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

Sponsor

Institut de Recherches Cliniques de Montreal (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01828125

Collaborator

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (Other)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Procedure: Hypoglycaemic hyperinsulinemic clamp Drug: Glucagon	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Care Provider)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Apr 1, 2013

Anticipated Primary Completion Date :

Dec 1, 2013

Anticipated Study Completion Date :

Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hyperinsulinemic hypoglycaemic clamp 1mg glucagon A 1.0mg glucagon dose will be given during the hyperinsulinemic hypoglycaemic clamp	Procedure: Hypoglycaemic hyperinsulinemic clamp 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. Drug: Glucagon
Active Comparator: Hyperinsulinemic hypoglycaemic clamp 0.1 or 0.2mg glucagon A dose of 0.1mg or 0.2mg will be given during the hyperinsulinemic hypoglycaemic clamp.	Procedure: Hypoglycaemic hyperinsulinemic clamp 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. Drug: Glucagon

Arm

Intervention/Treatment

Active Comparator: Hyperinsulinemic hypoglycaemic clamp 1mg glucagon

A 1.0mg glucagon dose will be given during the hyperinsulinemic hypoglycaemic clamp

Procedure: Hypoglycaemic hyperinsulinemic clamp

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.

Drug: Glucagon

Active Comparator: Hyperinsulinemic hypoglycaemic clamp 0.1 or 0.2mg glucagon

A dose of 0.1mg or 0.2mg will be given during the hyperinsulinemic hypoglycaemic clamp.

Procedure: Hypoglycaemic hyperinsulinemic clamp

Drug: Glucagon

Outcome Measures

Primary Outcome Measures

Incremental area under the curve of plasma glucose concentrations [30 minutes]
30-min incremental area under the curve of plasma glucose concentrations starting at the time glucagon is injected subcutaneously

Secondary Outcome Measures

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 [Up to 2.5 hours]
Time-to-peak plasma glucagon concentration after glucagon injection
Time for 25% of glucagon appearance [Up to 2.5 hours]
Time for 25% of glucagon appearance after glucagon injection
Time for 50% of glucagon appearance [Up to 2.5 hours]
Time for 50% of glucagon appearance after glucagon injection
Time for 75% of glucagon appearance [Up to 2.5 hours]
Time for 75% of glucagon appearance after glucagon injection

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.