<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/NCT02205996</url>
  </required_header>
  <id_info>
    <org_study_id>11/YH/0161</org_study_id>
    <nct_id>NCT02205996</nct_id>
  </id_info>
  <brief_title>The Effects of Hypoglycaemia in People With Type 2 Diabetes</brief_title>
  <official_title>The Effects of Hypoglycaemia on Platelets Function and Inflammatory Markers in People With Type 2 Diabetes and Normal Controls.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Hull</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hull University Teaching Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Hull</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Strict glycaemic control has been associated with increased hypoglycaemia and mortality rate,&#xD;
      the cause of which was unclear, in subjects with type 2 diabetes. In this study, we&#xD;
      hypothesised that acute hypoglycaemia will result in platelet activation in people with type&#xD;
      2 diabetes to a higher degree than controls.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Type 2 diabetes is associated with increased risk of cardiovascular disease. Although the&#xD;
      United Kingdom Prospective Diabetes Study (UKPDS) follow-up data suggested reduced&#xD;
      macrovascular complications with tight glycaemic control, recent studies in people with type&#xD;
      2 diabetes failed to replicate these findings. Furthermore, all-cause mortality was found to&#xD;
      be increased with strict glycaemic control in the Action to Control Cardiovascular Risk in&#xD;
      Diabetes (ACCORD) study. The cause of the increased deaths remains unclear.&#xD;
&#xD;
      Strict glycaemic control is associated with increased risk of hypoglycaemia. Although,&#xD;
      hypoglycaemia has traditionally been considered a complication of the treatment for type 1&#xD;
      diabetes, it has recently been recognised as a problem in people with type 2 diabetes&#xD;
      particularly those on insulin therapy. In the ACCORD study, the risk of death was&#xD;
      significantly increased in those with one or more episode of severe hypoglycaemia in both the&#xD;
      strict and standard study treatment arms. As plasma glucose falls to below 4.0 mmol/L, a&#xD;
      series of defence mechanisms occur, at an individualised glycaemic thresholds, to reverse&#xD;
      hypoglycaemia including a rise in catecholamine levels. This may lead to hypokalaemia,&#xD;
      prolonged QT interval, and cardiac arrhythmias. It may also lead to impaired cardiovascular&#xD;
      autonomic function for up to 16 hours afterwards; increased inflammatory markers; platelet&#xD;
      activation and promote vascular damage. As the majority of studies assessing the effects of&#xD;
      hypoglycaemia on cardiovascular risk markers are conducted in people with type 1 diabetes and&#xD;
      healthy controls, their findings may not necessarily be applicable to people with type 2&#xD;
      diabetes. In particular, the effects of hypoglycaemia on platelet function and thrombotic&#xD;
      risk in people with type 2 diabetes require further clarification. In this study, we&#xD;
      hypothesised that acute hypoglycaemia will result in platelet activation in people with type&#xD;
      2 diabetes to a higher degree than controls.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2011</start_date>
  <completion_date type="Actual">May 2013</completion_date>
  <primary_completion_date type="Actual">May 2013</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To examine the effect of hypoglycaemia on platelet surface expression of platelet activation markers P-selectin and fibrinogen binding.</measure>
    <time_frame>Up to 24 hours after euglycaemic hypoglycaemic clamp</time_frame>
    <description>Platelet surface expression of activation markers, P-selectin and fibrinogen binding, were measured in the resting state (unstimulated samples) and in response to stimulation with platelet agonist adenosine diphosphate, and platelet inhibitor prostacyclin.&#xD;
A change in platelet function from times 0 (baseline), to 2 hours (euglycaemia), 4 hours (hypoglycaemia) and 24 hours after the clamp studies was measured and compared between the two groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To measure changes in markers of inflammation (high sensitivity C-reactive protein) and endothelial function using EndoPat 2000</measure>
    <time_frame>Up to 24h after euglycaemic hypoglycaemic clamp</time_frame>
    <description>High sensitivity C-reactive protein was measured at baseline (time 0), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and 24 hours after clamp studies. Changes from baseline were compared between the groups.&#xD;
EndoPat was measured before the insulin clamp and 24 hours afterwards and changes were compared between the two groups.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>To assess the effects of hypoglycaemia on participants scores on cognitive function tests</measure>
    <time_frame>Up to 24h after euglycaemic hypoglycaemic clamp</time_frame>
    <description>Three cognitive function tests (Tower of Hanoi; Dual Task test and The Digit symbol-coding) were measured at baseline (time 0), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and 24 hours after insulin clamp studies. Changes from baseline in each of these tests in response to the insulin clamp were compared between the two groups.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Type 2 Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Weight-matched healthy controls. Euglycaemic Hypoglycaemic insulin clamp. Using hyperinsulinaemic clamps, blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Type 2 diabetes</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>People with a known diagnosis of type 2 diabetes. Euglycaemic Hypoglycaemic Insulin clamp. Using hyperinsulinaemic clamps, blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Insulin (Humulin S)</intervention_name>
    <description>Using insulin and glucose infusions (hyperinsulinaemic clamps), blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.</description>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>Type 2 diabetes</arm_group_label>
    <other_name>Glucose (20% Dextrose).</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Euglycaemic Hypoglycaemic Insulin clamp</intervention_name>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>Type 2 diabetes</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy volunteers:&#xD;
&#xD;
               -  Males or females&#xD;
&#xD;
               -  On no medications except for the contraceptive pill and without medical illnesses&#xD;
                  in the last three months.&#xD;
&#xD;
               -  Non-smokers&#xD;
&#xD;
               -  40 - 60 years of age.&#xD;
&#xD;
          2. T2DM subjects:&#xD;
&#xD;
               -  Males or females&#xD;
&#xD;
               -  Diagnosis of T2DM&#xD;
&#xD;
               -  40 - 60 years of age&#xD;
&#xD;
               -  HbA1C: 6.5 - 9.5%&#xD;
&#xD;
               -  Duration of diabetes 1 - 10 years&#xD;
&#xD;
               -  Diabetes treated with diet, or tablets only.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Healthy volunteers:&#xD;
&#xD;
               -  Pregnancy&#xD;
&#xD;
               -  Lack of contraception in women of child bearing age&#xD;
&#xD;
               -  Chronic medical conditions&#xD;
&#xD;
               -  Current smokers&#xD;
&#xD;
               -  Evidence of ischaemia on ECG&#xD;
&#xD;
               -  Drop attacks&#xD;
&#xD;
               -  Alcohol or drug abuse&#xD;
&#xD;
               -  Psychiatric illness&#xD;
&#xD;
               -  Previous history of seizure&#xD;
&#xD;
               -  Alcohol or drug abuse&#xD;
&#xD;
          2. Type 2 diabetes subjects:&#xD;
&#xD;
               -  Pregnancy&#xD;
&#xD;
               -  Current smokers&#xD;
&#xD;
               -  Recurrent episodes of hypoglycaemia&#xD;
&#xD;
               -  Treatment with anti-platelet or anti-coagulation therapy&#xD;
&#xD;
               -  History of ischaemic heart disease, stroke or peripheral vascular disease&#xD;
&#xD;
               -  Epilepsy&#xD;
&#xD;
               -  Drop attacks&#xD;
&#xD;
               -  Evidence of ischaemia on ECG&#xD;
&#xD;
               -  Insulin treated T2DM&#xD;
&#xD;
               -  History of microvascular disease (retinopathy, nephropathy or neuropathy).&#xD;
&#xD;
               -  Alcohol or drug abuse&#xD;
&#xD;
               -  Psychiatric illness&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen L Atkin, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hull York Medical School</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hull Royal Infirmary</name>
      <address>
        <city>Hull</city>
        <zip>HU3 2RW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 28, 2014</study_first_submitted>
  <study_first_submitted_qc>July 31, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 1, 2014</study_first_posted>
  <last_update_submitted>July 31, 2014</last_update_submitted>
  <last_update_submitted_qc>July 31, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 1, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Hull</investigator_affiliation>
    <investigator_full_name>Thozhukat Sathyapalan</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <keyword>Type 2 diabetes</keyword>
  <keyword>Hypoglycaemia</keyword>
  <keyword>Platelets</keyword>
  <keyword>Inflammation</keyword>
  <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>
    <mesh_term>Hypoglycemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin</mesh_term>
    <mesh_term>Insulin, Globin Zinc</mesh_term>
    <mesh_term>Hypoglycemic Agents</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02205996
org study id: 11/YH/0161
nct id: NCT02205996
lead sponsor: 
collaborator: 
has dmc: Yes
Strict glycaemic control has been associated with increased hypoglycaemia and mortality rate,
      the cause of which was unclear, in subjects with type 2 diabetes. In this study, we
      hypothesised that acute hypoglycaemia will result in platelet activation in people with type
      2 diabetes to a higher degree than controls.
Type 2 diabetes is associated with increased risk of cardiovascular disease. Although the
      United Kingdom Prospective Diabetes Study (UKPDS) follow-up data suggested reduced
      macrovascular complications with tight glycaemic control, recent studies in people with type
      2 diabetes failed to replicate these findings. Furthermore, all-cause mortality was found to
      be increased with strict glycaemic control in the Action to Control Cardiovascular Risk in
      Diabetes (ACCORD) study. The cause of the increased deaths remains unclear.

      Strict glycaemic control is associated with increased risk of hypoglycaemia. Although,
      hypoglycaemia has traditionally been considered a complication of the treatment for type 1
      diabetes, it has recently been recognised as a problem in people with type 2 diabetes
      particularly those on insulin therapy. In the ACCORD study, the risk of death was
      significantly increased in those with one or more episode of severe hypoglycaemia in both the
      strict and standard study treatment arms. As plasma glucose falls to below 4.0 mmol/L, a
      series of defence mechanisms occur, at an individualised glycaemic thresholds, to reverse
      hypoglycaemia including a rise in catecholamine levels. This may lead to hypokalaemia,
      prolonged QT interval, and cardiac arrhythmias. It may also lead to impaired cardiovascular
      autonomic function for up to 16 hours afterwards; increased inflammatory markers; platelet
      activation and promote vascular damage. As the majority of studies assessing the effects of
      hypoglycaemia on cardiovascular risk markers are conducted in people with type 1 diabetes and
      healthy controls, their findings may not necessarily be applicable to people with type 2
      diabetes. In particular, the effects of hypoglycaemia on platelet function and thrombotic
      risk in people with type 2 diabetes require further clarification. In this study, we
      hypothesised that acute hypoglycaemia will result in platelet activation in people with type
      2 diabetes to a higher degree than controls.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: To examine the effect of hypoglycaemia on platelet surface expression of platelet activation markers P-selectin and fibrinogen binding.
time frame: Up to 24 hours after euglycaemic hypoglycaemic clamp
description: Platelet surface expression of activation markers, P-selectin and fibrinogen binding, were measured in the resting state (unstimulated samples) and in response to stimulation with platelet agonist adenosine diphosphate, and platelet inhibitor prostacyclin.
A change in platelet function from times 0 (baseline), to 2 hours (euglycaemia), 4 hours (hypoglycaemia) and 24 hours after the clamp studies was measured and compared between the two groups.
measure: To measure changes in markers of inflammation (high sensitivity C-reactive protein) and endothelial function using EndoPat 2000
time frame: Up to 24h after euglycaemic hypoglycaemic clamp
description: High sensitivity C-reactive protein was measured at baseline (time 0), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and 24 hours after clamp studies. Changes from baseline were compared between the groups.
EndoPat was measured before the insulin clamp and 24 hours afterwards and changes were compared between the two groups.
measure: To assess the effects of hypoglycaemia on participants scores on cognitive function tests
time frame: Up to 24h after euglycaemic hypoglycaemic clamp
description: Three cognitive function tests (Tower of Hanoi; Dual Task test and The Digit symbol-coding) were measured at baseline (time 0), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and 24 hours after insulin clamp studies. Changes from baseline in each of these tests in response to the insulin clamp were compared between the two groups.
arm group label: Controls
arm group type: Active Comparator
description: Weight-matched healthy controls. Euglycaemic Hypoglycaemic insulin clamp. Using hyperinsulinaemic clamps, blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.
arm group label: Type 2 diabetes
arm group type: Active Comparator
description: People with a known diagnosis of type 2 diabetes. Euglycaemic Hypoglycaemic Insulin clamp. Using hyperinsulinaemic clamps, blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.
intervention type: Drug
intervention name: Insulin (Humulin S)
description: Using insulin and glucose infusions (hyperinsulinaemic clamps), blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.
arm group label: Controls
arm group label: Type 2 diabetes
other name: Glucose (20% Dextrose).
intervention type: Device
intervention name: Euglycaemic Hypoglycaemic Insulin clamp
arm group label: Controls
arm group label: Type 2 diabetes
criteria: 
gender: All
minimum age: 40 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Stephen L Atkin, PhD
role: Principal Investigator
affiliation: Hull York Medical School
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Hull
investigator full name: Thozhukat Sathyapalan
investigator title: Dr
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Hypoglycemia
mesh term: Insulin
mesh term: Insulin, Globin Zinc
mesh term: Hypoglycemic Agents