Evaluation of Safety and Diabetes Status Upon Oral Treatment With GABA in Patients With Longstanding Type-1 Diabetes

Phase 1

Completed

• Conditions: Type 1 Diabetes Mellitus
• Interventions: Drug: Gamma-Aminobutyric Acid (GABA); Drug: Alprazolam

• Registration Number: NCT03635437
• Lead Sponsor: Per-Ola Carlsson

Brief Summary

The main goal of this study is to find a reasonably safe and tolerable treatment for adult patients with type 1-diabetes and that regain some of the endogenous insulin secretion, improve the patients' quality of life (QoL) and reduce the risk of both short- and long-term complications. The hypothesis tested is that oral GABA treatment with the newly develope...

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-08-09
• Study First Submitted QC: 2018-08-14
• Study First Posted: 2018-08-17
• Study Start: 2018-09-05
• Primary Completion: 2022-09-27
• Study Completion: 2022-09-27
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-01
• Last Update Posted: 2022-11-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 35

Inclusion Criteria

1. Informed consent given by patients according to national regulations

2. Type 1 diabetes diagnosed ≥ 5 years at the time of screening

3. Must have been diagnosed with Type 1-diabetes before the age of 25

4. Age ≥18 and ≤50

5. Fasting c-peptide levels should be in the range from not detectable levels up to <0.12 nmol/L

6. For males of childbearing potential adequate contraception is as follows:

   1. condom (male)

   2. abstinence from heterosexual intercourse

   3. female partner using contraception as below listed:

      • oral (except low-dose gestagen (lynestrenol and norethisterone)), injectable, or implanted hormonal contraceptives
      • combined (estrogen and progestogen containing)
      • oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation
      • intrauterine device
      • intrauterine hormone-releasing system (for example, progestin-releasing coil)
      • bilateral tubal occlusion

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Exclusion Criteria

1. Females of child-bearing potential
2. Previous or current treatment with immunosuppressant therapy (although topical and inhalation steroids are accepted)
3. Treatment with any oral or injected anti-diabetic medications other than insulin
4. Patients on medications which may disturb GABA action, such as Baclofen, Valium, Acamprosate, Neurontin, or Lyrica
5. HbA1c > 90 mmol/mol
6. eGFR <60 ml/min
7. Increased plasma concentrations of alanine aminotransferase (>0.75 μkatl/l for females or >1.1 μkat/l for males) and/or aspartate aminotransferase (>0.60 μkat/l for females or >0.75μkat/l for males).
8. Known cancer disease
9. Known sleeping apnea or pulmonary disorder with carbon dioxide rentention in blood
10. Previous history of pancreatitis or other exocrine pancreatic disorder
11. A history of epilepsy, myasthenia gravis, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
12. A history of alcohol or drug abuse
13. A significant illness other than diabetes within 2 weeks prior to first dosing
14. Known human immunodeficiency virus (HIV) or hepatitis
15. Females who are breastfeeding
16. Males not willing to use adequate contraception during the study period.
17. Known hypersensitivity agains benzodiazepins or any excipients of study drugs
18. Participation in other clinical trials with a new chemical entity within 3 months or 5 half-lives of the new chemical entity, whatever longest.
19. Inability or unwillingness to comply with the provisions of this protocol
20. Deemed by the investigator not being able to follow instructions and/or follow the study protocol or other reasons that, at the investigator's discretion, could affect the subject's current clinical condition during study procedures.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High dose gamma-aminobutyric acid (GABA) + Alprazolam	Gamma-Aminobutyric Acid (GABA)	Oral Alprazolam treatment 0.5 mg daily combined with oral GABA treatment 600 mg daily for 3 months. Alprazolam treatment thereafter ended, and study subjects will continue with oral GABA treatment 600 mg daily only for another 3 months.
Low dose gamma-aminobutyric acid (GABA)	Gamma-Aminobutyric Acid (GABA)	Oral GABA treatment 200 mg daily for 6 months
High dose gamma-aminobutyric acid (GABA)	Gamma-Aminobutyric Acid (GABA)	Oral GABA treatment 600 mg daily for 6 months
High dose gamma-aminobutyric acid (GABA) + Alprazolam	Alprazolam	Oral Alprazolam treatment 0.5 mg daily combined with oral GABA treatment 600 mg daily for 3 months. Alprazolam treatment thereafter ended, and study subjects will continue with oral GABA treatment 600 mg daily only for another 3 months.

Primary Outcome Measures

Name	Time	Method
Adverse events possibly or probably related to GABA treatment	6 months	To evaluate the acute and long-term safety of oral GABA treatment. The endpoint will investigate number of adverse events possibly or probably related to GABA treatment.

Secondary Outcome Measures

Name	Time	Method
Change in exogenous insulin consumption by treatment	7 months	Change in exogenous insulin consumption between 0,3 and 6 months of treatment and at the follow-up one month later.
Change in variables that indicate effects on immune system	7 months	Change by treatment in variables that indicate effects on the immune system such as serum autoantibodies to GAD65 and islet antigen-2, and immune cells
Change in diabetes treatment satisfaction questionnaire	7 months	Measurements of patient diabetes treatment satisfaction by questionnaire during study. Each of eight questions have a 7-graded scale from 0-6. 48 points are therefore maximal treatment satisfaction and comparisons will be made to score before treatment start.
Difference in C-peptide response to mixed meal tolerance test before and directly after treatment	6 months	Difference in C-peptide (Area under the curve 0-120 min) during a mixed meal tolerance test between baseline and after 6 months of oral GABA treatment
Difference in glucagon response during a hypoglycemic clamp before and after treatment	7 months	Difference in glucagon (area under the curve) during a hypoglycemic clamp between baseline and 6 months of treatment
Change in HbA1c by treatment	7 months	Change in HbA1c between 0,3 and 6 months of treatment and at the follow-up one month later.
Change in fasting C-peptide by treatment	7 months	Change in fasting C-peptide levels between 0,3 and 6 months of treatment and at the follow-up one month later.
Difference in C-peptide response to mixed meal tolerance test during and after treatment	7 months	Difference in C-peptide (Area under the curve 0-120 min) during a mixed meal tolerance test between baseline and after 3 and and 6 months of treatment and between baseline and the follow-up visit
Difference in maximum stimulated C-peptide to mixed meal tolerance test during and after treatment	7 months	Difference in maximum stimulated C-peptide during a mixed meal tolerance test between baseline and after 3 and 6 months of treatment and between baseline and the follow-up visit.
Difference in C-peptide response to mixed meal tolerance test during and after treatment between treatment groups	7 months	Difference in C-peptide (Area under the curve 0-120 min) during a mixed meal tolerance test between treatment group 1 and 2 and after 3 and 6 months of treatment and between baseline and the follow-up visit
Difference in glucagon response during a hypoglycemic clamp between treatment groups before and after treatment	7 months	Difference in glucagon (area under the curve) during a hypoglycemic clamp between treatment group 1 and 2 between baseline and 6 months of treatment
Change in GABA plasma levels	7 months	Analysis of GABA plasma levels after 0, 3 and 6 months of treatment and at the follow-up visit one month later.

Trial Locations

Locations (1)

Uppsala University Hospital; 🇸🇪 Uppsala, Sweden