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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dasiglucagon | Experimental | single fixed dose (subcutaneous injection) of dasiglucagon |
|
| Placebo | Placebo Comparator | single fixed dose (subcutaneous injection) of placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dasiglucagon | Drug | Glucagon analogue |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 0-45 minutes after dosing |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 0-30 minutes after dosing |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christina M Sylvest, MSc Pharm | Zealand Pharma A/S | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ProSciento, Inc. | Chula Vista | California | 91911 | United States | ||
| AMCR Institute |
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| ID | Title | Description |
|---|---|---|
| FG000 | Dasiglucagon 0.6 mg | single fixed dose (subcutaneous injection) of dasiglucagon Dasiglucagon: Glucagon analogue |
| FG001 | Placebo | single fixed dose (subcutaneous injection) of placebo Placebo: Placebo for dasiglucagon |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The safety population of all randomized subjects who received at least one dose of trial drug
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| ID | Title | Description |
|---|---|---|
| BG000 | Dasiglucagon 0.6 mg | single fixed dose (subcutaneous injection) of dasiglucagon Dasiglucagon: Glucagon analogue |
| BG001 | Placebo | single fixed dose (subcutaneous injection) of placebo Placebo: Placebo for dasiglucagon |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Median | 95% Confidence Interval | minutes | 0-45 minutes after dosing |
|
8 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dasiglucagon 0.6 mg | single fixed dose (subcutaneous injection) of dasiglucagon Dasiglucagon: Glucagon analogue |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Kim Mark Knudsen | Zealand Pharma A/S | +4550603780 | KMKnudsen@zealandpharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 4, 2018 | Mar 25, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 24, 2019 | Mar 25, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D007003 | Hypoglycemia |
| D003922 | Diabetes Mellitus, Type 1 |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D003920 | Diabetes Mellitus |
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| ID | Term |
|---|---|
| C000710373 | dasiglucagon |
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| Placebo | Drug | Placebo for dasiglucagon |
|
|
| 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). | 0-30 minutes after dosing |
| 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 | 0-45 minutes after dosing |
| 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. | 0-30 minutes after dosing |
| Pharmacokinetics - Area Under the Plasma Concentration Curve | Area under the drug concentration curve (AUC) from time zero to 90 minutes, AUC0-90min | 0-90 minutes after dosing |
| Pharmacokinetics - Area Under the Plasma Concentration Curve | Area under the drug concentration curve (AUC) from time zero to 120 minutes, AUC0-120min | 0-120 minutes after dosing |
| Pharmacokinetics - Maximum Plasma Concentration | Maximum plasma dasiglucagon concentration (Cmax) | 0-120 minutes after dosing |
| Pharmacokinetics - Time to Maximum Plasma Concentration | Time to maximum plasma dasiglucagon concentration (tmax) | 0-120 minutes after dosing |
| Immunogenicity - Occurrence of Anti-drug Antibodies | Occurrence of antibodies against dasiglucagon. Presented as percentage of patients with antibodies. | 58 days |
| 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 | 0-45 minutes after dosing |
| 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 | 0-45 minutes after dosing |
| Escondido |
| California |
| 92025 |
| United States |
| Rainier Clinical Research, Inc. | Renton | Washington | 98057 | United States |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Body weight | Mean | Standard Deviation | kg |
|
| Body mass index | Mean | Standard Deviation | kg per square metre |
|
| Duration of diabetes | Mean | Standard Deviation | years |
|
single fixed dose (subcutaneous injection) of placebo Placebo: Placebo for dasiglucagon |
|
|
|
| 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. | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Count of Participants | Participants | 0-30 minutes after dosing |
|
|
|
|
| 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). | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Mean | Standard Deviation | mg/dL | 0-30 minutes after dosing |
|
|
|
|
| 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 | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Median | 95% Confidence Interval | minutes | 0-45 minutes after dosing |
|
|
|
|
| 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. | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Mean | Standard Deviation | hr*mg/dL | 0-30 minutes after dosing |
|
|
|
|
| Secondary | Pharmacokinetics - Area Under the Plasma Concentration Curve | Area under the drug concentration curve (AUC) from time zero to 90 minutes, AUC0-90min | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Geometric Mean | Geometric Coefficient of Variation | hr*pmol/L | 0-90 minutes after dosing |
|
|
|
| Secondary | Pharmacokinetics - Area Under the Plasma Concentration Curve | Area under the drug concentration curve (AUC) from time zero to 120 minutes, AUC0-120min | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Geometric Mean | Geometric Coefficient of Variation | hr*pmol/L | 0-120 minutes after dosing |
|
|
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| Secondary | Pharmacokinetics - Maximum Plasma Concentration | Maximum plasma dasiglucagon concentration (Cmax) | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Geometric Mean | Geometric Coefficient of Variation | pmol/L | 0-120 minutes after dosing |
|
|
|
| Secondary | Pharmacokinetics - Time to Maximum Plasma Concentration | Time to maximum plasma dasiglucagon concentration (tmax) | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Median | Full Range | minutes | 0-120 minutes after dosing |
|
|
|
| Secondary | Immunogenicity - Occurrence of Anti-drug Antibodies | Occurrence of antibodies against dasiglucagon. Presented as percentage of patients with antibodies. | The safety analysis set of all randomized subjects who received at least one dose of trial drug (same as the full analysis set) | Posted | Count of Participants | Participants | 58 days |
|
|
|
| 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 | The full analysis set of all randomized subjects who received at least one dose of trial drug (same as the safety analysis set) | Posted | Count of Participants | Participants | 0-45 minutes after dosing |
|
|
|
| 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 | Only the patients who received IV glucose administration are included. | Posted | Number | minutes | 0-45 minutes after dosing |
|
|
|
| 0 |
| 34 |
| 0 |
| 34 |
| 24 |
| 34 |
| EG001 | Placebo | single fixed dose (subcutaneous injection) of placebo Placebo: Placebo for dasiglucagon | 0 | 10 | 0 | 10 | 3 | 10 |
| Vomiting | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Injection site pain | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Infusion site extravasation | General disorders | MedDRA 22.0 | Systematic Assessment |
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| Injection site erythema | General disorders | MedDRA 22.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Phlebitis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| Glucose recovery within 15 minutes |
|
| Glucose recovery within 10 minutes |
|
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. |
| Fisher Exact |
| <0.0001 |
| Superiority |
| 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. | Fisher Exact | <0.0001 | Superiority |
| 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. | Fisher Exact | 0.0006 | Superiority |
| At 15 minutes |
|
| At 10 minutes |
|
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. |
| ANCOVA |
| <0.0001 |
| Superiority |
| 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. | ANCOVA | <0.0001 | Superiority |
| 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. | ANCOVA | <0.0001 | Superiority |