<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/NCT02998203</url>
  </required_header>
  <id_info>
    <org_study_id>CyprusUT</org_study_id>
    <nct_id>NCT02998203</nct_id>
  </id_info>
  <brief_title>Organic Diet Intervention in Primary School Children</brief_title>
  <acronym>ORGANIKO</acronym>
  <official_title>Organic Diet and Children's Health - ORGANIKO LIFE+</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cyprus University of Technology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Commission</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cyprus University of Technology</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study aims to evaluate the hypothesized benefits of a systematic organic diet for&#xD;
      children, over those of a conventional diet. The specific objectives of this study are to: i)&#xD;
      Demonstrate the decreased body burden of pesticides for those children consuming an organic&#xD;
      diet, and ii) Evaluate the effects in specific biomarkers of inflammation and oxidative&#xD;
      stress in children systematically consuming an organic diet.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A single-blinded, randomised 2 x 2 cross-over study is conducted to evaluate the effect of a&#xD;
      40-day organic diet compared to a 40-day conventional diet on biomarkers of exposure&#xD;
      (pesticides metabolites) and biomarkers of effect (oxidative stress/inflammation markers) in&#xD;
      children. The study is approved by the Cyprus National Bioethics Committee (ΕΕΒΚ/ΕΠ/2016/25)&#xD;
      and the Cyprus Ministry of Education and Culture (7.15.06.15/2). Written informed consent for&#xD;
      children to participate in the study is obtained from children's parents or legal guardians.&#xD;
      Study participants are recruited from public primary schools in Limassol, Cyprus following&#xD;
      communication with the school's headmaster. Each school that participates in the study is&#xD;
      randomized to one of the two study arms; conventional-organic or organic-conventional.&#xD;
      Participants' blinding is not possible since children know which diet they have at each&#xD;
      phase. However, all documents and urine containers are coded, so that researchers are blinded&#xD;
      to subjects' identity and group allocation.&#xD;
&#xD;
      Participants provide 6 first morning urine samples during the duration of the study; 1&#xD;
      baseline sample, 2 samples in the conventional phase and 3 samples in the organic phase.&#xD;
      Anthropometric measurements (weight, height, waist circumference) are taken at the beginning&#xD;
      and end of the study by trained researchers at the school area. A baseline questionnaire is&#xD;
      administered to parents at the beginning of the study through a telephone interview to&#xD;
      collect information on demographic characteristics, pesticide use at household and children's&#xD;
      activities. A food frequency questionnaire is administered to parents at the end of the&#xD;
      conventional phase through a telephone interview to collect information about the food habits&#xD;
      of the children during the 40-day conventional period. A food diary is given to parents at&#xD;
      the beginning of the study and parents use it during the organic phase, to collect&#xD;
      information about the compliance of the children to the organic dietary menu, the children's&#xD;
      health status and the pesticide use at home.&#xD;
&#xD;
      In order to encourage adherence to the organic diet menu, an event is organised during the&#xD;
      organic phase of both groups, with activities for children and free sampling of organic food&#xD;
      products.&#xD;
&#xD;
      Descriptive statistics are used to summarize the demographic characteristics for&#xD;
      participating children. Categorical variables are described as sample size and percentages,&#xD;
      normally-distributed continuous variables as mean±SD and non-normal continuous variables as&#xD;
      median and interquartile range (Q1-Q3) or the appropriate transformation is conducted, such&#xD;
      as the log transformation. For testing whether characteristics of interest are different&#xD;
      among groups the Student's t-test are utilized for continuous normally distributed variables&#xD;
      and the chi-square test for categorical characteristics. For continuous data that are not&#xD;
      normally distributed, the Wilcoxon non-parametric analysis is used instead or a&#xD;
      transformation of the data is conducted first in order to meet the normality criterion.&#xD;
&#xD;
      Linear mixed-effects models are used to account for the correlation among repeat urine&#xD;
      samples collected from the same child and determine whether mean pesticide metabolite and&#xD;
      biomarkers concentrations differ between the organic phase and the conventional phase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 3, 2017</start_date>
  <completion_date type="Actual">April 18, 2017</completion_date>
  <primary_completion_date type="Actual">April 18, 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>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Pesticide Metabolite 3-phenoxybenzoic Acid (3-PBA) Levels in Urine Between Organic and Conventional Periods*</measure>
    <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
    <description>Percent change in pesticide metabolite 3-phenoxybenzoic acid (3-PBA) levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Difference in Median 3-PBA Levels in Urine Between the Conventional and Organic Periods*</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>Overall difference in median 3-PBA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Effect of Organic Treatment in 3-PBA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>A linear mixed-effect regression model was fitted for 3-PBA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Difference in Median 6-chloronicotininc Acid (6-CN) Levels in Urine Between the Conventional and Organic Periods*</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>Overall difference in median 6-CN levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Effect of Organic Treatment in 6-CN Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period - Odds Ratio Calculated Based on the Fit of a Logistic Mixed-effect Model</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>A logistic model was fitted for 6-CN (binary variable; above and below LOD) due to the high number of values below LOD. The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Oxidative Stress/Inflammation Biomarker 8-OHdG Levels in Urine Between Organic and Conventional Periods*</measure>
    <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
    <description>Percent change in oxidative stress/inflammation biomarker 8-OHdG levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Difference in Median 8-OHdG Levels in Urine Between the Conventional and Organic Periods*</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>Overall difference in median 8-OHdG levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Organic Treatment in 8-OHdG Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>A linear mixed-effect regression model was fitted for 8-OHdG (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Oxidative Stress/Inflammation Biomarker 8-iso-PGF2a Levels in Urine Between Organic and Conventional Periods*</measure>
    <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
    <description>Percent change in oxidative stress/inflammation biomarker 8-iso-PGF2a levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Difference in Median 8-iso-PGF2a Levels in Urine Between the Conventional and Organic Periods*</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>Overall difference in median 8-iso-PGF2a levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Organic Treatment in 8-iso-PGF2a Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>A linear mixed-effect regression model was fitted for 8-iso-PGF2a (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Oxidative Stress/Inflammation Biomarker MDA Levels in Urine Between Organic and Conventional Periods*</measure>
    <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
    <description>Percent change in oxidative stress/inflammation biomarker MDA levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Difference in Median MDA Levels in Urine Between the Conventional and Organic Periods*</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>Overall difference in median MDA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Organic Treatment in MDA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</measure>
    <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
    <description>A linear mixed-effect regression model was fitted for MDA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">191</enrollment>
  <condition>Oxidative Stress</condition>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Conventional phase</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>During the conventional phase, participants are asked to maintain their usual dietary choices for 40 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Organic phase</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During the organic phase, participants are asked to follow strictly the two 20-day organic dietary menus provided to them for 40 days. The organic dietary menus were prepared by a certified dietitian. The meals of the organic phase are prepared by a certified organic restaurant and are delivered to school every day except Sunday. For the meals of breakfast and afternoon snacks, children choose their preferred options for the week on the Friday of the previous week according to a list of organic food items and the products for these meals are delivered on Saturday along with the rest meals. Parents are responsible to pick-up the organic meals from school and ensure that the participating children have access to them.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Organic diet</intervention_name>
    <description>Full organic diet from certified organic products as obtained from certified producers and cooked by a certified organic restaurant. five meals each day delivered to students.</description>
    <arm_group_label>Organic phase</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy children aged 10-12 years, residing in Cyprus over the last five years who&#xD;
             consume primarily (&gt; 80%) conventional food (non-organic).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Children with chronic conditions (e.g. diabetes, asthma) or allergies in food (e.g.&#xD;
             gluten, lactose tolerance)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>12 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Konstantinos C Makris</last_name>
    <role>Study Director</role>
    <affiliation>Cyprus University of Technology</affiliation>
  </overall_official>
  <results_reference>
    <citation>Makris KC, Konstantinou C, Andrianou XD, Charisiadis P, Kyriacou A, Gribble MO, Christophi CA. A cluster-randomized crossover trial of organic diet impact on biomarkers of exposure to pesticides and biomarkers of oxidative stress/inflammation in primary school children. PLoS One. 2019 Sep 4;14(9):e0219420. doi: 10.1371/journal.pone.0219420. eCollection 2019.</citation>
    <PMID>31483785</PMID>
  </results_reference>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <results_first_submitted>March 13, 2020</results_first_submitted>
  <results_first_submitted_qc>September 4, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">September 7, 2023</results_first_posted>
  <last_update_submitted>September 4, 2023</last_update_submitted>
  <last_update_submitted_qc>September 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cyprus University of Technology</investigator_affiliation>
    <investigator_full_name>Konstantinos Makris</investigator_full_name>
    <investigator_title>Associate Professor of Environmental Health</investigator_title>
  </responsible_party>
  <keyword>organic diet</keyword>
  <keyword>health</keyword>
  <keyword>pesticides</keyword>
  <keyword>inflammation biomarkers</keyword>
  <keyword>oxidative stress biomarkers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Following the publication of the manuscript, all relevant info is made available to the public.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Following the publication of the manuscript, all relevant info is made available to the public.</ipd_time_frame>
    <ipd_access_criteria>Following the publication of the manuscript, all relevant info is made available to the public.</ipd_access_criteria>
  </patient_data>
  <study_docs>
    <study_doc>
      <doc_type>Manuscript and supplementary files</doc_type>
      <doc_url>https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219420</doc_url>
    </study_doc>
  </study_docs>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 8, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT02998203/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT02998203/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Group 1 (Organic Period First, Then Conventional Period)</title>
          <description>Schools in Group 1 began first with the organic period and continued with the conventional period.&#xD;
The organic period was organized in two 20-day cycles with differences in the menu to allow for greater variety in the meals, so that the participants' compliance to the organic treatment would be enhanced. During the organic period, participants were asked to strictly follow the two 20-day organic dietary menus provided to them for a total of 40 days.&#xD;
During the conventional period, participants were asked to maintain their usual dietary habits and choices (&gt;80% conventional diet) for a total of maximum 40 days.</description>
        </group>
        <group group_id="P2">
          <title>Group 2 (Conventional Period First, Then Organic Period)</title>
          <description>Schools in Group 2 began first with the conventional period and then switched to the organic period.&#xD;
During the conventional period, participants were asked to maintain their usual dietary habits and choices (&gt;80% conventional diet) for a total of maximum 40 days.&#xD;
The organic period was organized in two 20-day cycles with differences in the menu to allow for greater variety in the meals, so that the participants' compliance to the organic treatment would be enhanced. During the organic period, participants were asked to strictly follow the two 20-day organic dietary menus provided to them for a total of 40 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Period (40 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="67"/>
                <participants group_id="P2" count="124"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="43"/>
                <participants group_id="P2" count="124"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Second Period (40 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="43"/>
                <participants group_id="P2" count="124"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="43"/>
                <participants group_id="P2" count="106"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Group 1</title>
          <description>Schools in Group 1 began first with the organic period and continued with the conventional period.&#xD;
The organic period was organized in two 20-day cycles with differences in the menu to allow for greater variety in the meals, so that the participants' compliance to the organic treatment would be enhanced. During the organic period, participants were asked to strictly follow the two 20-day organic dietary menus provided to them for a total of 40 days.&#xD;
During the conventional period, participants were asked to maintain their usual dietary habits and choices (&gt;80% conventional diet) for a total of maximum 40 days.</description>
        </group>
        <group group_id="B2">
          <title>Group 2</title>
          <description>Schools in Group 2 began first with the conventional period and then switched to the organic period.&#xD;
During the conventional period, participants were asked to maintain their usual dietary habits and choices (&gt;80% conventional diet) for a total of maximum 40 days.&#xD;
The organic period was organized in two 20-day cycles with differences in the menu to allow for greater variety in the meals, so that the participants' compliance to the organic treatment would be enhanced. During the organic period, participants were asked to strictly follow the two 20-day organic dietary menus provided to them for a total of 40 days.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="43"/>
            <count group_id="B2" value="106"/>
            <count group_id="B3" value="149"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="43"/>
                    <count group_id="B2" value="106"/>
                    <count group_id="B3" value="149"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11.03" spread="0.53"/>
                    <measurement group_id="B2" value="11.21" spread="0.61"/>
                    <measurement group_id="B3" value="11.16" spread="0.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="43"/>
                    <count group_id="B2" value="106"/>
                    <count group_id="B3" value="149"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="59"/>
                    <measurement group_id="B3" value="73"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Pesticide Metabolite 3-phenoxybenzoic Acid (3-PBA) Levels in Urine Between Organic and Conventional Periods*</title>
        <description>Percent change in pesticide metabolite 3-phenoxybenzoic acid (3-PBA) levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
        <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
        <group_list>
          <group group_id="O1">
            <title>% Change in 3-PBA Between Last Sample of Conventional Period and Last Sample of Organic Period</title>
            <description>Percent change in 3-PBA levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last urine sample of organic treatment period. The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels. A one-sample t-test was used to assess whether the percent change was different than zero.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Pesticide Metabolite 3-phenoxybenzoic Acid (3-PBA) Levels in Urine Between Organic and Conventional Periods*</title>
          <description>Percent change in pesticide metabolite 3-phenoxybenzoic acid (3-PBA) levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
          <units>% change</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="132"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.4" lower_limit="5.7" upper_limit="17.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>A one-sample t-test was used to assess whether the percent change was different than zero.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-sample t-test</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <method>One-sample t-test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Overall Difference in Median 3-PBA Levels in Urine Between the Conventional and Organic Periods*</title>
        <description>Overall difference in median 3-PBA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Median 3-PBA Levels in the Conventional Period</title>
            <description>Median 3-PBA levels (creatinine-adjusted) in the conventional period by pooling all conventional samples (including the baseline) for all participants</description>
          </group>
          <group group_id="O2">
            <title>Median 3-PBA Levels in the Organic Period</title>
            <description>Median 3-PBA levels (creatinine-adjusted) in the organic period by pooling all organic samples for all participants, regardless of the duration for which they followed the organic treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Difference in Median 3-PBA Levels in Urine Between the Conventional and Organic Periods*</title>
          <description>Overall difference in median 3-PBA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ng/g creatinine</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2088" lower_limit="689" upper_limit="5273"/>
                    <measurement group_id="O2" value="576" lower_limit="164" upper_limit="1681"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The overall differences in the medians of biomarkers between the conventional and the organic periods were assessed with the non-parametric Wilcoxon rank sum test</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>non-parametric Wilcoxon rank sum test</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <method>Wilcoxon rank sum test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Effect of Organic Treatment in 3-PBA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
        <description>A linear mixed-effect regression model was fitted for 3-PBA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Linear Mixed-effect Model of Log-transformed Pesticide Metabolite 3-PBA</title>
            <description>A linear mixed-effect regression model was fitted for 3-PBA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Organic Treatment in 3-PBA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
          <description>A linear mixed-effect regression model was fitted for 3-PBA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ng/g creatinine (log-transformed)</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.214" lower_limit="-1.44" upper_limit="-0.987"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear mixed-effect regression model</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <p_value_desc>Multiple testing was accounted for using the Benjamini-Hochberg method, considering 58 regression parameter tests of the aforementioned models. Q-value&lt;0.05 were considered statistically significant (controlling the false discovery rate at 5%).</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Overall Difference in Median 6-chloronicotininc Acid (6-CN) Levels in Urine Between the Conventional and Organic Periods*</title>
        <description>Overall difference in median 6-CN levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Median 6-CN Levels in the Conventional Period</title>
            <description>Median 6-CN levels (creatinine-adjusted) in the conventional period by pooling all conventional samples (including the baseline) for all participants</description>
          </group>
          <group group_id="O2">
            <title>Median 6-CN Levels in the Organic Period</title>
            <description>Median 6-CN levels (creatinine-adjusted) in the organic period by pooling all organic samples for all participants, regardless of the duration for which they followed the organic treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Difference in Median 6-chloronicotininc Acid (6-CN) Levels in Urine Between the Conventional and Organic Periods*</title>
          <description>Overall difference in median 6-CN levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ng/g creatinine</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26" lower_limit="6" upper_limit="180"/>
                    <measurement group_id="O2" value="20" lower_limit="5" upper_limit="79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The overall differences in the medians of biomarkers between the conventional and the organic periods were assessed with the non-parametric Wilcoxon rank sum test</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Wilcoxon rank sum test</non_inferiority_desc>
            <p_value>0.017</p_value>
            <method>Wilcoxon rank sum test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Effect of Organic Treatment in 6-CN Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period - Odds Ratio Calculated Based on the Fit of a Logistic Mixed-effect Model</title>
        <description>A logistic model was fitted for 6-CN (binary variable; above and below LOD) due to the high number of values below LOD. The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Logistic Mixed-effect Model of Pesticide Metabolite 6-CN</title>
            <description>A logistic model was fitted for 6-CN (binary variable; above and below LOD) due to the high number of values below LOD. The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Organic Treatment in 6-CN Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period - Odds Ratio Calculated Based on the Fit of a Logistic Mixed-effect Model</title>
          <description>A logistic model was fitted for 6-CN (binary variable; above and below LOD) due to the high number of values below LOD. The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>Odds Ratio</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.651" lower_limit="0.463" upper_limit="0.917"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Logistic mixed-effect model</non_inferiority_desc>
            <p_value>0.014</p_value>
            <p_value_desc>Multiple testing was accounted for using the Benjamini-Hochberg method, considering 58 regression parameter tests of the aforementioned models. Q-value&lt;0.05 were considered statistically significant (controlling the false discovery rate at 5%).</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Oxidative Stress/Inflammation Biomarker 8-OHdG Levels in Urine Between Organic and Conventional Periods*</title>
        <description>Percent change in oxidative stress/inflammation biomarker 8-OHdG levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
        <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
        <group_list>
          <group group_id="O1">
            <title>% Change in 8-OHdG Between Last Sample of Conventional Period and Last Sample of Organic Period</title>
            <description>Percent change in 8-OHdG levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last urine sample of organic treatment period. The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels. A one-sample t-test was used to assess whether the percent change was different than zero.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Oxidative Stress/Inflammation Biomarker 8-OHdG Levels in Urine Between Organic and Conventional Periods*</title>
          <description>Percent change in oxidative stress/inflammation biomarker 8-OHdG levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
          <units>% change</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="132"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.7" lower_limit="-0.7" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>A one-sample t-test was used to assess whether the percent change was different than zero.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-sample t-test</non_inferiority_desc>
            <p_value>0.167</p_value>
            <method>One-sample t-test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Difference in Median 8-OHdG Levels in Urine Between the Conventional and Organic Periods*</title>
        <description>Overall difference in median 8-OHdG levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Median 8-OHdG Levels in the Conventional Period</title>
            <description>Median 8-OHdG levels (creatinine-adjusted) in the conventional period by pooling all conventional samples (including the baseline) for all participants</description>
          </group>
          <group group_id="O2">
            <title>Median 8-OHdG Levels in the Organic Period</title>
            <description>Median 8-OHdG levels (creatinine-adjusted) in the organic period by pooling all organic samples for all participants, regardless of the duration for which they followed the organic treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Difference in Median 8-OHdG Levels in Urine Between the Conventional and Organic Periods*</title>
          <description>Overall difference in median 8-OHdG levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ug/g creatinine</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="323" lower_limit="222" upper_limit="471"/>
                    <measurement group_id="O2" value="296" lower_limit="202" upper_limit="447"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The overall differences in the medians of biomarkers between the conventional and the organic periods were assessed with the non-parametric Wilcoxon rank sum test</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Wilcoxon rank sum test</non_inferiority_desc>
            <p_value>0.07</p_value>
            <method>Wilcoxon rank sum test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Organic Treatment in 8-OHdG Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
        <description>A linear mixed-effect regression model was fitted for 8-OHdG (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Linear Mixed-effect Model of Log-transformed Oxidative Stress/Inflammation Biomarker 8-OHdG</title>
            <description>A linear mixed-effect regression model was fitted for 8-OHdG (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Organic Treatment in 8-OHdG Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
          <description>A linear mixed-effect regression model was fitted for 8-OHdG (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ug/g creatinine (log-transformed)</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.119" lower_limit="-0.213" upper_limit="-0.024"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear mixed-effect regression model</non_inferiority_desc>
            <p_value>0.014</p_value>
            <p_value_desc>Multiple testing was accounted for using the Benjamini-Hochberg method, considering 58 regression parameter tests of the aforementioned models. Q-value&lt;0.05 were considered statistically significant (controlling the false discovery rate at 5%).</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Oxidative Stress/Inflammation Biomarker 8-iso-PGF2a Levels in Urine Between Organic and Conventional Periods*</title>
        <description>Percent change in oxidative stress/inflammation biomarker 8-iso-PGF2a levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
        <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
        <group_list>
          <group group_id="O1">
            <title>% Change in 8-iso-PGF2a Between Last Sample of Conventional Period and Last Sample of Organic Period</title>
            <description>Percent change in 8-iso-PGF2a levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last urine sample of organic treatment period. The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels. A one-sample t-test was used to assess whether the percent change was different than zero.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Oxidative Stress/Inflammation Biomarker 8-iso-PGF2a Levels in Urine Between Organic and Conventional Periods*</title>
          <description>Percent change in oxidative stress/inflammation biomarker 8-iso-PGF2a levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
          <units>% change</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="132"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6" lower_limit="0.2" upper_limit="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>A one-sample t-test was used to assess whether the percent change was different than zero.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-sample t-test</non_inferiority_desc>
            <p_value>0.023</p_value>
            <method>One-sample t-test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Difference in Median 8-iso-PGF2a Levels in Urine Between the Conventional and Organic Periods*</title>
        <description>Overall difference in median 8-iso-PGF2a levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Median 8-iso-PGF2a Levels in the Conventional Period</title>
            <description>Median 8-iso-PGF2a levels (creatinine-adjusted) in the conventional period by pooling all conventional samples (including the baseline) for all participants</description>
          </group>
          <group group_id="O2">
            <title>Median 8-iso-PGF2a Levels in the Organic Period</title>
            <description>Median 8-iso-PGF2a levels (creatinine-adjusted) in the organic period by pooling all organic samples for all participants, regardless of the duration for which they followed the organic treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Difference in Median 8-iso-PGF2a Levels in Urine Between the Conventional and Organic Periods*</title>
          <description>Overall difference in median 8-iso-PGF2a levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ug/g creatinine</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2964" lower_limit="2112" upper_limit="3871"/>
                    <measurement group_id="O2" value="3028" lower_limit="2300" upper_limit="3955"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The overall differences in the medians of biomarkers between the conventional and the organic periods were assessed with the non-parametric Wilcoxon rank sum test</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Wilcoxon rank sum test</non_inferiority_desc>
            <p_value>0.259</p_value>
            <method>Wilcoxon rank sum test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Organic Treatment in 8-iso-PGF2a Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
        <description>A linear mixed-effect regression model was fitted for 8-iso-PGF2a (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Linear Mixed-effect Model of Log-transformed Oxidative Stress/Inflammation Biomarker 8-iso-PGF2a</title>
            <description>A linear mixed-effect regression model was fitted for 8-iso-PGF2a (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was included in the model since it met the threshold of p-value&lt;0. 05.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Organic Treatment in 8-iso-PGF2a Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
          <description>A linear mixed-effect regression model was fitted for 8-iso-PGF2a (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>ug/g creatinine (log-transformed)</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.408" lower_limit="0.232" upper_limit="0.584"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The interaction term for time and treatment was included in the models since it met the threshold of p-value&lt;0. 05. Specifically, for the interaction term of time and organic treatment b=-0.016, 95% CI=[-0.023,-0.010], p-value=&lt;0.001.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear mixed-effect regression model</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <p_value_desc>Multiple testing was accounted for using the Benjamini-Hochberg method, considering 58 regression parameter tests of the aforementioned models. Q-value&lt;0.05 were considered statistically significant (controlling the false discovery rate at 5%).</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Oxidative Stress/Inflammation Biomarker MDA Levels in Urine Between Organic and Conventional Periods*</title>
        <description>Percent change in oxidative stress/inflammation biomarker MDA levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>Last sample of the conventional period and the last sample of organic period, up to 40 days for each period</time_frame>
        <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
        <group_list>
          <group group_id="O1">
            <title>% Change in MDA Between Last Sample of Conventional Period and Last Sample of Organic Period</title>
            <description>Percent change in MDA levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last urine sample of organic treatment period. The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels. A one-sample t-test was used to assess whether the percent change was different than zero.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Oxidative Stress/Inflammation Biomarker MDA Levels in Urine Between Organic and Conventional Periods*</title>
          <description>Percent change in oxidative stress/inflammation biomarker MDA levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>The percent change was estimated only for the participants who completed the full course of the organic treatment, using the log-transformed, creatinine-adjusted biomarker levels.</population>
          <units>% change</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="132"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.1" lower_limit="-1.1" upper_limit="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>A one-sample t-test was used to assess whether the percent change was different than zero.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-sample t-test</non_inferiority_desc>
            <p_value>0.913</p_value>
            <method>One-sample t-test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Difference in Median MDA Levels in Urine Between the Conventional and Organic Periods*</title>
        <description>Overall difference in median MDA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Median MDA Levels in the Conventional Period</title>
            <description>Median MDA levels (creatinine-adjusted) in the conventional period by pooling all conventional samples (including the baseline) for all participants</description>
          </group>
          <group group_id="O2">
            <title>Median MDA Levels in the Organic Period</title>
            <description>Median MDA levels (creatinine-adjusted) in the organic period by pooling all organic samples for all participants, regardless of the duration for which they followed the organic treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Difference in Median MDA Levels in Urine Between the Conventional and Organic Periods*</title>
          <description>Overall difference in median MDA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.&#xD;
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>umol/g creatinine</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="858" lower_limit="691" upper_limit="1016"/>
                    <measurement group_id="O2" value="846" lower_limit="725" upper_limit="1029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The overall differences in the medians of biomarkers between the conventional and the organic periods were assessed with the non-parametric Wilcoxon rank sum test</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Wilcoxon rank sum test</non_inferiority_desc>
            <p_value>0.338</p_value>
            <method>Wilcoxon rank sum test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Organic Treatment in MDA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
        <description>A linear mixed-effect regression model was fitted for MDA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
        <time_frame>1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period</time_frame>
        <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Linear Mixed-effect Model of Log-transformed Oxidative Stress/Inflammation Biomarker MDA</title>
            <description>A linear mixed-effect regression model was fitted for MDA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was included in the model since it met the threshold of p-value&lt;0. 05.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Organic Treatment in MDA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period</title>
          <description>A linear mixed-effect regression model was fitted for MDA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value&lt;0. 05.</description>
          <population>Three schools were randomly allocated to Group 1 (67 children) and the other three to Group 2 (124 children). In total, 24 children from Group 1 and 18 children from Group 2 who withdrew from the study 1-11 days after the beginning of the organic period and did not provide an organic period urine sample, were excluded from the data analysis.</population>
          <units>umol/g creatinine (log-transformed)</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <units_analyzed>schools</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>schools</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.189" lower_limit="0.083" upper_limit="0.295"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The interaction term for time and treatment was included in the models since it met the threshold of p-value&lt;0. 05. Specifically, for the interaction term of time and organic treatment b=-0.016, 95% CI=[-0.023,-0.010], p-value=0.01.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear mixed-effect regression model</non_inferiority_desc>
            <p_value>0.001</p_value>
            <p_value_desc>Multiple testing was accounted for using the Benjamini-Hochberg method, considering 58 regression parameter tests of the aforementioned models. Q-value&lt;0.05 were considered statistically significant (controlling the false discovery rate at 5%).</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <desc>All-Cause Mortality, Serious, and Other [Not Including Serious] Adverse Events were not monitored/assessed. Based on the study design and the inclusion/exclusion criteria no adverse events were expected and no adverse events were reported during the study period (up to 80 days).</desc>
      <group_list>
        <group group_id="E1">
          <title>Group 1</title>
          <description>Schools in Group 1 began first with the organic period and continued with the conventional period.&#xD;
The organic period was organized in two 20-day cycles with differences in the menu to allow for greater variety in the meals, so that the participants' compliance to the organic treatment would be enhanced. During the organic period, participants were asked to strictly follow the two 20-day organic dietary menus provided to them for a total of 40 days.&#xD;
During the conventional period, participants were asked to maintain their usual dietary habits and choices (&gt;80% conventional diet) for a total of maximum 40 days.</description>
        </group>
        <group group_id="E2">
          <title>Group 2</title>
          <description>Schools in Group 2 began first with the conventional period and then switched to the organic period.&#xD;
During the conventional period, participants were asked to maintain their usual dietary habits and choices (&gt;80% conventional diet) for a total of maximum 40 days.&#xD;
The organic period was organized in two 20-day cycles with differences in the menu to allow for greater variety in the meals, so that the participants' compliance to the organic treatment would be enhanced. During the organic period, participants were asked to strictly follow the two 20-day organic dietary menus provided to them for a total of 40 days.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The reported compliance may not reflect the actual compliance of the children to the organic diet, as children could either not consume all meal portion, or families could provide them with extra organic food items.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Konstantinos C. Makris</name_or_title>
      <organization>Cyprus University of Technology</organization>
      <phone>00357-25-002398</phone>
      <email>konstantinos.makris@cut.ac.cy</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02998203
org study id: CyprusUT
nct id: NCT02998203
lead sponsor: 
collaborator: 
has dmc: Yes
The study aims to evaluate the hypothesized benefits of a systematic organic diet for
      children, over those of a conventional diet. The specific objectives of this study are to: i)
      Demonstrate the decreased body burden of pesticides for those children consuming an organic
      diet, and ii) Evaluate the effects in specific biomarkers of inflammation and oxidative
      stress in children systematically consuming an organic diet.
A single-blinded, randomised 2 x 2 cross-over study is conducted to evaluate the effect of a
      40-day organic diet compared to a 40-day conventional diet on biomarkers of exposure
      (pesticides metabolites) and biomarkers of effect (oxidative stress/inflammation markers) in
      children. The study is approved by the Cyprus National Bioethics Committee (ΕΕΒΚ/ΕΠ/2016/25)
      and the Cyprus Ministry of Education and Culture (7.15.06.15/2). Written informed consent for
      children to participate in the study is obtained from children's parents or legal guardians.
      Study participants are recruited from public primary schools in Limassol, Cyprus following
      communication with the school's headmaster. Each school that participates in the study is
      randomized to one of the two study arms; conventional-organic or organic-conventional.
      Participants' blinding is not possible since children know which diet they have at each
      phase. However, all documents and urine containers are coded, so that researchers are blinded
      to subjects' identity and group allocation.

      Participants provide 6 first morning urine samples during the duration of the study; 1
      baseline sample, 2 samples in the conventional phase and 3 samples in the organic phase.
      Anthropometric measurements (weight, height, waist circumference) are taken at the beginning
      and end of the study by trained researchers at the school area. A baseline questionnaire is
      administered to parents at the beginning of the study through a telephone interview to
      collect information on demographic characteristics, pesticide use at household and children's
      activities. A food frequency questionnaire is administered to parents at the end of the
      conventional phase through a telephone interview to collect information about the food habits
      of the children during the 40-day conventional period. A food diary is given to parents at
      the beginning of the study and parents use it during the organic phase, to collect
      information about the compliance of the children to the organic dietary menu, the children's
      health status and the pesticide use at home.

      In order to encourage adherence to the organic diet menu, an event is organised during the
      organic phase of both groups, with activities for children and free sampling of organic food
      products.

      Descriptive statistics are used to summarize the demographic characteristics for
      participating children. Categorical variables are described as sample size and percentages,
      normally-distributed continuous variables as mean±SD and non-normal continuous variables as
      median and interquartile range (Q1-Q3) or the appropriate transformation is conducted, such
      as the log transformation. For testing whether characteristics of interest are different
      among groups the Student's t-test are utilized for continuous normally distributed variables
      and the chi-square test for categorical characteristics. For continuous data that are not
      normally distributed, the Wilcoxon non-parametric analysis is used instead or a
      transformation of the data is conducted first in order to meet the normality criterion.

      Linear mixed-effects models are used to account for the correlation among repeat urine
      samples collected from the same child and determine whether mean pesticide metabolite and
      biomarkers concentrations differ between the organic phase and the conventional phase.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Single (Investigator)
measure: Change in Pesticide Metabolite 3-phenoxybenzoic Acid (3-PBA) Levels in Urine Between Organic and Conventional Periods*
time frame: Last sample of the conventional period and the last sample of organic period, up to 40 days for each period
description: Percent change in pesticide metabolite 3-phenoxybenzoic acid (3-PBA) levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Overall Difference in Median 3-PBA Levels in Urine Between the Conventional and Organic Periods*
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: Overall difference in median 3-PBA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Effect of Organic Treatment in 3-PBA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: A linear mixed-effect regression model was fitted for 3-PBA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value<0. 05.
measure: Overall Difference in Median 6-chloronicotininc Acid (6-CN) Levels in Urine Between the Conventional and Organic Periods*
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: Overall difference in median 6-CN levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Effect of Organic Treatment in 6-CN Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period - Odds Ratio Calculated Based on the Fit of a Logistic Mixed-effect Model
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: A logistic model was fitted for 6-CN (binary variable; above and below LOD) due to the high number of values below LOD. The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value<0. 05.
measure: Change in Oxidative Stress/Inflammation Biomarker 8-OHdG Levels in Urine Between Organic and Conventional Periods*
time frame: Last sample of the conventional period and the last sample of organic period, up to 40 days for each period
description: Percent change in oxidative stress/inflammation biomarker 8-OHdG levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Overall Difference in Median 8-OHdG Levels in Urine Between the Conventional and Organic Periods*
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: Overall difference in median 8-OHdG levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Effect of Organic Treatment in 8-OHdG Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: A linear mixed-effect regression model was fitted for 8-OHdG (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value<0. 05.
measure: Change in Oxidative Stress/Inflammation Biomarker 8-iso-PGF2a Levels in Urine Between Organic and Conventional Periods*
time frame: Last sample of the conventional period and the last sample of organic period, up to 40 days for each period
description: Percent change in oxidative stress/inflammation biomarker 8-iso-PGF2a levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Overall Difference in Median 8-iso-PGF2a Levels in Urine Between the Conventional and Organic Periods*
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: Overall difference in median 8-iso-PGF2a levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Effect of Organic Treatment in 8-iso-PGF2a Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: A linear mixed-effect regression model was fitted for 8-iso-PGF2a (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value<0. 05.
measure: Change in Oxidative Stress/Inflammation Biomarker MDA Levels in Urine Between Organic and Conventional Periods*
time frame: Last sample of the conventional period and the last sample of organic period, up to 40 days for each period
description: Percent change in oxidative stress/inflammation biomarker MDA levels between the last sample of the conventional treatment period (before the start of the organic treatment) and the last sample of organic treatment period. A one-sample t-test was used to assess whether the percent change was different than zero.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Overall Difference in Median MDA Levels in Urine Between the Conventional and Organic Periods*
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: Overall difference in median MDA levels between the conventional and organic periods. The overall differences in the medians of biomarkers between the conventional and the organic phase were assessed with the non-parametric Wilcoxon rank sum test on the creatinine-adjusted concentrations pooling all conventional samples (including the baseline) and the organic samples for all participants, regardless of the duration for which they followed the organic treatment.
*Note: This test does not take into account the repeated measures for each participant and the organic treatment duration. The results of the linear-mixed effect models are the ones considered (reported in a section below) as they take into account the repeated measures for each participant and the organic treatment duration.
measure: Effect of Organic Treatment in MDA Levels in Urine, Taking in Account the Repeated Measures and Duration of Organic Period
time frame: 1 baseline sample, 2 samples in the conventional period (typical conventional diet) and 3 samples in the organic period, up to 40 days for each Period
description: A linear mixed-effect regression model was fitted for MDA (log-transformed, creatinine-adjusted). The model accounted for the duration and the effect of treatment. It included student-level (repeated measures within person) and school-level (multiple students clustered within each school) random intercepts with an unstructured covariance matrix. Continuous variables, other than time (days of treatment), were centered at the population means. The model included fixed effects for treatment condition (organic or conventional) and time (days of treatment), where time = 0 was used for the start of the treatment. The model was adjusted for the baseline value (first urine sample for all children) of the outcome to account for the background participant levels. An interaction term for time and treatment was considered and subsequently dropped if it did not meet the threshold of p-value<0. 05.
arm group label: Conventional phase
arm group type: No Intervention
description: During the conventional phase, participants are asked to maintain their usual dietary choices for 40 days.
arm group label: Organic phase
arm group type: Experimental
description: During the organic phase, participants are asked to follow strictly the two 20-day organic dietary menus provided to them for 40 days. The organic dietary menus were prepared by a certified dietitian. The meals of the organic phase are prepared by a certified organic restaurant and are delivered to school every day except Sunday. For the meals of breakfast and afternoon snacks, children choose their preferred options for the week on the Friday of the previous week according to a list of organic food items and the products for these meals are delivered on Saturday along with the rest meals. Parents are responsible to pick-up the organic meals from school and ensure that the participating children have access to them.
intervention type: Dietary Supplement
intervention name: Organic diet
description: Full organic diet from certified organic products as obtained from certified producers and cooked by a certified organic restaurant. five meals each day delivered to students.
arm group label: Organic phase
criteria: 
gender: All
minimum age: 10 Years
maximum age: 12 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Konstantinos C Makris
role: Study Director
affiliation: Cyprus University of Technology
citation: Makris KC, Konstantinou C, Andrianou XD, Charisiadis P, Kyriacou A, Gribble MO, Christophi CA. A cluster-randomized crossover trial of organic diet impact on biomarkers of exposure to pesticides and biomarkers of oxidative stress/inflammation in primary school children. PLoS One. 2019 Sep 4;14(9):e0219420. doi: 10.1371/journal.pone.0219420. eCollection 2019.
PMID: 31483785
responsible party type: Principal Investigator
investigator affiliation: Cyprus University of Technology
investigator full name: Konstantinos Makris
investigator title: Associate Professor of Environmental Health
mesh term: Inflammation
sharing ipd: Yes
ipd description: Following the publication of the manuscript, all relevant info is made available to the public.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Analytic Code
ipd time frame: Following the publication of the manuscript, all relevant info is made available to the public.
ipd access criteria: Following the publication of the manuscript, all relevant info is made available to the public.
study doc: 
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The reported compliance may not reflect the actual compliance of the children to the organic diet, as children could either not consume all meal portion, or families could provide them with extra organic food items.
point of contact: 