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    Clinical Trial Results:
    A pilot study on safety, feasibility and insulin-promotion by intra-inguinal lymph node injections of glutamic acid decarboxylase (GAD) in patients with LADA type of diabetes.

    Summary
    EudraCT number
    		 2019-002692-34
    Trial protocol
    		 NO   SE  
    Global end of trial date
    05 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2023
    First version publication date
    24 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GADinLADA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04262479
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NTNU, Dept of Clinical and Molecular Medicine, Gastrosenteret
    Sponsor organisation address
    Postboks 8905, Trondheim, Norway, 7491
    Public contact
    Ingrid K Hals, NTNU, Dep of Clinical and Molecular Medicine, Gastrosenteret , ingrid.hals@ntnu.no
    Scientific contact
    Ingrid K Hals, NTNU, Dep of Clinical and Molecular Medicine, Gastrosenteret , ingrid.hals@ntnu.no
    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
    05 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the trial is to evaluate the effects of 3 intra-nodal injections of GAD-alum in a population of LADA patients with high GADA titers. The primary objective is to evaluate safety and feasibility of this treatment regimen. The pilot study will be performed in order to support the launch of a larger placebo controlled clinical trial in the LADA population.
    Protection of trial subjects
    Regional ethical committees, drug administration agencies and data protection authorities in Norway and Sweden approved the proposed trial. Informed consent was obtained from all study participants.
    Background therapy
    		 Vitamin D 1 tablet/day, total daily dose of 2000 IE given per os from day -30 through day 90.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Sweden: 8
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    14
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 14
    Number of subjects completed
    		 14

    Period 1
    Period 1 title
    Baseline (month 0)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 rhGAD65
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhGAD65
    Investigational medicinal product code
    Other name
    Diamyd (R)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel 3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart.

    Number of subjects in period 1
    		rhGAD65
    Started
    14
    Completed
    14
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 rhGAD65
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rhGAD65
    Investigational medicinal product code
    Other name
    Diamyd (R)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel 3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart.

    Number of subjects in period 2
    		rhGAD65
    Started
    14
    Completed
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline (month 0)
    Reporting group description
    		 -

    Reporting group values
    		 Baseline (month 0) Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 46.6 (30 to 62) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 7 7
    BMI (kg/m^2)
    Units: Subjects
        Non-obese (BMI<=30)
    		 10 10
        Obese (BMI >30)
    		 4 4
    HLA characterization
    Units: Subjects
        DR3-DQ2+
    		 7 7
        DR3-DQ2-
    		 7 7
    Time from diagnosis
    Time from diagnosis to informed consent
    Units: month
        arithmetic mean (standard deviation)
    		 5.3 ± 3.8 -
    Subject analysis sets

    Subject analysis set title
    TP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total population set will include all patients who receive at least 1 dose of GAD-alum regardless of withdrawal.

    Subject analysis sets values
    		 TP
    Number of subjects
    14
    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)
    14
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    46.6 (30 to 62)
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    7
    BMI (kg/m^2)
    Units: Subjects
        Non-obese (BMI<=30)
    10
        Obese (BMI >30)
    4
    HLA characterization
    Units: Subjects
        DR3-DQ2+
    7
        DR3-DQ2-
    7
    Time from diagnosis
    Time from diagnosis to informed consent
    Units: month
        arithmetic mean (standard deviation)
    5.3 ± 3.8

    End points

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    End points reporting groups
    Reporting group title
    rhGAD65
    Reporting group description
    		 -
    Reporting group title
    rhGAD65
    Reporting group description
    		 -

    Subject analysis set title
    TP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total population set will include all patients who receive at least 1 dose of GAD-alum regardless of withdrawal.

    Primary: Change in GAD65A titer serum levels

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    End point title
    		 Change in GAD65A titer serum levels
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to month 12
    End point values
    		 rhGAD65 rhGAD65 TP
    Number of subjects analysed
    14
    14
    14
    Units: unit(s)/millilitre
        arithmetic mean (standard deviation)
    180406.14 ± 634160.18
    163356.07 ± 457735.54
    -17050.07 ± 178422.15
    Statistical analysis title
    		 Change from baseline to Month 12
    Comparison groups
    rhGAD65 v rhGAD65
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0002
    Method
    		 Wilcoxon Signed Rank test
    Confidence interval
    Notes
    [1] - Pairwise comparison of change from baseline (14 subjects are included in the analysis with baseline and month 12 values)

    Secondary: Change in HbA1c

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    End point title
    		 Change in HbA1c
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to Month 12
    End point values
    		 rhGAD65 rhGAD65 TP
    Number of subjects analysed
    14
    14
    14
    Units: mmol/mol
        arithmetic mean (standard deviation)
    43.00 ± 6.03
    48.07 ± 12.27
    5.07 ± 7.51
    Statistical analysis title
    		 Change from baseline to Month 12
    Comparison groups
    rhGAD65 v rhGAD65
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0024
    Method
    		 Wilcoxon Signed Rank test
    Confidence interval
    Notes
    [2] - Pairwise comparison of change from baseline (14 subjects are included in the analysis with baseline and month 12 values)

    Secondary: Change in maximum C-peptide during MMTT

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    End point title
    		 Change in maximum C-peptide during MMTT
    End point description
    Maximum C-peptide during Mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    Change from baseline to month 12
    End point values
    		 rhGAD65 rhGAD65 TP
    Number of subjects analysed
    14
    14
    14
    Units: nmol/l
        arithmetic mean (standard deviation)
    2.04 ± 0.51
    1.78 ± 0.52
    -0.26 ± 0.38
    Statistical analysis title
    		 Change from baseline to Month 12
    Comparison groups
    rhGAD65 v rhGAD65
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0437
    Method
    		 Wilcoxon Signed Rank test
    Confidence interval
    Notes
    [3] - Pairwise comparison of change from baseline (14 subjects are included in the analysis with baseline and month 12 values)

    Secondary: Change in fasting glucose

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    End point title
    		 Change in fasting glucose
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to month 12
    End point values
    		 rhGAD65 rhGAD65 TP
    Number of subjects analysed
    14
    14
    14
    Units: mmol/mol
        arithmetic mean (standard deviation)
    6.92 ± 1.49
    7.16 ± 1.62
    0.24 ± 1.03
    Statistical analysis title
    		 Change from baseline to Month 12
    Comparison groups
    rhGAD65 v rhGAD65
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.7209
    Method
    		 Wilcoxon Signed Rank test
    Confidence interval
    Notes
    [4] - Pairwise comparison of change from baseline (14 subjects are included in the analysis with baseline and month 12 values)

    Secondary: Change in AUC C-peptide

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    End point title
    		 Change in AUC C-peptide
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to month 12
    End point values
    		 rhGAD65 rhGAD65 TP
    Number of subjects analysed
    14
    14
    14
    Units: ug/ml
        arithmetic mean (standard deviation)
    5.36 ± 1.21
    5.51 ± 1.24
    1.03 ± 1.13
    Statistical analysis title
    		 Change from baseline to Month 12
    Comparison groups
    rhGAD65 v rhGAD65
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.5
    Method
    		 Wilcoxon Signed Rank test
    Confidence interval
    Notes
    [5] - Pairwise comparison of change from baseline (14 subjects are included in the analysis with baseline and month 12 values)

    Secondary: Change in Fasting C-Peptide

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    End point title
    		 Change in Fasting C-Peptide
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12 (6 min)
    End point values
    		 rhGAD65 rhGAD65 TP
    Number of subjects analysed
    14
    14
    14
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.71 ± 0.37
    0.64 ± 0.33
    -0.06 ± 0.10
    Statistical analysis title
    		 Change from baseline to Month 12
    Comparison groups
    rhGAD65 v rhGAD65
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0313
    Method
    		 Wilcoxon Signed Rank test
    Confidence interval
    Notes
    [6] - Pairwise comparison of change from baseline (14 subjects are included in the analysis with baseline and month 12 values)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening to end of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Total Population
    Reporting group description
    		 Total population will include all patients who receive at least 1 dose of GAD-alum regardless of withdrawal

    Serious adverse events
    		 Total Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Muscle rupture
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blood urine present
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Procedural dizziness
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Wrong product administered
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injection site erythema
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Injection site haemorrhage
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injection site pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Vertigo positional
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Social circumstances
    Menopause
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Pancreatic cystadenoma
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Throat irritation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    Nightmare
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2019
    Study participants (with vitamin D levels <100 nmol/L) will receive oral supplementation of vitamin D in addition to the investigational medicinal product
    10 Jul 2020
    Changes in inclusion criteria stated in item 2 in Section 6.3.
    29 Jan 2021
    Specification regarding total number of trial subjects in Section 3.6, and change in exclusion criteria, item 4 in Section 6.3.

    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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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