Diabetes Mellitus, Type 1, Hypoglycemia Unawareness
Conditions
Keywords
glucagon, hypoglycemia counter-regulation
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.
Interventions
DRUGGlucagon
CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.
DRUGPlacebo
The placebo solution is a non-active formulation containing excipients only.
Sponsors
Integrated Medical Development
Xeris Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
double-blind, placebo-controlled
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.
Eligibility
Sex/Gender
ALL
Age
21 Years to 64 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CSGI High Infusion Rate Glucagon given as a continuous subcutaneous infusion for 28 days
Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon. | 15 |
| CSGI Low Infusion Rate Glucagon given as a continuous subcutaneous infusion for 28 days
Glucagon: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon. | 17 |
| Placebo High Infusion Rate Placebo given as a continuous subcutaneous infusion for 28 days
Placebo: The placebo solution is a non-active formulation containing excipients only. | 16 |
| Total | 48 |
Baseline characteristics
| Characteristic | CSGI High Infusion Rate | CSGI Low Infusion Rate | Placebo High Infusion Rate | Total |
|---|---|---|---|---|
| Age, Continuous | 47 years | 37 years | 39 years | 41.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 13 Participants | 16 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 13 Participants | 13 Participants | 37 Participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 8 Participants | 29 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 8 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 7 / 15 | 4 / 17 | 2 / 16 |
| serious Total, serious adverse events | 2 / 15 | 0 / 17 | 0 / 16 |
Outcome results
Primary
Plasma Epinephrine
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CSGI High Infusion Rate | Plasma Epinephrine | 100.0 Pg/mL | Standard Deviation 150.1 |
| CSGI Low Infusion Rate | Plasma Epinephrine | 144.4 Pg/mL | Standard Deviation 168.56 |
| Placebo High Infusion Rate | Plasma Epinephrine | 167.3 Pg/mL | Standard Deviation 138.87 |