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

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ClinicalTrials.gov Identifier: NCT03635437
Recruitment Status : Recruiting
First Posted : August 17, 2018
Last Update Posted : September 11, 2018
Sponsor:
Collaborator:
Diamyd Medical AB
Information provided by (Responsible Party):
Per-Ola Carlsson, Uppsala University Hospital

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 two-arm, open label, single center, clinical trial. Eligible patients will be randomized into one of two active treatment arms to receive oral GABA treatment for 6 months.

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Mellitus Drug: Gamma-Aminobutyric Acid (GABA) Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, 2-Arm, Open Label, Single Centre Study to Investigate the Safety and Effect of Oral GABA Therapy on Beta-Cell Regeneration in Type 1-diabetes Patients
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : April 30, 2020
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Experimental: Low dose gamma-aminobutyric acid (GABA)
Oral GABA treatment 200 mg daily for 6 months
Drug: Gamma-Aminobutyric Acid (GABA)
Patients eligible for the main study will be randomized in a 1:1 ratio stratified by the C-peptide level to receive 200 or 600 mg of of GABA (Remygen) for 6 months. The start of the arm 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.
Other Name: Remygen

Experimental: High dose gamma-aminobutyric acid (GABA)
Oral GABA treatment 600 mg daily for 6 months
Drug: Gamma-Aminobutyric Acid (GABA)
Patients eligible for the main study will be randomized in a 1:1 ratio stratified by the C-peptide level to receive 200 or 600 mg of of GABA (Remygen) for 6 months. The start of the arm 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.
Other Name: Remygen




Primary Outcome Measures :
  1. Adverse events possibly or probably related to GABA treatment [ Time Frame: 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 :
  1. Difference in C-peptide response to mixed meal tolerance test before and directly after treatment [ Time Frame: 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

  2. Difference in C-peptide response to mixed meal tolerance test during and after treatment [ Time Frame: 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

  3. Difference in maximum stimulated C-peptide to mixed meal tolerance test during and after treatment [ Time Frame: 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.

  4. Difference in C-peptide response to mixed meal tolerance test during and after treatment between treatment groups [ Time Frame: 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

  5. Difference in glucagon response during a hypoglycemic clamp before and after treatment [ Time Frame: 7 months ]
    Difference in glucagon (area under the curve) during a hypoglycemic clamp between baseline and 6 months of treatment

  6. Difference in glucagon response during a hypoglycemic clamp between treatment groups before and after treatment [ Time Frame: 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

  7. Change in HbA1c by treatment [ Time Frame: 7 months ]
    Change in HbA1c between 0,3 and 6 months of treatment and at the follow-up one month later.

  8. Change in exogenous insulin consumption by treatment [ Time Frame: 7 months ]
    Change in exogenous insulin consumption between 0,3 and 6 months of treatment and at the follow-up one month later.

  9. Change in fasting C-peptide by treatment [ Time Frame: 7 months ]
    Change in fasting C-peptide levels between 0,3 and 6 months of treatment and at the follow-up one month later.

  10. Change in variables that indicate effects on immune system [ Time Frame: 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

  11. Change in GABA plasma levels [ Time Frame: 7 months ]
    Analysis of GABA plasma levels after 0, 3 and 6 months of treatment and at the follow-up visit one month later.

  12. Change in diabetes treatment satisfaction questionnaire [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Previous history of pancreatitis or other exocrine pancreatic disorder
  10. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
  11. A history of alcohol or drug abuse
  12. A significant illness other than diabetes within 2 weeks prior to first dosing
  13. Known human immunodeficiency virus (HIV) or hepatitis
  14. Females who are breastfeeding
  15. Males not willing to use adequate contraception during the study period.
  16. Participation in other clinical trials with a new chemical entity within 3 months or 5 half-lives of the new chemical entity, whatever longest.
  17. Inability or unwillingness to comply with the provisions of this protocol
  18. 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.

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): NCT03635437


Contacts
Contact: Per-Ola Carlsson, MD, PhD +46184714425 per-ola.carlsson@mcb.uu.se

Locations
Sweden
Uppsala University Hospital Recruiting
Uppsala, Sweden, 75185
Contact: Per-Ola P Carlsson, MD, PhD    +46702721167    per-ola.carlsson@mcb.uu.se   
Sponsors and Collaborators
Per-Ola Carlsson
Diamyd Medical AB
Investigators
Principal Investigator: Per-Ola Carlsson, MD, PhD Uppsala University Hospital

Responsible Party: Per-Ola Carlsson, Professor, Senior consultant, Uppsala University Hospital
ClinicalTrials.gov Identifier: NCT03635437     History of Changes
Other Study ID Numbers: Regenerate-1 (G/P2/18/1)
First Posted: August 17, 2018    Key Record Dates
Last Update Posted: September 11, 2018
Last Verified: September 2018

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

Keywords provided by Per-Ola Carlsson, Uppsala University Hospital:
Remygen
GABA

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