Study of Antithymocyte Globulin for Treatment of New-onset T1DM

New-onset Type 1 Diabetes Mellitus Clinical Trial

— START  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00515099
• Other study ID #: DAIT ITN028AI
• Status: Terminated
• Phase: Phase 2
• First received: August 10, 2007
• Last updated: January 15, 2016
• Start date: August 2007
• Est. completion date: July 2013

Study information

• Verified date: January 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 58
• Est. completion date: July 2013
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 35 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• New-onset Type 1 Diabetes Mellitus

Intervention

Drug:
• Antithymocyte globulin
Daily 4-day escalating dose
• Placebo
Daily 4-day saline solution

Locations

Country	Name	City	State
United States	Emory Children's Center	Atlanta	Georgia
United States	Barbara Davis Center for Childhood Diabetes, University of Colorado	Aurora	Colorado
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Children's Hospital/USC School of Medicine	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital and Research Center	Oakland	California
United States	University of Pennsylvania/Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	UCSD/San Diego Children's Hospital	San Diego	California
United States	Diabetes Center at UCSF	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Immune Tolerance Network (ITN)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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 pat — View 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. — View 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. Erratum in: Diabetes. 2004 Jul;53(7):1934. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No

External Links

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