Glucagon Ready-to-Use (RTU) for Prevention of Exercise-Induced Hypoglycemia During Aerobic Exercise in Adults With T1D

Study Overview
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Brief Summary
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This study is a randomized, placebo-controlled, double-blind, 2-treatment, 2-period, crossover comparison in a clinical research center (CRC) setting, followed by a randomized, placebo-controlled, double-blinded, 2-arm parallel comparison with a third open-label arm in an outpatient setting. The purpose of the study is to evaluate the preliminary efficacy and safety of Glucagon Ready-to-Use [RTU] to prevent exercise-induced hypoglycemia (EIH) in adults with Type 1 diabetes mellitus (T1D), who perform regular, moderate-to-high intensity aerobic exercise.

Detailed Description
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There were 2 phases of this study: CRC and Outpatient. The initial posting of this study reflected the 3 treatment arms included in the Outpatient Phase of the study, without including the CRC and Outpatient Phases separately. CRC Phase: The CRC Phase was comprised of 2 visits that included daytime exercise sessions at the CRC or a comparable setting. Subjects were randomized to receive their first treatment at Visit 3 and crossed over (2 to 28 day washout) to their second treatment at Visit 4. The treatments were a single treatment with 30 microliters of either Glucagon RTU (0.15 mg) or placebo with a 50% insulin pump reduction. Blood glucose was assessed 15 minutes prior to the start of exercise, at the start of exercise, and then 15, 30, 45, 60, and 75 minutes from the start of exercise. Outpatient Phase: After completion of the CRC Phase, subjects entered the 12-week Outpatient Phase. Subjects were to maintain a weekly exercise average of 2 to 3 sessions of at least 30 minutes duration. Subjects were assigned randomly in 1:1:1 ratio to administer 30 microliters of one of the following prior to the exercise sessions: Glucagon RTU (0.15 mg) with a 50% insulin pump reduction, placebo with a 50% pump reduction or Glucagon RTU (0.15 mg) without an insulin pump reduction. Blood glucose was assessed 15 minutes prior to the start of exercise, just before exercise, after 30 minutes of exercise, at the end of exercise (if longer than 30 minutes), and 30 minutes post-exercise.

Official Title
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Phase 2 Randomized Placebo-Controlled Double-Blind Parallel Study to Evaluate Glucagon RTU (Glucagon Injection) Compared to Standard of Care for Prevention of Exercise-Induced Hypoglycemia During Regular Aerobic Exercise in Adults With T1D

Conditions
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Hypoglycemia

Intervention / Treatment
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* Drug: Glucagon RTU Injection With Insulin Pump Reduction
* Other: Vehicle for Glucagon RTU Injection With Insulin Pump Reduction
* Drug: Glugaon RTU Injection Without Insulin Pump Reduction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of presumed autoimmune type 1 diabetes, receiving daily insulin via continuous subcutaneous insulin infusion. Age 18 to < 65 years. Duration of type 1 diabetes ≥ 2 years. Random C-peptide < 0.6 ng/mL (<198 pmol/L). Using insulin therapy by continuous subcutaneous insulin infusion pump for at least 6 months. History of exercise-related hypoglycemia. Performs aerobic exercise regularly (2-3 times per week), and desires to exercise per American Diabetes Association guidelines (150 minutes per week). Examples of aerobic exercise include: power walking, hiking, running/jogging, cycling, swimming, cross country skiing, and aerobic fitness classes. Will abstain from the use of non-insulin diabetes therapies such as sodium glucose co-transporter 2, glucagon like peptide-1, and metformin for the duration of the study. Subject must be willing to adhere to the protocol requirements for the duration of the study. Subject has provided informed consent as evidenced by a signed/dated informed consent form completed before any trial-related activities occur. Exclusion Criteria: Frequently experience hyperglycemia with exercise, in the clinical judgement of the investigator. Pregnant and/ or Nursing: For female 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 week after the last dose of study drug. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an intra-uterine device, the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence. One or more severe hypoglycemic episodes in the past 12 months (as defined by an episode that required third party assistance for treatment). Uses inhaled insulin. Hemoglobin A1c > 9.0% at Screening. Renal insufficiency (serum creatinine greater than 3 mg/dL (0.17 mmol/L)). Serum alanine aminotransferase or aspartate aminotransferase equal to or greater than 3 times the upper limit of normal. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3 mg/dL (0.17 mmol/L); or serum bilirubin greater than 2 mg/dL (0.11 mmol/L). Hematocrit of less than or equal to 30%. Mean of triplicate blood pressure (BP) readings at Screening where systolic BP <90 or >150 mm Hg, or diastolic BP <50 or >100 mm Hg. Clinically significant electrocardiogram abnormalities. Use of > 2.0 U/kg total insulin dose per day. Inadequate bilateral venous access in both arms. Congestive heart failure, New York Heart Association class III or IV. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin cancers. Major surgical operation within 90 days prior to screening, or planned surgical operation during the study. History of seizure disorders. Bleeding disorder, treatment with warfarin or any anticoagulants, or platelet count below 50,000 mm3 at Screening. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (multiple endocrine neoplasia type 2, neurofibromatosis, or Von Hippel-Lindau disease). History of insulinoma. 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 (dimethylsulfoxide, mannitol, & trehalose) in the investigational formulation. History of glycogen storage disease. Subject tests positive for human immunodeficiency virus, hepatitis C virus, or active hepatitis B virus infection at Screening. Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen. Active substance or alcohol abuse, in the opinion of the investigator. Subjects reporting active marijuana use or testing positive for tetrahydrocannabinol via rapid urine test will be allowed to participate in the study at the discretion of the investigator. Participation in other studies involving administration of an investigational therapeutic agent (drug or device) within 30 days or 5 half-lives, whichever is longer, before Screening for the current study and during participation in the current study. Any reason the investigator deems exclusionary.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: CRC Phase: randomized, placebo-controlled, double-blind, two-treatment, two-period, crossover comparison in a clinical research center (CRC) setting. The subjects were re-randomized into the Outpatient Phase: randomized, placebo-controlled, partially double-blind, 3-arm parallel comparison in an outpatient setting.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CRC Phase: Glucagon RTU With Insulin Pump Reduction<br>CRC Phase: 2-arm randomized double-blind crossover, Glucagon RTU Injection 30 microliters of 0.15 mg injection with 50% reduction in the insulin pump | Drug: Glucagon RTU Injection With Insulin Pump Reduction<br>* 0.15 mg injection with 50% pump reduction<br>* Other names: XP-3994;|
| Placebo Comparator: CRC Phase: Vehicle for Glucagon RTU With Insulin Pump Reduction<br>CRC Phase: 2-arm randomized double-blind crossover, Vehicle for Glucagon RTU Injection 30 microliters vehicle with 50% reduction in the insulin pump | Other: Vehicle for Glucagon RTU Injection With Insulin Pump Reduction<br>* vehicle injection with 50% pump reduction<br>* Other names: Placebo;|
| Experimental: Outpatient Phase: Glucagon RTU With Insulin Pump Reduction<br>Outpatient Phase: 3-arm randomized comparison (2-arm double-blind, 1-arm open-label), Glucagon RTU Injection 30 microliters of 0.15 mg injection with 50% reduction in the insulin pump (double-blind arm) | Drug: Glucagon RTU Injection With Insulin Pump Reduction<br>* 0.15 mg injection with 50% pump reduction<br>* Other names: XP-3994;|
| Placebo Comparator: Outpatient Phase: Vehicle for Glucagon RTU With Insulin Pump Reduction<br>Outpatient Phase: 3-arm randomized comparison (2-arm double-blind, 1-arm open-label), Vehicle for Glucagon RTU Injection 30 microliters vehicle with 50% reduction in the insulin pump (double-blind arm) | Other: Vehicle for Glucagon RTU Injection With Insulin Pump Reduction<br>* vehicle injection with 50% pump reduction<br>* Other names: Placebo;|
| Experimental: Outpatient Phase: Glucagon RTU Without Insulin Pump Reduction<br>Outpatient Phase: 3-arm randomized comparison (2-arm double-blind, 1-arm open-label), Glucagon RTU Injection 30 microliters of 0.15 mg injection without a reduction in the insulin pump (open-label arm) | Drug: Glugaon RTU Injection Without Insulin Pump Reduction<br>* 0.15 mg injection without pump reduction<br>* Other names: XP-3994;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Outpatient Phase: Incidence Rate of Hypoglycemia During and After Moderate to High Intensity Aerobic Exercise. | Mean incidence rate of hypoglycemia during and after sessions of moderate to high intensity aerobic exercise in 12-week Outpatient Phase. Incidence rate is defined as the number of hypoglycemic events divided by the total number of qualified exercise sessions, assessed at group level. Qualified exercise session is: (1) confirmed blood glucose of 100-180 mg/dL prior to start of exercise, (2) self-administered study drug no more than 10 min prior to exercise (5 min target), (3) conducted a protocol allowed exercise of moderate to high intensity for at least 30 min and no longer than 75 min, and (4) achieved a target heart rate of 80% of maximum calculated heart rate at least once during session. Exercise sessions were to occur at least 2-3 times per week. Only 1 qualified exercise session/subject/day was included in the analysis (the first if >1). Hypoglycemic event defined as any hypoglycemic event occurring within 30 (+2) min after completion of a qualified exercise session. | Daily; During the 12-week Outpatient Phase qualified exercise sessions were assessed daily and associated hypoglycemia events were assessed continuously during and within the 30 (+2) minute period following a qualified exercise session. | 
| Outpatient Phase: Mean Number of Hypoglycemic Events | Outpatient Phase: Mean number of hypoglycemic events associated with the qualified exercise sessions, assessed at group level. A qualified exercise session was defined as one were (1) a confirmed blood glucose value of 100-180 mg/dL prior to start of exercise, (2) self-administered the study drug no more than 10 minutes prior to exercise (5 minutes was the target), (3) conducted a protocol allowed exercise for moderate to high intensity for at least 30 minutes and no longer than 75 minutes, and (4) achieved a target heart rate of 80% of maximum calculated heart rate at least once during the session. A hypoglycemic event was defined as any hypoglycemic event occurring during or within 30 (+2) minutes after completion of a qualified exercise session. Exercise sessions were expected to occur at least 2 to 3 times per week. Only 1 qualified exercise session per subject per day was included in the analysis (the first if >1). | Daily; During the 12-week Outpatient Phase qualified exercise sessions were assessed daily and associated hypoglycemia events were assessed continuously throughout the 30 (+2) minute period following a qualified exercise session. | 
| Outpatient Phase: Mean Number of Qualified High Intensity Aerobic Exercise Sessions | Outpatient Phase: Mean number of qualified exercise sessions, assessed at group level. A qualified exercise session was defined as one were (1) a confirmed blood glucose value of 100-180 mg/dL prior to start of exercise, (2) self-administered the study drug no more than 10 minutes prior to exercise (5 minutes was the target), (3) conducted a protocol allowed exercise for moderate to high intensity for at least 30 minutes and no longer than 75 minutes, and (4) achieved a target heart rate of 80% of maximum calculated heart rate at least once during the session. Exercise sessions were expected to occur at least 2 to 3 times per week. Only 1 qualified exercise session per subject per day was included in the analysis (the first if >1). | Daily; During the 12-week Outpatient Phase the occurrence of qualified exercise sessions were assessed daily. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRC Phase: Interstitial Glucose Below Target Range | Analysis of interstitial glucose (IG) was performed by treatment, independent of the order of treatment during the randomized cross-over CRC Phase. The number of participants are categorized by the following IG levels: Below range, as defined by IG <= 70 mg/dl (<=3.89 mmol/L); Between range, as defined by IG between 54 to 70 mg/dL (3 to 3.89 mmol/L); Below range, as defined by IG <54 mg/dL (<3 mmol/L) | Visit 3 (Day 1) and Visit 4 (Day 3 or any day up to Day 29); Assessed continuously 0-300 minutes following the start of the exercise session corresponding to each of the treatments during the corresponding in-clinic visit during the CRC Phase. | 
| Outpatient Phase: Interstitial Glucose Levels Below Target Range | Analysis of interstitial glucose (IG) was performed by treatment, during the randomized Outpatient Phase. The number of participants are categorized by the following IG levels: Below range, as defined by IG <= 70 mg/dl (<=3.89 mmol/L); Between range, as defined by IG between 54 to 70 mg/dL (3 to 3.89 mmol/L); Below range, as defined by IG <54 mg/dL (<3 mmol/L) | Visit 3 (Day 1) and Visit 4 (Day 3 or any day up to Day 29); Assessed continuously 0-300 minutes following the start of each qualified exercise session corresponding to each of the treatments during the Outpatient Phase. | 
| Outpatient Phase: Insulin Use Change From Baseline | Insulin use as reported by subject as Change from Outpatient Phase Baseline at Study Weeks 4, 8, and 12 | Insulin use measured continuously from Study Baseline to End of Study and assessed during Outpatient Phase as Change from Outpatient Phase Baseline at Study Weeks 4, 8, and 12 | 
| Outpatient Phase: Barriers to Physical Activity Diabetes (Type 1): BAPAD-1 Change From Baseline | Change from Baseline to End of the Outpatient Phase in Score on Barriers to Physical Activity in Type 1 Diabetes (BAPAD-1) Questionnaire A total of 12 factors were scored from 1=unlikely (min.) to 7=extremely likely (max.) for their propensity to keep the subject from practicing regular physical exercise during the next 6 months. Lower scores are considered better, while higher scores are considered worse outcomes. The higher the score (1 to 7), the less likely the subject was to engage in exercise. The mean of the scores of the 12 factors were calculated for each subject and the overall mean for the subjects was calculated at a group level with overall mean and standard deviation calculated at Baseline (Visit 3) and Follow-up/Early Termination (Visit 11) to calculate change from Baseline. Subject level and overall means could range from 1 to 7. | Baseline to End of Study measured at Outpatient Phase Baseline (Visit 3, Day 1) and Follow-up (Visit 11, 14-21 days after last exercise session, up to Day 134) or Early Termination (at time of discontinuation) | 
| Outpatient Phase: HFS-II Overall Score Change From Baseline | Change from Baseline in Score on Hypoglycemia Fear Survey-II (HFS-II) A total of 33 items were scored from 0=never (min.) to 4=almost always (max.) for how often in the past 6 months they had done the following: Behavior (15 items): things that people with diabetes often do to avoid low blood sugar. Worry (18 items): things that people with diabetes often worry about because of low blood sugar. Lower scores are considered better outcomes, higher scores are considered worse outcomes. The higher the score (0 to 4), the greater the subject's fear of hypoglycemia. The mean of the scores of the 33 items were calculated for each subject and the overall mean for the subjects was calculated at a group level with overall mean and standard deviation calculated at Baseline (Visit 3) and Follow-up/Early Termination (Visit 11) to calculate change from Baseline. Subject level and overall means could range from 0 to 4. | Baseline to End of Study measured at Outpatient Phase Baseline (Visit 3, Day 1) and Follow-up (Visit 11, 14-21 days after last exercise session, up to Day 134) or Early Termination (at time of discontinuation) | 
| Outpatient Phase: Hypoglycemic Confidence Scale (HCS) Change From Baseline | Change from Baseline in Score on Hypoglycemia Confidence Scale (HCS) The 9-item scale assessed a subject's confidence about safety regarding hypoglycemia. The questionnaire had 4 responses possible for each question, ranging from 1=not confident at all (min.) to 4=very confident (max.). Higher scores are considered better outcomes, while lower scores are considered worse outcomes. The lower the score (1 to 4), the less likely the subject was to engage in exercise. The mean of the scores of the 9 items were calculated for each subject and the overall mean for the subjects was calculated at a group level with overall mean and standard deviation calculated at Baseline (Visit 3) and Follow-up/Early Termination (Visit 11) to calculate change from Baseline. Subject level and overall means could range from 1 to 4. | Baseline to End of Study measured at Outpatient Phase Baseline (Visit 3, Day 1) and Follow-up (Visit 11, 14-21 days after last exercise session, up to Day 134) or Early Termination (at time of discontinuation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Glucagon, Insulin