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    Clinical Trial Results:
    DIAGNODE-B, A Phase I/II Open Label Pilot Study to evaluate the safety and feasibility of an additional intralymphatic booster administration of GAD-alum (Diamyd®) in individuals with Type 1 diabetes

    Summary
    EudraCT number
    		 2021-005441-32
    Trial protocol
    		 SE  
    Global end of trial date
    29 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2024
    First version publication date
    12 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DIAGNODE-B
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05351879
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Linköping University
    Sponsor organisation address
    Crown Princess Victoria Children´s Hospital and Div of Pediatrics, Department of Biomedical and Cli, Linköping, Sweden, 58183
    Public contact
    Johnny Ludvigsson, Linköping University, Johnny.Ludvigsson@liu.se
    Scientific contact
    Johnny Ludvigsson, Linköping University, Johnny.Ludvigsson@liu.se
    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
    07 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate feasibility and safety of administering an additional intralymphatic booster dose of Diamyd.
    Protection of trial subjects
    After the injection of Diamyd each trial participant was to remain at the study clinic for at least 1 h and monitored by the study personnel.
    Background therapy
    		 All patients was to continue to receive standard of care treatment for Type 1 diabetes during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2021
    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
    Sweden: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    1
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In total, 6 patients (2 from the DIAGNODE-1 cohort and 4 from the DIAGNODE-2 cohort) were screened for the study and all met the eligibility criteria and were enrolled in the study.

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

    Arms
    Arm title
    		 ALUM-rhGAD65 + Vitamin D
    Arm description
    		 All patients received one dose of Diamyd 4 μg as a 0.1 mL intralymphatic injection into an inguinal lymph node. Vitamin D (cholecalciferol 2000 IE) was administered as tablets 2000 IU daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd
    Investigational medicinal product code
    Other name
    ALUM-rhGAD65
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    GAD-alum (Diamyd®; 4 μg) was administered as a 0.1 mL intralymphatic injection into an inguinal lymph node.

    Investigational medicinal product name
    Vitamin D
    Investigational medicinal product code
    Other name
    Caliciferol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Commercially available vitamin D (cholecalciferol; trade name Divisun® 2000 IE) was administered as tablets 2000 IU daily.

    Number of subjects in period 1
    		ALUM-rhGAD65 + Vitamin D
    Started
    6
    Completed
    6
    Period 2
    Period 2 title
    Overall Study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 ALUM-rhGAD65 + Vitamin D
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd
    Investigational medicinal product code
    Other name
    ALUM-rhGAD65
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    GAD-alum (Diamyd®; 4 μg) was administered as a 0.1 mL intralymphatic injection into an inguinal lymph node.

    Investigational medicinal product name
    Vitamin D
    Investigational medicinal product code
    Other name
    Caliciferol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Commercially available vitamin D (cholecalciferol; trade name Divisun® 2000 IE) was administered as tablets 2000 IU daily.

    Number of subjects in period 2
    		ALUM-rhGAD65 + Vitamin D
    Started
    6
    Completed
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 6 6
    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)
    		 1 1
        Adults (18-64 years)
    		 5 5
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.3 ( 5.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 4 4
    Time since type 1 diagnosis
    Units: month
        median (full range (min-max))
    		 54.5 (44 to 76) -
    Time since last Diamyd injection
    Units: month
        median (full range (min-max))
    		 43 (38 to 48) -

    End points

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    End points reporting groups
    Reporting group title
    ALUM-rhGAD65 + Vitamin D
    Reporting group description
    		 All patients received one dose of Diamyd 4 μg as a 0.1 mL intralymphatic injection into an inguinal lymph node. Vitamin D (cholecalciferol 2000 IE) was administered as tablets 2000 IU daily.
    Reporting group title
    ALUM-rhGAD65 + Vitamin D
    Reporting group description
    		 -

    Primary: Injection site reactions

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    End point title
    		 Injection site reactions [1]
    End point description
    End point type
    Primary
    End point timeframe
    From enrollment up to 1 year after the booster injection
    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: Too few patients and no comparator arm to enable statistical analysis.
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: Number of patients
    3
    No statistical analyses for this end point

    Secondary: Change in C-peptide (AUCmean 0-120 min) during MMTT from baseline to 12 months

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    End point title
    		 Change in C-peptide (AUCmean 0-120 min) during MMTT from baseline to 12 months
    End point description
    Change ratio
    End point type
    Secondary
    End point timeframe
    Change from baseline to 12 months
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: nmol/L/min
        median (full range (min-max))
    0.636 (0.333 to 0.895)
    No statistical analyses for this end point

    Secondary: Change in HbA1c from baseline to 12 months

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    End point title
    		 Change in HbA1c from baseline to 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 12
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: mmol/mol
        arithmetic mean (standard deviation)
    2.3 ( 4.1 )
    No statistical analyses for this end point

    Secondary: Change in daily exogenous insulin consumption from baseline to 12 months

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    End point title
    		 Change in daily exogenous insulin consumption from baseline to 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 12
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: IU/kg
        arithmetic mean (standard deviation)
    -0.147 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Change in IDAA1C (Insulin-dose-adjusted HbA1c levels) from baseline to 12 months

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    End point title
    		 Change in IDAA1C (Insulin-dose-adjusted HbA1c levels) from baseline to 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 12
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: mmol/mol
        arithmetic mean (standard deviation)
    -0.4 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Change in time in glycemic target range 3.9 to 10 mmol/L (70 to 180 mg/dL) from baseline to 12 months

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    End point title
    		 Change in time in glycemic target range 3.9 to 10 mmol/L (70 to 180 mg/dL) from baseline to 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 12
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: hours
        arithmetic mean (standard deviation)
    12.9 ( 66.4 )
    No statistical analyses for this end point

    Secondary: Change in time in hyperglycemic range > 10 mmol/L (> 180 mg/dL) from baseline to 12 months

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    End point title
    		 Change in time in hyperglycemic range > 10 mmol/L (> 180 mg/dL) from baseline to 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 12
    End point values
    		 ALUM-rhGAD65 + Vitamin D
    Number of subjects analysed
    6
    Units: hours
        arithmetic mean (standard deviation)
    -26.8 ( 25.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment up to 1 year after the booster injection.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    ALUM-rhGAD65 + Vitamin D
    Reporting group description
    		 All patients received one dose of Diamyd 4 μg as a 0.1 mL intralymphatic injection into an inguinal lymph node. Vitamin D (cholecalciferol 2000 IE) was administered as tablets 2000 IU daily.

    Serious adverse events
    		 ALUM-rhGAD65 + Vitamin D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ALUM-rhGAD65 + Vitamin D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The main limitation of the present pilot study is the low number of participants, and the results obtained herein, especially the efficacy results, should therefore be taken with caution.
    For support, Contact us.
    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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