Hypoglycemia, Diabetes Mellitus, Type 1
Conditions
Keywords
glucagon
Brief summary
A randomized, double-blind, parallel-group trial to confirm the clinical efficacy and safety of dasiglucagon in the rescue treatment of hypoglycemia in subjects with type 1 diabetes mellitus (T1DM) compared to placebo
Detailed description
Subjects were randomized in a ratio of 3:1 to receive a single subcutaneous dose of dasiglucagon (0.6 mg) or matching placebo. Randomization also determined whether the subject was to be injected in the buttock or deltoid. During the dosing visit (Visit 2), hypoglycemia was induced by a fast-acting insulin glulisine (Apidra®) infusion, and trial drug was administered when the subject's plasma glucose level was 45-60 mg/dL (2.5-3.3 mmol/L). During the insulin-induced hypoglycemia, pharmacokinetic and pharmacodynamic samples were drawn, and plasma glucose levels were monitored closely at site for safety reasons. A rescue glucose infusion could be administered to ameliorate persistent hypoglycemia. Subjects were followed for at least 28 days after dosing to perform an adequate immunogenicity evaluation of treatment.
Interventions
DRUGDasiglucagon
Glucagon analogue
DRUGPlacebo
Placebo for dasiglucagon
Sponsors
Zealand Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Female or male subjects with T1DM for at least 1 year; diagnostic criteria as defined by the American Diabetes Association (3). * Treated with insulin for T1DM for at least 1 year and with stable insulin treatment (defined as no more than a 10-unit daily variation in total daily insulin dose) 30 days prior to screening * Hemoglobin A1c \<10%. * Aged between 18 and 75 years, both inclusive.
Exclusion criteria
* Previous participation in a clinical trial within the dasiglucagon in the rescue treatment of hypoglycemia program. * Known or suspected allergy to trial drug(s) or related products. * History of anaphylaxis or symptoms of severe systemic allergy (such as angioedema). * Previous participation in this trial. Participation being defined by signing the informed consent document.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Plasma Glucose Recovery. | 0-45 minutes after dosing | Plasma glucose recovery was defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp procedure without administration of rescue intravenous (IV) glucose. Patients who received rescue IV glucose before 45 minutes and patients not recovering within 45 minutes after dosing were censored at 45 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose Changes From Baseline | 0-30 minutes after dosing | Plasma glucose changes from baseline at 30 minutes, at 20 minutes, at 15 minutes, and at 10 minutes after trial drug injection or at the time of rescue (patient level). |
| Time to Target Plasma Glucose Concentration | 0-45 minutes after dosing | Time to first plasma glucose concentration ≥70 mg/dL (3.9 mmol/L) without administration of rescue intravenous glucose |
| Pharmacodynamics - Area Under the Effect Curve | 0-30 minutes after dosing | Plasma glucose response as area under the effect curve (AUE) above baseline from time zero to 30 minutes, AUE0-30min. |
| Pharmacokinetics - Area Under the Plasma Concentration Curve | 0-90 minutes after dosing | Area under the drug concentration curve (AUC) from time zero to 90 minutes, AUC0-90min |
| Plasma Glucose Recovery After Trial Drug Injection | 0-30 minutes after dosing | Plasma glucose recovery (patient has achieved increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L)) within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after trial drug injection without administration of rescue intravenous (IV) glucose. |
| Pharmacokinetics - Time to Maximum Plasma Concentration | 0-120 minutes after dosing | Time to maximum plasma dasiglucagon concentration (tmax) |
| Immunogenicity - Occurrence of Anti-drug Antibodies | 58 days | Occurrence of antibodies against dasiglucagon. Presented as percentage of patients with antibodies. |
| Rescue Infusions of IV Glucose After Trial Drug Administration | 0-45 minutes after dosing | Presented as number of patients with rescue infusions of IV glucose after trial drug administration. This was a safety outcome measure. IV = intravenous |
| Time to First Rescue Infusion of IV Glucose After Trial Drug Administration | 0-45 minutes after dosing | Safety outcome measure: time to first rescue infusion of IV glucose after trial drug administration. IV = intravenous |
| Pharmacokinetics - Maximum Plasma Concentration | 0-120 minutes after dosing | Maximum plasma dasiglucagon concentration (Cmax) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dasiglucagon 0.6 mg single fixed dose (subcutaneous injection) of dasiglucagon
Dasiglucagon: Glucagon analogue | 34 |
| Placebo single fixed dose (subcutaneous injection) of placebo
Placebo: Placebo for dasiglucagon | 10 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Dasiglucagon 0.6 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 42.4 years STANDARD_DEVIATION 13.49 | 36.5 years STANDARD_DEVIATION 12.8 | 41.0 years STANDARD_DEVIATION 13.42 |
| Body mass index | 28.41 kg per square metre STANDARD_DEVIATION 5.802 | 27.92 kg per square metre STANDARD_DEVIATION 3.975 | 28.30 kg per square metre STANDARD_DEVIATION 5.402 |
| Body weight | 84.49 kg STANDARD_DEVIATION 20.102 | 83.69 kg STANDARD_DEVIATION 10.812 | 84.30 kg STANDARD_DEVIATION 18.295 |
| Duration of diabetes | 22.5 years STANDARD_DEVIATION 13.82 | 21.2 years STANDARD_DEVIATION 13.42 | 22.2 years STANDARD_DEVIATION 13.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 7 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 7 Participants | 41 Participants |
| Region of Enrollment United States | 34 Participants | 10 Participants | 44 Participants |
| Sex: Female, Male Female | 18 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Male | 16 Participants | 9 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 10 |
| other Total, other adverse events | 24 / 34 | 3 / 10 |
| serious Total, serious adverse events | 0 / 34 | 0 / 10 |
Outcome results
Primary
Time to Plasma Glucose Recovery.
Plasma glucose recovery was defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline during the hypoglycemic clamp procedure without administration of rescue intravenous (IV) glucose. Patients who received rescue IV glucose before 45 minutes and patients not recovering within 45 minutes after dosing were censored at 45 minutes.
Time frame: 0-45 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Time to Plasma Glucose Recovery. | 10.0 minutes |
| Placebo | Time to Plasma Glucose Recovery. | 35.0 minutes |
Comparison: The recovery rates of dasiglucagon and placebo were evaluated using a Kaplan Meier (KM) approach, with treatment group as a stratification factor. Differences between the KM curves (dasiglucagon versus placebo) were evaluated inferentially using pairwise two-sided log-rank tests stratified by injection site.p-value: <0.0001Log Rank
Secondary
Immunogenicity - Occurrence of Anti-drug Antibodies
Occurrence of antibodies against dasiglucagon. Presented as percentage of patients with antibodies.
Time frame: 58 days
Population: The safety analysis set of all randomized subjects who received at least one dose of trial drug (same as the full analysis set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasiglucagon 0.6 mg | Immunogenicity - Occurrence of Anti-drug Antibodies | 0 Participants |
| Placebo | Immunogenicity - Occurrence of Anti-drug Antibodies | 0 Participants |
Secondary
Pharmacodynamics - Area Under the Effect Curve
Plasma glucose response as area under the effect curve (AUE) above baseline from time zero to 30 minutes, AUE0-30min.
Time frame: 0-30 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacodynamics - Area Under the Effect Curve | 19.9 hr*mg/dL | Standard Deviation 8.41 |
| Placebo | Pharmacodynamics - Area Under the Effect Curve | 2.67 hr*mg/dL | Standard Deviation 3.06 |
Comparison: The analysis was an analysis of covariance (ANCOVA) model with treatment group as factor and the baseline of the dependent variable plasma glucose as a covariate.p-value: <0.000195% CI: [2.71, 6.05]ANCOVA
Secondary
Pharmacokinetics - Area Under the Plasma Concentration Curve
Area under the drug concentration curve (AUC) from time zero to 90 minutes, AUC0-90min
Time frame: 0-90 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Area Under the Plasma Concentration Curve | 1480 hr*pmol/L | Geometric Coefficient of Variation 34.6 |
Secondary
Pharmacokinetics - Area Under the Plasma Concentration Curve
Area under the drug concentration curve (AUC) from time zero to 120 minutes, AUC0-120min
Time frame: 0-120 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Area Under the Plasma Concentration Curve | 1780 hr*pmol/L | Geometric Coefficient of Variation 31.6 |
Secondary
Pharmacokinetics - Maximum Plasma Concentration
Maximum plasma dasiglucagon concentration (Cmax)
Time frame: 0-120 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Maximum Plasma Concentration | 1350 pmol/L | Geometric Coefficient of Variation 38.2 |
Secondary
Pharmacokinetics - Time to Maximum Plasma Concentration
Time to maximum plasma dasiglucagon concentration (tmax)
Time frame: 0-120 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Time to Maximum Plasma Concentration | 35 minutes |
Secondary
Plasma Glucose Changes From Baseline
Plasma glucose changes from baseline at 30 minutes, at 20 minutes, at 15 minutes, and at 10 minutes after trial drug injection or at the time of rescue (patient level).
Time frame: 0-30 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 30 minutes | 85.29 mg/dL | Standard Deviation 29.696 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 20 minutes | 52.95 mg/dL | Standard Deviation 20.298 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 15 minutes | 41.62 mg/dL | Standard Deviation 17.077 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 10 minutes | 24.54 mg/dL | Standard Deviation 12.56 |
| Placebo | Plasma Glucose Changes From Baseline | At 10 minutes | 0.62 mg/dL | Standard Deviation 6.1 |
| Placebo | Plasma Glucose Changes From Baseline | At 30 minutes | 15.14 mg/dL | Standard Deviation 9.328 |
| Placebo | Plasma Glucose Changes From Baseline | At 15 minutes | 5.23 mg/dL | Standard Deviation 6.686 |
| Placebo | Plasma Glucose Changes From Baseline | At 20 minutes | 9.67 mg/dL | Standard Deviation 8.846 |
Comparison: Change from baseline in plasma glucose at 30 minutes after investigational product injection was calculated using nominal sampling times and analyzed using an analysis of variance model with treatment, age group and injection site for each endpoint. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001ANCOVA
Comparison: Change from baseline in plasma glucose at 20 minutes after investigational product injection was calculated using nominal sampling times and analyzed using an analysis of variance model with treatment, age group and injection site for each endpoint. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001ANCOVA
Comparison: Change from baseline in plasma glucose at 15 minutes after investigational product injection was calculated using nominal sampling times and analyzed using an analysis of variance model with treatment, age group and injection site for each endpoint. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001ANCOVA
Comparison: Change from baseline in plasma glucose at 10 minutes after investigational product injection was calculated using nominal sampling times and analyzed using an analysis of variance model with treatment, age group and injection site for each endpoint. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001ANCOVA
Secondary
Plasma Glucose Recovery After Trial Drug Injection
Plasma glucose recovery (patient has achieved increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L)) within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after trial drug injection without administration of rescue intravenous (IV) glucose.
Time frame: 0-30 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 30 minutes | 33 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 20 minutes | 32 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 15 minutes | 30 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 10 minutes | 21 Participants |
| Placebo | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 10 minutes | 0 Participants |
| Placebo | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 30 minutes | 5 Participants |
| Placebo | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 15 minutes | 0 Participants |
| Placebo | Plasma Glucose Recovery After Trial Drug Injection | Glucose recovery within 20 minutes | 1 Participants |
Comparison: Assessed at 30 minutes. The recovery rates of dasiglucagon and placebo were compared at each time point using a Fisher's exact test. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: 0.0012Fisher Exact
Comparison: Assessed at 20 minutes. The recovery rates of dasiglucagon and placebo were compared at each time point using a Fisher's exact test. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001Fisher Exact
Comparison: Assessed at 15 minutes. The recovery rates of dasiglucagon and placebo were compared at each time point using a Fisher's exact test. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: <0.0001Fisher Exact
Comparison: Assessed at 10 minutes. The recovery rates of dasiglucagon and placebo were compared at each time point using a Fisher's exact test. Testing followed an a priori defined hierarchical inferential test order, proceeding until the first failure to reject the null hypothesis comparing dasiglucagon versus placebo.p-value: 0.0006Fisher Exact
Secondary
Rescue Infusions of IV Glucose After Trial Drug Administration
Presented as number of patients with rescue infusions of IV glucose after trial drug administration. This was a safety outcome measure. IV = intravenous
Time frame: 0-45 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasiglucagon 0.6 mg | Rescue Infusions of IV Glucose After Trial Drug Administration | 1 Participants |
| Placebo | Rescue Infusions of IV Glucose After Trial Drug Administration | 1 Participants |
Secondary
Time to First Rescue Infusion of IV Glucose After Trial Drug Administration
Safety outcome measure: time to first rescue infusion of IV glucose after trial drug administration. IV = intravenous
Time frame: 0-45 minutes after dosing
Population: Only the patients who received IV glucose administration are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasiglucagon 0.6 mg | Time to First Rescue Infusion of IV Glucose After Trial Drug Administration | 10 minutes |
| Placebo | Time to First Rescue Infusion of IV Glucose After Trial Drug Administration | 14 minutes |
Secondary
Time to Target Plasma Glucose Concentration
Time to first plasma glucose concentration ≥70 mg/dL (3.9 mmol/L) without administration of rescue intravenous glucose
Time frame: 0-45 minutes after dosing
Population: The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Time to Target Plasma Glucose Concentration | 9.0 minutes |
| Placebo | Time to Target Plasma Glucose Concentration | 27.5 minutes |
Comparison: Evaluated using a Kaplan Meier (KM) approach, with treatment group as a stratification factor, analogous to that used for the primary endpoint analysis. Differences between the KM curves (dasiglucagon versus placebo) were evaluated inferentially using pairwise two-sided log-rank tests. Subjects whose time to first plasma glucose concentration ≥70 mg/dL (3.9 mmol/L) was not met within 45 minutes post-dosing were censored, at the time of the last valid plasma glucose measurement up to 45 minutes.p-value: <0.0001Log Rank