Effects of Recombinant Human Glutamic Acid Decarboxylase . . . - Full Text View

Sponsor:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators:	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institute of Allergy and Infectious Diseases (NIAID) National Center for Research Resources (NCRR) American Diabetes Association Juvenile Diabetes Research Foundation
Information provided by:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:	NCT00529399

Purpose

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).

Condition	Intervention	Phase
Type 1 Diabetes Mellitus	Drug: GAD-Alum Drug: Aluminum hydroxide	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Diabetes Medicines Diabetes Type 1

Drug Information available for: Glutamic acid Aluminum sulfate Alum, Potassium Aluminum hydroxide Algeldrate Aluminum

U.S. FDA Resources

Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:

The primary outcome is the area under the stimulated C-peptide curve (AUC) over tghe first 2 years of a 4-hour mixed meal tolerance test (MMTT). [ Time Frame: Based on MMTT conducted at the two year visit ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Difference in loss of 2 hr peak C-peptide <0.2 pmol/ml; Mean HbA1c, insulin dose (units/kg), blood glucose ; prevalence of autoantibody positivity ; rates of severe hypoglycemic and adverse events. [ Time Frame: Comparison of values repeated over time per protocol ] [ Designated as safety issue: No ]

Estimated Enrollment:	126
Study Start Date:	February 2009
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 3 injections of GAD-Alum vaccine	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. Other Name: Diamyd
Experimental: 2 2 injections of GAD-Alum vaccine and one injection with Aluminum hydroxide alone	Drug: GAD-Alum 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. Other Name: Diamyd
Placebo Comparator: 3 3 injections of Aluminum hydroxide alone	Drug: 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. Other Name: Alhydrogel

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

Ages Eligible for Study:	3 Years to 45 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00529399

Locations

United States, California
Childrens Hospital of Los Angeles
Los Angeles, California, United States, 90027
Stanford University
Palo Alto, California, United States, 94305
University of California-San Francisco
San Francisco, California, United States, 94143
United States, Colorado
Barbara Davis Center for Childhood Diabetes/University of Colorado Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06520
United States, Florida
University of Florida
Gainesville, Florida, United States
University of Miami/ Miller School of Medicine
Miami, Florida, United States, 33136
United States, Indiana
Indiana University School of Medicine
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Joslin Diabetes Center
Boston, Massachusetts, United States, 02215
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, New York
Columbia University
New York, New York, United States, 10032
United States, Pennsylvania
Childrens Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
University of Texas/Southwestern Medical School
Dallas, Texas, United States, 75390-8858
United States, Washington
Benaroya Research Institute
Seattle, Washington, United States, 98101
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Allergy and Infectious Diseases (NIAID)

National Center for Research Resources (NCRR)

American Diabetes Association

Juvenile Diabetes Research Foundation

Investigators

Principal Investigator:	Diane Wherrett, M.D.	University of Toronto, Hospital for Sick Children
Study Chair:	Jay Skyler, M.D.	University of Miami

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

Publications:

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.

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.

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.

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.

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.

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.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Epub 2011 Jun 27.

Responsible Party:	Ellen Leschek, NIDDK
ClinicalTrials.gov Identifier:	NCT00529399 History of Changes
Other Study ID Numbers:	GAD65 (IND)
Study First Received:	September 12, 2007
Last Updated:	January 31, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

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

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Aluminum Hydroxide

Aluminum sulfate
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antacids
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 12, 2012