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

Type 1 Diabetes Mellitus Clinical Trial

— TN09  

Official title:

Effects of CTLA-4 Ig (Abatacept) On The Progression of Type 1 Diabetes In New Onset Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00505375
• Other study ID #: TN09 CTLA
• Secondary ID: U01DK061055UC4DK
• Status: Completed
• Phase: Phase 2
• Start date: February 2008
• Est. completion date: May 2012

Study information

• Verified date: April 2020
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 112
• Est. completion date: May 2012
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes Mellitus

Intervention

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:
• Placebo
Intravenous infusions of placebo every other week for the first two doses and then every 28 days for a total of 27 doses

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	The Barbara Davis Center for Childhood Diabetes	Aurora	Colorado
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	University of Texas, Southwestern Medical School	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Columbia University, Naomi Berrie Diabetes Center	New York	New York
United States	University of Pittsburgh, Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of California - San Francisco	San Francisco	California
United States	Benaroya Research Institute	Seattle	Washington
United States	Stanford University	Stanford	California

Sponsors (5)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	American Diabetes Association, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Juvenile Diabetes Research Foundation, National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (8)

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. — View Citation

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. — View Citation

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

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

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	2 years of follow up

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