<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/NCT03227484</url>
  </required_header>
  <id_info>
    <org_study_id>Empabrain01</org_study_id>
    <nct_id>NCT03227484</nct_id>
  </id_info>
  <brief_title>Effect of Empagliflozin Versus Placebo on Brain Insulin Sensitivity in Patients With Prediabetes</brief_title>
  <official_title>A Double-blind Randomized Study to Determine the Effect of Empagliflozin Versus Placebo on Brain Insulin Sensitivity in Patients With Prediabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Tuebingen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital Tuebingen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Recently, various sodium glucose cotransporter 2 (SGLT2) inhibitors have been approved for&#xD;
      the treatment of type 2 diabetes mellitus. Empagliflozin is a preparation of this class of&#xD;
      substances. SGLT2 inhibitors also lead to a reduction in body weight in addition to their&#xD;
      blood glucose lowering effect. The basis for this is probably the calorie loss by the&#xD;
      increased glucose excretion over the urine. However, this weight-reducing effect is lost&#xD;
      after a few weeks of treatment and the body weight subsequently stabilizes at a lower level&#xD;
      than before. However, patients continue to lose energy via the urine. Hence, the weight&#xD;
      stabilization could be due to an increased energy intake as a possible consequence of a&#xD;
      changed brain setpoint for the body weight. As the main weight loss is achieved during the&#xD;
      first 6-8 weeks of treatment, the investigators assume that the underlying central nervous&#xD;
      mechanisms will be present after this time.&#xD;
&#xD;
      Furthermore, clinical-experimental observations show that treatment with empagliflozin&#xD;
      promotes endogenous glucose production in the liver. This presumably compensatory mechanism&#xD;
      also occurs after only a few weeks of treatment. The common mechanism, which could be based&#xD;
      both on energy intake and on the endogenous glucose production effect, is still unclear. The&#xD;
      investigators suspect that regulatory circuits in the brain contribute to these observed&#xD;
      effects.&#xD;
&#xD;
      In fact, several studies in animals as well as initial clinical studies in humans show that&#xD;
      the brain is involved in eating behavior and peripheral metabolism. In particular, effects of&#xD;
      the hormone insulin modulate the dietary intake via the brain, thereby affecting human body&#xD;
      weight.&#xD;
&#xD;
      Many of the experiments on the insulin sensitivity of the human brain used a specific&#xD;
      approach to the selective delivery of insulin into the brain: the application of insulin as a&#xD;
      nasal spray. Although this application route has no therapeutic value, this technique allows&#xD;
      the administration of insulin to the central nervous system with little effect on the&#xD;
      circulating insulin levels. By combining nasal insulin administration with functional MRI,&#xD;
      regional insulin sensitivity of the brain can be quantified. The investigators recently found&#xD;
      that the insulin action of the brain (stimulated by nasal insulin) regulates both endogenous&#xD;
      glucose production and peripheral glucose uptake during hyperinsulinemic euglycemic glucose&#xD;
      clamps. The signals from the brain seem to reach the periphery via the autonomic nervous&#xD;
      system in order to modulate metabolic processes. A central brain area in this regard is the&#xD;
      hypothalamus. This brain region receives afferents over various systems such as the autonomic&#xD;
      nervous system and various endocrine systems (including insulin). The investigators recently&#xD;
      characterized the hypothalamus as an insulin-sensitive brain area in humans. The hypothalamus&#xD;
      is the key area for homeostatic control throughout the body.&#xD;
&#xD;
      Since the dietary intake and the endogenous glucose production are modulated by a&#xD;
      hypothalamic insulin effect in humans, we suspect that the observed effects of SGLT2&#xD;
      inhibitors on both processes could be due to altered insulin activity in the brain. Since the&#xD;
      SGLT2 inhibition by empagliflozin modulates the autonomic nervous system in the kidneys,&#xD;
      signals from the kidney may be transmitted to the brain via the autonomic nervous system,&#xD;
      thereby changing specific setpoints, including e.g. insulin sensitivity of the brain.&#xD;
&#xD;
      In order to test this hypothesis, a precise phenotyping of prediabetic volunteers with regard&#xD;
      to regional brain insulin sensitivity as well as the brain effect on metabolism before and&#xD;
      after 8 weeks of treatment with empagliflozin compared to placebo is planned.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 9, 2017</start_date>
  <completion_date type="Actual">November 18, 2019</completion_date>
  <primary_completion_date type="Actual">October 25, 2019</primary_completion_date>
  <phase>Phase 2</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>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>effect of treatment with 25 mg empagliflozin daily versus placebo on regional brain insulin sensitivity</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by functional magnetic resonance imaging (fMRI) combined with nasal insulin administration as change from baseline to 8 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>effects of treatment with empagliflozin versus placebo on glucose tolerance in prediabetes</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by 75g oral glucose tolerance test (oGTT) as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effects of treatment with empagliflozin versus placebo on body fat composition</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by whole body MRI and liver MR-spectroscopy and bioimpedance analysis as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effect of treatment with empagliflozin versus placebo on brain-insulin derived modulation of peripheral metabolism</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by hyperinsulinemic euglycemic clamp combined with nasal insulin administration as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effect of treatment with empagliflozin versus placebo on autonomous nervous system activity</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by analysis of heart rate variability as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effect of treatment with empagliflozin versus placebo on the brain responsiveness to food cues and nutrient-specific food preference</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by fMRI combined with nasal insulin administration as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effect of treatment with empagliflozin versus placebo on the correlation between insulin secretion capacity and regional brain insulin sensitivity</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by fMRI combined with nasal insulin administration and 75g oGTT as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>effect of treatment with empagliflozin versus placebo on energy expenditure</measure>
    <time_frame>baseline and after 8 weeks of treatment</time_frame>
    <description>assessed by indirect calorimetry as change from baseline to 8 weeks</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>PreDiabetes</condition>
  <condition>Body Weight</condition>
  <arm_group>
    <arm_group_label>Empagliflozin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>25mg Empagliflozin once daily over 8 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching placebo tablet once daily over 8 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin 25mg</intervention_name>
    <description>Once daily over 8 weeks</description>
    <arm_group_label>Empagliflozin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Once daily over 8 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Fasting blood glucose between 100 and 125 mg/dl and/or 2-hour post load glucose&#xD;
             between 140 and 199 mg/dl during a 75 g oral glucose tolerance test.&#xD;
&#xD;
          -  Body mass index (BMI) between 25 and 40 kg/m².&#xD;
&#xD;
          -  Understand and voluntarily sign an informed consent document prior to any study&#xD;
             related assessments/procedures.&#xD;
&#xD;
          -  Ability to adhere to the study visit schedule and other protocol requirements.&#xD;
&#xD;
          -  Females of childbearing potential (FCBP1) must agree&#xD;
&#xD;
          -  to utilize two reliable forms of contraception simultaneously or practice complete&#xD;
             abstinence from heterosexual contact for at least 28 days before starting study drug,&#xD;
             while participating in the study (including dose interruptions), and for at least 28&#xD;
             days after study treatment discontinuation and must agree to pregnancy testing during&#xD;
             this timeframe&#xD;
&#xD;
          -  to abstain from breastfeeding during study participation and 28 days after study drug&#xD;
             discontinuation.&#xD;
&#xD;
          -  Males must agree&#xD;
&#xD;
          -  to use a latex condom during any sexual contact with FCBP while participating in the&#xD;
             study and for 28 days following discontinuation from this study, even if he has&#xD;
             undergone a successful vasectomy&#xD;
&#xD;
          -  to refrain from donating semen or sperm while participating in this study and for 28&#xD;
             days after discontinuation from this study treatment.&#xD;
&#xD;
          -  All subjects must agree to refrain from donating blood while on study drug and for 28&#xD;
             days after discontinuation from this study treatment.&#xD;
&#xD;
          -  All subjects must agree not to share medication.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women during pregnancy and lactation.&#xD;
&#xD;
          -  History of hypersensitivity to the investigational medicinal product or to any drug&#xD;
             with similar chemical structure or to any excipient present in the pharmaceutical form&#xD;
             of the investigational medicinal products. This includes empagliflozin, placebo and&#xD;
             human insulin.&#xD;
&#xD;
          -  Participation in other clinical trials or observation period of competing trials up to&#xD;
             30 days prior to this study.&#xD;
&#xD;
          -  Diabetes mellitus&#xD;
&#xD;
          -  Known malformation of the central nervous system&#xD;
&#xD;
          -  Persons working nightshift&#xD;
&#xD;
          -  Treatment with glucose lowering drugs, drugs with central nervous actions or systemic&#xD;
             steroid therapy&#xD;
&#xD;
          -  Any relevant (according to investigator's judgment) cardiovascular disease, e.g.&#xD;
             myocardial infarction, acute coronary syndrome, unstable angina pectoris, Percutaneous&#xD;
             transluminal coronary angioplasty (PTCA), heart failure (NYHA II-IV), stroke or&#xD;
             transient ischemic attack (TIA), within 12 months prior to screening.&#xD;
&#xD;
          -  Indication of liver disease, as per medical history or defined by serum levels of&#xD;
             either Alanine Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (AST [SGOT]),&#xD;
             or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during&#xD;
             screening.&#xD;
&#xD;
          -  Alcohol abuse, defined as more than 20 gr/day&#xD;
&#xD;
          -  Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) ≤ 60&#xD;
             ml/min (MDRD formula) as determined during screening.&#xD;
&#xD;
          -  Known structural and functional urogenital abnormalities, that predispose for&#xD;
             urogenital infections.&#xD;
&#xD;
          -  Subjects with a haemoglobin (Hb) ≤ 11.5 g/dl (for males) and Hb ≤ 10.5 g/dl (for&#xD;
             females) at screening.&#xD;
&#xD;
          -  Bariatric surgery within the past two years and other gastrointestinal surgeries that&#xD;
             induce chronic malabsorption within the last 5 years.&#xD;
&#xD;
          -  Medical history of cancer (except for basal cell carcinoma) and/or treatment for&#xD;
             cancer within the last 5 years.&#xD;
&#xD;
          -  Treatment with anti-obesity drugs 3 months prior to informed consent or any other&#xD;
             treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.)&#xD;
             leading to unstable body weight.&#xD;
&#xD;
          -  Known autoimmune disease (except autoimmune disease of the thyroid gland) or chronic&#xD;
             inflammatory condition.&#xD;
&#xD;
          -  Claustrophobia&#xD;
&#xD;
          -  Any other clinically significant major organ system disease at screening such as&#xD;
             relevant gastrointestinal, neurologic, psychiatric, endocrine (i.e. pancreatic),&#xD;
             hematologic, malignant, infection or other major systemic diseases making&#xD;
             implementation of the protocol or interpretation of the study results difficult.&#xD;
&#xD;
          -  Presence of any contraindication for the conduct of an MRI investigation, such as&#xD;
             cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system,&#xD;
             metallic splinters in the eye, ferromagnetic or electronically operated active devices&#xD;
             like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve&#xD;
             stimulators, prosthetic heart valves etc.&#xD;
&#xD;
          -  Refusal to get informed of unexpected detected pathological MRI findings&#xD;
&#xD;
        Any other clinical condition that would jeopardize subjects' safety while participating in&#xD;
        this clinical trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Martin Heni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital Tuebingen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Tuebingen, Department of Internal Medicine IV</name>
      <address>
        <city>Tübingen</city>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>June 7, 2017</study_first_submitted>
  <study_first_submitted_qc>July 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <last_update_submitted>April 28, 2020</last_update_submitted>
  <last_update_submitted_qc>April 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Prediabetic State</mesh_term>
    <mesh_term>Glucose Intolerance</mesh_term>
    <mesh_term>Body Weight</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Empagliflozin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03227484
org study id: Empabrain01
nct id: NCT03227484
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Recently, various sodium glucose cotransporter 2 (SGLT2) inhibitors have been approved for
      the treatment of type 2 diabetes mellitus. Empagliflozin is a preparation of this class of
      substances. SGLT2 inhibitors also lead to a reduction in body weight in addition to their
      blood glucose lowering effect. The basis for this is probably the calorie loss by the
      increased glucose excretion over the urine. However, this weight-reducing effect is lost
      after a few weeks of treatment and the body weight subsequently stabilizes at a lower level
      than before. However, patients continue to lose energy via the urine. Hence, the weight
      stabilization could be due to an increased energy intake as a possible consequence of a
      changed brain setpoint for the body weight. As the main weight loss is achieved during the
      first 6-8 weeks of treatment, the investigators assume that the underlying central nervous
      mechanisms will be present after this time.

      Furthermore, clinical-experimental observations show that treatment with empagliflozin
      promotes endogenous glucose production in the liver. This presumably compensatory mechanism
      also occurs after only a few weeks of treatment. The common mechanism, which could be based
      both on energy intake and on the endogenous glucose production effect, is still unclear. The
      investigators suspect that regulatory circuits in the brain contribute to these observed
      effects.

      In fact, several studies in animals as well as initial clinical studies in humans show that
      the brain is involved in eating behavior and peripheral metabolism. In particular, effects of
      the hormone insulin modulate the dietary intake via the brain, thereby affecting human body
      weight.

      Many of the experiments on the insulin sensitivity of the human brain used a specific
      approach to the selective delivery of insulin into the brain: the application of insulin as a
      nasal spray. Although this application route has no therapeutic value, this technique allows
      the administration of insulin to the central nervous system with little effect on the
      circulating insulin levels. By combining nasal insulin administration with functional MRI,
      regional insulin sensitivity of the brain can be quantified. The investigators recently found
      that the insulin action of the brain (stimulated by nasal insulin) regulates both endogenous
      glucose production and peripheral glucose uptake during hyperinsulinemic euglycemic glucose
      clamps. The signals from the brain seem to reach the periphery via the autonomic nervous
      system in order to modulate metabolic processes. A central brain area in this regard is the
      hypothalamus. This brain region receives afferents over various systems such as the autonomic
      nervous system and various endocrine systems (including insulin). The investigators recently
      characterized the hypothalamus as an insulin-sensitive brain area in humans. The hypothalamus
      is the key area for homeostatic control throughout the body.

      Since the dietary intake and the endogenous glucose production are modulated by a
      hypothalamic insulin effect in humans, we suspect that the observed effects of SGLT2
      inhibitors on both processes could be due to altered insulin activity in the brain. Since the
      SGLT2 inhibition by empagliflozin modulates the autonomic nervous system in the kidneys,
      signals from the kidney may be transmitted to the brain via the autonomic nervous system,
      thereby changing specific setpoints, including e.g. insulin sensitivity of the brain.

      In order to test this hypothesis, a precise phenotyping of prediabetic volunteers with regard
      to regional brain insulin sensitivity as well as the brain effect on metabolism before and
      after 8 weeks of treatment with empagliflozin compared to placebo is planned.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: effect of treatment with 25 mg empagliflozin daily versus placebo on regional brain insulin sensitivity
time frame: baseline and after 8 weeks of treatment
description: assessed by functional magnetic resonance imaging (fMRI) combined with nasal insulin administration as change from baseline to 8 weeks
measure: effects of treatment with empagliflozin versus placebo on glucose tolerance in prediabetes
time frame: baseline and after 8 weeks of treatment
description: assessed by 75g oral glucose tolerance test (oGTT) as change from baseline to 8 weeks
measure: effects of treatment with empagliflozin versus placebo on body fat composition
time frame: baseline and after 8 weeks of treatment
description: assessed by whole body MRI and liver MR-spectroscopy and bioimpedance analysis as change from baseline to 8 weeks
measure: effect of treatment with empagliflozin versus placebo on brain-insulin derived modulation of peripheral metabolism
time frame: baseline and after 8 weeks of treatment
description: assessed by hyperinsulinemic euglycemic clamp combined with nasal insulin administration as change from baseline to 8 weeks
measure: effect of treatment with empagliflozin versus placebo on autonomous nervous system activity
time frame: baseline and after 8 weeks of treatment
description: assessed by analysis of heart rate variability as change from baseline to 8 weeks
measure: effect of treatment with empagliflozin versus placebo on the brain responsiveness to food cues and nutrient-specific food preference
time frame: baseline and after 8 weeks of treatment
description: assessed by fMRI combined with nasal insulin administration as change from baseline to 8 weeks
measure: effect of treatment with empagliflozin versus placebo on the correlation between insulin secretion capacity and regional brain insulin sensitivity
time frame: baseline and after 8 weeks of treatment
description: assessed by fMRI combined with nasal insulin administration and 75g oGTT as change from baseline to 8 weeks
measure: effect of treatment with empagliflozin versus placebo on energy expenditure
time frame: baseline and after 8 weeks of treatment
description: assessed by indirect calorimetry as change from baseline to 8 weeks
arm group label: Empagliflozin
arm group type: Active Comparator
description: 25mg Empagliflozin once daily over 8 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Matching placebo tablet once daily over 8 weeks
intervention type: Drug
intervention name: Empagliflozin 25mg
description: Once daily over 8 weeks
arm group label: Empagliflozin
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Once daily over 8 weeks
arm group label: Placebo
criteria: 
gender: All
minimum age: 30 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Martin Heni, MD
role: Principal Investigator
affiliation: University Hospital Tuebingen
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Insulin Resistance
mesh term: Prediabetic State
mesh term: Glucose Intolerance
mesh term: Body Weight
mesh term: Empagliflozin
sharing ipd: No