<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/NCT03286816</url>
  </required_header>
  <id_info>
    <org_study_id>Lac_iv</org_study_id>
    <nct_id>NCT03286816</nct_id>
  </id_info>
  <brief_title>The Effect of Intravenous Lactate on Brain Lactate Concentrations During Hypoglycemia</brief_title>
  <official_title>The Effect of Intravenous Lactate Administration on Brain Lactate Concentrations and pH During Euglycemia and Hypoglycemia in Patients With Type 1 Diabetes With and Without Impaired Awareness of Hypoglycemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dutch Diabetes Research Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>European Foundation for the Study of Diabetes</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with type 1 diabetes (T1DM) who are unable to perceive symptoms of hypoglycemia,&#xD;
      referred to as impaired awareness of hypoglycemia (IAH), are at very high risk of severe&#xD;
      hypoglycemia. IAH affects approximately 25% of patients with T1DM. Brain lactate may be&#xD;
      involved in the development of IAH. A recent study indicated increased brain lactate&#xD;
      utilization during hypoglycemia in T1DM patients with IAH, which did not occur in patients&#xD;
      with normal awareness of hypoglycemia (NAH). Conversely, administration of lactate to&#xD;
      patients with NAH has been shown to attenuate counterregulatory hormone responses to and&#xD;
      symptomatic awareness of hypoglycemia, thus causing a situation that resembles IAH. It has,&#xD;
      however, not been demonstrated whether the excess of lactate is actually taken up or&#xD;
      metabolized by the brain, and if so whether this occurs under euglycemic or hypoglycemic&#xD;
      conditions or both.&#xD;
&#xD;
      This project consists of two related studies. The objective of part 1 is to investigate the&#xD;
      effect of elevated plasma lactate levels that are sufficient to impair awareness of&#xD;
      hypoglycemia on brain lactate concentrations during euglycemia and hypoglycemia in T1DM&#xD;
      patients with NAH. The objective of part 2 is to compare the effect of exogenous lactate on&#xD;
      brain lactate concentrations between T1DM patients with NAH and T1DM patients with IAH.&#xD;
&#xD;
      Furthermore, this study aims to determine the effect of acute hypoglycemia on the&#xD;
      inflammatory function and composition of peripheral blood mononuclear cells.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <completion_date type="Actual">August 2017</completion_date>
  <primary_completion_date type="Actual">May 2017</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>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>the effect of intravenous lactate administration, compared to placebo, on brain lactate concentrations during euglycemia and hypoglycemia in patients with T1DM and normal awareness of hypoglycemia</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>the effect of exogenous lactate on brain lactate concentrations during euglycemia and hypoglycemia between T1DM patients with normal awareness of hypoglycemia and T1DM patients with impaired awareness of hypoglycemia</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>The changes in counterregulatory hormone and to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The changes in and symptoms to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The changes in brain pH in response to intravenous lactate administration, compared to placebo</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in immune cell composition capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in immune cell cytokine production capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo</measure>
    <time_frame>during stable euglycemia (40 min) and hypoglycemia (45 min)</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Type 1 Diabetes Mellitus With Hypoglycemia</condition>
  <arm_group>
    <arm_group_label>Lactate infusion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive an intravenous lactate infusion to elevate plasma lactate levels</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NaCl infusion</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>As a control condition, subjects will receive intravenous NaCl infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SodiumChloride</intervention_name>
    <arm_group_label>NaCl infusion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sodium Lactate</intervention_name>
    <arm_group_label>Lactate infusion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diabetes duration ≥ 1 year&#xD;
&#xD;
          -  Age: 18-50 years&#xD;
&#xD;
          -  Body-Mass Index: 18-30 kg/m2&#xD;
&#xD;
          -  HbA1c: 42-75 mmol/mol (6-9%)&#xD;
&#xD;
          -  Outcome Clarke questionnaire: 0-1 or &gt;=3&#xD;
&#xD;
          -  Blood pressure: &lt;160/90 mmHg&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Use medication other than insulin, except for oral contraceptives or stable thyroxin&#xD;
             supplementation therapy&#xD;
&#xD;
          -  Presence of any other medical condition that might interfere with the study protocol,&#xD;
             such as brain injuries, epilepsy, a major cardiovascular disease event, known liver&#xD;
             disease, anxiety disorders or a history of panic attacks.&#xD;
&#xD;
          -  Microvascular complications of T1DM: Proliferative retinopathy, Symptomatic diabetic&#xD;
             neuropathy (including autonomic neuropathy), Nephropathy; clinical/overt albuminuria&#xD;
             or an estimated glomerular filtration rate &lt;60ml/min/1.73m2&#xD;
&#xD;
          -  MR(I) contraindications (pregnancy, severe claustrophobia, metal parts in body)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Radboud umc</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>De Feyter HM, Mason GF, Shulman GI, Rothman DL, Petersen KF. Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes. 2013 Sep;62(9):3075-80. doi: 10.2337/db13-0313. Epub 2013 May 28.</citation>
    <PMID>23715622</PMID>
  </reference>
  <reference>
    <citation>Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes. 1994 Nov;43(11):1311-7. doi: 10.2337/diab.43.11.1311.</citation>
    <PMID>7926305</PMID>
  </reference>
  <reference>
    <citation>Maran A, Crepaldi C, Trupiani S, Lucca T, Jori E, Macdonald IA, Tiengo A, Avogaro A, Del Prato S. Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and type I diabetic subjects. Diabetologia. 2000 Jun;43(6):733-41. doi: 10.1007/s001250051371.</citation>
    <PMID>10907119</PMID>
  </reference>
  <reference>
    <citation>Wiegers EC, Rooijackers HM, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2016 Jun;65(6):1601-5. doi: 10.2337/db16-0068. Epub 2016 Mar 18.</citation>
    <PMID>26993070</PMID>
  </reference>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>September 14, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 19, 2017</study_first_posted>
  <last_update_submitted>September 14, 2017</last_update_submitted>
  <last_update_submitted_qc>September 14, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>type 1 diabetes mellitus</keyword>
  <keyword>impaired awareness of hypoglycemia</keyword>
  <keyword>lactate</keyword>
  <keyword>MR spectroscopy</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 1</mesh_term>
    <mesh_term>Hypoglycemia</mesh_term>
  </condition_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/NCT03286816
org study id: Lac_iv
nct id: NCT03286816
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Patients with type 1 diabetes (T1DM) who are unable to perceive symptoms of hypoglycemia,
      referred to as impaired awareness of hypoglycemia (IAH), are at very high risk of severe
      hypoglycemia. IAH affects approximately 25% of patients with T1DM. Brain lactate may be
      involved in the development of IAH. A recent study indicated increased brain lactate
      utilization during hypoglycemia in T1DM patients with IAH, which did not occur in patients
      with normal awareness of hypoglycemia (NAH). Conversely, administration of lactate to
      patients with NAH has been shown to attenuate counterregulatory hormone responses to and
      symptomatic awareness of hypoglycemia, thus causing a situation that resembles IAH. It has,
      however, not been demonstrated whether the excess of lactate is actually taken up or
      metabolized by the brain, and if so whether this occurs under euglycemic or hypoglycemic
      conditions or both.

      This project consists of two related studies. The objective of part 1 is to investigate the
      effect of elevated plasma lactate levels that are sufficient to impair awareness of
      hypoglycemia on brain lactate concentrations during euglycemia and hypoglycemia in T1DM
      patients with NAH. The objective of part 2 is to compare the effect of exogenous lactate on
      brain lactate concentrations between T1DM patients with NAH and T1DM patients with IAH.

      Furthermore, this study aims to determine the effect of acute hypoglycemia on the
      inflammatory function and composition of peripheral blood mononuclear cells.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Single (Participant)
measure: the effect of intravenous lactate administration, compared to placebo, on brain lactate concentrations during euglycemia and hypoglycemia in patients with T1DM and normal awareness of hypoglycemia
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: the effect of exogenous lactate on brain lactate concentrations during euglycemia and hypoglycemia between T1DM patients with normal awareness of hypoglycemia and T1DM patients with impaired awareness of hypoglycemia
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: The changes in counterregulatory hormone and to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: The changes in and symptoms to hypoglycemia in response to lactate infusion, compared to placebo, in patients with normal awareness of hypoglycemia
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: The changes in brain pH in response to intravenous lactate administration, compared to placebo
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: Changes in immune cell composition capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
measure: Changes in immune cell cytokine production capacity in response to hypoglycemia compared to euglycemia and in response to lactate infusion compared to placebo
time frame: during stable euglycemia (40 min) and hypoglycemia (45 min)
arm group label: Lactate infusion
arm group type: Experimental
description: Subjects will receive an intravenous lactate infusion to elevate plasma lactate levels
arm group label: NaCl infusion
arm group type: Placebo Comparator
description: As a control condition, subjects will receive intravenous NaCl infusion
intervention type: Drug
intervention name: SodiumChloride
arm group label: NaCl infusion
intervention type: Drug
intervention name: Sodium Lactate
arm group label: Lactate infusion
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
facility: 
country: Netherlands
citation: De Feyter HM, Mason GF, Shulman GI, Rothman DL, Petersen KF. Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes. 2013 Sep;62(9):3075-80. doi: 10.2337/db13-0313. Epub 2013 May 28.
PMID: 23715622
citation: Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes. 1994 Nov;43(11):1311-7. doi: 10.2337/diab.43.11.1311.
PMID: 7926305
citation: Maran A, Crepaldi C, Trupiani S, Lucca T, Jori E, Macdonald IA, Tiengo A, Avogaro A, Del Prato S. Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and type I diabetic subjects. Diabetologia. 2000 Jun;43(6):733-41. doi: 10.1007/s001250051371.
PMID: 10907119
citation: Wiegers EC, Rooijackers HM, Tack CJ, Heerschap A, de Galan BE, van der Graaf M. Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia. Diabetes. 2016 Jun;65(6):1601-5. doi: 10.2337/db16-0068. Epub 2016 Mar 18.
PMID: 26993070
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Hypoglycemia