<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/NCT03022721</url>
  </required_header>
  <id_info>
    <org_study_id>S-383/2016</org_study_id>
    <nct_id>NCT03022721</nct_id>
  </id_info>
  <brief_title>Heidelberg Study on Diabetes and Complications</brief_title>
  <acronym>HEIST-DiC</acronym>
  <official_title>Heidelberg Study on Diabetes and Complications</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Heidelberg University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Heidelberg University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The prospective observational study entitled &quot;Heidelberg Study on Diabetes and Complications&quot;&#xD;
      is designed to Monitor the presence and development of diabetic complications in type 1 and&#xD;
      type 2 diabetic patients, as well as pre-diabetics. Mail Goal is to detect new metabolic&#xD;
      mechanisms or new risk factors for the development of diabetic complications in order to&#xD;
      identify risk-subgroups. Non-diabetic controls will be enrolled for reference and comparison.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The prospective observational study entitled &quot;Heidelberg Study on Diabetes and Complications&quot;&#xD;
      is designed to show that diabetes according to the current medical definition does not exist.&#xD;
      Without question, there is an autoimmune disease that destroys beta cells in the pancreas,&#xD;
      which leads to absolute insulin deficiency with consecutively elevated blood glucose levels.&#xD;
      This disease is defined as diabetes mellitus type 1. Insulin treatment is absolutely&#xD;
      necessary in this state, since absolute insulin deficiency leads to lipolysis with&#xD;
      consecutive ketoacidosis and eventually death. On the other hand, type 2 diabetes is&#xD;
      generally defined as relative insulin deficiency with consecutively elevated blood glucose&#xD;
      levels. This disease is often mentioned in the context of the metabolic syndrome, which&#xD;
      additionally comprises obesity, arterial hypertension, dyslipidemia, and cardiovascular&#xD;
      diseases. Therefore, only the name &quot;diabetes mellitus&quot; is shared by these two diseases, which&#xD;
      means &quot;sweet flow&quot;, therefore only describing a symptom.&#xD;
&#xD;
      Multiple interventional studies were aimed on avoiding or reducing the development of late&#xD;
      diabetic complications (nephropathy, neuropathy, retinopathy, microangiopathy). This is true&#xD;
      for both type 1 and type 2 diabetes. Up to this day, no study was able to demonstrate that&#xD;
      treatment of normalization of blood glucose levels reduces or even reverses development of&#xD;
      these complications. Moreover, several type 2 diabetic patients developed typical diabetic&#xD;
      complications before definitive manifestation of the actual disease.&#xD;
&#xD;
      Therefore, we hypothesize that late diabetic complications stand in no primary context with&#xD;
      blood glucose control, but are associated with other metabolic disorders. One aspect are&#xD;
      reactive metabolites (glyoxal, methylglyoxal, 3-DG), which are formed in glycolysis and&#xD;
      lipolysis in the context of energy production of cells. These metabolites are detoxified to&#xD;
      lactate by certain enzymes. In case this detoxification is compromised, or production of&#xD;
      these metabolites elevated, so called advanced glycation endproducts (AGEs) can form.&#xD;
      Moreover, within the process of energy production, reactive oxygen species (ROS) and&#xD;
      oxydative stress are more pronounced, which can have direct influence on cellular metabolism.&#xD;
      This interaction leads to inflammation and DNA damage. Survival of the cells is dependent on&#xD;
      defense mechanisms, which seem to be genetically determined, with cellular ageing playing a&#xD;
      role as well (cellular senescence). With advanced ageing, cells lose these defense mechanisms&#xD;
      against these permanent metabolic attacks.&#xD;
&#xD;
      Therefore, the following hypotheses arise:&#xD;
&#xD;
        1. Diabetes mellitus type 2 is no independent disease, but a late complication of metabolic&#xD;
           imbalance&#xD;
&#xD;
        2. Typical &quot;late diabetic complications&quot; are not based on insufficient blood glucose&#xD;
           lowering therapy, but on the basis of this metabolic imbalance, and can therefore affect&#xD;
           every patient, even without manifested &quot;diabetes mellitus type 2&quot;&#xD;
&#xD;
        3. Diabetes mellitus type 1 is an autoimmundisease with consecutive absolute insulin&#xD;
           deficiency, however manifestation of late diabetic complications is based on the same&#xD;
           metabolic dysbalance (overlap with type 2).&#xD;
&#xD;
      In order to investigate these hypotheses, study participants will be profoundly examined once&#xD;
      yearly concerning glycemic metabolic state and clinical findings related to micro- and&#xD;
      macrovascular diabetic complications, Moreover, reactive metabolites like AGEs, ROS,&#xD;
      methylglyoxal, and DNA damage as well as other parameters associated with cellular senescence&#xD;
      will be examined. We will also collect information concerning quality of life, well-being,&#xD;
      depression, and neuropathic pain.&#xD;
&#xD;
      This is the first study of its kind to include non-diabetics, pre-diabetics, and diabetics&#xD;
      with the possibility to study differences and common ground regarding cellular metabolism.&#xD;
      Moreover, to the best of our knowledge, there is no precise clinical characterization of&#xD;
      peripheral nerve function in pre-diabetics, although some of these patients already complain&#xD;
      about neuropathic symptoms. In addition to that, the natural clinical course not only in&#xD;
      diabetics, but also in pre-diabetics will be observed over a longer period of time. Finally,&#xD;
      changes in surrogate markers over the natural course of pre-diabetes can be observed for the&#xD;
      first time, onset of type 1 or type 2 diabetes can be registered immediately, and all&#xD;
      patients can be directly compared to healthy controls.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>September 2016</start_date>
  <completion_date type="Anticipated">September 2028</completion_date>
  <primary_completion_date type="Anticipated">September 2027</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Development of diabetic complications</measure>
    <time_frame>10 years</time_frame>
    <description>Diabetic complications include diabetic nephropathy, diabetic retinopathy, diabetic polyneuropathy, autonomous neuropathy, or macrovascular complications such as stroke, peripheral artery disease, or myocardial infarction.</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">500</enrollment>
  <condition>Diabetes Complications</condition>
  <arm_group>
    <arm_group_label>Patients with diabetes</arm_group_label>
    <description>Patients with both type 1 and type 2 Diabetes will be enrolled, Independent of Diabetes Duration, therapy etc.&#xD;
No interventions are planned.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pre-Diabetics</arm_group_label>
    <description>Patients who have either imparied fasting Glucose or impaired Glucose tolerance in the oral Glucose tolerance test.&#xD;
No interventions are planned.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
    <description>Study participants without Diabetes or Pre-diabetes in the oral Glucose tolerance test.&#xD;
no interventions are planned.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>No interventions are planned for this study.</intervention_name>
    <description>No interventions are planned for this study, it is purely observational.</description>
    <arm_group_label>Healthy controls</arm_group_label>
    <arm_group_label>Patients with diabetes</arm_group_label>
    <arm_group_label>Pre-Diabetics</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma, serum, PBMC, whole blood, urine. There is a possibility of DNA extraction from PBMC&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Study Population comprises patients with Diabetes, patients with pre-diabetes, and healthy&#xD;
        controls. In total, 500 participants shall be enrolled and observed for 10 years.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria Age between 18 and 75 years Persons with manifest diabetes mellitus type&#xD;
        1 or type 2 and diagnosis according to DDG guidelines 2011, that is HbA1c of 6,5 percent or&#xD;
        higher after exclusion of false values, more than 200 mg per dl two hours after glucose in&#xD;
        the oGTT, fasting glucose more than 126 mg per dl, spontaneous glucose more than 200 mg per&#xD;
        dl at least twice Healthy persons without diabetes or impairment of glucose metabolism in&#xD;
        the oGTT according to DDG guidelines 2011 fasting plasma glucose less than 100 mg per dl&#xD;
        and 2 hour plasma glucose less than 140 mg per dl Pre diabetics with impaired fasting&#xD;
        glucose between 100 mg per dl and 125 mg per dl, or impaired glucose tolerance with 2 hour&#xD;
        glucose values between 140 and 199 mg per dl in the oGTT, all values from venous plasma&#xD;
&#xD;
        Exclusion Criteria General exclusion criteria Secondary types of Diabetes, ADA criteria&#xD;
        type 3 B H Current pregnancy Acute infections or fever Immune suppressant therapy Severe&#xD;
        psychiatric diseases requiring treatment, including personality disorders, schizophrenia,&#xD;
        depression Known alcohol or drug dependency Severe heart NYHA stadium IV, kidney, or liver&#xD;
        insufficiency Non diabetic liver disease, for example PBC, PSC, Wilsons disease,&#xD;
        hemochromatosis, autoimmune hepatitis severe peripheral artery disease stadium IV non&#xD;
        diabetic glomerulopathy Cancer or other malignant diseases within the last 5 years&#xD;
        Infectious diseases like hepatitis B, C, E, or HIV Other severe autoimmune diseases Current&#xD;
        participation in an interventional study Anemia or disorders of bone marrow Exclusion&#xD;
        criteria for MRI Pacemaker or ICD Metallic and magnetic implants, for example mechanic&#xD;
        cardiac valves replacements, joint prostheses, clips after vascular surgery, middle or&#xD;
        inner ear implants, recent tooth implants, penile implants Waist circumference more than&#xD;
        135 cm Claustrophobia Allergies against MRI contrast Impaired kidney function with a GFR&#xD;
        less than 65 ml per min&#xD;
&#xD;
        Exclusion criteria for clamp study Past history of deep vein thrombosis or pulmonary&#xD;
        embolism Routine laboratory test results less than 80 percent below lower reference value&#xD;
        of Ferritin, iron, leucocytes, hemoglobin, hematocrite, RBC, platelets, blood alcohol Level&#xD;
&#xD;
        Exclusion criteria for bioimpedance measurement Pacemaker or ICD&#xD;
&#xD;
        Exclusion criteria for lung function testing Ignoring or non understanding of the&#xD;
        instructions Body weight more than 160 kg&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stefan Kopf, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Head of the Clinical Study Center for Diabetes Research</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Stefan Kopf, MD</last_name>
    <phone>+49-6221-56</phone>
    <phone_ext>37790</phone_ext>
    <email>stefan.kopf@med.uni-heidelberg.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jan B Groener, MD</last_name>
    <phone>+49-6221-56</phone>
    <phone_ext>37639</phone_ext>
    <email>jan.groener@med.uni-heidelberg.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Medicine, University of Heidelberg</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stefan Kopf, MD</last_name>
      <phone>+49-6221-</phone>
      <phone_ext>37790</phone_ext>
      <email>stefan.kopf@med.uni-heidelberg.de</email>
    </contact>
    <contact_backup>
      <last_name>Jan B Groener, MD</last_name>
      <phone>+49-6221-</phone>
      <phone_ext>37639</phone_ext>
      <email>jan.groener@med.uni-heidelberg.de</email>
    </contact_backup>
    <investigator>
      <last_name>Stefan Kopf, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jan B Groener, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Peter P Nawroth, Prof.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 12, 2017</study_first_submitted>
  <study_first_submitted_qc>January 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>January 12, 2017</last_update_submitted>
  <last_update_submitted_qc>January 12, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 16, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Heidelberg University</investigator_affiliation>
    <investigator_full_name>Stefan Kopf MD</investigator_full_name>
    <investigator_title>Head of the Clinical Study Center for Diabetes Research</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 Complications</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No sharing of individual participant data is planned.</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/NCT03022721
org study id: S-383/2016
nct id: NCT03022721
lead sponsor: 
has dmc: No
The prospective observational study entitled "Heidelberg Study on Diabetes and Complications"
      is designed to Monitor the presence and development of diabetic complications in type 1 and
      type 2 diabetic patients, as well as pre-diabetics. Mail Goal is to detect new metabolic
      mechanisms or new risk factors for the development of diabetic complications in order to
      identify risk-subgroups. Non-diabetic controls will be enrolled for reference and comparison.
The prospective observational study entitled "Heidelberg Study on Diabetes and Complications"
      is designed to show that diabetes according to the current medical definition does not exist.
      Without question, there is an autoimmune disease that destroys beta cells in the pancreas,
      which leads to absolute insulin deficiency with consecutively elevated blood glucose levels.
      This disease is defined as diabetes mellitus type 1. Insulin treatment is absolutely
      necessary in this state, since absolute insulin deficiency leads to lipolysis with
      consecutive ketoacidosis and eventually death. On the other hand, type 2 diabetes is
      generally defined as relative insulin deficiency with consecutively elevated blood glucose
      levels. This disease is often mentioned in the context of the metabolic syndrome, which
      additionally comprises obesity, arterial hypertension, dyslipidemia, and cardiovascular
      diseases. Therefore, only the name "diabetes mellitus" is shared by these two diseases, which
      means "sweet flow", therefore only describing a symptom.

      Multiple interventional studies were aimed on avoiding or reducing the development of late
      diabetic complications (nephropathy, neuropathy, retinopathy, microangiopathy). This is true
      for both type 1 and type 2 diabetes. Up to this day, no study was able to demonstrate that
      treatment of normalization of blood glucose levels reduces or even reverses development of
      these complications. Moreover, several type 2 diabetic patients developed typical diabetic
      complications before definitive manifestation of the actual disease.

      Therefore, we hypothesize that late diabetic complications stand in no primary context with
      blood glucose control, but are associated with other metabolic disorders. One aspect are
      reactive metabolites (glyoxal, methylglyoxal, 3-DG), which are formed in glycolysis and
      lipolysis in the context of energy production of cells. These metabolites are detoxified to
      lactate by certain enzymes. In case this detoxification is compromised, or production of
      these metabolites elevated, so called advanced glycation endproducts (AGEs) can form.
      Moreover, within the process of energy production, reactive oxygen species (ROS) and
      oxydative stress are more pronounced, which can have direct influence on cellular metabolism.
      This interaction leads to inflammation and DNA damage. Survival of the cells is dependent on
      defense mechanisms, which seem to be genetically determined, with cellular ageing playing a
      role as well (cellular senescence). With advanced ageing, cells lose these defense mechanisms
      against these permanent metabolic attacks.

      Therefore, the following hypotheses arise:

        1. Diabetes mellitus type 2 is no independent disease, but a late complication of metabolic
           imbalance

        2. Typical "late diabetic complications" are not based on insufficient blood glucose
           lowering therapy, but on the basis of this metabolic imbalance, and can therefore affect
           every patient, even without manifested "diabetes mellitus type 2"

        3. Diabetes mellitus type 1 is an autoimmundisease with consecutive absolute insulin
           deficiency, however manifestation of late diabetic complications is based on the same
           metabolic dysbalance (overlap with type 2).

      In order to investigate these hypotheses, study participants will be profoundly examined once
      yearly concerning glycemic metabolic state and clinical findings related to micro- and
      macrovascular diabetic complications, Moreover, reactive metabolites like AGEs, ROS,
      methylglyoxal, and DNA damage as well as other parameters associated with cellular senescence
      will be examined. We will also collect information concerning quality of life, well-being,
      depression, and neuropathic pain.

      This is the first study of its kind to include non-diabetics, pre-diabetics, and diabetics
      with the possibility to study differences and common ground regarding cellular metabolism.
      Moreover, to the best of our knowledge, there is no precise clinical characterization of
      peripheral nerve function in pre-diabetics, although some of these patients already complain
      about neuropathic symptoms. In addition to that, the natural clinical course not only in
      diabetics, but also in pre-diabetics will be observed over a longer period of time. Finally,
      changes in surrogate markers over the natural course of pre-diabetes can be observed for the
      first time, onset of type 1 or type 2 diabetes can be registered immediately, and all
      patients can be directly compared to healthy controls.
observational model: Cohort
time perspective: Prospective
measure: Development of diabetic complications
time frame: 10 years
description: Diabetic complications include diabetic nephropathy, diabetic retinopathy, diabetic polyneuropathy, autonomous neuropathy, or macrovascular complications such as stroke, peripheral artery disease, or myocardial infarction.
arm group label: Patients with diabetes
description: Patients with both type 1 and type 2 Diabetes will be enrolled, Independent of Diabetes Duration, therapy etc.
No interventions are planned.
arm group label: Pre-Diabetics
description: Patients who have either imparied fasting Glucose or impaired Glucose tolerance in the oral Glucose tolerance test.
No interventions are planned.
arm group label: Healthy controls
description: Study participants without Diabetes or Pre-diabetes in the oral Glucose tolerance test.
no interventions are planned.
intervention type: Other
intervention name: No interventions are planned for this study.
description: No interventions are planned for this study, it is purely observational.
arm group label: Healthy controls
arm group label: Patients with diabetes
arm group label: Pre-Diabetics
Plasma, serum, PBMC, whole blood, urine. There is a possibility of DNA extraction from PBMC
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Stefan Kopf, MD
role: Principal Investigator
affiliation: Head of the Clinical Study Center for Diabetes Research
last name: Stefan Kopf, MD
phone: +49-6221-56
phone ext: 37790
email: stefan.kopf@med.uni-heidelberg.de
last name: Jan B Groener, MD
phone: +49-6221-56
phone ext: 37639
email: jan.groener@med.uni-heidelberg.de
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: Heidelberg University
investigator full name: Stefan Kopf MD
investigator title: Head of the Clinical Study Center for Diabetes Research
mesh term: Diabetes Mellitus
mesh term: Diabetes Complications
sharing ipd: No
ipd description: No sharing of individual participant data is planned.