 weeks (i.e., until Week 24). At baseline, Week 12, and Week 24, subjects will receive a 9-hour primed constant infusion of amino acids in saline solution for quantification of kinetics of one-carbon metabolism.
intervention type: Dietary Supplement
intervention name: Folic acid
description: Supplement
arm group label: Folic acid supplementation
other name: Pteroylmonoglutamic acid
intervention type: Dietary Supplement
intervention name: 5-methyltetrahydrofolate, calcium salt
description: Supplement
arm group label: 5-MTHF supplementation
other name: 5-MTHF
other name: Metafolin (brand name)
other name: Levomefolic acid
criteria: 
gender: Female
minimum age: 20 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Yvonne Lamers, PhD
role: Principal Investigator
affiliation: University of British Columbia
last name: Yvonne Lamers, PhD
phone: 604-827-1776
email: yvonne.lamers@ubc.ca
last name: Amy McMahon, PhD
phone: 604-822-1250
email: amy.mcmahon@ubc.ca
facility: 
contact: 
contact backup: 
investigator: 
investigator: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Yvonne Lamers
investigator title: Principal Investigator
mesh term: Folic Acid
mesh term: Vitamin B Complex
mesh term: Calcium