Study of Antithymocyte Globulin for Treatment of New-onset T1DM

NCT00515099 | Terminated Phase 2 Results DMC

• 1 other identifier: DAIT ITN028AI
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 9

Brief Summary

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.

Conditions

New-onset Type 1 Diabetes Mellitus

Keywords

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; ATG; Rabbit antithymocyte globulin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)

  Baseline (Pre-treatment initiation), Month 12

• Insulin Use in Units Per Kilogram Body Weight Per Day

  Baseline (Pre-treatment), Months 12 and 24

• Number of Participants Who Are Exogenous-Insulin-Free

  Baseline (Pre-treatment), Months 12 , 18, and 24

• Number of Participants With Major Hypoglycemic Event(s) Post Treatment Randomization/Initiation

  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)

  Baseline (Pre-treatment), Month 24

Study Arms (2)

Antithymocyte globulin

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Antithymocyte globulin DRUG

Daily 4-day escalating dose

Also known as: ATG, Thymoglobulin®, Rabbit antithymocyte globulin, RATG

Antithymocyte globulin

Placebo DRUG

Daily 4-day saline solution

Also known as: Inactive drug (pharmacologically), Saline solution

Placebo

Eligibility Criteria

• Age: 12 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (9)

Children's Hospital/USC School of Medicine

Los Angeles, California, 90027, United States

Location

Children's Hospital and Research Center

Oakland, California, 92609, United States

Location

UCSD/San Diego Children's Hospital

San Diego, California, 92123, United States

Location

Diabetes Center at UCSF

San Francisco, California, 94143, United States

Location

Barbara Davis Center for Childhood Diabetes, University of Colorado

Aurora, Colorado, 80010, United States

Location

Emory Children's Center

Atlanta, Georgia, 30322, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

University of Pennsylvania/Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (6)

• 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.

  PMID: 14693724 BACKGROUND

• 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.

  PMID: 18628574 BACKGROUND

• 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.

  PMID: 24622416 RESULT

• 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.

  PMID: 27053235 RESULT

• 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.

  PMID: 28198767 RESULT

• 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.

  PMID: 27208317 DERIVED

Related Links

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

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Antilymphocyte Serum; thymoglobulin; Saline Solution

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Limitations and Caveats

Enrollment for this trial was closed at 58 participants and did not meet the planned sample size of 66 participants due to slow accrual.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Stephen Gitelman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2007
• First Posted: August 13, 2007
• Study Start: August 1, 2007
• Primary Completion: June 1, 2012
• Study Completion: July 1, 2013
• Last Updated: May 11, 2017
• Results First Posted: April 21, 2014

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will share

Locations

US (9)