<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/NCT02198209</url>
  </required_header>
  <id_info>
    <org_study_id>U1111-1138-7223</org_study_id>
    <nct_id>NCT02198209</nct_id>
  </id_info>
  <brief_title>Liraglutide Actions on the Liver: Effects on Glucose Phosphorylation</brief_title>
  <official_title>Liraglutide Actions on the Liver: Effects on Glucose Phosphorylation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cedars-Sinai Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cedars-Sinai Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Type 2 diabetes is a chronic disease that has reached epidemic proportions. In order to&#xD;
      improve our strategies for preventing and treating type 2 diabetes the investigators need to&#xD;
      better understand the mechanism of this disease, and the way in which current therapies, such&#xD;
      as the drug liraglutide, work to control blood sugar. It is known that liraglutide acts via&#xD;
      increasing the secretion of the hormone insulin from the pancreas, hormone that in turn&#xD;
      controls blood sugar. However, it is not known whether liraglutide also has actions on the&#xD;
      liver. Animal studies have suggested that liraglutide might act by controlling the liver&#xD;
      enzyme glucokinase (GCK), an enzyme that increases blood sugar uptake by the liver. This&#xD;
      could be a crucial mechanism in which liraglutide controls blood sugar independently of&#xD;
      insulin, thus making it beneficial not only in type 2 but also in type 1 diabetes. The effect&#xD;
      of liraglutide on GCK activity has not been yet measured in humans. The investigators propose&#xD;
      to investigate the acute and chronic effect of liraglutide on GCK by using a simple, widely&#xD;
      used procedure (an IntraVenous Glucose Tolerance Test-IVGTT) and a novel approach&#xD;
      (mathematical modeling of data obtained from this procedure), to assess GCK activity in&#xD;
      people with type 2 diabetes. The investigators will first compare data obtained form 2 IVGTTs&#xD;
      (with and without liraglutide) performed 1 week apart (acute effect). The investigators will&#xD;
      then give liraglutide to patients for 6 weeks and do another IVGTT to measure GCK activity&#xD;
      (chronic effects). Data obtained from this study will be used to further understand the&#xD;
      mechanism of liraglutide action and how to better employ our current therapeutic options and&#xD;
      develop new strategies for preventing and treating diabetes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      It is known that liraglutide impacts favorably glucose homeostasis in type 2 diabetic&#xD;
      patients, but not the exact mechanism of this effect. In particular, liraglutide's acute and&#xD;
      chronic effects on the liver are not well understood. The aim of our study is to determine&#xD;
      whether liraglutide acutely and/or chronically changes hepatic GCK activity in vivo in type 2&#xD;
      diabetic patients, and to quantify this effect. We hypothesize that liraglutide increases GCK&#xD;
      activity and that this results in increased hepatic glucose uptake, contributing to a&#xD;
      lowering of glycemia.&#xD;
&#xD;
      Our specific aims are:&#xD;
&#xD;
        1. to measure liraglutide's acute effect on GCK activity changes in vivo in type 2 diabetic&#xD;
           patients;&#xD;
&#xD;
        2. to assess whether chronic treatment with liraglutide determines a change in liver GCK&#xD;
           activity in type 2 diabetic patients, as assessed during an IVGTT.&#xD;
&#xD;
      We expect that liraglutide acutely and/or chronically increases GCK activity, thus&#xD;
      contributing to higher liver glucose uptake and lower glycemia.&#xD;
&#xD;
      Primary endpoints&#xD;
&#xD;
        1. GCK activity (acute effect) during IVGTTs with and without liraglutide administration.&#xD;
           GCK activity will be calculated based on lactate and glucose measurements during the&#xD;
           IVGTT&#xD;
&#xD;
        2. GCK activity during IVGTTs before and after 6 weeks of liraglutide treatment (IVGTT3).&#xD;
&#xD;
      Secondary endpoints&#xD;
&#xD;
        1. SI-IVGTT (insulin sensitivity during an intravenous glucose tolerance test) as&#xD;
           quantified by the MINMOD analysis of the IVGTT&#xD;
&#xD;
        2. Acute insulin response to glucose (AIRg) and the disposition index (DI-MINMOD), the&#xD;
           ability of beta cell to compensate for changes in insulin sensitivity.&#xD;
&#xD;
      This is a study designed to investigate the effect of liraglutide in type 2 diabetes&#xD;
      therefore subjects are selected from type 2 diabetes population of the Los Angeles basin&#xD;
      area. The study population is represented by type 2 diabetics (age 18-65 y old, T2DM&#xD;
      diagnosed by current American Diabetes Association diagnostic criteria ( HbA1c ≥ 6.5 % or&#xD;
      fasting plasma glucose ≥ 126 mg/dl or 2h plasma glucose ≥ 200 mg/dL during an OGTT or in a&#xD;
      patient with classic symptoms of hyperglycemia or hyperglycemic crisis a random plasma&#xD;
      glucose ≥ 200 mg/dl).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Investigator decided not to move forward with study prior to study start date&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 2019</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">July 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Liver glucokinase activity (acute effect)</measure>
    <time_frame>12 months</time_frame>
    <description>We will measure liver glucokinase (GCK) activity 'in vivo' during IVGTTs with and without liraglutide administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Liver glucokinase activity (chronic effect)</measure>
    <time_frame>12 months</time_frame>
    <description>We will measure liver glucokinase (GCK) activity 'in vivo' during IVGTTs before and after 6 weeks of daily liraglutide administration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>insulin sensitivity</measure>
    <time_frame>12 months</time_frame>
    <description>We will measure SI-IVGTT (insulin sensitivity during an intravenous glucose tolerance test) as quantified by the MINMOD analysis of the IVGTT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute insulin response to glucose and the disposition index</measure>
    <time_frame>12 months</time_frame>
    <description>We will assess the acute insulin response to glucose (AIRg) and the disposition index (DI-MINMOD)(the ability of beta cell to compensate for changes in insulin sensitivity)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Type 2 Diabetes</condition>
  <arm_group>
    <arm_group_label>single arm</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Liraglutide (Victoza)&#xD;
acute study: one injection of 0.6 mg s.c. before IVGTT&#xD;
chronic study: 6 weeks of daily liraglutide administration (1 week at 0.6 mg, 1 week at 1.2 mg, 4 weeks at 1.8 mg, s.c).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liraglutide</intervention_name>
    <description>acute study: one injection of 0.6 mg s.c. before IVGTT&#xD;
chronic study: 6 weeks of daily liraglutide administration (1 week at 0.6 mg, 1 week at 1.2 mg, 4 weeks at 1.8 mg, s.c).</description>
    <arm_group_label>single arm</arm_group_label>
    <other_name>Victoza</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18- 65 years of age (inclusive)&#xD;
&#xD;
          -  Ability to provide informed consent before any trial-related activities&#xD;
&#xD;
          -  Ability to communicate effectively with research staff&#xD;
&#xD;
          -  Ability to return for follow up visit&#xD;
&#xD;
          -  Adequate IV access&#xD;
&#xD;
          -  If a female of childbearing potential, non-pregnant and taking reliable contraception&#xD;
&#xD;
          -  Documented T2DM (per most recent American Diabetes Association criteria);&#xD;
&#xD;
          -  Drug naïve or treated with metformin only;&#xD;
&#xD;
          -  Diabetes should be well controlled (as defined by HbA1 ≤ 7.5%, FPG &lt;180 mg/dl).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate&#xD;
             contraceptive measures&#xD;
&#xD;
          -  Presence of cancer or any clinically significant cardiac, respiratory, renal, hepatic,&#xD;
             gastrointestinal, endocrinological, haematological, neurological, or psychiatric&#xD;
             diseases or disorders (inclusion will be discussed with attending physician)&#xD;
&#xD;
          -  Liver disease; history of alcoholism.&#xD;
&#xD;
          -  Known or suspected allergy to liraglutide&#xD;
&#xD;
          -  Contraindications to liraglutide: patients with a personal or family history of&#xD;
             medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome&#xD;
             type 2&#xD;
&#xD;
          -  Patients with a history of pancreatitits&#xD;
&#xD;
          -  Patients that have been treated with drugs that promote weight loss (e.g., Xenical®&#xD;
             [orlistat], Meridia® [sibutramine], Acomplia® [rimonabant], Acutrim®&#xD;
             [phenylpropanolamine], or similar over-the-counter medications) within 3 months of&#xD;
             study start&#xD;
&#xD;
          -  Patients that have been treated with diabetes drugs: injectables, (e.g GLP-1R agonists&#xD;
             (Byetta® [exenatide], Victoza® [liraglutide]) amylin analogues; insulin and insulin&#xD;
             analogues) or oral agents other than metformin (e.g.DPP-IV- inhibitors (Januvia®&#xD;
             [sitagliptin], Onglyza® [saxagliptin] or Janumet® [sitagliptin and metformin]),insulin&#xD;
             sensitizers (thiazolidindiones: pioglitazone [Actos®]); or sulfonylureas) within 3&#xD;
             months of study start.&#xD;
&#xD;
          -  The receipt of any investigational drug within 3 months prior to study start.&#xD;
&#xD;
          -  Type 1 diabetes&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Viorica Ionut, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cedars Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>July 21, 2014</study_first_submitted>
  <study_first_submitted_qc>July 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 23, 2014</study_first_posted>
  <last_update_submitted>September 26, 2019</last_update_submitted>
  <last_update_submitted_qc>September 26, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cedars-Sinai Medical Center</investigator_affiliation>
    <investigator_full_name>Marilyn Ader, PhD</investigator_full_name>
    <investigator_title>Associate Director, Diabetes &amp; Obesity Research Institute</investigator_title>
  </responsible_party>
  <keyword>liraglutide</keyword>
  <keyword>GLP-1</keyword>
  <keyword>liver glucokinase</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liraglutide</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/NCT02198209
org study id: U1111-1138-7223
nct id: NCT02198209
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Type 2 diabetes is a chronic disease that has reached epidemic proportions. In order to
      improve our strategies for preventing and treating type 2 diabetes the investigators need to
      better understand the mechanism of this disease, and the way in which current therapies, such
      as the drug liraglutide, work to control blood sugar. It is known that liraglutide acts via
      increasing the secretion of the hormone insulin from the pancreas, hormone that in turn
      controls blood sugar. However, it is not known whether liraglutide also has actions on the
      liver. Animal studies have suggested that liraglutide might act by controlling the liver
      enzyme glucokinase (GCK), an enzyme that increases blood sugar uptake by the liver. This
      could be a crucial mechanism in which liraglutide controls blood sugar independently of
      insulin, thus making it beneficial not only in type 2 but also in type 1 diabetes. The effect
      of liraglutide on GCK activity has not been yet measured in humans. The investigators propose
      to investigate the acute and chronic effect of liraglutide on GCK by using a simple, widely
      used procedure (an IntraVenous Glucose Tolerance Test-IVGTT) and a novel approach
      (mathematical modeling of data obtained from this procedure), to assess GCK activity in
      people with type 2 diabetes. The investigators will first compare data obtained form 2 IVGTTs
      (with and without liraglutide) performed 1 week apart (acute effect). The investigators will
      then give liraglutide to patients for 6 weeks and do another IVGTT to measure GCK activity
      (chronic effects). Data obtained from this study will be used to further understand the
      mechanism of liraglutide action and how to better employ our current therapeutic options and
      develop new strategies for preventing and treating diabetes.
It is known that liraglutide impacts favorably glucose homeostasis in type 2 diabetic
      patients, but not the exact mechanism of this effect. In particular, liraglutide's acute and
      chronic effects on the liver are not well understood. The aim of our study is to determine
      whether liraglutide acutely and/or chronically changes hepatic GCK activity in vivo in type 2
      diabetic patients, and to quantify this effect. We hypothesize that liraglutide increases GCK
      activity and that this results in increased hepatic glucose uptake, contributing to a
      lowering of glycemia.

      Our specific aims are:

        1. to measure liraglutide's acute effect on GCK activity changes in vivo in type 2 diabetic
           patients;

        2. to assess whether chronic treatment with liraglutide determines a change in liver GCK
           activity in type 2 diabetic patients, as assessed during an IVGTT.

      We expect that liraglutide acutely and/or chronically increases GCK activity, thus
      contributing to higher liver glucose uptake and lower glycemia.

      Primary endpoints

        1. GCK activity (acute effect) during IVGTTs with and without liraglutide administration.
           GCK activity will be calculated based on lactate and glucose measurements during the
           IVGTT

        2. GCK activity during IVGTTs before and after 6 weeks of liraglutide treatment (IVGTT3).

      Secondary endpoints

        1. SI-IVGTT (insulin sensitivity during an intravenous glucose tolerance test) as
           quantified by the MINMOD analysis of the IVGTT

        2. Acute insulin response to glucose (AIRg) and the disposition index (DI-MINMOD), the
           ability of beta cell to compensate for changes in insulin sensitivity.

      This is a study designed to investigate the effect of liraglutide in type 2 diabetes
      therefore subjects are selected from type 2 diabetes population of the Los Angeles basin
      area. The study population is represented by type 2 diabetics (age 18-65 y old, T2DM
      diagnosed by current American Diabetes Association diagnostic criteria ( HbA1c ≥ 6.5 % or
      fasting plasma glucose ≥ 126 mg/dl or 2h plasma glucose ≥ 200 mg/dL during an OGTT or in a
      patient with classic symptoms of hyperglycemia or hyperglycemic crisis a random plasma
      glucose ≥ 200 mg/dl).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Liver glucokinase activity (acute effect)
time frame: 12 months
description: We will measure liver glucokinase (GCK) activity 'in vivo' during IVGTTs with and without liraglutide administration
measure: Liver glucokinase activity (chronic effect)
time frame: 12 months
description: We will measure liver glucokinase (GCK) activity 'in vivo' during IVGTTs before and after 6 weeks of daily liraglutide administration
measure: insulin sensitivity
time frame: 12 months
description: We will measure SI-IVGTT (insulin sensitivity during an intravenous glucose tolerance test) as quantified by the MINMOD analysis of the IVGTT.
measure: Acute insulin response to glucose and the disposition index
time frame: 12 months
description: We will assess the acute insulin response to glucose (AIRg) and the disposition index (DI-MINMOD)(the ability of beta cell to compensate for changes in insulin sensitivity)
arm group label: single arm
arm group type: Other
description: Liraglutide (Victoza)
acute study: one injection of 0.6 mg s.c. before IVGTT
chronic study: 6 weeks of daily liraglutide administration (1 week at 0.6 mg, 1 week at 1.2 mg, 4 weeks at 1.8 mg, s.c).
intervention type: Drug
intervention name: Liraglutide
description: acute study: one injection of 0.6 mg s.c. before IVGTT
chronic study: 6 weeks of daily liraglutide administration (1 week at 0.6 mg, 1 week at 1.2 mg, 4 weeks at 1.8 mg, s.c).
arm group label: single arm
other name: Victoza
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Viorica Ionut, MD PhD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Cedars-Sinai Medical Center
investigator full name: Marilyn Ader, PhD
investigator title: Associate Director, Diabetes & Obesity Research Institute
mesh term: Liraglutide