Effects of Recombinant Human Glutamic Acid Decarboxylase on the Progression of Type 1 Diabetes in New Onset Subjects

Type 1 Diabetes Mellitus Clinical Trial

— TN08  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00529399
• Other study ID #: TN08 GAD65
• Secondary ID: U01DK061055UC4DK
• Status: Completed
• Phase: Phase 2
• Start date: February 2009
• 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 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: May 2012
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• GAD-Alum
Participants will receive 3 injections of 20 micrograms GAD-Alum subcutaneously. The first two injections are given 4 weeks apart and the second and third are given 8 weeks apart.
• GAD-Alum and Aluminum hydroxide
Participants will receive 3 injections subcutaneously. The first two will contain 20 micrograms GAD-Alum vaccine and are given 4 weeks apart. The third injection will be Aluminum hydroxide alone and will be given 8 weeks after the second injection.
• Aluminum hydroxide
Participants will receive 3 injections of Aluminum hydroxide alone, subcutaneously. The first two injections are given 4 weeks apart and the second and third are given 8 weeks apart.

Locations

Country	Name	City	State
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Barbara Davis Center for Childhood Diabetes/University of Colorado Health Sciences Center	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	Indiana University School of Medicine	Indianapolis	Indiana
United States	Childrens Hospital of Los Angeles	Los Angeles	California
United States	University of Miami/ Miller School of Medicine	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Stanford University	Palo Alto	California
United States	Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of California-San Francisco	San Francisco	California
United States	Benaroya Research Institute	Seattle	Washington

Sponsors (6)

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 Center for Research Resources (NCRR), National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (7)

Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001 Jul 21;358(9277):221-9. Review. Erratum in: Lancet. 2001 Sep 1;358(9283):766. — View 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. Epub 2002 Apr 4. — View 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. — View 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. — View 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. — View 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. — View 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 S — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One 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.	Based on mixed meal tolerance test (MMTT) conducted at the one year visit

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