xml: <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/NCT05987748</url>
    </required_header>
    <id_info>
      <org_study_id>NL83431.058.22</org_study_id>
      <nct_id>NCT05987748</nct_id>
    </id_info>
    <brief_title>The Clock Thickens: Morning or Evening Training for the Treatment of NAFLD?</brief_title>
    <acronym>TikTac</acronym>
    <official_title>The Clock Thickens: Morning or Evening Training for the Treatment of NAFLD? (TikTac Study)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Leiden University Medical Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Maag Lever Darm Stichting</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Leiden University Medical Center</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>
        The goal of this clinical trial is to investigate the different effect of morning and evening&#xD;
        exercise training in individuals with non-alcoholic fatty liver disease (NAFLD). The main&#xD;
        question it aims to answer is:&#xD;
  &#xD;
        • Is morning or evening exercise better for the treatment of NAFLD?&#xD;
  &#xD;
        Participants will follow a supervised exercise training program for three months with either&#xD;
        morning or evening training and the effect on liver health will be assessed. Researchers will&#xD;
        compare the morning to the evening exercise group to see if one training timepoint is more&#xD;
        effective than the other in reducing the amount of fat in the liver and improving liver&#xD;
        health.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The aim of the study is to identify the effect of exercise timing on NAFLD. Additionally, we&#xD;
        aim to increase the understanding of the exercise-related modulation of the metabolic and&#xD;
        inflammatory processes causing NAFLD, including insulin resistance and dysbiosis of the gut&#xD;
        microbiota. Forty obese patients with NAFLD will be enrolled by randomization to participate&#xD;
        in an exercise training program over 12 weeks, either in the morning (n=20) or evening&#xD;
        (n=20). Blood and stool samples will be collected before, during and after the intervention&#xD;
        to monitor diagnostic markers such as liver enzymes (AST, ALT, GGT, etc.) and changes of the&#xD;
        gut microbiota with exercise, respectively. Moreover, mixed meal tolerance tests will be&#xD;
        performed before and after the intervention to monitor insulin sensitivity and hepatic fat&#xD;
        content and cardiovascular parameters (e.g. arterial stiffness) will be monitored via MRI.&#xD;
        Throughout the study, physical fitness will be assessed and monitored using steep ramp tests.&#xD;
        Patients will be randomized for a supervised, standardized 50 min morning or evening&#xD;
        training, with both progressive endurance and strength elements, in a frequency of 3 times a&#xD;
        week for 12 weeks.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">September 1, 2024</completion_date>
    <primary_completion_date type="Anticipated">September 1, 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>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Liver fat content</measure>
      <time_frame>12 weeks</time_frame>
      <description>Liver fat content (in %) will be measured by MRI LiverMultiScan</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Hepatic fibrosis</measure>
      <time_frame>12 weeks</time_frame>
      <description>Hepatic stiffness (in kPa) will be measured as a proxy for liver fibrosis by Fibroscan (transient elastography)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Body mass index (BMI)</measure>
      <time_frame>12 weeks</time_frame>
      <description>Body weight (in kg) and height (in m) will be combined to report BMI in kg/m^2</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Fecal microbiota</measure>
      <time_frame>12 weeks</time_frame>
      <description>Fecal microbiota composition assessed via microbial sequencing</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cardiorespiratory fitness</measure>
      <time_frame>12 weeks</time_frame>
      <description>Peak workload (Wpeak) will be assessed with a the Steep Ramp Test (SRT) on a cycle ergometer</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Waist circumference</measure>
      <time_frame>12 weeks</time_frame>
      <description>Waist circumference (in cm) will be measured with a measuring tape</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Blood pressure</measure>
      <time_frame>12 weeks</time_frame>
      <description>Blood pressure (mmHg) will be measured using an arm cuff</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Plasma levels of liver enzymes</measure>
      <time_frame>12 weeks</time_frame>
      <description>Plasma levels of aspartate transaminase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) (all in units/L) and bilirubin (in umol/L) will be quantified in the laboratory</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Plasma insulin levels</measure>
      <time_frame>12 weeks</time_frame>
      <description>Plasma insulin (in pmol/L) will be measured during a mixed meal test after 0, 10, 20, 30, 40, 60, 90, 120 and 180 minutes of the ingestion of a mixed meal</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Plasma glucose levels</measure>
      <time_frame>12 weeks</time_frame>
      <description>Plasma glucose (in mmol/L) will be measured during a mixed meal test after 0, 10, 20, 30, 40, 60, 90, 120 and 180 minutes of the ingestion of a mixed meal</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Blood lipid levels</measure>
      <time_frame>12 weeks</time_frame>
      <description>Blood triglyceride, LDL-cholesterol and HDL-cholesterol levels (all in mmol/L) will be quantified in the laboratory</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Physical activity</measure>
      <time_frame>12 weeks</time_frame>
      <description>Self-reported physical activity (minutes of moderate-intensity activity per week) will be assessed with the International Physical Activity Questionnaire (IPAQ)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Sleep</measure>
      <time_frame>12 weeks</time_frame>
      <description>Sleeping habits (bedtime, time of falling asleep, time of waking up, sleep duration) will be assessed via the Munich Chronotype Questionnaire (MCTQs 5.0).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Food intake</measure>
      <time_frame>12 weeks</time_frame>
      <description>Self-reported food intake (type of food, quantity, time of intake) will be assessed with 3-day food diaries</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Non-Alcoholic Fatty Liver Disease</condition>
    <arm_group>
      <arm_group_label>Morning exercise</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Individuals will exercise train at 8 AM three times per week for 12 weeks.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Evening exercise</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Individuals will exercise train at 8 PM three times per week for 12 weeks.</description>
    </arm_group>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Exercise training</intervention_name>
      <description>Mixed exercise training containing strength and endurance elements carried out under supervision</description>
      <arm_group_label>Evening exercise</arm_group_label>
      <arm_group_label>Morning exercise</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age ≥ 45 years and ≤ 75&#xD;
  &#xD;
            -  Obese (BMI &gt; 27 kg/m2)&#xD;
  &#xD;
            -  Males and postmenopausal females&#xD;
  &#xD;
            -  Caucasian&#xD;
  &#xD;
            -  Hepatic steatosis defined as increased hyperechogenicity of the liver on abdominal&#xD;
               ultrasound, CAP score on Fibroscan &gt; 280, and/or histological signs of steatosis&#xD;
  &#xD;
            -  Sedentary lifestyle (maximum of 20 minutes of moderate-to-vigorous physical activity&#xD;
               per day on less than three days per week)&#xD;
  &#xD;
            -  Written informed consent&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Exclusion criteria for MRI (claustrophobia, pacemaker, metal implants, etc.)&#xD;
  &#xD;
            -  Any other liver disease than NAFLD/NASH&#xD;
  &#xD;
            -  Present excessive alcohol use defined as &gt; 2 units/day&#xD;
  &#xD;
            -  Recent use (&lt; 3 months) of antibiotics&#xD;
  &#xD;
            -  Recent changes in dosages of regular medication (&lt; 3 months)&#xD;
  &#xD;
            -  Recent (&lt; 3 months) weight change (&gt;5%)&#xD;
  &#xD;
            -  Recent (&lt; 3 months) substantial diet changes&#xD;
  &#xD;
            -  Cardiovascular co-morbidity defined as heart failure, coronary insufficiency and&#xD;
               hypertension in past history&#xD;
  &#xD;
            -  Comorbidity that contraindicates exercise training and exercise testing or that&#xD;
               affects exercise response and exercise capacity&#xD;
  &#xD;
            -  Ongoing or recent use of glucocorticoids, oral/transdermal hormonal substitution,&#xD;
               paclitaxel, theofyllin, amiodarone, myelosuppresive agents&#xD;
  &#xD;
            -  A psychiatric, addictive or any other disorder that compromises the subjects ability&#xD;
               to understand the study content and to give written informed consent for participation&#xD;
               in the study&#xD;
  &#xD;
            -  Working night or alternating shifts, known sleeping disorders such as narcolepsy or&#xD;
               insomnia&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>45 Years</minimum_age>
      <maximum_age>75 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Milena Schönke, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Leiden University Medical Center</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Milena Schönke, PhD</last_name>
      <phone>+31715268188</phone>
      <email>m.schoenke@lumc.nl</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Maarten E Tushuizen, MD PhD</last_name>
      <email>m.e.tushuizen@lumc.nl</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Leiden University Medical Center</name>
        <address>
          <city>Leiden</city>
          <state>South Holland</state>
          <zip>2333 ZA</zip>
          <country>Netherlands</country>
        </address>
      </facility>
      <contact>
        <last_name>Milena Schönke, PhD</last_name>
        <phone>+31715268188</phone>
        <email>m.schoenke@lumc.nl</email>
      </contact>
      <contact_backup>
        <last_name>Maarten E Tushuizen, MD PhD</last_name>
        <email>m.e.tushuizen@lumc.nl</email>
      </contact_backup>
      <investigator>
        <last_name>Milena Schönke, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Maarten E Tushuizen, MD PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Netherlands</country>
    </location_countries>
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    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 28, 2023</study_first_submitted>
    <study_first_submitted_qc>August 4, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 4, 2023</last_update_submitted>
    <last_update_submitted_qc>August 4, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Leiden University Medical Center</investigator_affiliation>
      <investigator_full_name>Milena Schoenke</investigator_full_name>
      <investigator_title>PhD</investigator_title>
    </responsible_party>
    <keyword>Exercise</keyword>
    <keyword>Circadian rhythms</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Liver Diseases</mesh_term>
      <mesh_term>Fatty Liver</mesh_term>
      <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>All IPD that underlie results in a publication</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_info_type>Analytic Code</ipd_info_type>
      <ipd_time_frame>Starting at publication</ipd_time_frame>
      <ipd_access_criteria>IPD that underlie results in a publication will be made available upon reasonable request</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05987748
  org study id: NL83431.058.22
  nct id: NCT05987748
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this clinical trial is to investigate the different effect of morning and evening
        exercise training in individuals with non-alcoholic fatty liver disease (NAFLD). The main
        question it aims to answer is:
  
        • Is morning or evening exercise better for the treatment of NAFLD?
  
        Participants will follow a supervised exercise training program for three months with either
        morning or evening training and the effect on liver health will be assessed. Researchers will
        compare the morning to the evening exercise group to see if one training timepoint is more
        effective than the other in reducing the amount of fat in the liver and improving liver
        health.
  The aim of the study is to identify the effect of exercise timing on NAFLD. Additionally, we
        aim to increase the understanding of the exercise-related modulation of the metabolic and
        inflammatory processes causing NAFLD, including insulin resistance and dysbiosis of the gut
        microbiota. Forty obese patients with NAFLD will be enrolled by randomization to participate
        in an exercise training program over 12 weeks, either in the morning (n=20) or evening
        (n=20). Blood and stool samples will be collected before, during and after the intervention
        to monitor diagnostic markers such as liver enzymes (AST, ALT, GGT, etc.) and changes of the
        gut microbiota with exercise, respectively. Moreover, mixed meal tolerance tests will be
        performed before and after the intervention to monitor insulin sensitivity and hepatic fat
        content and cardiovascular parameters (e.g. arterial stiffness) will be monitored via MRI.
        Throughout the study, physical fitness will be assessed and monitored using steep ramp tests.
        Patients will be randomized for a supervised, standardized 50 min morning or evening
        training, with both progressive endurance and strength elements, in a frequency of 3 times a
        week for 12 weeks.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Liver fat content
  time frame: 12 weeks
  description: Liver fat content (in %) will be measured by MRI LiverMultiScan
  measure: Hepatic fibrosis
  time frame: 12 weeks
  description: Hepatic stiffness (in kPa) will be measured as a proxy for liver fibrosis by Fibroscan (transient elastography)
  measure: Body mass index (BMI)
  time frame: 12 weeks
  description: Body weight (in kg) and height (in m) will be combined to report BMI in kg/m^2
  measure: Fecal microbiota
  time frame: 12 weeks
  description: Fecal microbiota composition assessed via microbial sequencing
  measure: Cardiorespiratory fitness
  time frame: 12 weeks
  description: Peak workload (Wpeak) will be assessed with a the Steep Ramp Test (SRT) on a cycle ergometer
  measure: Waist circumference
  time frame: 12 weeks
  description: Waist circumference (in cm) will be measured with a measuring tape
  measure: Blood pressure
  time frame: 12 weeks
  description: Blood pressure (mmHg) will be measured using an arm cuff
  measure: Plasma levels of liver enzymes
  time frame: 12 weeks
  description: Plasma levels of aspartate transaminase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) (all in units/L) and bilirubin (in umol/L) will be quantified in the laboratory
  measure: Plasma insulin levels
  time frame: 12 weeks
  description: Plasma insulin (in pmol/L) will be measured during a mixed meal test after 0, 10, 20, 30, 40, 60, 90, 120 and 180 minutes of the ingestion of a mixed meal
  measure: Plasma glucose levels
  time frame: 12 weeks
  description: Plasma glucose (in mmol/L) will be measured during a mixed meal test after 0, 10, 20, 30, 40, 60, 90, 120 and 180 minutes of the ingestion of a mixed meal
  measure: Blood lipid levels
  time frame: 12 weeks
  description: Blood triglyceride, LDL-cholesterol and HDL-cholesterol levels (all in mmol/L) will be quantified in the laboratory
  measure: Physical activity
  time frame: 12 weeks
  description: Self-reported physical activity (minutes of moderate-intensity activity per week) will be assessed with the International Physical Activity Questionnaire (IPAQ)
  measure: Sleep
  time frame: 12 weeks
  description: Sleeping habits (bedtime, time of falling asleep, time of waking up, sleep duration) will be assessed via the Munich Chronotype Questionnaire (MCTQs 5.0).
  measure: Food intake
  time frame: 12 weeks
  description: Self-reported food intake (type of food, quantity, time of intake) will be assessed with 3-day food diaries
  arm group label: Morning exercise
  arm group type: Experimental
  description: Individuals will exercise train at 8 AM three times per week for 12 weeks.
  arm group label: Evening exercise
  arm group type: Experimental
  description: Individuals will exercise train at 8 PM three times per week for 12 weeks.
  intervention type: Behavioral
  intervention name: Exercise training
  description: Mixed exercise training containing strength and endurance elements carried out under supervision
  arm group label: Evening exercise
  arm group label: Morning exercise
  criteria: 
  gender: All
  minimum age: 45 Years
  maximum age: 75 Years
  healthy volunteers: No
  last name: Milena Schönke, PhD
  role: Principal Investigator
  affiliation: Leiden University Medical Center
  last name: Milena Schönke, PhD
  phone: +31715268188
  email: m.schoenke@lumc.nl
  last name: Maarten E Tushuizen, MD PhD
  email: m.e.tushuizen@lumc.nl
  facility: 
  contact: 
  contact backup: 
  investigator: 
  investigator: 
  country: Netherlands
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  PMID: 9139168
  responsible party type: Principal Investigator
  investigator affiliation: Leiden University Medical Center
  investigator full name: Milena Schoenke
  investigator title: PhD
  mesh term: Liver Diseases
  mesh term: Fatty Liver
  mesh term: Non-alcoholic Fatty Liver Disease
  sharing ipd: Yes
  ipd description: All IPD that underlie results in a publication
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Clinical Study Report (CSR)
  ipd info type: Analytic Code
  ipd time frame: Starting at publication
  ipd access criteria: IPD that underlie results in a publication will be made available upon reasonable request