<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/NCT03794960</url>
  </required_header>
  <id_info>
    <org_study_id>TOL-3021-230</org_study_id>
    <nct_id>NCT03794960</nct_id>
  </id_info>
  <brief_title>Diabetes AutoimmunitY Withdrawn in Established Patients (DAY)</brief_title>
  <acronym>DAY</acronym>
  <official_title>A Phase 2b Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of TOL-3021 in Patients With Established Type 1 Diabetes Mellitus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tolerion, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tolerion, Inc.</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>
      The study is a prospective, randomized, double-blind, placebo-controlled, multicenter trial&#xD;
      in subjects with established T1D.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will include 216 male or female subjects aged 12 to 35 years diagnosed with T1D, as&#xD;
      defined by the American Diabetes Association (ADA) criteria and meeting enrollment criteria&#xD;
      as follows. Initial enrollment will be restricted to subjects aged 18-35 until an analysis of&#xD;
      data from subjects with 3 months' exposure to drug confirms safety. Upon completion of this&#xD;
      assessment, enrollment will be open without further restrictions for subjects aged 12-35.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Modification to Clinical Development Plan&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 14, 2019</start_date>
  <completion_date type="Anticipated">December 14, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 14, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Treatment Effect</measure>
    <time_frame>at Week 52</time_frame>
    <description>The primary outcome is the treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) after 52 weeks of TOL-3021 treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of Clinically important hypoglycemia as defined by measured glucose value of &lt;54 mg/dL (3.0 mM/L)</measure>
    <time_frame>at Week 52</time_frame>
    <description>By glucometer, a single blood glucose level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Clinically important hypoglycemia as defined by measured glucose value of &lt;54 mg/dL (3.0 mM/L)</measure>
    <time_frame>at Week 52</time_frame>
    <description>By CGM, ≥15 consecutive minutes with glucose &lt;54 mg/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Clinically important hypoglycemia as defined by measured glucose value of &lt;54 mg/dL (3.0 mM/L)</measure>
    <time_frame>at Week 52</time_frame>
    <description>Total daily insulin requirements in units per kilogram (kg) body weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Clinically important hypoglycemia as defined by measured glucose value of &lt;54 mg/dL (3.0 mM/L)</measure>
    <time_frame>at Week 52</time_frame>
    <description>HbA1c</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Proportion of subjects in each treatment arm with HbA1c levels less than 6.5% at Week 52</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Measure by GMS - Time in range 70 - 80 mg/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Measure by GMS - Time &gt;180 mg/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Measure by GMS - Time &gt;250 mg/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Measure by GMS - Mean Glucose Coefficient of Variation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Measure by GMS - Low Blood Glucose Index (LBGI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical responder analysis</measure>
    <time_frame>at Week 52</time_frame>
    <description>Measure by GMS - Glucose below 70 mg/dL Area Over the Curve (AOC70)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other measures of hypoglycemia</measure>
    <time_frame>at Week 52</time_frame>
    <description>Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other measures of hypoglycemia</measure>
    <time_frame>at Week 52</time_frame>
    <description>Documented symptomatic hypoglycemia (an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration &lt;70 mg/dl (3.9 mmol/L))</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other measures of hypoglycemia</measure>
    <time_frame>at Week 52</time_frame>
    <description>Total time &lt;70 mg/dL by CGM</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other measures of hypoglycemia</measure>
    <time_frame>at Week 52</time_frame>
    <description>Nocturnal hypoglycemia, severe or documented symptomatic episodes (as defined above) occurring after the subject has retired for the primary sleeping period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Quantum dot (Q-dot) responses within the qualifying subpopulation to confirm induction of specific autoantigen tolerance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Determine effect of treatment on and predictive value of regulatory/protective humoral immune response to proinsulin/insulin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Determine effect of treatment on and predictive value of serum insulin autoantibody affinity for subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Determine effect of treatment on and predictive value of Insulin autoantibody isotypes (IgA and IgM) and IgG subclasses</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Determine effect of treatment on and predictive value of serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by highly sensitive ECL assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunologic</measure>
    <time_frame>at Week 52</time_frame>
    <description>Determine effect of treatment on and predictive value of competition assays of serum insulin and proinsulin IgM and IgG antibodies</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Diabetes Mellitus, Type 1</condition>
  <arm_group>
    <arm_group_label>TOL-3021</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>TOL-3021 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TOL-3021</intervention_name>
    <description>A plasmid expression vector containing the coding sequences for full-length human proinsulin.</description>
    <arm_group_label>TOL-3021</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>TOL-3021 Placebo</intervention_name>
    <description>TOL-3021 Placebo</description>
    <arm_group_label>TOL-3021 Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of Type 1 Diabetes Mellitus based on American Diabetes Association (ADA)&#xD;
             criteria and within 1.0 to 5.0 years from diagnosis, defined as the first day of&#xD;
             insulin administration.&#xD;
&#xD;
          2. Adequate glycemic control for &gt;14 days, defined as 3 consecutive fasting glucose&#xD;
             levels by self-administered blood glucose (SMBG) or lab testing &lt;130 mg/dL.&#xD;
&#xD;
          3. Age at randomization of 12.0 - &lt;18.0 years (adolescent), 18.0 - &lt;36.0 years of age&#xD;
             (adult) .&#xD;
&#xD;
          4. HbA1c &lt;8.5% based on point-of-care or local lab measurement.&#xD;
&#xD;
             • Measurement can be repeated every 5-7 days if &gt;8.5%.&#xD;
&#xD;
          5. Presence of antibodies to at least one of the following antigens: GAD-65, IA-2, ZnT8;&#xD;
             or insulin.&#xD;
&#xD;
          6. Peak C-peptide during screening 4-hour mixed meal tolerance test (MMTT) ≥ 0.2pmol/mL.&#xD;
&#xD;
          7. Willingness to wear a continuous glucose monitoring (CGM) device for specified periods&#xD;
             of time.&#xD;
&#xD;
          8. Written informed consent, including authorization to release health information and&#xD;
             assent for adolescent subjects.&#xD;
&#xD;
          9. Willingness and ability of subject or adult guardian to comply with all study&#xD;
             procedures of the study protocol, including attending all clinic visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Body Mass Index (BMI) &gt;30 kg/m2 for adults; &gt;95 percentile BMI-for-age for subjects&#xD;
             under 18 years of age.&#xD;
&#xD;
          2. Previous immunotherapy for T1D.&#xD;
&#xD;
          3. Diagnosis of liver disease or hepatic enzymes, as defined by ALT and/or AST ≥ 2.5&#xD;
             times the upper limit of normal (ULN).&#xD;
&#xD;
          4. Hematology: white blood cells (WBC) &lt;3 x 109/L; platelets &lt;100 x 109/L; hemoglobin&#xD;
             &lt;10.0 g/dL. (Low WBC values may be repeated every 3-7 days, and results to be&#xD;
             discussed with the Medical Monitor.)&#xD;
&#xD;
          5. Serum creatinine &gt;1.5 times ULN.&#xD;
&#xD;
          6. History of malignancy, except for cancers in remission &gt;5 years, or basal cell or in&#xD;
             situ squamous cell carcinoma of the skin.&#xD;
&#xD;
          7. Significant cardiovascular disease (including inadequately controlled hypertension),&#xD;
             history of myocardial infarction, angina, use of anti-anginal medicines (e.g.,&#xD;
             nitroglycerin), or abnormal stress test, which, in the opinion of the Principal&#xD;
             Investigator (PI), would interfere with participation in the trial.&#xD;
&#xD;
          8. Immunosuppressive therapy (systemic corticosteroids, cyclosporine, azathioprine, or&#xD;
             biologics) within 30 days of screening.&#xD;
&#xD;
          9. Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides,&#xD;
             thiazolidinediones, GLP1-RAs, DPP-IV inhibitors, pramlintide, or SGLT-2 inhibitors.&#xD;
&#xD;
         10. Current use of verapamil or α-methyldopa.&#xD;
&#xD;
         11. History of any organ transplant, including islet cell transplant.&#xD;
&#xD;
         12. Active autoimmune or immune deficiency disorder other than T1D or well-controlled&#xD;
             autoimmune thyroid disease (e.g., sarcoidosis, rheumatoid arthritis,&#xD;
             moderate-to-severe psoriasis, inflammatory bowel disease, and other autoimmune&#xD;
             conditions that may require treatment with TNF or other biologics), unless approved by&#xD;
             the Medical Monitor.&#xD;
&#xD;
         13. Thyroid-stimulating hormone (TSH) at screening &gt;2.5 mIU/L.&#xD;
&#xD;
         14. History of adrenal insufficiency.&#xD;
&#xD;
         15. Evidence of infection with HBV (as defined by hepatitis B surface antigen, HBsAg), HCV&#xD;
             (anti-HCV antibodies), or HIV.&#xD;
&#xD;
         16. Positive urine pregnancy test: Females of childbearing potential must be excluded if&#xD;
             they have a positive urine pregnancy test at screening or randomization or if they are&#xD;
             not using medically acceptable methods of birth control. Acceptable methods of birth&#xD;
             control include oral or transdermal contraceptives, condom, spermicidal foam, IUD,&#xD;
             progestin implant or injection, abstinence, vaginal ring, or sterilization of partner.&#xD;
             The reason for non-childbearing potential, such as bilateral tubal ligation, bilateral&#xD;
             oophorectomy, hysterectomy, or 1 year or more postmenopausal must be specified in the&#xD;
             subject's Case Report Form (CRF).&#xD;
&#xD;
         17. Males of reproductive potential who are unwilling to use medically acceptable birth&#xD;
             control, unless the female partner is postmenopausal or surgically sterile.&#xD;
&#xD;
         18. Any social condition or medical condition that would, in the opinion of the PI,&#xD;
             prevent complete participation in the study or would pose a significant hazard to the&#xD;
             subject's participation.&#xD;
&#xD;
         19. Anticipated major surgery during the duration of the trial, which could interfere with&#xD;
             participation in the trial.&#xD;
&#xD;
         20. History of drug or alcohol dependence within 12 months of screening.&#xD;
&#xD;
         21. Psychiatric disorder that would prevent subjects from giving informed consent.&#xD;
&#xD;
         22. Participation in other studies involving the administration of an investigational drug&#xD;
             or device, including the administration of an experimental agent for T1D, at any time,&#xD;
             or use of an experimental device for T1D within 30 days prior to screening, unless&#xD;
             approved by the Medical Monitor.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>36 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>January 3, 2019</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 7, 2019</study_first_posted>
  <last_update_submitted>December 4, 2020</last_update_submitted>
  <last_update_submitted_qc>December 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Type 1 Diabetes</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>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03794960
org study id: TOL-3021-230
nct id: NCT03794960
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The study is a prospective, randomized, double-blind, placebo-controlled, multicenter trial
      in subjects with established T1D.
The study will include 216 male or female subjects aged 12 to 35 years diagnosed with T1D, as
      defined by the American Diabetes Association (ADA) criteria and meeting enrollment criteria
      as follows. Initial enrollment will be restricted to subjects aged 18-35 until an analysis of
      data from subjects with 3 months' exposure to drug confirms safety. Upon completion of this
      assessment, enrollment will be open without further restrictions for subjects aged 12-35.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Treatment Effect
time frame: at Week 52
description: The primary outcome is the treatment effect on log-transformed MMTT C-peptide area under the curve (AUC) after 52 weeks of TOL-3021 treatment
measure: Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
time frame: at Week 52
description: By glucometer, a single blood glucose level
measure: Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
time frame: at Week 52
description: By CGM, ≥15 consecutive minutes with glucose <54 mg/dL
measure: Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
time frame: at Week 52
description: Total daily insulin requirements in units per kilogram (kg) body weight
measure: Rate of Clinically important hypoglycemia as defined by measured glucose value of <54 mg/dL (3.0 mM/L)
time frame: at Week 52
description: HbA1c
measure: Clinical responder analysis
time frame: at Week 52
description: Proportion of subjects in each treatment arm with HbA1c levels less than 6.5% at Week 52
measure: Clinical responder analysis
time frame: at Week 52
description: Measure by GMS - Time in range 70 - 80 mg/dL
measure: Clinical responder analysis
time frame: at Week 52
description: Measure by GMS - Time >180 mg/dL
measure: Clinical responder analysis
time frame: at Week 52
description: Measure by GMS - Time >250 mg/dL
measure: Clinical responder analysis
time frame: at Week 52
description: Measure by GMS - Mean Glucose Coefficient of Variation
measure: Clinical responder analysis
time frame: at Week 52
description: Measure by GMS - Low Blood Glucose Index (LBGI)
measure: Clinical responder analysis
time frame: at Week 52
description: Measure by GMS - Glucose below 70 mg/dL Area Over the Curve (AOC70)
measure: Other measures of hypoglycemia
time frame: at Week 52
description: Severe hypoglycemia (SH) events (impaired or loss of consciousness requiring assistance of another)
measure: Other measures of hypoglycemia
time frame: at Week 52
description: Documented symptomatic hypoglycemia (an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <70 mg/dl (3.9 mmol/L))
measure: Other measures of hypoglycemia
time frame: at Week 52
description: Total time <70 mg/dL by CGM
measure: Other measures of hypoglycemia
time frame: at Week 52
description: Nocturnal hypoglycemia, severe or documented symptomatic episodes (as defined above) occurring after the subject has retired for the primary sleeping period
measure: Immunologic
time frame: at Week 52
description: Quantum dot (Q-dot) responses within the qualifying subpopulation to confirm induction of specific autoantigen tolerance
measure: Immunologic
time frame: at Week 52
description: Comparison of quantum dot responses within the qualifying subpopulation to clinical outcomes to confirm correlation with specific autoantigen tolerance.
measure: Immunologic
time frame: at Week 52
description: Determine effect of treatment on and predictive value of regulatory/protective humoral immune response to proinsulin/insulin
measure: Immunologic
time frame: at Week 52
description: Determine effect of treatment on and predictive value of serum insulin autoantibody affinity for subjects
measure: Immunologic
time frame: at Week 52
description: Determine effect of treatment on and predictive value of Insulin autoantibody isotypes (IgA and IgM) and IgG subclasses
measure: Immunologic
time frame: at Week 52
description: Determine effect of treatment on and predictive value of serum insulin, glutamic acid decarboxylase, IA-2, and ZnT8 antibodies by highly sensitive ECL assay
measure: Immunologic
time frame: at Week 52
description: Determine effect of treatment on and predictive value of competition assays of serum insulin and proinsulin IgM and IgG antibodies
arm group label: TOL-3021
arm group type: Experimental
arm group label: TOL-3021 Placebo
arm group type: Placebo Comparator
intervention type: Biological
intervention name: TOL-3021
description: A plasmid expression vector containing the coding sequences for full-length human proinsulin.
arm group label: TOL-3021
intervention type: Other
intervention name: TOL-3021 Placebo
description: TOL-3021 Placebo
arm group label: TOL-3021 Placebo
other name: Placebo
criteria: 
gender: All
minimum age: 12 Years
maximum age: 36 Years
healthy volunteers: No
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
sharing ipd: Undecided