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

• ClinicalTrials.gov Identifier: NCT02002130
• Recruitment Status: Completed
• First Posted: December 5, 2013
• Last Update Posted: May 6, 2022
• Sponsor: University of Alabama at Birmingham
• Collaborators: Diamyd Inc; NOW Foods; Janssen Pharmaceuticals; Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): Kenneth McCormick, University of Alabama at Birmingham

Study Description

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 Design

• 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
• Actual Primary Completion Date: October 15, 2021
• Actual Study Completion Date: April 15, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Compare the effect of oral GABA or oral GABA/GAD combination administration on pancreatic beta cell function by quantitative C-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 fasting and meal stimulated glucagon and pro-insulin levels. [ Time Frame: 12 months after baseline ]
   This will be assessed by meal stimulated glucagon and pro-insulin secretion in treatment cohorts compared with age matched placebo controls before and after 1 year of treatment.
2. Compare the effect of oral GABA or GABA/GAD administration on total daily insulin usage by participants and corrected Hemoglobin A1C. [ Time Frame: 12 months after baseline ]
   This will be assessed by measuring insulin usage and corrected Hemoglobin A1C linearly for each participant, in addition to comparison with age matched controls
3. Compare the effect of oral GABA or oral GABA/GAD administration on indices of immune system function. [ Time Frame: 12 months after baseline ]
   This will be assessed by measuring immunologic markers of inflammation linearly over the 12 month treatment course for each patient and comparing to age matched placebo controls.
4. Compare the effect of oral GABA or oral GABA/GAD administration on diabetes related autoantibodies [ Time Frame: 12 months after baseline ]
   This will be assessed by measuring GAD65, ICA512, and Zinc Transporter 8 antibodies throughout the treatment period.

Eligibility Criteria

• 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.)

Contacts and Locations

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; University of Alabama at Birmingham
• Principal Investigator: Gail Mick, MD; University of Alabama at Birmingham

  Study Documents (Full-Text)

Documents provided by Kenneth McCormick, University of Alabama at Birmingham:

Study Protocol and Statistical Analysis Plan  [PDF] October 20, 2020

More Information

Publications:

Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1909-20. doi: 10.1056/NEJMoa0804328. Epub 2008 Oct 8.

Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11692-7. doi: 10.1073/pnas.1102715108. Epub 2011 Jun 27.

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

Freese J, Al-Rawi R, Choat H, Martin A, Lunsford A, Tse H, Mick G, McCormick K. Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4318-e4326. doi: 10.1210/clinem/dgab463.

• Responsible Party: Kenneth McCormick, MD, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT02002130
• Other Study ID Numbers: GABA-GAD
• First Posted: December 5, 2013
• Last Update Posted: May 6, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

Diabetes

Additional relevant MeSH terms:

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