Trial Outcomes & Findings for Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia (NCT NCT03255629)

NCT ID: NCT03255629

Last Updated: 2022-09-06

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 18 participants
• Primary outcome timeframe: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
• Results posted on: 2022-09-06

Participant Flow

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.

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.

Participant milestones

Measure	Study Drug (Glucagon) First, Then Placebo (Randomized, Double-blind, Crossover Design) 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.	Placebo First, Then Study Drug (Glucagon) Second (Randomized, Double-blind, Crossover Design) 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.
Overall Study STARTED	8	8
Overall Study COMPLETED	5	7
Overall Study NOT COMPLETED	3	1

Reasons for withdrawal

Measure	Study Drug (Glucagon) First, Then Placebo (Randomized, Double-blind, Crossover Design) 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.	Placebo First, Then Study Drug (Glucagon) Second (Randomized, Double-blind, Crossover Design) 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.
Overall Study Adverse Event	1	0
Overall Study did not experience hypoglycemia	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Treatment Arm / Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design) n=12 Participants 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.
Age, Continuous	52 years STANDARD_DEVIATION 2.4 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
BMI	27.6 kg/m^2 STANDARD_DEVIATION 1.5 • n=5 Participants
Years since surgery	8.4 years STANDARD_DEVIATION 1.5 • n=5 Participants
Years from surgery to neuroglycopenia	2.2 years n=5 Participants
HbA1c	5.3 percent STANDARD_DEVIATION 0.1 • n=5 Participants
On any anti-hypoglycemic medications	10 Participants n=5 Participants
Treated with acarbose	5 Participants n=5 Participants
Treated with diazoxide	4 Participants n=5 Participants
Treated with octreotide	3 Participants n=5 Participants
Treated with pramlintide	2 Participants n=5 Participants

PRIMARY outcome

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

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

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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <65 mg/dL	1 participants	5 participants

PRIMARY outcome

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

Population: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <65 mg/dL	1 Participants	4 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <60 mg/dL	1 Participants	3 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Hypoglycemia Rescue Administered	0 Participants	7 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <60 mg/dL	0 Participants	3 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <55 mg/dL	0 Participants	5 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <55 mg/dL	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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 the final dose, which was either 1 or 2 doses depending on patient response

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Percent Time Plasma Glucose in Range After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response	0.852 percentage of time Standard Error 0.082	0.645 percentage of time Standard Error 0.074

SECONDARY outcome

Timeframe: 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 (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Percent Time Sensor Glucose in Range After Drug Delivery After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response	0.987 percentage of time Standard Error 0.013	0.815 percentage of time Standard Error 0.077

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Meal Provoked Nadir Plasma Glucose	67.4 mg/dL Standard Error 2.70	58.5 mg/dL Standard Error 1.87

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Meal Provoked Nadir Sensor Glucose	72.7 mg/dL Standard Error 2.21	65.3 mg/dL Standard Error 1.85

SECONDARY outcome

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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Time to Nadir Plasma Glucose After Mixed Meal (Min)	138 minutes Standard Error 11.9	125 minutes Standard Error 7.43

SECONDARY outcome

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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Time to Nadir Sensor Glucose After Mixed Meal (Min)	156 minutes Standard Error 11.6	134 minutes Standard Error 6.04

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Time to Alarm During Mixed Meal Testing (Minutes)	89.9 minutes Standard Error 3.90	87.7 minutes Standard Error 4.9975

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Time to Delivery (Min)	94 minutes Standard Error 5.52	89.3 minutes Standard Error 5.33

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)	134 mg/dL Standard Error 5.93	139 mg/dL Standard Error 4.92

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)	98.1 mg/dL Standard Error 7.30	109 mg/dL Standard Error 5.75

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)	85.7 mg/dL Standard Error 4.96	70.1 mg/dL Standard Error 2.26

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)	94.2 mg/dL Standard Error 1.70	91.7 mg/dL Standard Error 8.62

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
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).	4.00 pain score Standard Error 0.685	3.83 pain score Standard Error 0.815

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Study Drug (Glucagon) Phase n=12 Participants 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.	Placebo / Control Phase n=12 Participants 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.
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).	1.14 pain score Standard Error 0.615	1.31 pain score Standard Error 0.671

Adverse Events

Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design)

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Measure

Treatment Arm and Control Arm (Randomized, Double-Blind, Placebo-Controlled Crossover Design) n=18 participants at risk 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.

Metabolism and nutrition disorders Hypokalemia

5.6% 1/18 • Number of events 1 • 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. 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.

Other adverse events

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

Additional Information

Mary Elizabeth Patti, MD

Joslin Diabetes Center

Phone: (617) 309-2635

Email: MaryElizabeth.Patti@joslin.harvard.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place