## Protocol Section
### Identification Module
**NCT ID:** NCT04876079

**Acronym:** REVERSIBLE

**Brief Title:** Prevention of Mild-to-moderate Hypoglycemia in Type 1 Diabetes

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

#### Organization Study ID Info
**ID:** 2022-1119
#### Organization
**Class:** OTHER
**Full Name:** Institut de Recherches Cliniques de Montreal
### Status Module
#### Completion Date
**Date:** 2023-06-30

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-08-31

**Type:** ACTUAL

**Last Update Submit Date:** 2023-08-29

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2023-06-01

**Type:** ACTUAL

#### Start Date
**Date:** 2021-06-01

**Type:** ACTUAL

**Status Verified Date:** 2023-08

#### Study First Post Date
**Date:** 2021-05-06
**Type:** ACTUAL
**Study First Submit Date:** 2021-05-03
**Study First Submit QC Date:** 2021-05-03
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Institut de Recherches Cliniques de Montreal

#### Responsible Party

**Investigator Affiliation:** Institut de Recherches Cliniques de Montreal

**Investigator Full Name:** Rémi Rabasa-Lhoret

**Investigator Title:** Full professor

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** 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).

### Conditions Module

**Conditions:**

- Type 1 Diabetes

**Keywords:**

- Hypoglycemia

- Type 1 diabetes

- Carbohydrates

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 30

**Type:** ACTUAL

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 16g of carbohydrates will be given when glucose levels are below 4.0 mmol/L (management per guidelines)

**Intervention Names:**

- Other: Test to induce a decline in plasma glucose

- Device: Dexcom G6

- Other: Dex4

- Drug: Insulin

**Label:** 16g of carbohydrates - Plasma glucose < 4.0 mmol/L

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** 16g of carbohydrates will be given when glucose levels are equal or below 4.5 mmol/L.

**Intervention Names:**

- Other: Test to induce a decline in plasma glucose

- Device: Dexcom G6

- Other: Dex4

- Drug: Insulin

**Label:** 16g of carbohydrates - Plasma glucose ≤ 4.5 mmol/L

**Type:** ACTIVE_COMPARATOR

#### Arm Group 3

**Description:** 16g of carbohydrates will be given when glucose levels are equal or below 5.0 mmol/L.

**Intervention Names:**

- Other: Test to induce a decline in plasma glucose

- Device: Dexcom G6

- Other: Dex4

- Drug: Insulin

**Label:** 16g of carbohydrates - Plasma glucose ≤ 5.0 mmol/L

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- 16g of carbohydrates - Plasma glucose < 4.0 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 4.5 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 5.0 mmol/L

**Description:** 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.

**Name:** Test to induce a decline in plasma glucose

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- 16g of carbohydrates - Plasma glucose < 4.0 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 4.5 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 5.0 mmol/L

**Description:** Participants will have to wear a Dexcom G6 during study interventions

**Name:** Dexcom G6

**Type:** DEVICE

#### Intervention 3

**Arm Group Labels:**

- 16g of carbohydrates - Plasma glucose < 4.0 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 4.5 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 5.0 mmol/L

**Description:** When the glycemic threshold is reach, participants will be given 16g of Dex4

**Name:** Dex4

**Type:** OTHER

#### Intervention 4

**Arm Group Labels:**

- 16g of carbohydrates - Plasma glucose < 4.0 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 4.5 mmol/L

- 16g of carbohydrates - Plasma glucose ≤ 5.0 mmol/L

**Description:** A subcutaneous insulin bolus will be given to induce a decline in plasma glucose and reach the glycemic threshold.

**Name:** Insulin

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Measure:** Time spent of glucose levels < 4.0 mmol/L

**Time Frame:** 60 minutes after carbohydrates consumption

#### Secondary Outcomes

**Measure:** Plasma glucose levels at 5 minutes after carbohydrates consumption

**Time Frame:** 5 minutes after carbohydrates consumption

**Measure:** Plasma glucose levels at 10 minutes after carbohydrates consumption

**Time Frame:** 10 minutes after carbohydrates consumption

**Measure:** Plasma glucose levels at 15 minutes after carbohydrates consumption

**Time Frame:** 15 minutes after carbohydrates consumption

**Measure:** Plasma glucose levels at 20 minutes after carbohydrates consumption

**Time Frame:** 20 minutes after carbohydrates consumption

**Measure:** Plasma glucose levels at 30 minutes after carbohydrates consumption

**Time Frame:** 30 minutes after carbohydrates consumption

**Measure:** Plasma glucose levels at 45 minutes after carbohydrates consumption

**Time Frame:** 45 minutes after carbohydrates consumption

**Measure:** Plasma glucose levels at 60 minutes after carbohydrates consumption

**Time Frame:** 60 minutes after carbohydrates consumption

**Measure:** Lowest plasma glucose level eached after CHO consumption

**Time Frame:** 60 minutes after carbohydrates consumption

**Measure:** Time from CHO consumption to the lowest plasma glucose level reached

**Time Frame:** 60 minutes after carbohydrates consumption

**Measure:** Time from CHO consumption to plasma glucose < 3.5 mmol/L

**Time Frame:** 60 minutes after carbohydrates consumption

**Measure:** Percentage of participants reaching hypoglycemia (< 4.0 mmol/L) after CHO consumption

**Time Frame:** 60 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants for whom hypoglycemia was corrected at 10 minutes after CHO consumption

**Time Frame:** 10 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants for whom hypoglycemia was corrected at 15 minutes after CHO consumption

**Time Frame:** 15 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants for whom hypoglycemia was corrected at 20 minutes after CHO consumption

**Time Frame:** 20 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants for whom hypoglycemia was corrected at 25 minutes after CHO consumption

**Time Frame:** 25 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants for whom hypoglycemia was corrected at 30 minutes after CHO consumption

**Time Frame:** 30 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants for whom hypoglycemia was corrected at 35 minutes after CHO consumption

**Time Frame:** 35 minutes after carbohydrates consumption

**Description:** Only calculated for events with glucose level \< 4.0 mmol/L

**Measure:** Percentage of hypoglycemic events that were corrected at 10 minutes after CHO consumption

**Time Frame:** 10 minutes after carbohydrates consumption

**Description:** Only calculated for events with glucose level \< 4.0 mmol/L

**Measure:** Percentage of hypoglycemic events that were corrected at 15 minutes after CHO consumption

**Time Frame:** 15 minutes after carbohydrates consumption

**Description:** Only calculated for events with glucose level \< 4.0 mmol/L

**Measure:** Percentage of hypoglycemic events that were corrected at 20 minutes after CHO consumption

**Time Frame:** 20 minutes after carbohydrates consumption

**Description:** Only calculated for events with glucose level \< 4.0 mmol/L

**Measure:** Percentage of hypoglycemic events that were corrected at 25 minutes after CHO consumption

**Time Frame:** 25 minutes after carbohydrates consumption

**Description:** Only calculated for events with glucose level \< 4.0 mmol/L

**Measure:** Percentage of hypoglycemic events that were corrected at 30 minutes after CHO consumption

**Time Frame:** 30 minutes after carbohydrates consumption

**Description:** Only calculated for events with glucose level \< 4.0 mmol/L

**Measure:** Percentage of hypoglycemic events that were corrected at 35 minutes after CHO consumption

**Time Frame:** 35 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants requiring a second treatment with carbohydrates at 20 minutes after the first CHO consumption

**Time Frame:** 20 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants requiring a second treatment with carbohydrates at 40 minutes after the first CHO consumption

**Time Frame:** 40 minutes after carbohydrates consumption

**Description:** Only calculated for participants who will have glucose levels \< 4.0 mmol/L

**Measure:** Percentage of participants requiring a second treatment with carbohydrates at 60 minutes after the first CHO consumption

**Time Frame:** 60 minutes after carbohydrates consumption

**Measure:** Percentage of participants experiencing a rebound hyperglycemia (≥ 10.0 mmol/L) within the first hour following the first carbobydrates consumption

**Time Frame:** 60 minutes after carbohydrates consumption

### Eligibility Module

**Eligibility Criteria:** 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)

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Montreal

**Country:** Canada

**Facility:** Montreal Clinical Research Institute

**State:** Quebec

**Zip:** H2W 1R7

#### Overall Officials

**Official 1:**

**Affiliation:** Institut de recherches cliniques de Montréal

**Name:** Rémi Rabasa-Lhoret

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000044882

- Term: Glucose Metabolism Disorders

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000001327

- Term: Autoimmune Diseases

- ID: D000007154

- Term: Immune System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC20

- Name: Immune System Diseases

### Condition Browse Module - Browse Leaves

- ID: M7115

- Name: Diabetes Mellitus

- Relevance: HIGH

- As Found: Diabetes

- ID: M7117

- Name: Diabetes Mellitus, Type 1

- Relevance: HIGH

- As Found: Type 1 Diabetes

- ID: M10053

- Name: Hypoglycemia

- Relevance: HIGH

- As Found: Hypoglycemia

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M25403

- Name: Glucose Metabolism Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M4629

- Name: Autoimmune Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003920

- Term: Diabetes Mellitus

- ID: D000003922

- Term: Diabetes Mellitus, Type 1

- ID: D000007003

- Term: Hypoglycemia

### Intervention Browse Module - Ancestors

- ID: D000007004

- Term: Hypoglycemic Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Hypo

- Name: Hypoglycemic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M10365

- Name: Insulin

- Relevance: HIGH

- As Found: Day 1

- ID: M173166

- Name: Insulin, Globin Zinc

- Relevance: LOW

- As Found: Unknown

- ID: M10054

- Name: Hypoglycemic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000007328

- Term: Insulin

### Misc Info Module

- Version Holder: 2024-05-24
