<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/NCT02236754</url>
  </required_header>
  <id_info>
    <org_study_id>AAAJ5709</org_study_id>
    <secondary_id>R01DK077493-03</secondary_id>
    <nct_id>NCT02236754</nct_id>
  </id_info>
  <brief_title>Evaluation of 18F-FP-DTBZ Pancreatic PET Scanning as a Tool to Measure Beta Cell Mass</brief_title>
  <official_title>Scan Re-Scan Pancreatic Beta Cell Imaging Using PET Imaging and 18F-FP-DTBZ</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Columbia University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Type 1 diabetes mellitus (T1DM) develops when there is impaired insulin production due to&#xD;
      loss of insulin producing cells (beta cells). The amount of insulin that can be produced is&#xD;
      imperfectly correlated with beta cell mass (BCM). The development of a reliable method to&#xD;
      noninvasively quantify the total amount of insulin producing beta cells would be of great&#xD;
      benefit by providing an important endpoint for the development of new treatments of diabetes.&#xD;
      The investigators have previously identified a specific marker on islet cells called&#xD;
      vesicular monoamine transporter 2 (VMAT2) that the investigators now propose to use in&#xD;
      positron emission tomography (PET) scanning to determine islet beta cell mass. The PET&#xD;
      radiopharmaceutical 18F-fluoropropyl(FP)-dihydrotetrabenazine(DTBZ) has been used previously&#xD;
      in human subjects without adverse effects. It has shown promise in differentiating type 1&#xD;
      diabetes and non-diabetes. The investigators now hypothesize that repeat PET scans will be&#xD;
      reproducible in the same subject. Subjects with normal BCM will be recruited from among&#xD;
      normal weight non-diabetic people with plasma insulin levels within the normal range.&#xD;
      Subjects with predicted reduced BCM will be recruited from among patients with T1DM who have&#xD;
      low or non-measurable insulin levels. Two PET scan measurements will be taken in each subject&#xD;
      and the amount of VMAT2 in the pancreas will be and compared for reproducible findings.&#xD;
      Biochemical testing will also be performed and compared to PET scans as a potential indirect&#xD;
      marker of beta cell mass.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Diabetes results when the insulin secretory capacity of the beta cell population is lost or&#xD;
      severely compromised.Plasma insulin levels have been used as a surrogate marker of beta cell&#xD;
      mass (BCM) but insulin levels often do not correlate well. A &quot;gold standard of measurement&quot;&#xD;
      to obtain BCM would be of great value. The aim of the proposed study is to evaluate an islet&#xD;
      imaging technique using PET scanning to directly measure BCM and thus provide valuable&#xD;
      information for monitoring disease progress and response to therapy in people with diabetes&#xD;
      and in people at high risk for diabetes. Type 1 diabetes (T1DM) occurs when the beta cells&#xD;
      are selectively destroyed by a T cell mediated autoimmune process. People at high risk for&#xD;
      developing T1DM, such as first degree relatives of patients with T1DM, can sometimes be&#xD;
      identified before the disease develops by measuring autoantibodies to beta cells, however&#xD;
      this test is neither sensitive nor specific. Little is known about the natural history of&#xD;
      BCM, turnover and cell lifetime, or the course of inflammation in diabetes. This is&#xD;
      principally because the pancreas is a highly heterogeneous organ that is difficult to biopsy&#xD;
      without significant complications, and BCM only comprises 1 to 2% of the total volume.&#xD;
      Accurate assessment of BCM in human diabetes is limited to autopsy studies, which usually&#xD;
      suffer from inadequate clinical information; thus, the development of non-invasive means of&#xD;
      BCM measurement could be important for interventional therapies of T1DM, islet&#xD;
      regeneration/stem cell therapy and islet transplantation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Could not recruit participants&#xD;
  </why_stopped>
  <start_date type="Actual">July 2013</start_date>
  <completion_date type="Anticipated">March 1, 2017</completion_date>
  <primary_completion_date type="Actual">January 30, 2017</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean BPND (non-displaceable binding potential)</measure>
    <time_frame>Up to 2 months from enrollment</time_frame>
    <description>We will be evaluating pancreatic uptake of the radiotracer 18F-FP-DTBZ in subjects with and without long-standing type 1 diabetes mellitus.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Healthy Volunteers</condition>
  <condition>Diabetes Mellitus, Type 1</condition>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Pancreatic 18F-FP-DTBZ uptake will be measured with PET scanning in healthy controls: subjects with predicted normal BCM (healthy, normal weight, non-diabetic individuals who have stimulated insulin and c-peptide levels within the normal range).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients with T1D</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Pancreatic 18F-FP-DTBZ uptake will be measured with PET scanning in patients with longstanding T1D: subjects with predicted reduced beta cell mass (subjects with established T1DM who have low or no measurable stimulated insulin and c-peptide levels).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>18F-FP-DTBZ</intervention_name>
    <description>The drug, no carrier added [18F]-FP-DTBZ, is formulated in 5% (v/v) ethanol in 0.9% sterile saline solution to produce [18F]-FP-DTBZ for injection. Subjects will receive a single i.v. administration of no more than 7.6 mCi of [18F]-FP-DTBZ for injection immediately prior to imaging. The specific activity at time of injection will less than 1.0 mCi/microgram and thus for a 7.6 mCi dose the maximal mass dose will be less than 10 microgram.</description>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>Patients with T1D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>PET Scanning</intervention_name>
    <description>Individuals will be imaged continuously (i.e. dynamically) for 2 hours.</description>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>Patients with T1D</arm_group_label>
    <other_name>Positron Emission Tomography</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with type 1 diabetes may be enrolled if they meet all of the following&#xD;
             criteria:&#xD;
&#xD;
               1. Are males or females between 18 and 70 years of age, inclusive&#xD;
&#xD;
               2. Have a diagnosis of type 1 diabetes mellitus as defined by the American Diabetes&#xD;
                  Association (ADA) criteria or by diagnosed as per their endocrinologist; duration&#xD;
                  &gt;5 years; Insulin dose requirements &lt;0.8 units/kg/day&#xD;
&#xD;
               3. HbA1c level between 5% and 8.5%&#xD;
&#xD;
               4. Have fasting C-Peptide &lt; 0.1 ng/ml&#xD;
&#xD;
               5. Have a body mass index (BMI) between 18 and 32 kg/m2&#xD;
&#xD;
               6. Able to tolerate PET imaging&#xD;
&#xD;
               7. In the judgment of the physician, are capable of fasting 4 to 6 hours prior to&#xD;
                  screening and Day 1 imaging procedures&#xD;
&#xD;
               8. Give informed consent&#xD;
&#xD;
        Healthy volunteers may be enrolled if they meeting all of the following criteria:&#xD;
&#xD;
          1. Are males or females between 18 and 70 years of age, inclusive&#xD;
&#xD;
          2. Have no history of type 1 or type 2 diabetes in a first degree relative&#xD;
&#xD;
          3. Fasting blood glucose less than 100 mg/dL&#xD;
&#xD;
          4. HbA1c level less than 6%&#xD;
&#xD;
          5. Normal Mixed Meal Tolerance test at screening visit&#xD;
&#xD;
          6. BMI between 18 and 32 kg/m2&#xD;
&#xD;
          7. Able to tolerate PET imaging&#xD;
&#xD;
          8. In the judgment of the physician, are capable of fasting 4 to 6 hours prior to&#xD;
             screening and Day 1 imaging procedures, and&#xD;
&#xD;
          9. Give informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Potential participants must not have any of the following exclusion criteria:&#xD;
&#xD;
               1. Clinically significant renal dysfunction&#xD;
&#xD;
               2. Clinically significant liver dysfunction as determined by history, physical&#xD;
                  examination, and standard liver function testing at screening (aspartate&#xD;
                  aminotransferase (AST), alanine aminotransferase (ALT), Total/Direct Bilirubin,&#xD;
                  Alkaline Phosphatase)&#xD;
&#xD;
               3. Coagulopathy&#xD;
&#xD;
               4. Use medications known to affect dopaminergic function, including monoamine&#xD;
                  oxidase (MAO) inhibitors, tetrabenazine, or levodopa&#xD;
&#xD;
               5. Recent (within 3 months) or current treatment with drugs influencing beta cell&#xD;
                  function or insulin sensitivity (e.g. glucocorticoids, reserpine) medications&#xD;
                  known to affect dopaminergic function, including MAO inhibitors, tetrabenazine,&#xD;
                  or levodopa&#xD;
&#xD;
               6. Have polycystic ovarian syndrome&#xD;
&#xD;
               7. History of movement disorder such as Parkinson's Disease, Huntington's Disease&#xD;
&#xD;
               8. Clinically significant psychiatric disease or history of psychiatric illness such&#xD;
                  as depression, bipolar disease, anxiety or schizophrenia&#xD;
&#xD;
               9. Current use (within past year) of cocaine, methamphetamine, and/or ecstasy&#xD;
                  (3,4methylenedioxymethamphetamine (MDMA))&#xD;
&#xD;
              10. Have a recent history of alcohol or substance abuse or dependence&#xD;
&#xD;
              11. Clinically significant cardiovascular disease or clinically significant&#xD;
                  abnormalities on screening electrocardiogram (ECG) (including but not limited to&#xD;
                  QTc &gt; 450 msec)&#xD;
&#xD;
              12. Clinically significant pulmonary, renal or hepatic impairment, or cancer&#xD;
&#xD;
              13. Have clinically significant infectious disease, including acquired immune&#xD;
                  deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection or&#xD;
                  previous positive test for hepatitis B, hepatitis C, HIV1, or HIV2&#xD;
&#xD;
              14. Are women of childbearing potential not refraining from sexual activity or not&#xD;
                  using adequate contraception.&#xD;
&#xD;
                  Women must not be pregnant (negative serum human chorionic gonadotropin (hCG) at&#xD;
                  the time of screen) or breastfeeding at screening, and must agree to take&#xD;
                  appropriate steps not to become pregnant during for 30 days following the&#xD;
                  clinical trial&#xD;
&#xD;
              15. Require medications with a narrow therapeutic window (e.g., warfarin), are&#xD;
                  receiving any investigational medications, or have participated in a trial with&#xD;
                  investigational medications within the last 30 days&#xD;
&#xD;
              16. Weigh more than the manufacturer recommended limit for the PET/computed&#xD;
                  tomography (CT) camera being used&#xD;
&#xD;
              17. Any prior participation in other research protocols within the past month that&#xD;
                  involved radiation, with the exception of plain radiography studies (i.e., chest&#xD;
                  x-rays); And&#xD;
&#xD;
              18. Have received a diagnostic or therapeutic radiopharmaceutical within the past&#xD;
                  week&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chaitanya Divgi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Columbia University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Naomi Berrie Diabetes Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.nbdiabetes.org/news/using-nuclear-imaging-measure-beta-cell-mass-and-function</url>
    <description>Investigator web site</description>
  </link>
  <reference>
    <citation>Goland R, Freeby M, Parsey R, Saisho Y, Kumar D, Simpson N, Hirsch J, Prince M, Maffei A, Mann JJ, Butler PC, Van Heertum R, Leibel RL, Ichise M, Harris PE. 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls. J Nucl Med. 2009 Mar;50(3):382-9. doi: 10.2967/jnumed.108.054866. Epub 2009 Feb 17. Erratum In: J Nucl Med. 2009 Oct;50(10):1578.</citation>
    <PMID>19223416</PMID>
  </reference>
  <results_reference>
    <citation>Freeby MJ, Kringas P, Goland RS, Leibel RL, Maffei A, Divgi C, Ichise M, Harris PE. Cross-sectional and Test-Retest Characterization of PET with [(18)F]FP-(+)-DTBZ for beta Cell Mass Estimates in Diabetes. Mol Imaging Biol. 2016 Apr;18(2):292-301. doi: 10.1007/s11307-015-0888-7. Epub 2015 Sep 14.</citation>
    <PMID>26370678</PMID>
  </results_reference>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>January 28, 2014</study_first_submitted>
  <study_first_submitted_qc>September 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2014</study_first_posted>
  <last_update_submitted>January 30, 2017</last_update_submitted>
  <last_update_submitted_qc>January 30, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Columbia University</investigator_affiliation>
    <investigator_full_name>Paul E. Harris</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>dihydrotetrabenazine</keyword>
  <keyword>beta cell mass</keyword>
  <keyword>diabetes mellitus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <pending_results>
    <submitted>July 9, 2018</submitted>
    <returned>August 6, 2018</returned>
  </pending_results>
  <!-- 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/NCT02236754
org study id: AAAJ5709
secondary id: R01DK077493-03
nct id: NCT02236754
lead sponsor: 
collaborator: 
has dmc: Yes
Type 1 diabetes mellitus (T1DM) develops when there is impaired insulin production due to
      loss of insulin producing cells (beta cells). The amount of insulin that can be produced is
      imperfectly correlated with beta cell mass (BCM). The development of a reliable method to
      noninvasively quantify the total amount of insulin producing beta cells would be of great
      benefit by providing an important endpoint for the development of new treatments of diabetes.
      The investigators have previously identified a specific marker on islet cells called
      vesicular monoamine transporter 2 (VMAT2) that the investigators now propose to use in
      positron emission tomography (PET) scanning to determine islet beta cell mass. The PET
      radiopharmaceutical 18F-fluoropropyl(FP)-dihydrotetrabenazine(DTBZ) has been used previously
      in human subjects without adverse effects. It has shown promise in differentiating type 1
      diabetes and non-diabetes. The investigators now hypothesize that repeat PET scans will be
      reproducible in the same subject. Subjects with normal BCM will be recruited from among
      normal weight non-diabetic people with plasma insulin levels within the normal range.
      Subjects with predicted reduced BCM will be recruited from among patients with T1DM who have
      low or non-measurable insulin levels. Two PET scan measurements will be taken in each subject
      and the amount of VMAT2 in the pancreas will be and compared for reproducible findings.
      Biochemical testing will also be performed and compared to PET scans as a potential indirect
      marker of beta cell mass.
Diabetes results when the insulin secretory capacity of the beta cell population is lost or
      severely compromised.Plasma insulin levels have been used as a surrogate marker of beta cell
      mass (BCM) but insulin levels often do not correlate well. A "gold standard of measurement"
      to obtain BCM would be of great value. The aim of the proposed study is to evaluate an islet
      imaging technique using PET scanning to directly measure BCM and thus provide valuable
      information for monitoring disease progress and response to therapy in people with diabetes
      and in people at high risk for diabetes. Type 1 diabetes (T1DM) occurs when the beta cells
      are selectively destroyed by a T cell mediated autoimmune process. People at high risk for
      developing T1DM, such as first degree relatives of patients with T1DM, can sometimes be
      identified before the disease develops by measuring autoantibodies to beta cells, however
      this test is neither sensitive nor specific. Little is known about the natural history of
      BCM, turnover and cell lifetime, or the course of inflammation in diabetes. This is
      principally because the pancreas is a highly heterogeneous organ that is difficult to biopsy
      without significant complications, and BCM only comprises 1 to 2% of the total volume.
      Accurate assessment of BCM in human diabetes is limited to autopsy studies, which usually
      suffer from inadequate clinical information; thus, the development of non-invasive means of
      BCM measurement could be important for interventional therapies of T1DM, islet
      regeneration/stem cell therapy and islet transplantation.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Mean BPND (non-displaceable binding potential)
time frame: Up to 2 months from enrollment
description: We will be evaluating pancreatic uptake of the radiotracer 18F-FP-DTBZ in subjects with and without long-standing type 1 diabetes mellitus.
arm group label: Healthy Controls
arm group type: Other
description: Pancreatic 18F-FP-DTBZ uptake will be measured with PET scanning in healthy controls: subjects with predicted normal BCM (healthy, normal weight, non-diabetic individuals who have stimulated insulin and c-peptide levels within the normal range).
arm group label: Patients with T1D
arm group type: Other
description: Pancreatic 18F-FP-DTBZ uptake will be measured with PET scanning in patients with longstanding T1D: subjects with predicted reduced beta cell mass (subjects with established T1DM who have low or no measurable stimulated insulin and c-peptide levels).
intervention type: Drug
intervention name: 18F-FP-DTBZ
description: The drug, no carrier added [18F]-FP-DTBZ, is formulated in 5% (v/v) ethanol in 0.9% sterile saline solution to produce [18F]-FP-DTBZ for injection. Subjects will receive a single i.v. administration of no more than 7.6 mCi of [18F]-FP-DTBZ for injection immediately prior to imaging. The specific activity at time of injection will less than 1.0 mCi/microgram and thus for a 7.6 mCi dose the maximal mass dose will be less than 10 microgram.
arm group label: Healthy Controls
arm group label: Patients with T1D
intervention type: Radiation
intervention name: PET Scanning
description: Individuals will be imaged continuously (i.e. dynamically) for 2 hours.
arm group label: Healthy Controls
arm group label: Patients with T1D
other name: Positron Emission Tomography
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Chaitanya Divgi, MD
role: Principal Investigator
affiliation: Columbia University
facility: 
country: United States
url: http://www.nbdiabetes.org/news/using-nuclear-imaging-measure-beta-cell-mass-and-function
description: Investigator web site
citation: Goland R, Freeby M, Parsey R, Saisho Y, Kumar D, Simpson N, Hirsch J, Prince M, Maffei A, Mann JJ, Butler PC, Van Heertum R, Leibel RL, Ichise M, Harris PE. 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls. J Nucl Med. 2009 Mar;50(3):382-9. doi: 10.2967/jnumed.108.054866. Epub 2009 Feb 17. Erratum In: J Nucl Med. 2009 Oct;50(10):1578.
PMID: 19223416
citation: Freeby MJ, Kringas P, Goland RS, Leibel RL, Maffei A, Divgi C, Ichise M, Harris PE. Cross-sectional and Test-Retest Characterization of PET with [(18)F]FP-(+)-DTBZ for beta Cell Mass Estimates in Diabetes. Mol Imaging Biol. 2016 Apr;18(2):292-301. doi: 10.1007/s11307-015-0888-7. Epub 2015 Sep 14.
PMID: 26370678
responsible party type: Principal Investigator
investigator affiliation: Columbia University
investigator full name: Paul E. Harris
investigator title: Associate Professor of Medicine
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
submitted: July 9, 2018
returned: August 6, 2018