Hypoglycemia
Conditions
Keywords
Hypoglycemia, Glucagon
Brief summary
The purpose of this study is to demonstrate that G-Pen(TM) glucagon is comparable to Lilly Glucagon(TM) in terms of safety and efficacy, as a treatment for severe hypoglycemia, a complication of diabetes.
Detailed description
Primary objective: To Evaluate the Safety and Tolerability of G-Pen™ (Glucagon Injection) 1 mg Secondary objective (1): To Evaluate the pharmacodynamics (Efficacy) of G-Pen™ (Glucagon Injection) 1 mg Secondary objective (2):To compare the pharmacokinetics of G-Pen™ (glucagon injection) 1mg \[test\] administered as 0.5 mg and 1 mg injections, versus Lilly Glucagon™ (glucagon for injection \[rDNA origin\]) 1 mg (reference)
Interventions
DRUGLilly Glucagon(TM) 1 mg
DRUGG-Pen(TM) 0.5 mg
DRUGG-Pen(TM) 1 mg
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
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female subjects between the ages of 18 and 60 years of age, inclusive, at Screening. 2. Women must be of non-childbearing potential as defined by one of the following: * Females who are \>45 and \< 60 years of age at Screening and amenorrheic for at least 2 years * Females who have had a documented hysterectomy and/or bilateral oophorectomy. 3. Females of childbearing potential with a negative pregnancy test at Screening and Treatment visits, using one of the following forms of contraception for the duration of participation in the study (i.e., until Follow-up 7-14 days post last dose): * Oral contraceptive * Injectable progesterone * Subdermal implant * Spermicidal foam/gel/film/cream/suppository * Diaphragm with spermicide * Copper or hormonal containing intrauterine device (IUD) * Sterile male partner vasectomized \> 6 month pre-dosing. 4. Male subjects are required to use a condom and one of the methods of contraception in 2. or 3. above starting at Randomization and for the duration of the study. 5. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 6. Subjects must be willing and able to comply with scheduled visits, treatment, laboratory tests and study procedures.
Exclusion criteria
1. Recent (i.e., within three (3) months prior to Screening) evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, immunological, or clinically significant neurological disease. 2. Mean of triplicate set of seated BP readings at Screening, confirmed by 1 set of triplicate at Screening, if deemed necessary where systolic blood pressure (SBP) \<90 or \>140 mm Hg, and diastolic blood pressure (DBP) \<50 or \>90 mm Hg. 3. 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. 4. Clinically significant ECG abnormalities. 5. Study participants who are pregnant at Screening are not eligible for this study. 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. Allergies to glucagon, glucagon-like products or to any of the excipients in the investigational formulation. 10. Recent (i.e., within three (3) months prior to Screening) administration of glucagon. 11. Any prior cerebrovascular accident or major permanent neurological damage such as aphasia, hemiparesis, or dementia. 12. Peripheral artery disease with uncontrolled claudication 13. Current diagnosis or current clinical evidence of any New York Heart Association classification of heart failure. 14. Subjects with any of the following abnormalities in clinical laboratory tests at Screening, confirmed by a single repeat, if necessary: * Total bilirubin \> 1.5x upper limit of normal (ULN) * aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) ≥ 2.5x ULN. * Creatinine \> 2.5x ULN. 15. 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. 16. 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. 17. Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening. 18. 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 completion of the post-treatment follow-up visit, up to 6 weeks | Number of serious adverse events (SAEs) per treatment group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Cmax | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacodynamic parameter: Maximum concentration of glucose |
| Glucose Tmax | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacodynamic parameter: Time to Maximum Glucose Concentration |
| Glucose AUCex | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacodynamic parameter: Area Under the Glucose Excursion Curve |
| Glucose MAE | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacodynamic parameter: Maximum absolute glucose excursion from baseline |
| Glucose Area Under the Curve (AUC) | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacodynamic parameter: Glucose area under the curve from baseline to 240 minutes post-treatment |
| Glucagon AUC | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacokinetic parameter: Glucagon area under the curve from baseline to 240 minutes post-treatment |
| Glucagon Cmax | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacokinetic parameter: Maximum concentration of glucagon |
| Glucagon Tmax | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacokinetic parameter: Time to maximum concentration of glucagon |
| Glucose Tex | Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection | Pharmacodynamic parameter: Earliest reported time of MAE, based on within-subject changes from baseline |
Countries
United States
Participant flow
Recruitment details
This study involved healthy volunteers who were recruited from the local community surrounding a state-affiliated diabetes treatment center over a period of 3 months.
Pre-assignment details
Of a total of 41 individuals recruited, 4 declined participation, 7 did not meet eligibility criteria and 30 were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Total Study Group Includes all 30 randomized subjects | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Treatment Visit | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Second Treatment Visit | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total Study Group |
|---|---|
| Age, Continuous | 38.7 years STANDARD_DEVIATION 10.8 |
| Body Mass Index | 31.2 kg/m^2 STANDARD_DEVIATION 5.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 28 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 9 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 | 22 / 28 | 26 / 29 | 22 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 29 | 0 / 28 |
Outcome results
Primary
Serious Adverse Events
Number of serious adverse events (SAEs) per treatment group
Time frame: From first dose until completion of the post-treatment follow-up visit, up to 6 weeks
Population: All subjects receiving treatment were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| G-Pen(TM) 1 mg | Serious Adverse Events | 0 events |
| G-Pen(TM) 0.5 mg | Serious Adverse Events | 0 events |
| Lilly Glucagon(TM) 1 mg | Serious Adverse Events | 0 events |
Secondary
Glucagon AUC
Pharmacokinetic parameter: Glucagon area under the curve from baseline to 240 minutes post-treatment
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucagon AUC | 3259.9 min*pg/ml | Standard Deviation 3447.5 |
| G-Pen(TM) 0.5 mg | Glucagon AUC | 2105.3 min*pg/ml | Standard Deviation 2381.9 |
| Lilly Glucagon(TM) 1 mg | Glucagon AUC | 4781.7 min*pg/ml | Standard Deviation 2222.9 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Glucagon Cmax
Pharmacokinetic parameter: Maximum concentration of glucagon
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucagon Cmax | 2055.4 pg/ml | Standard Deviation 2052 |
| G-Pen(TM) 0.5 mg | Glucagon Cmax | 1318.8 pg/ml | Standard Deviation 1435.8 |
| Lilly Glucagon(TM) 1 mg | Glucagon Cmax | 4429.9 pg/ml | Standard Deviation 3970 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Glucagon Tmax
Pharmacokinetic parameter: Time to maximum concentration of glucagon
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucagon Tmax | 37.6 minutes | Standard Deviation 15.2 |
| G-Pen(TM) 0.5 mg | Glucagon Tmax | 33.3 minutes | Standard Deviation 13.2 |
| Lilly Glucagon(TM) 1 mg | Glucagon Tmax | 18.9 minutes | Standard Deviation 10.1 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Glucose Area Under the Curve (AUC)
Pharmacodynamic parameter: Glucose area under the curve from baseline to 240 minutes post-treatment
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucose Area Under the Curve (AUC) | 481.1 min*mg/dL | Standard Deviation 64.9 |
| G-Pen(TM) 0.5 mg | Glucose Area Under the Curve (AUC) | 467 min*mg/dL | Standard Deviation 47.9 |
| Lilly Glucagon(TM) 1 mg | Glucose Area Under the Curve (AUC) | 473.5 min*mg/dL | Standard Deviation 72.9 |
p-value: 0.24Mixed Models Analysis
Secondary
Glucose AUCex
Pharmacodynamic parameter: Area Under the Glucose Excursion Curve
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucose AUCex | 228.5 min*mg/dL | Standard Deviation 89.1 |
| G-Pen(TM) 0.5 mg | Glucose AUCex | 197.3 min*mg/dL | Standard Deviation 74.7 |
| Lilly Glucagon(TM) 1 mg | Glucose AUCex | 223 min*mg/dL | Standard Deviation 101.5 |
p-value: 0.76Mixed Models Analysis
Secondary
Glucose Cmax
Pharmacodynamic parameter: Maximum concentration of glucose
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucose Cmax | 148.04 mg/dL | Standard Deviation 24.94 |
| G-Pen(TM) 0.5 mg | Glucose Cmax | 140.32 mg/dL | Standard Deviation 23.59 |
| Lilly Glucagon(TM) 1 mg | Glucose Cmax | 154.9 mg/dL | Standard Deviation 28.02 |
p-value: 0.34Mixed Models Analysis
p-value: 0.01Mixed Models Analysis
Secondary
Glucose MAE
Pharmacodynamic parameter: Maximum absolute glucose excursion from baseline
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucose MAE | 50.8 mg/dL | Standard Deviation 22 |
| G-Pen(TM) 0.5 mg | Glucose MAE | 42.5 mg/dL | Standard Deviation 19.8 |
| Lilly Glucagon(TM) 1 mg | Glucose MAE | 53.2 mg/dL | Standard Deviation 18.8 |
p-value: 0.68Mixed Models Analysis
p-value: 0.02Mixed Models Analysis
Secondary
Glucose Tex
Pharmacodynamic parameter: Earliest reported time of MAE, based on within-subject changes from baseline
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucose Tex | 48.2 minutes | Standard Deviation 11.8 |
| G-Pen(TM) 0.5 mg | Glucose Tex | 61.6 minutes | Standard Deviation 52.3 |
| Lilly Glucagon(TM) 1 mg | Glucose Tex | 68.8 minutes | Standard Deviation 44.4 |
p-value: 0.16Mixed Models Analysis
Secondary
Glucose Tmax
Pharmacodynamic parameter: Time to Maximum Glucose Concentration
Time frame: Approximately 15 minutes before each injection and at 5, 10, 15, 20, 30, 45, 60, 120 and 240 minutes post-injection
Population: Per protocol analysis set. Two subjects were excluded from all analyses: one who completed no treatment visits and had no evaluable data and another who violated eligibility criteria. A third subject was excluded from analysis for the one treatment visit at which the subject's blood samples were inadvertently diluted with saline during collection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| G-Pen(TM) 1 mg | Glucose Tmax | 48.2 minutes | Standard Deviation 11.8 |
| G-Pen(TM) 0.5 mg | Glucose Tmax | 44.5 minutes | Standard Deviation 11.2 |
| Lilly Glucagon(TM) 1 mg | Glucose Tmax | 46.5 minutes | Standard Deviation 20.5 |
p-value: 0.95Mixed Models Analysis