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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Glucagon; Procedure: Hypoglycaemic hyperinsulinemic clamp

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 Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • Institut de Recherches Cliniques de Montreal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hyperinsulinemic hypoglycaemic clamp 1mg glucagon; A 1.0mg glucagon dose will be given during the hyperinsulinemic hypoglycaemic clamp	Drug: Glucagon; 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.
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.	Drug: Glucagon; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut de Recherches Cliniques de Montreal
• Collaborators: Centre de Recherche du Centre Hospitalier de l'Université de Montréal

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Anticipated): December 1, 2013
• Study Completion (Anticipated): December 1, 2013

Study Registration Dates

• First Submitted: April 2, 2013
• First Submitted That Met QC Criteria: April 9, 2013
• First Posted (Estimate): April 10, 2013

Study Record Updates

• Last Update Posted (Estimate): December 4, 2013
• Last Update Submitted That Met QC Criteria: December 3, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Hypoglycemia; Type 1 diabetes; Glucagon; Hypoglycaemic hyperinsulinemic clamp
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hypoglycemic Agents; Glucagon
• Other Study ID Numbers: Mini-doses glucagon