Preservation of Beta Cells by Glutamate Decarboxylase

谷氨酸脱羧酶保存 Beta 细胞

基本信息

批准号：
7285680
负责人：
DIANE K WHERRETT
金额：
$ 42.03万
依托单位：
HOSPITAL FOR SICK CHLDRN (TORONTO)
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-29 至 2008-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7285680
关键词：
8 year old A 7 Accounting Acute Address Adherence Adolescence Adult Adverse effects Adverse event Adverse reactions Advocate Affect Age Age of Onset Age-Months Age-Years Alleles American Amino Acids Amputation Analysis of Variance Ancillary Study Andro-Diane Animal Experimentation Animal Model Animals Antibodies Antibody Formation Antigen Targeting Antigen-Presenting Cells Antigens Apoptosis Apoptotic Appearance Area Arginine Aspartic Acid Asthma Attention Autoantibodies Autoantigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Azathioprine B-Lymphocytes B-insulin Beds Beta Cell Binding Biological Assay Biological Preservation Biometry Blindness Blood Blood Glucose Blood Pressure Blood Tests Blood Vessels Blood specimen Body Weight Books Breathing C-Peptide CD4 Positive T Lymphocytes Callithrix Carbohydrates Carboxy-Lyases Cardiac Cardiovascular Diseases Caregivers Caring Case Report Form Cattle Cell physiology Cell surface Cells Cellular Structures Cessation of life Characteristics Chemistry Chi-Square Tests Child Child Care Childhood Cholesterol Chromosomes, Human, Pair 6 Chronic Chronic Disease Class Classification Classification Scheme Clinic Clinical Clinical Trials Code Cohort Studies Colorado Communication Complications of Diabetes Mellitus Computer software Computers Condition Confidentiality Consultations Control Groups Core Facility Country Creatinine Cyclosporine Cyclosporins Daily Data Data Storage and Retrieval Databases Dendritic Cells Detection Developed Countries Developing Countries Development Diabetes Mellitus Diabetes autoantibodies Diabetes prevention Diabetic Ketoacidosis Diagnosis Diet Disease Disease Progression Disease remission Diuretics Dose Double-Blind Method Dropout Drug usage Early Diagnosis Educational workshop Elements Eligibility Determination Emerging Technologies End Point Enrollment Ensure Environment Environmental Risk Factor Enzymes Equilibrium Ethnic group Etiology European Evaluation Event Exanthema Excision Exclusion Exclusion Criteria Experimental Models Exposure to Eye Face Failure Family Family history of Family member Fasting Fathers Female Finland First Degree Relative France Frequencies Functional disorder Future Gender General Population Genes Genetic Genetic Polymorphism Genotype Germany Glucocorticoids Glucose Glutamate Decarboxylase Glutamic Acid Goals Gonadal structure Grant Group Therapy Health Sciences Healthcare Heat shock proteins Heating Helper-Inducer T-Lymphocyte Hematology Hepatic Histidine Histocompatibility Homologous Gene Hospitalization Hospitals Hour Human Human Resources Hyperglycemia Hypoglycemia IA-2 antibody IA-2 protein Immune Immune Targeting Immune Tolerance Immune response Immune system Immunity Immunization Immunologic Deficiency Syndromes Immunology Immunosuppression Immunosuppressive Agents Inbred NOD Mice Inbred Strains Mice Incidence Individual Infection Inflammation Informed Consent Infusion procedures Injection of therapeutic agent Inpatients Insecta Institution Insulin Insulin Antibodies Insulin-Dependent Diabetes Mellitus Interleukin-10 Interleukin-4 International Intervention Intervention Studies Intervention Trial Intraperitoneal Injections Intravenous Investments Iodide Peroxidase Islet Cell Islets of Langerhans Italy Ketoses Ketosis Kidney Kidney Failure Knock-out Knowledge Label Laboratories Lead Length Lesion Letters Life Life Table Analyses Link Location Long-Acting Insulin Lymphocyte Maintenance Major Histocompatibility Complex Malignant Neoplasms Mammalian Oviducts Maps Measurement Measures Mediating Medical Medical Care Team Medical History Medical Surveillance Medicine Meta-Analysis Metabolic Metabolic Control Metabolism Methodology Methods Methotrexate/Prednisone Milk Proteins Modeling Monitor Monoclonal Antibody HuM291 Monozygotic twins Mothers Multiple Sclerosis Multivariate Analysis Muromonab-CD3 Mus Myelin Myocardial Infarction Natural History Nature Negative Pregnancy Test Nervous system structure Neuraxis Neuro-Ocular System Neuro-Oncological Ventral Antigen 2 Neurotransmitters New Zealand Newborn Infant Newly Diagnosed Niacinamide Nicotinic Acids Non obese Normal saline North America Notification Numbers O Antigens OGTT Onset of illness Oral Oral Contraceptives Other Therapy Outcome Outcome Measure Pancreas Parents Pathogenesis Patient Care Patient Preferences Patient currently pregnant Patients Pattern Peptides Performance Peripheral Persons Pharmaceutical Preparations Pharmacy facility Phase Phase I Clinical Trials Physical Examination Physicians Physiologic pulse Pilot Projects Placebo Control Placebos Planned Pregnancy Plasma Play Policies Polyuria Population Population Heterogeneity Population Sizes Population Study Positioning Attribute Potassium Prediabetes syndrome Predictive Value Predisposition Pregnancy Prevalence Prevention Prevention therapy Preventive Primary Health Care Principal Investigator Privacy Probability Procedures Process Production Proline Protein Tyrosine Phosphatase Proteins Protocols documentation Publishing Pulse taking Race Randomized Randomized Controlled Clinical Trials Range Rate Rattus Reactive hypoglycemia Reading Recording of previous events Records Recovery Recurrence Regulation Relapse Relative (related person)Relative Risks Renal dialysis Reporting Research Research Design Research Infrastructure Research Institute Research Personnel Residual state Resolution Resources Review Committee Rheumatoid Arthritis Risk Risk Estimate Role Route Safety Sample Size Sampling Schedule Scientist Screening procedure Secure Self Tolerance Self-control as a personality trait Serine Serious Adverse Event Serum Severities Siblings Side Signal Transduction Significance Level Site Skin Societies Sodium Chloride Son Staging Standardization Standards of Weights and Measures Statistically Significant Steroids Stimulus Stratification Stroke Structure Subgroup Surrogate Markers Susceptibility/Resistance Gene Sweden Symptoms System T-Cell Activation T-Cell Receptor T-Lymphocyte Tail Techniques Teleconferences Terminology Testing Therapeutic Therapeutic Intervention Therapeutic immunosuppression Thinking Thymus Gland Time Tissues To autoantigen Toxic effect Toxin Transgenic Model Translations Transplantation Treatment Efficacy Treatment Protocols Triglycerides United States National Institutes of Health Universities Upper arm Uric Acid Urinalysis Utah Value Meaning Veins Venous Viral Antigens Virus Visit Weaning Week Weight Withdrawal Woman World Health Organization age group aluminum sulfate anergy antigen binding autoreactive T cell base birth control capillary carboxypeptidase H cardiovascular risk factor cell injury clinical Diagnosis cohort computer generated computerized concept coping copolymer copolymer 1 cost cytokine cytotoxic data management day design diabetes mellitus therapy diabetes risk diabetic dosage drinking drug testing exhaust experience falls feeding first phase insulin response follow-up gamma-Aminobutyric Acid glucose monitor glucose tolerance glycemic control human disease human subject immunotoxicity improved inclusion criteria infancy insight insulin secretion interest intravenous administration intravenous glucose tolerance test intravenous injection islet islet cell antibody khat male member model development mouse model non-diabetic normal aging oral glucose tolerance oral tolerance pediatric department peer peptide Q placebo controlled study plasma protein Z pre-clinical prevent proband programs research study response sex sperm cell statistics study characteristics subcutaneous success thiazide tool transmission process treatment effect trend volunteer willingness

项目摘要

DESCRIPTION (provided by applicant) The objectives of this application are: to describe the capability of the Hospital for Sick Children/University of Toronto site as a Clinical Center for TrialNet and to describe studies to determine whether intravenous treatment with glutamic acid decarboxylase (GAD) alters the immune response directed at islet cells thereby preventing ongoing B cell destruction in two groups of subjects: (1) patients with newly diagnosed Type 1 diabetes (DM1), using preservation of C-peptide secretion as the primary endpoint (Intervention); and (2) relatives of patients with DM1 who are at significant risk of diabetes, as defined by the presence of two islet antibodies, using prevention/delay of loss of first phase insulin release as the primary endpoint (Prevention). The clinical center includes: Principal and Co-investigators Drs. Diane Wherrett, Denis Daneman and Jeffrey Mahon, who have extensive experience in clinical trials, diabetes prevention trials, study design and immunology of Type 1 diabetes; the strong infrastructure of the Hospital for Sick Children Research Institute which provides the facilities, clinical trials, methodological and statistical support and scientific environment to carry out these studies; a network of pediatric and adult institutions within the Greater Toronto Area and beyond which will supply a large subject pool for study participation and have a proven track record of high levels of participation in diabetes prevention trials, both in ENDIT and DPT-1. The Intervention study will use a randomized, double-blind, placebo-controlled design to assess the efficacy and safety of parenteral GAD to maintain residual insulin secretion in persons with new-onset DM1. 132 patients with DM1 will be identified within 4 weeks of onset of insulin therapy. They will be randomized 2:1 to 2 different doses of GAD or placebo. The study endpoint will compare the mean meal-stimulated C-peptide level at 12 months in the GAD treated group versus placebo by a two-sided t-test. An interim analysis for safety will be carried out. The Prevention study will use a randomized, double-blind, placebo-controlled design to assess the efficacy of parenteral GAD in the prevention of loss of first phase insulin release in first degree relatives of those with Type 1 diabetes. It involves: screening first degree relatives for antibodies to insulin, IA-2, and GAD (and ICA in those with 1 positive antibody), if 2 of GAD, IA-2 or insulin antibodies are greater than the 97th percentile, then; staging with intravenous glucose tolerance test (IVGTT) to measure first phase insulin release (FPIR), HLA typing to exclude DQB10602 and confirmation of islet antibody status, if FPIR is greater than the 1st percentile for age and normal oral glucose tolerance, then; randomization 1:1 to intervention with GAD or control; follow up with IVGTT every 6 months, repeated if less than the 1st percentile, if confirmed, subject has reached study endpoint. The primary analysis will test the difference in proportion of subjects and controls with FPIR below 1st percentile for age, using a two-sided Chi Square test with continuity correction.

描述（由申请人提供）该应用程序的目标是：描述病童医院/多伦多大学作为临床中心 TrialNet 并描述确定是否进行静脉治疗的研究谷氨酸脱羧酶 (GAD) 会改变针对以下部位的免疫反应胰岛细胞从而阻止两组 B 细胞的持续破坏受试者：（1）新诊断的1型糖尿病（DM1）患者，使用将保留 C 肽分泌作为主要终点（干预）；和 (2) DM1患者的亲属有患糖尿病的显着风险，如由两种胰岛抗体的存在定义，使用预防/延迟损失第一阶段胰岛素释放作为主要终点（预防）。临床中心包括：首席研究员和联合研究员 Drs.黛安 Wherrett、Denis Daneman 和 Jeffrey Mahon 在以下方面拥有丰富的经验：临床试验、糖尿病预防试验、研究设计和免疫学 1型糖尿病；病童医院基础设施强大提供设施、临床试验、方法和统计支持以及科学环境来开展这些研究；大区内的儿科和成人机构网络多伦多地区及其他地区将提供大量的学习科目参与并拥有高水平参与的良好记录 ENDIT 和 DPT-1 中的糖尿病预防试验。干预研究将使用随机、双盲、安慰剂对照设计评估肠外 GAD 的有效性和安全性，以维持残留新发 DM1 患者的胰岛素分泌。 132 名 DM1 患者将被胰岛素治疗开始后 4 周内确定。他们将被随机分配 2:1 至 2 种不同剂量的 GAD 或安慰剂。研究终点将比较 GAD 治疗组 12 个月时膳食刺激的平均 C 肽水平通过双边 t 检验与安慰剂进行比较。安全性的中期分析将是执行。预防研究将使用随机、双盲、安慰剂对照的研究旨在评估胃肠外 GAD 在预防丢失中的功效 1 型患者一级亲属的第一阶段胰岛素释放糖尿病。它涉及：筛查一级亲属的抗体胰岛素、IA-2 和 GAD（以及具有 1 个阳性抗体的患者中的 ICA），如果其中 2 个 GAD、IA-2 或胰岛素抗体大于第 97 个百分位，则；通过静脉内葡萄糖耐量试验 (IVGTT) 进行分期以测量第一阶段胰岛素释放 (FPIR)、HLA 分型以排除 DQB10602 并确认胰岛抗体状态，如果 FPIR 大于年龄的第一个百分位数并且正常口服葡萄糖耐量，则； GAD 干预的 1:1 随机分组或控制；每 6 个月进行一次 IVGTT 随访，如果少于第一次则重复百分位数，如果得到确认，则受试者已达到研究终点。初级分析将测试受试者和对照比例的差异 FPIR 低于年龄第 1 个百分位，使用双面卡方检验连续性校正。