Continuous Monitoring of Glycemic Variability to Predict Dys- and Hyperglycemia in Asymptomatic Type 1 Diabetes

NCT ID: NCT05777330

Last Updated: 2025-09-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-09
• Study Completion Date: 2028-08-31

Brief Summary

The goal of this longitudinal clinical trial is to measure variability of interstitial glucose levels with a user-friendly real-time continuous glucose monitoring (CGM) technology at regular intervals in normo- and dysglycemic multiple autoantibody-positive individuals (age 5-39 years), in comparison with single autoantibody-positive individuals in the same age range. Participants will asked to undergo repeated oral glucose tolerance tests (OGTTs) (age 5-39 years) and hyperglycemic clamp tests (age 12-39 years) in parallel for a period of at least 2-3 years. In case of confirmed dysglycemia, we propose to perform CGM and OGTT every 3 months.

The main questions the study aims to answer are:

1. Do the amplitude and time trends of CGM-derived glycemic variability indices and OGTT- and clamp-derived variables differ between the intermediate, high and very high risk groups?

2. Can (changes in) CGM-derived glycemic variability indices predict/detect dysglycemia in initially normoglycemic (single or multiple autoantibody-positive) individuals with the same diagnostic efficiency as OGTT- or clamp-derived variables?

3. Can (changes in) CGM-derived glycemic variability indices predict clinical onset in (stage 1 or 2) multiple autoantibody-positive individuals with the same diagnostic efficiency as OGTT- or clamp-derived variables?

4. Can correlating (changes in) CGM-derived indices with (changes in) OGTT- and clamp-derived variables help to better understand the sequence of events leading to dysglycemia and clinical onset, as well as the relative contribution of beta cell function and insulin action to glycemic variability according to disease stage and biological and phenotypical characteristics of the individuals?

Detailed Description

Type 1 diabetes is a for now incurable disease caused by a major immune-mediated loss of insulin-producing pancreatic beta cells, can lead to potentially severe acute and chronic complications and requires a lifelong insulin treatment. Clinical onset of type 1 diabetes is preceded by an asymptomatic disease phase of highly variable duration, which is signaled by the presence of multiple (≥2) types of islet autoantibodies. Multiple autoantibody-positive individuals, with blood glucose levels still within normal limits (defined as stage 1 type 1 diabetes) have a 90% risk of developing symptomatic disease within the next 20 years. The development of dysglycemia (stage 2 type 1 diabetes) - i.e. disturbed blood glucose levels during an oral glucose tolerance test (OGTT) - dramatically raises the risk of impending clinical onset to 90% within 5 years. Identifying individuals at high risk of impending clinical onset of type 1 diabetes is important for early diagnosis, for reducing the incidence of inaugural ketoacidosis, and for enrolling participants of choice in immune intervention trials before and at clinical diagnosis, aiming to develop an effective cure or even better, prevention. The hyperglycemic clamp test is the gold standard for assessing beta cell function and has also been validated for estimating insulin action in parallel. Decreased clamp-derived measures of islet function and insulin action have been shown to outperform OGTT-derived variables for predicting progression to symptomatic disease. However, the repeated performance of both OGTTs and clamps are cumbersome and difficult to implement on a large scale in a seemingly healthy population. In contrast, continuous glucose monitoring (CGM) methods nowadays avoid the need of frequent calibration based on capillary blood measurements obtained by finger pricks. They also allow to detect more subtle glycemic fluctuations over longer observation periods and on a more frequent basis than achievable with OGTT, and to derive a wide variety of indices of glycemic variability. Preliminary findings suggest that repeated CGM metrics in stage 1 asymptomatic diabetes could represent a minimally invasive alternative to OGTT for early detection or prediction of stage 2 asymptomatic disease, provided that increased CGM-derived glycemic excursions can be shown to coincide with or precede OGTT-inferred dysglycemia, respectively, in a longitudinal study. In addition, it is anticipated that further increasing glycemic excursions may forecast impending clinical onset. Using the capacity of the nationwide network of the Belgian Diabetes Registry, we therefore propose a longitudinal study to measure variability of interstitial glucose levels with a userfriendly real-time CGM technology at regular intervals (every 6 months) during follow-up of multiple autoantibody-positive first-degree individuals (age 5-39 years; n>50) of type 1 diabetes patients, in comparison with single autoantibody-positive individuals (n>25). In parallel repeated OGTTs (age 5-39 years) and hyperglycemic clamp tests (age 12-39 years) will be performed for a period of at least 2-3 years. We anticipate that, especially when using up-to-date CGM technology, (i) the amplitude and time trends of various glycemic variability indices - alone or in combination - will differ between groups of individuals at moderate (single autoantibody-positive), high (stage 1), and very high (stage 2) risk of impending clinical onset (stage 3); (ii) (changes in) CGM-derived glycemic variability indices will be able to predict and/or diagnose stage 2 asymptomatic type 1 diabetes and clinical onset (stage 3) with a diagnostic efficiency equaling that of variables derived from (repeated) OGTT or clamp tests; (iii) correlating CGM metrics with hyperglycemic clamp- and OGTT-derived indices of beta cell function and insulin action will help to understand the relative contribution of both components to disease progression in general, and to glycemic variability in particular.

Conditions

Type1 Diabetes Mellitus

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

Autoantibody-positive individuals

Group Type: OTHER

Oral glucose tolerance test (OGTT)

Intervention Type: DIAGNOSTIC_TEST

Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals at moderate, high and very high risk of clinical onset of type 1 diabetes.

OGTT is performed every 6 months (every 3 months in case of dysglycemia) in all participants.

Hyperglycemic clamp test

Intervention Type: DIAGNOSTIC_TEST

Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals at moderate, high and very high risk of clinical onset of type 1 diabetes.

Clamp test is performed every 12 months in single autoantibody-positive participants and every 6 months in multiple autoantibody-positive participants. Clamp tests are not performed in participants aged between 5-11 years.

Continuous glucose monitoring

Intervention Type: DIAGNOSTIC_TEST

Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals at moderate, high and very high risk of clinical onset of type 1 diabetes.

A 10-day CGM recording is performed every 6 months (every 3 months in case of dysglycemia) in all participants.

Interventions

Oral glucose tolerance test (OGTT)

Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals at moderate, high and very high risk of clinical onset of type 1 diabetes.

OGTT is performed every 6 months (every 3 months in case of dysglycemia) in all participants.

Intervention Type: DIAGNOSTIC_TEST

Hyperglycemic clamp test

Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals at moderate, high and very high risk of clinical onset of type 1 diabetes.

Clamp test is performed every 12 months in single autoantibody-positive participants and every 6 months in multiple autoantibody-positive participants. Clamp tests are not performed in participants aged between 5-11 years.

Intervention Type: DIAGNOSTIC_TEST

Continuous glucose monitoring

Longitudinal study using repeated OGTT, CGM and hyperglycemic clamp tests to evaluate glycemic variability, beta cell function and insulin action in individuals at moderate, high and very high risk of clinical onset of type 1 diabetes.

A 10-day CGM recording is performed every 6 months (every 3 months in case of dysglycemia) in all participants.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

OGTT; clamp; Dexcom G6; CGM

Eligibility Criteria

Inclusion Criteria

1. aged 5-39 years at inclusion;

2. absence of diabetes meeting the clinical diagnostic American Diabetes Association (ADA) criteria;

3. persistently positive for one or multiple types of autoantibodies among IAA, GADA, IA-2A and ZnT8A.

Exclusion Criteria

1. Pregnancy or lactation in women; <6 months postpartum

2. Diabetes meeting the clinical diagnostic ADA criteria;

3. Use of illicit drugs, or overconsumption of alcohol, or history of drug or alcohol abuse;

4. Being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders;

5. Treatment with immune modulating or diabetogenic medication (e.g. corticosteroids) or medication that act to lower glycemia (oral antidiabetics) or agents that may influence insulin sensitivity or secretion;

6. Gastric bypass or banding;

7. History of acute or chronic pancreatitis, or (partial) pancreatectomy

8. History of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the subjects.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 39 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Breakthrough T1D

OTHER

Sponsor Role: collaborator

Universitair Ziekenhuis Brussel

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bart Keymeulen

Role: PRINCIPAL_INVESTIGATOR

Vrije Universiteit Brussel

Locations

Clinique CHC MontLégia

Liège, Liège, Belgium

Site Status: RECRUITING

A.Z. Sint-Jan Brugge

Bruges, West-Vlaanderen, Belgium

Site Status: RECRUITING

Universitair Ziekenhuis Antwerpen

Antwerp, , Belgium

Site Status: RECRUITING

Universitair Ziekenhuis Gent

Ghent, , Belgium

Site Status: RECRUITING

Universitair Ziekenhuis Brussel

Jette, , Belgium

Site Status: RECRUITING

Universitair Ziekenhuis Leuven

Leuven, , Belgium

Site Status: RECRUITING

Countries

Belgium

Central Contacts

Belgian Diabetes Registry

Role: CONTACT

contact@bdronline.be

02 477 45 46 ext. +32

Facility Contacts

Alexandra Van Eyck

Role: primary

Alexandra.VANEYCK@chc.be

04 355 42 14

Fabienne Beyaert

Role: primary

Fabienne.Beyaert@azsintjan.be

Beeldens Jente

Role: primary

Jente.Beeldens@uza.be

+3 436 8409

Rie Braspenning

Role: backup

Rie.Braspenning@uza.be

+32 3 821 4002

Nancy Platteau

Role: primary

Nancy.Platteau@uzgent.be

+329 332 6394

Els Feyen

Role: backup

Els.Feyen@uzgent.be

Karen Hanssens

Role: primary

CTU-diabeteskliniek@uzbrussel.be

+322 477 77 60

Natalie Van den Driessche

Role: primary

natalie.vandendriessche@uzleuven.be

+3216 34 85 54

Other Identifiers

PredicT1D

Identifier Type: -

Identifier Source: org_study_id