<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/NCT02985242</url>
  </required_header>
  <id_info>
    <org_study_id>M16-04EMPA-EYE</org_study_id>
    <secondary_id>2016-000825-38</secondary_id>
    <nct_id>NCT02985242</nct_id>
  </id_info>
  <brief_title>Empagliflozin Reduces Progression of Diabetic Retinopathy in Patients With High Risk of Diabetic Macular Edema</brief_title>
  <official_title>SGLT2-inhibition With Empagliflozin Reduces Progression of Diabetic Retinopathy in Patients With High Risk of Diabetic Macular Edema (The SUPER-Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hannover Medical School</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hannover Medical School</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, randomized, active control, two-arm parallel, double-blind, monocenter&#xD;
      phase IV clinical trial. The trial compares empagliflozin to glimepiride in patients with&#xD;
      type 2 diabetes mellitus in addition to standard of care treatment.&#xD;
&#xD;
      Patients with type 2 diabetes mellitus who are between 18 and 80 years of age will be&#xD;
      recruited for the clinical trial and randomly allocated to either receive empagliflozin or&#xD;
      glimepiride.&#xD;
&#xD;
      The assumption of the study is that empagliflozin slows down diabetic retinopathy progression&#xD;
      rate and thus a lower microaneurysm formation rate compared to subjects treated with&#xD;
      glimepiride by substantially decreased cellular glucotoxicity will be achieved.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    difficulties to recruit planned numbers of patients within reasonable time frame&#xD;
  </why_stopped>
  <start_date type="Actual">June 12, 2017</start_date>
  <completion_date type="Actual">August 16, 2018</completion_date>
  <primary_completion_date type="Actual">August 1, 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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Microaneurysm formation rate over 12 months, i.e. number of newly developed microaneurysms within 12 months</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in diabetic retinopathy stage (≥ 2 step change on ETDRS severity score)</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in microaneurysm count</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microaneurysm formation rate after 6 months (compared to baseline)</measure>
    <time_frame>after 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in retinal thickness (as measured by Optical Coherence Tomography)</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in retinal perfusion of microvasculature within the retina (flow in Optical Coherence Tomography Angiography)</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression to clinically significant macular edema (CSME)</measure>
    <time_frame>Up to 52 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intraocular lipid content (hard exsudates)</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in composite clinical outcome evaluating progression to proliferative diabetic retinopathy (PDR) based on photography, angiography plus clinically important events defining PDR (e.g. vitreous haemorrhage)</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in best corrected visual acuity (BCVA [ETDRS letters])</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in HbA1c</measure>
    <time_frame>Weeks 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 52 and 55</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fasting glucose</measure>
    <time_frame>Weeks 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 52 and 55</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in body weight and body fat mass</measure>
    <time_frame>Weeks 27, 52 and 55</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in ambulatory blood pressure</measure>
    <time_frame>Weeks 27 and 52</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Diabetes Mellitus, Type II</condition>
  <arm_group>
    <arm_group_label>Empagliflozin/glimepiride placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Empagliflozin 25 mg film-coated tablet p.o. daily and glimepiride matching placebo p.o. daily&#xD;
Duration of treatment: 12 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Glimepiride/empagliflozin placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Glimepiride 2 mg tablet p.o. daily and empagliflozin matching placebo p.o. daily&#xD;
Duration of treatment: 12 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin</intervention_name>
    <description>Empagliflozin film-coated tablet</description>
    <arm_group_label>Empagliflozin/glimepiride placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glimepiride</intervention_name>
    <description>Glimepiride tablet</description>
    <arm_group_label>Glimepiride/empagliflozin placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin placebo</intervention_name>
    <description>Placebo tablet manufactured to mimic Empagliflozin 25 mg film-coated tablet</description>
    <arm_group_label>Glimepiride/empagliflozin placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glimepiride placebo</intervention_name>
    <description>Placebo tablet manufactured to mimic Glimepiride 2 mg tablet</description>
    <arm_group_label>Empagliflozin/glimepiride placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. women and men between 18 - 80 years of age&#xD;
&#xD;
          2. type 2 diabetes mellitus&#xD;
&#xD;
          3. early to moderate stage diabetic retinopathy (ETDRS: 20 (microaneurysms only) to 35&#xD;
             (microaneurysms/ hemorrhages and/or hard exsudates)) in one or both eyes&#xD;
&#xD;
          4. stable HbA1c (± 0.5%) for at least 12 weeks&#xD;
&#xD;
          5. antidiabetic treatment with either diet, metformin, DPP4, GLP1, pioglitazone,&#xD;
             acarbose, or respective combinations&#xD;
&#xD;
          6. HbA1c ≥ 6.5 and ≤ 10.0 %&#xD;
&#xD;
          7. body mass index &lt; 46 kg/m2&#xD;
&#xD;
          8. office blood pressure ≤ 150/95 mmHg (confirmed on a second day; 24h ambulatory blood&#xD;
             pressure measurement (ABPM) is allowed to check accuracy of office values; inclusion&#xD;
             with 24h mean blood pressure ≤ 145/90 mm Hg is possible); patients with hypertension&#xD;
             should be treated according to current treatment guidelines&#xD;
&#xD;
          9. either women without childbearing potential defined by:&#xD;
&#xD;
               -  at least 6 weeks after surgical sterilization by bilateral tubal ligation or&#xD;
                  bilateral oophorectomy&#xD;
&#xD;
               -  hysterectomy&#xD;
&#xD;
               -  ≥ 50 years and in postmenopausal state &gt; 1 year&#xD;
&#xD;
               -  &lt; 50 years and in postmenopausal state &gt; 1 year with serum follicle stimulating&#xD;
                  hormone (FSH) &gt; 40 IU/l and serum estrogen &lt; 30 ng/l or a negative estrogen test,&#xD;
                  both at screening or women of childbearing potential with a negative serum beta&#xD;
                  human chorionic gonadotropin (ß-hCG) pregnancy test at screening who agree to&#xD;
                  meet one of the following criteria from the time of screening, during the study&#xD;
                  and for a period of 4 days following the last administration of study medication:&#xD;
&#xD;
               -  correct use of one of the following accepted contraception methods: hormonal&#xD;
                  contraceptives (combined oral contraceptives, implants, transdermal patches,&#xD;
                  hormonal vaginal devices or injections with prolonged release), intrauterine&#xD;
                  device (IUD/IUS) or a double barrier method, e.g. condom and occlusive cap&#xD;
                  (diaphragm or cervical/vault caps) with spermicide (foam, gel, film, cream or&#xD;
                  suppository)&#xD;
&#xD;
               -  true abstinence (periodic abstinence and withdrawal are not acceptable methods of&#xD;
                  contraception)&#xD;
&#xD;
               -  sexual relationship only with female partners&#xD;
&#xD;
               -  sterile male partners&#xD;
&#xD;
         10. signed written informed consent and willingness to comply with treatment and follow-up&#xD;
             procedures&#xD;
&#xD;
         11. capability of understanding the investigational nature, potential risks and benefits&#xD;
             of the clinical trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Type 1 diabetes&#xD;
&#xD;
          2. uncontrolled diabetes mellitus type 2 with fasting glucose &gt; 13.3 mmol/l confirmed on&#xD;
             a second day&#xD;
&#xD;
          3. known or suspected hypersensitivity to empagliflozin, glimepiride, or any excipients;&#xD;
             and / or known or suspected hypersensitivity to sulfonylureas, sulfonamides or SGLT2&#xD;
             inhibitors in general&#xD;
&#xD;
          4. history of multiple severe hypoglycemic episodes within the last two years&#xD;
&#xD;
          5. use of Insulin, SGLT2-inhibitor, sulfonylurea derivate or a glinide within past 3&#xD;
             months&#xD;
&#xD;
          6. clinical significant macular edema in both eyes and indication for intravitreal&#xD;
             anti-VEGF treatment for both eyes at screening or baseline visit. Eyes with a small&#xD;
             amount of intraretinal or subretinal fluid (seen in OCT) but no need for intravitreal&#xD;
             treatment as judged by the investigator (according to current practice patterns) may&#xD;
             be included. Eyes with a history of intravitreal treatment of macular edema which do&#xD;
             not need ongoing intravitreal treatment at the time of screening may be included.&#xD;
&#xD;
          7. eye diseases or pathologies that prevent clear ophthalmoscopy and evaluation of study&#xD;
             parameters, thus not allowing study participation according to the investigator´s&#xD;
             judgment, such as (but not only) vitreous hemorrhage, mature cataract, macular&#xD;
             pathologies other than diabetic maculopathy&#xD;
&#xD;
          8. history of ketoacidosis or metabolic acidosis&#xD;
&#xD;
          9. use of loop diuretics&#xD;
&#xD;
         10. history of &gt; 1 urogenital infection/year&#xD;
&#xD;
         11. any history of stroke, transient ischemic attack (TIA), instable angina pectoris or&#xD;
             myocardial infarction within last 3 months prior to baseline visit&#xD;
&#xD;
         12. congestive heart failure New York Heart Association (NYHA) III and IV&#xD;
&#xD;
         13. severe valvular or left ventricular outflow obstruction disease needing intervention;&#xD;
&#xD;
         14. atrial fibrillation/flutter with a mean ventricular response rate at rest &gt;100 beats&#xD;
             per minute&#xD;
&#xD;
         15. chronic lower urinary tract infections (but not simple asymptomatic bacteriuria)&#xD;
&#xD;
         16. eGFR &lt; 60 ml/min/1,73 m2 (MDRD-formula, confirmed on a second day)&#xD;
&#xD;
         17. chronic diarrhea, any clinical signs of volume depletion or a hematocrit &gt; 48 %&#xD;
             (women) and &gt; 53 % (men)&#xD;
&#xD;
         18. elevated risk for volume depletion, e.g. history of severe volume depletion that&#xD;
             required medical therapy&#xD;
&#xD;
         19. chronic liver disease (including known active hepatitis) and/or screening alanine&#xD;
             transaminase (ALT) or aspartate transaminase (AST) &gt; 3 x upper limit of normal (ULN)&#xD;
             (confirmed on a second day)&#xD;
&#xD;
         20. Subjects with known seropositivity to human immunodeficiency virus.&#xD;
&#xD;
         21. acute illness at screening or randomization according to judgement by the investigator&#xD;
             or patient&#xD;
&#xD;
         22. drug or alcohol abuse&#xD;
&#xD;
         23. psychosomatic or psychiatric diseases requiring hospitalization during the last 12&#xD;
             months&#xD;
&#xD;
         24. clinical evidence of current malignancy with exception of basal cell or squamous cell&#xD;
             carcinoma of the skin, and cervical intraepithelial neoplasia (5 years prior to&#xD;
             randomization)&#xD;
&#xD;
         25. any medical or surgical intervention planned for the next 13 months after&#xD;
             randomization not allowing study participation according to the investigator´s&#xD;
             judgment&#xD;
&#xD;
         26. current participation in any other clinical trial or participation in another clinical&#xD;
             trial within 30 days before screening&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amelie Pielen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hannover Medical School, University Eye Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hannover Medical School, University Eye Hospital and CRC Core Facility Hannover</name>
      <address>
        <city>Hanover</city>
        <state>Lower Saxony</state>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>November 25, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <last_update_submitted>September 26, 2018</last_update_submitted>
  <last_update_submitted_qc>September 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 27, 2018</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>Macular Edema</mesh_term>
    <mesh_term>Diabetic Retinopathy</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>Empagliflozin</mesh_term>
    <mesh_term>Glimepiride</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/NCT02985242
org study id: M16-04EMPA-EYE
secondary id: 2016-000825-38
nct id: NCT02985242
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a prospective, randomized, active control, two-arm parallel, double-blind, monocenter
      phase IV clinical trial. The trial compares empagliflozin to glimepiride in patients with
      type 2 diabetes mellitus in addition to standard of care treatment.

      Patients with type 2 diabetes mellitus who are between 18 and 80 years of age will be
      recruited for the clinical trial and randomly allocated to either receive empagliflozin or
      glimepiride.

      The assumption of the study is that empagliflozin slows down diabetic retinopathy progression
      rate and thus a lower microaneurysm formation rate compared to subjects treated with
      glimepiride by substantially decreased cellular glucotoxicity will be achieved.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Microaneurysm formation rate over 12 months, i.e. number of newly developed microaneurysms within 12 months
time frame: Weeks 27 and 52
measure: Change in diabetic retinopathy stage (≥ 2 step change on ETDRS severity score)
time frame: Weeks 27 and 52
measure: Change in microaneurysm count
time frame: Weeks 27 and 52
measure: Microaneurysm formation rate after 6 months (compared to baseline)
time frame: after 6 months
measure: Change in retinal thickness (as measured by Optical Coherence Tomography)
time frame: Weeks 27 and 52
measure: Change in retinal perfusion of microvasculature within the retina (flow in Optical Coherence Tomography Angiography)
time frame: Weeks 27 and 52
measure: Progression to clinically significant macular edema (CSME)
time frame: Up to 52 weeks
measure: Change in intraocular lipid content (hard exsudates)
time frame: Weeks 27 and 52
measure: Change in composite clinical outcome evaluating progression to proliferative diabetic retinopathy (PDR) based on photography, angiography plus clinically important events defining PDR (e.g. vitreous haemorrhage)
time frame: Weeks 27 and 52
measure: Change in best corrected visual acuity (BCVA [ETDRS letters])
time frame: Weeks 27 and 52
measure: Change in HbA1c
time frame: Weeks 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 52 and 55
measure: Change in fasting glucose
time frame: Weeks 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 52 and 55
measure: Change in body weight and body fat mass
time frame: Weeks 27, 52 and 55
measure: Change in ambulatory blood pressure
time frame: Weeks 27 and 52
arm group label: Empagliflozin/glimepiride placebo
arm group type: Experimental
description: Empagliflozin 25 mg film-coated tablet p.o. daily and glimepiride matching placebo p.o. daily
Duration of treatment: 12 months
arm group label: Glimepiride/empagliflozin placebo
arm group type: Active Comparator
description: Glimepiride 2 mg tablet p.o. daily and empagliflozin matching placebo p.o. daily
Duration of treatment: 12 months
intervention type: Drug
intervention name: Empagliflozin
description: Empagliflozin film-coated tablet
arm group label: Empagliflozin/glimepiride placebo
intervention type: Drug
intervention name: Glimepiride
description: Glimepiride tablet
arm group label: Glimepiride/empagliflozin placebo
intervention type: Drug
intervention name: Empagliflozin placebo
description: Placebo tablet manufactured to mimic Empagliflozin 25 mg film-coated tablet
arm group label: Glimepiride/empagliflozin placebo
intervention type: Drug
intervention name: Glimepiride placebo
description: Placebo tablet manufactured to mimic Glimepiride 2 mg tablet
arm group label: Empagliflozin/glimepiride placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Amelie Pielen, MD
role: Principal Investigator
affiliation: Hannover Medical School, University Eye Hospital
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Macular Edema
mesh term: Diabetic Retinopathy
mesh term: Diabetes Mellitus, Type 2
mesh term: Empagliflozin
mesh term: Glimepiride
sharing ipd: No