Glucagon Infusion in T1D Patients With Recurrent Severe Hypoglycemia: Effects on Counter-Regulatory Responses

• Sponsor: Xeris Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03490942
• Collaborator: Integrated Medical Development (Industry)
• Enrollment: 49
• Locations: 5
• Arms: 4
• Actual Duration (Months): 22.9
• Patients Per Site: 9.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a prospective, randomized, controlled, double-blind, parallel 4-group trial with the primary analysis after 4 weeks of treatment with continuous subcutaneous glucagon infusion (CSGI) or placebo. After a 1-week qualification on continuous glucose monitoring (CGM), subjects will have their baseline hypoglycemia counter-regulatory response hormones quantified using a step-wise hypoglycemia induction procedure. Subjects meeting eligibility requirements will be randomized to 1 of 4 treatment groups, 2 glucagon, 2 placebo. Subjects will receive blinded study drug for 4 weeks, and they will be followed for an additional 26 weeks post-treatment. Subjects' counter-regulatory hormone response will be measured at baseline, the end of treatment (4 weeks), and 13 and 26 weeks after treatment ends.

Condition or Disease	Intervention/Treatment	Phase
Hypoglycemia Unawareness; Diabetes Mellitus, Type 1	Drug: Glucagon; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a prospective, randomized, controlled, double-blind, parallel 4-group trial with the primary analysis after 4 weeks treatment with CSGI or placebo.This is a prospective, randomized, controlled, double-blind, parallel 4-group trial with the primary analysis after 4 weeks treatment with CSGI or placebo.
• Masking: Double (Participant, Investigator)
• Masking Description: double-blind, placebo-controlled
• Primary Purpose: Treatment
• Official Title: Fixed Rate Continuous Subcutaneous Glucagon Infusion (CSGI) vs Placebo in Type 1 Diabetes Mellitus Patients With Recurrent Severe Hypoglycemia: Effects on Counter-Regulatory Responses to Insulin-Induced Hypoglycemia
• Actual Study Start Date: Mar 15, 2018
• Actual Primary Completion Date: Nov 4, 2019
• Actual Study Completion Date: Feb 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CSGI high infusion rate Glucagon given as a continuous subcutaneous infusion for 28 days	Drug: Glucagon; CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.; Other Names: CSI-Glucagon CGSI
Experimental: CSGI low infusion rate Glucagon given as a continuous subcutaneous infusion for 28 days	Drug: Glucagon; CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.; Other Names: CSI-Glucagon CGSI
Placebo Comparator: Placebo high infusion rate Placebo given as a continuous subcutaneous infusion for 28 days	Drug: Placebo; The placebo solution is a non-active formulation containing excipients only.
Placebo Comparator: Placebo low infusion rate Placebo given as a continuous subcutaneous infusion for 28 days	Drug: Placebo; The placebo solution is a non-active formulation containing excipients only.

Outcome Measures

Primary Outcome Measures

1. Plasma Epinephrine [0-30 minutes]

   Plasma epinephrine concentration after 30 minutes of induced hypoglycemia. Change from baseline to the end of treatment will be assessed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males or females diagnosed with type 1 diabetes mellitus for at least 24 months.

2. Random serum C-peptide concentration < 0.5 ng/ml at Screening.

3. Current use of multiple daily dosing insulin treatment < 1 U/(kg*day) total daily dose either administered with subcutaneous injections or continuous subcutaneous insulin infusion (CSII).

4. Recurrent severe hypoglycemia as defined by minimally two events during the last year and at least one the last six months requiring not merely receiving third party intervention and either confirmation with a measured glucose < 50 mg/dl, or prompt recovery from impaired consciousness. Events must be documented in patient chart prior to study entry. Events induced as a part of clinical diagnostics or experimentation do not qualify.

5. Performs monitoring of glucose minimally 3 times a day. Patients using continuous glucose monitoring for monitoring should continue to do so during the course of the study.

6. Age 21-64 years, inclusive, at screening.

7. Willingness to provide informed consent and follow all study procedures, including using the Medtronic smart phone application "iPRO2mylog" for diabetes data logging and attending all scheduled visits.

Exclusion Criteria:

1. Subjects using CSII, who do not use a Medtronic pump.

2. Hemoglobin A1c ≥9.0% at Screening.

3. Chronic kidney disease stage 4 or 5.

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

5. Hematocrit of less than or equal to 30% at Screening.

6. Blood pressure (BP) reading at Screening where systolic BP <90 or >150 mm Hg, or diastolic BP <50 or >100 mm Hg.

7. Clinically significant echocardiogram (ECG) abnormalities at Screening.

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

9. History of myocardial infarction, unstable angina or revascularization within the past 6 months.

10. History of a cerebrovascular accident.

11. Current seizure disorder.

12. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (multiple endocrine neoplasia type 2, neurofibromatosis, or Von Hippel-Lindau disease).

13. History of insulinoma.

14. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin cancers. History of breast cancer or malignant melanoma will be exclusionary.

15. Major surgical operation within 30 days prior to Screening.

16. Current bleeding disorder, treatment with warfarin, or platelet count below 50,000 at Screening.

17. History of allergies to glucagon or glucagon-like products, or any history of significant hypersensitivity to glucagon or any related products or to any of the excipients in the investigational formulation.

18. History of glycogen storage disease.

19. Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen.

20. Whole blood donation of 1 pint (500 mL) within 8 weeks prior to Screening. Donations of plasma, packed red blood cells, platelets or quantities less than 500 mL are allowed at investigator discretion.

21. Active substance or alcohol abuse (more than 21 drinks/wk. for males or 14 drinks/wk. for females). Subjects reporting active marijuana use and/or testing positive for tetrahydrocannabinol via rapid urine test will be allowed to participate in the study at the discretion of the investigator. Subjects positive for other drugs of abuse via rapid urine test who report use of a prescription or over-the-counter medication that would explain such a finding will be allowed to participate at the discretion of the investigator.

22. Administration of glucagon within 14 days of Screening.

23. Pregnant and/or Lactating. For subjects of childbearing potential, there is a requirement for a negative urine pregnancy test and for agreement to use contraception and to refrain from breast feeding during the study and for at least 1 month after participating in the study. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an intra-uterine device, the double barrier method (the female uses a diaphragm and spermicide and the male uses a condom), or abstinence.

24. Inadequate venous access.

25. Participation in other studies involving administration of an investigational drug or interventional device within 30 days or 5 half-lives, whichever is longer, before Screening for the current study and during the four weeks of study product administration in the current study.

26. Any reason the principal investigator deems exclusionary.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama, Birmingham	Birmingham	Alabama	United States	35294
2	University of California, San Diego	San Diego	California	United States	92037
3	Emory University - Grady Memorial Hospital	Atlanta	Georgia	United States	30303
4	Atlanta Diabetes Associates	Atlanta	Georgia	United States	30318
5	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Xeris Pharmaceuticals
• Integrated Medical Development

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 21, 2018
• Statistical Analysis Plan - Dec 21, 2019

More Information

Publications

None provided.

• Responsible Party: Xeris Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03490942
• Other Study ID Numbers: XSGO-AF01
• First Posted: Apr 6, 2018
• Last Update Posted: Feb 21, 2021
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Xeris Pharmaceuticals: glucagon; hypoglycemia counter-regulation
• Additional relevant MeSH terms: Diabetes Mellitus; Hypoglycemia; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Like Peptide 1

Study Results

Participant Flow

Arm/Group Title	CSGI High Infusion Rate	CSGI Low Infusion Rate	Placebo High Infusion Rate
Arm/Group Description	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.	Placebo given as a continuous subcutaneous infusion for 28 days Placebo: The placebo solution is a non-active formulation containing excipients only.
Period Title: Overall Study
STARTED	15	18	16
COMPLETED	5	8	9
NOT COMPLETED	10	10	7

Baseline Characteristics

Arm/Group Title	CSGI High Infusion Rate	CSGI Low Infusion Rate	Placebo High Infusion Rate	Total
Arm/Group Description	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.	Placebo given as a continuous subcutaneous infusion for 28 days Placebo: The placebo solution is a non-active formulation containing excipients only.	Total of all reporting groups
Overall Participants	15	17	16	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47	37	39	41.5
Sex: Female, Male (Count of Participants)
Female	10 66.7%	11 64.7%	8 50%	29 60.4%
Male	5 33.3%	6 35.3%	8 50%	19 39.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.7%	4 23.5%	0 0%	5 10.4%
Not Hispanic or Latino	14 93.3%	13 76.5%	16 100%	43 89.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 5.9%	0 0%	1 2.1%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	4 26.7%	3 17.6%	2 12.5%	9 18.8%
White	11 73.3%	13 76.5%	13 81.3%	37 77.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 6.3%	1 2.1%

Outcome Measures

1. Primary Outcome

Title	Plasma Epinephrine
Description	Plasma epinephrine concentration after 30 minutes of induced hypoglycemia. Change from baseline to the end of treatment will be assessed.
Time Frame	0-30 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CSGI High Infusion Rate	CSGI Low Infusion Rate	Placebo High Infusion Rate
Arm/Group Description	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.	Placebo given as a continuous subcutaneous infusion for 28 days Placebo: The placebo solution is a non-active formulation containing excipients only.
Measure Participants	14	17	14
Mean (Standard Deviation) [Pg/mL]	100.0 (150.10)	144.4 (168.56)	167.3 (138.87)

Adverse Events

Time Frame	4 weeks
Arm/Group Title	CSGI High Infusion Rate		CSGI Low Infusion Rate		Placebo High Infusion Rate
Arm/Group Description	Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.		Glucagon given as a continuous subcutaneous infusion for 28 days Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.		Placebo given as a continuous subcutaneous infusion for 28 days Placebo: The placebo solution is a non-active formulation containing excipients only.
All Cause Mortality
	CSGI High Infusion Rate		CSGI Low Infusion Rate		Placebo High Infusion Rate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/17 (0%)		0/16 (0%)
Serious Adverse Events
	CSGI High Infusion Rate		CSGI Low Infusion Rate		Placebo High Infusion Rate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		0/17 (0%)		0/16 (0%)
Gastrointestinal disorders
Gastric emptying	1/15 (6.7%)	1	1/17 (5.9%)	1	1/16 (6.3%)	1
Injury, poisoning and procedural complications
Foot fracture	1/15 (6.7%)	1	1/17 (5.9%)	1	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	CSGI High Infusion Rate		CSGI Low Infusion Rate		Placebo High Infusion Rate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/15 (46.7%)		4/17 (23.5%)		2/16 (12.5%)
Gastrointestinal disorders
Nausea	3/15 (20%)	3	1/17 (5.9%)	1	0/16 (0%)	0
Vomiting	2/15 (13.3%)	2	2/17 (11.8%)	2	0/16 (0%)	0
General disorders
Headache	2/15 (13.3%)	2	1/17 (5.9%)	1	0/16 (0%)	0
Skin and subcutaneous tissue disorders
Erythema	0/15 (0%)	0	0/17 (0%)	0	2/16 (12.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.