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

Conditions:Endocrine, Diabetes, Diabetes
Therapuetic Areas:Endocrinology
Age Range:21 - 64
Start Date:March 15, 2018
End Date:September 30, 2019
Contact:Khaled Junaidi, MD

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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.

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

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

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

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

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.
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