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

NCT ID: NCT00529399

Last Updated: 2020-05-07

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

145 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-02-28

Study Completion Date

2012-05-31

Brief Summary

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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

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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.

Conditions

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Type 1 Diabetes Mellitus

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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1

3 injections of GAD-Alum vaccine

Group Type EXPERIMENTAL

GAD-Alum

Intervention Type DRUG

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.

2

2 injections of GAD-Alum vaccine and one injection with Aluminum hydroxide alone

Group Type EXPERIMENTAL

GAD-Alum and Aluminum hydroxide

Intervention Type DRUG

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.

3

3 injections of Aluminum hydroxide alone

Group Type PLACEBO_COMPARATOR

Aluminum hydroxide

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type DRUG

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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Diamyd Diamyd Alhydrogel

Eligibility Criteria

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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
Minimum Eligible Age

3 Years

Maximum Eligible Age

45 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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

NIH

Sponsor Role collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role collaborator

American Diabetes Association

OTHER

Sponsor Role collaborator

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role collaborator

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

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Diane Wherrett, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Toronto, Hospital for Sick Children

Jay Skyler, M.D.

Role: STUDY_CHAIR

University of Miami

Locations

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Childrens Hospital of Los Angeles

Los Angeles, California, United States

Site Status

Stanford University

Palo Alto, California, United States

Site Status

University of California-San Francisco

San Francisco, California, United States

Site Status

Barbara Davis Center for Childhood Diabetes/University of Colorado Health Sciences Center

Aurora, Colorado, United States

Site Status

Yale University School of Medicine

New Haven, Connecticut, United States

Site Status

University of Florida

Gainesville, Florida, United States

Site Status

University of Miami/ Miller School of Medicine

Miami, Florida, United States

Site Status

Indiana University School of Medicine

Indianapolis, Indiana, United States

Site Status

Joslin Diabetes Center

Boston, Massachusetts, United States

Site Status

University of Minnesota

Minneapolis, Minnesota, United States

Site Status

Columbia University

New York, New York, United States

Site Status

Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Site Status

University of Texas/Southwestern Medical School

Dallas, Texas, United States

Site Status

Benaroya Research Institute

Seattle, Washington, United States

Site Status

Hospital for Sick Children

Toronto, Ontario, Canada

Site Status

Countries

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United States Canada

References

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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.

Reference Type BACKGROUND
PMID: 11476858 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 7606872 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 8946834 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 9604865 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11160264 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 12107747 (View on PubMed)

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.

Reference Type RESULT
PMID: 21714999 (View on PubMed)

Related Links

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Other Identifiers

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U01DK061055

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UC4DK097835

Identifier Type: NIH

Identifier Source: secondary_id

View Link

TN08 GAD65

Identifier Type: -

Identifier Source: org_study_id

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