<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/NCT04406922</url>
  </required_header>
  <id_info>
    <org_study_id>COLD_RHYTHM</org_study_id>
    <nct_id>NCT04406922</nct_id>
  </id_info>
  <brief_title>Circadian Rhythmicity in Cold-induced Thermogenesis</brief_title>
  <acronym>COLDR</acronym>
  <official_title>The Impact of Circadian Rhythmicity in Cold-induced Thermogenesis in Lean and Obese Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Leiden University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Leiden University Medical Center</source>
  <oversight_info>
    <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 aims to investigate whether maximum cold-induced non-shivering thermogenesis (e.g.&#xD;
      thermogenesis as a consequence of BAT activity) differs between morning and evening.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Brown adipose tissue (BAT) recently emerged as a novel player in energy expenditure (EE) in&#xD;
      humans as it combusts fatty acids and glucose towards heat. Human BAT can be activated by&#xD;
      sympathetic stimulation resulting from cold exposure or treatment with sympathomimetic drugs.&#xD;
      Short-term acclimation to mild cold was shown to reduce fat mass in obese subjects and&#xD;
      decrease peripheral insulin resistance of patients with T2DM. Recently, in preclinical&#xD;
      studies the investigators showed that BAT has a circadian rhythm. It is currently unknown&#xD;
      whether this is also the case in humans. The investigators postulate that BAT activity should&#xD;
      display a circadian rhythm that adapts to changes in circadian behavior, and may determine&#xD;
      glucose/lipid levels throughout the day.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 23, 2019</start_date>
  <completion_date type="Actual">January 1, 2021</completion_date>
  <primary_completion_date type="Actual">January 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>The study design encompasses a single-arm randomized intervention study using cold exposure.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in cold-induced non-shivering thermogenesis between morning and evening</measure>
    <time_frame>Change in cold-induced non-shivering thermogenesis between morning (total duration of measurement 120 minutes) and evening (total duration of measurement 120 minutes). The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Thermogenesis is estimated by the change in energy expenditure after cold exposure, measured by indirect calorimetry. This will be measured in the morning and in the evening.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in glucose metabolism (mmol/L)</measure>
    <time_frame>Change between morning and evening: measured at several timepoints during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Serum glucose (mmol/L) before and during cold exposure in the morning versus the evening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in insulin (pmol/l)</measure>
    <time_frame>Change between morning and evening: measured at several timepoints during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Serum insulin (pmol/l) before and during cold exposure in the morning versus in the evening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lipid metabolism (cholesterol) (mmol/L)</measure>
    <time_frame>Change between morning and evening: measured at severaltime points during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Cholesterol (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) in serum (mmol/L). Before and during cold exposure in the morning and in the evening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lipid metabolism (triglycerides) (mmol/L)</measure>
    <time_frame>Change between morning and evening: measured at severaltime points during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Triglycerides, glycerol and free fatty acids in serum (mmol/L). Before and during cold exposure in the morning and in the evening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in markers for sympathetic output</measure>
    <time_frame>Change between morning and evening: measured before and after cold exposure. The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Norepinephrine, epinephrine (μM/ml)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Skin temperature</measure>
    <time_frame>Change between morning and evening: measured every 60 seconds during cold exposure on both study days. The time frame comprising both the morning and evening measurement will be 72 hours.</time_frame>
    <description>Wireless iButtons and infrared camera</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Healthy</condition>
  <condition>Obese</condition>
  <condition>Glucose Intolerance</condition>
  <arm_group>
    <arm_group_label>Intervention group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cold exposure in the morning and evening.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Personalized cooling protocol</intervention_name>
    <description>As an intervention, a personalized cooling protocol will be used in order to activate BAT and induce non-shivering thermogenesis. During the cooling procedure, subjects will be exposed to mild cold (approx. 14°C) for 150 min. Since the onset temperature of shivering shows a high interindividual variation, we will use a personal cooling protocol to ensure maximum non-shivering EE (and thus an equal maximum activation of BAT). The right temperature will be determined via a subjective method, e.g. to ask the subject if he or she experiences shivering. The time needed to achieve the right temperature is approximately 30-60 minutes. Then, the stable cooling period of 90 min is started. During this time the subject will be asked every 15 minutes whether he is experiencing shivering. If so, temperature will be increased with 2-3°C so that shivering just stops.</description>
    <arm_group_label>Intervention group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Dutch white Caucasian males or females&#xD;
&#xD;
          -  Age: 18-35 years&#xD;
&#xD;
          -  Lean group: BMI ≥ 18 and ≤ 25 kg/m2&#xD;
&#xD;
          -  Obese glucose tolerant group: BMI ≥ 30 and ≤ 42 kg/m2 and fasted plasma glucose levels&#xD;
             &lt; 5.5 and/or 2 h after OGTT ≤ 7.8 mM&#xD;
&#xD;
          -  Obese impaired glucose tolerant group: BMI ≥ 30 and ≤ 42 kg/m2 and fasted plasma&#xD;
             glucose levels ≥ 5.5 and/or 2 h after OGTT between 7.8 and 11.1 mM&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diabetes mellitus (determined on basis of fasting or OGTT defined by ADA criteria (30)&#xD;
&#xD;
          -  Any other active endocrine disease (thyroid disease, any signs of Cushing's syndrome,&#xD;
             adrenal disease and lipid-associated disorders such as familial hypercholesterolemia)&#xD;
&#xD;
          -  Any chronic renal or hepatic disease&#xD;
&#xD;
          -  Use of medication known to influence glucose and/or lipid metabolism or brown fat&#xD;
             activity (e.g. beta blockers, antidepressants)&#xD;
&#xD;
          -  Smoking&#xD;
&#xD;
          -  Abuse of alcohol or other substances&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Participation in an intensive weight-loss program or vigorous exercise program during&#xD;
             the last year before the start of the study&#xD;
&#xD;
          -  Current participation in another research projects that may influence the current&#xD;
             research project&#xD;
&#xD;
          -  Clinically relevant abnormalities in clinical chemistry at screening (to be judged by&#xD;
             the study physician)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mariette R Boon, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Leiden University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Leiden University Medical Center</name>
      <address>
        <city>Leiden</city>
        <zip>2333ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>January 21, 2020</study_first_submitted>
  <study_first_submitted_qc>May 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>April 14, 2021</last_update_submitted>
  <last_update_submitted_qc>April 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Leiden University Medical Center</investigator_affiliation>
    <investigator_full_name>mrboon</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>lean</keyword>
  <keyword>young</keyword>
  <keyword>healthy</keyword>
  <keyword>overweight</keyword>
  <keyword>obese</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glucose Intolerance</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/NCT04406922
org study id: COLD_RHYTHM
nct id: NCT04406922
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This study aims to investigate whether maximum cold-induced non-shivering thermogenesis (e.g.
      thermogenesis as a consequence of BAT activity) differs between morning and evening.
Brown adipose tissue (BAT) recently emerged as a novel player in energy expenditure (EE) in
      humans as it combusts fatty acids and glucose towards heat. Human BAT can be activated by
      sympathetic stimulation resulting from cold exposure or treatment with sympathomimetic drugs.
      Short-term acclimation to mild cold was shown to reduce fat mass in obese subjects and
      decrease peripheral insulin resistance of patients with T2DM. Recently, in preclinical
      studies the investigators showed that BAT has a circadian rhythm. It is currently unknown
      whether this is also the case in humans. The investigators postulate that BAT activity should
      display a circadian rhythm that adapts to changes in circadian behavior, and may determine
      glucose/lipid levels throughout the day.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: The study design encompasses a single-arm randomized intervention study using cold exposure.
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in cold-induced non-shivering thermogenesis between morning and evening
time frame: Change in cold-induced non-shivering thermogenesis between morning (total duration of measurement 120 minutes) and evening (total duration of measurement 120 minutes). The time frame comprising both the morning and evening measurement will be 72 hours.
description: Thermogenesis is estimated by the change in energy expenditure after cold exposure, measured by indirect calorimetry. This will be measured in the morning and in the evening.
measure: Change in glucose metabolism (mmol/L)
time frame: Change between morning and evening: measured at several timepoints during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.
description: Serum glucose (mmol/L) before and during cold exposure in the morning versus the evening.
measure: Change in insulin (pmol/l)
time frame: Change between morning and evening: measured at several timepoints during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.
description: Serum insulin (pmol/l) before and during cold exposure in the morning versus in the evening.
measure: Change in lipid metabolism (cholesterol) (mmol/L)
time frame: Change between morning and evening: measured at severaltime points during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.
description: Cholesterol (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) in serum (mmol/L). Before and during cold exposure in the morning and in the evening.
measure: Change in lipid metabolism (triglycerides) (mmol/L)
time frame: Change between morning and evening: measured at severaltime points during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.
description: Triglycerides, glycerol and free fatty acids in serum (mmol/L). Before and during cold exposure in the morning and in the evening.
measure: Change in markers for sympathetic output
time frame: Change between morning and evening: measured before and after cold exposure. The time frame comprising both the morning and evening measurement will be 72 hours.
description: Norepinephrine, epinephrine (μM/ml)
measure: Skin temperature
time frame: Change between morning and evening: measured every 60 seconds during cold exposure on both study days. The time frame comprising both the morning and evening measurement will be 72 hours.
description: Wireless iButtons and infrared camera
arm group label: Intervention group
arm group type: Experimental
description: Cold exposure in the morning and evening.
intervention type: Procedure
intervention name: Personalized cooling protocol
description: As an intervention, a personalized cooling protocol will be used in order to activate BAT and induce non-shivering thermogenesis. During the cooling procedure, subjects will be exposed to mild cold (approx. 14°C) for 150 min. Since the onset temperature of shivering shows a high interindividual variation, we will use a personal cooling protocol to ensure maximum non-shivering EE (and thus an equal maximum activation of BAT). The right temperature will be determined via a subjective method, e.g. to ask the subject if he or she experiences shivering. The time needed to achieve the right temperature is approximately 30-60 minutes. Then, the stable cooling period of 90 min is started. During this time the subject will be asked every 15 minutes whether he is experiencing shivering. If so, temperature will be increased with 2-3°C so that shivering just stops.
arm group label: Intervention group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mariette R Boon, MD, PhD
role: Principal Investigator
affiliation: Leiden University Medical Center
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Leiden University Medical Center
investigator full name: mrboon
investigator title: Principal Investigator
mesh term: Glucose Intolerance
sharing ipd: No