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

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

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.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 1; Hypoglycemia Unawareness
• Intervention / Treatment: Drug: Glucagon; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama, Birmingham
  • California
    • San Diego, California, United States, 92037
      • University of California, San Diego
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University - Grady Memorial Hospital
    • Atlanta, Georgia, United States, 30318
      • Atlanta Diabetes Associates
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Xeris Pharmaceuticals
• Collaborators: Integrated Medical Development

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2018
• Primary Completion (Actual): November 4, 2019
• Study Completion (Actual): February 10, 2020

Study Registration Dates

• First Submitted: March 25, 2018
• First Submitted That Met QC Criteria: April 1, 2018
• First Posted (Actual): April 6, 2018

Study Record Updates

• Last Update Posted (Actual): February 21, 2021
• Last Update Submitted That Met QC Criteria: February 2, 2021
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: glucagon; hypoglycemia counter-regulation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Glucagon; Glucagon-Like Peptide 1
• Other Study ID Numbers: XSGO-AF01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No