Clinical trial NCT06570278: Role of High-Throughput Whole Genome Sequencing for the Diagnosis and Care of Atypical Diabetes
Official title: Role of High-Throughput Whole Genome Sequencing for the Diagnosis and Care of Atypical Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Diabetes Mellitus
Keywords: Next generation sequencing genome
Diagnostic study
Medico-economic study
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: Commissariat A L'energie Atomique
name: Rennes University Hospital
name: Central Hospital, Nancy, France
name: Nantes University Hospital
name: Imagine Institute
name: APHP
name: Hospices Civils de Lyon
name: Université Lumière Lyon 2
name: University Hospital, Toulouse
First posted: 2024-08-26
Enrollment: 1020
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: We plan to randomize one patient in the control group for two in the intervention group.
Primary purpose: DIAGNOSTIC

Brief summary: The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice, in a randomized trial.

Notably, the questions it aims to answer are:

* The feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes,
* The contribution of WGS coupled with MCM on number of genetic alterations likely causal of diabetes identified and with a modification in care and support of patients.

After inclusion and sampling for genotyping, patients will be followed for 5 years.

The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.

Detailed description: The prevalence of diabetes is 7.4% in France among people aged 20 to 79 years in 2015. We must also consider \&#34;pre-diabetes\&#34; (subjects with glucose intolerance), whose prevalence is equivalent to that of diabetes (2012 estimate). The incidence of diabetes is exploding both for type 2 diabetes, which represents 85% of diabetes, and for type 1 diabetes, which represents 10% of cases and starts one out of two times before the age of 20. Diabetes typing is essential to guide therapeutic choices, particularly the use of insulin. This typing is based on the pathophysiology of the disease, distinguishing insulinopenia from autoimmune causes in type 1 diabetes, monogenic diabetes, secondary or atypical diabetes and type 2 diabetes, where insulinopenia and insulin resistance coexist. Thus, while a formal biological diagnosis is possible for some forms of atypical diabetes and for type 1 diabetes, no biological parameter is currently available for type 2 diabetes, which remains a diagnosis of exclusion. As a result, diabetes represents a source of diagnostic and therapeutic erraticism, amplified by the clinical heterogeneity of type 2 diabetes, which is obvious and underestimated, and by a clinical phenotyping of patients that is often defective. The economic consequences are important because the health costs are very different depending on whether or not patients are treated with insulin. Type 1 and type 2 diabetes are examples of chronic, non-transmissible, multigenic, multifactorial diseases. However, less than 10% of the heritability of type 2 diabetes is currently explained by the associated genetic variants. And although genetic tests exist to diagnose certain monogenic diabetes, this diagnosis is made in less than 20% of cases, mainly in the presence of an atypical clinical presentation of diabetes. Moreover, there is no reason to rule out the hypothesis of paucigenic forms, at the interface of monogenic diabetes and multigenic forms as usually envisaged, as has been observed in chronic pancreatitis, which is also accompanied by diabetes.

The study will be conducted according to a randomized trial design comparing two diagnostic strategies defined as follows:

* Control strategy: in silico analysis of a panel of validated genes (ISApanel - Diabetome 1). Patients recruited along the control procedure will stay in their group using current genetic diagnosis practices and standard of care that may differ from one center to another.
* Intervention strategy: whole genome sequencing coupled with multidisciplinary conciliation meeting.

We plan to randomize one patient in the control group for two in the intervention group.

The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice.

The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.

Eligibility criteria: Inclusion Criteria:

* Subjects ≥18 years with confirmed diabetes mellitus according to WHO criteria (World Health Organization: Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: Report of a WHO/IDF Consultation. Geneva, World Health Org., 2006.)
* Age ≤ 45 years at diabetes diagnosis
* Body mass index ≤ 35 kg/m² at diabetes diagnosis
* Negative results of specific antibodies determination (GAD65, IA2, ZnT8) until the inclusion visit
* Presenting atypical diabetes defined by at least one of the following:
* Exocrine pancreatic disease
* Familial history: diabetes diagnosed in first degree relatives from at least 2 generations
* Notion of familial consanguinity
* Syndromic clinical features (dysmorphy, developmental delay, mental retardation...) or unusual abnormalities/features that are not part of diabetic complications or co-morbidities;
* Early occurrence of microvascular complications (≤ 5 years after diabetes diagnosis)
* Major insulinopenia at diagnosis (C peptide \&lt;0.2 nmol/L and/or documented ketosis)
* Patient who conserved endogenous insulin secretion (positive C peptide value) but a need for insulin therapy initiation during the first year following diagnosis due to therapeutic failure of well conducted therapeutic intensification
* Stated willingness to comply with all study procedures and availability for the duration of the study
* Patient with a social security number in compliance with the French law (dispositions relatives aux recherches impliquant la personne humaine prévues aux articles L 1121-1 et suivants du Code de la Santé Publique)
* Signed and dated informed consent form

Exclusion Criteria:

* Pregnant or breastfeeding woman,
* Any contraindication to the study exams including known allergies or contraindication to contrasts for the scan
* Patient with known monogenic diabetes (defined as identification of class 4 and 5 variants according to ACMG)
* First or second-degree relatives with monogenic diabetes established by molecular genetics (class 4 and 5 variants according to ACMG)
* Patient with known secondary diabetes (i.e. endocrine disorders such as Cushing syndrome, pancreatectomy, drug-induced diabetes)
* Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol,
* Individuals under legal protection (sauvegarde de justice).

Primary outcomes:
measure: Number of patients with one or several genetic alterations likely causal of diabetes
timeFrame: At 6 months in control group and 12 months in interventional group
Secondary outcomes:
measure: Number of patients with an impact on treatment modification
timeFrame: 5 years
measure: Number of genetic alterations likely causal of diabetes
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Feasibility of the whole genome sequencing (WGS) coupled with multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes: time to access to the genetic data
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and MCM
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and access to WGS report
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and date of the WGS result visit
timeFrame: 5 years
measure: Genotype-Insulin secretion phenotype association
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Genotype-Insulin sensitivity phenotype association
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Genotype-body composition phenotype association
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Glycemic control without insulin treatment
timeFrame: 5 years
measure: Glycemic control without severe hypoglycemia
timeFrame: 5 years
measure: Number of long-term micro and macro vascular complications associated with diabetes and time to occurrence of the first complication
timeFrame: 5 years
measure: Patient-Reported Outcomes (PROs), evaluated with SF36 questionnaire
timeFrame: 5 years
measure: Patient-Reported Outcomes (PROs), evaluated with Euroquol Dimension (EQ-5D-5L) questionnaire
timeFrame: 5 years
measure: Patient-Reported Outcomes (PROs), evaluated with Audit of Diabetes Dependent Quality of Life (ADDQOL) questionnaire
timeFrame: 5 years
measure: Number of participants agreeing to have access to secondary findings (SF)
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Number and type of SFs (class 4 or 5 variant(s)) identified in participants that specifically consent to have access to SF
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Percentage of SFs in the studied population
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Number and type of medical consequences following identification of SFs
timeFrame: 5 years
measure: Direct costs associated with current diagnosis practices (ISApanel)
timeFrame: 5 years
measure: Direct costs associated with WGS coupled with MCM
timeFrame: 5 years
measure: Incremental cost-effectiveness ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)
timeFrame: 5 years
measure: Incremental cost-utility ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)
timeFrame: 5 years
measure: Cost-benefit of WGS coupled with MCM compared to current diagnosis practices
timeFrame: 5 years
measure: Psychosocial issues related to genetic testing for atypical diabetes
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Psychosocial issues related to genetic testing for atypical diabetes
timeFrame: 5 years
measure: Psychosocial issues related to patients' experience of the GLUCOGEN trial
timeFrame: 18 months
measure: Psychosocial issues related to professional's experience of the GLUCOGEN research protocol
timeFrame: 12 months
Other outcomes:
measure: Number and characteristics of new genomic variations responsible for diabetes development
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Number and characteristics of genomic variations and their association with defined phenotypes including integrated diagnostic biomarkers
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Number and characteristics of genomic variations known as drug targets
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Number and characteristics of genomic variations of metabolism, transport or drug targets of diabetes and their consequences on treatment response
timeFrame: At 6 months in control group and 12 months in interventional group
measure: Number and characteristics of molecular targets in atypical diabetes
timeFrame: At 6 months in control group and 12 months in interventional group
Locations:
city: Amiens
country: France
facility: University Hospital
city: Angers
country: France
facility: University Hospital
city: Besançon
country: France
facility: University Hospital Jean Minjoz
city: Bordeaux
country: France
facility: University Hospital Haut Lévêque
city: Brest
country: France
facility: University Hospital Cavale Blanche
city: Corbeil-Essonnes
country: France
facility: Centre Hospitalier Sud Francilien
city: Dijon
country: France
facility: University Hospital Bocage
city: Grenoble
country: France
facility: University Hospital Michallon
city: Le Kremlin-Bicêtre
country: France
facility: Assistance Publique Hôpitaux de Paris, Bicêtre Hospital
city: Lyon
country: France
facility: University Hospital Louis Pradel
city: Lyon
country: France
facility: University Hospital Sud
city: Marseille
country: France
facility: University Hospital Conception
city: Montpellier
country: France
facility: University Hospital Lapeyronie
city: Nancy
country: France
facility: University Hospital
city: Nantes
country: France
facility: University Hospital Laennec
city: Nice
country: France
facility: University Hospital L'Archet
city: Paris
country: France
facility: Assistance Publique Hôpitaux de Paris, Bichat - Claude Bernard Hospital
city: Paris
country: France
facility: Assistance Publique Hôpitaux de Paris, Cochin Hospital
city: Paris
country: France
facility: Assistance Publique Hôpitaux de Paris, Lariboisière Hospital
city: Paris
country: France
facility: Assistance Publique Hôpitaux de Paris, Saint Antoine Hospital
city: Paris
country: France
facility: Assistance Publique Hôpitaux de Paris- La Pitié Salpêtrière Hospital
city: Poitiers
country: France
facility: University Hospital
city: Rennes
country: France
facility: Rennes University Hospital
city: Rouen
country: France
facility: University Hospital Bois Guillaume
city: Strasbourg
country: France
facility: Strasbourg University Hospital
city: Toulouse
country: France
facility: University Hospital Rangueil
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Jean-François GAUTIER
role: PRINCIPAL_INVESTIGATOR
References: