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The Use of Glutamic Acid Decarboxylase (GAD) and Gamma-Amino Butyric Acid (GABA) in the Treatment of Type I Diabetes (GABA)

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ClinicalTrials.gov Identifier: NCT02002130
Recruitment Status : Active, not recruiting
First Posted : December 5, 2013
Last Update Posted : August 31, 2018
Sponsor:
Collaborators:
Diamyd Inc
NOW Foods
Janssen Pharmaceuticals
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Kenneth L. McCormick, University of Alabama at Birmingham

Brief Summary:
Type I Diabetes is an auto immune disease in which the body's immune system attacks and destroys the insulin-producing beta cells of the pancreas. Therefore, children affected by this condition present with high blood sugars. This condition affects 1:400/500 persons worldwide.Type I Diabetes, previously known as Juvenile Diabetes,usually strikes in childhood, adolescence, or young adulthood, but lasts for a lifetime. To date, there has been no treatments that can arrest, or reverse the ongoing beta cell destruction. We hypothesize that GABA, a naturally occurring substance, has the potential to reduce the inflammation and protect the pancreatic beta cells from autoimmune destruction. GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent onset, Type I Diabetes.

Condition or disease Intervention/treatment Phase
Type I Diabetes Drug: Placebo GABA and Placebo GAD-alum Drug: GABA and Placebo GAD-alum Drug: Active Oral GABA and Active GAD-alum injection Phase 1

Detailed Description:

The primary defect in autoimmune Type I Diabetes Mellitus (T1DM) involves the infiltration of the pancreatic islet cells by T-lymphocytes, macrophages, and other immune cells, and consequent loss of beta cells. At the onset of T1DM more than 70% of the beta cells are destroyed, whereas the residual beta cells most likely represent the only reservoir for the potential regeneration of the islet beta cell mass. A series of immunological abnormalities have been reported in those with T1DM including, but not limited to, the production of autoantibodies (i.e., glutamic acid decarboxylase (GAD-65), tyrosine phosphatase-related islet antigen 2 (IA2), Zinc Transporter 8 (ZnT8A), or insulin (IAA) as well as alterations in the capacity of regulatory T cells (Treg) to suppress the action of effector T cells (Teff); the latter population thought as playing a key role in the immune destructive process. Therefore, a vast majority of studies attempting to prevent or reverse the disease have focused on immune suppression. While some of these studies have shown limited promise, many has side effects which were significant enough that one must question the value of short term benefits associated with utilizing these drugs.

GABA is a naturally occurring substance in physiology and has the potential to locally reduce inflammation and protect pancreatic beta cells from auto-immune destruction. GABA, synthesized from glutamate by GAD, is a well known neurotransmitter in the CNS and acts mainly through the GABAA receptor (GABAAR). GABA is locally produced by the pancreatic beta cells. GABAARs are also expressed in various immune cells, including T-cells, peripheral blood mononuclear cells, and are known to exert immune-inhibitory effects. BABA appears to play multiple roles in the pancreas. GABA promotes beta-cell growth and survival, and GABA can also act on the GABA(A) receptors in the pancreatic alpha cells, in so doing suppressing glucagon secretion, and GABA suppresses inflammation and increases regulatory T-cell numbers. Based on the aforementioned information, we envisage that administering GABA to those with new onset T1DM may preserve or increase residual insulin production, suppress glucagon release, and decrease inflammation surrounding the pancreas. With this, GABA may prolong the beta-cell life after diagnosis. Combining with GAD-alum injections, which aim to halt the autoimmune attack by inducing tolerance thereby saving residual insulin production, may improve glycemic control even more and significantly decrease the risk of hypoglycemia and long-term complications in the future.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 101 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Use of Glutamic Acid Decarboxylase (GAD)and Gamma-Amino Butyric Acid(GABA)in the Treatment of Type I Diabetes.
Actual Study Start Date : January 2015
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Placebo Comparator: Placebo GABA and Placebo GAD-alum

Placebo formulation, Maltodextrin, for Gamma-Amino Butyric Acid (GABA) capsule-identical in appearance and taste, but no active medication will be taken with meals.Number of pills based on body surface area.

Placebo GAD-alum(Glutamic Acid Decarboxylase in alum) injection- identical in appearance but no active medication will be received at baseline and 1 month.

Drug: Placebo GABA and Placebo GAD-alum
Maltodextrin as a placebo formulation for GABA Placebo GAD-alum injection
Other Name: Placebo for Gamma-Amino Butyric Acid

Active Comparator: GABA and placebo GAD-alum

Patients will receive the Active GABA (Gamma-Amino Butyric Acid) capsules. Each capsule 250mg. Dosage will be calculated according to body surface area of the child and divided between 2 meals/day. Larger dose taken with larger meal.

Patients will receive the GAD-alum( Glutamic Acid Decarboxylase in alum) placebo at baseline and 1 month.

Drug: GABA and Placebo GAD-alum
Oral Active GABA with Placebo GAD-alum

Active Comparator: Active Oral GABA and Active GAD-alum Injection

Patients will receive Oral GABA(Gamma-Amino Butyric Acid) 250mg capsules. Dosage (# of capsules) based on body surface area and divided between 2 meals/day.

Patients will receive a primary (at baseline)injection of recombinant human GAD(Glutamic Acid Decarboxylase) in a standard vaccine formulation with alum, and a booster injection of the same at 1 month after baseline.

Drug: Active Oral GABA and Active GAD-alum injection
Active Oral GABA and Active GAD-alum injection




Primary Outcome Measures :
  1. Compare the effect of oral GABA or oral GABA/GAD combination administration on pancreatic beta cell function by use of insulin [ Time Frame: 12 months after baseline ]
    This will be assessed by total daily insulin dose in treatment cohorts compared to age matched placebo controls before and after 1 year of treatment

  2. Compare the effect of oral GABA or oral GABA/GAD combination administration on pancreatic beta cell function by peptide secretion [ Time Frame: 12 months after baseline ]
    This will be assessed by meal stimulated C-peptide secretion in treatment cohorts compared to age matched placebo controls before and after 1 year of treatment


Secondary Outcome Measures :
  1. Compare the effect of oral GABA or GABA/GAD administration on diabetes autoantibodies GAD-65 [ Time Frame: 12 months after baseline ]
  2. Compare the effect of oral GABA or GABA/GAD administration on diabetes autoantibodies IA2 [ Time Frame: 12 months after baseline ]
  3. Compare the effect of oral GABA or GABA/GAD administration on diabetes autoantibodies ICA [ Time Frame: 12 months after baseline ]


Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be positive for GAD-65 antibody.
  • They must meet ADA criteria for diabetes: classic symptoms, plus blood sugar > 200mg/dL or fasting blood sugar > 126 mg/dL.
  • Must be enrolled with 5 weeks of diagnosis
  • Females who are post-menarchal must use 2 forms of contraception if not abstinent. The types of contraception deemed acceptable would be oral contraceptives, intrauterine devices, and barrier methods.
  • Signed informed consent form.

Exclusion Criteria:

  • Chronic systemic steroid use, including inhaled compounds, or any medication which can alter glucose metabolism
  • Obesity, defined as BMI > 95% or BMI > 27 in adolescents with acanthosis score between 1-1.5.
  • Pregnant and/or breast feeding
  • History of seizure disorder
  • Patients on medications that may disturb GABA action, such as Baclofen, Valium, Acamprosate, Neurontin, or Lyrica
  • history of any alcoholism or substance abuse.
  • Chronic Disease (such as liver, cancer, cystic fibrosis, or renal failure)
  • Chromosome abnormality (such as Trisomy 21, Turner Syndrome, etc.)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02002130


Locations
United States, Alabama
Children's of Alabama
Birmingham, Alabama, United States, 35233
Sponsors and Collaborators
University of Alabama at Birmingham
Diamyd Inc
NOW Foods
Janssen Pharmaceuticals
Juvenile Diabetes Research Foundation
Investigators
Principal Investigator: Kenneth McCormick, MD Division Director Pediatric Endocrinology
Study Chair: Heather Choat, MD Pediatric Endocrinology

Publications:
Responsible Party: Kenneth L. McCormick, MD, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02002130     History of Changes
Other Study ID Numbers: GABA-GAD
First Posted: December 5, 2013    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 2018

Keywords provided by Kenneth L. McCormick, University of Alabama at Birmingham:
Diabetes

Additional relevant MeSH terms:
gamma-Aminobutyric Acid
GABA Agents
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Aluminum sulfate
Butyric Acid
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Histamine Antagonists
Histamine Agents