Role of High-Throughput Whole Genome Sequencing for the Diagnosis and Care of Atypical Diabetes
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 1,020
- 试验地点
- 30
- 主要终点
- Number of patients with one or several genetic alterations likely causal of diabetes
研究概览
简要总结
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.
详细描述
The prevalence of diabetes is 7.4% in France among people aged 20 to 79 years in 2015. We must also consider "pre-diabetes" (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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 a parent, child or sibling
- •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 < 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
排除标准
- •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)
- •Patient who had a bone marrow transplant
- •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).
研究组 & 干预措施
control procedure
In-silico analysis of a panel of validated genes (ISApanel). Patients recruited along control procedure will stay in their arm using current genetic diagnosis practices and standard of care that may differ from one center to another
intervention procedure
WGS coupled with MCM
干预措施: WGS coupled with MCM (Diagnostic Test)
结局指标
主要结局
Number of patients with one or several genetic alterations likely causal of diabetes
时间窗: At 6 months in control group and 12 months in interventional group
Number of patients in each group with one or several genetic alterations likely causal of diabetes
次要结局
- Genotype-Insulin secretion phenotype association(At 6 months in control group and 12 months in interventional group)
- Genotype-body composition phenotype association(At 6 months in control group and 12 months in interventional group)
- Glycemic control without insulin treatment(5 years)
- Number and type of SFs (class 4 or 5 variant(s)) identified in participants that specifically consent to have access to SF(At 6 months in control group and 12 months in interventional group)
- Direct costs associated with current diagnosis practices (ISApanel)(5 years)
- Direct costs associated with WGS coupled with MCM(5 years)
- Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and MCM(At 6 months in control group and 12 months in interventional group)
- Genotype-Insulin sensitivity phenotype association(At 6 months in control group and 12 months in interventional group)
- Cost-benefit of WGS coupled with MCM compared to current diagnosis practices(5 years)
- Glycemic control without severe hypoglycemia(5 years)
- Number of long-term micro and macro vascular complications associated with diabetes and time to occurrence of the first complication(5 years)
- Incremental cost-utility ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)(5 years)
- Patient-Reported Outcomes (PROs), evaluated with SF36 questionnaire(5 years)
- Number of patients with an impact on treatment modification(5 years)
- Number of genetic alterations likely causal of diabetes(At 6 months in control group and 12 months in interventional group)
- 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(At 6 months in control group and 12 months in interventional group)
- Patient-Reported Outcomes (PROs), evaluated with Euroquol Dimension (EQ-5D-5L) questionnaire(5 years)
- Percentage of SFs in the studied population(At 6 months in control group and 12 months in interventional group)
- Number and type of medical consequences following identification of SFs(5 years)
- Patient-Reported Outcomes (PROs), evaluated with Audit of Diabetes Dependent Quality of Life (ADDQOL) questionnaire(5 years)
- Number of participants agreeing to have access to secondary findings (SF)(At 6 months in control group and 12 months in interventional group)
- Incremental cost-effectiveness ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)(5 years)
- Psychosocial issues related to genetic testing for atypical diabetes(5 years)
- Psychosocial issues related to patients' experience of the GLUCOGEN trial(18 months)
- Psychosocial issues related to professional's experience of the GLUCOGEN research protocol(12 months)
- Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and access to WGS report(At 6 months in control group and 12 months in interventional group)
- 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(5 years)
- Psychosocial issues related to genetic testing for atypical diabetes(At 6 months in control group and 12 months in interventional group)