<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/NCT04405895</url>
  </required_header>
  <id_info>
    <org_study_id>0118-20-WOMC</org_study_id>
    <nct_id>NCT04405895</nct_id>
  </id_info>
  <brief_title>Effect of Meal Timing in T2D on Hepatocytes SRIT1 and Clock Genes</brief_title>
  <acronym>Liver-CG</acronym>
  <official_title>Effect Meal Timing in Type 2 Diabetes on Serum Induced SIRT1 and Clock Gene Expression in Hepatocytes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tel Aviv University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tel Aviv University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is undertaken to explore in T2D, the effect of meal timing on serum induced SIRT1&#xD;
      and Clock Genes mRNA expression in cultured hepatocytes. Fasting serum samples were collected&#xD;
      from T2D participants, following two different meal timing schedules, either a diet with&#xD;
      large breakfast and lunch with small dinner Breakfast Diet (3Mdiet) or an isocaloric diet&#xD;
      with 6 small meals evenly distributed along the day Allday Diet (6Mdiet). The researchers&#xD;
      will use an ex-vivo/in-vitro approach in which cultured medium will be conditioned with the&#xD;
      fasted human serum collected from the two groups of T2D participants at baseline, after 2&#xD;
      weeks and after 12 week of the diet intervention.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The timing of many physiological processes, including glucose metabolism, is coordinated by&#xD;
      the circadian clock gene system. The circadian clock regulation, optimize glucose metabolism&#xD;
      for the consumption of high energy and carbohydrate (CH) meals in the early hours of the day&#xD;
      and for fasting at evening and night. Circadian disruption which occurs when the meal timing&#xD;
      is not aligned with the circadian clock rhythms like skipping breakfast, overeating CH at&#xD;
      night or eating CH all day, lead to desynchronized clock genes and can result in adverse&#xD;
      health outcomes like insulin resistance, obesity hyperglycemia and T2D. Although the clock&#xD;
      genes are disseminated in almost all peripheral tissues, those localized in the liver, are&#xD;
      particularly important for the regulation of glucose metabolism, influencing the enzymatic&#xD;
      determinants of the hepatic glucose output, by enhancing glycogen storage and suppressing&#xD;
      nocturnal hepatic glucose production (glycogenolysis and gluconeogenesis&#xD;
      sequentially).Therefore, the disruption of the hepatic clock genes lead to fasting,&#xD;
      nocturnal, and to postprandial hyperglycemia in T2D. The researchers had previously shown in&#xD;
      T2D, that compared to 6Mdiet, the 3Meal diet timing schedule, was most effective in reducing&#xD;
      body weight, HbA1c, overall hyperglycemia, and led to up-regulation of SIRT1 and Clock Genes&#xD;
      mRNA expression in leukocytes. However, this effect of meal timing had never been explored in&#xD;
      liver cells. The investigators hypothesized that compared to Allday Diet (6Mdiet), the serum&#xD;
      collected from T2D participants following Breakfast Diet (3Mdiet) will up-regulate SIRT1 and&#xD;
      Clock Genes oscillatory mRNA expression in cultured hepatocytes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">May 31, 2020</start_date>
  <completion_date type="Anticipated">October 20, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 20, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The researcher will explore the effect of serum samples collected from T2D participants following either Breakfast Diet (3Mdiet) or Allday Diet (6Mdiet) schedule, on SIRT1 and Clock Gene circadian expression of cultured hepatocytes using the ex-vivo/in-vitro approach</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Clock Genes mRNA</measure>
    <time_frame>Baseline and at 2 weeks post diet intervention</time_frame>
    <description>Change from baseline serum-induced hepatocyte Clock Gene mRNA expression, will be assessed at 2 weeks post diet intervention in the two groups:Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Clock Genes expression</measure>
    <time_frame>Baseline and at 12 weeks post diet intervention</time_frame>
    <description>Change from baseline serum-induced hepatocyte Clock Gene expression, will be assessed at 12 weeks post diet intervention in the two groups: Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in SIRT1 mRNA expression</measure>
    <time_frame>Baseline and at 2 weeks post diet intervention</time_frame>
    <description>Change from baseline serum-induced hepatocyte SIRT1 mRNA expression, will be assessed at 2 weeks post diet intervention in the two groups: Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Overall Glycemia</measure>
    <time_frame>Baseline and at 12 weeks post diet intervention</time_frame>
    <description>Change from baseline in overall glycemia will be assessed at 12 weeks post diet intervention in the two groups: Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet) Overall glycemia will be test by using continuous blood monitoring system</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">24</enrollment>
  <condition>Type 2 Diabetes</condition>
  <condition>Obesity</condition>
  <arm_group>
    <arm_group_label>Breakfast Diet (3Mdiet)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The Breakfast Diet (3Mdiet) will consist in 3 meals with distribution of calories: breakfast 50%, lunch 33% and dinner 17%.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Allday Diet (6Mdiet)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The Allday Diet (6Mdiet) will consist on 6 meals (breakfast, lunch and dinner and 3 snacks) with distribution of calories: breakfast 15%, lunch 25%, dinner 30% and 10% in each of the three snacks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Breakfast Diet</intervention_name>
    <description>Breakfast Diet (3Mdiet) consist on high-energy breakfast and reduced in energy and carbohydrate (CH) dinner. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 3Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 3Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.</description>
    <arm_group_label>Breakfast Diet (3Mdiet)</arm_group_label>
    <other_name>3Mdiet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Allday Diet</intervention_name>
    <description>Allday Diet (6Mdiet) consist in 6 small meals: breakfast, lunch and dinner and 3 snacks, with calories and carbohydrates (CH) evenly distributed throughout the day. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 6Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 6Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.</description>
    <arm_group_label>Allday Diet (6Mdiet)</arm_group_label>
    <other_name>6Mdiet</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  T2D patients with stable treatment for at least 3 month preceding the study.&#xD;
&#xD;
          -  HgA1c &gt;7.5 %.&#xD;
&#xD;
          -  Age &gt; 30 years.&#xD;
&#xD;
          -  BMI: 27-34 kg/m2.&#xD;
&#xD;
          -  Treatment with antidiabetic drugs (i.e. metformin, DPP4 inhibitors, glinides) and&#xD;
             GLP-1 analogs, will be allowed&#xD;
&#xD;
          -  Anti-hypertensive treatment will be allowed.&#xD;
&#xD;
          -  Lipid-lowering medication also allowed&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Type 1 diabetes.&#xD;
&#xD;
          -  Major illnesses (liver, heart, kidney, infectious, neurological, psychiatric,&#xD;
             immunological, active malignancy).&#xD;
&#xD;
          -  Change in weight of &gt; 4.5 kg within 3 month prior the diet onset.&#xD;
&#xD;
          -  Night or rotating shift workers.&#xD;
&#xD;
          -  Those who crossed more than 2 time zones during 2-week period prior to study onset.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daniela Jakubowicz, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wolfson Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Shani Tsameret, RD</last_name>
    <role>Principal Investigator</role>
    <affiliation>E. Wolfson Medical Center.</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Daniela Jakubowicz, MD</last_name>
    <phone>+972508105552</phone>
    <email>daniela.jak@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Zohar Landau, MD</last_name>
    <phone>+972544822792</phone>
    <email>landau.zohar@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Wolfson Medical Center</name>
      <address>
        <city>Holon</city>
        <state>Please Select</state>
        <zip>58100</zip>
        <country>Israel</country>
      </address>
    </facility>
    <contact>
      <last_name>Daniela Jakubowicz, MD</last_name>
      <phone>0508105552</phone>
      <email>daniela.jak@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Zohar Landau, MD</last_name>
      <phone>972544822792</phone>
      <email>landau.zohar@gmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 19, 2020</study_first_submitted>
  <study_first_submitted_qc>May 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>May 22, 2020</last_update_submitted>
  <last_update_submitted_qc>May 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 28, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tel Aviv University</investigator_affiliation>
    <investigator_full_name>Daniela Jakubowicz</investigator_full_name>
    <investigator_title>Daniela Jakubowicz, MD: Clinical Profesor Head of Obesity Clinic at Diabetes Unit.</investigator_title>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Meal Timing</keyword>
  <keyword>Clock Genes</keyword>
  <keyword>Hepatocytes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04405895
org study id: 0118-20-WOMC
nct id: NCT04405895
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study is undertaken to explore in T2D, the effect of meal timing on serum induced SIRT1
      and Clock Genes mRNA expression in cultured hepatocytes. Fasting serum samples were collected
      from T2D participants, following two different meal timing schedules, either a diet with
      large breakfast and lunch with small dinner Breakfast Diet (3Mdiet) or an isocaloric diet
      with 6 small meals evenly distributed along the day Allday Diet (6Mdiet). The researchers
      will use an ex-vivo/in-vitro approach in which cultured medium will be conditioned with the
      fasted human serum collected from the two groups of T2D participants at baseline, after 2
      weeks and after 12 week of the diet intervention.
The timing of many physiological processes, including glucose metabolism, is coordinated by
      the circadian clock gene system. The circadian clock regulation, optimize glucose metabolism
      for the consumption of high energy and carbohydrate (CH) meals in the early hours of the day
      and for fasting at evening and night. Circadian disruption which occurs when the meal timing
      is not aligned with the circadian clock rhythms like skipping breakfast, overeating CH at
      night or eating CH all day, lead to desynchronized clock genes and can result in adverse
      health outcomes like insulin resistance, obesity hyperglycemia and T2D. Although the clock
      genes are disseminated in almost all peripheral tissues, those localized in the liver, are
      particularly important for the regulation of glucose metabolism, influencing the enzymatic
      determinants of the hepatic glucose output, by enhancing glycogen storage and suppressing
      nocturnal hepatic glucose production (glycogenolysis and gluconeogenesis
      sequentially).Therefore, the disruption of the hepatic clock genes lead to fasting,
      nocturnal, and to postprandial hyperglycemia in T2D. The researchers had previously shown in
      T2D, that compared to 6Mdiet, the 3Meal diet timing schedule, was most effective in reducing
      body weight, HbA1c, overall hyperglycemia, and led to up-regulation of SIRT1 and Clock Genes
      mRNA expression in leukocytes. However, this effect of meal timing had never been explored in
      liver cells. The investigators hypothesized that compared to Allday Diet (6Mdiet), the serum
      collected from T2D participants following Breakfast Diet (3Mdiet) will up-regulate SIRT1 and
      Clock Genes oscillatory mRNA expression in cultured hepatocytes.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The researcher will explore the effect of serum samples collected from T2D participants following either Breakfast Diet (3Mdiet) or Allday Diet (6Mdiet) schedule, on SIRT1 and Clock Gene circadian expression of cultured hepatocytes using the ex-vivo/in-vitro approach
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Clock Genes mRNA
time frame: Baseline and at 2 weeks post diet intervention
description: Change from baseline serum-induced hepatocyte Clock Gene mRNA expression, will be assessed at 2 weeks post diet intervention in the two groups:Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet)
measure: Change in Clock Genes expression
time frame: Baseline and at 12 weeks post diet intervention
description: Change from baseline serum-induced hepatocyte Clock Gene expression, will be assessed at 12 weeks post diet intervention in the two groups: Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet)
measure: Change in SIRT1 mRNA expression
time frame: Baseline and at 2 weeks post diet intervention
description: Change from baseline serum-induced hepatocyte SIRT1 mRNA expression, will be assessed at 2 weeks post diet intervention in the two groups: Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet)
measure: Change in Overall Glycemia
time frame: Baseline and at 12 weeks post diet intervention
description: Change from baseline in overall glycemia will be assessed at 12 weeks post diet intervention in the two groups: Breakfast Diet (3Mdiet) and Allday Diet (6Mdiet) Overall glycemia will be test by using continuous blood monitoring system
arm group label: Breakfast Diet (3Mdiet)
arm group type: Experimental
description: The Breakfast Diet (3Mdiet) will consist in 3 meals with distribution of calories: breakfast 50%, lunch 33% and dinner 17%.
arm group label: Allday Diet (6Mdiet)
arm group type: Active Comparator
description: The Allday Diet (6Mdiet) will consist on 6 meals (breakfast, lunch and dinner and 3 snacks) with distribution of calories: breakfast 15%, lunch 25%, dinner 30% and 10% in each of the three snacks.
intervention type: Other
intervention name: Breakfast Diet
description: Breakfast Diet (3Mdiet) consist on high-energy breakfast and reduced in energy and carbohydrate (CH) dinner. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 3Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 3Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.
arm group label: Breakfast Diet (3Mdiet)
other name: 3Mdiet
intervention type: Other
intervention name: Allday Diet
description: Allday Diet (6Mdiet) consist in 6 small meals: breakfast, lunch and dinner and 3 snacks, with calories and carbohydrates (CH) evenly distributed throughout the day. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 6Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 6Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.
arm group label: Allday Diet (6Mdiet)
other name: 6Mdiet
criteria: 
gender: All
minimum age: 30 Years
maximum age: 70 Years
healthy volunteers: No
last name: Daniela Jakubowicz, MD
role: Principal Investigator
affiliation: Wolfson Medical Center
last name: Shani Tsameret, RD
role: Principal Investigator
affiliation: E. Wolfson Medical Center.
last name: Daniela Jakubowicz, MD
phone: +972508105552
email: daniela.jak@gmail.com
last name: Zohar Landau, MD
phone: +972544822792
email: landau.zohar@gmail.com
facility: 
contact: 
contact backup: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Tel Aviv University
investigator full name: Daniela Jakubowicz
investigator title: Daniela Jakubowicz, MD: Clinical Profesor Head of Obesity Clinic at Diabetes Unit.
mesh term: Diabetes Mellitus, Type 2