Intravenous CTLA4-lg Treatment in Recent Onset Type 1 Diabetes Mellitus (TN09)

• ClinicalTrials.gov Identifier: NCT00505375
• Recruitment Status: Completed
• First Posted: July 23, 2007
• Results First Posted: August 16, 2016
• Last Update Posted: May 6, 2020
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation; American Diabetes Association
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Description

Brief Summary:

The purpose of this study is to determine whether treatment with CTLA4-Ig (Abatacept) in individuals with new onset T1DM will improve insulin secretion (C-peptide production) compared to placebo.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: CTLA-4 Ig; Other: Placebo	Phase 2

Detailed Description:

Type 1 diabetes mellitus (T1DM) is a T-cell mediated autoimmune disease in which insulin-producing beta cells are completely or near completely destroyed resulting in life-long dependence on exogenous insulin.

CTLA4-Ig (Abatacept) inhibits a crucial stimulatory pathway in the activation of T cells. By this mechanism, the drug is thought to arrest or slow the T cell mediated autoimmune destruction of beta-cells and preserve their function. At the time of clinical onset of T1DM, a significant amount of insulin producing beta cells are destroyed, but as many as 10-20% are still capable of insulin production. By using CTLA4-Ig close to the onset of T1DM, we hope to arrest or slow down the autoimmune destruction of these beta-cells and extend the endogenous insulin production. CTLA4-Ig regulates T cell function but does not deplete T cells. Therefore, its safety profile appears to be better than other immunosuppressive agents.

Eligible participants will be randomized to the experimental or control groups. The experimental group will receive intravenous infusions of CTLA-4 Ig. The first infusion will occur at the time of randomization, followed by another infusion 2 and 4 weeks later. Subsequent infusions will be given monthly for two years during the treatment phase of the study. There is a total of 27 infusions during the treatment phase of the study.

Participants in the control group will receive intravenous infusions of placebo according to the same schedule outlined above.

Both groups will receive standard intensive diabetes treatment with insulin and dietary management.

All participants randomized into the study will be seen at study site monthly for 24 months and then every 6 months for up to an additional 2 years. Participants will undergo assessments of their insulin production, immunologic status, overall health and well being and diabetes care.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 112 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Effects of CTLA-4 Ig (Abatacept) On The Progression of Type 1 Diabetes In New Onset Subjects
• Actual Study Start Date: February 2008
• Actual Primary Completion Date: May 2012
• Actual Study Completion Date: May 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Intravenous infusions of CTLA-4 Ig	Drug: CTLA-4 Ig; Intravenous infusion of 10 mg/kg of CTLA-4 Ig every other week for the first two doses and then every 28 days for a total of 27 doses; Other Name: Abatacept
Placebo Comparator: 2; Intravenous infusions of placebo	Other: Placebo; Intravenous infusions of placebo every other week for the first two doses and then every 28 days for a total of 27 doses

Outcome Measures

Primary Outcome Measures :

1. Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 2 Year Visit [ Time Frame: 2 years of follow up ]
   The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes.

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 45 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 6-45
2. Within 3 months (100 days) of diagnosis of T1DM based on ADA criteria
3. At least one diabetes-related autoantibody
4. Stimulated C-peptide level >0.2 pmol/ml by MMTT conducted 21 days after diagnosis of T1DM and within 37 days of randomization
5. At least three months from last live immunization received and willing to forgo live vaccinations for three months following last dose of study treatment

Exclusion Criteria:

1. Immunodeficiency, chronic lymphopenia, active infection, positive PPD result or a history of malignancy
2. Serologic evidence of current or past HIV, Hepatitis B or C
3. Pregnancy, lactation, or intention of pregnancy while on study
4. Current use of immunosuppressive agents, or medications known to influence glucose tolerance or glycemic control
5. Current participation in another T1DM treatment study

Contacts and Locations

Locations

United States, California

Childrens Hospital Los Angeles

Los Angeles, California, United States, 90027

University of California - San Francisco

San Francisco, California, United States, 94143

Stanford University

Stanford, California, United States, 94305

United States, Colorado

The Barbara Davis Center for Childhood Diabetes

Aurora, Colorado, United States, 80045

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610-0296

University of Miami

Miami, Florida, United States, 33136

United States, Massachusetts

Joslin Diabetes Center

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, New York

Columbia University, Naomi Berrie Diabetes Center

New York, New York, United States, 10032

United States, Pennsylvania

University of Pittsburgh, Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

University of Texas, Southwestern Medical School

Dallas, Texas, United States, 75235-8858

United States, Washington

Benaroya Research Institute

Seattle, Washington, United States, 98101

Canada, Ontario

The Hospital for Sick Children

Toronto, Ontario, Canada, M5G-1X8

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Juvenile Diabetes Research Foundation

American Diabetes Association

Investigators

• Principal Investigator: Tihamer Orban, MD; Joslin Diabetes Center
• Study Chair: Jay Skyler, MD; University of Miami

More Information

Additional Information:

Related Info 

Related Info 

Publications of Results:

Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Rodriguez H, Russell WE, Schatz D, Wherrett D, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jul 30;378(9789):412-9. doi: 10.1016/S0140-6736(11)60886-6. Epub 2011 Jun 28.

Other Publications:

Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994 Aug;15(4):516-42. Review.

Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):185-90.

Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001 Dec;1(3):220-8. Review.

Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992 Aug 7;257(5071):789-92.

Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe BS, Menter A, Lowe NJ, Krueger G, Brown MJ, Weiner RS, Birkhofer MJ, Warner GL, Berry KK, Linsley PS, Krueger JG, Ochs HD, Kelley SL, Kang S. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest. 1999 May;103(9):1243-52.

Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, Lebwohl MG, Guzzo CA, Jegasothy BV, Linsley PS, Krueger JG. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med. 2000 Sep 4;192(5):681-94.

Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P, Cohen S, Luggen M, Shergy W, Nuamah I, Becker JC. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum. 2002 Jun;46(6):1470-9.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Orban T, Beam CA, Xu P, Moore K, Jiang Q, Deng J, Muller S, Gottlieb P, Spain L, Peakman M; Type 1 Diabetes TrialNet Abatacept Study Group. Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline. Diabetes. 2014 Oct;63(10):3449-57. doi: 10.2337/db14-0047. Epub 2014 May 16.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00505375
• Other Study ID Numbers: TN09 CTLA; U01DK061055 ( U.S. NIH Grant/Contract ); UC4DK097835 ( U.S. NIH Grant/Contract )
• First Posted: July 23, 2007
• Results First Posted: August 16, 2016
• Last Update Posted: May 6, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data are available at the NIDDK Central Repository: https://repository.niddk.nih.gov/studies/tn09-ctla4-ig/?query=TN09
• URL: https://repository.niddk.nih.gov/studies/tn09-ctla4-ig/?query=TN09

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

CTLA4-Ig; Abatacept; Beta-cell function; T-cells; DPT-1; treatment; treatment of type 1 diabetes; new onset type 1 diabetes; juvenile diabetes; T1D; diabetes mellitus; Type 1 diabetes TrialNet; TrialNet

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Abatacept; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents