Safety of Overestimation of a Meal Insulin Bolus in the Context of Dual-hormone Closed-loop Operation

A Single-blind, Randomized, Two-way, Cross-over Study to Examine the Safety of Overestimation of a Meal Insulin Bolus in the Context of Dual-hormone Closed-loop Operation Combined With a Simplified Qualitative Meal-size Estimation in Adults With Type 1 Diabetes

In previous studies, investigators have studied if a pre-meal insulin bolus based on estimated carbohydrate meal size would alleviate the burden of carbohydrate counting without a significant degradation in postprandial glucose control. With this strategy, the patient would only have to evaluate the size of the meal in terms of carbohydrate (snack, regular, large or very large) It is however important to establish safety of this simplified meal bolus approach. The safety of overestimating a meal insulin bolus in the context of single and dual-hormone CLS with the simplified meal strategy needs to be determined. Computer simulation will be used to get a reasonable estimate of risks related to over-estimation with single-hormone closed-loop while over-estimation with dual-hormone closed-loop will be tested in adults with type 1 diabètes

Investigators hypothesize that dual-hormone closed-loop with overestimated meal size bolus will not increase time below 4.0 mmol/L compared to dual-hormone closed-loop with an adequately estimated meal size bolus

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Insulin; Drug: Glucagon; Other: Dual-hormone closed-loop; Device: Dexcom G4 Platinum glucose sensor; Device: Accu Chek Combo insulin pump

• Study Type: Interventional
• Enrollment (Actual): 10
• 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:

1. Males and females ≥ 18 years old.
2. Clinical diagnosis of type 1 diabetes for at least one year.
3. The subject will have been on insulin pump therapy for at least 3 months and currently using a fast actin insulin analog (Lispro, Aspart or Guilisine).
4. Last (less than 3 months) HbA1c ≤ 10%.
5. Currently using carbohydrate counting as the meal insulin dose strategy.

Exclusion Criteria:

1. Clinically significant microvascular complications: nephropathy (estimated glomerular filtration rate below 40 ml/min), neuropathy (especially diagnosed gastroparesis) or severe proliferative retinopathy as judged by the investigator.
2. Recent (< 3 months) acute macrovascular event e.g. acute coronary syndrome or cardiac surgery.
3. Pregnancy.
4. Severe hypoglycemic episode within 1 month of screening.
5. Agents affecting gastric emptying (Motilium®, Prandase®, Victoza®, Byetta® and Symlin®) as well as oral anti-diabetic agents (Metformin, SGLT-2 inhibitors and DPP-4 inhibitors) if not at a stable dose for 3 months. Otherwise, these medications are acceptable and will be kept stable during the entire protocol.
6. Oral steroids unless patients present a low stable dose (e.g. 10 mg or less of prednisone per day or physiological doses, less than 35 mg/day, of hydrocortisone Cortef®). Inhale steroids at stable dose in the last month are acceptable.
7. Other serious medical illness likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator (e.g. unstable psychiatric condition).
8. Failure to comply with team's recommendations (e.g. not willing to change pump parameters, follow algorithm's suggestions, etc).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dual-hormone CL with overestimation of meal size category; A large size standardized meal of 75g of carbohydrates will be provided to the patient and the meal size will be overestimated by one category, which will result in a meal insulin bolus for a meal of 95g of carbohydrates.	Drug: Insulin; Participant's usual fast-acting insulin analog will be used: Lispro (Humalog), Aspart (NovoRapid) or Glulisine (Apidra); Drug: Glucagon; Glucagon (Eli Lilly) will be used during dual-hormone closed-loop strategy.; Other: Dual-hormone closed-loop; Interventions will be undertaken one to 5 days after sensor insertion. Subjects will be admitted at the research center at 7:00 am. Subject's pump will be substituted with the study pump and an additional pump containing glucagon will be installed. At 7:00, CLS will be initiated. At 9:00, a standardized breakfast (75g CHO) will be served. Study subjects will consume the same meal on the two intervention days. During the intervention, patients will be allowed to do sedentary activities. Patients will allowed to consume caffeine during the intervention, but will have to replicate their caffeine consumption on both interventions.The intervention day will end at 13:00.; Device: Dexcom G4 Platinum glucose sensor; Device: Accu Chek Combo insulin pump
Active Comparator: Dual-hormone CL with adequate estimation of meal size category; A large size standardized meal of 75g of carbohydrates will be provided to the patient and the meal size will be adequately estimated, which will result in a meal insulin bolus for a meal of 65g of carbohydrates.	Drug: Insulin; Participant's usual fast-acting insulin analog will be used: Lispro (Humalog), Aspart (NovoRapid) or Glulisine (Apidra); Drug: Glucagon; Glucagon (Eli Lilly) will be used during dual-hormone closed-loop strategy.; Other: Dual-hormone closed-loop; Interventions will be undertaken one to 5 days after sensor insertion. Subjects will be admitted at the research center at 7:00 am. Subject's pump will be substituted with the study pump and an additional pump containing glucagon will be installed. At 7:00, CLS will be initiated. At 9:00, a standardized breakfast (75g CHO) will be served. Study subjects will consume the same meal on the two intervention days. During the intervention, patients will be allowed to do sedentary activities. Patients will allowed to consume caffeine during the intervention, but will have to replicate their caffeine consumption on both interventions.The intervention day will end at 13:00.; Device: Dexcom G4 Platinum glucose sensor; Device: Accu Chek Combo insulin pump

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of time below 4.0 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean glucose	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Percentage of time of glucose concentrations between 4.0 and 8.0 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Percentage of time of glucose concentrations between 4.0 and 10.0 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Percentage of time of glucose concentrations below 3.1 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Area under the curve of glucose values below 4.0 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Area under the curve of glucose values below 3.1 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Number of patients with at least one hypoglycemic event with or without symptoms	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Total number of hypoglycemic event below 3.1 mmol/L	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Total carbohydrate intake for hypoglycemia correction	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Total insulin delivery	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.
Total glucagon delivery	The outcome measure will be calculated over the 4 hours following the breakfast meal given on the dual-hormone closed-loop intervention. The 4-hour period is from 9:00 to 13:00.

Collaborators and Investigators

• Sponsor: Institut de Recherches Cliniques de Montreal

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: December 3, 2015
• First Submitted That Met QC Criteria: December 9, 2015
• First Posted (Estimate): December 10, 2015

Study Record Updates

• Last Update Posted (Estimate): June 10, 2016
• Last Update Submitted That Met QC Criteria: June 9, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Insulin; Hypoglycemia; Type 1 diabetes; Glucagon; Artificial pancreas; Closed-loop system; Postprandial glucose control
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Insulin; Insulin, Globin Zinc; Glucagon; Hormones
• Other Study ID Numbers: CLASS Safety meal study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No