<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/NCT02188186</url>
  </required_header>
  <id_info>
    <org_study_id>Triple</org_study_id>
    <nct_id>NCT02188186</nct_id>
  </id_info>
  <brief_title>Therapeutic Efficacy of Triple Combination in Drug-naïve Korean Type 2 Diabetic Patients</brief_title>
  <official_title>Therapeutic Efficacy of Triple Combination of Metformin, DPP4 Inhibitor and Thiazolidinedione in Drug-naïve Korean Type 2 Diabetic Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seoul National University Bundang Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Seoul National University Bundang Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Triple combination of metformin, DPP4 inhibitor and Thiazolidinedione would be a good option&#xD;
      in the treatment of drug-naïve Korean type 2 diabetic patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Thiazolidionedione, a PPARgamman agonist, is an strong insulin sensitizer. It has shown that&#xD;
      durable glucose lowering effect and beta cell preservation. It is an important treatment&#xD;
      option in patients with type 2 diabetes.&#xD;
&#xD;
      It has been well established that inhibition of dipeptidyl peptidase-4 (DPP-4) reduces blood&#xD;
      glucose levels in both fasting and postprandial states, and preserves pancreatic β-cell&#xD;
      function in patients with type 2 diabetes. The mechanism of action of DPP-4 inhibitors is to&#xD;
      increase levels of active incretin, glucagon-like peptide-1 (GLP-1) and glucose-dependent&#xD;
      insulinotropic polypeptide (GIP), which stimulate insulin secretion as well as insulin&#xD;
      biosynthesis while inhibiting glucagon release from pancreatic islets.&#xD;
&#xD;
      DPP4 inhibitors also have better safety and tolerability profiles (e.g., weight neutrality&#xD;
      and less hypoglycemia) compared to other hypoglycemic agents. When considering combination&#xD;
      therapy with DPP-4 inhibitors, metformin is the most commonly used agent which has been shown&#xD;
      to be effective and well tolerated from previous studies. Besides the glucose lowering effect&#xD;
      by reducing hepatic glucose output and improving insulin resistance, metformin without&#xD;
      inhibiting DPP-4 activity,also increases active GLP-1 concentrations by 1.5- to 2-fold&#xD;
      following an oral glucose load in obese, nondiabetic subjects. Accordingly, this effect of&#xD;
      metformin may provide a unique benefit when combined with DPP-4 inhibitors through a&#xD;
      substantial enhancement of the incretin axis, which provides effective and potentially&#xD;
      additive glycemic improvement.&#xD;
&#xD;
      Because of its favorable pharmacological properties, combination of a DPP-4 inhibitor,&#xD;
      metformin, and thiazolidinedione has been increasingly used to achieve rapid glycemic goal&#xD;
      with low risk of hypoglycemia and no weight gain, and to delay the need for subsequent&#xD;
      regimen changes. DPP-4 inhibitors block DPP-4 enzyme and preserve endogenous incretins&#xD;
      whereas metformin increases the active form of GLP-1, both of which may enhance the secretory&#xD;
      function of pancreas. However, the response to DPP-4 inhibitors and metformin combination&#xD;
      therapy may be different in individuals according to their pancreatic function and insulin&#xD;
      resistance status. In fact, previous studies with DPP-4 inhibitors showed different potency&#xD;
      in glycemic controls depending on various patient characteristics including severity of&#xD;
      diabetes and the use of other antidiabetic drug.Consequently, it would be clinically&#xD;
      important to investigate effect of this triple combination therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 2014</start_date>
  <completion_date type="Actual">September 2018</completion_date>
  <primary_completion_date type="Actual">September 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change of HbA1c</measure>
    <time_frame>12 months</time_frame>
    <description>Therapeutic efficacy of triple combination of metform, sitagliptin, and lobeglitazone compared with sulfonylurea and metformin in drug-naïve Korean type 2 diabetic patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>beta-cell function</measure>
    <time_frame>12 months</time_frame>
    <description>Changes of beta-cell function after one year treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin resistance</measure>
    <time_frame>12 months</time_frame>
    <description>Changes of Insulin resistance after one year treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose homeostasis</measure>
    <time_frame>12 months</time_frame>
    <description>Changes in fasting glucose concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose metabolism</measure>
    <time_frame>12 months</time_frame>
    <description>Area under the curve of glucose during OGTT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose metabolism</measure>
    <time_frame>12 months</time_frame>
    <description>Area under the curve of insulin during OGTT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microalbuminuria</measure>
    <time_frame>12 months</time_frame>
    <description>urine microalbumin to creatinine ratio</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lipid profile</measure>
    <time_frame>12 months</time_frame>
    <description>Changes in TG/HDL/LDL-concentrations</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Hypoglycemia</measure>
    <time_frame>12 months</time_frame>
    <description>Incidence of hypoglycemia during study period</description>
  </other_outcome>
  <other_outcome>
    <measure>Body weight</measure>
    <time_frame>12 months</time_frame>
    <description>Changes of body weight after one year treatment</description>
  </other_outcome>
  <other_outcome>
    <measure>Body composition</measure>
    <time_frame>12 months</time_frame>
    <description>Changes of body composition after one year treatment</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">200</enrollment>
  <condition>Type 2 Diabetes</condition>
  <arm_group>
    <arm_group_label>Conventional treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Initial dual combination therapy with sulfonylurea and metfomin. Dose of sulfonylurea (glimepride 2-8 mg) and metfomin (500-2550 mg) can be ecalated at investigator's discreition at every visit.&#xD;
Insulin therpy can be added as a rescue therapy at investigator's discreition.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Initial triple combination treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Initial dual combination therapy with metformin, sitagliptin (Januvia 100 mg), and lobeglitazone (Duvie 0.5 mg).&#xD;
Insulin therpy can be added as a rescue therapy at investigator's discreition.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Initial triple combination</intervention_name>
    <description>Initial triple combination arm</description>
    <arm_group_label>Initial triple combination treatment</arm_group_label>
    <other_name>metformin+sitagliptin (Januvia)+lobeglitazone (Duvie)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Conventional treatment</intervention_name>
    <description>Conventioanl treament with dose escalation</description>
    <arm_group_label>Conventional treatment</arm_group_label>
    <other_name>metformin+sulfonylurea with dose escalation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HbA1c 9-12%&#xD;
&#xD;
          -  No treatment with insulin or oral agents for recent 6 months&#xD;
&#xD;
          -  20 ≤ Age &lt; 80 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to sitagliptin or metformin or thiazolidinedione&#xD;
&#xD;
          -  Pregnant or breast feeding women&#xD;
&#xD;
          -  Type 1 diabetes, gestational diabetes, or secondary forms of diabetes&#xD;
&#xD;
          -  Not appropriate for oral antidiabetic agent&#xD;
&#xD;
          -  Medication which affect glycemic control&#xD;
&#xD;
          -  Disease which affect efficacy and safety of drugs&#xD;
&#xD;
          -  Any major illness (Liver disease, Renal failure, Heart disease, Cancer, etc)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Seoul National University Bundang Hospital</name>
      <address>
        <city>Seongnam</city>
        <state>Gyeonggi</state>
        <zip>463-707</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 11, 2014</study_first_posted>
  <last_update_submitted>March 14, 2019</last_update_submitted>
  <last_update_submitted_qc>March 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Seoul National University Bundang Hospital</investigator_affiliation>
    <investigator_full_name>Soo Lim</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>triple combination</keyword>
  <keyword>metformin</keyword>
  <keyword>sitagliptin</keyword>
  <keyword>thiazolidinedione</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Sitagliptin Phosphate</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/NCT02188186
org study id: Triple
nct id: NCT02188186
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Triple combination of metformin, DPP4 inhibitor and Thiazolidinedione would be a good option
      in the treatment of drug-naïve Korean type 2 diabetic patients.
Thiazolidionedione, a PPARgamman agonist, is an strong insulin sensitizer. It has shown that
      durable glucose lowering effect and beta cell preservation. It is an important treatment
      option in patients with type 2 diabetes.

      It has been well established that inhibition of dipeptidyl peptidase-4 (DPP-4) reduces blood
      glucose levels in both fasting and postprandial states, and preserves pancreatic β-cell
      function in patients with type 2 diabetes. The mechanism of action of DPP-4 inhibitors is to
      increase levels of active incretin, glucagon-like peptide-1 (GLP-1) and glucose-dependent
      insulinotropic polypeptide (GIP), which stimulate insulin secretion as well as insulin
      biosynthesis while inhibiting glucagon release from pancreatic islets.

      DPP4 inhibitors also have better safety and tolerability profiles (e.g., weight neutrality
      and less hypoglycemia) compared to other hypoglycemic agents. When considering combination
      therapy with DPP-4 inhibitors, metformin is the most commonly used agent which has been shown
      to be effective and well tolerated from previous studies. Besides the glucose lowering effect
      by reducing hepatic glucose output and improving insulin resistance, metformin without
      inhibiting DPP-4 activity,also increases active GLP-1 concentrations by 1.5- to 2-fold
      following an oral glucose load in obese, nondiabetic subjects. Accordingly, this effect of
      metformin may provide a unique benefit when combined with DPP-4 inhibitors through a
      substantial enhancement of the incretin axis, which provides effective and potentially
      additive glycemic improvement.

      Because of its favorable pharmacological properties, combination of a DPP-4 inhibitor,
      metformin, and thiazolidinedione has been increasingly used to achieve rapid glycemic goal
      with low risk of hypoglycemia and no weight gain, and to delay the need for subsequent
      regimen changes. DPP-4 inhibitors block DPP-4 enzyme and preserve endogenous incretins
      whereas metformin increases the active form of GLP-1, both of which may enhance the secretory
      function of pancreas. However, the response to DPP-4 inhibitors and metformin combination
      therapy may be different in individuals according to their pancreatic function and insulin
      resistance status. In fact, previous studies with DPP-4 inhibitors showed different potency
      in glycemic controls depending on various patient characteristics including severity of
      diabetes and the use of other antidiabetic drug.Consequently, it would be clinically
      important to investigate effect of this triple combination therapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Outcomes Assessor)
measure: Change of HbA1c
time frame: 12 months
description: Therapeutic efficacy of triple combination of metform, sitagliptin, and lobeglitazone compared with sulfonylurea and metformin in drug-naïve Korean type 2 diabetic patients
measure: beta-cell function
time frame: 12 months
description: Changes of beta-cell function after one year treatment
measure: Insulin resistance
time frame: 12 months
description: Changes of Insulin resistance after one year treatment
measure: Glucose homeostasis
time frame: 12 months
description: Changes in fasting glucose concentration
measure: Glucose metabolism
time frame: 12 months
description: Area under the curve of glucose during OGTT
measure: Glucose metabolism
time frame: 12 months
description: Area under the curve of insulin during OGTT
measure: Microalbuminuria
time frame: 12 months
description: urine microalbumin to creatinine ratio
measure: Lipid profile
time frame: 12 months
description: Changes in TG/HDL/LDL-concentrations
measure: Hypoglycemia
time frame: 12 months
description: Incidence of hypoglycemia during study period
measure: Body weight
time frame: 12 months
description: Changes of body weight after one year treatment
measure: Body composition
time frame: 12 months
description: Changes of body composition after one year treatment
arm group label: Conventional treatment
arm group type: Active Comparator
description: Initial dual combination therapy with sulfonylurea and metfomin. Dose of sulfonylurea (glimepride 2-8 mg) and metfomin (500-2550 mg) can be ecalated at investigator's discreition at every visit.
Insulin therpy can be added as a rescue therapy at investigator's discreition.
arm group label: Initial triple combination treatment
arm group type: Experimental
description: Initial dual combination therapy with metformin, sitagliptin (Januvia 100 mg), and lobeglitazone (Duvie 0.5 mg).
Insulin therpy can be added as a rescue therapy at investigator's discreition.
intervention type: Drug
intervention name: Initial triple combination
description: Initial triple combination arm
arm group label: Initial triple combination treatment
other name: metformin+sitagliptin (Januvia)+lobeglitazone (Duvie)
intervention type: Drug
intervention name: Conventional treatment
description: Conventioanl treament with dose escalation
arm group label: Conventional treatment
other name: metformin+sulfonylurea with dose escalation
criteria: 
gender: All
minimum age: 20 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Seoul National University Bundang Hospital
investigator full name: Soo Lim
investigator title: Professor
mesh term: Metformin
mesh term: Sitagliptin Phosphate