<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/NCT03798717</url>
  </required_header>
  <id_info>
    <org_study_id>003AS</org_study_id>
    <nct_id>NCT03798717</nct_id>
  </id_info>
  <brief_title>To Bathe or Not to Bathe</brief_title>
  <official_title>The Effect of Acute, Passive Heating on Glucose Tolerance in Individuals With Type 2 Diabetes Mellitus: a Randomised, Balanced Crossover, Control Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Portsmouth</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Portsmouth Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Portsmouth</source>
  <oversight_info>
    <has_dmc>No</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>
      Type 2 diabetes mellitus (T2DM) is characterised by chronic high blood sugar concentration&#xD;
      (hyperglycaemia) and insulin resistance leading to a reduction in insulin sensitivity. These&#xD;
      hyperglycaemic excursions can seriously impact metabolic, micro and macrovascular health. The&#xD;
      total cost of the direct and indirect care of individuals with diabetes (~90% T2DM) in the UK&#xD;
      (United Kingdom) is £23.7 billion, equating to ~20% of the annual national health service&#xD;
      (NHS) budget, with this projected to become unsustainable. Low-cost interventions to improve&#xD;
      glycaemic control in these individuals are therefore warranted. Current interventions include&#xD;
      pharmaceuticals, exercise and calorie restrictive diets. Pharmaceutical interventions carry a&#xD;
      high financial cost, while exercise and diet programmes have a low adherence rate in&#xD;
      individuals with T2DM.&#xD;
&#xD;
      Heat therapy offers one potential low cost therapy. Immersion in a hot tub for 30 mins.day-1&#xD;
      for 10 days has been shown to reduce fasting plasma [glucose] and HbA1c in individuals with&#xD;
      T2DM, which may be explained by acute (e.g. muscle) and chronic (e.g. reduced inflammatory&#xD;
      status and increased heat shock proteins (HSP)) adaptations, although experimental evidence&#xD;
      for these hypothesis are sparse. Other potential benefits include improved glycaemic control,&#xD;
      insulin sensitivity, elevated resting metabolic rate and improved micro- and macrovascular&#xD;
      function.&#xD;
&#xD;
      The aim of the present study is to determine whether acute hot water immersion can improve&#xD;
      glucose tolerance in individuals with T2DM and whether it is more beneficial to undertake&#xD;
      this before or after a OGTT (oral glucose tolerance test).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Visit 1 (consent, screening and familiarisation) During visit 1, participants will give their&#xD;
      informed consent, followed by a health screening questionnaire. In addition to the health&#xD;
      screening questionnaire, medical history and a blood sample will be collected and analysed&#xD;
      for a full blood count, glycated haemoglobin (HbA1c), liver and kidney function. Finally, a&#xD;
      resting electrocardiogram (ECG) will also be recorded and then examined for irregularities,&#xD;
      where a clinical decision will be made on further participation to the study by consultants&#xD;
      at QA (Queen Alexandra) hospital. Participants will then be shown the rest of the equipment&#xD;
      and taken through the procedure for the next 3 visits and, if the participant is happy to&#xD;
      continue the study, the next visit will be organised.&#xD;
&#xD;
      Visit 2, 3 and 4 Participants will arrive at the laboratory at ~9 am for conditions 1 and 2&#xD;
      and 8 am for condition 3. Prior to a 15 min resting period (supine) before any measures are&#xD;
      taken participants will be asked to insert a rectal thermistor (participants will be given&#xD;
      clear instructions using the investigator's SoPs (standard operating procedure)). Condition&#xD;
      1, 2 and 3 will be balanced and participants randomly allocated to begin the study in either&#xD;
      visit 2, 3 or 4 using a blinded member of the team.&#xD;
&#xD;
      For all visits (see figure 2), participants will lie in a semi recumbent position in minimal&#xD;
      clothing (bathing shorts and a t-shirt) for the entirety of the visit. Initially,&#xD;
      participants will be cannulated (Versatus winged and ported IV cannula, Terumo, Japan) and&#xD;
      blood samples drawn for analysis of osmolality (Lithium Heparin (LH) tubes BD (Becton,&#xD;
      Dickinson and Company), USA) plasma [glucose] (Fluoride/Oxalate tubes, BD, USA), [insulin]&#xD;
      (Ethylenediaminetetraacetic acid (EDTA) K2, BD, USA), and [eHSP70 (extracellular heat shock&#xD;
      protein 70)] (EDTA K2, BD, USA) at baseline and every 30 min of each experimental visit.&#xD;
      Following cannulation an 180 min OGTT (75g) (Rapilose OGTT solution, Penlan healthcare,&#xD;
      Japan) will commence in a thermoneutral room (~ 23oC). A maximum of 18 mL of blood being&#xD;
      drawn at each time point (max 126 mL per visit). To maintain the patency of the cannula and&#xD;
      to reduce the risk of infection, after every sample is taken, 5 mL of saline will be flushed&#xD;
      through the cannula. Then before every sample is taken, 2.5 mL of blood will be drawn out of&#xD;
      the cannula to ensure any remaining saline will not interfere with the samples and data&#xD;
      interpretation (additional 17.5mL per visit). During the OGTT, HR (heart rate) (via&#xD;
      electrocardiogram) will be measured continuously, whilst blood pressure (M5-1, Omron, Japan),&#xD;
      deep body temperature (rectal probe) and resting metabolic rate (indirect calorimetry) (Quark&#xD;
      CPET (cardiopulmonary exercise test), Cosmed, Italy) will be assessed every 30 min.&#xD;
&#xD;
      Condition 2 will employ identical procedures to condition 1, except thirty minutes into the&#xD;
      OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water&#xD;
      temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC&#xD;
      using water between 37.5 and 39oC, and then participants will be removed horizontally back&#xD;
      into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried&#xD;
      and given a towelled robe to wear. Condition 3 will employ identical procedures to condition&#xD;
      2, with the exception that the heating via immersion will start as soon as the participant is&#xD;
      instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the&#xD;
      60 min immersion time for a further 180 min (see figure 2 for a schematic).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 20, 2019</start_date>
  <completion_date type="Actual">March 9, 2020</completion_date>
  <primary_completion_date type="Actual">March 9, 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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean AUC (Area Under the Curve) Plasma [Glucose]</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does an acute bout of passive, warm water therapy reduce plasma [glucose]? Units for AUC are AU (arbitrary units) which have been derived from the trapezoidal method and have been published as such. Trapezoidal method: AUC = Δx ((y0/2)+y1+y2+y3+...+(yn/2)).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Plasma [Insulin]</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does plasma [insulin] reduce more if the passive, warm water therapy is conducted before or after the OGTT?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Insulin Sensitivity</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does insulin sensitivity increase following an acute bout of warm water therapy? Calculation of insulin sensitivity is measured in AU which have been derived from the Gutt method and have been published as such. Gutt insulin sensitivity = [75,000 + (G0-G120) × 0.19 × BW]/(120 × log [(I0 + I120)/2] × [(G0 + G120)/2]). Where G = plasma [glucose], I = plasma [insulin] and BW = body weight.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Fuel Utilisation</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does carbohydrate and fat (RER) utilisation alter during and following an acute bout of warm water therapy?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cardiovascular Status</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does heart rate (variability) change during or after an acute bout of warm water therapy?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in eHSP70 (Extracellular Heat Shock Protein 70)</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does eHSP increases during and following an acute bout of warm water therapy?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Inflammatory Status</measure>
    <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
    <description>Does inflammatory status (IL-6 &amp; IL-10) change during or after an acute bout of warm water therapy?</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pre OGTT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Post OGTT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Heating</intervention_name>
    <description>Warm water immersion</description>
    <arm_group_label>Post OGTT</arm_group_label>
    <arm_group_label>Pre OGTT</arm_group_label>
    <other_name>Bath</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        The participants must meet all of the following criteria to be considered eligible for the&#xD;
        study:&#xD;
&#xD;
          -  Male or female (either post-menopausal or in the early-follicular phase (3-5 days&#xD;
             after the onset of menstruation) of the menstrual cycle), aged 35 years or above.&#xD;
&#xD;
          -  Diagnosed with T2DM as defined by the WHO (World Health Organisation).&#xD;
&#xD;
          -  Participant is willing and able to give informed consent for participation in the&#xD;
             study.&#xD;
&#xD;
          -  Participant is able to understand and fully cooperate with the study protocol.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        The participant may not enter / be withdrawn from the study if any of the following apply:&#xD;
&#xD;
          -  Severe peripheral neuropathy (to the point to which they cannot sense temperature)&#xD;
&#xD;
          -  Uncontrolled hypertension (≥180 systolic / 100 diastolic mmHg)&#xD;
&#xD;
          -  Taking any medication which may interfere with data interpretation or safety&#xD;
&#xD;
          -  Who have had a myocardial infarction or cerebro-vascular event&#xD;
&#xD;
          -  Any cardiac abnormalities which restrict hard exercise&#xD;
&#xD;
          -  Current smokers or who have stopped within 3 months&#xD;
&#xD;
          -  Participant is unable to understand and/or fully cooperate with the study protocol&#xD;
&#xD;
          -  Any other serious medical condition which would interfere with data interpretation or&#xD;
             safety will be excluded from participation.&#xD;
&#xD;
          -  Any skin conditions including ulcerations&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Sport and Exercise Science</name>
      <address>
        <city>Portsmouth</city>
        <state>Hampshire</state>
        <zip>PO1 2ER</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>January 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 10, 2019</study_first_posted>
  <results_first_submitted>April 29, 2021</results_first_submitted>
  <results_first_submitted_qc>June 28, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">July 19, 2021</results_first_posted>
  <last_update_submitted>July 19, 2021</last_update_submitted>
  <last_update_submitted_qc>July 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Portsmouth</investigator_affiliation>
    <investigator_full_name>Ant Shepherd</investigator_full_name>
    <investigator_title>Senior Lecturer</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to release IPD (individual patient data), until all avenues of further funding have been exhausted.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 5, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/17/NCT03798717/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>440 individuals were screened for eligibility (200 clinical letters, 40 from day events and 200 from local diabetes education group). 420 declined and 0 were excluded. Once participants were randomly allocated to arm sequence 5 withdrew before starting. Three in-between experimental visits. Twelve completed the study and data analysed.</recruitment_details>
      <pre_assignment_details>Participants were excluded from the study before assignment to groups if they did not pass screening criteria. Balanced randomisation of order in which individuals completed each arm (cross-over) was carried out. Therefore there was an equal number of individuals completing all combinations of arms.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Control - Pre OGTT - Post OGTT</title>
          <description>Participants first underwent a 3 h OGTT (oral glucose tolerance test) with no passive heating. Then approximately a week later underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT.</description>
        </group>
        <group group_id="P2">
          <title>Control - Post OGTT - Pre OGTT</title>
          <description>Participants first underwent a 3 h OGTT with no passive heating. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then approximately a week later underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT.</description>
        </group>
        <group group_id="P3">
          <title>Pre OGTT - Control - Post OGTT</title>
          <description>Participants first underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT.</description>
        </group>
        <group group_id="P4">
          <title>Pre OGTT - Post OGTT - Control</title>
          <description>Participants first underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating.</description>
        </group>
        <group group_id="P5">
          <title>Post OGTT - Control - Pre OGTT</title>
          <description>Participants first underwent underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating. Then, approximately a week later underwent 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT.</description>
        </group>
        <group group_id="P6">
          <title>Post OGTT - Pre OGTT - Control</title>
          <description>Participants first underwent underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="3"/>
                <participants group_id="P6" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="2"/>
                <participants group_id="P6" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Failed Screening</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>COVID-19 (coronavirus disease) Lockdown</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Individuals with T2DM</population>
      <group_list>
        <group group_id="B1">
          <title>Control - Pre OGTT - Post OGTT</title>
          <description>Participants first underwent a 3 h OGTT with no passive heating. Then approximately a week later underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT.</description>
        </group>
        <group group_id="B2">
          <title>Control - Post OGTT - Pre OGTT</title>
          <description>Participants first underwent a 3 h OGTT with no passive heating. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then approximately a week later underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT.</description>
        </group>
        <group group_id="B3">
          <title>Pre OGTT - Control - Post OGTT</title>
          <description>Participants first underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT.</description>
        </group>
        <group group_id="B4">
          <title>Pre OGTT - Post OGTT - Control</title>
          <description>Participants first underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating.</description>
        </group>
        <group group_id="B5">
          <title>Post OGTT - Control - Pre OGTT</title>
          <description>Participants first underwent underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating. Then, approximately a week later underwent 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT.</description>
        </group>
        <group group_id="B6">
          <title>Post OGTT - Pre OGTT - Control</title>
          <description>Participants first underwent underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating.</description>
        </group>
        <group group_id="B7">
          <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="4"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="3"/>
            <count group_id="B4" value="4"/>
            <count group_id="B5" value="3"/>
            <count group_id="B6" value="3"/>
            <count group_id="B7" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</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="4"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="3"/>
                    <count group_id="B4" value="4"/>
                    <count group_id="B5" value="3"/>
                    <count group_id="B6" value="3"/>
                    <count group_id="B7" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                    <measurement group_id="B7" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="1"/>
                    <measurement group_id="B7" value="11"/>
                  </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="4"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="3"/>
                    <count group_id="B4" value="4"/>
                    <count group_id="B5" value="3"/>
                    <count group_id="B6" value="3"/>
                    <count group_id="B7" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                    <measurement group_id="B7" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="15"/>
                  </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 group_id="B4" value="0"/>
                    <count group_id="B5" value="0"/>
                    <count group_id="B6" value="0"/>
                    <count group_id="B7" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B7" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Mean AUC (Area Under the Curve) Plasma [Glucose]</title>
        <description>Does an acute bout of passive, warm water therapy reduce plasma [glucose]? Units for AUC are AU (arbitrary units) which have been derived from the trapezoidal method and have been published as such. Trapezoidal method: AUC = Δx ((y0/2)+y1+y2+y3+...+(yn/2)).</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>Individuals with T2DM (type 2 diabetes mellitus)</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR (heart rate) will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Mean AUC (Area Under the Curve) Plasma [Glucose]</title>
          <description>Does an acute bout of passive, warm water therapy reduce plasma [glucose]? Units for AUC are AU (arbitrary units) which have been derived from the trapezoidal method and have been published as such. Trapezoidal method: AUC = Δx ((y0/2)+y1+y2+y3+...+(yn/2)).</description>
          <population>Individuals with T2DM (type 2 diabetes mellitus)</population>
          <units>AU</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1677" spread="386"/>
                    <measurement group_id="O2" value="1797" spread="340"/>
                    <measurement group_id="O3" value="1662" spread="364"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Plasma [Insulin]</title>
        <description>Does plasma [insulin] reduce more if the passive, warm water therapy is conducted before or after the OGTT?</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>Individuals with T2DM</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Plasma [Insulin]</title>
          <description>Does plasma [insulin] reduce more if the passive, warm water therapy is conducted before or after the OGTT?</description>
          <population>Individuals with T2DM</population>
          <units>µU/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.18" spread="68.94"/>
                    <measurement group_id="O2" value="48.79" spread="35.11"/>
                    <measurement group_id="O3" value="79.86" spread="63.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Insulin Sensitivity</title>
        <description>Does insulin sensitivity increase following an acute bout of warm water therapy? Calculation of insulin sensitivity is measured in AU which have been derived from the Gutt method and have been published as such. Gutt insulin sensitivity = [75,000 + (G0-G120) × 0.19 × BW]/(120 × log [(I0 + I120)/2] × [(G0 + G120)/2]). Where G = plasma [glucose], I = plasma [insulin] and BW = body weight.</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>Individuals with T2DM</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Insulin Sensitivity</title>
          <description>Does insulin sensitivity increase following an acute bout of warm water therapy? Calculation of insulin sensitivity is measured in AU which have been derived from the Gutt method and have been published as such. Gutt insulin sensitivity = [75,000 + (G0-G120) × 0.19 × BW]/(120 × log [(I0 + I120)/2] × [(G0 + G120)/2]). Where G = plasma [glucose], I = plasma [insulin] and BW = body weight.</description>
          <population>Individuals with T2DM</population>
          <units>AU</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.00" spread="11.56"/>
                    <measurement group_id="O2" value="47.45" spread="13.86"/>
                    <measurement group_id="O3" value="56.51" spread="13.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Fuel Utilisation</title>
        <description>Does carbohydrate and fat (RER) utilisation alter during and following an acute bout of warm water therapy?</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>Individuals with T2DM</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Fuel Utilisation</title>
          <description>Does carbohydrate and fat (RER) utilisation alter during and following an acute bout of warm water therapy?</description>
          <population>Individuals with T2DM</population>
          <units>kcal</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="263" spread="33"/>
                    <measurement group_id="O2" value="278" spread="40"/>
                    <measurement group_id="O3" value="304" spread="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Cardiovascular Status</title>
        <description>Does heart rate (variability) change during or after an acute bout of warm water therapy?</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>0 participants analysed due to immersion for passive heating causing too much noise in the data for it to be valid.</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR (heart rate) will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cardiovascular Status</title>
          <description>Does heart rate (variability) change during or after an acute bout of warm water therapy?</description>
          <population>0 participants analysed due to immersion for passive heating causing too much noise in the data for it to be valid.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in eHSP70 (Extracellular Heat Shock Protein 70)</title>
        <description>Does eHSP increases during and following an acute bout of warm water therapy?</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>Individuals with T2DM</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Change in eHSP70 (Extracellular Heat Shock Protein 70)</title>
          <description>Does eHSP increases during and following an acute bout of warm water therapy?</description>
          <population>Individuals with T2DM</population>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="324" spread="154"/>
                    <measurement group_id="O2" value="507" spread="112"/>
                    <measurement group_id="O3" value="364" spread="81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Inflammatory Status</title>
        <description>Does inflammatory status (IL-6 &amp; IL-10) change during or after an acute bout of warm water therapy?</description>
        <time_frame>Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks</time_frame>
        <population>0 participants analysed due to lack of funds as a result of the COVID-19 pandemic. Data for this has not been collected and will not be in the future.</population>
        <group_list>
          <group group_id="O1">
            <title>Control</title>
            <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR (heart rate) will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
          </group>
          <group group_id="O2">
            <title>Pre OGTT</title>
            <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
          </group>
          <group group_id="O3">
            <title>Post OGTT</title>
            <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Inflammatory Status</title>
          <description>Does inflammatory status (IL-6 &amp; IL-10) change during or after an acute bout of warm water therapy?</description>
          <population>0 participants analysed due to lack of funds as a result of the COVID-19 pandemic. Data for this has not been collected and will not be in the future.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3h for the OGTT plus the 1 h of passive heating in the passive heating arms at Visit 2, 3 and 4. 3 times in total, until study completion, up to approximately 8 weeks.</time_frame>
      <desc>Safety population included all participants who underwent the OGTT and passive heating.</desc>
      <group_list>
        <group group_id="E1">
          <title>Control</title>
          <description>Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.</description>
        </group>
        <group group_id="E2">
          <title>Pre OGTT</title>
          <description>Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.&#xD;
Heating: Warm water immersion</description>
        </group>
        <group group_id="E3">
          <title>Post OGTT</title>
          <description>Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.&#xD;
Heating: Warm water immersion</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="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <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="12"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Vasovagal syncope</sub_title>
                <description>Vasovagal syncope (1 on existing the water, 1 during study assessments).</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Pain on cannulation</sub_title>
                <description>Participant experienced pain on cannulation</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>
    <point_of_contact>
      <name_or_title>Dr. Ant Shepherd</name_or_title>
      <organization>University of Portsmouth</organization>
      <phone>02392845289</phone>
      <email>ant.shepherd@port.ac.uk</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/NCT03798717
org study id: 003AS
nct id: NCT03798717
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Type 2 diabetes mellitus (T2DM) is characterised by chronic high blood sugar concentration
      (hyperglycaemia) and insulin resistance leading to a reduction in insulin sensitivity. These
      hyperglycaemic excursions can seriously impact metabolic, micro and macrovascular health. The
      total cost of the direct and indirect care of individuals with diabetes (~90% T2DM) in the UK
      (United Kingdom) is £23.7 billion, equating to ~20% of the annual national health service
      (NHS) budget, with this projected to become unsustainable. Low-cost interventions to improve
      glycaemic control in these individuals are therefore warranted. Current interventions include
      pharmaceuticals, exercise and calorie restrictive diets. Pharmaceutical interventions carry a
      high financial cost, while exercise and diet programmes have a low adherence rate in
      individuals with T2DM.

      Heat therapy offers one potential low cost therapy. Immersion in a hot tub for 30 mins.day-1
      for 10 days has been shown to reduce fasting plasma [glucose] and HbA1c in individuals with
      T2DM, which may be explained by acute (e.g. muscle) and chronic (e.g. reduced inflammatory
      status and increased heat shock proteins (HSP)) adaptations, although experimental evidence
      for these hypothesis are sparse. Other potential benefits include improved glycaemic control,
      insulin sensitivity, elevated resting metabolic rate and improved micro- and macrovascular
      function.

      The aim of the present study is to determine whether acute hot water immersion can improve
      glucose tolerance in individuals with T2DM and whether it is more beneficial to undertake
      this before or after a OGTT (oral glucose tolerance test).
Visit 1 (consent, screening and familiarisation) During visit 1, participants will give their
      informed consent, followed by a health screening questionnaire. In addition to the health
      screening questionnaire, medical history and a blood sample will be collected and analysed
      for a full blood count, glycated haemoglobin (HbA1c), liver and kidney function. Finally, a
      resting electrocardiogram (ECG) will also be recorded and then examined for irregularities,
      where a clinical decision will be made on further participation to the study by consultants
      at QA (Queen Alexandra) hospital. Participants will then be shown the rest of the equipment
      and taken through the procedure for the next 3 visits and, if the participant is happy to
      continue the study, the next visit will be organised.

      Visit 2, 3 and 4 Participants will arrive at the laboratory at ~9 am for conditions 1 and 2
      and 8 am for condition 3. Prior to a 15 min resting period (supine) before any measures are
      taken participants will be asked to insert a rectal thermistor (participants will be given
      clear instructions using the investigator's SoPs (standard operating procedure)). Condition
      1, 2 and 3 will be balanced and participants randomly allocated to begin the study in either
      visit 2, 3 or 4 using a blinded member of the team.

      For all visits (see figure 2), participants will lie in a semi recumbent position in minimal
      clothing (bathing shorts and a t-shirt) for the entirety of the visit. Initially,
      participants will be cannulated (Versatus winged and ported IV cannula, Terumo, Japan) and
      blood samples drawn for analysis of osmolality (Lithium Heparin (LH) tubes BD (Becton,
      Dickinson and Company), USA) plasma [glucose] (Fluoride/Oxalate tubes, BD, USA), [insulin]
      (Ethylenediaminetetraacetic acid (EDTA) K2, BD, USA), and [eHSP70 (extracellular heat shock
      protein 70)] (EDTA K2, BD, USA) at baseline and every 30 min of each experimental visit.
      Following cannulation an 180 min OGTT (75g) (Rapilose OGTT solution, Penlan healthcare,
      Japan) will commence in a thermoneutral room (~ 23oC). A maximum of 18 mL of blood being
      drawn at each time point (max 126 mL per visit). To maintain the patency of the cannula and
      to reduce the risk of infection, after every sample is taken, 5 mL of saline will be flushed
      through the cannula. Then before every sample is taken, 2.5 mL of blood will be drawn out of
      the cannula to ensure any remaining saline will not interfere with the samples and data
      interpretation (additional 17.5mL per visit). During the OGTT, HR (heart rate) (via
      electrocardiogram) will be measured continuously, whilst blood pressure (M5-1, Omron, Japan),
      deep body temperature (rectal probe) and resting metabolic rate (indirect calorimetry) (Quark
      CPET (cardiopulmonary exercise test), Cosmed, Italy) will be assessed every 30 min.

      Condition 2 will employ identical procedures to condition 1, except thirty minutes into the
      OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water
      temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC
      using water between 37.5 and 39oC, and then participants will be removed horizontally back
      into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried
      and given a towelled robe to wear. Condition 3 will employ identical procedures to condition
      2, with the exception that the heating via immersion will start as soon as the participant is
      instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the
      60 min immersion time for a further 180 min (see figure 2 for a schematic).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Mean AUC (Area Under the Curve) Plasma [Glucose]
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does an acute bout of passive, warm water therapy reduce plasma [glucose]? Units for AUC are AU (arbitrary units) which have been derived from the trapezoidal method and have been published as such. Trapezoidal method: AUC = Δx ((y0/2)+y1+y2+y3+...+(yn/2)).
measure: Change in Plasma [Insulin]
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does plasma [insulin] reduce more if the passive, warm water therapy is conducted before or after the OGTT?
measure: Mean Insulin Sensitivity
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does insulin sensitivity increase following an acute bout of warm water therapy? Calculation of insulin sensitivity is measured in AU which have been derived from the Gutt method and have been published as such. Gutt insulin sensitivity = [75,000 + (G0-G120) × 0.19 × BW]/(120 × log [(I0 + I120)/2] × [(G0 + G120)/2]). Where G = plasma [glucose], I = plasma [insulin] and BW = body weight.
measure: Change in Fuel Utilisation
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does carbohydrate and fat (RER) utilisation alter during and following an acute bout of warm water therapy?
measure: Change in Cardiovascular Status
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does heart rate (variability) change during or after an acute bout of warm water therapy?
measure: Change in eHSP70 (Extracellular Heat Shock Protein 70)
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does eHSP increases during and following an acute bout of warm water therapy?
measure: Change in Inflammatory Status
time frame: Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks
description: Does inflammatory status (IL-6 & IL-10) change during or after an acute bout of warm water therapy?
arm group label: Control
arm group type: No Intervention
description: Participants will lie in a semi recumbent position in minimal clothing for the entirety of the visit. Initially, participants will be cannulated and blood samples drawn.every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) will commence in a thermoneutral room (~ 23C). During the OGTT, HR will be measured continuously, whilst blood pressure, deep body temperature (rectal probe) and resting metabolic rate will be assessed every 30 min.
arm group label: Pre OGTT
arm group type: Experimental
description: Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear.
arm group label: Post OGTT
arm group type: Experimental
description: Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min.
intervention type: Diagnostic Test
intervention name: Heating
description: Warm water immersion
arm group label: Post OGTT
arm group label: Pre OGTT
other name: Bath
criteria: 
gender: All
minimum age: 35 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Portsmouth
investigator full name: Ant Shepherd
investigator title: Senior Lecturer
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
sharing ipd: No
ipd description: There is no plan to release IPD (individual patient data), until all avenues of further funding have been exhausted.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 