Intravenous CTLA4-lg Treatment in Recent Onset Type 1 Diabetes Mellitus
NCT ID: NCT00505375
Last Updated: 2020-05-06
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
112 participants
INTERVENTIONAL
2008-02-29
2012-05-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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1
Intravenous infusions of CTLA-4 Ig
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
2
Intravenous infusions of placebo
Placebo
Intravenous infusions of placebo every other week for the first two doses and then every 28 days for a total of 27 doses
Interventions
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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
Placebo
Intravenous infusions of placebo every other week for the first two doses and then every 28 days for a total of 27 doses
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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
6 Years
45 Years
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
Juvenile Diabetes Research Foundation
OTHER
American Diabetes Association
OTHER
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH
Responsible Party
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Principal Investigators
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Tihamer Orban, MD
Role: PRINCIPAL_INVESTIGATOR
Joslin Diabetes Center
Jay Skyler, MD
Role: STUDY_CHAIR
University of Miami
Locations
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Childrens Hospital Los Angeles
Los Angeles, California, United States
University of California - San Francisco
San Francisco, California, United States
Stanford University
Stanford, California, United States
The Barbara Davis Center for Childhood Diabetes
Aurora, Colorado, United States
University of Florida
Gainesville, Florida, United States
University of Miami
Miami, Florida, United States
Joslin Diabetes Center
Boston, Massachusetts, 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 Texas, Southwestern Medical School
Dallas, Texas, United States
Benaroya Research Institute
Seattle, Washington, United States
The Hospital for Sick Children
Toronto, Ontario, Canada
Countries
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References
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Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994 Aug;15(4):516-42. doi: 10.1210/edrv-15-4-516.
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. doi: 10.1073/pnas.96.1.185.
Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001 Dec;1(3):220-8. doi: 10.1038/35105024.
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. doi: 10.1126/science.1323143.
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. doi: 10.1172/JCI5857.
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. doi: 10.1084/jem.192.5.681.
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. doi: 10.1002/art.10294.
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.
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.
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