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

NCT03635437 | Completed Phase 1 DMC

• 1 other identifier: Regenerate-1 (G/P2/18/1)
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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 developed compound Remygen will be safe and induce regain of some endogenous insulin secretion in adult patients with type 1-diabetes diagnosis for more than five years. The first part of the study will include 6 patients and be performed as a Safety and Dose Escalation study in three steps. The main study is a three-arm, open label, single center, clinical trial. Eligible patients will be randomized into one of three active treatment arms to receive oral GABA treatment for 6 months.

Conditions

Type 1 Diabetes Mellitus

Keywords

Remygen; GABA

Outcome Measures

Primary Outcomes (1)

• Adverse events possibly or probably related to GABA treatment

  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.

  6 months

Secondary Outcomes (12)

• Difference in C-peptide response to mixed meal tolerance test before and directly after treatment

  6 months

• Difference in C-peptide response to mixed meal tolerance test during and after treatment

  7 months

• Difference in maximum stimulated C-peptide to mixed meal tolerance test during and after treatment

  7 months

• Difference in C-peptide response to mixed meal tolerance test during and after treatment between treatment groups

  7 months

• Difference in glucagon response during a hypoglycemic clamp before and after treatment

  7 months

Study Arms (3)

Low dose gamma-aminobutyric acid (GABA)

EXPERIMENTAL

Oral GABA treatment 200 mg daily for 6 months

Drug: Gamma-Aminobutyric Acid (GABA)

High dose gamma-aminobutyric acid (GABA)

EXPERIMENTAL

Oral GABA treatment 600 mg daily for 6 months

Drug: Gamma-Aminobutyric Acid (GABA)

High dose gamma-aminobutyric acid (GABA) + Alprazolam

EXPERIMENTAL

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.

Drug: Gamma-Aminobutyric Acid (GABA); Drug: Alprazolam

Interventions

Gamma-Aminobutyric Acid (GABA) DRUG

Patients eligible for the main study will be randomized in a 1:1:1 ratio stratified by the C-peptide level to receive 200 mg of GABA (Remygen) for 6 months, 600 mg of GABA (Remygen) for 6 months, or Alprazolam 0.5 mg combined with GABA 600 mg (Remygen) for 3 months followed by treatment with GABA 600 mg (Remygen) only for another 3 months. The start of the arms with high dose GABA will be delayed and started first after that a data safety monitoring board has evaluated and approved the safety data of the first 4 patients included in the arm with low dose GABA. All patients will continue to receive intensive insulin treatment from their personal physicians during the whole study period.

Also known as: GABA (Remygen)

High dose gamma-aminobutyric acid (GABA); High dose gamma-aminobutyric acid (GABA) + Alprazolam; Low dose gamma-aminobutyric acid (GABA)

Alprazolam DRUG

Patients eligible for the main study will be randomized in a 1:1:1 ratio stratified by the C-peptide level to receive 200 mg of GABA (Remygen) for 6 months, 600 mg of GABA (Remygen) for 6 months, or Alprazolam 0.5 mg combined with GABA 600 mg (Remygen) for 3 months followed by treatment with GABA 600 mg (Remygen) only for another 3 months. The start of the arms with high dose GABA will be delayed and started first after that a data safety monitoring board has evaluated and approved the safety data of the first 4 patients included in the arm with low dose GABA. All patients will continue to receive intensive insulin treatment from their personal physicians during the whole study period.

High dose gamma-aminobutyric acid (GABA) + Alprazolam

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Informed consent given by patients according to national regulations
• Type 1 diabetes diagnosed ≥ 5 years at the time of screening
• Must have been diagnosed with Type 1-diabetes before the age of 25
• Age ≥18 and ≤50
• Fasting c-peptide levels should be in the range from not detectable levels up to \<0.12 nmol/L
• For males of childbearing potential adequate contraception is as follows:
• condom (male)
• abstinence from heterosexual intercourse
• 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

You may not qualify if:

• Females of child-bearing potential
• Previous or current treatment with immunosuppressant therapy (although topical and inhalation steroids are accepted)
• Treatment with any oral or injected anti-diabetic medications other than insulin
• Patients on medications which may disturb GABA action, such as Baclofen, Valium, Acamprosate, Neurontin, or Lyrica
• HbA1c \> 90 mmol/mol
• eGFR \<60 ml/min
• 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).
• Known cancer disease
• Known sleeping apnea or pulmonary disorder with carbon dioxide rentention in blood
• Previous history of pancreatitis or other exocrine pancreatic disorder
• A history of epilepsy, myasthenia gravis, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
• A history of alcohol or drug abuse
• A significant illness other than diabetes within 2 weeks prior to first dosing
• Known human immunodeficiency virus (HIV) or hepatitis
• Females who are breastfeeding

Sponsors & Collaborators

• Per-Ola Carlsson: lead
• Diamyd Medical AB: collaborator

Study Sites (1)

Uppsala University Hospital

Uppsala, 75185, Sweden

Location

Related Publications (1)

• Espes D, Liljeback H, Hill H, Elksnis A, Caballero-Corbalan J, Carlsson PO. GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes. BMJ Open Diabetes Res Care. 2021 Oct;9(1):e002442. doi: 10.1136/bmjdrc-2021-002442.

  PMID: 34635547 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

gamma-Aminobutyric Acid; Alprazolam

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Per-Ola Carlsson, MD, PhD

  Uppsala University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Senior consultant

Study Record Dates

• First Submitted: August 9, 2018
• First Posted: August 17, 2018
• Study Start: September 5, 2018
• Primary Completion: September 27, 2022
• Study Completion: September 27, 2022
• Last Updated: November 2, 2022

Record last verified: 2022-11

Locations

SE (1)