Clinical trial NCT00505375: Intravenous CTLA4-lg Treatment in Recent Onset Type 1 Diabetes Mellitus
Official title: Effects of CTLA-4 Ig (Abatacept) On The Progression of Type 1 Diabetes In New Onset Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
Keywords: 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
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Juvenile Diabetes Research Foundation
name: American Diabetes Association
First posted: 2007-07-23
Enrollment: 112
Sex: ALL
Minimum age (years): 6
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: 2 years of follow up
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: The Barbara Davis Center for Childhood Diabetes
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University, Naomi Berrie Diabetes Center
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh, Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas, Southwestern Medical School
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Joslin Diabetes Center
name: Tihamer Orban, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Jay Skyler, MD
role: STUDY_CHAIR
References:
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citation: 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.
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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. doi: 10.1172/JCI5857.
citation: 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.
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. doi: 10.1002/art.10294.
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 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.
citation: 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.