Hypoglycemia, Diabetes Mellitus, Type 1
Conditions
Keywords
Dasiglucagon, Glucagon analog
Brief summary
The objective of the trial is to demonstrate superiority of dasiglucagon compared to placebo following a single subcutaneous dose administered to subjects with type 1 diabetes mellitus (T1DM) with insulin-induced hypoglycemia. Additionally to compare the glycemic response observed after administration dasiglucagon with that of GlucaGen®.
Detailed description
This was a global, multicenter, randomized, parallel, and double-blind clinical trial confirming the efficacy and safety of dasiglucagon for insulin-induced hypoglycemia in patients with T1DM. The patients were randomized 2:1:1 to receive a single subcutaneous 0.6 mg dose of dasiglucagon, placebo, or a 1 mg dose of GlucaGen and followed for at least 28 days after receiving treatment.
Interventions
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 type 1 diabetes mellitus (T1DM) for at least 1 year, diagnostic criteria as defined by the American Diabetes Association * 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%
Exclusion criteria
* Previously treated with dasiglucagon (previously referred to as ZP4207) * Known or suspected allergy to trial product(s) or related products * Females who are pregnant according to a positive pregnancy test, are actively attempting to get pregnant, or are lactating. * History of hypoglycemic events associated with seizures in the last year prior to screening * History of severe hypoglycemia in the last month prior to screening * Active malignancy within the last 5 years * Current bleeding disorder, including anti-coagulant treatment * Known presence or history of pheochromocytoma (i.e. adrenal gland tumor) or insulinoma (i.e. insulin secreting pancreas tumor) * Use of a daily systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this trial * Clinically significant abnormal ECG at screening as judged by the investigator * Donation of blood or plasma in the past month, or in excess of 500 mL within 12 weeks prior to screening * Surgery or trauma with significant blood loss within the last 2 months prior to screening * A positive result in the alcohol and/or urine drug screen at the screening visit. Significant history of alcoholism or drug abuse as judged by the investigator or consuming more than 24 g alcohol per day for men, or more than 12 g alcohol per day for women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Plasma Glucose Recovery | 0-45 minutes after dosing | Plasma glucose recovery is defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue intravenous glucose. The outcome measure used a Kaplan-Meier estimate with 95% confidence interval. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose Changes From Baseline | 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection | Plasma glucose changes from baseline at 30 minutes, 20 minutes, 15 minutes and 10 minutes after study drug injection without administration of rescue intravenous glucose |
| Time to Target | 0-45 minutes after dosing | Time to first plasma glucose concentration ≥70 mg/dL (3.9 mmol/L) without administration of rescue intravenous glucose. The outcome measure used a Kaplan-Meier estimate with 95% confidence interval. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time. |
| 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. Samples were collected pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 25 and 30 minutes after dosing. |
| Pharmacokinetics - Area Under the Plasma Concentration Curve | 0-90 minutes after dosing | Area under the drug concentration curve from time zero to 90 minutes, AUC0-90min. To calculate the AUC the standard trapezoidal method was used, based on actual rather than nominal time points. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing. |
| Plasma Glucose Recovery | 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection | Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after study drug injection without administration of rescue IV glucose. Plasma glucose recovery was defined as the first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue intravenous glucose. |
| Pharmacokinetics - Time to Maximum Plasma Concentration | 0-120 minutes after dosing | Time to maximum plasma drug concentration (tmax). Median Tmax was determined as the time point where the maximum of all valid plasma dasiglucagon/glucagon concentration measurements for each measurement series was observed. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing. |
| Immunogenicity - Occurence of Anti-drug Antibodies | 28 days | Occurence of antibodies against dasiglucagon/GlucaGen |
| Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure | 0-45 minutes after dosing | Number of patients receiving administration of rescue infusion of IV glucose during the hypoglycemic clamp procedure. IV = intravenous |
| Time to First Rescue Infusion of IV Glucose | 0-45 minutes after dosing | Time to first rescue administration of rescue infusion of IV glucose. IV = intravenous |
| Pharmacokinetics - Maximum Plasma Concentration | 0-120 minutes after dosing | Maximum plasma drug concentration (Cmax). Maximum plasma drug concentration was determined as the maximum of all valid plasma dasiglucagon/glucagon concentrations. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing. |
Countries
Austria, Canada, Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dasiglucagon 0.6 mg Single fixed dose (s.c.injection) of dasiglucagon
Dasiglucagon: Glucagon analog | 82 |
| Placebo Single fixed dose (s.c.injection) of placebo
Placebo: Placebo for dasiglucagon | 43 |
| GlucaGen® 1.0 mg Single fixed dose (s.c.injection) of GlucaGen®
GlucaGen: Native glucagon | 43 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | GlucaGen® 1.0 mg | Dasiglucagon 0.6 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 13.1 | 40.2 years STANDARD_DEVIATION 11.5 | 39.2 years STANDARD_DEVIATION 12.1 | 39.1 years STANDARD_DEVIATION 12.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 40 Participants | 80 Participants | 161 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 39 Participants | 39 Participants | 76 Participants | 154 Participants |
| Region of Enrollment Austria | 0 participants | 0 participants | 33 participants | 33 participants |
| Region of Enrollment Canada | 10 participants | 10 participants | 18 participants | 38 participants |
| Region of Enrollment Germany | 27 participants | 27 participants | 19 participants | 73 participants |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 32 Participants | 63 Participants |
| Sex: Female, Male Male | 27 Participants | 28 Participants | 50 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 43 | 0 / 43 |
| other Total, other adverse events | 66 / 82 | 14 / 43 | 32 / 43 |
| serious Total, serious adverse events | 0 / 82 | 0 / 43 | 0 / 43 |
Outcome results
Primary
Time to Plasma Glucose Recovery
Plasma glucose recovery is defined as first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue intravenous glucose. The outcome measure used a Kaplan-Meier estimate with 95% confidence interval. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time.
Time frame: 0-45 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Time to Plasma Glucose Recovery | 10 minutes |
| Placebo | Time to Plasma Glucose Recovery | 40 minutes |
| GlucaGen® 1.0 mg | Time to Plasma Glucose Recovery | 12 minutes |
Comparison: The treatment group difference between dasiglucagon and placebo was evaluated inferentially using a pairwise two-sided log rank test. Kaplan-Meier estimate with 95% CI, p-value based on treatment group difference between dasiglucagon and placebo using a two-sided log-rank test stratified by injection site. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time.p-value: <0.001Log Rank
Secondary
Immunogenicity - Occurence of Anti-drug Antibodies
Occurence of antibodies against dasiglucagon/GlucaGen
Time frame: 28 days
Population: The safety analysis set of all randomized patients who received trial medication (which was the same as the full analysis set)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Immunogenicity - Occurence of Anti-drug Antibodies | Anti-drug antibodies at follow-up day 28 | 1 Participants |
| Dasiglucagon 0.6 mg | Immunogenicity - Occurence of Anti-drug Antibodies | Anti-drug antibodies at second follow up | 0 Participants |
| Placebo | Immunogenicity - Occurence of Anti-drug Antibodies | Anti-drug antibodies at follow-up day 28 | 0 Participants |
| Placebo | Immunogenicity - Occurence of Anti-drug Antibodies | Anti-drug antibodies at second follow up | 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. Samples were collected pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 25 and 30 minutes after dosing.
Time frame: 0-30 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacodynamics - Area Under the Effect Curve | 21.0 mg*h/dL | Standard Deviation 5.26 |
| Placebo | Pharmacodynamics - Area Under the Effect Curve | 3.57 mg*h/dL | Standard Deviation 2.86 |
| GlucaGen® 1.0 mg | Pharmacodynamics - Area Under the Effect Curve | 20.4 mg*h/dL | Standard Deviation 5.49 |
Comparison: The log-transformed AUC endpoint was analyzed using an analysis of covariance model with treatment as fixed effect and baseline plasma glucose modeled as a covariate. The least squares means treatment group differences were back-transformed (anti-logged) for presentation as a ratio of the treatment group geometric means, with their corresponding 95% confidence interval.p-value: <0.00195% CI: [0.1, 0.171]ANCOVA
Secondary
Pharmacokinetics - Area Under the Plasma Concentration Curve
Area under the drug concentration curve from time zero to 120 minutes, AUC0-120min. To calculate the AUC the standard trapezoidal method was used, based on actual rather than nominal time points. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.
Time frame: 0-120 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product. No results are presented for the placebo group, as no active drug was given in this group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Area Under the Plasma Concentration Curve | 1770 pmol*h/L | Geometric Coefficient of Variation 31.2 |
| Placebo | Pharmacokinetics - Area Under the Plasma Concentration Curve | 1490 pmol*h/L | Geometric Coefficient of Variation 27.2 |
Comparison: Least square mean ratio for GlucaGen: dasiglucagonp-value: 0.00695% CI: [0.749, 0.951]ANCOVA
Secondary
Pharmacokinetics - Area Under the Plasma Concentration Curve
Area under the drug concentration curve from time zero to 90 minutes, AUC0-90min. To calculate the AUC the standard trapezoidal method was used, based on actual rather than nominal time points. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.
Time frame: 0-90 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product. No results are presented for the placebo group, as no active drug was given in this group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Area Under the Plasma Concentration Curve | 1430 pmol*h/L | Geometric Coefficient of Variation 34.2 |
| Placebo | Pharmacokinetics - Area Under the Plasma Concentration Curve | 1300 pmol*h/L | Geometric Coefficient of Variation 27.5 |
Comparison: Least square mean ratio for GlucaGen: dasiglucagonp-value: 0.14495% CI: [0.801, 1.033]ANCOVA
Secondary
Pharmacokinetics - Maximum Plasma Concentration
Maximum plasma drug concentration (Cmax). Maximum plasma drug concentration was determined as the maximum of all valid plasma dasiglucagon/glucagon concentrations. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.
Time frame: 0-120 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product. No results are presented for the placebo group, as no active drug was given in this group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Maximum Plasma Concentration | 1280 pmol/L | Geometric Coefficient of Variation 37.7 |
| Placebo | Pharmacokinetics - Maximum Plasma Concentration | 1490 pmol/L | Geometric Coefficient of Variation 34.5 |
Secondary
Pharmacokinetics - Time to Maximum Plasma Concentration
Time to maximum plasma drug concentration (tmax). Median Tmax was determined as the time point where the maximum of all valid plasma dasiglucagon/glucagon concentration measurements for each measurement series was observed. Samples were collected pre-dose, and at 15, 30, 35, 40, 50, 60, 90 and 120 minutes after dosing.
Time frame: 0-120 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product. No results are presented for the placebo group, as no active drug was given in this group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Pharmacokinetics - Time to Maximum Plasma Concentration | 0.670 hours |
| Placebo | Pharmacokinetics - Time to Maximum Plasma Concentration | 0.250 hours |
Secondary
Plasma Glucose Changes From Baseline
Plasma glucose changes from baseline at 30 minutes, 20 minutes, 15 minutes and 10 minutes after study drug injection without administration of rescue intravenous glucose
Time frame: 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection
Population: Full analysis set of all randomized patients who received at least one dose of trial product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 30 minutes | 90.9 mg/dL | Standard Deviation 18.2 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 20 minutes | 59.7 mg/dL | Standard Deviation 15 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 15 minutes | 43.5 mg/dL | Standard Deviation 12.51 |
| Dasiglucagon 0.6 mg | Plasma Glucose Changes From Baseline | At 10 minutes | 23.9 mg/dL | Standard Deviation 9.84 |
| Placebo | Plasma Glucose Changes From Baseline | At 10 minutes | -0.14 mg/dL | Standard Deviation 5.65 |
| Placebo | Plasma Glucose Changes From Baseline | At 30 minutes | 19.1 mg/dL | Standard Deviation 13 |
| Placebo | Plasma Glucose Changes From Baseline | At 15 minutes | 6.65 mg/dL | Standard Deviation 6.82 |
| Placebo | Plasma Glucose Changes From Baseline | At 20 minutes | 8.7 mg/dL | Standard Deviation 10.8 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 10 minutes | 22.0 mg/dL | Standard Deviation 10 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 20 minutes | 58.4 mg/dL | Standard Deviation 15.6 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 15 minutes | 44.1 mg/dL | Standard Deviation 14 |
| GlucaGen® 1.0 mg | Plasma Glucose Changes From Baseline | At 30 minutes | 88.5 mg/dL | Standard Deviation 19.2 |
Comparison: Plasma glucose (PG) change from baseline at rescue was carried forward in patients who required rescue intravenous (IV) glucose before reaching PG recovery. Change from baseline was analyzed using an ANCOVA, with treatment group as fixed effect and baseline PG as covariate. Group difference was evaluated inferentially following an a priori defined hierarchical test order, proceeding until the first failure to reject the null hypothesis.p-value: <0.001ANCOVA
Secondary
Plasma Glucose Recovery
Plasma glucose recovery within 30 minutes, within 20 minutes, within 15 minutes, and within 10 minutes after study drug injection without administration of rescue IV glucose. Plasma glucose recovery was defined as the first increase in plasma glucose of ≥20 mg/dL (1.1 mmol/L) from baseline without administration of rescue intravenous glucose.
Time frame: 0-30 minutes after dosing: assessed at 10, 15, 20 and 30 minutes after study drug injection
Population: Full analysis set of all randomized patients who received at least one dose of trial product
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 20 minutes | 81 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 10 minutes | 53 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 15 minutes | 81 Participants |
| Dasiglucagon 0.6 mg | Plasma Glucose Recovery | Glucose recovery at 30 minutes | 82 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 20 minutes | 6 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 30 minutes | 20 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 10 minutes | 0 Participants |
| Placebo | Plasma Glucose Recovery | Glucose recovery at 15 minutes | 1 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 30 minutes | 43 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 10 minutes | 21 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 15 minutes | 41 Participants |
| GlucaGen® 1.0 mg | Plasma Glucose Recovery | Glucose recovery at 20 minutes | 42 Participants |
Comparison: Pairwise test of independent binomial proportions with Fisher's Exact test comparing dasiglucagon versus placebo. 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: <0.001Fisher Exact
Secondary
Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure
Number of patients receiving administration of rescue infusion of IV glucose during the hypoglycemic clamp procedure. IV = intravenous
Time frame: 0-45 minutes after dosing
Population: The safety analysis set of all randomized patients who received trial medication (which was the same as the full analysis set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dasiglucagon 0.6 mg | Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure | 0 Participants |
| Placebo | Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure | 0 Participants |
| GlucaGen® 1.0 mg | Rescue Infusion of IV Glucose During the Hypoglycemic Clamp Procedure | 0 Participants |
Secondary
Time to First Rescue Infusion of IV Glucose
Time to first rescue administration of rescue infusion of IV glucose. IV = intravenous
Time frame: 0-45 minutes after dosing
Population: No patients received IV glucose infusions therefore there are no data available for this outcome measure
Secondary
Time to Target
Time to first plasma glucose concentration ≥70 mg/dL (3.9 mmol/L) without administration of rescue intravenous glucose. The outcome measure used a Kaplan-Meier estimate with 95% confidence interval. Treatment groups without censoring utilized a distribution free method to compute the confidence interval for median time.
Time frame: 0-45 minutes after dosing
Population: Full analysis set of all randomized patients who received at least one dose of trial product
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasiglucagon 0.6 mg | Time to Target | 8 minutes |
| Placebo | Time to Target | 25 minutes |
| GlucaGen® 1.0 mg | Time to Target | 8 minutes |
Comparison: The treatment group difference between dasiglucagon and placebo was evaluated using a Kaplan-Meier estimate with 95% confidence interval, p-value based on a pairwise two-sided log-rank test versus placebo.p-value: <0.001Log Rank