<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/NCT03243058</url>
  </required_header>
  <id_info>
    <org_study_id>20170301</org_study_id>
    <secondary_id>20170301</secondary_id>
    <nct_id>NCT03243058</nct_id>
  </id_info>
  <brief_title>Low-dose IL-2 in Established T1D - The &quot;PROREG&quot; Study</brief_title>
  <official_title>A Randomized, Double Blind, Phase I/II Trial of Low-Dose Interlekin-2 Immunotherapy in Established Type 1 Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jay S. Skyler</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Diabetes Research Institute Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Miami</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Randomized, controlled, double-blinded, multicenter, phase I/II clinical trial to evaluate&#xD;
      the safety of low-dose IL-2 and determine whether low-dose IL-2 therapy for one year, can&#xD;
      prevent further loss of beta-cell function in patients with established T1D, (primary&#xD;
      outcome). The study will carefully examine various effects of low-dose IL-2 on the immune&#xD;
      system in patients with T1D, including effects on Treg and other cell subsets, and&#xD;
      disease-specific autoimmune responses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Randomized, controlled, double-blinded, multicenter, phase I/II clinical trial to evaluate&#xD;
      the safety of low-dose IL-2 and determine whether low-dose IL-2 therapy for one year, can&#xD;
      prevent further loss of beta-cell function in patients with established T1D, (primary&#xD;
      outcome). The study will carefully examine various effects of low-dose IL-2 on the immune&#xD;
      system in patients with T1D, including effects on Treg and other cell subsets, and&#xD;
      disease-specific autoimmune responses.&#xD;
&#xD;
      Patients will be treated with ILT-101 or placebo. ILT-101 will be given at doses of 0.5&#xD;
      million IU (body surface area &lt;2 m2) or 1 million IU (body surface area &gt;2 m2), via&#xD;
      subcutaneous (s.c.) injections. Patients will receive a course of 5 daily injections (days&#xD;
      1-5. Starting on day 15, patients will receive an s.c. injection (same dose) every 15 days&#xD;
      for 1 year. Thus, patients will receive 29 injections during the first year of treatment. At&#xD;
      the end of the first year, approximately half of those randomized to ILT-101 will continue&#xD;
      receiving treatment every 15 days, until the end of the second year (23 doses). The other&#xD;
      half will stop therapy and will be switched to a placebo.&#xD;
&#xD;
      A group of patients will be randomly assigned to a placebo for the duration of the study.&#xD;
      Patients to be included in this study are those diagnosed with T1D who would have had T1D&#xD;
      from 4 months to 1 year at the time of randomization, who have a current or past&#xD;
      demonstration of autoimmunity (using autoantibodies), and maintain preserved β-cell function,&#xD;
      defined as an MMTT stimulated C-peptide &gt;0.2 nmol/L. This population is chosen because it&#xD;
      will extend the scope of therapy beyond the immediate time following diagnosis when most&#xD;
      previous studies of immunotherapy in T1D have been conducted. This trial can further impact&#xD;
      the field if a therapeutic benefit is shown when the disease is more established.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Funding withdrawal and COVID-19 environment.&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 2021</start_date>
  <completion_date type="Anticipated">October 2025</completion_date>
  <primary_completion_date type="Anticipated">August 2025</primary_completion_date>
  <phase>Phase 1/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>
    <intervention_model_description>ILT-101 (aldesleukin; Interleukin-2, IL-2), 0.5 million IU (body surface area &lt;2 m2) or 1 million IU (body surface area &gt;2 m2), or placebo, will be given for 5 consecutive days (days 1-5), and then on day 15 and every 15 days thereafter, for one year; at the one-year endpoint, approximately half the subjects on ILT-101 will continue therapy and the other half will switch to placebo for 1 more year.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>The randomization will be performed by the Coordinating Center at the University of Miami. The participants will not be informed regarding the intervention assignment until the end of the study. The investigators and clinic personnel will also be masked as to study assignment. Laboratories performing assays for this protocol will be masked as to the identity and group assignment of biological materials to be studied.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>C-peptide response</measure>
    <time_frame>1 year primary outcome</time_frame>
    <description>Preservation of insulin secretion (measured as c-peptide nmol/L) based on stimulated area under the curve (AUC) during a 4-hour MMTT at 1 year</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>C-peptide response</measure>
    <time_frame>2 year secondary outcome</time_frame>
    <description>Preservation of insulin secretion (measured as c-peptide nmol/L) based on stimulated area under the curve (AUC) during a 4-hour MMTT at 2 years</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Proportions of regulatory T cells at (a) 1 year, (b) 2 years</measure>
    <time_frame>1 Year and 2 Years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Changes in insulin requirements</measure>
    <time_frame>1 Year and 2 Years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>HbA1c level</measure>
    <time_frame>1 Year and 2 Years</time_frame>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Diabetes Mellitus, Type 1</condition>
  <condition>Diabetes</condition>
  <condition>Diabetes, Autoimmune</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ILT-101 (Aldesleukin; IL-2), 0.5 million IU/m2 (up to a maximum of 1 million IU), or placebo, will be given for 5 consecutive days (days 1-5), and then on day 15 and every 15 days thereafter, for two years.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment-Placebo Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this group will receive study drug ILT-101 for one year, and then placebo for the second year.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants in this group will receive a placebo injection for two years.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ILT-101 (Aldesleukin; IL-2)</intervention_name>
    <description>Administration of Low-Dose Interleukin-2 (ILT-101) for two years</description>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_label>Treatment-Placebo Arm</arm_group_label>
    <other_name>IL-2</other_name>
    <other_name>Interleukin-2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Treatment-Placebo Arm</intervention_name>
    <description>Administration of Low-Dose Interleukin-2 (ILT-101) for one year, and then placebo for the second year.</description>
    <arm_group_label>Treatment-Placebo Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo Arm</intervention_name>
    <description>Participants in this group will receive a placebo injection for two years.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  8-21 years of age&#xD;
&#xD;
          -  T1D, demonstrated by at least one islet autoantibody&#xD;
&#xD;
          -  T1D duration 4-12 months at the time of the first dose&#xD;
&#xD;
          -  Peak stimulated C-peptide &gt;0.2 nmol/L during a 4-hour MMTT&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment with oral anti-diabetic agents&#xD;
&#xD;
          -  Illnesses that would preclude use of low-dose IL-2&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jay S Skyler, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Professor of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alberto Pugliese, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Professor of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David A Baidal, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistant Professor of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Diabetes Research Institute, University of Miami Miller School of Medicine</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 20, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 8, 2017</study_first_posted>
  <last_update_submitted>September 8, 2023</last_update_submitted>
  <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Miami</investigator_affiliation>
    <investigator_full_name>Jay S. Skyler</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Type 1 Diabetes</keyword>
  <keyword>Autoimmune</keyword>
  <keyword>Diabetes, Autoimmune</keyword>
  <keyword>Interleukin-2</keyword>
  <keyword>Interleukin</keyword>
  <keyword>IL-2</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aldesleukin</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>A participant's privacy and confidentiality will be respected throughout the study. Each participant will be assigned a unique identification number and these numbers rather than names will be used to collect, store, and report participant information. Site personnel will not transmit documents containing personal health identifiers (PHI) to the study sponsor or their representatives.</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/NCT03243058
org study id: 20170301
secondary id: 20170301
nct id: NCT03243058
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Randomized, controlled, double-blinded, multicenter, phase I/II clinical trial to evaluate
      the safety of low-dose IL-2 and determine whether low-dose IL-2 therapy for one year, can
      prevent further loss of beta-cell function in patients with established T1D, (primary
      outcome). The study will carefully examine various effects of low-dose IL-2 on the immune
      system in patients with T1D, including effects on Treg and other cell subsets, and
      disease-specific autoimmune responses.
Randomized, controlled, double-blinded, multicenter, phase I/II clinical trial to evaluate
      the safety of low-dose IL-2 and determine whether low-dose IL-2 therapy for one year, can
      prevent further loss of beta-cell function in patients with established T1D, (primary
      outcome). The study will carefully examine various effects of low-dose IL-2 on the immune
      system in patients with T1D, including effects on Treg and other cell subsets, and
      disease-specific autoimmune responses.

      Patients will be treated with ILT-101 or placebo. ILT-101 will be given at doses of 0.5
      million IU (body surface area <2 m2) or 1 million IU (body surface area >2 m2), via
      subcutaneous (s.c.) injections. Patients will receive a course of 5 daily injections (days
      1-5. Starting on day 15, patients will receive an s.c. injection (same dose) every 15 days
      for 1 year. Thus, patients will receive 29 injections during the first year of treatment. At
      the end of the first year, approximately half of those randomized to ILT-101 will continue
      receiving treatment every 15 days, until the end of the second year (23 doses). The other
      half will stop therapy and will be switched to a placebo.

      A group of patients will be randomly assigned to a placebo for the duration of the study.
      Patients to be included in this study are those diagnosed with T1D who would have had T1D
      from 4 months to 1 year at the time of randomization, who have a current or past
      demonstration of autoimmunity (using autoantibodies), and maintain preserved β-cell function,
      defined as an MMTT stimulated C-peptide >0.2 nmol/L. This population is chosen because it
      will extend the scope of therapy beyond the immediate time following diagnosis when most
      previous studies of immunotherapy in T1D have been conducted. This trial can further impact
      the field if a therapeutic benefit is shown when the disease is more established.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: ILT-101 (aldesleukin; Interleukin-2, IL-2), 0.5 million IU (body surface area <2 m2) or 1 million IU (body surface area >2 m2), or placebo, will be given for 5 consecutive days (days 1-5), and then on day 15 and every 15 days thereafter, for one year; at the one-year endpoint, approximately half the subjects on ILT-101 will continue therapy and the other half will switch to placebo for 1 more year.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: The randomization will be performed by the Coordinating Center at the University of Miami. The participants will not be informed regarding the intervention assignment until the end of the study. The investigators and clinic personnel will also be masked as to study assignment. Laboratories performing assays for this protocol will be masked as to the identity and group assignment of biological materials to be studied.
measure: C-peptide response
time frame: 1 year primary outcome
description: Preservation of insulin secretion (measured as c-peptide nmol/L) based on stimulated area under the curve (AUC) during a 4-hour MMTT at 1 year
measure: C-peptide response
time frame: 2 year secondary outcome
description: Preservation of insulin secretion (measured as c-peptide nmol/L) based on stimulated area under the curve (AUC) during a 4-hour MMTT at 2 years
measure: Proportions of regulatory T cells at (a) 1 year, (b) 2 years
time frame: 1 Year and 2 Years
measure: Changes in insulin requirements
time frame: 1 Year and 2 Years
measure: HbA1c level
time frame: 1 Year and 2 Years
arm group label: Treatment Arm
arm group type: Active Comparator
description: ILT-101 (Aldesleukin; IL-2), 0.5 million IU/m2 (up to a maximum of 1 million IU), or placebo, will be given for 5 consecutive days (days 1-5), and then on day 15 and every 15 days thereafter, for two years.
arm group label: Treatment-Placebo Arm
arm group type: Experimental
description: Participants in this group will receive study drug ILT-101 for one year, and then placebo for the second year.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants in this group will receive a placebo injection for two years.
intervention type: Biological
intervention name: ILT-101 (Aldesleukin; IL-2)
description: Administration of Low-Dose Interleukin-2 (ILT-101) for two years
arm group label: Treatment Arm
arm group label: Treatment-Placebo Arm
other name: IL-2
other name: Interleukin-2
intervention type: Other
intervention name: Treatment-Placebo Arm
description: Administration of Low-Dose Interleukin-2 (ILT-101) for one year, and then placebo for the second year.
arm group label: Treatment-Placebo Arm
intervention type: Other
intervention name: Placebo Arm
description: Participants in this group will receive a placebo injection for two years.
arm group label: Placebo
criteria: 
gender: All
minimum age: 8 Years
maximum age: 21 Years
healthy volunteers: No
last name: Jay S Skyler, M.D.
role: Principal Investigator
affiliation: Professor of Medicine
last name: Alberto Pugliese, M.D.
role: Principal Investigator
affiliation: Professor of Medicine
last name: David A Baidal, M.D.
role: Principal Investigator
affiliation: Assistant Professor of Medicine
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Miami
investigator full name: Jay S. Skyler
investigator title: Professor of Medicine
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Aldesleukin
mesh term: Interleukin-2
sharing ipd: No
ipd description: A participant's privacy and confidentiality will be respected throughout the study. Each participant will be assigned a unique identification number and these numbers rather than names will be used to collect, store, and report participant information. Site personnel will not transmit documents containing personal health identifiers (PHI) to the study sponsor or their representatives.