Clinical trial NCT00515099: Study of Antithymocyte Globulin for Treatment of New-onset T1DM
Official title: Effect of Antithymocyte Globulin on Preserving Beta Cell Function in New Onset Type 1 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
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
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2007-08-13
Enrollment: 58
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (Pre-treatment initiation), Month 12
Secondary outcomes:
measure: 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (Pre-treatment initiation), Month 12
measure: Insulin Use in Units Per Kilogram Body Weight Per Day
timeFrame: Baseline (Pre-treatment), Months 12 and 24
measure: Number of Participants Who Are Exogenous-Insulin-Free
timeFrame: Baseline (Pre-treatment), Months 12 , 18, and 24
measure: Number of Participants With Major Hypoglycemic Event(s) Post Treatment Randomization/Initiation
timeFrame: Baseline (Pre-treatment), Months 12 , and 24
measure: 2-Hour and 4-Hour C-peptide Area Under the Curve (AUC) Results in Response to Standardized Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (Pre-treatment), Month 24
measure: Hemoglobin A1c
timeFrame: Baseline (Pre-treatment), Months 12 and 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital/USC School of Medicine
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center
state: California
city: San Diego
country: United States
facility: UCSD/San Diego Children's Hospital
state: California
city: San Francisco
country: United States
facility: Diabetes Center at UCSF
state: California
city: Aurora
country: United States
facility: Barbara Davis Center for Childhood Diabetes, University of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Emory Children's Center
state: Georgia
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Philadelphia
country: United States
facility: University of Pennsylvania/Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: University of California, San Francisco
name: Stephen Gitelman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.