Prevention of Mild-to-moderate Hypoglycemia in Type 1 Diabetes (REVERSIBLE)

Towards Prevention of Mild-to-moderate Hypoglycemia in Type 1 Diabetes With Oral Glucose at a Higher Blood Glucose Threshold

According to guidelines, when a mild-to-moderate hypoglycemia occurs (capillary blood glucose < 4.0 mmol/L), 15-20g of rapidly absorbed carbohydrates should be ingested. Patients should re-test and re-ingest 15-20g carbohydrates every 15 minutes until they recover from hypoglycemia. These recommendations were principally based on two studies conducted in the 80s before the introduction of intensive insulin therapy. In practice, only 32-50% of patients follow the current guidelines. In addition, recent studies suggest that under current intensive insulin therapies, an initial correction with 15g of oral glucose may be insufficient to rapidly correct mild-to-moderate hypoglycemia. With the development and increasing usage of newer glucose monitoring technologies, the community is witnessing a shift in hypoglycemia management, from a reactive to a proactive approach (e.g., prevent imminent episodes rather than treating established episodes).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Other: Test to induce a decline in plasma glucose; Device: Dexcom G6; Other: Dex4; Drug: Insulin

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Delphine Bouchard; Phone Number: 3295 514 987-5500; Email: delphine.bouchard@ircm.qc.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • Montreal Clinical Research Institute

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Males and females ≥ 18 years old
2. Clinical diagnosis of type 1 diabetes for at least one year
3. Treatment with multiple daily insulin injections or insulin pump therapy with insulin analogs (rapid, ultra-rapid and basal insulin)
4. A glycated hemoglobin A1c ≤ 10%

Exclusion Criteria:

1. Clinically significant microvascular complications: nephropathy (eGFR < 40 ml/min), severe proliferative retinopathy as judged by the investigator, neuropathy (particularly diagnosed gastroparesis)
2. Recent (< 3 months) acute macrovascular event (e.g., acute coronary syndrome or cardiac surgery)
3. Known significant cardiac rhythm abnormality based on investigator's judgement
4. Known significant neurological abnormality (e.g., seizure disorder) based on investigator's judgement
5. Ongoing pregnancy or breastfeeding
6. Severe hypoglycemia episode within 1 month of screening
7. Known uncorrected hypokalemia within the past 3 months (potassium < 3.5 mmol/L)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 16g of carbohydrates - Plasma glucose < 4.0 mmol/L; 16g of carbohydrates will be given when glucose levels are below 4.0 mmol/L (management per guidelines)	Other: Test to induce a decline in plasma glucose; Participants will be admitted at the research center at 7:00 after an overnight fast. A venous catheter will be inserted into an arm vein for blood sampling purposes. A subcutaneous insulin bolus will be administered to bring plasma glucose to the glycemic threshold. Oral carbohydrates (16g) will be given when plasma glucose levels are at the target threshold. Sixty minutes after carbohydrates consumption, a standardized meal will be provided and participants will be discharged 90 minutes after the meal.; Device: Dexcom G6; Participants will have to wear a Dexcom G6 during study interventions; Other: Dex4; When the glycemic threshold is reach, participants will be given 16g of Dex4; Drug: Insulin; A subcutaneous insulin bolus will be given to induce a decline in plasma glucose and reach the glycemic threshold.
Active Comparator: 16g of carbohydrates - Plasma glucose ≤ 4.5 mmol/L; 16g of carbohydrates will be given when glucose levels are equal or below 4.5 mmol/L.	Other: Test to induce a decline in plasma glucose; Participants will be admitted at the research center at 7:00 after an overnight fast. A venous catheter will be inserted into an arm vein for blood sampling purposes. A subcutaneous insulin bolus will be administered to bring plasma glucose to the glycemic threshold. Oral carbohydrates (16g) will be given when plasma glucose levels are at the target threshold. Sixty minutes after carbohydrates consumption, a standardized meal will be provided and participants will be discharged 90 minutes after the meal.; Device: Dexcom G6; Participants will have to wear a Dexcom G6 during study interventions; Other: Dex4; When the glycemic threshold is reach, participants will be given 16g of Dex4; Drug: Insulin; A subcutaneous insulin bolus will be given to induce a decline in plasma glucose and reach the glycemic threshold.
Active Comparator: 16g of carbohydrates - Plasma glucose ≤ 5.0 mmol/L; 16g of carbohydrates will be given when glucose levels are equal or below 5.0 mmol/L.	Other: Test to induce a decline in plasma glucose; Participants will be admitted at the research center at 7:00 after an overnight fast. A venous catheter will be inserted into an arm vein for blood sampling purposes. A subcutaneous insulin bolus will be administered to bring plasma glucose to the glycemic threshold. Oral carbohydrates (16g) will be given when plasma glucose levels are at the target threshold. Sixty minutes after carbohydrates consumption, a standardized meal will be provided and participants will be discharged 90 minutes after the meal.; Device: Dexcom G6; Participants will have to wear a Dexcom G6 during study interventions; Other: Dex4; When the glycemic threshold is reach, participants will be given 16g of Dex4; Drug: Insulin; A subcutaneous insulin bolus will be given to induce a decline in plasma glucose and reach the glycemic threshold.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time spent of glucose levels < 4.0 mmol/L	60 minutes after carbohydrates consumption

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma glucose levels at 5 minutes after carbohydrates consumption		5 minutes after carbohydrates consumption
Plasma glucose levels at 10 minutes after carbohydrates consumption		10 minutes after carbohydrates consumption
Plasma glucose levels at 15 minutes after carbohydrates consumption		15 minutes after carbohydrates consumption
Plasma glucose levels at 20 minutes after carbohydrates consumption		20 minutes after carbohydrates consumption
Plasma glucose levels at 30 minutes after carbohydrates consumption		30 minutes after carbohydrates consumption
Plasma glucose levels at 45 minutes after carbohydrates consumption		45 minutes after carbohydrates consumption
Plasma glucose levels at 60 minutes after carbohydrates consumption		60 minutes after carbohydrates consumption
Lowest plasma glucose level eached after CHO consumption		60 minutes after carbohydrates consumption
Time from CHO consumption to the lowest plasma glucose level reached		60 minutes after carbohydrates consumption
Time from CHO consumption to plasma glucose < 3.5 mmol/L		60 minutes after carbohydrates consumption
Percentage of participants reaching hypoglycemia (< 4.0 mmol/L) after CHO consumption		60 minutes after carbohydrates consumption
Percentage of participants for whom hypoglycemia was corrected at 10 minutes after CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	10 minutes after carbohydrates consumption
Percentage of participants for whom hypoglycemia was corrected at 15 minutes after CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	15 minutes after carbohydrates consumption
Percentage of participants for whom hypoglycemia was corrected at 20 minutes after CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	20 minutes after carbohydrates consumption
Percentage of participants for whom hypoglycemia was corrected at 25 minutes after CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	25 minutes after carbohydrates consumption
Percentage of participants for whom hypoglycemia was corrected at 30 minutes after CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	30 minutes after carbohydrates consumption
Percentage of participants for whom hypoglycemia was corrected at 35 minutes after CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	35 minutes after carbohydrates consumption
Percentage of hypoglycemic events that were corrected at 10 minutes after CHO consumption	Only calculated for events with glucose level < 4.0 mmol/L	10 minutes after carbohydrates consumption
Percentage of hypoglycemic events that were corrected at 15 minutes after CHO consumption	Only calculated for events with glucose level < 4.0 mmol/L	15 minutes after carbohydrates consumption
Percentage of hypoglycemic events that were corrected at 20 minutes after CHO consumption	Only calculated for events with glucose level < 4.0 mmol/L	20 minutes after carbohydrates consumption
Percentage of hypoglycemic events that were corrected at 25 minutes after CHO consumption	Only calculated for events with glucose level < 4.0 mmol/L	25 minutes after carbohydrates consumption
Percentage of hypoglycemic events that were corrected at 30 minutes after CHO consumption	Only calculated for events with glucose level < 4.0 mmol/L	30 minutes after carbohydrates consumption
Percentage of hypoglycemic events that were corrected at 35 minutes after CHO consumption	Only calculated for events with glucose level < 4.0 mmol/L	35 minutes after carbohydrates consumption
Percentage of participants requiring a second treatment with carbohydrates at 20 minutes after the first CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	20 minutes after carbohydrates consumption
Percentage of participants requiring a second treatment with carbohydrates at 40 minutes after the first CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	40 minutes after carbohydrates consumption
Percentage of participants requiring a second treatment with carbohydrates at 60 minutes after the first CHO consumption	Only calculated for participants who will have glucose levels < 4.0 mmol/L	60 minutes after carbohydrates consumption
Percentage of participants experiencing a rebound hyperglycemia (≥ 10.0 mmol/L) within the first hour following the first carbobydrates consumption		60 minutes after carbohydrates consumption

Collaborators and Investigators

• Sponsor: Institut de Recherches Cliniques de Montreal
• Investigators: Principal Investigator: Remi Rabasa-Lhoret, Institut de Recherches Cliniques de Montreal

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: May 3, 2021
• First Submitted That Met QC Criteria: May 3, 2021
• First Posted (Actual): May 6, 2021

Study Record Updates

• Last Update Posted (Estimated): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Hypoglycemia; Type 1 diabetes; Carbohydrates
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: 2022-1119

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No