<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/NCT03809299</url>
  </required_header>
  <id_info>
    <org_study_id>2018-9671</org_study_id>
    <secondary_id>5P30DK020541</secondary_id>
    <nct_id>NCT03809299</nct_id>
  </id_info>
  <brief_title>2-A-Day Study: Twice a Day Meals Study.</brief_title>
  <official_title>2-A-Day Study: Twice a Day Meals Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Albert Einstein College of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Albert Einstein College of Medicine</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>
      Caloric restriction increases lifespan and/or healthspan across multiple species. However&#xD;
      implementation of long-term CR in humans is problematic and unacceptable to many individuals.&#xD;
      As a result, intermittent fasting models have been developed to improve adherence. Such&#xD;
      models have been shown to improve blood pressure, insulin sensitivity, decrease hepatic fat&#xD;
      content and body weight. Investigators established an isocaloric twice-a-day (ITAD) feeding&#xD;
      plan in mice, wherein test mice were acclimatized to consume over two hour periods (8-10am&#xD;
      and 5-7pm), the same amount of food as ad-libitum mice. This intervention prevented obesity&#xD;
      and age-associated type 2 diabetes via system-wide activation of autophagy. The investigators&#xD;
      will perform further studies of the same feeding model in humans in a randomized crossover&#xD;
      design. The objective is to test the hypothesis that restricting eating periods to twice a&#xD;
      day (TAD), when compared to isocaloric ad lib meal timing (ALMT), will have beneficial&#xD;
      effects on glucose metabolism, body composition, energy expenditure and autophagy in human&#xD;
      subjects at risk for diabetes&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Caloric restriction (CR) increases lifespan and/or healthspan across multiple species&#xD;
      including non-human primates. However, implementation of long-term CR in humans is&#xD;
      problematic and unacceptable to many individuals. Further, since CR leads to loss of muscle&#xD;
      mass in mice, it is likely that its implementation as a restorative strategy during aging may&#xD;
      exacerbate age-associated muscle loss. As a result, intermittent fasting models, e.g.,&#xD;
      alternate-day fasting, alternate day-modified fasting, the 5:2 diet, and the more recently&#xD;
      elucidated early time-restricted feeding (eTRF)3 were developed as alternative strategies to&#xD;
      improve adherence. Intermittent fasting increases glucose clearance/improves insulin&#xD;
      sensitivity, decreases hepatic fat content, lowers blood pressure and body weight by varying&#xD;
      degrees (at least when calories were unmatched). Despite these metabolic advantages, these&#xD;
      approaches have also shown poor adherence in humans. For instance, alternate-day fasted&#xD;
      subjects remained hungry on the fast days, which led to the conclusion that this approach&#xD;
      cannot be continued for extended periods of time, and that adding one small meal on the&#xD;
      fasting day may make this model more acceptable. Accordingly, in alternate day-modified&#xD;
      fasting, fasted days (25% caloric intake) alternated with feasting days (125% calories),&#xD;
      which improved compliance although dropout rates remained relatively high (38%) when compared&#xD;
      to control group (26%). In addition, this feeding approach was not found to be superior to&#xD;
      daily caloric restricted controls in terms of adherence, weight loss or cardiovascular&#xD;
      benefits. More recently, eTRF wherein men with prediabetes were subjected to a 6-hr feeding&#xD;
      interval with dinner before 1 pm displayed a number of metabolic benefits when compared to&#xD;
      individuals on a 12-hr feeding time-frame. Nevertheless, due to vocational or societal&#xD;
      factors, it is plausible that a vast majority of individuals may not be able to adhere to a&#xD;
      regimen requiring the consumption of three meals within the first 6 hr of the diurnal cycle.&#xD;
      In the attempt to offset compliance-related issues and to pursue a simpler approach,&#xD;
      investigators established an isocaloric twice-a-day (ITAD) feeding plan in mice, wherein test&#xD;
      mice are acclimatized to consume over two 2hr-periods (8:00-10:00am and 5:00-7:00pm) the same&#xD;
      amount of food as ad libitum-fed mice. This would effectively translate to a breakfast and&#xD;
      dinner (two meals) in humans. It has been shown that two periods of food restriction per day&#xD;
      in mice prevents obesity and age-associated type 2 diabetes via system-wide activation of&#xD;
      autophagy. This study is to determine if twice-a-day feeding will restore normoglycemia and&#xD;
      promote metabolic correction in older men with prediabetes.&#xD;
&#xD;
      Autophagy is a lysosomal degradative pathway that plays key roles in maintaining &quot;clean&quot;&#xD;
      cells. It is well-established that basal autophagy levels begin to decline progressively in&#xD;
      aged organisms. Maintaining higher autophagy levels improves organ function and stress&#xD;
      response. For instance, liver-specific overexpression of autophagy genes protects against&#xD;
      diet-induced obesity and tumor necrosis factor-mediated acute hepatotoxicity. In the&#xD;
      investigators' studies with ITAD feeding in mice, blocking autophagy in distinct tissues&#xD;
      resulted in loss of the metabolic benefits from this feeding strategy. Consequently, it is&#xD;
      propose that establishing ITAD feeding in humans will yield a cost-effective, practical and&#xD;
      immediately translatable strategy to prolong health-span by preventing diabetes and&#xD;
      sarcopenia as well as the vast number of secondary diseases caused by sustained&#xD;
      hyperglycemia.&#xD;
&#xD;
      This study will investigate the feasibility of a TAD eating regimen and collect preliminary&#xD;
      data to inform a larger-scale and more definitive trial.&#xD;
&#xD;
      Specific Aims:&#xD;
&#xD;
      Aim 1: To assess the feasibility of implementing a structured TAD eating regimen using&#xD;
      study-provided meals 1a. To design meal plans that are isocaloric with habitual intake and&#xD;
      intended to maintain weight and to develop methods to prepare, package and deliver the meals.&#xD;
&#xD;
      1b. To develop and evaluate methods to enhance and monitor participant adherence to TAD&#xD;
      eating; this will include patient logs, photo records of food intake and continuous&#xD;
      (participant blinded) glucose monitoring.&#xD;
&#xD;
        1. c. To assess participant satisfaction with TAD meal restriction, using validated&#xD;
           instruments to evaluate hunger, satiety and well-being Aim 2: To collect preliminary&#xD;
           data on the effect of TAD meal restriction to inform design of an adequately powered RCT&#xD;
&#xD;
        2. a. To collect preliminary data on the effect of TAD meal restriction on glucose&#xD;
           tolerance, insulin sensitivity and secretion, body composition and energy expenditure&#xD;
&#xD;
      2b. To collect preliminary data on the effect of TAD meal restriction on cellular processes&#xD;
      related to autophagy&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 20, 2019</start_date>
  <completion_date type="Anticipated">January 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Insulin sensitivity</measure>
    <time_frame>5 weeks</time_frame>
    <description>insulin sensitivity as measured by the Matsuda Index</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Glucose tolerance</measure>
    <time_frame>5 weeks</time_frame>
    <description>Glucose level after oral glucose tolerance test as measured by glucose area under the curve.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body Composition</measure>
    <time_frame>5 weeks</time_frame>
    <description>Fat mass as estimated by bioimpedance analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Energy expenditure</measure>
    <time_frame>5 weeks</time_frame>
    <description>Resting energy expenditure as estimated by indirect calorimetry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Autophagy level</measure>
    <time_frame>1 week</time_frame>
    <description>Expression of levels of autophagosome marker LC3 by immunoblotting</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>PreDiabetes</condition>
  <arm_group>
    <arm_group_label>Ad libitum meal timing first</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This arm will receive the ad libitum meal timing intervention first, followed by the twice a day feeding intervention.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Twice a day meals first</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This arm will receive the twice a day feeding intervention first, followed by the ad libitum meal timing intervention.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ad libitum meal timing</intervention_name>
    <description>Research participants will eat meals provided by the study throughout the day, ad libitum</description>
    <arm_group_label>Ad libitum meal timing first</arm_group_label>
    <arm_group_label>Twice a day meals first</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Twice a day meals</intervention_name>
    <description>Research participants will eat meals provided by the study at two intervals during the day, and fast in between.</description>
    <arm_group_label>Ad libitum meal timing first</arm_group_label>
    <arm_group_label>Twice a day meals first</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ● Men, age 30-70 years. In this preliminary study, recruitment is limited to men&#xD;
             because data from the relevant animal studies showed marked sexual dimorphism, with&#xD;
             more pronounced metabolic effects in males. Future studies will include both males and&#xD;
             females.&#xD;
&#xD;
               -  IFG or IGT based on 75g OGTT (fasting plasma glucose 100 -125 mg/dl and/or 2-hr&#xD;
                  glucose between 140 - 199 mg/dl); Or diabetes (FPG &gt; 126 mg/dl or 2 hr glucose &gt;&#xD;
                  200 mg/dl) not on treatment and with HbA1c &lt; 6.8% can also be enrolled.&#xD;
&#xD;
                    -  BMI 25-35 kg/m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Type 2 diabetes with A1C ≥6.8% or on drug treatment; Type 1 diabetes&#xD;
&#xD;
          -  Treatment with drugs known to influence glucose metabolism (diabetes medications,&#xD;
             systemic glucocorticoids, niacin &gt; 500 mg/day)&#xD;
&#xD;
          -  Current smoking, alcohol or drug abuse&#xD;
&#xD;
          -  Vigorous habitual physical activity (e.g., marathon runner, heavy weights trainers)&#xD;
&#xD;
          -  Subjects with symptomatic gastrointestinal disorders or intolerance (e.g., food&#xD;
             allergies, lactose intolerance, gluten sensitivity, etc.) or other conditions&#xD;
             requiring special diet or meal timing.&#xD;
&#xD;
          -  Subjects with serious chronic illness: severe (activity limiting) COPD, NYHA class 3&#xD;
             or 4 heart failure, kidney disease (eGFR&lt;45ml/min), liver enzyme abnormalities (ALT &gt;&#xD;
             2 times ULN), stroke, MI or ACS within last 6 months, cancer or HIV disease under&#xD;
             treatment.&#xD;
&#xD;
          -  Any other disease/condition that the investigator believes may interfere with&#xD;
             participation in the study (e.g., eating disorder).&#xD;
&#xD;
          -  Unstable weight conditions: gain or loss of &gt; 5 pounds or 2.5% body weight in past 3&#xD;
             months.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jill Crandall, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Albert Einstein College of Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jill Crandall</last_name>
    <phone>7184303765</phone>
    <email>jill.crandall@einsteinmed.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Albert Einstein College of Medicine of Yeshiva University</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 16, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>February 7, 2023</last_update_submitted>
  <last_update_submitted_qc>February 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Caloric restriction</keyword>
  <keyword>Fasting</keyword>
  <keyword>intermittent fasting</keyword>
  <keyword>isocaloric ad lib meal timing</keyword>
  <keyword>Twice-a-day feeding</keyword>
  <keyword>insulin</keyword>
  <keyword>glucose metabolism</keyword>
  <keyword>normoglycemia</keyword>
  <keyword>hyperglycemia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prediabetic State</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03809299
org study id: 2018-9671
secondary id: 5P30DK020541
nct id: NCT03809299
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Caloric restriction increases lifespan and/or healthspan across multiple species. However
      implementation of long-term CR in humans is problematic and unacceptable to many individuals.
      As a result, intermittent fasting models have been developed to improve adherence. Such
      models have been shown to improve blood pressure, insulin sensitivity, decrease hepatic fat
      content and body weight. Investigators established an isocaloric twice-a-day (ITAD) feeding
      plan in mice, wherein test mice were acclimatized to consume over two hour periods (8-10am
      and 5-7pm), the same amount of food as ad-libitum mice. This intervention prevented obesity
      and age-associated type 2 diabetes via system-wide activation of autophagy. The investigators
      will perform further studies of the same feeding model in humans in a randomized crossover
      design. The objective is to test the hypothesis that restricting eating periods to twice a
      day (TAD), when compared to isocaloric ad lib meal timing (ALMT), will have beneficial
      effects on glucose metabolism, body composition, energy expenditure and autophagy in human
      subjects at risk for diabetes
Caloric restriction (CR) increases lifespan and/or healthspan across multiple species
      including non-human primates. However, implementation of long-term CR in humans is
      problematic and unacceptable to many individuals. Further, since CR leads to loss of muscle
      mass in mice, it is likely that its implementation as a restorative strategy during aging may
      exacerbate age-associated muscle loss. As a result, intermittent fasting models, e.g.,
      alternate-day fasting, alternate day-modified fasting, the 5:2 diet, and the more recently
      elucidated early time-restricted feeding (eTRF)3 were developed as alternative strategies to
      improve adherence. Intermittent fasting increases glucose clearance/improves insulin
      sensitivity, decreases hepatic fat content, lowers blood pressure and body weight by varying
      degrees (at least when calories were unmatched). Despite these metabolic advantages, these
      approaches have also shown poor adherence in humans. For instance, alternate-day fasted
      subjects remained hungry on the fast days, which led to the conclusion that this approach
      cannot be continued for extended periods of time, and that adding one small meal on the
      fasting day may make this model more acceptable. Accordingly, in alternate day-modified
      fasting, fasted days (25% caloric intake) alternated with feasting days (125% calories),
      which improved compliance although dropout rates remained relatively high (38%) when compared
      to control group (26%). In addition, this feeding approach was not found to be superior to
      daily caloric restricted controls in terms of adherence, weight loss or cardiovascular
      benefits. More recently, eTRF wherein men with prediabetes were subjected to a 6-hr feeding
      interval with dinner before 1 pm displayed a number of metabolic benefits when compared to
      individuals on a 12-hr feeding time-frame. Nevertheless, due to vocational or societal
      factors, it is plausible that a vast majority of individuals may not be able to adhere to a
      regimen requiring the consumption of three meals within the first 6 hr of the diurnal cycle.
      In the attempt to offset compliance-related issues and to pursue a simpler approach,
      investigators established an isocaloric twice-a-day (ITAD) feeding plan in mice, wherein test
      mice are acclimatized to consume over two 2hr-periods (8:00-10:00am and 5:00-7:00pm) the same
      amount of food as ad libitum-fed mice. This would effectively translate to a breakfast and
      dinner (two meals) in humans. It has been shown that two periods of food restriction per day
      in mice prevents obesity and age-associated type 2 diabetes via system-wide activation of
      autophagy. This study is to determine if twice-a-day feeding will restore normoglycemia and
      promote metabolic correction in older men with prediabetes.

      Autophagy is a lysosomal degradative pathway that plays key roles in maintaining "clean"
      cells. It is well-established that basal autophagy levels begin to decline progressively in
      aged organisms. Maintaining higher autophagy levels improves organ function and stress
      response. For instance, liver-specific overexpression of autophagy genes protects against
      diet-induced obesity and tumor necrosis factor-mediated acute hepatotoxicity. In the
      investigators' studies with ITAD feeding in mice, blocking autophagy in distinct tissues
      resulted in loss of the metabolic benefits from this feeding strategy. Consequently, it is
      propose that establishing ITAD feeding in humans will yield a cost-effective, practical and
      immediately translatable strategy to prolong health-span by preventing diabetes and
      sarcopenia as well as the vast number of secondary diseases caused by sustained
      hyperglycemia.

      This study will investigate the feasibility of a TAD eating regimen and collect preliminary
      data to inform a larger-scale and more definitive trial.

      Specific Aims:

      Aim 1: To assess the feasibility of implementing a structured TAD eating regimen using
      study-provided meals 1a. To design meal plans that are isocaloric with habitual intake and
      intended to maintain weight and to develop methods to prepare, package and deliver the meals.

      1b. To develop and evaluate methods to enhance and monitor participant adherence to TAD
      eating; this will include patient logs, photo records of food intake and continuous
      (participant blinded) glucose monitoring.

        1. c. To assess participant satisfaction with TAD meal restriction, using validated
           instruments to evaluate hunger, satiety and well-being Aim 2: To collect preliminary
           data on the effect of TAD meal restriction to inform design of an adequately powered RCT

        2. a. To collect preliminary data on the effect of TAD meal restriction on glucose
           tolerance, insulin sensitivity and secretion, body composition and energy expenditure

      2b. To collect preliminary data on the effect of TAD meal restriction on cellular processes
      related to autophagy
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Insulin sensitivity
time frame: 5 weeks
description: insulin sensitivity as measured by the Matsuda Index
measure: Glucose tolerance
time frame: 5 weeks
description: Glucose level after oral glucose tolerance test as measured by glucose area under the curve.
measure: Body Composition
time frame: 5 weeks
description: Fat mass as estimated by bioimpedance analysis
measure: Energy expenditure
time frame: 5 weeks
description: Resting energy expenditure as estimated by indirect calorimetry
measure: Autophagy level
time frame: 1 week
description: Expression of levels of autophagosome marker LC3 by immunoblotting
arm group label: Ad libitum meal timing first
arm group type: Other
description: This arm will receive the ad libitum meal timing intervention first, followed by the twice a day feeding intervention.
arm group label: Twice a day meals first
arm group type: Other
description: This arm will receive the twice a day feeding intervention first, followed by the ad libitum meal timing intervention.
intervention type: Other
intervention name: Ad libitum meal timing
description: Research participants will eat meals provided by the study throughout the day, ad libitum
arm group label: Ad libitum meal timing first
arm group label: Twice a day meals first
intervention type: Other
intervention name: Twice a day meals
description: Research participants will eat meals provided by the study at two intervals during the day, and fast in between.
arm group label: Ad libitum meal timing first
arm group label: Twice a day meals first
criteria: 
gender: Male
minimum age: 30 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jill Crandall, MD
role: Principal Investigator
affiliation: Albert Einstein College of Medicine
last name: Jill Crandall
phone: 7184303765
email: jill.crandall@einsteinmed.edu
facility: 
status: Recruiting
country: United States
responsible party type: Sponsor
mesh term: Prediabetic State
sharing ipd: No