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Study of Antithymocyte Globulin for Treatment of New-onset T1DM (START)

This study has been terminated.
(Slow accrual)
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00515099
First received: August 10, 2007
Last updated: March 25, 2014
Last verified: March 2014

August 10, 2007
March 25, 2014
August 2007
June 2012   (final data collection date for primary outcome measure)
2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline (Pre-treatment initiation), Month 12 ] [ Designated as safety issue: No ]
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.
2-hour C-peptide AUC in response to MMTT [ Time Frame: Month 12 ]
Complete list of historical versions of study NCT00515099 on ClinicalTrials.gov Archive Site
  • 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline (Pre-treatment initiation), Month 12 ] [ Designated as safety issue: No ]
    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.
  • Insulin Use in Units Per Kilogram Body Weight Per Day [ Time Frame: Months 12 and 24 ] [ Designated as safety issue: No ]
    The need to use insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.
  • Proportion of Subjects Who Are Exogenous-Insulin-Free [ Time Frame: Months 12, 18, and 24; possibly up to 60 months ] [ Designated as safety issue: No ]
    The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Subjects who are exogenous-insulin-free are producing normal or near normal endogenous insulin, which means low disease activity.
  • Major Hypoglycemic Events Occurring Since Treatment Randomization [ Time Frame: Baseline through Months 12 and 24 ] [ Designated as safety issue: Yes ]
    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.
  • 2-Hour and 4-Hour C-peptide Area Under the Curve (AUC) Results in Response to Standardized Mixed Meal Tolerance Test (MMTT) [ Time Frame: Month 24 ] [ Designated as safety issue: No ]
    C-peptide, a substance released by the pancreas into the bloodstream in equal amounts to insulin, 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 (120 minutes) and 4-hour (240 minutes) post-meal C-peptide AUCs 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 2 years 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.
  • Hemoglobin A1c [ Time Frame: Months 12 and 24 ] [ Designated as safety issue: No ]
    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% or less is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes Mellitus (T1DM). The closer HbA1c levels are to normal, the better controlled the disease.
  • Changes in Mean C-peptide Area Under the Curve ( AUC ) Results in Response to Standardized 2-hour and 4- Hour MMTTs Over Time [ Time Frame: Months 12 and 24 ] [ Designated as safety issue: No ]
    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.
  • 4-hour C-peptide AUC in response to MMTT [ Time Frame: Month 12 ]
  • Insulin use in units per kilogram body weight per day [ Time Frame: Months 12 and 24 ]
  • Proportion of subjects who are exogenous-insulin-free [ Time Frame: Months 12, 18, and 24, possibly up to 60 months ]
  • Hypoglycemic events occurring since randomization [ Time Frame: months 12 and 24 ]
  • 2-hour and 4-hour C-peptide AUC in response to an MMTT [ Time Frame: Months 12 and 24 ]
  • HbA1C levels [ Time Frame: Months 12 and 24 ]
  • Changes of C-peptide AUC (2 and 4 hours) over time [ Time Frame: Months 12 and 24 ]
  • Safety (adverse events frequency, severity)
Not Provided
Not Provided
 
Study of Antithymocyte Globulin for Treatment of New-onset T1DM
Effect of Antithymocyte Globulin on Preserving Beta Cell Function in New Onset Type 1 Diabetes Mellitus

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
New-onset Type 1 Diabetes Mellitus
  • Drug: Antithymocyte globulin
    Daily 4-day escalating dose
    Other Names:
    • ATG
    • Thymoglobulin®
    • Rabbit antithymocyte globulin
    • RATG
  • Drug: Placebo
    Daily 4-day saline solution
    Other Names:
    • Inactive drug (pharmacologically)
    • Saline solution
  • Experimental: Antithymocyte globulin
    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.
    Intervention: Drug: Antithymocyte globulin
  • Placebo Comparator: Placebo
    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.
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
58
July 2013
June 2012   (final data collection date for primary outcome measure)

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
Both
12 Years to 35 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00515099
DAIT ITN028AI
Yes
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Principal Investigator: Stephen Gitelman, MD University of California, San Francisco
National Institute of Allergy and Infectious Diseases (NIAID)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP