Study of Antithymocyte Globulin for Treatment of New-onset T1DM

Study Overview
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Brief Summary
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Antithymocyte globulin (e.g., Thymoglobulin®) is an antibody preparation that is commonly used to treat and prevent organ transplant rejection. The START trial aims to determine whether antithymocyte globulin (ATG) treatment can halt the progression of newly diagnosed type 1 diabetes when given within 12 weeks of disease diagnosis.

Detailed Description
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Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Without these cells, the body cannot maintain proper blood glucose levels in response to daily activities, such as eating or exercise. Generally, at the time someone is diagnosed with T1DM, not all of a person's beta cells have been destroyed - between 15-40% remain healthy and are still able to produce insulin. Importantly, even small amounts of naturally produced insulin can improve blood sugar control, make daily management of diabetes less complicated, and reduce the risk of long term complications. Preserving the remaining precious beta cells is therefore the goal of the START trial. The medication being tested in the START trial is antithymocyte globulin (e.g., Thymoglobulin®), a mixture of specialized proteins called antibodies. ATG attaches itself to white blood cells known as T cells, some of which are responsible for the immune system's attack on beta cells that occurs in T1DM. ATG can change how T cells work, and can eliminate a large proportion of the T cells from the bloodstream temporarily. Treatment of new onset T1DM with ATG is therefore expected to alter the behavior of the T cells to halt their attack, and also reduce T cell numbers, so that new T cells that grow in their place will learn to accept the beta cells, rather than attacking them. Following an initial screening appointment, eligible participants will be randomly assigned to one of two groups: the Experimental Group will receive the study treatment while the Control Group that will receive placebo. Each participant has a 2 in 3 chance of being assigned to the treatment group, and a 1 in 3 chance of being assigned to the placebo. The START trial is a blinded study, so neither participants nor study physicians will know to which group an individual has been assigned. All participants will receive intensive diabetes management. Participants in both groups will be admitted to the hospital for 5-8 days to receive infusions of either the study drug or placebo. The duration of the study is 2 years. Participants will have 8 follow-up appointments in the first year and 4 visits in the second year. Most of these visits will last 1- 2 hours. A review of interval health, a physical exam, an assessment of diabetes control including recent 5 day insulin use and blood sugar (e.g., glucose) testing, and blood collection for laboratory testing will occur at each visit. Four of the visits will last about 5 hours, during which participants will undergo mixed-meal tolerance testing (MMTT). This involves drinking a special drink, similar to a milkshake, and having blood specimens taken over a 4-hour period. Subjects will be reimbursed for travel and parking expenses, and will receive compensation for their participation in the longer mixed meal tolerance test visits.

Official Title
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Effect of Antithymocyte Globulin on Preserving Beta Cell Function in New Onset Type 1 Diabetes Mellitus

Conditions
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New-onset Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Antithymocyte globulin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of type 1 diabetes (according to American Diabetes Association [ADA] criteria) within100 days of enrollment Positive for one or more autoantibodies (anti-glutamic acid decarboxylase [GAD], anti-insulin, or IA-2 autoantibodies) Peak stimulated C-peptide level >0.4 pmol/mL or >1.2ng/mL following an MMTT Serologic evidence of prior Epstein-Barr virus (EBV) infection (EBV seropositive) Willing to use acceptable forms of contraception Exclusion Criteria: Any sign of active infection (e.g., hepatitis, tuberculosis, EBV, cytomegalovirus (CMV), or toxoplasmosis) at screening Positive for human immunodeficiency virus (HIV), tuberculosis, or hepatitis B surface antigen (HBsAg) at screening Prior history of any significant cardiac disease, such as congestive heart failure, arrhythmia, or structural defects, or suspicion thereof Use of glucocorticoids in the 28 days prior to study entry; or topical use of glucocorticoids Use of diabetes medications (other than insulin) that may affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, or amylin Evidence of liver dysfunction Evidence of kidney disease Pregnancy or plan to become pregnant Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500neutrophils/µL), lymphopenia (<800 lymphocytes/µL), or thrombocytopenia (<125,000 platelets/µL). Prior treatment with rabbit ATG or known hypersensitivity or exposure to rabbit sera-derived products Vaccination with a live virus within the last 6 weeks before enrollment Prior or current therapy that is known to cause a significant, ongoing change in the course of T1DM or immunologic status Any condition that may compromise study participation or may confound the interpretation of the study results

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antithymocyte globulin<br>This group received a total of 6.5 mg/kg of antithymocyte globulin (e.g., Thymoglobulin®) divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg. | Drug: Antithymocyte globulin<br>* Daily 4-day escalating dose<br>* Other names: RATG;|
| Placebo Comparator: Placebo<br>This group received a saline solution to match the Thymoglobulin doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg. | Drug: Placebo<br>* Daily 4-day saline solution<br>* Other names: Saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) | C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint. | Baseline (Pre-treatment initiation), Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) | C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint. | Baseline (Pre-treatment initiation), Month 12 | 
| Insulin Use in Units Per Kilogram Body Weight Per Day | The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. | Baseline (Pre-treatment), Months 12 and 24 | 
| Number of Participants Who Are Exogenous-Insulin-Free | The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. | Baseline (Pre-treatment), Months 12 , 18, and 24 | 
| Number of Participants With Major Hypoglycemic Event(s) Post Treatment Randomization/Initiation | Major hypoglycemic events are defined as a glucose concentration <55 mg/dL (grades 2-5, NCI-CTCAE version 3.0), or clinically: involving seizure(s) or involving loss of consciousness (coma), or requiring assistance from another individual in order to recover. | Baseline (Pre-treatment), Months 12 , and 24 | 
| 2-Hour and 4-Hour C-peptide Area Under the Curve (AUC) Results in Response to Standardized Mixed Meal Tolerance Test (MMTT) | C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) and 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the CDER at the FDA as a valid efficacy endpoint. | Baseline (Pre-treatment), Month 24 | 
| Hemoglobin A1c | Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of <\=5.6% is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM). | Baseline (Pre-treatment), Months 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATG, New-onset Type 1 Diabetes Mellitus, New-onset T1DM, New-onset Type 1 Diabetes, New-onset T1D, Newly Diagnosed Type 1 Diabetes Mellitus, Autoimmune diabetes, Thymoglobulin, Rabbit antithymocyte globulin