TYPE 1 DIABETES TRIALNET COORDINATING CENTER (TRIALNET)
Principal Investigator: John M. Lachin, Sc.D.
Co-Investigator: Naji Younes, Ph.D.
Co-Investigator: Heidi Krause-Steinrauf, M.S.
The Type 1 Diabetes TrialNet is jointly funded by theNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and National Institute of Child Health and Development (NICHD) with additional support from the Juvenile Diabetes Research Foundation International (JDRFI). The Biostatistics Center serves as the Coordinating Center for the project. The overall purpose of Trialnet is to conduct clinical research and clinical trials in the preservation of insulin-generating islet cells in those newly diagnosed with type 1 diabetes mellitus (T1DM), and in the etiology and prevention of the onset of diabetes in individuals at high risk for developing diabetes.
In 2003, it was estimated that worldwide about 194 million individuals had diabetes mellitus. Type 1 diabetes accounts for 5% to 10% of all diagnosed cases of diabetes. In the US alone, approximately 20.8 million individuals, or 7.0% of the total population have diabetes. About one in every 400 to 600 children and adolescents has type 1 diabetes. The onset of type 1 diabetes mellitus is one step in a chain of events that begins at the moment of conception. Genetic polymorphisms, principally HLA haplotypes, have been identified that confer an increased risk of developing diabetes, or are protective. Genetic defects render an individual susceptible to an aberrant immunologic response to one of possibly many environmental insults. Following the environmental trigger, the T-cells begin an assault on the insulin-producing beta or islet cells of the pancreas. This autoimmune response is manifest by the appearance of antibodies and the subsequent loss of first phase insulin response. Thereafter beta cell function declines. This makes it feasible to conduct studies of the genetics of type 1 diabetes and immune tolerance, the role of environmental pathogens, the characterization of autoimmunity and immune tolerance, evaluation of the risk of developing diabetes, and various interventions aimed at immune tolerance or preservation of beta cell function.
TrialNet is conducting a nationwide program of screening of first degree relatives of subjects with T1DM to identify individuals at exceptionally high risk of diabetes who have measurable levels of antibodies to insulin products and islet cells which indicate that the autoimmune process of rejection has been initiated. Subjects with auto-immune pre-diabetes are followed to evaluate factors associated with development of diabetes. Such subjects will also be enrolled in studies of agents to prevent diabetes onset. TrialNet is also conducting studies of the use of immunosuppression or immunomodulation to preserve beta cell function in subjects newly diagnosed with T1DM. A study of dietary intervention to prevent the onset of autoimmunity in newborns is also being conducted, as well as methodologic studies related to the evaluation of the metabolic and immunologic status of subjects with diabetes or at risk of diabetes.
TrialNet consists of 14 Clinical Centers in the United States and Canada, one in Australia and 3 in Europe. Each Clinical Center has a network of Affiliate sites, numbering in the hundreds. In 2006, 15 Major Affiliate sites were designated in North America. The study is chaired by Jay Skyler, MD of the University of Miami. The study is supported by a Central Pharmacy, an insulin autoantibody laboratory, an islet cell antibody laboratory, a class II major histocompatibility and DNA extraction lab, a Beta Cell function laboratory, Central Virology Laboratory and Central Biochemistry Laboratory - all funded by subcontracts through the GWU Coordinating Center.
Funded by NIH/NIDDK Cooperative Agreement U01-DK061055, 2001- 2008.
A description of current ongoing and completed studies follows:
Natural History Study (2004 - ) This study is screening first degree relatives of subjects with type 1 diabetes to identify subjects with insulin or islet cell autoimmunity who are then further evaluated with metabolic tests to attempt to determine the risk of developing type 1 diabetes over the coming 5 years. Subjects with autoimmunity are then eligible to enroll in a long-term follow-up study aimed at identifying risk factors for diabetes onset and the precise quantification of the 5 year diabetes risk. Such subjects may also be eligible to enroll in studies aimed at the prevention of diabetes onset, or if diabetes is diagnosed, in studies aimed at preservation of Beta-cell function in subjects newly diagnosed with diabetes. Clinical centers in North America, Europe and Australasia, and their affiliates, are screening 10 to 20 thousand or more such subjects annually.
Mycophenolate Mofetil Daclizumab Clinical Trial (2004 - ) This randomized, double-blind, placebo controlled clinical trial enrolled a total of 126 subjects at 13 participating sites (11 in North America, 2 in Europe). The study aims to compare Mycophenolate mofetil (MMF) alone and in combination with Daclizumab (DZB) against placebo in preserving beta cell function, as measured by stimulated C- peptide, in subjects newly diagnosed with type 1 diabetes. All subjects will be on treatment for two years, followed by at least one year of post-treatment follow-up. The first subject enrolled in the study began treatment in July 2004, and the last subjects enrolled will complete the treatment period in December 2008.
Mixed Meal Tolerance Test vs Glucagon Stimulation Test (2004-2005) The primary objective of this study was to evaluate the reproducibility and tolerability in two tests measuring C- peptide as a measure of Beta cell function. In the Mixed Meal Tolerance Test (MMTT), the stimulus is provided via ingestion of a liquid meal (Sustacal/Boost) when in the fasting state, with timed measurement of C-peptide levels over the subsequent 2 hours (sometimes 4 hours). In the Glucagon Stimulation Test (GST) the stimulus is an injection of glucagon with timed measurements over the subsequent 10 minutes. 166 participants were enrolled in 14 North American and 2 international centers, of whom 148 underwent at least one test. The first visit took place on September, 2004 and the last visit took place In December 2005.
T Cell Validation Study (2005 - 2007) Type 1 diabetes is a consequence of prolonged autoimmunity mediated by progressive T-cell destruction of the insulin secreting Beta-cells or islet cells of the pancreas. Although it is known that T-cell mediated autoimmunity is the underlying pathogenesis of type 1 diabetes, there has been modest progress in the development of reliable and valid assays of T-cell activity. The purpose of this study is to evaluate four different T-cell assays in 5 different laboratories with respect to their ability to discriminate subjects with diabetes versus normal controls, and to assess the qualitative and quantitative reproducibility of each assay.
Effects of Rituximab on the Progression of Type 1 Diabetes in New Onset Subjects (2006 - ) The Anti-CD20 study is a multicenter, two-arm, randomized, double-masked, placebo-controlled clinical trial to assess whether Beta-cell function, as measured by stimulated C- peptide, among subjects receiving rituximab differs significantly from that for placebo subjects assessed at one year of follow-up. Sixty-six participants will be randomized, in a 2:1 ratio, to receive rituximab (anti-CD20 monoclonal antibody) at a dose of 375mg/m2 or matching placebo administered weekly for a period of 4 weeks. Study activities initiated April 2006. Twelve sites (US and international combined) are conducting the study. Enrollment was closed in July of 2007.
Nutritional Intervention to Prevent (NIP) Type 1 Diabetes Pilot Trial (2006 - ) This is a multicenter, randomized, placebo controlled, double masked study to evaluate whether dietary supplementation with docosahexaenoic acid (DHA) starting prior to or immediately after birth will prevent development of insulin or islet cell autoimmunity in children at genetic risk of Type 1 Diabetes. This clinical trial pilot is being conducted at 9 sites in the United States. Subjects enter through one of two pathways. The first pathway enrolls pregnant women whose infant has a first degree relative with T1D while in their third trimester of pregnancy. The mother is randomized to receive either placebo or DHA capsules throughout her pregnancy. The infant continues in the study if they are determined to be eligible based on HLA typing after birth. The second pathway enrolls infants who have a first degree relative with T1D up to age six months of age. These infants will either receive DHA or placebo via formula feedings. In the case of a nursing mother, the infant will receive DHA or placebo via breast milk as the mother will take either DHA or placebo capsules. A total of 90 subjects will be enrolled in one year's time and followed for a year after which the feasibility of conducting a large scale trial will be assessed.
Oral Insulin for the Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes (2007 - ) The Oral Insulin trial is a multicenter, randomized, double-masked, placebo-controlled clinical trial to assess whether oral insulin administration will delay or prevent the onset of T1DM to subjects at risk for the disease by virtue of the presence of insulin or islet cell autoimmunity but without glucose intolerance. This trial is conducted under a maximum information design in which subjects will be followed until the required amount of statistical information is obtained so as to provide 85% power to detect a 40% reduction in the risk of type 1 diabetes onset, or a relative hazard of 0.6. It is projected that approximately 300 subjects followed for up to 8 years may be required. Participants will be randomized, in a 1:1 ratio, to receive daily doses of insulin capsule (7.5 mg of recombinant human insulin) or matching placebo for the duration of the trial. Trial activities initiated February 1, 2007. Approximately 100 sites (US and international combined) will conduct the trial.)