Objective
The aims of the proposed study, an extension of the ADIR study, are preventing DKA episodes at the clinical presentation of T1D, establishing a mandatory population-based screening program in Israel, creating a cohort of children at risk for developing T1D for future early interventions for disease prevention, studying disease pathogenesis, and developing new biological markers.
Specifically, the second screen proposed in this study will allow us to describe the rate and age of the appearance of IA in our population. This second screen is crucial for defining an optimal screening age in an anticipated national screening program for the general population.
The main goal of the entire ADIR study is to create an efficient screening program in the general Israeli population to detect children at risk for developing diabetes to prevent DKA episodes at the clinical presentation of T1D. Diagnosis of T1D at the pre-clinical stage can prevent the occurrence of DKA at the clinical presentation of the disease. An additional significant goal of the study is to create a cohort of children at-risk for developing T1D and offer them the opportunity to enjoy future early interventions for disease prevention. Combining the ongoing ADIR study and this study, we expect to detect 200-400 children at risk of developing diabetes.
The proposed study is a feasibility study formed for the strategic mission of creating an efficient screening program for T1D in Israel. If our study successfully prevents or reduces the rate of DKA upon presentation of T1D, we anticipate implementing a universal screening program in Israel. We believe that our program will create an excellent infrastructure for further research. The screening program is the first and fundamental step in our plans to perform a network dedicated to the study, prevention, and early treatment of T1D. This network, namely the Israel prevention network (IPN), which was established as part of the ADIR study, leads a comprehensive and intensive effort of Israeli clinicians, academia, industry, funders, regulatory authorities, health care providers, and the diabetes community.
Background Rationale
The global incidence of type-1 diabetes (T1D) is dramatically increasing, threatening to double over the next decade. T1D is an autoimmune disease with no cure, requiring lifelong insulin treatment. About 90% of the children diagnosed have no family history related to T1D. Thus, in most cases, the disease appears out of the blue startling the children and their families. Worldwide, about 30-40% of all newly diagnosed T1D patients present with diabetic ketoacidosis (DKA), a life-threatening event associated with long-term sequels, including detrimental neurocognitive outcomes, poor long-term glycemic control, and an increased risk for cardiovascular complications.
Diagnosing T1D at the preclinical stage, years before it presents, can prevent the occurrence of DKA at the clinical presentation of the disease. It may also open a path for future disease prevention programs. To date, early detection of T1D at its preclinical stages is possible by detecting islet autoantibodies (IA) attacking the insulin-producing cells in the pancreas. About 80% of the children diagnosed with T1D have multiple IA before age 5, with an estimated progression rate to symptomatic diabetes of about 84% by 15 years. An efficient general-population screening program based on IA can identify children at risk of developing diabetes years before its clinical appearance. Detecting these at-risk children will enable caregivers to prepare the children and their families for future insulin treatment, prevent DKA episodes upon clinical presentation, and aid in the search for an effective therapy for T1D.
On April 2021, we initiated the Antibody detection Israeli Research (ADIR) supported by the JDRF. The ADIR study aims to screen 20,000 children aged 9-18 months all over Israel for IA. The infrastructure of ADIR includes 29 community-based screening sites, 6 diabetes centers, a central laboratory dedicated to the study, and a coordinating center. Uniquely for a general population screening program, the assay used to detect IA is the innovative and ultrasensitive Antibody Detection by Agglutination PCR (ADAP). Recruitment of children for the study began on October 4th, 2021. As of December 1st, 2022, 2773 children were enrolled in the study. Ten children were found to be at risk for developing diabetes according to the study's criteria. The ADIR study will reach recruitment goals by August 2025. We aim to recruit additional 5,000 children aged 9 month-5 years and complete a second screen at ages 2-5years in 15,000 of the 25,000 children recruited in both studies.
Description of Project
The global incidence of type-1 diabetes (T1D) is dramatically increasing, threatening to double over the next decade. Worldwide, about 30-40% of all newly diagnosed T1D patients are presented with diabetic ketoacidosis (DKA), a life-threatening event associated with long-term sequels, including decreased metabolic control and an increased risk for cardiovascular complications. Diagnosis of T1D at the pre-clinical stage can prevent the occurrence of DKA at the clinical presentation of the disease. It may also open a path for future disease prevention programs. To date, early detection of T1D is possible by detecting islet autoantibodies (IA). About 80% of the children diagnosed with T1D have multiple IA before the age of 5 years, long before the appearance of their clinical disease. Thus, children with multiple IA, who are at risk of developing diabetes later in life, can be detected by an efficient general-population screening program based on these IA. Early detection will enable caregivers to prepare children at-risk and their families for future insulin treatment, prevent DKA episodes at clinical presentation, and aid in the search for an effective therapy for T1D. On April 2021, we initiated the Antibody detection Israeli Research (ADIR) supported by the JDRF. The ADIR study aims to screen 20,000 children aged 9-18 months all over Israel for IA. As of December 1st, 2022, 2773 children were enrolled in the study, and ten children were found to be at risk for developing diabetes. The ADIR study will reach recruitment goals by August 2025.
The proposed study is an extension of the original ADIR study. We suggest expanding the screening program described above using the existing infrastructure of the ADIR. We aim to complete 40,000 screening samples by screening additional 5,000 children to the 20,000 screened in the ongoing ADIR study and completing a second screen for 15,000 children of the 25,000 children screened in the two studies. To enhance recruitment rates, we will expand the ages of children recruited to the proposed study to 9 months-5 years. Children screened for the second time will be screened gradually at ages 2, 3, or 4-5 years. As in the ADIR study, Antibodies will be measured in capillary blood using the Ultrasensitive Antibody Detection by Agglutination-PCR (ADAP) technology by Enable Biosciences. Children at risk for developing diabetes will be followed in one of the participating diabetes centers for the appearance of clinical signs of diabetes and invited along with their families to attend a diabetes-related educational program.
The ADIR and the proposed study are feasibility studies formed for the strategic mission of creating an efficient screening program for T1D in Israel and worldwide. If our study successfully prevents or reduces the rate of DKA upon presentation of T1D, we anticipate implementing a universal screening program in Israel. Aside from preventing DKA, an additional significant goal of these studies is to create a cohort of children at-risk for developing T1D, offering them the opportunity to enjoy future early interventions for disease prevention
Anticipated Outcome
An efficient screening program will identify children at risk of developing diabetes during childhood, enable caregivers to prepare at-risk children and their families for future insulin treatment, prevent DKA episodes upon clinical presentation, and aid in the search for an effective therapy for T1D. We anticipate creating a cohort of 200-400 children at risk of developing diabetes. These children will be followed for the appearance of clinical diabetes and will be offered to participate in future prevention studies.
Our initial results from the ongoing ADIR study are encroaching, suggesting that the ADAP technology was able to detect children at risk of developing diabetes at a very young age. Therefore, as shown in previous studies, we can hope we can reduce the DKA rate at T1D presentation to less than 5%.
Children at risk of developing diabetes will be followed up routinely at one of the diabetes centers participating in the study. Parents will be invited to join a 2-3-hour education session. Trained team members will perform this unified education program at the collaborating diabetes centers. The program will include diabetes education emphasizing DKA prevention, symptoms of hyperglycemia, the pathogenesis of T1D, instructions about urine and blood glucose monitoring when required, and knowledge about normal and pathological blood glucose levels. Stress assessment of the children at risk and their families will be done using validated questionnaires and a psychological interview. When needed, interventions to alleviate the stress generated will be delivered as a part of the program. Clinically, the at-risk children will be evaluated routinely for the appearance of clinical signs of diabetes
The proposed study is a feasibility study formed for the strategic mission of creating an efficient screening program for T1D in Israel. If our study successfully prevents or reduces the rate of DKA upon presentation of T1D, we anticipate implementing a universal screening program in Israel. We believe that our program will create an excellent infrastructure for further research. The screening program is the first and fundamental step in our plans to develop a network dedicated to the study, prevention, and early treatment of T1D. This network, namely the Israel prevention network (IPN), which was established as part of the ADIR study, leads a comprehensive and intensive effort of Israeli clinicians, academia, industry, funders, regulatory authorities, health care providers, and the diabetes community.
Relevance to T1D
An efficient screening program will identify children at risk of developing diabetes during childhood, enable caregivers to prepare at-risk children and their families for future insulin treatment, prevent DKA episodes upon clinical presentation, and aid in the search for an effective therapy for T1D. We anticipate creating a cohort of 200-400 children at risk of developing diabetes. These children will be followed for the appearance of clinical diabetes and will be offered to participate in future prevention studies.
The proposed research plan is unique on many levels: our initial screening for IA is done at an early age compared to other screening programs, our protocol includes serial measurements of IA in a large general population cohort, and we use the ADAP innovative and ultrasensitive technology for screening. Also, it is the first general-population screening program done outside Europe and USA in a population that is different in Its characteristics. Thus, our study addresses a few essential issues. Does a screening program, as suggested in the study, reduce the rate of DKA at the clinical presentation of T1D? What is the efficiency of screening for islet antibodies at the early age of one year? Is the ADAP technology valid for such a screening program, and is it better than the currently used methods? What is the age of appearance of IA in our population, and what is the optimal age for screening in a future population-based screening program? Also, we create a cohort of children at risk for developing T1D to evaluate future early interventions for disease prevention, research on disease pathogenesis, and the development of new biological markers.
Our initial results from the ongoing ADIR study are encroaching, suggesting that the ADAP technology was able to detect children at risk of developing diabetes at a very young age. Therefore, we firmly believe that our study's unique characteristics may inspire future screening programs worldwide and aid in understanding the pathophysiology and dynamics of T1D progression. Indeed, if our goal of reducing the rate of DKA upon presentation of the disease is achieved, we think it will validate the need for a cost-effective screening program in Israel. Furthermore, recent studies have demonstrated that immunotherapy can delay the progression to clinically overt disease in children at risk of developing diabetes. Our program will detect such children at very young ages, opening the path for early interventions.