<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/NCT03234491</url>
  </required_header>
  <id_info>
    <org_study_id>2000020715</org_study_id>
    <nct_id>NCT03234491</nct_id>
  </id_info>
  <brief_title>Improving Post-Prandial Blood Glucose Control With Afrezza During Closed-Loop Therapy</brief_title>
  <official_title>Improving Post-Prandial Blood Glucose Control With Afrezza During Closed-Loop Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Yale University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study will be conducted in two phases; an in-patient meal study phase (Phase I) and an&#xD;
      outpatient home study (Phase II). The two phase study design is chosen to enhance safety by&#xD;
      testing the Afrezza Closed-Loop (CL) system in controlled in-clinic setting under study staff&#xD;
      supervision before it could be investigated at the outpatient home setting. Phase II will not&#xD;
      begin without the establishment of safety in Phase I.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There are 2 primary study aims that this research will address. The first study aim will be&#xD;
      to determine whether use of Afrezza inhaled insulin with ultra-fast kinetics will improve the&#xD;
      performance of a closed-loop (CL) system, both with respect to immediate post-prandial&#xD;
      hyperglycemia and the subsequent late post-prandial hypoglycemia as compared to hybrid CL&#xD;
      (HCL) with subcutaneous (SC) rapid-acting insulin (RAI) pre-meal bolus.&#xD;
&#xD;
      The second study aim will be to examine the efficiency and feasibility of Afrezza inhaled&#xD;
      insulin as a pre-meal bolus and a missed meal correction bolus on mitigating post-prandial&#xD;
      blood glucose control during outpatient CL therapy.&#xD;
&#xD;
      This study will test the hypothesis that Afrezza inhaled insulin given before a meal to mimic&#xD;
      physiologic first phase insulin release will limit the magnitude and rate of rise of glucose&#xD;
      levels following a meal and will achieve greater percent time spent within target blood&#xD;
      glucose range as compared to conventional hybrid CL therapy without inhaled insulin both in&#xD;
      the in-clinic research and outpatient real-life setting.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 22, 2017</start_date>
  <completion_date type="Actual">July 22, 2019</completion_date>
  <primary_completion_date type="Actual">July 22, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PostPrandial Blood Glucose</measure>
    <time_frame>Up to 4 hours following meal</time_frame>
    <description>Continuous glucose monitoring (CGM) using Yellow Springs Instrument (YSI) will be used to measure blood glucose (mg/dl). Data will be collected for a maximum 4 hours following each meal.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Insulin Levels</measure>
    <time_frame>Up to 4 hours following meal</time_frame>
    <description>Insulin levels will be monitored during the study. It will will be calculated and reported by each one of the three treatment groups with the appropriate metric (mean(SD) or median(IRQ)).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Venous Glucose Levels</measure>
    <time_frame>Up to 4 hours following meal</time_frame>
    <description>The changes in venous levels from t=0 to peak and the peaks will be calculated and reported by each one of the three treatment groups with the appropriate metric (mean(SD) or median(IRQ)).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Post-Prandial Hyperglycemia</condition>
  <condition>Post-Prandial Hypoglycemia</condition>
  <arm_group>
    <arm_group_label>A-HCL low</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Trial arms will entail (a) HCL with RAI analog (insulin lispro or aspart) pre-meal bolus (R-HCL visit), (b) ACL with pre-meal dose titrated down to the lower dose inhaled insulin (AHCL low visit), and (c) ACL with pre-meal dose titrated up to higher dose inhaled insulin (A-HCL high visit).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>A-HCL high</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Trial arms will entail (a) HCL with RAI analog (insulin lispro or aspart) pre-meal bolus (R-HCL visit), (b) ACL with pre-meal dose titrated down to the lower dose inhaled insulin (AHCL low visit), and (c) ACL with pre-meal dose titrated up to higher dose inhaled insulin (A-HCL high visit).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>R-HCL</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Trial arms will entail (a) HCL with RAI analog (insulin lispro or aspart) pre-meal bolus (R-HCL visit), (b) ACL with pre-meal dose titrated down to the lower dose inhaled insulin (AHCL low visit), and (c) ACL with pre-meal dose titrated up to higher dose inhaled insulin (A-HCL high visit).</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>DiAS</intervention_name>
    <description>Diabetes Assistant (DiAS) hybrid closed loop system.</description>
    <arm_group_label>A-HCL high</arm_group_label>
    <arm_group_label>A-HCL low</arm_group_label>
    <arm_group_label>R-HCL</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afrezza low dose</intervention_name>
    <description>Afrezza inhaled insulin low dose.</description>
    <arm_group_label>A-HCL low</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afrezza high dose</intervention_name>
    <description>Afrezza inhaled insulin high dose.</description>
    <arm_group_label>A-HCL high</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The age inclusion criterion is 18-29 years for phase I and 18-50y for phase II&#xD;
&#xD;
          -  Previously diagnosed with Type 1 Diabetes Mellitus, as determined by the judgment of&#xD;
             the Principal Investigator, based on clinical presentation and as documented in the&#xD;
             clinic record (formal antibody or genetic testing will not be required).&#xD;
&#xD;
          -  Diabetes duration at least 1 year.&#xD;
&#xD;
          -  Willing to have an intravenous (IV) line inserted for frequent blood sampling and&#xD;
             infusion of glucose.&#xD;
&#xD;
          -  Hemoglobin A1c (HbA1c) ≤10%&#xD;
&#xD;
          -  Speak and understand English.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  HbA1c &gt;10.0% at the time of screening&#xD;
&#xD;
          -  Insulin pump naïve subjects and subjects with unstable insulin dosing parameters&#xD;
             requiring daily adjustments in insulin sensitivity factor, insulin to carbohydrate&#xD;
             ratio and basal rates other than the established temporary rates that are determined&#xD;
             to manage specific conditions such as exercise.&#xD;
&#xD;
          -  History of an episode of severe hypoglycemia or Diabetic Ketoacidosis (DKA) requiring&#xD;
             inpatient management within six months prior to the screening visit and/or subjects&#xD;
             with history of clinician diagnosed hypoglycemia unawareness.&#xD;
&#xD;
          -  History of recurrent DKA defined as more than three episodes of admissions for DKA&#xD;
             during the past 12 months.&#xD;
&#xD;
          -  Subjects requiring an insulin total daily dose &lt;0.1u/kg/day and &gt;3u/kg/day.&#xD;
&#xD;
          -  History of physician diagnosis of asthma or any other clinically important pulmonary&#xD;
             disease, or use of any medications to treat such conditions within the last year&#xD;
&#xD;
          -  Allergy or know hypersensitivity for Afrezza or to drugs with similar chemical&#xD;
             structure&#xD;
&#xD;
          -  Any disease or exposure to any medication which, in the judgment of the principal&#xD;
             investigator, may impact glucose metabolism.&#xD;
&#xD;
          -  FEV1 &lt;70% of NHANES III; Forced vital capacity (FVC) &lt; 70% of NHANES III predicted for&#xD;
             children ≥8 years of age.&#xD;
&#xD;
          -  Positive urine pregnancy test for female patients of childbearing, breast feeding, or&#xD;
             intention to become pregnant.&#xD;
&#xD;
          -  Smoking of tobacco or other substances.&#xD;
&#xD;
          -  Subjects who discontinued smoking (including cigarettes, cigars, pipes) within the&#xD;
             past 6 months.&#xD;
&#xD;
          -  History of abnormal spirometry or chest X-ray suggestive of lung disease.&#xD;
&#xD;
          -  History of respiratory tract malignancy.&#xD;
&#xD;
          -  Any condition or medication that may result in pulmonary toxicity (e.g. current or&#xD;
             previous chemotherapy or radiation therapy or history of or current use of&#xD;
             amiodarone).&#xD;
&#xD;
          -  Inability to perform study procedures including pulmonary function testing and Afrezza&#xD;
             inhalation using the BluHale system.&#xD;
&#xD;
          -  Patients who take acetaminophen containing medications on a regular basis or&#xD;
             anticipate taking during the study period and are unable and/or unwilling to&#xD;
             substitute with a non-acetaminophen containing medication.&#xD;
&#xD;
          -  Use of a device that may pose electromagnetic compatibility issues and/or&#xD;
             radiofrequency interference with the DexCom CGM (implantable cardioverter&#xD;
             defibrillator, electronic pacemaker, neurostimulator, intrathecal pump, and cochlear&#xD;
             implants).&#xD;
&#xD;
          -  Active gastroparesis requiring current medical therapy.&#xD;
&#xD;
          -  Known bleeding diathesis or dyscrasia.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Yale Diabetes Research Clinic</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06511</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>May 17, 2022</last_update_submitted>
  <last_update_submitted_qc>May 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Insulin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypoglycemia</mesh_term>
    <mesh_term>Hyperglycemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin</mesh_term>
    <mesh_term>Insulin, Globin Zinc</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03234491
org study id: 2000020715
nct id: NCT03234491
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
is unapproved device: Yes
is us export: Yes
The study will be conducted in two phases; an in-patient meal study phase (Phase I) and an
      outpatient home study (Phase II). The two phase study design is chosen to enhance safety by
      testing the Afrezza Closed-Loop (CL) system in controlled in-clinic setting under study staff
      supervision before it could be investigated at the outpatient home setting. Phase II will not
      begin without the establishment of safety in Phase I.
There are 2 primary study aims that this research will address. The first study aim will be
      to determine whether use of Afrezza inhaled insulin with ultra-fast kinetics will improve the
      performance of a closed-loop (CL) system, both with respect to immediate post-prandial
      hyperglycemia and the subsequent late post-prandial hypoglycemia as compared to hybrid CL
      (HCL) with subcutaneous (SC) rapid-acting insulin (RAI) pre-meal bolus.

      The second study aim will be to examine the efficiency and feasibility of Afrezza inhaled
      insulin as a pre-meal bolus and a missed meal correction bolus on mitigating post-prandial
      blood glucose control during outpatient CL therapy.

      This study will test the hypothesis that Afrezza inhaled insulin given before a meal to mimic
      physiologic first phase insulin release will limit the magnitude and rate of rise of glucose
      levels following a meal and will achieve greater percent time spent within target blood
      glucose range as compared to conventional hybrid CL therapy without inhaled insulin both in
      the in-clinic research and outpatient real-life setting.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: PostPrandial Blood Glucose
time frame: Up to 4 hours following meal
description: Continuous glucose monitoring (CGM) using Yellow Springs Instrument (YSI) will be used to measure blood glucose (mg/dl). Data will be collected for a maximum 4 hours following each meal.
measure: Insulin Levels
time frame: Up to 4 hours following meal
description: Insulin levels will be monitored during the study. It will will be calculated and reported by each one of the three treatment groups with the appropriate metric (mean(SD) or median(IRQ)).
measure: Venous Glucose Levels
time frame: Up to 4 hours following meal
description: The changes in venous levels from t=0 to peak and the peaks will be calculated and reported by each one of the three treatment groups with the appropriate metric (mean(SD) or median(IRQ)).
arm group label: A-HCL low
arm group type: Active Comparator
description: Trial arms will entail (a) HCL with RAI analog (insulin lispro or aspart) pre-meal bolus (R-HCL visit), (b) ACL with pre-meal dose titrated down to the lower dose inhaled insulin (AHCL low visit), and (c) ACL with pre-meal dose titrated up to higher dose inhaled insulin (A-HCL high visit).
arm group label: A-HCL high
arm group type: Active Comparator
description: Trial arms will entail (a) HCL with RAI analog (insulin lispro or aspart) pre-meal bolus (R-HCL visit), (b) ACL with pre-meal dose titrated down to the lower dose inhaled insulin (AHCL low visit), and (c) ACL with pre-meal dose titrated up to higher dose inhaled insulin (A-HCL high visit).
arm group label: R-HCL
arm group type: Active Comparator
description: Trial arms will entail (a) HCL with RAI analog (insulin lispro or aspart) pre-meal bolus (R-HCL visit), (b) ACL with pre-meal dose titrated down to the lower dose inhaled insulin (AHCL low visit), and (c) ACL with pre-meal dose titrated up to higher dose inhaled insulin (A-HCL high visit).
intervention type: Device
intervention name: DiAS
description: Diabetes Assistant (DiAS) hybrid closed loop system.
arm group label: A-HCL high
arm group label: A-HCL low
arm group label: R-HCL
intervention type: Drug
intervention name: Afrezza low dose
description: Afrezza inhaled insulin low dose.
arm group label: A-HCL low
intervention type: Drug
intervention name: Afrezza high dose
description: Afrezza inhaled insulin high dose.
arm group label: A-HCL high
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor
mesh term: Hypoglycemia
mesh term: Hyperglycemia
mesh term: Insulin
mesh term: Insulin, Globin Zinc