Glucagon Infusion in T1D Patients With Recurrent Severe Hypoglycemia: Effects on Counter-Regulatory Responses
Condition: Hypoglycemia Unawareness; Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Hypoglycemia; Diabetes Mellitus, Type 1
Intervention: Glucagon; Placebo
Intervention description: CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.; The placebo solution is a non-active formulation containing excipients only.
Intervention MeSH terms: Glucagon; Glucagon-Like Peptide 1
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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.
Masking: Double (Participant, Investigator)
Masking description: double-blind, placebo-controlled
Enrollment: 49.0
Sex: All
Minimum age: 21 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: glucagon; hypoglycemia counter-regulation

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.
    

Eligibility criteria:

        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.