<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/NCT03255629</url>
  </required_header>
  <id_info>
    <org_study_id>2016-27</org_study_id>
    <secondary_id>1R44DK107114</secondary_id>
    <nct_id>NCT03255629</nct_id>
  </id_info>
  <brief_title>Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia</brief_title>
  <official_title>Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Joslin Diabetes Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Xeris Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Harvard University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Joslin Diabetes Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To assess the efficacy of a closed loop glucagon system to prevent and treat hypoglycemia&#xD;
      occurring in patients with Post-Bariatric Hypoglycemia (PBH) in response to meals and&#xD;
      exercise.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A control system for sensor-guided delivery was previously developed and tested in a&#xD;
      Proof-of-Concept (POC) study in a clinical research setting during 9 mixed meal tolerance&#xD;
      tests in 8 unique patients with severe hypoglycemia following bariatric surgery. This&#xD;
      optimized algorithm will now be implemented to deliver stable glucagon in a closed-loop&#xD;
      system.&#xD;
&#xD;
      A randomized, placebo-controlled, masked trial will be conducted to assess the efficacy of&#xD;
      the closed loop system to prevent and treat hypoglycemia occurring in patients with PBH in&#xD;
      response to meals (part 1). Part 2 will test whether the closed loop system can also prevent&#xD;
      and treat hypoglycemia in patients with PBH in response to exercise. A manufacturing program&#xD;
      from our collaborating team at Xeris Pharmaceuticals will continue to produce supplies of&#xD;
      glucagon for the clinical trial in a current good manufacturing practice (cGMP) facility,&#xD;
      with continued shelf-life stability testing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 19, 2017</start_date>
  <completion_date type="Actual">August 22, 2018</completion_date>
  <primary_completion_date type="Actual">August 22, 2018</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>Crossover Assignment</intervention_model>
    <intervention_model_description>A randomization scheme will be devised to assign half the subjects to receive glucagon during their first challenge visit and the other half to receive vehicle during their first challenge visit. At their second challenge subjects will be assigned to the product not received during their first challenge. The label will include a subject randomization number and information as to which vial should be administered during the first challenge and which should be administered during the second challenge.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Study medication will be provided in vials which are labeled with randomization information only but not contents of vial.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;65 mg/dL</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>A primary endpoint for this study is the prevention of meal provoked hypoglycemia, defined as sensor glucose levels below &lt;65 mg/dl, comparing study drug to control.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;65 mg/dL</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>A primary endpoint for this study is prevention of meal provoked hypoglycemia, defined as plasma glucose levels below &lt;65 mg/dl, comparing study drug to control</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;60 mg/dL</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below &lt;60 mg/dl, comparing vehicle to control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge will be conducted within two weeks of the first.</time_frame>
    <description>Compare outcomes for glucagon versus vehicle infusions for prevention of rebound hyperglycemia (defined as glucose levels above 180 mg/dl).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Hypoglycemia Rescue Administered</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Protocol-specified rescue delivery of IV glucose was performed if plasma glucose &lt;55 mg/dL and/or significant neuroglycopenia developed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;60 mg/dL</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below &lt;60 mg/dl, comparing vehicle to control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;55 mg/dL</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below &lt;55 mg/dl, comparing vehicle to control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;55 mg/dL</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below &lt;55 mg/dl, comparing vehicle to control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Time Plasma Glucose in Range After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Time Sensor Glucose in Range After Drug Delivery After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Meal Provoked Nadir Plasma Glucose</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Meal Provoked Nadir Sensor Glucose</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Nadir Plasma Glucose After Mixed Meal (Min)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Nadir Sensor Glucose After Mixed Meal (Min)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Alarm During Mixed Meal Testing (Minutes)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Time to alarm represents the time for the first alarm to occur during mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Delivery (Min)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>Time to delivery (min) of study drug during mixed meal testing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>This is the sensor glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>This is the capillary glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>This is the sensor glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)</measure>
    <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
    <description>This is the capillary glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Score at Time of First Dose Delivery of Study Drug, Versus Pain Score at Time of First Dose Delivery of Placebo (Comparing First Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).</measure>
    <time_frame>The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).</time_frame>
    <description>Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the first administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores for the first administration of study drug vs. first administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Score at Time of Second Dose Delivery of Study Drug, Versus Pain Score at Time of Second Dose Delivery of Placebo (Comparing Second Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).</measure>
    <time_frame>The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).</time_frame>
    <description>Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the second administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores from the second administration of study drug vs. second administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Post-bariatric Hypoglycemia</condition>
  <arm_group>
    <arm_group_label>Study drug (glucagon) first, placebo second</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Each subject will have two mixed meal tolerance tests performed. Each will be randomized to receive either glucagon or matched placebo during the first testing session. A participant could receive 2 doses of the study drug or placebo at each study visit. The opposite treatment will be given during the second testing session after a 1-2 week washout period. Both participants and the study team will be blinded to the intervention being used during each session.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first, study drug (glucagon) second</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Each subject will have two mixed meal tolerance tests performed. Each will be randomized to receive either glucagon or matched placebo during the first testing session. A participant could receive 2 doses of the study drug or placebo at each study visit. The opposite treatment will be given during the second testing session after a 1-2 week washout period. Both participants and the study team will be blinded to the intervention being used during each session.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>glucagon</intervention_name>
    <description>novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals</description>
    <arm_group_label>Study drug (glucagon) first, placebo second</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Closed loop glucagon pump</intervention_name>
    <description>a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
    <arm_group_label>Placebo first, study drug (glucagon) second</arm_group_label>
    <arm_group_label>Study drug (glucagon) first, placebo second</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males or females diagnosed with ongoing post-bariatric hypoglycemia with prior&#xD;
             episodes of neuroglycopenia, unresponsive to dietary intervention (low glycemic index,&#xD;
             controlled carbohydrate portions) and trial of acarbose therapy at the maximally&#xD;
             tolerated dose.&#xD;
&#xD;
          2. Age 18-65 years of age, inclusive, at screening.&#xD;
&#xD;
          3. Willingness to provide informed consent and follow all study procedures, including&#xD;
             attending all scheduled visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Documented hypoglycemia occurring in the fasting state (&gt; 12 hours fast);&#xD;
&#xD;
          2. Chronic kidney disease stage 4 or 5 (including end-stage renal disease);&#xD;
&#xD;
          3. Hepatic disease, including serum alanine transaminase (ALT) or aspartate&#xD;
             aminotransferase (AST) greater than or equal to 3 times the upper limit of normal;&#xD;
             hepatic synthetic insufficiency as defined as serum albumin &lt; 3.0 g/dL; or serum&#xD;
             bilirubin &gt; 2.0;&#xD;
&#xD;
          4. Congestive heart failure, New York Heart Association (NYHA )class II, III or IV;&#xD;
&#xD;
          5. History of myocardial infarction, unstable angina or revascularization within the past&#xD;
             6 months or 2 or more risk factors for coronary artery disease including diabetes,&#xD;
             uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use;&#xD;
&#xD;
          6. History of cardiac arrhythmia or arrhythmia detected by EKG during the screening&#xD;
             visit;&#xD;
&#xD;
          7. History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia&#xD;
&#xD;
          8. Concurrent administration of β-blocker therapy;&#xD;
&#xD;
          9. History of a cerebrovascular accident;&#xD;
&#xD;
         10. Seizure disorder (other than with suspect or documented hypoglycemia);&#xD;
&#xD;
         11. Active treatment with any diabetes medications except for acarbose;&#xD;
&#xD;
         12. Active malignancy, except basal cell or squamous cell skin cancers;&#xD;
&#xD;
         13. Personal or family history of pheochromocytoma or disorder with increased risk of&#xD;
             pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);&#xD;
&#xD;
         14. Known insulinoma or glucagonoma;&#xD;
&#xD;
         15. Major surgical operation within 30 days prior to screening;&#xD;
&#xD;
         16. Hematocrit &lt; 33%;&#xD;
&#xD;
         17. Bleeding disorder, treatment with warfarin, or platelet count &lt;50,000;&#xD;
&#xD;
         18. Blood donation (1 pint of whole blood) within the past 2 months;&#xD;
&#xD;
         19. Active alcohol abuse or substance abuse;&#xD;
&#xD;
         20. Current administration of oral or parenteral corticosteroids;&#xD;
&#xD;
         21. Pregnancy and/ or Lactation: For women of childbearing potential: there is a&#xD;
             requirement for a negative urine pregnancy test and for agreement to use contraception&#xD;
             during the study and for at least 1 month after participating in the study. Acceptable&#xD;
             contraception includes birth control pill / patch / vaginal ring, Depo-Provera,&#xD;
             Norplant, an intrauterine device (IUD), the double barrier method (the woman uses a&#xD;
             diaphragm and spermicide and the man uses a condom), or abstinence;&#xD;
&#xD;
         22. Use of an investigational drug within 30 days prior to screening;&#xD;
&#xD;
         23. Current use of anticholinergic medications;&#xD;
&#xD;
         24. Allergy to a component of the study drug.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mary E Patti, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Joslin Diabetes Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Joslin Diabetes Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Mulla CM, Zavitsanou S, Laguna Sanz AJ, Pober D, Richardson L, Walcott P, Arora I, Newswanger B, Cummins MJ, Prestrelski SJ, Doyle FJ, Dassau E, Patti ME. A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia. J Clin Endocrinol Metab. 2020 Apr 1;105(4):e1260-71. doi: 10.1210/clinem/dgz197.</citation>
    <PMID>31714583</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>August 10, 2017</study_first_submitted>
  <study_first_submitted_qc>August 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <results_first_submitted>November 9, 2021</results_first_submitted>
  <results_first_submitted_qc>July 25, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">July 26, 2022</results_first_posted>
  <last_update_submitted>August 7, 2022</last_update_submitted>
  <last_update_submitted_qc>August 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypoglycemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glucagon</mesh_term>
    <mesh_term>Glucagon-Like Peptide 1</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 6, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT03255629/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants with a history of Roux-en-Y gastric bypass (RYGB) and post-bariatric hypoglycemia (PBH) with neuroglycopenia, uncontrolled on medical nutrition therapy and medications, were recruited from the Joslin Diabetes Center hypoglycemia clinic and other endocrine clinics in the region.</recruitment_details>
      <pre_assignment_details>Between September 2017 and August 2018, 23 individuals were screened and 18 enrolled (consort diagram, Fig. 2). Two participants withdrew before the first mixed-meal study visit because of inability to obtain adequate intravenous access.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Study Drug (Glucagon) First, Then Placebo (Randomized, Double-blind, Crossover Design)</title>
          <description>Each subject underwent two mixed meal tolerance tests, and was randomized to receive either glucagon or placebo during the first testing session (opposite treatment was given during the second testing session). These participants received glucagon first, and then the placebo at the second visit. A participant could receive 2 doses of the study drug or placebo at each study visit.&#xD;
Glucagon: novel, stable, non-aqueous glucagon formulation provided by Xeris Pharmaceuticals.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
        </group>
        <group group_id="P2">
          <title>Placebo First, Then Study Drug (Glucagon) Second (Randomized, Double-blind, Crossover Design)</title>
          <description>Each subject underwent two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
These participants received placebo at the fist visit, and the study drug glucagon at the second visit. A participant could receive 2 doses of the study drug or placebo at each study visit.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this group - they received placebo first) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5">One participant developed intractable nausea and emesis after consuming the mixed meal, and was withdrawn.&#xD;
Two participants were withdrawn due to not experiencing hypoglycemia during mixed meal testing.</participants>
                <participants group_id="P2" count="7">One participant was withdrawn due to not experiencing hypoglycemia during mixed meal testing.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>did not experience hypoglycemia</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Demographic Information for 12 Enrolled Participants Who Completed 2 Mixed-Meal Study Visits and Were Included in the Analysis</population>
      <group_list>
        <group group_id="B1">
          <title>Treatment Arm / Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)</title>
          <description>Each subject will have two mixed meal tolerance tests performed. Each will be randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment will be given during the second testing session. Both participants and the study team will be blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52" spread="2.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="27.6" spread="1.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Years since surgery</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8.4" spread="1.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Years from surgery to neuroglycopenia</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2.2" lower_limit="1.4" upper_limit="6.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>HbA1c</title>
          <units>percent</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5.3" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>On any anti-hypoglycemic medications</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Treated with acarbose</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Treated with diazoxide</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Treated with octreotide</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Treated with pramlintide</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;65 mg/dL</title>
        <description>A primary endpoint for this study is the prevention of meal provoked hypoglycemia, defined as sensor glucose levels below &lt;65 mg/dl, comparing study drug to control.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <population>12 Enrolled Participants Completed 2 Mixed-Meal Study Visits and Were Included in the Analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 wk washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;65 mg/dL</title>
          <description>A primary endpoint for this study is the prevention of meal provoked hypoglycemia, defined as sensor glucose levels below &lt;65 mg/dl, comparing study drug to control.</description>
          <population>12 Enrolled Participants Completed 2 Mixed-Meal Study Visits and Were Included in the Analysis</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.103</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;65 mg/dL</title>
        <description>A primary endpoint for this study is prevention of meal provoked hypoglycemia, defined as plasma glucose levels below &lt;65 mg/dl, comparing study drug to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <population>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</population>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;65 mg/dL</title>
          <description>A primary endpoint for this study is prevention of meal provoked hypoglycemia, defined as plasma glucose levels below &lt;65 mg/dl, comparing study drug to control</description>
          <population>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.180</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;60 mg/dL</title>
        <description>Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below &lt;60 mg/dl, comparing vehicle to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;60 mg/dL</title>
          <description>Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below &lt;60 mg/dl, comparing vehicle to control</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).</title>
        <description>Compare outcomes for glucagon versus vehicle infusions for prevention of rebound hyperglycemia (defined as glucose levels above 180 mg/dl).</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge will be conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).</title>
          <description>Compare outcomes for glucagon versus vehicle infusions for prevention of rebound hyperglycemia (defined as glucose levels above 180 mg/dl).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.317</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Hypoglycemia Rescue Administered</title>
        <description>Protocol-specified rescue delivery of IV glucose was performed if plasma glucose &lt;55 mg/dL and/or significant neuroglycopenia developed.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Hypoglycemia Rescue Administered</title>
          <description>Protocol-specified rescue delivery of IV glucose was performed if plasma glucose &lt;55 mg/dL and/or significant neuroglycopenia developed.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.008</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;60 mg/dL</title>
        <description>Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below &lt;60 mg/dl, comparing vehicle to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;60 mg/dL</title>
          <description>Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below &lt;60 mg/dl, comparing vehicle to control</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.083</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;55 mg/dL</title>
        <description>Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below &lt;55 mg/dl, comparing vehicle to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose &lt;55 mg/dL</title>
          <description>Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below &lt;55 mg/dl, comparing vehicle to control</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.025</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;55 mg/dL</title>
        <description>Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below &lt;55 mg/dl, comparing vehicle to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose &lt;55 mg/dL</title>
          <description>Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below &lt;55 mg/dl, comparing vehicle to control</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Time Plasma Glucose in Range After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response</title>
        <description>Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Time Plasma Glucose in Range After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response</title>
          <description>Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response</description>
          <units>percentage of time</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.852" spread="0.082"/>
                    <measurement group_id="O2" value="0.645" spread="0.074"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.049</p_value>
            <method>Mixed Models Analysis</method>
            <method_desc>Linear mixed effects models to account for correlation within subjects over time</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Time Sensor Glucose in Range After Drug Delivery After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response</title>
        <description>Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Time Sensor Glucose in Range After Drug Delivery After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response</title>
          <description>Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response</description>
          <units>percentage of time</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.987" spread="0.013"/>
                    <measurement group_id="O2" value="0.815" spread="0.077"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.056</p_value>
            <method>Mixed Models Analysis</method>
            <method_desc>Linear mixed effects models to account for correlation within subjects over time</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Meal Provoked Nadir Plasma Glucose</title>
        <description>Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Meal Provoked Nadir Plasma Glucose</title>
          <description>Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67.4" spread="2.70"/>
                    <measurement group_id="O2" value="58.5" spread="1.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.004</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Meal Provoked Nadir Sensor Glucose</title>
        <description>Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Meal Provoked Nadir Sensor Glucose</title>
          <description>Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72.7" spread="2.21"/>
                    <measurement group_id="O2" value="65.3" spread="1.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.059</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Nadir Plasma Glucose After Mixed Meal (Min)</title>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Nadir Plasma Glucose After Mixed Meal (Min)</title>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="138" spread="11.9"/>
                    <measurement group_id="O2" value="125" spread="7.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.195</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Nadir Sensor Glucose After Mixed Meal (Min)</title>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Nadir Sensor Glucose After Mixed Meal (Min)</title>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="156" spread="11.6"/>
                    <measurement group_id="O2" value="134" spread="6.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.043</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Alarm During Mixed Meal Testing (Minutes)</title>
        <description>Time to alarm represents the time for the first alarm to occur during mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Arm</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Alarm During Mixed Meal Testing (Minutes)</title>
          <description>Time to alarm represents the time for the first alarm to occur during mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89.9" spread="3.90"/>
                    <measurement group_id="O2" value="87.7" spread="4.9975"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.659</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Delivery (Min)</title>
        <description>Time to delivery (min) of study drug during mixed meal testing</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Delivery (Min)</title>
          <description>Time to delivery (min) of study drug during mixed meal testing</description>
          <units>minutes</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="94" spread="5.52"/>
                    <measurement group_id="O2" value="89.3" spread="5.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.406</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)</title>
        <description>This is the sensor glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)</title>
          <description>This is the sensor glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="134" spread="5.93"/>
                    <measurement group_id="O2" value="139" spread="4.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.611</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)</title>
        <description>This is the capillary glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)</title>
          <description>This is the capillary glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98.1" spread="7.30"/>
                    <measurement group_id="O2" value="109" spread="5.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.183</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)</title>
        <description>This is the sensor glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Arm</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)</title>
          <description>This is the sensor glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.7" spread="4.96"/>
                    <measurement group_id="O2" value="70.1" spread="2.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.009</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)</title>
        <description>This is the capillary glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
        <time_frame>Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)</title>
          <description>This is the capillary glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose &lt; 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="94.2" spread="1.70"/>
                    <measurement group_id="O2" value="91.7" spread="8.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.789</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pain Score at Time of First Dose Delivery of Study Drug, Versus Pain Score at Time of First Dose Delivery of Placebo (Comparing First Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).</title>
        <description>Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the first administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores for the first administration of study drug vs. first administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.</description>
        <time_frame>The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Pain Score at Time of First Dose Delivery of Study Drug, Versus Pain Score at Time of First Dose Delivery of Placebo (Comparing First Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).</title>
          <description>Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the first administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores for the first administration of study drug vs. first administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.</description>
          <units>pain score</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.00" spread="0.685"/>
                    <measurement group_id="O2" value="3.83" spread="0.815"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.865</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pain Score at Time of Second Dose Delivery of Study Drug, Versus Pain Score at Time of Second Dose Delivery of Placebo (Comparing Second Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).</title>
        <description>Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the second administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores from the second administration of study drug vs. second administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.</description>
        <time_frame>The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Drug (Glucagon) Phase</title>
            <description>This phase represents when the participant received the study drug - glucagon. A participant could receive 2 doses of the study drug at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
          <group group_id="O2">
            <title>Placebo / Control Phase</title>
            <description>This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit.&#xD;
Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session after a 1-2 week washout period. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation (for this phase containing placebo vs. glucagon) together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
          </group>
        </group_list>
        <measure>
          <title>Pain Score at Time of Second Dose Delivery of Study Drug, Versus Pain Score at Time of Second Dose Delivery of Placebo (Comparing Second Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).</title>
          <description>Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the second administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores from the second administration of study drug vs. second administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.</description>
          <units>pain score</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.14" spread="0.615"/>
                    <measurement group_id="O2" value="1.31" spread="0.671"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.875</p_value>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were collected over the the duration of each individuals participation, a 2 to 3 week period of time, encompassing the time of enrollment, to the completion of visit 5.</time_frame>
      <desc>Regarding discrepancy between participant flow and number of participants at risk: 18 participants enrolled, however two participants withdrew before the first mixed-meal study visit because of inability to obtain adequate intravenous access. Sixteen participants completed the first mixed-meal study visit; 12 participants completed both mixed meal study visits and were included in analysis.</desc>
      <group_list>
        <group group_id="E1">
          <title>Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)</title>
          <description>Each subject had two mixed meal tolerance tests performed. Each was randomized to receive either glucagon or matched placebo during the first testing session. The opposite treatment was given during the second testing session. Both participants and the study team were blinded to the intervention being used during each session.&#xD;
glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals&#xD;
Closed loop glucagon pump: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <description>Pt was not randomized. hypokalemia discovered during screening visit; admitted to hospital. resolved without sequelae.&#xD;
not related to study protocol or intervention.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>MCH above normal limit of refrence range at screening visit.</sub_title>
                <description>No treatment. Complete blood count (CBC) repeated on 2/28/2018.Labs were acceptable to begin study visit.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>WBC above normal limit of reference range at screening visit</sub_title>
                <description>No treatment. CBC repeated on 2/28/2018.Labs were acceptable to begin study visit.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>Related to MMTT. Resolved without sequelae.</description>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoglycemia during study (MMTT)</sub_title>
                <description>Related to MMTT in population understudy. Resolved.</description>
                <counts group_id="E1" events="21" subjects_affected="13" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Thirsty after alarm (placebo visit)</sub_title>
                <description>AE linked to MMTT, hypoglycemia, and delivery of placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoglycemia following lunch (gluagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoglycemia following lunch (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoglycemia after dinner the night following the study visit (glucagon visit)</sub_title>
                <description>Possibly related to study visit and study drug (glucagon).</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurry vision after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Blurry vision after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Blurry vision after alarm (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea after intake of mixed meal (prior to glucagon OR placebo)</sub_title>
                <description>Related to mixed meal tolerance test (MMTT). Resolved without sequelae.</description>
                <counts group_id="E1" events="16" subjects_affected="12" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Emesis after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>Adverse event (AE) linked to meal tolerance test, especially in patient population under study. Required ER evaluation in 1 participant due to repetitive vomiting. All resolved.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Stomach ache / cramping after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Bloated / uncomfortably full after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nausea after alarm (glucagon visit)</sub_title>
                <description>AE linked to MMTT, hypoglycemia, and delivery of study drug.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Vomiting after alarm (glucagon visit)</sub_title>
                <description>Participant also vomited during mixed meal, prior to study drug administration. AE linked to MMTT, hypoglycemia, and delivery of study drug.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Bowel urgency after alarm (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Bowel movement after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Stomach cramping / pain after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT and placebo.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nausea prior to lunch (glucagon visit)</sub_title>
                <description>This participant was also nauseous after intake of mixed meal, prior to receiving the study drug. AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Stomach pains after lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nausea after lunch (glucagon visit)</sub_title>
                <description>Participant also had nausea after intake of mixed meal, prior to delivery of study drug. AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Vomiting after lunch (glucagon visit)</sub_title>
                <description>This participant had nausea which started after intake of mixed meal, prior to study drug administration. AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness day after study visit (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headache prior to start of MMTT</sub_title>
                <description>Not related to study drug or placebo as was present upon arrival.</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness prior to start of MMTT</sub_title>
                <description>Not related to study drug or placebo as was present upon arrival to study visit.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Headache after intake of mixed meal (prior to glucagon OR placebo)</sub_title>
                <description>Related to MMTT. Resolved without sequelae.</description>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling cold / chills after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>Related to MMTT, resolved.</description>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling hot / warm after intake of mixed meal (prior to study drug or placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Thirsty after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>Related to MMTT. Resolved.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tingling (paresthesia) in shoulders after intake of mixed meal (prior to study drug or placebo)</sub_title>
                <description>Related to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tingling (paresthesia) around the mouth after intake of mixed meal (prior to study drug or placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dizzy after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling unwell (&quot;icky... drunk&quot;) after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tearful after intake of mixed meal (prior to study drug OR placebo)</sub_title>
                <description>AE linked to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pain at pump site during MMTT (prior to delivery of study drug or placebo)</sub_title>
                <description>Related to study device. Resolved.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Irritation / pain at IV site with IV administration of dextrose</sub_title>
                <description>AE related to administration of D50 at placebo visit. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tearful when IV dextrose (D50) administered</sub_title>
                <description>Related to MMTT &amp; hypoglycemia, at visit where placebo was administered. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Burning pain / pricking at pump site after alarm (placebo visit)</sub_title>
                <description>AE linked to placebo and study device.</description>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Buring pain at pump site after alarm (glucagon visit)</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling hot after alarm (glucagon visit)</sub_title>
                <description>AE linked to MMTT, hypoglycemia, and delivery of study drug.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling hot after alarm (placebo visit)</sub_title>
                <description>AE linked to MMTT, hypoglycemia, and delivery of placebo.</description>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Headace after alarm (glucagon visit)</sub_title>
                <description>Both participants with headache following alarm also had headache prior to the alarm during mixed meal testing. AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tearful during alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dizzy / lightheaded after alarm (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Low blood pressure after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness after alarm (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pale after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Weakness prior to lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling hot prior to lunch (glucagon visit)</sub_title>
                <description>This participant also felt hot following intake of mixed meal, prior to delivery of study drug. AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling hot after lunch (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, placebo.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness after lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness after lunch (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Feeling cold after lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Headache after lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Shaky following lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Ears ringing after lunch</sub_title>
                <description>AE related to MMTT. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Foggy feeling after lunch (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dry mouth following alarm (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dizzy after discharge (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tiredness day after study visit (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalemia at screening visit</sub_title>
                <description>Discovered at screening visit. No treatment. Labs were repeated at Visit 2, potassium was within reference range.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Lower extremity cramping after alarm (glucagon visit)</sub_title>
                <description>Legs and toes cramping. AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Back pain after lunch (placebo visit)</sub_title>
                <description>Not related. Participant with chronic back pain.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Confusion after alarm (glucagon visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Speech slowed after alarm (placebo visit)</sub_title>
                <description>AE related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Migraine headache one night following study visit (placebo visit)</sub_title>
                <description>Possibly related to MMTT, hypoglycemia, and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritis at pump insertion site during MMTT (prior to delivery of study drug or placebo)</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Erythema at site of CGM sensor</sub_title>
                <description>Related to continuous glucose monitoring (CGM) device (sensor or adhesive). Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hematoma under CGM sensor</sub_title>
                <description>AE related to CGM sensor device.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Erythema at pump infusion site (placebo visit)</sub_title>
                <description>AE related to study device and placebo.</description>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Erythema at pump infusion site (glucagon visit)</sub_title>
                <description>AE related to study device and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Edema at pump infusion site (placebo visit)</sub_title>
                <description>AE related to study device and placebo.</description>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Edema at pump infusion site (glucagon visit)</sub_title>
                <description>AE related to study device and study drug - glucagon.</description>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pruritis at pump site after alarm (placebo visit)</sub_title>
                <description>AE related to study device and placebo.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Erythema a pump infusion site 1 day following discharge (glucagon visit)</sub_title>
                <description>2&quot; diameter corresponding with area of the adhesive. AE related to pump device adhesive. This participant had erythema as well documented on the day of the study visit. Resolved.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Mary Elizabeth Patti, MD</name_or_title>
      <organization>Joslin Diabetes Center</organization>
      <phone>(617) 309-2635</phone>
      <email>MaryElizabeth.Patti@joslin.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03255629
org study id: 2016-27
secondary id: 1R44DK107114
nct id: NCT03255629
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
To assess the efficacy of a closed loop glucagon system to prevent and treat hypoglycemia
      occurring in patients with Post-Bariatric Hypoglycemia (PBH) in response to meals and
      exercise.
A control system for sensor-guided delivery was previously developed and tested in a
      Proof-of-Concept (POC) study in a clinical research setting during 9 mixed meal tolerance
      tests in 8 unique patients with severe hypoglycemia following bariatric surgery. This
      optimized algorithm will now be implemented to deliver stable glucagon in a closed-loop
      system.

      A randomized, placebo-controlled, masked trial will be conducted to assess the efficacy of
      the closed loop system to prevent and treat hypoglycemia occurring in patients with PBH in
      response to meals (part 1). Part 2 will test whether the closed loop system can also prevent
      and treat hypoglycemia in patients with PBH in response to exercise. A manufacturing program
      from our collaborating team at Xeris Pharmaceuticals will continue to produce supplies of
      glucagon for the clinical trial in a current good manufacturing practice (cGMP) facility,
      with continued shelf-life stability testing.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: A randomization scheme will be devised to assign half the subjects to receive glucagon during their first challenge visit and the other half to receive vehicle during their first challenge visit. At their second challenge subjects will be assigned to the product not received during their first challenge. The label will include a subject randomization number and information as to which vial should be administered during the first challenge and which should be administered during the second challenge.
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Study medication will be provided in vials which are labeled with randomization information only but not contents of vial.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <65 mg/dL
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: A primary endpoint for this study is the prevention of meal provoked hypoglycemia, defined as sensor glucose levels below <65 mg/dl, comparing study drug to control.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <65 mg/dL
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: A primary endpoint for this study is prevention of meal provoked hypoglycemia, defined as plasma glucose levels below <65 mg/dl, comparing study drug to control
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <60 mg/dL
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <60 mg/dl, comparing vehicle to control
measure: Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge will be conducted within two weeks of the first.
description: Compare outcomes for glucagon versus vehicle infusions for prevention of rebound hyperglycemia (defined as glucose levels above 180 mg/dl).
measure: Number of Participants With Hypoglycemia Rescue Administered
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Protocol-specified rescue delivery of IV glucose was performed if plasma glucose <55 mg/dL and/or significant neuroglycopenia developed.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <60 mg/dL
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <60 mg/dl, comparing vehicle to control
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <55 mg/dL
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <55 mg/dl, comparing vehicle to control
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <55 mg/dL
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <55 mg/dl, comparing vehicle to control
measure: Percent Time Plasma Glucose in Range After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response
measure: Percent Time Sensor Glucose in Range After Drug Delivery After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response
measure: Meal Provoked Nadir Plasma Glucose
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control
measure: Meal Provoked Nadir Sensor Glucose
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control
measure: Time to Nadir Plasma Glucose After Mixed Meal (Min)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Time to Nadir Sensor Glucose After Mixed Meal (Min)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Time to Alarm During Mixed Meal Testing (Minutes)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Time to alarm represents the time for the first alarm to occur during mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.
measure: Time to Delivery (Min)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: Time to delivery (min) of study drug during mixed meal testing
measure: Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: This is the sensor glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.
measure: Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: This is the capillary glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.
measure: Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: This is the sensor glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.
measure: Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)
time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
description: This is the capillary glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.
measure: Pain Score at Time of First Dose Delivery of Study Drug, Versus Pain Score at Time of First Dose Delivery of Placebo (Comparing First Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).
time frame: The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).
description: Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the first administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores for the first administration of study drug vs. first administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.
measure: Pain Score at Time of Second Dose Delivery of Study Drug, Versus Pain Score at Time of Second Dose Delivery of Placebo (Comparing Second Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).
time frame: The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).
description: Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the second administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores from the second administration of study drug vs. second administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.
arm group label: Study drug (glucagon) first, placebo second
arm group type: Other
description: Each subject will have two mixed meal tolerance tests performed. Each will be randomized to receive either glucagon or matched placebo during the first testing session. A participant could receive 2 doses of the study drug or placebo at each study visit. The opposite treatment will be given during the second testing session after a 1-2 week washout period. Both participants and the study team will be blinded to the intervention being used during each session.
arm group label: Placebo first, study drug (glucagon) second
arm group type: Other
description: Each subject will have two mixed meal tolerance tests performed. Each will be randomized to receive either glucagon or matched placebo during the first testing session. A participant could receive 2 doses of the study drug or placebo at each study visit. The opposite treatment will be given during the second testing session after a 1-2 week washout period. Both participants and the study team will be blinded to the intervention being used during each session.
intervention type: Drug
intervention name: glucagon
description: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals
arm group label: Study drug (glucagon) first, placebo second
intervention type: Device
intervention name: Closed loop glucagon pump
description: a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.
arm group label: Placebo first, study drug (glucagon) second
arm group label: Study drug (glucagon) first, placebo second
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Mary E Patti, MD
role: Principal Investigator
affiliation: Joslin Diabetes Center
facility: 
country: United States
citation: Mulla CM, Zavitsanou S, Laguna Sanz AJ, Pober D, Richardson L, Walcott P, Arora I, Newswanger B, Cummins MJ, Prestrelski SJ, Doyle FJ, Dassau E, Patti ME. A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia. J Clin Endocrinol Metab. 2020 Apr 1;105(4):e1260-71. doi: 10.1210/clinem/dgz197.
PMID: 31714583
responsible party type: Sponsor
mesh term: Hypoglycemia
mesh term: Glucagon
mesh term: Glucagon-Like Peptide 1
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 