Efficacy of Small Subcutaneous Glucagon Dose to Treat Hypoglycemia in Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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In the unfortunate case of severe hypoglycaemia, glucagon is the first-line treatment because of its potent and rapid action starting as fast as 5 minutes after subcutaneous or intramuscular injection. Large dose of glucagon such as 1 mg subcutaneous is usually associated with undesirable side-effects such as nausea, vomiting, bloating and headache. The overall objective of this research proposal is to assess the efficacy of lower subcutaneous doses of glucagon (0.1 mg or 0.2 mg) to correct hypoglycaemia compared to the standard dose (1.0 mg) in adults with type 1 diabetes mellitus (T1D). It is postulated that much lower dosages of glucagon (0.1 or 0.2 mg) injected subcutaneously will be just as effective as the current recommended dose of 1.0 mg to correct hypoglycaemia without the undesirable gastro-intestinal side effects.

Detailed Description
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In the unfortunate case of severe hypoglycaemia, glucagon is the first-line treatment because of its potent and rapid action starting as fast as 5 minutes after subcutaneous or intramuscular injection. Current instructions for the treatment of severe hypoglycaemia call for the immediate injection of 1 mg of glucagon subcutaneously or intramuscularly. Large dose of glucagon such as 1 mg subcutaneous is usually associated with undesirable side-effects such as nausea, vomiting, bloating and headache. Moreover, glucagon emergency kits are relatively expensive (around $100 per kit), thus increasing the financial burden of diabetes on patients and the health care system. The primary objective of this research project is to the study the pharmacological effects of different doses of glucagon injected subcutaneously to correct hypoglycaemia during controlled conditions mimicking a hypoglycaemic event in adults with type 1 diabetes. More specifically, we will be looking at the effects of subcutaneous glucagon injected at 0.1 or 0.2 mg and 1.0 mg to normalized plasma glucose during a hypoglycaemic hyperinsulinemic clamp in subjects with type 1 diabetes.

Official Title
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A Double-blinded, Randomized, Two-way, Cross-over Study to Assess the Efficacy of Small Subcutaneous Glucagon Dose Against the Conventional 1 mg Dose to Treat Hypoglycemia in Adults With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Procedure: Hypoglycaemic hyperinsulinemic clamp
* Drug: Glucagon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥ 18 years of old Clinical diagnosis of type 1 diabetes for at least two years. Exclusion Criteria: Clinically significant nephropathy (MDRD < 60 mL/min/1.73 m2). Pregnancy Severe hypoglycemic episode within two weeks of screening Current use of glucocorticoid medication (except low stable dose) Pheochromocytoma or primary adrenal insufficiency (e.g. Addison's disease) Medical condition likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hyperinsulinemic hypoglycaemic clamp 1mg glucagon<br>A 1.0mg glucagon dose will be given during the hyperinsulinemic hypoglycaemic clamp | Procedure: Hypoglycaemic hyperinsulinemic clamp<br>* A first catheter will be inserted for infusion of D-[6,6-2H2] glucose and insulin. A second catheter will be inserted for infusion of dextrose. Dextrose infusion will be enriched with D-[6,6-2H2] glucose. A third catheter will be inserted for sampling. D-[6,6-2H2] glucose will be administered as a priming dose followed by a constant infusion throughout the experiment. Insulin will be administered as a primed continuous infusion. The first two hours will serve as an equilibration period for the tracer while glucose infusion will be adjusted to achieve a plasma glucose concentration of 5 mmol/L. The third hour is considered the baseline period. Following this, dextrose infusion rate will be decreased over a period of 1 hour to attain hypoglycaemia with a target blood glucose level at 2.8 mmol/L. At the end of the fourth hour, a subcutaneous glucagon dose will be given and plasma samples will be drawn for the determination of labelled and unlabelled glucose, plasma insulin and glucagon.<br>Drug: Glucagon<br> <br> |
| Active Comparator: Hyperinsulinemic hypoglycaemic clamp 0.1 or 0.2mg glucagon<br>A dose of 0.1mg or 0.2mg will be given during the hyperinsulinemic hypoglycaemic clamp. | Procedure: Hypoglycaemic hyperinsulinemic clamp<br>* A first catheter will be inserted for infusion of D-[6,6-2H2] glucose and insulin. A second catheter will be inserted for infusion of dextrose. Dextrose infusion will be enriched with D-[6,6-2H2] glucose. A third catheter will be inserted for sampling. D-[6,6-2H2] glucose will be administered as a priming dose followed by a constant infusion throughout the experiment. Insulin will be administered as a primed continuous infusion. The first two hours will serve as an equilibration period for the tracer while glucose infusion will be adjusted to achieve a plasma glucose concentration of 5 mmol/L. The third hour is considered the baseline period. Following this, dextrose infusion rate will be decreased over a period of 1 hour to attain hypoglycaemia with a target blood glucose level at 2.8 mmol/L. At the end of the fourth hour, a subcutaneous glucagon dose will be given and plasma samples will be drawn for the determination of labelled and unlabelled glucose, plasma insulin and glucagon.<br>Drug: Glucagon<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental area under the curve of plasma glucose concentrations | 30-min incremental area under the curve of plasma glucose concentrations starting at the time glucagon is injected subcutaneously | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach glucose levels ≥ 4 mmol/L |  | Up to 2.5 hours | 
| Time to reach glucose levels ≥ 5 mmol/L |  | Up to 2.5 hours | 
| Time-to-peak plasma glucagon concentration | Time-to-peak plasma glucagon concentration after glucagon injection | Up to 2.5 hours | 
| Time for 25% of glucagon appearance | Time for 25% of glucagon appearance after glucagon injection | Up to 2.5 hours | 
| Time for 50% of glucagon appearance | Time for 50% of glucagon appearance after glucagon injection | Up to 2.5 hours | 
| Time for 75% of glucagon appearance | Time for 75% of glucagon appearance after glucagon injection | Up to 2.5 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Hypoglycemia, Glucagon, Hypoglycaemic hyperinsulinemic clamp