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

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.

Study Overview

• Status: Terminated
• Conditions: New-onset Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Antithymocyte globulin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital/USC School of Medicine
    • Oakland, California, United States, 92609
      • Children's Hospital and Research Center
    • San Diego, California, United States, 92123
      • UCSD/San Diego Children's Hospital
    • San Francisco, California, United States, 94143
      • Diabetes Center at UCSF
  • Colorado
    • Aurora, Colorado, United States, 80010
      • Barbara Davis Center for Childhood Diabetes, University of Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania/Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 35 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Antithymocyte globulin; Daily 4-day escalating dose; Other Names: ATG; Thymoglobulin®; Rabbit antithymocyte globulin; RATG
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.	Drug: Placebo; Daily 4-day saline solution; Other Names: Saline solution; Inactive drug (pharmacologically)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN)
• Investigators: Principal Investigator: Stephen Gitelman, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004 Jan;53(1):250-64. doi: 10.2337/diabetes.53.1.250. Erratum In: Diabetes. 2004 Jul;53(7):1934.
• Greenbaum CJ, Mandrup-Poulsen T, McGee PF, Battelino T, Haastert B, Ludvigsson J, Pozzilli P, Lachin JM, Kolb H; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care. 2008 Oct;31(10):1966-71. doi: 10.2337/dc07-2451. Epub 2008 Jul 15.
• Gitelman SE, Gottlieb PA, Rigby MR, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Aggarwal S, Phippard D, Sayre PH, Ding L, Bluestone JA, Ehlers MR; START Study Team. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2013 Dec;1(4):306-16. doi: 10.1016/S2213-8587(13)70065-2. Epub 2013 Aug 28.
• Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Harris KM, Kanaparthi S, Phippard D, Ding L, Bluestone JA, Ehlers MR; ITN START Study Team. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia. 2016 Jun;59(6):1153-61. doi: 10.1007/s00125-016-3917-4. Epub 2016 Apr 6.
• Salama A, Evanno G, Lim N, Rousse J, Le Berre L, Nicot A, Bach JM, Brouard S, Harris KM, Ehlers MR, Gitelman SE, Soulillou JP. Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Transplantation. 2017 Oct;101(10):2501-2507. doi: 10.1097/TP.0000000000001686.
• Boyle KD, Keyes-Elstein L, Ehlers MR, McNamara J, Rigby MR, Gitelman SE, Weiner LJ, Much KL, Herold KC. Two- and Four-Hour Tests Differ in Capture of C-Peptide Responses to a Mixed Meal in Type 1 Diabetes. Diabetes Care. 2016 Jun;39(6):e76-8. doi: 10.2337/dc15-2077. Epub 2016 Apr 13. No abstract available.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• ITN TrialShare: open public access to study level information
• Click here for the Immune Tolerance Network (ITN) Web site

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (ACTUAL): June 1, 2012
• Study Completion (ACTUAL): July 1, 2013

Study Registration Dates

• First Submitted: August 10, 2007
• First Submitted That Met QC Criteria: August 10, 2007
• First Posted (ESTIMATE): August 13, 2007

Study Record Updates

• Last Update Posted (ACTUAL): May 11, 2017
• Last Update Submitted That Met QC Criteria: April 5, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Thymoglobulin; ATG; New-onset Type 1 Diabetes Mellitus; New-onset T1DM; New-onset T1D; New-onset Type 1 Diabetes; Newly Diagnosed Type 1 Diabetes Mellitus; Autoimmune diabetes; Rabbit antithymocyte globulin
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: DAIT ITN028AI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant level data and additional relevant materials are available to the public in TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal. ITN TrialShare makes data from the consortium's clinical trials publicly available.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: START ITN028AI
   Information comments: START ITN028AI is the Study Identifier in the Immune Tolerance Network (ITN) TrialShare Clinical Trials Research Portal
2. Study Protocol
   Information identifier: START ITN028AI
   Information comments: START ITN028AI is the Study Identifier in the Immune Tolerance Network (ITN) TrialShare Clinical Trials Research Portal
3. Study overview, -data and reports, -manuscripts and abstracts, -availability of biospecimens, et al
   Information identifier: START ITN028AI
   Information comments: START ITN028AI is the Study Identifier in the Immune Tolerance Network (ITN) TrialShare Clinical Trials Research Portal