Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia

• Sponsor: Joslin Diabetes Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03255629
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Xeris Pharmaceuticals (Industry), Harvard University (Other)
• Enrollment: 18
• Location: 1
• Arms: 2
• Actual Duration (Months): 11.1
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Post-bariatric Hypoglycemia	Drug: glucagon; Device: Closed loop glucagon pump	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• 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.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.
• 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.
• Primary Purpose: Prevention
• Official Title: Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia
• Actual Study Start Date: Sep 19, 2017
• Actual Primary Completion Date: Aug 22, 2018
• Actual Study Completion Date: Aug 22, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Study drug (glucagon) first, placebo second 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.	Drug: glucagon; novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals; Device: 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.
Other: Placebo first, study drug (glucagon) second 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.	Device: 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <65 mg/dL [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   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.

2. Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <65 mg/dL [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   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

Secondary Outcome Measures

1. Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <60 mg/dL [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <60 mg/dl, comparing vehicle to control

2. Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl). [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge will be conducted within two weeks of the first.]

   Compare outcomes for glucagon versus vehicle infusions for prevention of rebound hyperglycemia (defined as glucose levels above 180 mg/dl).

3. Number of Participants With Hypoglycemia Rescue Administered [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Protocol-specified rescue delivery of IV glucose was performed if plasma glucose <55 mg/dL and/or significant neuroglycopenia developed.

4. Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <60 mg/dL [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <60 mg/dl, comparing vehicle to control

5. Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <55 mg/dL [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <55 mg/dl, comparing vehicle to control

6. Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <55 mg/dL [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <55 mg/dl, comparing vehicle to control

7. Percent Time Plasma Glucose in Range After Drug Delivery [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after drug delivery

8. Percent Time Sensor Glucose in Range After Drug Delivery [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (65-180mg/dL) after drug delivery

9. Meal Provoked Nadir Plasma Glucose [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

   Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control

10. Meal Provoked Nadir Sensor Glucose [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control

11. Time to Nadir Plasma Glucose After Mixed Meal (Min) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

12. Time to Nadir Sensor Glucose After Mixed Meal (Min) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

13. Time to Alarm During Mixed Meal Testing (Minutes) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    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.

14. Time to Delivery (Min) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    Time to delivery (min) of study drug during mixed meal testing

15. Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    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.

16. Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    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.

17. Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    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.

18. Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL) [Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.]

    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.

19. 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). [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).]

    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.

20. 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). [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).]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males or females diagnosed with ongoing post-bariatric hypoglycemia with prior episodes of neuroglycopenia, unresponsive to dietary intervention (low glycemic index, controlled carbohydrate portions) and trial of acarbose therapy at the maximally tolerated dose.

2. Age 18-65 years of age, inclusive, at screening.

3. Willingness to provide informed consent and follow all study procedures, including attending all scheduled visits.

Exclusion Criteria:

1. Documented hypoglycemia occurring in the fasting state (> 12 hours fast);

2. Chronic kidney disease stage 4 or 5 (including end-stage renal disease);

3. Hepatic disease, including serum alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin < 3.0 g/dL; or serum bilirubin > 2.0;

4. Congestive heart failure, New York Heart Association (NYHA )class II, III or IV;

5. History of myocardial infarction, unstable angina or revascularization within the past 6 months or 2 or more risk factors for coronary artery disease including diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use;

6. History of cardiac arrhythmia or arrhythmia detected by EKG during the screening visit;

7. History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia

8. Concurrent administration of β-blocker therapy;

9. History of a cerebrovascular accident;

10. Seizure disorder (other than with suspect or documented hypoglycemia);

11. Active treatment with any diabetes medications except for acarbose;

12. Active malignancy, except basal cell or squamous cell skin cancers;

13. Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);

14. Known insulinoma or glucagonoma;

15. Major surgical operation within 30 days prior to screening;

16. Hematocrit < 33%;

17. Bleeding disorder, treatment with warfarin, or platelet count <50,000;

18. Blood donation (1 pint of whole blood) within the past 2 months;

19. Active alcohol abuse or substance abuse;

20. Current administration of oral or parenteral corticosteroids;

21. Pregnancy and/ or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an intrauterine device (IUD), the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence;

22. Use of an investigational drug within 30 days prior to screening;

23. Current use of anticholinergic medications;

24. Allergy to a component of the study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Joslin Diabetes Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Joslin Diabetes Center
• National Institutes of Health (NIH)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Xeris Pharmaceuticals
• Harvard University

Investigators

• Principal Investigator: Mary E Patti, MD, Joslin Diabetes Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 6, 2018

More Information

Publications

• 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). pii: dgz197. doi: 10.1210/clinem/dgz197.

• Responsible Party: Joslin Diabetes Center
• ClinicalTrials.gov Identifier: NCT03255629
• Other Study ID Numbers: 2016-27; 1R44DK107114
• First Posted: Aug 21, 2017
• Last Update Posted: Jul 26, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Hypoglycemia; Glucagon; Glucagon-Like Peptide 1

Study 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.
Pre-assignment Detail	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.

Arm/Group Title	Study Drug (Glucagon) First, Then Placebo (Randomized, Double-blind, Crossover Design)	Placebo First, Then Study Drug (Glucagon) Second (Randomized, Double-blind, Crossover Design)
Arm/Group 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. Glucagon: novel, stable, non-aqueous glucagon formulation provided by Xeris Pharmaceuticals. 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.	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. 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. 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.
Period Title: Overall Study
STARTED	8	8
COMPLETED	5	7
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Treatment Arm / Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)
Arm/Group 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (2.4)
Sex: Female, Male (Count of Participants)
Female	11 91.7%
Male	1 8.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 8.3%
Not Hispanic or Latino	10 83.3%
Unknown or Not Reported	1 8.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	11 91.7%
More than one race	1 8.3%
Unknown or Not Reported	0 0%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.6 (1.5)
Years since surgery (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.4 (1.5)
Years from surgery to neuroglycopenia (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	2.2
HbA1c (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	5.3 (0.1)
On any anti-hypoglycemic medications (Count of Participants)
Count of Participants [Participants]	10 83.3%
Treated with acarbose (Count of Participants)
Count of Participants [Participants]	5 41.7%
Treated with diazoxide (Count of Participants)
Count of Participants [Participants]	4 33.3%
Treated with octreotide (Count of Participants)
Count of Participants [Participants]	3 25%
Treated with pramlintide (Count of Participants)
Count of Participants [Participants]	2 16.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <65 mg/dL
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.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

12 Enrolled Participants Completed 2 Mixed-Meal Study Visits and Were Included in the Analysis

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Number [participants]	1 8.3%	5 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.103
	Comments
	Method	McNemar
	Comments

2. Primary Outcome

Title	Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <65 mg/dL
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
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	1 8.3%	4 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments
	Method	McNemar
	Comments

3. Secondary Outcome

Title	Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <60 mg/dL
Description	Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <60 mg/dl, comparing vehicle to control
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	1 8.3%	3 NaN

4. Secondary Outcome

Title	Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).
Description	Compare outcomes for glucagon versus vehicle infusions for prevention of 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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	0 0%	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.317
	Comments
	Method	McNemar
	Comments

5. Secondary Outcome

Title	Number of Participants With Hypoglycemia Rescue Administered
Description	Protocol-specified rescue delivery of IV glucose was performed if plasma glucose <55 mg/dL and/or significant neuroglycopenia developed.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	0 0%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	McNemar
	Comments

6. Secondary Outcome

Title	Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <60 mg/dL
Description	Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <60 mg/dl, comparing vehicle to control
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	0 0%	3 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments
	Method	McNemar
	Comments

7. Secondary Outcome

Title	Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <55 mg/dL
Description	Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <55 mg/dl, comparing vehicle to control
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	0 0%	5 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	McNemar
	Comments

8. Secondary Outcome

Title	Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <55 mg/dL
Description	Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <55 mg/dl, comparing vehicle to control
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Count of Participants [Participants]	0 0%	0 NaN

9. Secondary Outcome

Title	Percent Time Plasma Glucose in Range After Drug Delivery
Description	Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after drug delivery
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [percentage of time]	0.852 (0.082)	0.645 (0.074)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed effects models to account for correlation within subjects over time

10. Secondary Outcome

Title	Percent Time Sensor Glucose in Range After Drug Delivery
Description	Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (65-180mg/dL) after drug delivery
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [percentage of time]	0.987 (0.013)	0.815 (0.077)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments
	Method	Mixed Models Analysis
	Comments	Linear mixed effects models to account for correlation within subjects over time

11. Secondary Outcome

Title	Meal Provoked Nadir Plasma Glucose
Description	Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [mg/dL]	67.4 (2.70)	58.5 (1.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments

12. Secondary Outcome

Title	Meal Provoked Nadir Sensor Glucose
Description	Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [mg/dL]	72.7 (2.21)	65.3 (1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	Mixed Models Analysis
	Comments

13. Secondary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [minutes]	138 (11.9)	125 (7.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments
	Method	Mixed Models Analysis
	Comments

14. Secondary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [minutes]	156 (11.6)	134 (6.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments
	Method	Mixed Models Analysis
	Comments

15. Secondary Outcome

Title	Time to Alarm During Mixed Meal Testing (Minutes)
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.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Arm
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [minutes]	89.9 (3.90)	87.7 (4.9975)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.659
	Comments
	Method	Mixed Models Analysis
	Comments

16. Secondary Outcome

Title	Time to Delivery (Min)
Description	Time to delivery (min) of study drug during mixed meal testing
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [minutes]	94 (5.52)	89.3 (5.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.406
	Comments
	Method	Mixed Models Analysis
	Comments

17. Secondary Outcome

Title	Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)
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.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [mg/dL]	134 (5.93)	139 (4.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.611
	Comments
	Method	Mixed Models Analysis
	Comments

18. Secondary Outcome

Title	Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)
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.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [mg/dL]	98.1 (7.30)	109 (5.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.183
	Comments
	Method	Mixed Models Analysis
	Comments

19. Secondary Outcome

Title	Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)
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.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Arm
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [mg/dL]	85.7 (4.96)	70.1 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Mixed Models Analysis
	Comments

20. Secondary Outcome

Title	Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)
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.
Time Frame	Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [mg/dL]	94.2 (1.70)	91.7 (8.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.789
	Comments
	Method	Mixed Models Analysis
	Comments

21. Secondary Outcome

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).
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.
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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [pain score]	4.00 (0.685)	3.83 (0.815)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.865
	Comments
	Method	McNemar
	Comments

22. Secondary Outcome

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).
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.
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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Drug (Glucagon) Phase	Placebo / Control Phase
Arm/Group 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. 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.	This phase represents when the participant received the placebo. A participant could receive 2 doses of the placebo at this visit. 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. 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.
Measure Participants	12	12
Mean (Standard Error) [pain score]	1.14 (0.615)	1.31 (0.671)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Drug (Glucagon) Phase, Placebo / Control Phase
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.875
	Comments
	Method	McNemar
	Comments

Adverse 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.
Adverse Event Reporting Description	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.
Arm/Group Title	Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)
Arm/Group 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. glucagon: novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals 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.
All Cause Mortality
	Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)
	Affected / at Risk (%)	# Events
Total	0/18 (0%)
Serious Adverse Events
	Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)
	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)
Metabolism and nutrition disorders
Hypokalemia	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)
	Affected / at Risk (%)	# Events
Total	16/18 (88.9%)
Blood and lymphatic system disorders
MCH above normal limit of refrence range at screening visit.	1/18 (5.6%)	1
WBC above normal limit of reference range at screening visit	1/18 (5.6%)	1
Cardiac disorders
Palpitations after intake of mixed meal (prior to study drug OR placebo)	6/18 (33.3%)
Endocrine disorders
Hypoglycemia during study (MMTT)	13/18 (72.2%)	21
Thirsty after alarm (placebo visit)	1/18 (5.6%)
Hypoglycemia following lunch (gluagon visit)	1/18 (5.6%)
Hypoglycemia following lunch (placebo visit)	1/18 (5.6%)
Hypoglycemia after dinner the night following the study visit (glucagon visit)	1/18 (5.6%)
Eye disorders
Blurry vision after intake of mixed meal (prior to study drug OR placebo)	1/18 (5.6%)
Blurry vision after alarm (placebo visit)	1/18 (5.6%)
Blurry vision after alarm (glucagon visit)	1/18 (5.6%)
Gastrointestinal disorders
Nausea after intake of mixed meal (prior to glucagon OR placebo)	12/18 (66.7%)	16
Emesis after intake of mixed meal (prior to study drug OR placebo)	2/18 (11.1%)
Stomach ache / cramping after intake of mixed meal (prior to study drug OR placebo)	2/18 (11.1%)
Bloated / uncomfortably full after intake of mixed meal (prior to study drug OR placebo)	1/18 (5.6%)	2
Nausea after alarm (glucagon visit)	1/18 (5.6%)
Vomiting after alarm (glucagon visit)	1/18 (5.6%)
Bowel urgency after alarm (glucagon visit)	1/18 (5.6%)
Bowel movement after alarm (placebo visit)	1/18 (5.6%)
Stomach cramping / pain after alarm (placebo visit)	2/18 (11.1%)
Nausea prior to lunch (glucagon visit)	1/18 (5.6%)
Stomach pains after lunch (glucagon visit)	1/18 (5.6%)
Nausea after lunch (glucagon visit)	1/18 (5.6%)
Vomiting after lunch (glucagon visit)	1/18 (5.6%)
Tiredness day after study visit (placebo visit)	3/18 (16.7%)
General disorders
Headache prior to start of MMTT	2/18 (11.1%)	2
Tiredness prior to start of MMTT	1/18 (5.6%)	1
Headache after intake of mixed meal (prior to glucagon OR placebo)	7/18 (38.9%)
Feeling cold / chills after intake of mixed meal (prior to study drug OR placebo)	3/18 (16.7%)
Feeling hot / warm after intake of mixed meal (prior to study drug or placebo)	6/18 (33.3%)
Thirsty after intake of mixed meal (prior to study drug OR placebo)	1/18 (5.6%)	1
Tiredness after intake of mixed meal (prior to study drug OR placebo)	11/18 (61.1%)
Tingling (paresthesia) in shoulders after intake of mixed meal (prior to study drug or placebo)	1/18 (5.6%)
Tingling (paresthesia) around the mouth after intake of mixed meal (prior to study drug or placebo)	1/18 (5.6%)
Dizzy after intake of mixed meal (prior to study drug OR placebo)	1/18 (5.6%)
Feeling unwell ("icky... drunk") after intake of mixed meal (prior to study drug OR placebo)	1/18 (5.6%)
Tearful after intake of mixed meal (prior to study drug OR placebo)	1/18 (5.6%)
Pain at pump site during MMTT (prior to delivery of study drug or placebo)	2/18 (11.1%)
Irritation / pain at IV site with IV administration of dextrose	1/18 (5.6%)
Tearful when IV dextrose (D50) administered	1/18 (5.6%)
Burning pain / pricking at pump site after alarm (placebo visit)	10/18 (55.6%)
Buring pain at pump site after alarm (glucagon visit)	13/18 (72.2%)
Feeling hot after alarm (glucagon visit)	2/18 (11.1%)
Feeling hot after alarm (placebo visit)	3/18 (16.7%)
Headace after alarm (glucagon visit)	2/18 (11.1%)
Tearful during alarm (placebo visit)	1/18 (5.6%)
Dizzy / lightheaded after alarm (glucagon visit)	2/18 (11.1%)
Low blood pressure after alarm (placebo visit)	1/18 (5.6%)
Tiredness after alarm (glucagon visit)	2/18 (11.1%)
Tiredness after alarm (placebo visit)	1/18 (5.6%)
Pale after alarm (placebo visit)	1/18 (5.6%)
Weakness prior to lunch (glucagon visit)	1/18 (5.6%)
Feeling hot prior to lunch (glucagon visit)	1/18 (5.6%)
Feeling hot after lunch (placebo visit)	2/18 (11.1%)
Tiredness after lunch (glucagon visit)	1/18 (5.6%)
Tiredness after lunch (placebo visit)	1/18 (5.6%)
Feeling cold after lunch (glucagon visit)	1/18 (5.6%)
Headache after lunch (glucagon visit)	2/18 (11.1%)
Shaky following lunch (glucagon visit)	1/18 (5.6%)
Ears ringing after lunch	1/18 (5.6%)
Foggy feeling after lunch (glucagon visit)	1/18 (5.6%)
Dry mouth following alarm (glucagon visit)	1/18 (5.6%)
Dizzy after discharge (placebo visit)	1/18 (5.6%)
Tiredness day after study visit (glucagon visit)	4/18 (22.2%)
Metabolism and nutrition disorders
Hyperkalemia at screening visit	1/18 (5.6%)	1
Musculoskeletal and connective tissue disorders
Lower extremity cramping after alarm (glucagon visit)	2/18 (11.1%)
Back pain after lunch (placebo visit)	1/18 (5.6%)
Nervous system disorders
Confusion after alarm (placebo visit)	1/18 (5.6%)
Confusion after alarm (glucagon visit)	1/18 (5.6%)
Speech slowed after alarm (placebo visit)	1/18 (5.6%)
Migraine headache one night following study visit (placebo visit)	1/18 (5.6%)
Skin and subcutaneous tissue disorders
Pruritis at pump insertion site during MMTT (prior to delivery of study drug or placebo)	2/18 (11.1%)
Erythema at site of CGM sensor	1/18 (5.6%)
Hematoma under CGM sensor	1/18 (5.6%)
Erythema at pump infusion site (placebo visit)	10/18 (55.6%)
Erythema at pump infusion site (glucagon visit)	11/18 (61.1%)
Edema at pump infusion site (placebo visit)	4/18 (22.2%)
Edema at pump infusion site (glucagon visit)	6/18 (33.3%)
Pruritis at pump site after alarm (placebo visit)	1/18 (5.6%)
Erythema a pump infusion site 1 day following discharge (glucagon visit)	1/18 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.