Hypoglycemia
Conditions
Keywords
Hypoglycemia, Glucagon, Diabetes
Brief summary
The purpose of the study is to demonstrate that mini-doses of stable liquid glucagon (G-Pen Mini) produced by Xeris Pharmaceuticals are safe and effective as a treatment for mild to moderate hypoglycemia, a complication of diabetes.
Interventions
stable, pre-mixed, liquid glucagon for subcutaneous injection
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Emissary International LLC
Xeris Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female subjects on insulin infusion pump therapy for treatment of type 1 diabetes 2. Between the ages of 18 and 50 years of age, inclusive, at Screening. 3. Females of childbearing potential with a negative serum pregnancy test prior at screening and negative urine pregnancy tests prior to the Treatment visits, using an approved forms of contraception for the duration of participation in the study (i.e. until after last dose). 4. Male subjects are required to use a condom and another of the methods of contraception in #3 above starting at Randomization and for the duration of the study. 5. Hemoglobin A1c (HbA1c) \< 9.0 %. 6. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 7. Subjects must be willing and able to comply with scheduled visits, treatment, laboratory tests and study procedures.
Exclusion criteria
1. Clinical evidence of microvascular complication(s) other than mild microalbuminuria or history of mild non-proliferative retinopathy 2. Any chronic diseases or illness that interferes with glucose metabolism, except for T1DM, or medications other than hypothyroidism on appropriate thyroid hormone replacement. 3. Blood pressure (BP) readings at Screening where Systemic BP \<90 or \>140 mm Hg, and Diastolic BP \<50 or \>90 mm Hg. 4. Cardiovascular event within 6 months prior to screening such as unstable angina, acute coronary syndrome, myocardial infarction, therapeutic coronary procedure (e.g., stent placement, Percutaneous Transluminal Coronary Angioplasty (PTCA), Coronary Artery By-pass Grafting (CABG)), stroke or transient ischemic attack. 5. Study participants who are pregnant at Screening. 6. Breast feeding must be discontinued if a subject wishes to participate in this study. 7. Positive test for hepatitis B, hepatitis C, or HIV found at Screening. 8. Positive urine drug test for illicit drugs at Screening. 9. History of allergies to glucagon, glucagon-like products or to any of the excipients in the investigational formulation. 10. Known presence of hereditary problems of glycogen storage disease, galactose and /or lactose intolerance 11. Administration of glucagon more than once within the three (3) months prior to Screening 12. Subjects with any of the following abnormalities in clinical laboratory tests at Screening, confirmed by a single repeat, if necessary: * Hemoglobin (Hb) below the lower limits of normal for the laboratory * Total bilirubin above the upper limits of normal for the laboratory * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above the upper limits of normal for the laboratory * Creatinine above the upper limits of normal for the laboratory 13. History of regular alcohol consumption as defined by alcohol intake in a quantity exceeding 7 drinks per week for females or 14 drinks per week for males, where 1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor. 14. Participation in other studies involving administration of an investigational 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 15. 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. 16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | From first dose until follow-up call, up to 7 weeks per subject | Number of serious adverse events (SAEs) per treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucagon Cmax (Fasting) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection | Pharmacokinetic parameter: Maximum concentration of glucagon |
| Glucagon Cmax (Post-insulin) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacokinetic parameter: Maximum concentration of glucagon |
| Glucagon Area Under the Curve (AUC) (Fasting) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacokinetic parameter: Area under the glucagon concentration curve from 0 to 120 minutes |
| Glucagon AUC (Post-insulin) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacokinetic parameter: Area under the glucagon concentration curve from 0 to 120 minutes |
| Glucagon Tmax (Fasting) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection | Pharmacokinetic parameter: Time to reach maximum concentration of glucagon |
| Glucagon Tmax (Post-insulin) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacokinetic parameter: Time to reach maximum concentration of glucagon |
| Glucose Cmax (Fasting) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection | Pharmacodynamic parameter: Maximum concentration of glucose |
| Glucose Cmax (Post-insulin) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacodynamic parameter: Maximum concentration of glucose |
| Glucose AUC (Fasting) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacodynamic parameter: baseline adjusted area under the glucagon concentration curve from 0 to 120 minutes |
| Glucose AUC (Post-insulin) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacodynamic parameter: baseline adjusted area under the glucose concentration curve from 0-120 minutes |
| Glucose Tmax (Fasting) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection | Pharmacodynamic parameter: Time to reach maximum concentration of glucose |
| Glucose Tmax (Post-insulin) | Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection | Pharmacodynamic parameter: Time to reach maximum concentration of glucose |
Countries
United States
Participant flow
Recruitment details
A total of 13 adults \< 50 years of age with type 1 diabetes were recruited over a period of 5 months to receive treatment at a university-affiliated state hospital-based endocrinology clinic.
Pre-assignment details
A total of 13 subjects were randomized to treatment. Due to poor venous access an IV could not be started in one subject, so only 12 subjects received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Total Study Group Includes all 12 treated subjects | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Total Study Group |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 26.4 years STANDARD_DEVIATION 9.1 |
| Body Weight | 73.6 kg STANDARD_DEVIATION 12.08 |
| Duration of Diabetes | 11.6 years STANDARD_DEVIATION 6.02 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HbA1c | 7.7 percent STANDARD_DEVIATION 0.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 12 | 11 / 12 | 11 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Serious Adverse Events
Number of serious adverse events (SAEs) per treatment
Time frame: From first dose until follow-up call, up to 7 weeks per subject
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Serious Adverse Events | 0 participants |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Serious Adverse Events | 0 participants |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Serious Adverse Events | 0 participants |
Secondary
Glucagon Area Under the Curve (AUC) (Fasting)
Pharmacokinetic parameter: Area under the glucagon concentration curve from 0 to 120 minutes
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucagon Area Under the Curve (AUC) (Fasting) | 265.4 (pg/ml)*hour | Standard Error 35.4 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucagon Area Under the Curve (AUC) (Fasting) | 389.6 (pg/ml)*hour | Standard Error 35.4 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucagon Area Under the Curve (AUC) (Fasting) | 735.3 (pg/ml)*hour | Standard Error 35.4 |
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
Secondary
Glucagon AUC (Post-insulin)
Pharmacokinetic parameter: Area under the glucagon concentration curve from 0 to 120 minutes
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucagon AUC (Post-insulin) | 277.4 (pg/ml)*hour | Standard Error 29.9 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucagon AUC (Post-insulin) | 386.8 (pg/ml)*hour | Standard Error 29.9 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucagon AUC (Post-insulin) | 635.3 (pg/ml)*hour | Standard Error 29.7 |
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
Secondary
Glucagon Cmax (Fasting)
Pharmacokinetic parameter: Maximum concentration of glucagon
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucagon Cmax (Fasting) | 233.8 pg/ml | Standard Error 34 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucagon Cmax (Fasting) | 380.7 pg/ml | Standard Error 34 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucagon Cmax (Fasting) | 663.6 pg/ml | Standard Error 34 |
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
Secondary
Glucagon Cmax (Post-insulin)
Pharmacokinetic parameter: Maximum concentration of glucagon
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subject who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucagon Cmax (Post-insulin) | 253.4 pg/ml | Standard Error 30.1 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucagon Cmax (Post-insulin) | 335.4 pg/ml | Standard Error 30.1 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucagon Cmax (Post-insulin) | 561.7 pg/ml | Standard Error 29.9 |
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
Secondary
Glucagon Tmax (Fasting)
Pharmacokinetic parameter: Time to reach maximum concentration of glucagon
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucagon Tmax (Fasting) | 29.2 minutes | Standard Error 3.6 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucagon Tmax (Fasting) | 29.8 minutes | Standard Error 3.6 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucagon Tmax (Fasting) | 36.5 minutes | Standard Error 3.6 |
p-value: >0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
Secondary
Glucagon Tmax (Post-insulin)
Pharmacokinetic parameter: Time to reach maximum concentration of glucagon
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucagon Tmax (Post-insulin) | 24 minutes | Standard Error 2.7 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucagon Tmax (Post-insulin) | 33.1 minutes | Standard Error 2.7 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucagon Tmax (Post-insulin) | 34.1 minutes | Standard Error 2.7 |
p-value: >0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
Secondary
Glucose AUC (Fasting)
Pharmacodynamic parameter: baseline adjusted area under the glucagon concentration curve from 0 to 120 minutes
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucose AUC (Fasting) | 4872.0 (mg/dl)*minutes | Standard Error 1495.9 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucose AUC (Fasting) | 8565.2 (mg/dl)*minutes | Standard Error 1492.8 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucose AUC (Fasting) | 12420.0 (mg/dl)*minutes | Standard Error 1500.6 |
p-value: <0.05Mixed Models Analysis
p-value: 0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
Secondary
Glucose AUC (Post-insulin)
Pharmacodynamic parameter: baseline adjusted area under the glucose concentration curve from 0-120 minutes
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucose AUC (Post-insulin) | 2263.2 (mg/dl)*minutes | Standard Error 717.1 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucose AUC (Post-insulin) | 2408.1 (mg/dl)*minutes | Standard Error 718.4 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucose AUC (Post-insulin) | 3928.5 (mg/dl)*minutes | Standard Error 703.4 |
p-value: >0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
Secondary
Glucose Cmax (Fasting)
Pharmacodynamic parameter: Maximum concentration of glucose
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucose Cmax (Fasting) | 155.1 mg/dl | Standard Error 11.2 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucose Cmax (Fasting) | 186.2 mg/dl | Standard Error 11.1 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucose Cmax (Fasting) | 213.5 mg/dl | Standard Error 11.2 |
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
Secondary
Glucose Cmax (Post-insulin)
Pharmacodynamic parameter: Maximum concentration of glucose
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucose Cmax (Post-insulin) | 99.7 mg/dl | Standard Error 8.6 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucose Cmax (Post-insulin) | 105.7 mg/dl | Standard Error 8.6 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucose Cmax (Post-insulin) | 122.6 mg/dl | Standard Error 8.4 |
p-value: >0.05Mixed Models Analysis
p-value: <0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
Secondary
Glucose Tmax (Fasting)
Pharmacodynamic parameter: Time to reach maximum concentration of glucose
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 180 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucose Tmax (Fasting) | 81.5 minutes | Standard Error 10.2 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucose Tmax (Fasting) | 80.7 minutes | Standard Error 10.2 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucose Tmax (Fasting) | 67.8 minutes | Standard Error 10.3 |
p-value: >0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
Secondary
Glucose Tmax (Post-insulin)
Pharmacodynamic parameter: Time to reach maximum concentration of glucose
Time frame: Approximately 15 and 0 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, and 120 minutes post-injection
Population: All randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen Mini™ (Glucagon Injection) 75 ug | Glucose Tmax (Post-insulin) | 53.5 minutes | Standard Error 7.1 |
| G-Pen Mini™ (Glucagon Injection) 150 ug | Glucose Tmax (Post-insulin) | 69.5 minutes | Standard Error 7.1 |
| G-Pen Mini™ (Glucagon Injection) 300 ug | Glucose Tmax (Post-insulin) | 57.4 minutes | Standard Error 6.9 |
p-value: >0.05Mixed Models Analysis
p-value: >0.05Mixed Models Analysis
p-value: >0.05Regression, Linear