<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/NCT04504045</url>
  </required_header>
  <id_info>
    <org_study_id>AKF-395</org_study_id>
    <secondary_id>2020-000162-42</secondary_id>
    <nct_id>NCT04504045</nct_id>
  </id_info>
  <brief_title>Metformin's Effect on Drug Metabolism in Patients With Type 2 Diabetes</brief_title>
  <official_title>INFLAMMATION AND DRUG METABOLISM - Does the Effect of Drugs Decrease When Patients With Type 2 Diabetes Initiate Antidiabetic Treatment?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Southern Denmark</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>
      Type 2 diabetes is a major public health concern. It is widely established that type 2&#xD;
      diabetes in linked to activated innate immunity and increased levels of C-reactive protein&#xD;
      and interleukin-6 (IL-6) in plasma. Studies in humans and in liver cells has shown that IL-6&#xD;
      downregulates important drug metabolizing enzymes in the liver (cytochrome P450 (CYP)&#xD;
      enzymes). More than half of the most prescribed drugs are eliminated by biotransformation of&#xD;
      these enzymes.&#xD;
&#xD;
      The investigators have previously shown that initiating glucose-lowering treatment (e.g.&#xD;
      metformin, sulphonylureas and insulin) leads to decreased therapeutic efficacy of the&#xD;
      blood-thinning vitamin-K antagonist warfarin. Due to the non-specific effect of glucose&#xD;
      lowering drugs, the investigators hypothesize that this is caused by the glucose-lowering&#xD;
      effect rather than drug-drug interactions caused by the individual drugs.&#xD;
&#xD;
      Based on the proposal that reversal of increased plasma glucose affects drug metabolism, the&#xD;
      investigators will perform a clinical pharmacokinetic trial. The purpose of the study is to&#xD;
      elucidate whether initiation of glucose-lowering treatment causes altered drug metabolism&#xD;
      among patients with type 2 diabetes. The study will include newly diagnosed and untreated&#xD;
      type 2 diabetes patients who will ingest a 6-drug cocktail consisting of probes for specific&#xD;
      CYP enzymes. Plasma and urine will be drawn over 6 hours to determine concentrations of the&#xD;
      drugs and their metabolites. Patients will then initiate metformin treatment and to assess&#xD;
      both short- and long-term impact of glucose-lowering, the same 6-drug cocktail will be&#xD;
      ingested, and concentrations measured, after three weeks and three months. To help understand&#xD;
      the mechanism and the putative involvement of inflammation, markers of inflammation such as&#xD;
      cytokines, transcription factors, etc. will also be assesses.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow recruitment due to COVID-19, the study was stopped when recruited numbers fulfilled the&#xD;
    pre-defined lower sample size.&#xD;
  </why_stopped>
  <start_date type="Actual">September 1, 2020</start_date>
  <completion_date type="Actual">May 10, 2022</completion_date>
  <primary_completion_date type="Actual">May 10, 2022</primary_completion_date>
  <phase>Phase 1</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in activity of the drug metabolizing enzyme CYP3A4 following treatment with the glucose lowering drug metformin in 3 weeks. Assessment of the change is based on a change in the metabolic rate, which is the ratio between the concentration of midazolam and its primary metabolite is plasma (Probe drug for CYP3A4).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in activity of the drug metabolizing enzyme CYP3A4 following treatment with the glucose lowering drug metformin in 12 weeks. Assessment of the change is based on a change in the metabolic rate, which is the ratio between the concentration of midazolam and its primary metabolite is plasma (Probe drug for CYP3A4).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP1A2 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug caffeine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP1A2 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug caffeine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2B6 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Efavirenz.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2B6 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Efavirenz.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2C9 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Losartan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2C9 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Losartan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2C19 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Omeprazole.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2C19 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Omeprazole.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2D6 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Metoprolol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in activity of the drug metabolizing enzymes CYP2D6 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Metoprolol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in HbA1c at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in the regulation of blood glucose over time assessed by HbA1c</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in HbA1c at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in the regulation of blood glucose over time assessed by HbA1c</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in insulin resistance at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>An oral glucose tolerance test will be performed and glucose, insulin and c-peptide will be measured and combined by the Homeostatic Model Assessment (HOMA) to report insulin resistance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in insulin resistance at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>An oral glucose tolerance test will be performed and glucose, insulin and c-peptide will be measured and combined by the Homeostatic Model Assessment (HOMA) to report insulin resistance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-1-B at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-1-B.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-1-B at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-1-B.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-2 at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-2 at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-6 at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-6 at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-10 at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interleukin-10 at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interleukin-10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interferon-a at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interferon-a.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interferon-a at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interferon-a.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interferon-B at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interferon-B.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interferon-B at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interferon-B.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interferon-y at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interferon-y.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Interferon-y at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Interferon-y.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Tumor Necrosis Factor-a at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Tumor Necrosis Factor-a.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Tumor Necrosis Factor-a at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of Tumor Necrosis Factor-a.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in High Sensitivity C-Reactive Protein at Week 3.</measure>
    <time_frame>Baseline and Week 3.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of High Sensitivity C-Reactive Protein.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in High Sensitivity C-Reactive Protein at Week 12.</measure>
    <time_frame>Baseline and Week 12.</time_frame>
    <description>Change in patients inflammatory status assessed by measurement of High Sensitivity C-Reactive Protein.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive metformin 1000-2000 mg daily for 12 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>500 mg tablet</description>
    <arm_group_label>Metformin</arm_group_label>
    <other_name>Glucose lowering treatment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Caffeine</intervention_name>
    <description>As part of a 6-drug cocktail caffeine 100 mg tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP1A2 activity.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Efavirenz</intervention_name>
    <description>As part of a 6-drug cocktail efavirenz 50 mg coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2B6 activity.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Losartan</intervention_name>
    <description>As part of a 6-drug cocktail losartan 12.5 mg coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2C9 activity.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Omeprazol</intervention_name>
    <description>As part of a 6-drug cocktail Omeprazol 10 mg enteric-coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2C19 activity.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metoprolol</intervention_name>
    <description>As part of a 6-drug cocktail metoprolol 12.5 mg release tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2D6 activity.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>As part of a 6-drug cocktail midazolam 2 mg oral solution will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP3A4 activity.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 2 diabetes, not treated metformin.&#xD;
&#xD;
          -  Hemoglobin 1Ac (HbA1c): ≥48 mmol/mol&#xD;
&#xD;
          -  Age: 18-75 years&#xD;
&#xD;
          -  Body Mass Index (BMI) ≤ 40 kg/m2&#xD;
&#xD;
          -  Estimated Glomerular Filtration Rate (eGFR) &gt; 60 mL/min&#xD;
&#xD;
          -  Alanine Aminotransferase (ALAT), bilirubin and hemoglobin within reference range or&#xD;
             clinically insignificant differ from this.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Acute or chronic infection or inflammation&#xD;
&#xD;
          -  Active cancer&#xD;
&#xD;
          -  Glutamic acid decarboxylase (GAD)-antibodies&#xD;
&#xD;
          -  Known hypersensitivity to one or several of the drugs&#xD;
&#xD;
          -  Intake of medications which can influence the safety of the patient or the results of&#xD;
             the study&#xD;
&#xD;
          -  Alcohol consumption above the limits recommended by the Danish Health Authorities (Men&#xD;
             14 units/week, women 7 units/week)&#xD;
&#xD;
          -  Participation in other trials with interventions.&#xD;
&#xD;
          -  Women: Positive pregnancy test at inclusion or on one of the test-days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ann-Cathrine Dunvald, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Southern Denmark</name>
      <address>
        <city>Odense</city>
        <state>Region Of Southern Denmark</state>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Stage TB, Pottegard A, Henriksen DP, Christensen MM, Hojlund K, Brosen K, Damkier P. Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study. J Thromb Haemost. 2016 Jan;14(1):129-33. doi: 10.1111/jth.13187. Epub 2015 Dec 29.</citation>
    <PMID>26559049</PMID>
  </reference>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>July 29, 2020</study_first_submitted>
  <study_first_submitted_qc>August 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>June 14, 2022</last_update_submitted>
  <last_update_submitted_qc>June 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Southern Denmark</investigator_affiliation>
    <investigator_full_name>Ann-Cathrine Dunvald</investigator_full_name>
    <investigator_title>Principal Investigator</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Efavirenz</mesh_term>
    <mesh_term>Losartan</mesh_term>
    <mesh_term>Metoprolol</mesh_term>
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Caffeine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Individual participant data cannot be shared due to general data protection regulation (GDPR).</ipd_description>
  </patient_data>
  <!-- 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/NCT04504045
org study id: AKF-395
secondary id: 2020-000162-42
nct id: NCT04504045
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Type 2 diabetes is a major public health concern. It is widely established that type 2
      diabetes in linked to activated innate immunity and increased levels of C-reactive protein
      and interleukin-6 (IL-6) in plasma. Studies in humans and in liver cells has shown that IL-6
      downregulates important drug metabolizing enzymes in the liver (cytochrome P450 (CYP)
      enzymes). More than half of the most prescribed drugs are eliminated by biotransformation of
      these enzymes.

      The investigators have previously shown that initiating glucose-lowering treatment (e.g.
      metformin, sulphonylureas and insulin) leads to decreased therapeutic efficacy of the
      blood-thinning vitamin-K antagonist warfarin. Due to the non-specific effect of glucose
      lowering drugs, the investigators hypothesize that this is caused by the glucose-lowering
      effect rather than drug-drug interactions caused by the individual drugs.

      Based on the proposal that reversal of increased plasma glucose affects drug metabolism, the
      investigators will perform a clinical pharmacokinetic trial. The purpose of the study is to
      elucidate whether initiation of glucose-lowering treatment causes altered drug metabolism
      among patients with type 2 diabetes. The study will include newly diagnosed and untreated
      type 2 diabetes patients who will ingest a 6-drug cocktail consisting of probes for specific
      CYP enzymes. Plasma and urine will be drawn over 6 hours to determine concentrations of the
      drugs and their metabolites. Patients will then initiate metformin treatment and to assess
      both short- and long-term impact of glucose-lowering, the same 6-drug cocktail will be
      ingested, and concentrations measured, after three weeks and three months. To help understand
      the mechanism and the putative involvement of inflammation, markers of inflammation such as
      cytokines, transcription factors, etc. will also be assesses.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 3.
time frame: Baseline and Week 3.
description: Change in activity of the drug metabolizing enzyme CYP3A4 following treatment with the glucose lowering drug metformin in 3 weeks. Assessment of the change is based on a change in the metabolic rate, which is the ratio between the concentration of midazolam and its primary metabolite is plasma (Probe drug for CYP3A4).
measure: Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 12.
time frame: Baseline and Week 12.
description: Change in activity of the drug metabolizing enzyme CYP3A4 following treatment with the glucose lowering drug metformin in 12 weeks. Assessment of the change is based on a change in the metabolic rate, which is the ratio between the concentration of midazolam and its primary metabolite is plasma (Probe drug for CYP3A4).
measure: Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 3.
time frame: Baseline and Week 3.
description: Change in activity of the drug metabolizing enzymes CYP1A2 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug caffeine.
measure: Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 12.
time frame: Baseline and Week 12.
description: Change in activity of the drug metabolizing enzymes CYP1A2 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug caffeine.
measure: Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 3.
time frame: Baseline and Week 3.
description: Change in activity of the drug metabolizing enzymes CYP2B6 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Efavirenz.
measure: Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 12.
time frame: Baseline and Week 12.
description: Change in activity of the drug metabolizing enzymes CYP2B6 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Efavirenz.
measure: Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 3.
time frame: Baseline and Week 3.
description: Change in activity of the drug metabolizing enzymes CYP2C9 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Losartan.
measure: Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 12.
time frame: Baseline and Week 12.
description: Change in activity of the drug metabolizing enzymes CYP2C9 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Losartan.
measure: Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 3.
time frame: Baseline and Week 3.
description: Change in activity of the drug metabolizing enzymes CYP2C19 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Omeprazole.
measure: Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 12.
time frame: Baseline and Week 12.
description: Change in activity of the drug metabolizing enzymes CYP2C19 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Omeprazole.
measure: Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 3.
time frame: Baseline and Week 3.
description: Change in activity of the drug metabolizing enzymes CYP2D6 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Metoprolol.
measure: Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 12.
time frame: Baseline and Week 12.
description: Change in activity of the drug metabolizing enzymes CYP2D6 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Metoprolol.
measure: Change from Baseline in HbA1c at Week 3.
time frame: Baseline and Week 3.
description: Change in the regulation of blood glucose over time assessed by HbA1c
measure: Change from Baseline in HbA1c at Week 12.
time frame: Baseline and Week 12.
description: Change in the regulation of blood glucose over time assessed by HbA1c
measure: Change from Baseline in insulin resistance at Week 3.
time frame: Baseline and Week 3.
description: An oral glucose tolerance test will be performed and glucose, insulin and c-peptide will be measured and combined by the Homeostatic Model Assessment (HOMA) to report insulin resistance.
measure: Change from Baseline in insulin resistance at Week 12.
time frame: Baseline and Week 12.
description: An oral glucose tolerance test will be performed and glucose, insulin and c-peptide will be measured and combined by the Homeostatic Model Assessment (HOMA) to report insulin resistance.
measure: Change from Baseline in Interleukin-1-B at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interleukin-1-B.
measure: Change from Baseline in Interleukin-1-B at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interleukin-1-B.
measure: Change from Baseline in Interleukin-2 at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interleukin-2.
measure: Change from Baseline in Interleukin-2 at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interleukin-2.
measure: Change from Baseline in Interleukin-6 at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interleukin-6.
measure: Change from Baseline in Interleukin-6 at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interleukin-6.
measure: Change from Baseline in Interleukin-10 at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interleukin-10.
measure: Change from Baseline in Interleukin-10 at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interleukin-10.
measure: Change from Baseline in Interferon-a at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interferon-a.
measure: Change from Baseline in Interferon-a at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interferon-a.
measure: Change from Baseline in Interferon-B at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interferon-B.
measure: Change from Baseline in Interferon-B at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interferon-B.
measure: Change from Baseline in Interferon-y at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Interferon-y.
measure: Change from Baseline in Interferon-y at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Interferon-y.
measure: Change from Baseline in Tumor Necrosis Factor-a at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of Tumor Necrosis Factor-a.
measure: Change from Baseline in Tumor Necrosis Factor-a at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of Tumor Necrosis Factor-a.
measure: Change from Baseline in High Sensitivity C-Reactive Protein at Week 3.
time frame: Baseline and Week 3.
description: Change in patients inflammatory status assessed by measurement of High Sensitivity C-Reactive Protein.
measure: Change from Baseline in High Sensitivity C-Reactive Protein at Week 12.
time frame: Baseline and Week 12.
description: Change in patients inflammatory status assessed by measurement of High Sensitivity C-Reactive Protein.
arm group label: Metformin
arm group type: Experimental
description: Patients will receive metformin 1000-2000 mg daily for 12 weeks.
intervention type: Drug
intervention name: Metformin
description: 500 mg tablet
arm group label: Metformin
other name: Glucose lowering treatment
intervention type: Drug
intervention name: Caffeine
description: As part of a 6-drug cocktail caffeine 100 mg tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP1A2 activity.
arm group label: Metformin
intervention type: Drug
intervention name: Efavirenz
description: As part of a 6-drug cocktail efavirenz 50 mg coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2B6 activity.
arm group label: Metformin
intervention type: Drug
intervention name: Losartan
description: As part of a 6-drug cocktail losartan 12.5 mg coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2C9 activity.
arm group label: Metformin
intervention type: Drug
intervention name: Omeprazol
description: As part of a 6-drug cocktail Omeprazol 10 mg enteric-coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2C19 activity.
arm group label: Metformin
intervention type: Drug
intervention name: Metoprolol
description: As part of a 6-drug cocktail metoprolol 12.5 mg release tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2D6 activity.
arm group label: Metformin
intervention type: Drug
intervention name: Midazolam
description: As part of a 6-drug cocktail midazolam 2 mg oral solution will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP3A4 activity.
arm group label: Metformin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Ann-Cathrine Dunvald, MD
role: Principal Investigator
affiliation: University of Southern Denmark
facility: 
country: Denmark
citation: Stage TB, Pottegard A, Henriksen DP, Christensen MM, Hojlund K, Brosen K, Damkier P. Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study. J Thromb Haemost. 2016 Jan;14(1):129-33. doi: 10.1111/jth.13187. Epub 2015 Dec 29.
PMID: 26559049
responsible party type: Principal Investigator
investigator affiliation: University of Southern Denmark
investigator full name: Ann-Cathrine Dunvald
investigator title: Principal Investigator
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Metformin
mesh term: Efavirenz
mesh term: Losartan
mesh term: Metoprolol
mesh term: Midazolam
mesh term: Caffeine
sharing ipd: No
ipd description: Individual participant data cannot be shared due to general data protection regulation (GDPR).