Type 1 Diabetes
Conditions
Keywords
bionic pancreas, artificial pancreas, insulin, glucagon, clamp
Brief summary
This study will test the hypothesis that micro-doses of Xerisol Glucagon (Xeris Pharmaceuticals) will be non-inferior by pharmacokinetic and pharmacodynamic criteria vs. micro-doses of Glucagon for Injection (Eli Lilly).
Detailed description
This study will test the hypothesis that micro-doses of a new formulation of stable glucagon, Xerisol Glucagon (Xeris Pharmaceuticals), will be non-inferior by pharmacokinetic and pharmacodynamic criteria vs. micro-doses of a freshly reconstituted formulation of glucagon that has poor stability in solution, Glucagon for Injection (Eli Lilly).
Interventions
DRUGXeris glucagon
The subject is given an injection of xeris glucagon
DRUGLilly glucagon
The subject is given an injection of lilly glucagon
Sponsors
Steven J. Russell, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 21 to 80 years old with type 1 diabetes for at least one year. * Diabetes managed using an insulin infusion pump using rapid-acting insulin such as insulin aspart (NovoLog), insulin lispro (Humalog), and insulin glulisine (Apidra) for at least one week prior to enrollment.
Exclusion criteria
* Unable to provide informed consent. * Unable to comply with study procedures. * Current participation in another diabetes-related clinical trial that, in the judgment of the principle investigator, will compromise the results of the clamp study or the safety of the subject. * Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the immediate future, or sexually active without use of contraception. * End stage renal disease on dialysis (hemodialysis or peritoneal dialysis). * Hemoglobin \< 11.5 gm/dl. * History of pheochromocytoma. Fractionated metanephrines will be tested in patients with history increasing the risk for a catecholamine secreting tumor (paroxysms of tachycardia, pallor, or headache; personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or von Hippel-Lindau disease; episodic or treatment of refractory hypertension, defined as requiring 4 or more medications to achieve normotension). * History of adverse reaction to glucagon (including allergy) besides nausea, vomiting, or headache. * Inadequate venous access as determined by study nurse or physician at time of screening. * Liver failure or cirrhosis. * Any other factors that, in the judgment of the principal investigator, would interfere with the safe completion of the study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | every 2 minutes for 1 hour post-dose of each glucagon | tmax for Xeris vs. Lilly (non-inferiority) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GIRmin | every 2 minutes for 1 hour post-dose of each glucagon | Minimal glucose infusion rate (GIRmin) for Xeris vs. Lilly (non-inferiority) |
| t½Max | every 2 minutes for 1 hour post-dose of each glucagon | Glucagon t½max for Xeris vs. Lilly (non-inferiority) |
| Injection Pain | immediately after injection | Quantitation of adverse events related to glucagon injection for Xeris vs. Lilly: -average Injection pain on a 10 cm standard VAS: 0 = no pain, 10 = worst imaginable pain reported immediately after injection of glucagon |
| AOCGIR | every 2 minutes for 1 hour post-dose of each glucagon | Area over the curve for glucose infusion rate in the hour following administration (AOCGIR) for Xeris vs. Lilly (non-inferiority) |
| Maximal Nausea | within 1 hour of injection | Quantitation of adverse events related to glucagon injection for Xeris vs. Lilly: -Maximal nausea within 1 hour of injection on a 10 cm VAS: no nausea = 0, vomiting = 10 |
| Dermal Response (Draize Scale for Erythema and Eschar Formation) | within 1 hour of injection | Average grade on the erythema and eschar formation portion of the Draize scale for dermal response (0 being the lowest, 4 being the highest) |
| Dermal Response (Draize Scale Grade for Edema Formation) | within 1 hour of injection | Average grade on the edema formation portion of the Draize scale for dermal response (0 being the lowest, 4 being the highest) |
| Injection Site Erythema | within 1 hour of injection | Quantitation of adverse events related to glucagon injection for Xeris vs. Lilly: -Injection site erythema or other local reaction, maximum diameter within 1 hour of injection |
Countries
United States
Participant flow
Pre-assignment details
20 subjects were enrolled in this study. One was ineligible after enrollment. 4 were enrolled and eligible, but were not able to schedule their study visit. 2 participated in test run experiments as we adjusted glucagon doses to account for concentration differences. 13 subjects completed experiments using the same protocol.
Participants by arm
| Arm | Count |
|---|---|
| Xeris Glucagon First, Then Lilly Glucagon Xeris glucagon 50 micrograms, subcutaneous injection, then Lilly glucagon 30 micrograms, subcutaneous injection
Xeris glucagon: The subject is given an injection of xeris glucagon Lilly glucagon: The subject is given an injection of lilly glucagon | 7 |
| Lilly Glucagon First, Then Xeris Glucagon Lilly glucagon 30 micrograms, subcutaneous injection, then Xeris glucagon 50 micrograms, subcutaneous injection
Lilly glucagon: The subject is given an injection of lilly glucagon Xeris glucagon: The subject is given an injection of xeris glucagon | 6 |
| Total | 13 |
Baseline characteristics
| Characteristic | Xeris Glucagon First, Then Lilly Glucagon | Lilly Glucagon First, Then Xeris Glucagon | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 11.8 | 45.6 years STANDARD_DEVIATION 11.9 | 51.7 years STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Hemoglobin A1c | 7.4 percent STANDARD_DEVIATION 1.3 | 7.0 percent STANDARD_DEVIATION 0.6 | 7.2 percent STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Tmax
tmax for Xeris vs. Lilly (non-inferiority)
Time frame: every 2 minutes for 1 hour post-dose of each glucagon
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | Tmax | 23.8 minutes | Standard Deviation 9.3 |
| Lilly Glucagon | Tmax | 15.7 minutes | Standard Deviation 3 |
Secondary
AOCGIR
Area over the curve for glucose infusion rate in the hour following administration (AOCGIR) for Xeris vs. Lilly (non-inferiority)
Time frame: every 2 minutes for 1 hour post-dose of each glucagon
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | AOCGIR | 201.1 mg*min/kg | Standard Deviation 275.5 |
| Lilly Glucagon | AOCGIR | 132.2 mg*min/kg | Standard Deviation 87.9 |
Secondary
Dermal Response (Draize Scale for Erythema and Eschar Formation)
Average grade on the erythema and eschar formation portion of the Draize scale for dermal response (0 being the lowest, 4 being the highest)
Time frame: within 1 hour of injection
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | Dermal Response (Draize Scale for Erythema and Eschar Formation) | 0 score on draize scale | Standard Deviation 0 |
| Lilly Glucagon | Dermal Response (Draize Scale for Erythema and Eschar Formation) | 0 score on draize scale | Standard Deviation 0 |
Secondary
Dermal Response (Draize Scale Grade for Edema Formation)
Average grade on the edema formation portion of the Draize scale for dermal response (0 being the lowest, 4 being the highest)
Time frame: within 1 hour of injection
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | Dermal Response (Draize Scale Grade for Edema Formation) | 0 score on draize scale | Standard Deviation 0 |
| Lilly Glucagon | Dermal Response (Draize Scale Grade for Edema Formation) | 0 score on draize scale | Standard Deviation 0 |
Secondary
GIRmin
Minimal glucose infusion rate (GIRmin) for Xeris vs. Lilly (non-inferiority)
Time frame: every 2 minutes for 1 hour post-dose of each glucagon
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | GIRmin | 2.9 dextrose mg/kg/min | Standard Deviation 2.2 |
| Lilly Glucagon | GIRmin | 2.9 dextrose mg/kg/min | Standard Deviation 1.8 |
Secondary
Injection Pain
Quantitation of adverse events related to glucagon injection for Xeris vs. Lilly: -average Injection pain on a 10 cm standard VAS: 0 = no pain, 10 = worst imaginable pain reported immediately after injection of glucagon
Time frame: immediately after injection
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | Injection Pain | 13.8 cm | Standard Deviation 17.7 |
| Lilly Glucagon | Injection Pain | 7.6 cm | Standard Deviation 8.7 |
Secondary
Injection Site Erythema
Quantitation of adverse events related to glucagon injection for Xeris vs. Lilly: -Injection site erythema or other local reaction, maximum diameter within 1 hour of injection
Time frame: within 1 hour of injection
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | Injection Site Erythema | 0 cm | Standard Deviation 0 |
| Lilly Glucagon | Injection Site Erythema | 0 cm | Standard Deviation 0 |
Secondary
Maximal Nausea
Quantitation of adverse events related to glucagon injection for Xeris vs. Lilly: -Maximal nausea within 1 hour of injection on a 10 cm VAS: no nausea = 0, vomiting = 10
Time frame: within 1 hour of injection
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xeris Glucagon | Maximal Nausea | 1.0 cm |
| Lilly Glucagon | Maximal Nausea | 2.3 cm |
Secondary
t½Max
Glucagon t½max for Xeris vs. Lilly (non-inferiority)
Time frame: every 2 minutes for 1 hour post-dose of each glucagon
Population: 13 subjects completed the study following a consistent protocol using the glucagon doses described in the arm/group description. 7 subjects were randomized to get Xeris glucagon first, 6 subjects were randomized to get Lilly glucagon first. All 13 subjects received both glucagon injections, and the data is reported for each drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Xeris Glucagon | t½Max | 11.3 minutes | Standard Deviation 3.1 |
| Lilly Glucagon | t½Max | 5.9 minutes | Standard Deviation 2.1 |