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

NCT ID: NCT03635437

Last Updated: 2022-11-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-05
• Study Completion Date: 2022-09-27

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low dose gamma-aminobutyric acid (GABA)

Oral GABA treatment 200 mg daily for 6 months

Group Type: EXPERIMENTAL

Gamma-Aminobutyric Acid (GABA)

Intervention Type: 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)

Oral GABA treatment 600 mg daily for 6 months

Group Type: EXPERIMENTAL

Gamma-Aminobutyric Acid (GABA)

Intervention Type: 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

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.

Group Type: EXPERIMENTAL

Gamma-Aminobutyric Acid (GABA)

Intervention Type: 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.

Alprazolam

Intervention Type: 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.

Interventions

Gamma-Aminobutyric Acid (GABA)

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.

Intervention Type: DRUG

Alprazolam

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.

Intervention Type: DRUG

Other Intervention Names

GABA (Remygen)

Eligibility Criteria

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

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Diamyd Medical AB

INDUSTRY

Sponsor Role: collaborator

Per-Ola Carlsson

OTHER

Sponsor Role: lead

Responsible Party

Per-Ola Carlsson

Professor, Senior consultant

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Per-Ola Carlsson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Uppsala University Hospital

Locations

Uppsala University Hospital

Uppsala, , Sweden

Countries

Sweden

References

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.

Reference Type: DERIVED

PMID: 34635547 (View on PubMed)

Other Identifiers

Regenerate-1 (G/P2/18/1)

Identifier Type: -

Identifier Source: org_study_id