Clinical trial NCT00529399: Effects of Recombinant Human Glutamic Acid Decarboxylase on the Progression of Type 1 Diabetes in New Onset Subjects
Official title: Effects of Recombinant Human Glutamic Acid Decarboxylase (rhGAD65) Formulated in Alum (GAD-alum) 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: immune tolerance
immunotherapy
antigen-specific tolerance
vaccine induced tolerance
Beta-cell function
T-cells
DPT-1
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: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Center for Research Resources (NCRR)
name: American Diabetes Association
name: Juvenile Diabetes Research Foundation
First posted: 2007-09-14
Enrollment: 145
Sex: ALL
Minimum age (years): 3
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 multiple injections of GAD-Alum will preserve the body's own (endogenous) insulin production in patients who have been recently diagnosed with type 1 diabetes mellitus (T1DM).

Detailed description: Type 1 diabetes (T1D) is an autoimmune disease. This means that the immune system (the part of the body which helps fight infections) mistakenly attacks and destroys the cells that produce insulin (islet cells found in the pancreas called islet cells). As these cells are destroyed, the body's ability to produce insulin decreases. Glutamic acid decarboxylase (GAD) is one of the major autoantigens (a protein that the immune system is reacting to) involved in the autoimmune process underlying T1DM.

GAD-Alum is Recombinant human (rhGAD65) and is used as an antigen-specific immune modulator. Previous studies have shown that it may slow or prevent autoimmune destruction of pancreatic islet cells by introducing "immune tolerance". By administering excess autoantigen, the body may stop its attack on its own cells that produce insulin. If the immune system's attack can be halted in a patient with recent onset T1DM, than residual insulin secretion may be maintained. This may be beneficial in decreasing acute and long-term diabetic complications as well as improving glucose control.

Eligibility criteria: Inclusion Criteria:

* Age 3 to 45 years - Insulin dependent type 1-diabetes mellitus diagnosed within the previous 3 months
* Stimulated C-peptide levels greater than or equal to 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) conducted 3 weeks from diagnosis of diabetes
* Presence of GAD65 antibodies
* At least one month from last immunization
* Willing to comply with intensive diabetes management
* If participant is a woman with reproductive potential, she must be willing to avoid pregnancy and have a negative pregnancy test
* Willing to forgo routine clinical immunizations during the first 100 days after initial study drug administration

Exclusion Criteria:

* Immunodeficiency or clinically significant chronic lymphopenia
* Active infection
* Positive PPD test result
* Pregnant or lactating or anticipating becoming pregnant for 24 months following first injection
* Ongoing use of medications known to influence glucose tolerance
* Require use of systemic immunosuppressant(s)
* Serologic evidence of current or past HIV, Hep B, or Hep C infection
* History of malignancies
* Ongoing use of non-insulin pharmaceuticals to affect glycemic control
* Participation in another clinical trial with a new chemical entity within the past 3 months
* Complicating medical issues or abnormal clinical laboratory results that interfere with study conduct or cause increased risk including neurological, or clinically significant blood count abnormalities (such as lymphopenia, leukopenia, or thrombocytopenia)
* History of epilepsy, head trauma or cerebrovascular accident or clinical
* History of alcohol or drug abuse

Primary outcomes:
measure: The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One Year Visit
timeFrame: Based on mixed meal tolerance test (MMTT) conducted at the one year visit
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital of Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California-San Francisco
state: California
city: Aurora
country: United States
facility: Barbara Davis Center for Childhood Diabetes/University of Colorado Health Sciences Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami/ Miller School of Medicine
state: Florida
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
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
state: New York
city: Pittsburgh
country: United States
facility: Childrens 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: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of Toronto, Hospital for Sick Children
name: Diane Wherrett, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Jay Skyler, M.D.
role: STUDY_CHAIR
References:
citation: Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001 Jul 21;358(9277):221-9. doi: 10.1016/S0140-6736(01)05415-0.
citation: Pleau JM, Fernandez-Saravia F, Esling A, Homo-Delarche F, Dardenne M. Prevention of autoimmune diabetes in nonobese diabetic female mice by treatment with recombinant glutamic acid decarboxylase (GAD 65). Clin Immunol Immunopathol. 1995 Jul;76(1 Pt 1):90-5. doi: 10.1006/clin.1995.1092.
citation: Tian J, Clare-Salzler M, Herschenfeld A, Middleton B, Newman D, Mueller R, Arita S, Evans C, Atkinson MA, Mullen Y, Sarvetnick N, Tobin AJ, Lehmann PV, Kaufman DL. Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat Med. 1996 Dec;2(12):1348-53. doi: 10.1038/nm1296-1348.
citation: Tisch R, Liblau RS, Yang XD, Liblau P, McDevitt HO. Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. Diabetes. 1998 Jun;47(6):894-9. doi: 10.2337/diabetes.47.6.894.
citation: Tisch R, Wang B, Weaver DJ, Liu B, Bui T, Arthos J, Serreze DV. Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination. J Immunol. 2001 Feb 1;166(3):2122-32. doi: 10.4049/jimmunol.166.3.2122.
citation: Jun HS, Chung YH, Han J, Kim A, Yoo SS, Sherwin RS, Yoon JW. Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase. Diabetologia. 2002 May;45(5):668-76. doi: 10.1007/s00125-002-0806-9. Epub 2002 Apr 4.
citation: Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Herold KC, Marks JB, Monzavi R, Moran A, Orban T, Palmer JP, Raskin P, Rodriguez H, Schatz D, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet GAD Study Group. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 2011 Jul 23;378(9788):319-27. doi: 10.1016/S0140-6736(11)60895-7. Epub 2011 Jun 27.