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    Clinical Trial Results:
    A Phase I/II, 2-Arm, Open Label, Single Centre Study to Investigate the Safety and Effect of Oral GABA Therapy on β-cell Regeneration in Type 1-diabetes Patients

    Summary
    EudraCT number
    		 2018-001115-73
    Trial protocol
    		 SE  
    Global end of trial date
    27 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Oct 2023
    First version publication date
    12 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Regenerate-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03635437
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Uppsala University Hospital
    Sponsor organisation address
    Akademiska sjukhuset , Uppsala, Sweden, 75185
    Public contact
    Per-Ola Carlsson, Uppsala University Hospital, 46 18 471 44 25,
    Scientific contact
    Per-Ola Carlsson, Uppsala University Hospital, 46 18 471 44 25 ,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the acute and long-term safety of oral GABA treatment.
    Protection of trial subjects
    In the first dose-escalation part of the study, 6 patients were treated with 200 mg, 600 mg and 1200 mg GABA. The IDMC reviewed the safety data for the first patient before allowing the following five patients to begin the dose-escalation steps. After all patients had completed the dose-escalation study, the IDMC again reviewed the data to ensure safe continuation of the main study where patients were randomized to one of three treatment arms receiving a daily dose of 200 mg GABA, 600 mg GABA or 600 mg GABA + 0.5 mg alprazolam. Safety parameters, plasma concentration of GABA, insulin and glucose tolerance was evaluated for each patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    35
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Male patients with type 1 diabetes at Uppsala University Hospital, Sweden, diagnosed ≥ 5 years at the time of screening were given information about the study and asked to participate in the trial.

    Pre-assignment
    Screening details
    		 A total of 49 patients were screened for inclusion in the Main study, of which 12 were excluded due to a screen failure and 2 because of other reasons (difficult to find appropriate blood vessels and not possible to participate due to work).

    Period 1
    Period 1 title
    Before treatment with GABA
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was an open label trial, so no blinding or code breaking procedures were needed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 200 mg GABA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remygen (GABA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg, once daily taken together with food

    Arm title
    		 600 mg GABA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remygen (GABA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg, once daily taken together with food

    Arm title
    		 600 mg GABA + 0.5 mg alprazolam
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remygen (GABA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg, once daily taken together with food

    Investigational medicinal product name
    Alprazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, once daily, taken together with food.

    Number of subjects in period 1
    		200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Started
    13
    11
    11
    Completed
    13
    11
    9
    Not completed
    0
    0
    2
         Consent withdrawn by subject
    -
    -
    2
    Period 2
    Period 2 title
    Treatment with GABA
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was an open label trial, so no blinding or code breaking procedures were needed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 200 mg GABA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remygen (GABA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg, once daily taken together with food

    Arm title
    		 600 mg GABA
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remygen (GABA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg, once daily taken together with food

    Arm title
    		 600 mg GABA + 0.5 mg alprazolam
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remygen (GABA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg, once daily taken together with food

    Investigational medicinal product name
    Alprazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, once daily, taken together with food.

    Number of subjects in period 2
    		200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Started
    13
    11
    9
    Completed
    12
    7
    7
    Not completed
    1
    4
    2
         Physician decision
    -
    1
    -
         Consent withdrawn by subject
    -
    2
    -
         Adverse event, non-fatal
    1
    -
    1
         Unable to attend all study visits.
    -
    1
    -
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    200 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA + 0.5 mg alprazolam
    Reporting group description
    		 -

    Reporting group values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam Total
    Number of subjects
    		 13 11 11 35
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.5 ( 5.3 ) 31.1 ( 7.6 ) 27.4 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 13 11 11 35

    End points

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    End points reporting groups
    Reporting group title
    200 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA + 0.5 mg alprazolam
    Reporting group description
    		 -
    Reporting group title
    200 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA + 0.5 mg alprazolam
    Reporting group description
    		 -

    Primary: Safety endpoint: Number of AEs

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    End point title
    		 Safety endpoint: Number of AEs [1]
    End point description
    Number of AEs probably or possibly related to the study treatment.
    End point type
    Primary
    End point timeframe
    From start of treatment until one month after end of treatment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    13
    11
    9
    Units: Number of events
    14
    20
    25
    No statistical analyses for this end point

    Primary: Safety endpoint: Number of SAEs

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    End point title
    		 Safety endpoint: Number of SAEs [2]
    End point description
    Number of SAEs probably or possibly related to the study treatment.
    End point type
    Primary
    End point timeframe
    From start of treatment until one month after end of treatment.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    13
    11
    9
    Units: Number of events
    1
    0
    0
    No statistical analyses for this end point

    Primary: Change in vital signs from baseline: weight

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    End point title
    		 Change in vital signs from baseline: weight [3]
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to Day 210 of treatment
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    12
    7
    7
    Units: kg
        arithmetic mean (standard deviation)
    1.2 ( 1.5 )
    -0.3 ( 3.8 )
    0.2 ( 3.7 )
    No statistical analyses for this end point

    Primary: Change in vital signs from baseline: diastolic blood pressure

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    End point title
    		 Change in vital signs from baseline: diastolic blood pressure [4]
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to Day 180 of treatment
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    12
    8
    7
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.9 ( 7.7 )
    -3.0 ( 11.8 )
    -4.7 ( 9.8 )
    No statistical analyses for this end point

    Primary: Change in vital signs from baseline: systolic blood pressure

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    End point title
    		 Change in vital signs from baseline: systolic blood pressure [5]
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to Day 180 of treatment
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    12
    8
    7
    Units: mmHg
        arithmetic mean (standard deviation)
    0.9 ( 11.7 )
    -8.1 ( 12.5 )
    -6.7 ( 9.6 )
    No statistical analyses for this end point

    Primary: Change in laboratory parameters from baseline: WBC

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    End point title
    		 Change in laboratory parameters from baseline: WBC [6]
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to Day 210 of treatment
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    12
    7
    7
    Units: 10^9/L
        arithmetic mean (standard deviation)
    0.07 ( 0.89 )
    -0.8 ( 0.73 )
    0.1 ( 0.94 )
    No statistical analyses for this end point

    Primary: Physical examination

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    End point title
    		 Physical examination [7]
    End point description
    The physical examination included: General appearance, skin, mouth, throat, cardiovascular system, abdomen, lymphatic glands, and neurological/musculoskeletal (incl. reflexes).
    End point type
    Primary
    End point timeframe
    Percentage of patients with normal physical examination at baseline who had a normal physical examination at Day 210 of treatment
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis according to protocol.
    End point values
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Number of subjects analysed
    11
    7
    7
    Units: % of patients
    100
    100
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment until one month after end of treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    200 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA
    Reporting group description
    		 -

    Reporting group title
    600 mg GABA + 0.5 mg alprazolam
    Reporting group description
    		 -

    Serious adverse events
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Drug-induced liver injury
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 200 mg GABA 600 mg GABA 600 mg GABA + 0.5 mg alprazolam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 13 (53.85%)
    7 / 11 (63.64%)
    9 / 9 (100.00%)
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 11 (27.27%)
    3 / 9 (33.33%)
         occurrences all number
    6
    7
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    3 / 9 (33.33%)
         occurrences all number
    0
    1
    4
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    5 / 9 (55.56%)
         occurrences all number
    0
    1
    7
    Flushing
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    1
    Nausea
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 11 (18.18%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    1
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2019
    - Addition of the exclusion criteria: 1. Females of child-bearing potential 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). 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. - Addition of further information regarding GABA sampling - The trial is no longer labeled “first in human” - Addition of a third arm to the main study that would receive a high dose of GABA (600 mg) in combination with 0.5 mg Alprazolam for 3 months. - Addition of 12 patients to the main study population
    24 Aug 2020
    - Addition of genotyping for HLA. - Liver function will be tested in 1- to 2-week intervals after start of study treatment - A hypoglycemic clamp will be performed twice after the 6-month treatment period

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34635547
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