Diabetes Mellitus, Type 1
Conditions
Brief summary
The purpose of this study is to assess the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of 3 milligrams (mg) glucagon (glucagon nasal powder) administered nasally compared with commercially available glucagon given by intramuscular injection.
Detailed description
Each glucagon dosing visit was conducted after an overnight fast of at least 8 h with a starting plasma glucose \>= 90 mg/dL. Hypoglycemia was induced by an intravenous (IV) infusion of regular insulin diluted in normal saline during the clinic visit. Five minutes after stopping the insulin infusion (once the plasma glucose was \<60 mg/dL), participants were treated with either a 3 mg glucagon dose nasally or 1 mg of glucagon administered by intramuscular (IM) injection. After a wash-out period of 7 days or more, participants returned to the clinic and the procedure repeated with each participant crossed over to the other treatment. As such, each participant underwent two episodes of insulin-induced hypoglycemia in random order and received glucagon nasal powder during one episode and commercially available glucagon (GlucaGen, Novo Nordisk) by IM injection during the other episode.
Interventions
Sponsors
T1D Exchange Clinic Network Coordinating Center
Locemia Solutions ULC
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
To be eligible, the following inclusion criteria must be met: * Clinical diagnosis of either type 1 diabetes receiving daily insulin since the time of diagnosis for at least 2 years or type 2 diabetes receiving multiple daily insulin doses for at least 2 years * At least 18.0 years of age and less than 65.0 years * Body mass index (BMI) greater than or equal to 20.0 and below or equal to 35.0 kilograms per meter squared (kg/m²) * Weighs at least 50 kg (110 pounds) * Females must meet one of the following criteria: * Of childbearing potential but agree to use an accepted contraceptive regimen as described in the study procedure manual throughout the entire duration of the study (from the screening until study completion) * Of non-childbearing potential, defined as a female who has had a hysterectomy or tubal ligation, is clinically considered infertile or is in a menopausal state (at least 1 year without menses) * In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the Investigator is a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations * Willingness to adhere to the study requirements
Exclusion criteria
An individual is not eligible if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL From Glucose Nadir | Within 30 minutes after receiving glucagon at both dosing visits (glucose was measured at pre-dose; 5, 10, 15, 20, 25, and 30 minutes following glucagon administration) | Increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from glucose nadir within 30 minutes after receiving study glucagon, without receiving additional actions to increase the blood glucose level defines treatment success. Due to the residual activity of circulating insulin, glucose nadir was defined as the minimum glucose measurement at the time of, or within 10 minutes following glucagon administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Change From Baseline Concentration (Cmax) of Glucose | Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration | — |
| Nasal and Non-nasal Effects/Symptoms | Pre-dose; 15, 30, 60, and 90 post glucagon administration | Symptoms of runny nose, nasal congestion and/or itching, sneezing, watery and/or itchy eyes, redness of eyes, and itching of ears and/or throat were assessed. This was done via the Nasal Non-nasal Score Questionnaire. Each of the 9 symptoms is assigned an integer value from 0 to 3; higher values indicate more severe symptoms (a score of 0 indicates no symptoms). The reported results indicate the cohort median out of a possible maximum value of 27 (summing all 9 questions for each subject and reporting the median/IQR across participants). |
| Recovery From Symptoms of Hypoglycemia | Pre-dose;15, 30, 45 and 60 minutes following administration of glucagon | Recovery from hypoglycemia symptoms were assessed using the Edinburgh Hypoglycemia Scale. The Edinburgh Hypoglycemia Symptom Scale measures the intensity of 15 commonly experienced hypoglycemic symptoms on a 7-point Likert scale (1 = not present, 7 = very intense). The higher the score, the more intense the hypoglycemia symptoms. The sum of each symptom score would yield a range of 15 to 105 (i.e., 15 x 7 =105). The total score was calculated as the sum of each symptom score minus 15, and summarized at each time point by treatment group. |
| Time From Glucagon Administration to Blood Glucose >/=70 mg/dL or an Increase ≥20 mg/dL in Blood Glucose From Nadir | Pre-dose; 5, 10, 15, 20, 25, and 30 minutes following glucagon administration | The mean time from glucagon administration to blood glucose \>/=70 mg/dL or an increase ≥20 mg/dL in blood glucose from nadir. |
| Area Under the Effect Concentration Time Curve (AUEC0-1.5) of Baseline-Adjusted Glucose From Time Zero up to 90 Minutes | Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration | — |
| Maximum Change From Baseline Concentration (Cmax) of Glucagon | Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration | — |
| Time to Maximum Change From Baseline Concentration (Tmax) of Glucagon | Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration | — |
| Time to Maximum Change From Baseline Concentration (Tmax) of Glucose | Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration | — |
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Baseline-Adjusted Glucagon | Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration | — |
Countries
United States
Participant flow
Recruitment details
77 Type 1 (T1D) and 6 Type 2 diabetes (T2D) participants were recruited. Results reported include T1D participants only since this was the pre-specified primary population.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants At one visit, a nasal glucagon (NG) dose of 3 mg. At another visit, 1 mg intramuscular (IM) glucagon The order of the visits were randomized. | 77 |
| Total | 77 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 77 Participants |
| Age, Continuous | 33 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 2 Participants |
| Race (NIH/OMB) White | 74 Participants |
| Region of Enrollment United States | 77 Participants |
| Sex: Female, Male Female | 45 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 77 | 35 / 76 |
| serious Total, serious adverse events | 0 / 77 | 0 / 77 |
Outcome results
Primary
Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL From Glucose Nadir
Increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from glucose nadir within 30 minutes after receiving study glucagon, without receiving additional actions to increase the blood glucose level defines treatment success. Due to the residual activity of circulating insulin, glucose nadir was defined as the minimum glucose measurement at the time of, or within 10 minutes following glucagon administration.
Time frame: Within 30 minutes after receiving glucagon at both dosing visits (glucose was measured at pre-dose; 5, 10, 15, 20, 25, and 30 minutes following glucagon administration)
Population: All enrolled participants who completed both eligible Study/Dosing Visits.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nasal Glucagon (NG) | Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL From Glucose Nadir | 98.7 percentage of participants |
| Intramuscular (IM) Glucagon | Increase in Plasma Glucose Level to >=70mg/dL or an Increase of >=20mg/dL From Glucose Nadir | 100 percentage of participants |
Secondary
Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Baseline-Adjusted Glucagon
Time frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with available pharmacokinetics (PK) data. Study dosing visits occurred on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nasal Glucagon (NG) | Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Baseline-Adjusted Glucagon | 1882.48 hour*picograms per milliliter (hr*pg/mL) | Standard Deviation 1216.27 |
| Intramuscular (IM) Glucagon | Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Baseline-Adjusted Glucagon | 2521.87 hour*picograms per milliliter (hr*pg/mL) | Standard Deviation 971.07 |
Secondary
Area Under the Effect Concentration Time Curve (AUEC0-1.5) of Baseline-Adjusted Glucose From Time Zero up to 90 Minutes
Time frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with available pharmacodynamics (PD) data. Study dosing visits occurred on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nasal Glucagon (NG) | Area Under the Effect Concentration Time Curve (AUEC0-1.5) of Baseline-Adjusted Glucose From Time Zero up to 90 Minutes | 106.39 hr*mg/dL | Standard Deviation 42.6 |
| Intramuscular (IM) Glucagon | Area Under the Effect Concentration Time Curve (AUEC0-1.5) of Baseline-Adjusted Glucose From Time Zero up to 90 Minutes | 124.47 hr*mg/dL | Standard Deviation 38.95 |
Secondary
Maximum Change From Baseline Concentration (Cmax) of Glucagon
Time frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with available pharmacokinetics (PK) data. Study dosing visits occurred on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nasal Glucagon (NG) | Maximum Change From Baseline Concentration (Cmax) of Glucagon | 3025.37 picograms per milliliter (pg/mL) | Standard Deviation 1981.62 |
| Intramuscular (IM) Glucagon | Maximum Change From Baseline Concentration (Cmax) of Glucagon | 3553.43 picograms per milliliter (pg/mL) | Standard Deviation 1746.66 |
Secondary
Maximum Change From Baseline Concentration (Cmax) of Glucose
Time frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with available pharmacodynamics (PD) data. Study dosing visits occurred on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nasal Glucagon (NG) | Maximum Change From Baseline Concentration (Cmax) of Glucose | 114.80 milligrams per deciliter (mg/dL) | Standard Deviation 47.45 |
| Intramuscular (IM) Glucagon | Maximum Change From Baseline Concentration (Cmax) of Glucose | 130.72 milligrams per deciliter (mg/dL) | Standard Deviation 44.15 |
Secondary
Nasal and Non-nasal Effects/Symptoms
Symptoms of runny nose, nasal congestion and/or itching, sneezing, watery and/or itchy eyes, redness of eyes, and itching of ears and/or throat were assessed. This was done via the Nasal Non-nasal Score Questionnaire. Each of the 9 symptoms is assigned an integer value from 0 to 3; higher values indicate more severe symptoms (a score of 0 indicates no symptoms). The reported results indicate the cohort median out of a possible maximum value of 27 (summing all 9 questions for each subject and reporting the median/IQR across participants).
Time frame: Pre-dose; 15, 30, 60, and 90 post glucagon administration
Population: All enrolled T1D participants that completed the required dosing visits. Study dosing visits occur on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nasal Glucagon (NG) | Nasal and Non-nasal Effects/Symptoms | 15 minutes post glucagon administration | 2.00 units on a scale |
| Nasal Glucagon (NG) | Nasal and Non-nasal Effects/Symptoms | 60 minutes post glucagon administration | 1.00 units on a scale |
| Nasal Glucagon (NG) | Nasal and Non-nasal Effects/Symptoms | 30 minutes post glucagon administration | 1.00 units on a scale |
| Nasal Glucagon (NG) | Nasal and Non-nasal Effects/Symptoms | 90 minutes post glucagon administration | 1.00 units on a scale |
| Nasal Glucagon (NG) | Nasal and Non-nasal Effects/Symptoms | Pre-dose | 0.00 units on a scale |
| Intramuscular (IM) Glucagon | Nasal and Non-nasal Effects/Symptoms | 90 minutes post glucagon administration | 0.00 units on a scale |
| Intramuscular (IM) Glucagon | Nasal and Non-nasal Effects/Symptoms | Pre-dose | 0.00 units on a scale |
| Intramuscular (IM) Glucagon | Nasal and Non-nasal Effects/Symptoms | 15 minutes post glucagon administration | 0.00 units on a scale |
| Intramuscular (IM) Glucagon | Nasal and Non-nasal Effects/Symptoms | 30 minutes post glucagon administration | 0.00 units on a scale |
| Intramuscular (IM) Glucagon | Nasal and Non-nasal Effects/Symptoms | 60 minutes post glucagon administration | 0.00 units on a scale |
Secondary
Recovery From Symptoms of Hypoglycemia
Recovery from hypoglycemia symptoms were assessed using the Edinburgh Hypoglycemia Scale. The Edinburgh Hypoglycemia Symptom Scale measures the intensity of 15 commonly experienced hypoglycemic symptoms on a 7-point Likert scale (1 = not present, 7 = very intense). The higher the score, the more intense the hypoglycemia symptoms. The sum of each symptom score would yield a range of 15 to 105 (i.e., 15 x 7 =105). The total score was calculated as the sum of each symptom score minus 15, and summarized at each time point by treatment group.
Time frame: Pre-dose;15, 30, 45 and 60 minutes following administration of glucagon
Population: All enrolled participants who completed at least one post administration survey.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nasal Glucagon (NG) | Recovery From Symptoms of Hypoglycemia | 15 minutes post glucagon administration | 8.8 units on a scale | Standard Deviation 8.3 |
| Nasal Glucagon (NG) | Recovery From Symptoms of Hypoglycemia | 45 minutes post glucagon administration | 3.8 units on a scale | Standard Deviation 3.1 |
| Nasal Glucagon (NG) | Recovery From Symptoms of Hypoglycemia | 30 minutes post glucagon administration | 4.9 units on a scale | Standard Deviation 4.7 |
| Nasal Glucagon (NG) | Recovery From Symptoms of Hypoglycemia | 60 minutes post glucagon administration | 3.9 units on a scale | Standard Deviation 3.1 |
| Nasal Glucagon (NG) | Recovery From Symptoms of Hypoglycemia | Pre-dose | 8.0 units on a scale | Standard Deviation 7.7 |
| Intramuscular (IM) Glucagon | Recovery From Symptoms of Hypoglycemia | 60 minutes post glucagon administration | 3.1 units on a scale | Standard Deviation 2.9 |
| Intramuscular (IM) Glucagon | Recovery From Symptoms of Hypoglycemia | Pre-dose | 7.8 units on a scale | Standard Deviation 7.1 |
| Intramuscular (IM) Glucagon | Recovery From Symptoms of Hypoglycemia | 15 minutes post glucagon administration | 5.3 units on a scale | Standard Deviation 5.2 |
| Intramuscular (IM) Glucagon | Recovery From Symptoms of Hypoglycemia | 30 minutes post glucagon administration | 3.5 units on a scale | Standard Deviation 3.9 |
| Intramuscular (IM) Glucagon | Recovery From Symptoms of Hypoglycemia | 45 minutes post glucagon administration | 3.0 units on a scale | Standard Deviation 3 |
Secondary
Time From Glucagon Administration to Blood Glucose >/=70 mg/dL or an Increase ≥20 mg/dL in Blood Glucose From Nadir
The mean time from glucagon administration to blood glucose \>/=70 mg/dL or an increase ≥20 mg/dL in blood glucose from nadir.
Time frame: Pre-dose; 5, 10, 15, 20, 25, and 30 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with eligible glucose and glucagon levels. Study dosing visits occur on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nasal Glucagon (NG) | Time From Glucagon Administration to Blood Glucose >/=70 mg/dL or an Increase ≥20 mg/dL in Blood Glucose From Nadir | 16.2 minutes |
| Intramuscular (IM) Glucagon | Time From Glucagon Administration to Blood Glucose >/=70 mg/dL or an Increase ≥20 mg/dL in Blood Glucose From Nadir | 12.2 minutes |
Secondary
Time to Maximum Change From Baseline Concentration (Tmax) of Glucagon
Time frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with available pharmacokinetics (PK) data. Study dosing visits occurred on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nasal Glucagon (NG) | Time to Maximum Change From Baseline Concentration (Tmax) of Glucagon | 0.33 hours |
| Intramuscular (IM) Glucagon | Time to Maximum Change From Baseline Concentration (Tmax) of Glucagon | 0.25 hours |
Secondary
Time to Maximum Change From Baseline Concentration (Tmax) of Glucose
Time frame: Pre-dose; 5, 10, 15, 20, 25, 30, 40, 50, 60 and 90 minutes following glucagon administration
Population: All enrolled participants that completed the required dosing visits with available pharmacodynamics (PD) data. Study dosing visits occurred on Day 0 and then again after the washout period between Day 7 to Day 28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nasal Glucagon (NG) | Time to Maximum Change From Baseline Concentration (Tmax) of Glucose | 1.5 hours |
| Intramuscular (IM) Glucagon | Time to Maximum Change From Baseline Concentration (Tmax) of Glucose | 1.5 hours |