<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/NCT03800875</url>
  </required_header>
  <id_info>
    <org_study_id>Triple Hormone</org_study_id>
    <nct_id>NCT03800875</nct_id>
  </id_info>
  <brief_title>Insulin-plus-pramlintide Closed-loop Strategy to Regulate Glucose Levels Without Carbohydrate Counting</brief_title>
  <acronym>Dual</acronym>
  <official_title>A Randomized, Controlled, Crossover Trial to Assess a Dual-hormone (Insulin-pramlintide) Closed-loop Delivery Without Carbohydrate Counting in Regulating Glucose Levels in Adults With Type 1 Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>McGill University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Diabetes Canada</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>McGill University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Closed-loop system systems that are shown to alleviate the burden of carbohydrate counting&#xD;
      without degrading glucose control are still lacking. In this proposal, the investigators aim&#xD;
      to develop a novel, fully-automated, closed-loop system that delivers insulin and pramlintide&#xD;
      that controls postprandial glucose levels without any input from the user.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Meal carbohydrate content is the main determinant of prandial insulin needs, and&#xD;
      consequently, accurate carbohydrate counting is recommended for type 1 diabetes. Advances in&#xD;
      glucose sensors have motivated the development of the closed-loop system to automatically&#xD;
      regulate glucose levels in individuals with type 1 diabetes. In the closed-loop system, a&#xD;
      dosing algorithm adjusts the pump insulin infusion rate based on continuous glucose sensor&#xD;
      readings.&#xD;
&#xD;
      Closed-loop system systems that are shown to alleviate the burden of carbohydrate counting&#xD;
      without degrading glucose control are still lacking. In this proposal, the investigators aim&#xD;
      to develop a novel, fully-automated, closed-loop system that delivers insulin and pramlintide&#xD;
      that controls postprandial glucose levels without any input from the user. Thus, the two&#xD;
      hormones' role in the postprandial state will be as follows:&#xD;
&#xD;
        1. Insulin: to reduce plasma glucose levels. Insulin delivery needs to be aggressive to&#xD;
           counter-act fast increase in post-meal glucose levels.&#xD;
&#xD;
        2. Pramlintide: to slow gastric emptying and aim insulin in efficiently controlling&#xD;
           postprandial glucose levels.&#xD;
&#xD;
      The aim of this study is to assess a fully automated, dual-hormone, closed-loop system that&#xD;
      delivers insulin, and pramlintide to control glucose levels without degrading overall&#xD;
      glycemic control compared to an insulin-alone closed-loop system with carbohydrate-matched&#xD;
      boluses.&#xD;
&#xD;
      The investigators hypothesize that the dual-hormone closed-loop system will alleviate&#xD;
      carbohydrate-counting burden (fully reactive system) without degrading glucose control&#xD;
      compared to the insulin-alone closed-loop system.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 8, 2019</start_date>
  <completion_date type="Actual">September 19, 2020</completion_date>
  <primary_completion_date type="Actual">September 19, 2020</primary_completion_date>
  <phase>Phase 2</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>Total percentage of time (22:00-22:00) that the glucose concentration remained within 3.9 and 10.0 mmol/L</measure>
    <time_frame>24 hours</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total percentage of time (22:00-22:00) that the glucose concentration remained within specified ranges.</measure>
    <time_frame>24 hours</time_frame>
    <description>a. between 3.9 and 7.8 mmol/L; b. below 3.9 mmol/L; c. between 3.9 and 10 mmol/L d. below 3.3 mmol/L; e. below 2.8 mmol/L; f. above 7.8 mmol/L; g. above 10 mmol/L; h. above 13.9 mmol/L; i. above 16.7 mmol/L.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of overnight time (24:00-8:00) that the glucose concentration remained within specified ranges.</measure>
    <time_frame>8 hours</time_frame>
    <description>a. between 3.9 and 7.8 mmol/L; b. between 3.9 and 10 mmol/L; c. below 3.9 mmol/L; d. below 3.3 mmol/L; e. below 2.8 mmol/L; f. above 7.8 mmol/L; g. above 10 mmol/L; h. above 13.9 mmol/L; i. above 16.7 mmol/L.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total amount of insulin delivered to the participant</measure>
    <time_frame>24 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean sensor glucose concentration during the overnight stay</measure>
    <time_frame>8 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants experiencing hypoglycemia requiring oral treatment during: a. the overall study period; b. the night; c. the day</measure>
    <time_frame>27 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number and severity of gastrointestinal sysmptoms experienced by a participant</measure>
    <time_frame>27 hours</time_frame>
    <description>GI symptoms include: nausea, vomiting, bloating and heartburn</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean daytime insulin concentration</measure>
    <time_frame>14 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean daytime concentration of amylin</measure>
    <time_frame>14 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total amount of pramlintide delivered to the participant</measure>
    <time_frame>24 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean glucose level</measure>
    <time_frame>24-hour period</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Diabetes Mellitus, Type 1</condition>
  <arm_group>
    <arm_group_label>Insulin-Pramlintide Closed-Loop Strategy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fast-acting insulin will be delivered using two separate infusion pumps. The pumps' infusion rates will then be changed manually based on the computer-generated recommendation. The computer-generated recommendations are based on a dosing algorithm. With no-meal announcement or carbohydrate counting, the dual-hormone closed-loop system will be fully reactive, and insulin and pramlintide dosages will be based solely on sensor readings</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Insulin-alone Closed Loop Strategy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fast-acting insulin will be delivered by a subcutaneous insulin infusion pump based on an algorithm that automatically adjusts insulin rates based on a dosing algorithm. The carbohydrate content for every ingested meal will be entered into the algorithm to calculate the insulin prandial bolus based on each participant's insulin-to-carbohydrate ratio. The carbohydrate content will be entered at the onset of the meal.&#xD;
Drug(s): Insulin (FiAsp)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>27-hour inpatient intervention</intervention_name>
    <description>Subjects will be admitted at the research facility at 19:00. Each 27-hour intervention visit includes 3 standardized meals (8:00, 12:00, and 17:00), an evening snack (22:00) and an overnight stay. The glucose level as measured by the real time sensor will be entered manually into the computer every 10 minutes. The infusion rate of either insulin alone or insulin and pramlintide will be changed manually based on the computer generated recommendation. The computer generated recommendations are based on a predictive algorithm.</description>
    <arm_group_label>Insulin-Pramlintide Closed-Loop Strategy</arm_group_label>
    <arm_group_label>Insulin-alone Closed Loop Strategy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males and females ≥ 18 years of age.&#xD;
&#xD;
          2. Clinical diagnosis of type 1 diabetes for at least 12 months. The diagnosis of type 1&#xD;
             diabetes is based on the investigator's judgment; C peptide level and antibody&#xD;
             determinations are not needed.&#xD;
&#xD;
          3. Insulin pump therapy for at least 6 months.&#xD;
&#xD;
          4. HbA1c ≤ 12% in the last 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Current or ≤ 1 month use of other antihyperglycemic agents (SGLT2, GLP-1, Metformin,&#xD;
             Acarbose, etc.…).&#xD;
&#xD;
          2. Severe hypoglycemic episode within one month of admission.&#xD;
&#xD;
          3. Severe diabetic ketoacidosis episode within one month of admission.&#xD;
&#xD;
          4. Pregnancy.&#xD;
&#xD;
          5. Known or suspected allergy to the study drugs.&#xD;
&#xD;
          6. Gastroparesis.&#xD;
&#xD;
          7. Use of prokinetic drugs that stimulate gastric emptying (domperidone, cisapride,&#xD;
             metoclopramide).&#xD;
&#xD;
          8. Clinically significant nephropathy, neuropathy or retinopathy as judged by the&#xD;
             investigator.&#xD;
&#xD;
          9. Recent (&lt; 6 months) acute macrovascular event e.g. acute coronary syndrome or cardiac&#xD;
             surgery.&#xD;
&#xD;
         10. Current use of glucocorticoid medication.&#xD;
&#xD;
         11. Other serious medical illness likely to interfere with study participation or with the&#xD;
             ability to complete the trial by the judgment of the investigator.&#xD;
&#xD;
         12. Failure to comply with team's recommendations (e.g. not willing to eat meals/snacks,&#xD;
             not willing to change pump parameters, etc.).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Tsoukas</last_name>
    <role>Principal Investigator</role>
    <affiliation>McGill University Health Centre/Research Institute of the McGill University Health Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>McGill University Health Centre</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H4A 3J1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>June 27, 2018</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>June 3, 2021</last_update_submitted>
  <last_update_submitted_qc>June 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes Mellitus, Type 1</keyword>
  <keyword>Pramlintide</keyword>
  <keyword>Insulin</keyword>
  <keyword>Dual-Hormone</keyword>
  <keyword>Closed-Loop</keyword>
  <keyword>Artificial Pancreas</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>Yes</sharing_ipd>
    <ipd_description>The raw data (i.e., insulin delivery, glucose levels, individual participant data) and informed consent form could be shared by the corresponding author, ahmad.haidar@mcgill.ca, upon reasonable request for academic purposes, subject to Material Transfer Agreement and approval of McGill University Health Center's Research Ethics Board. All data shared will be de-identified. The study protocol will be available with publication.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
  </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/NCT03800875
org study id: Triple Hormone
nct id: NCT03800875
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
Closed-loop system systems that are shown to alleviate the burden of carbohydrate counting
      without degrading glucose control are still lacking. In this proposal, the investigators aim
      to develop a novel, fully-automated, closed-loop system that delivers insulin and pramlintide
      that controls postprandial glucose levels without any input from the user.
Meal carbohydrate content is the main determinant of prandial insulin needs, and
      consequently, accurate carbohydrate counting is recommended for type 1 diabetes. Advances in
      glucose sensors have motivated the development of the closed-loop system to automatically
      regulate glucose levels in individuals with type 1 diabetes. In the closed-loop system, a
      dosing algorithm adjusts the pump insulin infusion rate based on continuous glucose sensor
      readings.

      Closed-loop system systems that are shown to alleviate the burden of carbohydrate counting
      without degrading glucose control are still lacking. In this proposal, the investigators aim
      to develop a novel, fully-automated, closed-loop system that delivers insulin and pramlintide
      that controls postprandial glucose levels without any input from the user. Thus, the two
      hormones' role in the postprandial state will be as follows:

        1. Insulin: to reduce plasma glucose levels. Insulin delivery needs to be aggressive to
           counter-act fast increase in post-meal glucose levels.

        2. Pramlintide: to slow gastric emptying and aim insulin in efficiently controlling
           postprandial glucose levels.

      The aim of this study is to assess a fully automated, dual-hormone, closed-loop system that
      delivers insulin, and pramlintide to control glucose levels without degrading overall
      glycemic control compared to an insulin-alone closed-loop system with carbohydrate-matched
      boluses.

      The investigators hypothesize that the dual-hormone closed-loop system will alleviate
      carbohydrate-counting burden (fully reactive system) without degrading glucose control
      compared to the insulin-alone closed-loop system.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Total percentage of time (22:00-22:00) that the glucose concentration remained within 3.9 and 10.0 mmol/L
time frame: 24 hours
measure: Total percentage of time (22:00-22:00) that the glucose concentration remained within specified ranges.
time frame: 24 hours
description: a. between 3.9 and 7.8 mmol/L; b. below 3.9 mmol/L; c. between 3.9 and 10 mmol/L d. below 3.3 mmol/L; e. below 2.8 mmol/L; f. above 7.8 mmol/L; g. above 10 mmol/L; h. above 13.9 mmol/L; i. above 16.7 mmol/L.
measure: Percentage of overnight time (24:00-8:00) that the glucose concentration remained within specified ranges.
time frame: 8 hours
description: a. between 3.9 and 7.8 mmol/L; b. between 3.9 and 10 mmol/L; c. below 3.9 mmol/L; d. below 3.3 mmol/L; e. below 2.8 mmol/L; f. above 7.8 mmol/L; g. above 10 mmol/L; h. above 13.9 mmol/L; i. above 16.7 mmol/L.
measure: Total amount of insulin delivered to the participant
time frame: 24 hours
measure: Mean sensor glucose concentration during the overnight stay
time frame: 8 hours
measure: Number of participants experiencing hypoglycemia requiring oral treatment during: a. the overall study period; b. the night; c. the day
time frame: 27 hours
measure: The number and severity of gastrointestinal sysmptoms experienced by a participant
time frame: 27 hours
description: GI symptoms include: nausea, vomiting, bloating and heartburn
measure: Mean daytime insulin concentration
time frame: 14 hours
measure: Mean daytime concentration of amylin
time frame: 14 hours
measure: Total amount of pramlintide delivered to the participant
time frame: 24 hours
measure: Mean glucose level
time frame: 24-hour period
arm group label: Insulin-Pramlintide Closed-Loop Strategy
arm group type: Experimental
description: Fast-acting insulin will be delivered using two separate infusion pumps. The pumps' infusion rates will then be changed manually based on the computer-generated recommendation. The computer-generated recommendations are based on a dosing algorithm. With no-meal announcement or carbohydrate counting, the dual-hormone closed-loop system will be fully reactive, and insulin and pramlintide dosages will be based solely on sensor readings
arm group label: Insulin-alone Closed Loop Strategy
arm group type: Active Comparator
description: Fast-acting insulin will be delivered by a subcutaneous insulin infusion pump based on an algorithm that automatically adjusts insulin rates based on a dosing algorithm. The carbohydrate content for every ingested meal will be entered into the algorithm to calculate the insulin prandial bolus based on each participant's insulin-to-carbohydrate ratio. The carbohydrate content will be entered at the onset of the meal.
Drug(s): Insulin (FiAsp)
intervention type: Drug
intervention name: 27-hour inpatient intervention
description: Subjects will be admitted at the research facility at 19:00. Each 27-hour intervention visit includes 3 standardized meals (8:00, 12:00, and 17:00), an evening snack (22:00) and an overnight stay. The glucose level as measured by the real time sensor will be entered manually into the computer every 10 minutes. The infusion rate of either insulin alone or insulin and pramlintide will be changed manually based on the computer generated recommendation. The computer generated recommendations are based on a predictive algorithm.
arm group label: Insulin-Pramlintide Closed-Loop Strategy
arm group label: Insulin-alone Closed Loop Strategy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Tsoukas
role: Principal Investigator
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
sharing ipd: Yes
ipd description: The raw data (i.e., insulin delivery, glucose levels, individual participant data) and informed consent form could be shared by the corresponding author, ahmad.haidar@mcgill.ca, upon reasonable request for academic purposes, subject to Material Transfer Agreement and approval of McGill University Health Center's Research Ethics Board. All data shared will be de-identified. The study protocol will be available with publication.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)